CardiologyNews. Neurologic Events Higher With TAVR BY MITCHEL L. FDA Panel Wants Answers on Trilipix Effectiveness WHAT S NEWS

Transcription

1 CardiologyNews V OL. 9, NO. 6 The Leading Independent Newspaper for the Cardiologist J UNE 2011 WHAT S NEWS Medical therapy for elderly Medicare patients with aortic stenosis not only shortened survival, but cost more than replacing the valve. 4 Health care providers and medical societies eye the playing field for Accountable Care Organization programs. 6 Rosiglitazone will be available only from mail-order pharmacies starting in November, further limiting its use, the FDA announced. 9 Atrial fibrillation patients who ve had ablation can continue to have episodes without their knowledge, results of the DISCERN AF study show. 16 A totally subcutaneous ICD accurately detected and converted ventricular fibrillation episodes in a Dutch study. It can t provide antitachycardia pacing, however. 19 Transplantation specialists are turning down hearts from high-risk donors, perhaps because left ventricular assist devices offer a viable alternative. 26 A plan to finally replace Medicare s much maligned Sustainable Growth Rate payment formula could be unveiled by this summer. 39 Neurologic Events Higher With TAVR BY MITCHEL L. ZOLER FROM THE AMERICAN ASSOCIATION FOR THORACIC SURGERY ANNUAL MEETING PHILADELPHIA The percutaneous, transcatheter replacement of stenotic aortic valves has captured attention as an option for patients who are either too sick to undergo surgical aortic valve replacement, or who are surgical candidates but would prefer to avoid sternotomy. Despite early success with the use of transcatheter aortic valve repair (TAVR) in the two parts of a recent pivotal trial, Dr. D. Craig Miller said the approach has two important limitations: the poorly defined long-term durability of percutaneous aortic valves (which thus far have track records of less than 3 years) and the significantly increased risk of a neurologic event from TAVR, compared with conventional open aortic valve repair (AVR). A summary analysis of neurologic events following TAVR in the Placement of Aortic Transcatheter Valve (PART- NER) trial showed a total, 1-year event rate of 6% in the as-treated TAVR patients who received their valves via the trans- See TAVR page 4 FDA Panel Wants Answers on Trilipix Effectiveness BY ELIZABETH MECHCATIE FROM A MEETING OF THE FDA S ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE SILVER SPRING, MD. Members of a Food and Drug Administration advisory panel were divided on how and whether the label for fenofibric acid should reflect trial results showing no benefit of fibrate therapy in reducing cardiovascular disease risk when added to a statin in patients with type 2 diabetes, but agreed that a new trial is the only way to get a definitive answer. At a meeting, 6 of the 13 members of the panel agreed that the marketing of fenofibric acid should be allowed to continue, with the addition to the label of the main findings of the study the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial. Four panelists, however, voted to recommend that the co-administration indication be withdrawn, citing the lack of solid evidence to support the indication. The remaining three panelists voted to allow continued marketing with no changes to the label. Fenofibric acid, formulated in a delayed-release capsule and marketed by Abbott Laboratories as Trilipix, was approved by the FDA in December The drug s indication includes its use Patients with smaller, tighter aortic valves were more likely to experience an early neurologic event. Deciding which patients should undergo TAVR will require defining the line between utility and futility, said Dr. D. Craig Miller, who presented the neurological outcomes of the PARTNER trial. with a statin as an adjunct to diet to reduce serum triglyceride (TG) levels and increase serum HDL cholesterol levels in patients with mixed dyslipidemia and coronary heart disease (CHD) or a CHD risk equivalent who are on optimal statin therapy to achieve their LDL cholesterol goal. Fenofibric acid is the active ingredient of fenofibrate, a fibrate approved in 1993 that is now available in generic formulations. It is also approved as monotherapy, so any changes to the co-administration indication would not affect its availability. The FDA convened the panel to review the co-administration indication See Trilipix page 8 Thinking about a change? Interested in relocating? Go where the jobs are... CATHERINE HARRELL/ELSEVIER GLOBAL MEDICAL NEWS CARDIOLOGY NEWS CHANGE SERVICE REQUESTED 60 Columbia Rd., Bldg. B, 2 nd flr. Morristown, NJ Presorted Standard U.S. Postage PAID Permit No. 384 Lebanon Jct. KY

2 2 NEWS JUNE 2011 CARDIOLOGY NEWS HEART OF THE MATTER On Transcatheter Aortic Valves SIDNEY GOLDSTEIN, M.D. The natural history and pathology of aortic stenosis has been well described since the mid-18th century by John Baptist Morgagni. Its latency period usually runs 6-7 decades before expressing its classic symptoms. Once the symptoms of heart failure, angina, and syncope occur, the life span of patients is measured in 1-2 years. Because of the increased number of octogenarians around these days, aortic stenosis has become a larger therapeutic problem to cardiologists. Unfortunately, when octogenarians come to the doctor with the symptoms of aortic stenosis, they usually bring a number of other comorbidities, such as coronary artery disease, diabetes, pulmonary insufficiency, and renal dysfunction, just to name a few. Surgical intervention in these patients carries high risk and both the patient and surgeon are reluctant to proceed with high-risk surgery in such a complex medical environment. The recent development of a percutaneous aortic valve that can be implanted either transvenously or transapically has provided interesting options for these elderly patients. Several transcatheter aortic valves are now available in Europe, but until the last few months there have been no randomized clinical trials evaluating there efficacy. The two most recent trials, the PART- NER trials, using a SAPIEN heart valve system (Edwards Lifesciences) have provided an opportunity to consider the potential benefits of transcatheter aorticvalve replacement (TAVR). The first reported trial compared TAVR to standard medical therapy in patients with severe aortic stenosis deemed inoperable for traditional aortic valve replacement (AVR). A second group of patient with severe aortic stenosis was randomized to either TAVR or AVR. Both studies have provided optimism that these percutaneous devices can provided significant benefit. The initial PARTNER study randomized 358 stenosis patients who were considered to be inoperable, to either TAVR or standard medical therapy including in some case balloon aortic valvulotomy (N. Engl. J. Med. 2010; 363: ). That trial reported a 30-day mortality of 5.0% and 2.8% and a 1-year mortality of 30.7% and 50.7% in the TAVR and standard medical therapy groups, respectively. Associated with this improvement in mortality, there was both symptomatic improvement and decrease in hospitalization in the TAVR treated patients. There was, however, an increase occurrence of major strokes, at 5.0% in the TAVR patients compared with 1.1% in the medical patients. The most recent PARTNER trial reported at the annual meeting of the American Cardiology compared TAVR to standard surgical AVR in patients with severe aortic stenosis. In that trial, 699 patients with mean aortic valve area of cm 2, most of whom were in New York Heart Association functional class III-IV, the 30-day mortality was 3.4% vs. 6.5% and the 1-year mortality was 24.2% vs. 26.8% in the TAVR compared to AVR respectively. There was, however, an increase in all strokes in the TAVR patients compared to AVR, 4.6 % compared to 2.4%. Although most of the SAPIEN valves were implanted by the transfemoral approach, approximately onethird required the transapical approach because of poor femoral artery access. The device used in PART- NER is currently approved for use in Europe and soon to be available in the United States. Several other transcatheter valve systems are currently in development by device companies, and one, the CoreValve (Medtronics) is currently undergoing clinical trials in the United States. The devices included in the early trials have been improved upon and investigators using the Edwards Lifesciences device are currently testing the fourth generation of that valve, which is smaller and easier to pass through the femoral artery. In addition, protection devices are being developed to deal with the observed increased stroke morbidity. Although stroke remains a problem, emboli have not been limited to the brain but some reports suggest that, there is evidence for intracoronary embolism. The development of these valves are obviously on the fast track but unfortunately little is known about their long-term durability. There are some follow-up data from Europe where the valve has been in use for about 2 years. When weighed against the years of experience and the excellent durability of the current AVR there should be some reticence to the application of these valves in patients at better surgical risks. Although the operative risks for either TAVR or AVR are acceptable, considering the natural history of the disease, unfortunately the long-term risks of the elderly patients with aortic stenosis remains high even after successful valve replacement. DR. GOLDSTEIN, medical editor of CARDIOLOGY NEWS, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies. Editor in Chief Mary Jo M. Dales Executive Editors Denise Fulton, Kathy Scarbeck Managing Editor Catherine Hackett Senior Editors Christina Chase, Kathryn DeMott, Jeff Evans, Lori Buckner Farmer, Keith Haglund, Gina L. Henderson, Sally Koch Kubetin, Teresa Lassman, Mark S. Lesney, Jane Salodof MacNeil, Renée Matthews, Catherine Cooper Nellist, Amy Pfeiffer, Terry Rudd, Leanne Sullivan, Elizabeth Wood Editorial Production Manager Carol Nicotera-Ward Associate Editors Felicia Rosenblatt Black, Therese Borden, Lorinda Bullock, Jay C. Cherniak, Richard Franki, Virginia Ingram- Wells, Jane Locastro, January W. Payne Reporters Chicago: Patrice Wendling; Denver: Bruce Jancin; Germany: Jennie Smith; Miami: Damian McNamara; Mid-Atlantic: Michele G. Sullivan; New England: Diana Mahoney; New York: Mary Ellen Schneider; Philadelphia: Mitchel L. Zoler; San Diego: Doug Brunk; San Francisco: Sherry Boschert, Robert Finn; Washington: Alicia Ault, Frances Correa, Elizabeth Mechcatie, Naseem S. Miller, Heidi Splete, Miriam E. Tucker, Kerri Wachter Multimedia Producer Nick Piegari Contributing Writers Christine Kilgore, Mary Ann Moon Project Manager Susan D. Hite Assignments Manager Megan Evans Editorial Offices 5635 Fishers Lane, Suite 6000, Rockville, MD 20852, , cardiologynews@elsevier.com Address Changes Fax change of address (with old mailing label) to or change to subs@elsevier.com Director of Information Technology Doug Sullivan Senior Systems Administrators Lee J. Unger, Kreg M. Williams Systems Administrator/Application Support Peter Ayinde CARDIOLOGY NEWS is an independent newspaper that provides the practicing specialist with timely and relevant news and commentary about clinical developments in the field and about the impact of health care policy on the specialty and the physician s practice. The ideas and opinions expressed in CARDIOLOGY NEWS do not necessarily reflect those of the Publisher. International Medical News Group, LLC, an Elsevier company, will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Cardiology News Executive Director, Operations Jim Chicca Director, Production/Manufacturing Yvonne Evans Struss Production Manager Judi Sheffer Production Specialists Maria Aquino, Anthony Draper, Rebecca Slebodnik Creative Director Louise A. Koenig Design Supervisor Elizabeth Byrne Lobdell Senior Designers Sarah L.G. Breeden, Yenling Liu Designer Lisa M. Marfori Photo Editor Catherine Harrell Web Production Engineer Jon Li Web Production Specialist Jennifer Calhoun POSTMASTER Send changes of address (with old mailing label) to CARDIOLOGY NEWS Circulation, 60 Columbia Rd., Bldg. B, 2 nd flr., Morristown, NJ CARDIOLOGY NEWS (ISSN ) is published monthly by International Medical News Group, LLC, an Elsevier company, 60 Columbia Rd., Bldg. B, 2 nd flr., Morristown, NJ 07960, , fax Subscription price is $ per year. Copyright 2011, by Elsevier Inc. INTERNATIONAL MEDICAL NEWS GROUP Hypertension Treatment and Control Increased Significantly From to Prevalence (%) % 30.9% Hypertension President, IMNG Alan J. Imhoff VVIITTAALL SSIIGGNNSS 60.3% 69.9% Treatment* Sales Director, IMNG Mark E. Altier, , m.altier@elsevier.com National Account Manager Courtney Leonard, , c.leonard@elsevier.com Advertising Offices 60 Columbia Rd., Bldg. B, 2 nd flr., Morristown, NJ 07960, , fax Classified Sales Manager, IMNG Robert Zwick , fax , r.zwick@elsevier.com Classified Sales Representative Andrea LaMonica , fax , a.lamonica@elsevier.com Reprints/Eprints Contact Wright s Media Sr. Program Manager, Customized Programs Malika Wicks Audience Development Manager Barbara Cavallaro, , b.cavallaro@elsevier.com Program/Marketing Manager Jennifer Eckert Business Controller Dennis Quirk Adv. Services Manager Joan Friedman Credit Supervisor Patricia H. Ramsey Manager, Administration/Conventions Lynne Kalish Receptionist Linda Wilson Accounts Payable Coordinator Daniela Silva 33.2% Control* 45.8% *Among those with hypertension. Note: Based on data from the National Health and Nutrition Examination Survey. Source: Morbidity and Mortality Weekly Report 2011;60:103-8 ELSEVIER GLOBAL MEDICAL NEWS

3 Another heart attack is this far away Are you helping to keep it away? Despite medical guidelines, millions of at-risk patients remain unprotected by aspirin. 1,2 Aspirin can reduce the risk of recurrent MI by 30%. 3,4 Counsel your patients today. Say aspirin. Help save lives.

4 4 NEWS JUNE 2011 CARDIOLOGY NEWS Valve Area May Be a Factor TAVR from page 1 femoral route, compared with a 2% rate in the open AVR patients, a statistically significant difference, Dr. Miller said at the meeting. As-treated patients who received a TAVR via the transapical route had a 1- year neurologic event rate of 14%, compared with a 10% rate in patients treated with open AVR, also a significant difference. The higher rate of events in patients assigned to the transapical arm of the study related to the higher atherosclerotic burden in these patients. More than half of the neurologic event risk seen with TAVR occurred during the first 2 weeks after treatment, suggesting a periprocedural cause, said Dr. Miller, professor of cardiovascular surgery at Stanford (Calif.) University. The early neurologic events are undoubtedly due to particulate embolization, although we can t prove it, he said. A cerebral protection device, such as a deflector across the ostium, may reduce the event rate. He cited a report on initial clinical experience using a percutaneously deployed deflector in three patients undergoing TAVR ( J. Am. Coll. Cardiol. Intv. 2010;3:1133-8). Other changes to TAVR that might reduce neurologic events include improved antiplatelet and antithrombotic therapy VITALS Major Finding: Patients who underwent transcatheter aortic valve replacement via the transfemoral approach had a 6% rate of all neurologic events at 1 year after treatment. Patients randomized to open aortic valve replacement had a 2% rate of all neurologic events after 1 year, a statistically significant difference. Data Source: Data from 657 as-treated patients randomized in cohort A of the multicenter PARTNER trial. Disclosures: PARTNER was sponsored by Edwards Lifesciences. Dr. Miller has been the Stanford Principal Investigator for PARTNER and has served as an unpaid consultant to Edwards. He has also been a consultant to Abbott Vascular, Medtronic Cardiovascular, and St. Jude Medical. with clopidogrel, aspirin, warfarin, and dabigatran. Development of smaller TAVR devices might also further reduce neurologic events, he said. Analysis of the correlates of the early neurologic events showed that they significantly linked with a lower aortic valve area index. In other words, patients with smaller, tighter aortic valves were more likely to experience an early event. During the late, nonperiprocedural phase, the risk for neurologic events was increased for patients with higher New York Heart Association heart failure stage, those who had had a stroke or transient ischemic attack within the prior 12 months, or those who were not candidates for transfemoral TAVR. Patients enrolled in the randomized portion of the trial had a low rate of major strokes, with a total of 29 events (18 in the TAVR patients and 11 in those undergoing open AVR), a nonsignificant difference. The analysis therefore also included minor strokes and transient ischemic attacks to total an adequate number of events to potentially show a significant difference between the TAVR and open AVR subgroups, Dr. Miller said. Deciding which patients should undergo TAVR will require defining the line between utility and futility he commented. You don t want to empty every nursing home in California of patients with aortic stenosis, and on the young side, you don t want the percutaneous option used in patients at low surgical risk. Concern about using TAVR on patients who are good open surgery candidates focuses on the unknown longterm durability of TAVR, and the high price to pay in neurologic events, at least in the current version of TAVR, he said. The data Dr. Miller reported came from cohort A of the PARTNER trial, the cohort that focused on patients who could be randomized to either TAVR or open AVR. The primary end point of allcause mortality in this cohort, reported in April at the annual meeting of the American College of Cardiology, showed that 1-year survival following TAVR was not inferior to open AVR (CARDIOLOGY NEWS, May 2011, p. 1). Another prior report, for cohort B (patients considered too sick to undergo open AVR), showed that TAVR produced superior outcomes, compared with conventional medical management (N. Engl. J. Med. 2010;363: ). Medical Tx of Severe Aortic Stenosis Raises Mortality, Costs BY MITCHEL L. ZOLER FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY NEW ORLEANS Elderly patients with severe aortic stenosis who did not undergo aortic valve replacement and received only medical management had a poor survival rate of less than 2 years, and also incurred a lot of VITALS Major Finding: Following hospitalization for severe aortic stenosis, Medicare patients who did not undergo aortic valve replacement had an average survival of 1.8 years, and incurred average medical care costs of more than $29,000 per year. Data Source: Analysis of 2,150 patients included in the Medicare Standard Analytic Files who were hospitalized with severe aortic stenosis in 2003 and medically managed. Disclosures: The study was funded by Edwards Lifesciences, a company that is developing a transcatheter replacement valve for aortic stenosis. Ms. Clark said that she had no other relevant financial disclosures. Two coauthors on the study are employees of Edwards Lifesciences. medical expenses, averaging about $29,000 a year, based on a review of more than 2,000 Medicare patients. Transcatheter aortic valve replacement surgery shows promise in treating the most severe AS [aortic stenosis] patients at highest risk for mortality and potentially reducing long-term costs to the Medicare program, Mary Ann Clark said at the meeting. Based on the cost findings in this analysis, which included a 5-year follow-up of Medicare records for patients with an index hospitalization for severe AS in 2003, the cumulative annual cost to Medicare for the estimated 43,000 elderly American patients with severe AS reached nearly $1.3 billion, said Ms. Clark, vice president for health economics and reimbursement at Neocure, a medical economics analysis company in Washington. These patients are really sick, they die [fairly quickly], and they cost a lot of money. If you have the transcatheter aortic valve replacement option, that may be a cost-effective solution, Ms. Clark said in an interview. An unrelated report at the meeting showed the cost effectiveness of transcatheter aortic valve replacement, documenting a cost of just over $50,000 per life-year gained, on the basis of data collected in the portion of the PARTNER (Placement of Aortic Transcatheter Valve) trial that randomized inoperable patients with severe AS to either transcatheter valve replacement or medical management. The analysis reported by Ms. Clark and her associates used data collected on 2,150 patients with severe AS hospitalized in 2003, a 5% sample of Medicare patients contained in the program s Standard Analytic Files. The analysis subdivided the patients into two groups: high-risk patients who had a Euroscore a predicted operative mortality rate from cardiac surgery of 20% or more, and non high-risk patients, who had a Euroscore of less than 20%. The 651 high-risk patients averaged 85 years old, 71% were women, and their average Euroscore was 34%. The non high-risk patients averaged 81 years old, 60% were women, and their average Euroscore was 10%. Medicare records during for these 2,150 patients showed their overall average survival reached 1.8 years, with an average survival rate of 1.4 years in the high-risk patients and 2.0 years in the non high-risk patients. The 5-year survival rate ran 12% in all patients, and 5% in the high-risk group. The average 5-year costs for all patients in the study reached nearly $64,000, with half of these costs being for follow-up inpatient hospitalizations. The average cost worked out to somewhat more than $29,000 per patient per year, after the cost of their index hospitalization was excluded. In multivariate analyses, factors that significantly contributed to higher mortality included active endocarditis and metastatic cancer or acute leukemia. Factors significantly linked with an increased risk for death included the need for dialysis and diabetes, Ms. Clark said. EDITORIAL ADVISORY BOARD SIDNEY GOLDSTEIN, M.D., Wayne State University, Detroit MEDICAL EDITOR ERIC R. BATES, M.D., University of Michigan, Ann Arbor GEORGE BELLER, M.D., University of Virginia, Charlottesville ROBERT M. CALIFF, M.D., Duke University, Durham, N.C. PRAKASH C. DEEDWANIA, M.D., University of California, San Francisco, Fresno JOHN FLACK, M.D., Wayne State University, Detroit ANTONIO M. GOTTO JR., M.D., Cornell University, New York DAVID L. HAYES, M.D., Mayo Clinic, Rochester, Minn. DAVID R. HOLMES JR., M.D., Mayo Clinic, Rochester, Minn. BARRY M. MASSIE, M.D., University of California, San Francisco CHRISTOPHER M. O CONNOR, M.D., Duke University, Durham, N.C. GEORGE J. PHILIPPIDES, M.D., Boston University ILEANA L. PIÑA, M.D., Case Western Reserve University, Cleveland OTELIO RANDALL, M.D., Howard University, Washington RITA F. REDBERG, M.D., University of California, San Francisco HOWARD (HANK) ROSMAN, M.D., St. John Hospital and Medical Center, Detroit THOMAS J. RYAN, M.D., Boston University HANI N. SABBAH, PH.D., Henry Ford Hospital, Detroit LESLIE ANNE SAXON, M.D., University of Southern California, Los Angeles DAVID H. SPODICK, M.D., University of Massachusetts, Worcester RICHARD M. STEINGART, M.D., Memorial Sloan Kettering Cancer Center, New York PAUL D. THOMPSON, M.D., Hartford (Conn.) Hospital CHRISTOPHER J. WHITE, M.D., Oschner Clinic Foundation, New Orleans ROBERTA WILLIAMS, M.D., University of Southern California, Los Angeles

5 NEW: TESTING IS NOW IN THE ACCF/AHA GUIDELINES

6 6 NEWS JUNE 2011 CARDIOLOGY NEWS Health Providers Examine Promise of ACOs BY MARY ELLEN SCHNEIDER The medical model of the more you do, the more you make is out, according to Dr. William Chin, and so is the idea that the physician needs to do everything personally. If a service can be provided more efficiently by a nurse or social worker, that may be the way to go under the next big thing in health care the accountable care organization. Dr. Chin, executive medical director for HealthCare Partners, an independent physician association (IPA) based in Torrance, Calif., said his group plans to participate in the new Medicare shared savings program for ACOs, which will launch in January. The group has been preparing for the transition for a while: They are currently also working with Anthem Blue Cross in California to test how an ACO would work in the commercial market as well as testing ACO accreditation standards being developed by the National Committee for Quality Assurance (NCQA). Cardiologists are in a good position to thrive in accountable care organizations, according to Dr. Jack Lewin, CEO of the American College of Cardiology. Tools for sharing information between cardiologists, like the National Cardiovascular Data Registry, are already in place and will make it easier for cardiologists to transition to ACOs, Dr. Lewin said. But even with electronic health records in place, Dr. Lewin said, all practices seeking to become ACOs will have to integrate economically and share their registries. ACOs have been a hot topic in health care circles since they were written into the Affordable Care Act. The law includes the shared savings program through Medicare, which will allow ACOs to earn additional payments if they can both save the government money and meet quality benchmarks. As the program goes forward, physicians also would assume some financial risk if they are unable to provide cost-effective care. Officials at the Centers for Medicare and Medicaid Services released a proposed regulation on March 31 outlining how the Medicare ACO program will work. Under the new voluntary program, ACOs could include physicians in group practices, networks of individual practices, hospitals that employ physicians, and partnerships between these entities, as well as other providers. An ACO will be a partnership among both primary care and specialist physicians; however, only primary care providers will be able to form an ACO, according to the proposed regulation. Providers working in an ACO would continue to receive regular payments under Medicare fee for service, but could qualify for additional payments if they save money for the program. The proposed regulation requires that ACOs meet quality standards and demonstrate that they have reduced costs in order to be eligible to share in savings. The proposal outlines 65 quality measures in five domains: patient experience, care coordination, patient safety, preventive health, and metrics for the care of at-risk and frail elderly populations. It is integration of care that is most critical, Dr. Lewin said. Even as cardiologists may be better situated for the transition, their challenge will be to meet the quality measures, as 20 of the 65 measures apply specifically to cardiovascular disease, according to Dr. Lewin. MULTAQ is an antiarrhythmic drug indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AFib) or atrial flutter (AFL), with a recent episode of AFib/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter 50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted. Important Safety Information MULTAQ is contraindicated in patients with NYHA Class IV heart failure, or NYHA Class II III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. In the ANDROMEDA Study, a greater than two-fold increase in mortality was observed in this unstable population (see full boxed WARNING). Important Update: Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with MULTAQ in the postmarketing setting. A liver injury section has been added to the Important Safety Information. Please see additional Important Safety Information and brief summary of Prescribing Information, including boxed WARNING, on adjacent pages. Make MULTAQ your first-choice AAD In EURIDIS/ADONIS Prolonged time to first recurrence and reduced the symptomatic burden of AFib 1 25% RRR of first symptomatic or asymptomatic AFib recurrence mg tablet bid, with morning and evening meals The absolute bioavailability of MULTAQ increases when administered with a full meal Absolute difference in recurrence rate of about 11% at 1 year (P<0.001; primary endpoint) The majority of recurrences were symptomatic 62.3% In ATHENA The first and only AAD with proven efficacy in an outcomes trial 2,3 24% RRR* One area in which physicians may need to make investments is in health information technology. Jonathan Blum, director of the Center for Medicare Management, said the ACO proposal is closely aligned with the Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009 and the electronic health record incentive programs. Coordinating the ACO quality measures with those in the EHR incentive programs reduces the burden on physicians and hospitals that are submitting data through the various programs, Mr. Blum said. It also offers the potential for physicians to offset some of their technology costs through the bonus payments they can earn by achieving meaningful use of their EHRs. The move to ACOs will be a major shift, said Dr. Paul Grundy, director of health care transformation for IBM and president of MULTAQ patients were free of symptomatic AFib recurrence vs 54% on placebo at 1 year (P<0.001; secondary endpoint) 1 in CV hospitalization or mortality, the combined primary endpoint (P<0.0001, entirely attributable to CV hospitalizations) 2,3 * Relative risk reduction (RRR) observed over the study period (median 22-month treatment and follow-up; minimum 12 months, maximum 30 months). 2,3 NO hospital initiation required 2 NO loading dose 2 NO titration 2 Visit

7 JUNE NEWS 7 of the Patient-Centered Primary Care Collaborative. You ve got a $2.7 trillion stream going in the wrong direction, he said. That s a huge river to overcome. But despite the financial and cultural barriers that have prevented these types of shifts from occurring in the past, the medical community is ready to make a change toward the patient-centered medical home concept and ACOs, he said. The trend is being driven by more than just the provisions in the Affordable Care Act, he said. The escalating cost of health care is pushing businesses and other health care purchasers to look for alternatives to keep costs down. At the same time, there are finally data to show how patients are being managed and what types of care are cost effective. Additionally, younger consumers want to access health care the same way they do their banking and shopping. For them to be told by a practice that they can t access their laboratory data online, they ll just keep looking until they find someone who can, Dr. Grundy said. Another player in the ACO field is the NCQA. The not-for-profit organization offers recognition programs for physicians, hospitals, and health plans in a number of areas. Starting this summer, the organization plans to unveil its standards for ACO accreditation. The first ACOs to go through the program could receive accreditation in 2012, according to Raena Grant Akin-Deko, assistant vice president for development at the NCQA. The standards could be a road map for organizations to begin to build the capabilities to become an ACO, she said. What we ve done through these standards can help people understand what the important capabilities are and give them some direction about what that they should be thinking about. The NCQA recently concluded testing of its standards with 10 organizations that represent IPAs, multispecialty practice groups, and integrated delivery systems. One issue that came up during the testing is the importance of leadership within the ACO. We can define structural features that are important for [ACOs], but I think you cannot underestimate the importance of leadership and the cultural change toward patient centered care in forming these organizations, she said. Alicia Ault and Naseem S. Miller contributed to this report. Important Safety Information for MULTAQ Contraindications WARNING: HEART FAILURE MULTAQ is contraindicated in patients with NYHA Class IV heart failure, or NYHA Class II III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. In a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms (the ANDROMEDA Study), patients given MULTAQ had a greater than two-fold increase in mortality. Such patients should not be given MULTAQ. MULTAQ is also contraindicated in patients with second- or third-degree atrioventricular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker), bradycardia <50 bpm, QTc Bazett interval 500 msec or PR interval >280 msec, and severe hepatic impairment MULTAQ should not be given to patients who are or may become pregnant (Category X) or nursing. MULTAQ may cause fetal harm when administered to a pregnant woman MULTAQ should not be coadministered with strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir, or drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine antipsychotics, tricyclic antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics New or Worsening Heart Failure Postmarketing cases of new onset and worsening heart failure have been reported during treatment with MULTAQ. Advise patients to consult a physician if they develop signs and symptoms of heart failure, such as weight gain, dependent edema, or increasing shortness of breath. If heart failure develops or worsens, consider the suspension or discontinuation of MULTAQ. Liver Injury Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with MULTAQ in the postmarketing setting. Advise patients treated with MULTAQ to report immediately symptoms suggesting hepatic injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching). Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment. It is not known whether routine periodic monitoring of serum enzymes will prevent the development of severe liver injury. If hepatic injury is suspected, promptly discontinue MULTAQ and test serum enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase, as well as serum bilirubin, to establish whether there is liver injury. If liver injury is found, institute appropriate treatment and investigate the probable cause. Do not restart MULTAQ in patients without another explanation for the observed liver injury. Hypokalemia and Hypomagnesemia with Potassium- Depleting Diuretics Hypokalemia and hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium levels should be within the normal range prior to administration of MULTAQ and maintained in the normal range during administration of MULTAQ. QT Interval Prolongation MULTAQ induces a moderate (average of about 10 msec but much greater effects have been observed) QTc (Bazett) prolongation. If the QTc Bazett interval is 500 msec, MULTAQ should be stopped. Increase in Creatinine Serum creatinine levels increase by about 0.1 mg/dl following MULTAQ treatment initiation. The elevation has a rapid onset, reaches a plateau after 7 days and is reversible after discontinuation. If an increase in serum creatinine occurs and plateaus, this increased value should be used as the patient s new baseline. The change in creatinine levels has been shown to be the result of an inhibition of creatinine s tubular secretion, with no effect upon the glomerular filtration rate. Drug-Drug Interactions Treatment with Class I or III antiarrhythmics or drugs that are strong inhibitors of CYP 3A must be stopped before starting MULTAQ (see Contraindications) Patients should be instructed to avoid grapefruit juice beverages while taking MULTAQ Calcium channel blockers and beta-blockers could potentiate the effects of MULTAQ on conduction Increased digoxin levels and gastrointestinal disorders have been observed when MULTAQ was coadministered with digoxin. Digoxin can also potentiate the electrophysiologic effects of MULTAQ (such as decreased AV-node conduction); the need for digoxin therapy should be reconsidered when prescribing MULTAQ. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity Postmarketing cases of increased INR with or without bleeding events have been reported in warfarin-treated patients initiated with MULTAQ. Monitor INR after initiating MULTAQ in patients taking warfarin Adverse Reactions In studies, the most common adverse reactions observed with MULTAQ were diarrhea, nausea, abdominal pain, vomiting, and asthenia. Please see brief summary of Prescribing Information, including boxed WARNING, on adjacent pages. References: 1. Singh BN, Connolly SJ, Crijns HJGM, et al; for the EURIDIS and ADONIS Investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357: MULTAQ (dronedarone) Prescribing Information. Sanofi-aventis U.S. LLC; 2011, Bridgewater, NJ. 3. Hohnloser SH, Crijns HJGM, van Eickels M, et al; for the ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360: US.DRO April sanofi-aventis U.S. LLC

8 8 NEWS JUNE 2011 CARDIOLOGY NEWS Subgroup Analyses Treacherous Trilipix from page 1 of fenofibric acid in the context of the ACCORD Lipid study results. That study found no benefit of combination treatment with fenofibrate and simvastatin on major cardiovascular events, compared with treatment with simvastatin alone, over a mean of almost 5 years of follow-up. The study enrolled more than 5,500 patients with type 2 diabetes at high risk of cardiovascular disease, with a range of TG and HDL levels. Among women in the study, the rate of major adverse cardiovascular events was higher (9.1%) than that among those on the statin alone (6.6%). In another subgroup of patients, however, those with elevated TG levels (204 mg/dl or higher) and reduced HDL cholesterol levels (34 mg/dl or lower), there was a suggestion of benefit with combination therapy (N. Engl. J. Med. 2010;362: ). Panelists said they were not comfortable drawing any conclusions from analyses of patient subgroups in what they considered a negative trial. They voted 13-0 that the FDA should require Abbott to conduct a study to test the hypothesis that add-on therapy with fenofibric acid, compared with placebo, significantly lowers the risk of major adverse cardiovascular I don t see how we can allow this to be an indication for cotherapy [with a statin] if we re acknowledging the lack of good evidence for it. events in high-risk patients who have reached their LDL cholesterol goal with a statin but have residual high serum TG and low serum HDL levels. Subgroup analyses are tempting, but they are treacherous, said panelist Dr. Sanjay Kaul, director of the Cardiology Fellowship Training Program and the Cardiology Consult Service at Cedars- MULTAQ (dronedarone) Tablets Brief Summary of Prescribing Information Rx Only WARNING: HEART FAILURE MULTAQ is contraindicated in patients with NYHA Class IV heart failure, or NYHA Class II III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic [see Contraindications (4)]. In a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms (the ANDROMEDA Study), patients given dronedarone had a greater than two-fold increase in mortality. Such patients should not be given dronedarone [see Clinical Studies (14.3) in the full prescribing information]. 1 INDICATIONS AND USAGE MULTAQ is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter 50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted [see Clinical Studies (14) in the full prescribing information]. 2 DOSAGE AND ADMINISTRATION The only recommended dosage of MULTAQ is 400 mg twice daily in adults. MULTAQ should be taken as one tablet with the morning meal and one tablet with the evening meal. Treatment with Class I or III antiarrhythmics (e.g., amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong inhibitors of CYP3A (e.g., ketoconazole) must be stopped before starting MULTAQ [see Contraindications (4)]. 4 CONTRAINDICATIONS MULTAQ is contraindicated in patients with: NYHA Class IV heart failure or NYHA Class II III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic [see Boxed Warning and Clinical Studies (14.3) in the full prescribing information] Second- or third-degree atrioventricular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker) Bradycardia <50 bpm Concomitant use of strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir [see Drug Interactions (7.2)] Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics QTc Bazett interval 500 ms or PR interval >280 ms Severe hepatic impairment Pregnancy (Category X): MULTAQ may cause fetal harm when administered to a pregnant woman. MULTAQ is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Nursing mothers [see Use in Specific Populations (8.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Patients with New or Worsening Heart Failure during Treatment Postmarketing cases of new onset and worsening heart failure have been reported during treatment with Multaq. Advise patients to consult a physician if they develop signs or symptoms of heart failure, such as weight gain, dependent edema, or increasing shortness of breath. If heart failure develops or worsens, consider the suspension or discontinuation of MULTAQ. 5.2 Liver Injury Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with MULTAQ in the post-marketing setting. Advise patients treated with MULTAQ to report immediately symptoms suggesting hepatic injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching). Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment. It is not known whether routine periodic monitoring of serum enzymes will prevent the development of severe liver injury. If hepatic injury is suspected, promptly discontinue MULTAQ and test serum enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase, as well as serum bilirubin, to establish whether there is liver injury. If liver injury is found, institute appropriate treatment and investigate the probable cause. Do not restart MULTAQ in patients without another explanation for the observed liver injury. 5.3 Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics Hypokalemia or hypomagnesemia may occur with concomitant administration of potassiumdepleting diuretics. Potassium levels should be within the normal range prior to administration of MULTAQ and maintained in the normal range during administration of MULTAQ. 5.4 QT Interval Prolongation Dronedarone induces a moderate (average of about 10 ms but much greater effects have been observed) QTc (Bazett) prolongation [see Clinical Pharmacology (12.2) in the full prescribing information and Clinical Studies (14.1) in the full prescribing information]. If the QTc Bazett interval is 500 ms, MULTAQ should be stopped [see Contraindications (4)]. 5.5 Increase in Creatinine after Treatment Initiation Serum creatinine levels increase by about 0.1 mg/dl following dronedarone treatment initiation. The elevation has a rapid onset, reaches a plateau after 7 days and is reversible after discontinuation. If an increase in serum creatinine occurs and plateaus, this increased value should be used as the patient s new baseline. The change in creatinine levels has been shown to be the result of an inhibition of creatinine s tubular secretion, with no effect upon the glomerular filtration rate. 5.6 Women of Childbearing Potential Premenopausal women who have not undergone a hysterectomy or oophorectomy must use effective contraception while using MULTAQ. Dronedarone caused fetal harm in animal studies at doses equivalent to recommended human doses. Women of childbearing potential should be counseled regarding appropriate contraceptive choices taking into consideration their underlying medical conditions and lifestyle preferences [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS The following safety concerns are described elsewhere in the label: New or worsening heart failure [see Warnings and Precautions (5.1)] Liver Injury [see Warnings and Precautions (5.2)] Hypokalemia and hypomagnesemia with potassium-depleting diuretics [see Warnings and Precautions (5.3)] QT prolongation [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience The safety evaluation of dronedarone 400 mg twice daily in patients with AF or AFL is based on 5 placebo controlled studies, ATHENA, EURIDIS, ADONIS, ERATO and DAFNE. In these studies, a total of 6285 patients were randomized and treated, 3282 patients with MULTAQ 400 mg twice daily, and 2875 with placebo. The mean exposure across studies was 12 months. In ATHENA, the maximum follow-up was 30 months. In clinical trials, premature discontinuation because of adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% of the placebo-treated group. The most common reasons for discontinuation of therapy with MULTAQ were gastrointestinal disorders (3.2 % versus 1.8% in the placebo group) and QT prolongation (1.5% versus 0.5% in the placebo group). The most frequent adverse reactions observed with MULTAQ 400 mg twice daily in the 5 studies were diarrhea, nausea, abdominal pain, vomiting, and asthenia. Table 1 displays adverse reactions more common with dronedarone 400 mg twice daily than with placebo in AF or AFL patients, presented by system organ class and by decreasing order of frequency. Adverse laboratory and ECG effects are presented separately in Table 2. Table 1: Adverse Drug Reactions that Occurred in at Least 1% of Patients and Were More Frequent than Placebo Gastrointestinal Placebo Dronedarone 400 mg twice daily (N=2875) (N=3282) Diarrhea 6% 9% Nausea 3% 5% Abdominal pain 3% 4% Vomiting 1% 2% Dyspeptic signs and symptoms 1% 2% General Asthenic conditions 5% 7% Cardiac Bradycardia 1% 3% Skin and subcutaneous tissue Including rashes (generalized, macular, maculo-papular, erythematous), pruritus, eczema, dermatitis, dermatitis allergic 3% 5% Photosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with MULTAQ. The following laboratory data/ecg parameters were reported with MULTAQ 400 mg twice daily. Table 2: Laboratory data/ecg parameters not necessarily reported as adverse events Serum creatinine increased 10% five days after treatment initiation QTc Bazett prolonged (>450 ms in males >470 ms in females) Placebo (N=2875) MULTAQ 400 mg twice daily (N=3282) 21% 51% (N=2237) (N=2701) 19% 28% Assessment of demographic factors such as gender or age on the incidence of treatmentemergent adverse events did not suggest an excess of adverse events in any particular sub-group. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of MULTAQ. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac: Heart failure [see Warnings and Precautions (5.1)].

9 JUNE NEWS 9 Sinai Medical Center, Los Angeles. He described the available data in patients with elevated TGs and low HDL as hypothesis generating, not hypothesis validating and voted for withdrawal of the indication, citing a disconnect between the marketing and the evidence for cotherapy. Agreeing, Dr. Terry Smith, professor of internal medicine, in the division of endocrinology and diabetes, University of Michigan, Ann Arbor, said, I don t see how we can allow this to be an indication for cotherapy if we re acknowledging the lack of good evidence for it. The panel chair, Dr. Allison Goldfine, Postmarketing cases of new onset and worsening heart failure have been reported during treatment with MULTAQ. Hepatic: Serum hepatic enzymes and serum bilirubin increase: Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported [see Warnings and Precautions (5.2)]. 7 DRUG INTERACTIONS Dronedarone is metabolized primarily by CYP 3A and is a moderate inhibitor of CYP 3A and CYP 2D6 [see Clinical Pharmacology (12.3) in the full prescribing information]. Dronedarone s blood levels can therefore be affected by inhibitors and inducers of CYP 3A, and dronedarone can interact with drugs that are substrates of CYP 3A and CYP 2D6. Dronedarone has no significant potential to inhibit CYP 1A2, CYP 2C9, CYP 2C19, CYP 2C8 and CYP 2B6. It has the potential to inhibit P-glycoprotein (P-gP) transport. Pharmacodynamic interactions can be expected with beta-blockers; calcium antagonists and digoxin [see Drug Interactions (7.1)]. In clinical trials, patients treated with dronedarone received concomitant medications including beta-blockers, digoxin, calcium antagonists (including those with heart rate-lowering effects), statins and oral anticoagulants. 7.1 Pharmacodynamic Interactions Drugs prolonging the QT interval (inducing Torsade de Pointes) Co-administration of drugs prolonging the QT interval (such as certain phenothiazines, tricyclic antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics) is contraindicated because of the potential risk of Torsade de Pointes-type ventricular tachycardia [see Contraindications (4)]. Digoxin Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). In clinical trials, increased levels of digoxin were observed when dronedarone was co-administered with digoxin. Gastrointestinal disorders were also increased. Because of the pharmacokinetic interaction [see Drug Interaction (7.3)] and possible pharmacodynamic interaction, reconsider the need for digoxin therapy. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity. Calcium channel blockers Calcium channel blockers with depressant effects on the sinus and AV nodes could potentiate dronedarone s effects on conduction. Give low doses of calcium channel blockers initially and increase only after ECG verification of good tolerability [see Drug Interactions (7.3)]. Beta-blockers In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers. Give low dose of beta-blockers initially, and increase only after ECG verification of good tolerability [see Drug Interactions (7.3)]. 7.2 Effects of Other Drugs on Dronedarone Ketoconazole and other potent CYP 3A inhibitors Repeated doses of ketoconazole, a strong CYP 3A inhibitor, resulted in a 17-fold increase in dronedarone exposure and a 9-fold increase in C max. Concomitant use of ketoconazole as well as other potent CYP 3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated [see Contraindications (4)]. Grapefruit juice Grapefruit juice, a moderate inhibitor of CYP 3A, resulted in a 3-fold increase in dronedarone exposure and a 2.5-fold increase in C max. Therefore, patients should avoid grapefruit juice beverages while taking MULTAQ. Rifampin and other CYP 3A inducers Rifampin decreased dronedarone exposure by 80%. Avoid rifampin or other CYP 3A inducers such as phenobarbital, carbamazepine, phenytoin, and St John s wort with dronedarone because they decrease its exposure significantly. Calcium channel blockers Verapamil and diltiazem are moderate CYP 3A inhibitors and increase dronedarone exposure by approximately 1.4-to 1.7-fold [see Drug Interactions (7.1, 7.3)]. Pantoprazole Pantoprazole, a drug that increases gastric ph, did not have a significant effect on dronedarone pharmacokinetics. 7.3 Effects of Dronedarone on Other Drugs Statins Dronedarone increased simvastatin/simvastatin acid exposure by 4- and 2-fold, respectively. Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with CYP 3A and P-gP inhibitors such as dronedarone. Calcium channel blockers Dronedarone increases calcium channel blocker (verapamil, diltiazem or nifedipine) exposure by 1.4- to 1.5-fold [see Drug Interactions (7.1)]. Sirolimus, tacrolimus, and other CYP3A substrates with narrow therapeutic range Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP 3A substrates with a narrow therapeutic range when given orally. Monitor plasma concentrations and adjust dosage appropriately. Beta-blockers and other CYP 2D6 substrates Dronedarone increased propranolol exposure by approximately 1.3-fold following single dose administration. Dronedarone increased metoprolol exposure by 1.6-fold following multiple dose administration [see Drug Interaction (7.1)]. Other CYP 2D6 substrates, including other betablockers, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have increased exposure upon co-administration with dronedarone. P-glycoprotein substrates Digoxin Dronedarone increased digoxin exposure by 2.5-fold by inhibiting the P-gP transporter [see Drug Interactions (7.1)]. section head of clinical research at Joslin Diabetes, Boston, was among those who supported a change in the label that incorporated the ACCORD Lipid results in the label, with clear written descriptions about the quality of the data, and especially the concern for women. The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting; occasionally, they may be given a waiver, but not at this meeting. ACCORD Lipid was sponsored by the National Heart, Lung, and Blood Institute. MULTAQ (dronedarone) Tablets Dabigatran Exposure to dabigatran is higher when it is administered with dronedarone than when it is administered alone (1.7- to 2-fold). Other P-gP substrates are expected to have increased exposure when co-administered with dronedarone. Warfarin and losartan (CYP 2C9 substrates) Losartan No interaction was observed between dronedarone and losartan. Warfarin When healthy subjects were administered dronedarone 600 mg twice daily, exposure to S-warfarin was higher than when warfarin was administered alone (1.2-fold). Exposure to R-warfarin was unchanged and there were no clinically significant increases in INR. More patients experienced clinically significant INR elevations ( 5) usually within 1 week after starting dronedarone vs. placebo in patients taking oral anticoagulants in ATHENA. However, no excess risk of bleeding was observed in the dronedarone group. Postmarketing cases of increased INR with or without bleeding events have been reported in warfarin-treated patients initiated on dronedarone. Monitor INR after initiating dronedarone in patients taking warfarin. Theophylline (CYP 1A2 substrate) Dronedarone does not increase steady state theophylline exposure. Oral contraceptives No decreases in ethinylestradiol and levonorgestrel concentrations were observed in healthy subjects receiving dronedarone concomitantly with oral contraceptives. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Contraindications (4)] MULTAQ may cause fetal harm when administered to a pregnant woman. In animal studies, dronedarone was teratogenic in rats at the maximum recommended human dose (MRHD), and in rabbits at half the MRHD. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. When pregnant rats received dronedarone at oral doses greater than or equal to the MRHD (on a mg/m 2 basis), fetuses had increased rates of external, visceral and skeletal malformations (cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused carotid arteries, truncus arteriosus, abnormal lobation of the liver, partially duplicated inferior vena cava, brachydactyly, ectrodactylia, syndactylia, and anterior and/or posterior club feet). When pregnant rabbits received dronedarone, at a dose approximately half the MRHD (on a mg/m 2 basis), fetuses had an increased rate of skeletal abnormalities (anomalous ribcage and vertebrae, pelvic asymmetry) at doses 20 mg/kg (the lowest dose tested and approximately half the MRHD on a mg/m 2 basis). Actual animal doses: rat ( 80 mg/kg/day); rabbit ( 20 mg/kg) 8.3 Nursing Mothers It is not known whether MULTAQ is excreted in human milk. Dronedarone and its metabolites are excreted in rat milk. During a pre- and post-natal study in rats, maternal dronedarone administration was associated with minor reduced body-weight gain in the offspring. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MULTAQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Contraindications (4)]. 8.4 Pediatric Use Safety and efficacy in children below the age of 18 years have not been established. 8.5 Geriatric Use More than 4500 patients with AF or AFL aged 65 years or above were included in the MULTAQ clinical program (of whom more than 2000 patients were 75 years or older). Efficacy and safety were similar in elderly and younger patients. 8.6 Renal Impairment Patients with renal impairment were included in clinical studies. Because renal excretion of dronedarone is minimal [see Clinical Pharmacology (12.3) in the full prescribing information], no dosing alteration is needed. 8.7 Hepatic Impairment Dronedarone is extensively metabolized by the liver. There is little clinical experience with moderate hepatic impairment and none with severe impairment. No dosage adjustment is recommended for moderate hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3) in the full prescribing information]. 10 OVERDOSAGE In the event of overdosage, monitor the patient s cardiac rhythm and blood pressure. Treatment should be supportive and based on symptoms. It is not known whether dronedarone or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis or hemofiltration). There is no specific antidote available. Issued March 2011 Manufactured by Sanofi Winthrop Industrie 1, rue de la Vierge Ambares, France sanofi-aventis, 2011 All rights reserved. MULTAQ is a trademark of sanofi-aventis. The brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC. sanofi-aventis U.S. LLC Bridgewater, NJ DRO-BPLR-SA-MAR11 Rosiglitazone Restricted To Mail Orders, FDA Says BY MIRIAM E. FROM THE FDA TUCKER The Food and Drug Administration has further restricted use of the diabetes drug rosiglitazone and all other medications containing rosiglitazone by requiring that health care providers and patients enroll in a special program, and by removing the drugs from all retail pharmacies by Nov. 18, The new restrictions are part of the FDA s REMS (Risk Evaluation and Mitigation Strategy), a program for managing serious risks of marketed drugs. The initial decision to restrict access to rosiglitazone was made on Sept. 23, 2010, based on data suggesting an elevated risk of heart attacks in patients who were treated with the glucose-lowering agent. Previously, the REMS consisted of a medication guide. Now, the FDA has modified the REMS to include a restricted access and distribution program, which applies to Avandia, Avandamet, and Avandaryl. The officially titled Avandia-Rosiglitazone Medicines Access Program limits the use of all three drugs to patients who are already being successfully treated with them, or to those whose blood sugar cannot be controlled with any other medications and who do not wish to use pioglitazone-containing drugs (Actos, Actoplus Met, Actoplus Met XR, or Duetact). Furthermore, health care providers and patients must now be enrolled in the Avandia-Rosiglitazone Medicines Access Program in order to prescribe and receive rosiglitazone medicines. Patients who are enrolled in that program will receive their medicine by mail order through specially certified participating pharmacies. Heath care providers should determine whether their patients are appropriate candidates to receive treatment with rosiglitazone medicines, based on the risks and benefits compared with other therapies. Enrollment in the Avandia-Rosiglitazone Medicines Access Program is required for health care providers who wish to prescribe rosiglitazone medicines to outpatients or to patients in long-term care facilities. To enroll, health care providers must review the prescriber overview and the full prescribing information, including the medication guide, and must complete and sign the prescriber enrollment form. A copy of the medication guide must be provided to and reviewed by the patient or caregiver, and the health care provider must enroll eligible patients into the program by completing and signing a patient enrollment form. If a patient who has been taking a rosiglitazone medicine is hospitalized, the patient must be enrolled in the Avandia- Rosiglitazone Medicines Access Program to continue receiving the medicine; however, the patient s health care provider in the hospital is not required to be enrolled. Any adverse events involving rosiglitazone medicines should be reported to the FDA MedWatch program at medwatch.

10 10 INTERVENTIONAL CARDIOLOGY JUNE 2011 CARDIOLOGY NEWS New LVAD May Benefit High-Risk PCI Patients BY MITCHEL L. ZOLER FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OR CARDIOLOGY VITALS Major Finding: High-risk patients who were aided during PCI with an LVAD (Impella 2.5) had a 41% rate of major adverse events at 90 days, significantly better than the 51% rate in patients treated with a standard intra-aortic balloon pump. But in the intention-to-treat analysis, outcomes did not differ for the two groups at either 30 days or 90 days. Data Source: PROTECT II, a randomized trial comparing LV support with the Impella 2.5 device and an intra-aortic balloon pump in 447 patients who were treated at 72 sites worldwide. Disclosures: PROTECT II was funded by Abiomed, which markets the Impella device. Dr. O Neill has been a consultant to Medtronic. Dr. Waksman has been a consultant to or received honoraria from Medtronic Vascular, Abbott Vascular, Biotronik, Merck, and Boston Scientific. NEW ORLEANS Introduced to the U.S. market in 2008 as an upgraded alternative to the intra-arterial balloon pump, the Impella 2.5 showed clear signs of better performance in high-risk patients undergoing percutaneous coronary intervention in a multicenter, randomized trial with 447 patients. But once Impella 2.5 entered the U.S. market, enrollment into the study slowed dramatically. Eventually, researchers stopped the trial substantially short of its enrollment target, and the pivotal study s primary end point did not show a statistically significant benefit for Impella 2.5. The trial also ran into a second problem with a major confounding issue: Interventional cardiologists used rotational atherectomy more aggressively in Impella-treated patients. They seemingly were emboldened by the added cardiac support, and Impella-treated patients had an unbalanced rate of adverse effects. Despite these problems, the trial results showed a role for the Impella device in high-risk, low-cardiac-output patients undergoing PCI, Dr. William O Neill said at the meeting. This device produces superb hemodynamic support during high-risk interventions. It really allows a more complete procedure that leads to fewer late events, explained Dr. O Neill, an interventional cardiologist and executive dean for clinical affairs at the University of Miami. With these [high-risk] patients, we skate rapidly over thin ice. This device allows us the luxury of taking more time and doing a more complete and safer procedure. I think [that capability] will translate into increased use [of the device] in these high-risk patients, he added. Experts who heard the trial results were split on their interpretation of the findings. This was a negative study. What is driving the differences you see? I don t understand how to reconcile the results with your conclusion to go ahead [with using] this device, commented Dr. Ron Waksman, director of experimental angioplasty at Washington (D.C.) Hospital Center. But Dr. Roxanna Mehran gave the findings a much more positive spin (see box, below right). PROTECT II was a prospective, multicenter, randomized, controlled trial of the Impella Recover LP 2.5 system vs. IABP (intra-aortic balloon pump) in patients undergoing nonemergent, highrisk PCI. The trial began in November 2007 at 67 U.S. sites, 4 sites in Canada, and 1 site in the Netherlands. It enrolled patients with either unprotected left main coronary disease and a left ventricular ejection fraction of 35% or less, or patients with triple-vessel coronary disease and an ejection fraction of 30% or less. The primary end point was the 30-day rate of death, MI, stroke, need for repeat revascularization, need for cardiovascular surgery or vascular surgery for limb ischemia, acute renal dysfunction, increased aortic insufficiency, severe hypotension, need for cardiopulmonary resuscitation, ventricular tachycardia, or failure to reopen the target coronaries by PCI. The patients averaged 67 years old, 80% were men, and 56% had New York Heart Association class III or IV heart failure. Their average Society of Thoracic Surgeons (STS) mortality score was 6, their average SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score was 30, and 63% were considered ineligible for surgery. The population was extraordinarily high risk, the most complex patients ever enrolled in a multicenter, randomized, controlled trial, Dr. O Neill said. There were 447 patients enrolled in PROTECT II before the study s data and safety monitoring board stopped the trial last December citing futility on the primary end point. This number was 70% of the number of patients originally identified as needed to produce a statistically significant result for the primary end point. Enrollment into the study sharply slowed once the Impella device came onto the U.S. market in June During PCI, the participating operators generally managed the Impella patients more aggressively. Heparin was given to 94% in the Impella arm and to 82% in the IABP control arm. Rotational atherectomy was performed in 15% of the Impella patients and in 10% of patients in the IABP arm, a statistically significant difference. Also, participating operators used atherectomy more aggressively in the Impella patients, with an average of five atherectomy passes per patient, compared with two passes in the IABP patients. Although this shift in treatment approach may have ultimately benefited some of the Impella patients, it also increased the major adverse event rate and confounded the analysis, Dr. O Neill said. About 70% of patients treated with atherectomy in the Impella group had an adverse event primarily rises in the level of creatine kinase myoglobin compared with about 35% treated with atherectomy in the IABP group, he said in an interview. It was a procedural imbalance that was hard to control for in the safety and efficacy analysis. There was no statistically significant difference for the study s primary outcome, the combined major adverse event rate in the intention-to-treat analysis at 30 days after treatment, as well as at 90 days after treatment. However, at both time points, patients in the Impella arm showed trends toward lower major adverse events rates. At 30 days, the Impella patients had a 36% rate, compared with a 40% rate in the IABP patients. At 90 days, the rates reached 41% and 50%, respectively. In the per-protocol analysis, at 30 days the Impella patients had a major adverse event rate of 35%, compared with 43% in the IABP patients, which was not a statistically significant difference. At 90 days, the rates reached 41% and 51%, respectively, a difference that was statistically significant. Dr. O Neill addressed concerns that the major adverse event measure included many elements of sharply differing clinical importance. What drove the difference [between the two study arms] VIEW ON THE NEWS was death, myocardial infarction, and need for urgent revascularization not the small stuff. The real major adverse cardiac events were significantly better when the Impella device was used, he said in an interview. An analysis of several prespecified subgroups also highlighted certain types of patients who had significant benefit from the Impella device for the study s primary end point. Among the 88% of patients in the study who were not treated with rotational atherectomy, the 30-day major adverse event rate reached 30%, compared with 42% in the IABP patients, a statistically significant difference. A significant difference in the primary outcome in favor of the Impella patients also occurred in the subgroup that had an STS mortality score lower than 10. The results also showed a strong trend toward a better primary outcome in the Impella-treated patients when the analysis excluded the first Impellatreated patient for each operator, a finding that highlighted an important learning curve in using the device, Dr. O Neill said. Analysis also showed that the 90-day rate of major adverse events in the Impella patients fell from 48% in 2008 to 39% in 2009 and to 37% in In contrast, the rate in the IABP patients stayed fairly constant (at 47%-52%) in all 3 years, again highlighting the role of experience with the Impella device in achieving better patient outcomes, he said. I think many clinicians will see [from these data] that Impella provides a lot of safety, Dr. O Neill said. Device Useful for Selected Patients The results that Dr. O Neill presented support the use of the Impella 2.5 device in certain clinical situations, specifically in extremely high-risk patients who have a low left ventricular ejection fraction and need protection when undergoing multivessel PCI. Having access to this type of adjunctive device is important, especially for high-risk patients. I can see myself using this device in patients similar to those enrolled in PROTECT II. It s unfortunate that the trial did not give a definitive answer to the questions posed in the study. The trial was designed as a superiority trial and did not meet its primary end point. The results do not give us a scientific answer on when to use the device because the study stopped early. But studies like this can inform us tremendously on how to manage very high-risk patients. It s a tremendous effort to undertake the study and find the patients who would benefit from this device. We saw in the results that physicians who used the Impella device had the confidence to more aggressively use atherectomy. That can t be proved, but it appears to be so. The higher use of rotational atherectomy resulted in more creatine kinase myoglobin elevations in that arm, but the Impella group had fewer critically important MIs (defined as a CK-MB rise of more than eight times the upper limit of normal). ROXANA MEHRAN, M.D., is professor of medicine and director of interventional cardiovascular research at Mount Sinai Medical Center in New York. She has been a consultant to or received honoraria from Cardiva, Ortho-McNeil, Regado, the Medicines Company, Abbott Vascular, AstraZeneca, and Cordis. She has received research grants from Bristol- Myers Squibb and Sanofi-Aventis. Pages 10a 10b

11 JUNE INTERVENTIONAL CARDIOLOGY 11 Shorter Antiplatelet Tx After Stenting Safe BY CAROLINE HELWICK FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY NEW ORLEANS Short and standard durations of dual-antiplatelet therapy were equally protective against target vessel failure in drug-eluting stent recipients, Korean researchers reported at the meeting. With the exception of patients who Hypertriglyceridemia: Patients with fasting serum TG levels above 500 mg/dl were excluded from the diabetes clinical trials. In the phase 3 diabetes trials, 637 (63%) patients had baseline fasting serum TG levels less than 200 mg/dl, 261 (25%) had baseline fasting serum TG levels between 200 and 300 mg/dl, 111 (11%) had baseline fasting serum TG levels between 300 and 500 mg/dl, and 9 (1%) had fasting serum TG levels greater than or equal to 500 mg/dl. The median baseline fasting TG concentration for the study population was 172 mg/dl; the median post-treatment fasting TG was 195 mg/dl in the WELCHOL group and 177 mg/dl in the placebo group. WELCHOL therapy resulted in a median placebo-corrected increase in serum TG of 5% (p=0.22), 22% (p<0.001), and 18% (p<0.001) when added to metformin, insulin and sulfonylureas, respectively [See Warnings and Precautions (5.2) and Clinical Studies (14.2) in the full prescribing information]. In comparison, WELCHOL resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week mono therapy lipid-lowering trial [See Clinical Studies (14.1) in the full prescribing information]. Treatment-emergent fasting TG concentrations 500 mg/dl occurred in 4.1% of WELCHOL-treated patients compared to 2.0% of placebo-treated patients. Among these patients, the TG concentrations with WELCHOL (median 604 mg/dl; interquartile range mg/dl) were similar to that observed with placebo (median 644 mg/dl; interquartile range mg/dl). Two (0.4%) patients on WELCHOL and 2 (0.4%) patients on placebo developed TG elevations 1000 mg/dl. In all WELCHOL clinical trials, including studies in patients with type 2 diabetes and patients with primary hyperlipidemia, there were no reported cases of acute pancreatitis associated with hypertriglyceridemia. It is unknown whether patients with more uncontrolled, baseline hypertriglyceridemia would have greater increases in serum TG levels with WELCHOL [See Contraindications (4) and Warnings and Precautions (5.2)]. Cardiovascular adverse events: During the diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 3% (17/566) in the WELCHOL group and 2% (10/562) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown. Hypoglycemia: Adverse events of hypoglycemia were reported based on the clinical judgment of the blinded investigators and did not require confirmation with fingerstick glucose testing. The overall reported incidence of hypoglycemia was 3.0% in patients treated with WELCHOL and 2.3% in patients treated with placebo. No WELCHOL treated patients developed severe hypoglycemia. 6.2 Post-marketing Experience The following additional adverse reactions have been identified during post-approval use of WELCHOL. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Drug Interactions with concomitant WELCHOL administration include: K!>3B51C54C59JEB513D9F9DI?B453B51C54 phenytoin levels in patients receiving phenytoin. Phenytoin should be administered 4 hours prior to WELCHOL. K)54E354!>D5B>1D9?>1<&?B=1<9J54)1D9?!&)9>@1D95>DCB5359F9>7G1B61B9> D85B1@I!>G1B61B9>DB51D54@1D95>DC!&) should be monitored frequently during WELCHOL initiation then periodically thereafter. K<5F1D54D8IB?94CD9=E<1D9>78?B=?>5 (TSH) in patients receiving thyroid hormone replacement therapy. Thyroid hormone replacement should be administered 4 hours prior to WELCHOL [See Drug Interactions (7)]. 1CDB?9>D5CD9>1<4F5BC5)513D9?>C Bowel obstruction (in patients with a history of bowel obstruction or resection), dysphagia or esophageal obstruction (occasionally requiring medical intervention), fecal impaction, pancreatitis, abdominal distension, exacerbation of hemorrhoids, and increased transaminases. Laboratory Abnormalities Hypertriglyceridemia 7 DRUG INTERACTIONS Table 4 lists the drugs that have been tested in in vitro binding or in vivo drug interaction studies with colesevelam and/or drugs with postmarketing reports consistent with potential drug-drug interactions. Orally administered drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to WELCHOL. Alternatively, the physician should monitor drug levels of the coadministered drug. Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports Drugs with a known interaction with colesevelam a Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL Drugs that do not interact with colesevelam based on in vitro or in vivo testing had diabetes, the overall 12-month clinical event rates were not different between 6- and 12-month treatment duration groups for all-cause mortality, cardiac death, MI cerebrovascular accident, target vessel revascularization (TVR), stent thrombosis, major bleeding, or various composites of the above end points, reported Dr. Hyeon-Cheol Gwon of Samsung Medical Center at Sungkyunkwan University in Seoul. cyclosporine c, glyburide a, levothyroxine a, and oral contraceptives containing ethinyl estradiol and norethindrone phenytoin a, warfarin b cephalexin, ciprofloxacin, digoxin, warfarin b, fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil a Should be administered at least 4 hours prior to WELCHOL b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics!&) [See Post-marketing Experience (6.2)] c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL. In an in vivo drug interaction study, WELCHOL and warfarin coadministration had no effect on warfarin drug levels. This study did not assess the effect of WELCHOL and warfarin coadministration?>!&)!>@?cd=1b;5d9>7b5@?bdc concomitant use of WELCHOL and warfarin has been associated with reduced!&)+85b56?b59>@1d95>dc?>g1b61b9> D85B1@ID85!&)C8?E<425=?>9D?B54 before initiating WELCHOL and frequently enough during early WELCHOL therapy to 5>CEB5D81D>?C97>96931>D1<D5B1D9?>9>!&)?33EBC'>35D85!&)9CCD12<53?>D9>E5D? =?>9D?BD85!&)1D9>D5BF1<CECE1<<I recommended for patients on warfarin. [See Post-marketing Experience (6.2)] 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B. There are no adequate and well-controlled studies of colesevelam use in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of fetal harm. )5AE9B5=5>DC6?BF9D1=9>C1>4?D85B nutrients are increased in pregnancy. However, the effect of colesevelam on the absorption of fat-soluble vitamins has not been studied in pregnant women. This drug should be used during pregnancy only if clearly needed. In animal reproduction studies, colesevelam revealed no evidence of fetal harm when administered to rats and rabbits at doses 50 and 17 times the maximum human dose, respectively. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. 8.3 Nursing Mothers Colesevelam hydrochloride is not expected to be excreted in human milk because colesevelam hydrochloride is not absorbed systemically from the gastrointestinal tract. 8.4 Pediatric Use The safety and effectiveness of WELCHOL as monotherapy or in combination with a statin were evaluated in children, 10 to 17 years of age with hefh [See Clinical Studies (14.1) in the full prescribing information]. The adverse reaction profile was similar to that of patients treated with placebo. In this limited controlled study, there were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo /*554F5BC5)513D9?>C0. Due to tablet size, WELCHOL for Oral Suspension is recommended for use in the pediatric population. Dose adjustments are not required when WELCHOL is administered to children 10 to 17 years of age. WELCHOL has not been studied in children younger than 10 years of age or in pre-menarchal girls. 8.5 Geriatric Use Primary Hyperlipidemia: Of the 1350 patients enrolled in the hyperlipidemia clinical studies, 349 (26%) were 65 years old, and 58 (4%) were 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. At least in low-risk patients getting drug-eluting stents, that is, nondiabetics, maybe we can safely discontinue clopidogrel at 6 months, he said. Current guidelines recommend at least 12 months of anticoagulation to prevent venous thromboembolism. Current guidelines recommend at least 12 months of anticoagulation to prevent venous thromboembolism. Type 2 Diabetes Mellitus: Of the 1128 patients enrolled in the four diabetes studies, 249 (22%) were 65 years old, and 12 (1%) were 75 years old. In these trials, WELCHOL 3.8 g/day or placebo was added onto background anti-diabetic therapy. No overall differences in safety or effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No special considerations or dosage adjustments are recommended when WELCHOL is administered to patients with hepatic impairment. 8.7 Renal Impairment Type 2 Diabetes Mellitus: Of the 1128 patients enrolled in the four diabetes studies, 696 (62%) had mild renal insufficiency (creatinine clearance [CrCl] 50-<80 ml/min), 53 (5%) had moderate renal insufficiency (CrCl 30-<50 ml/ min), and none had severe renal insufficiency (CrCl <30 ml/min), as estimated from baseline serum creatinine using the %?496931D9?>?695D9>)5>1<9C51C5 %)5AE1D9?>&??F5B1<<49665B5>35C in safety or effectiveness were observed between patients with CrCl <50 ml/min (n=53) and those with a CrCl 50 ml/min (n=1075). 10 OVERDOSAGE Doses of WELCHOL in excess of 4.5 g/day have not been tested. Because WELCHOL is not absorbed, the risk of systemic toxicity is low. However, excessive doses of WELCHOL may cause more severe local gastrointestinal effects (e.g., constipation) than recommended doses. Marketed by: P Daiichi Sankyo, Inc. Parsippany, New Jersey Early discontinuation of antiplatelet therapy might be particularly relevant for patients at high risk of bleeding or those anticipating subsequent procedures, which are often delayed while the drugs are withdrawn. But Dr. Sanjay Kaul of Cedars-Sinai Medical Center, Los Angeles, questioned VITALS Major Finding: The rates of 12- month TVF were 4.7% for drugeluting stent recipients given 6months of clopidogrel and aspirin and 4.4% for those given 12 months of antiplatelet therapy. By Kaplan-Meier analysis, the cumulative proportional estimate of target vessel failure at 1 year was 5.2% for the 6-month regimen and 4.3% for the 12-month regimen. Data Source: A study of 1,443 patients receiving everolimus- or sirolimus-eluting stents and randomized to either 6 or 12 months of clopidogrel and aspirin. Disclosures: Dr. Gwon reported consulting fees and honoraria from Cordis and Medtronic as well as research support from Abbott Korea and Medtronic Korea. Dr. Kaul has received consulting fees and honoraria from Novo Nordisk and Hoffman-LaRoche. the researchers use of target vessel failure (TVF) as the primary study end point. TVF was defined as a composite of cardiac death, MI, or TVR. Dr. Gwon acknowledged that, saying We recognize our study is hypothesis generating. The trial involved 1,443 patients with greater than 50% stenosis and evidence of myocardial ischemia. Patients receiving everolimus- or sirolimus-eluting stents were randomized to receive 6 or 12 months of dual-antiplatelet therapy with clopidogrel and aspirin. The study found that discontinuing clopidogrel and aspirin after 6 months did not increase the rate of 12-month TVF. The rates were 4.7% for the 6- month group and 4.4% for the 12-month group. By Kaplan-Meier analysis, the cumulative proportional TVF estimate at 1 year was 5.2% for the 6-month regimen and 4.3% for the 12-month regimen, which met the noninferiority end point in a highly significant manner (P =.0031; upper 1-sided 97.5% confidence interval 0.9%-3.6%), Dr. Gwon said. The cumulative incidence of major adverse cardiac or coronary events was 7.5% with 6-month therapy and 8.4% with 12-month therapy. There was, however, a significantly higher risk for primary TVF with early discontinuation of antiplatelet therapy for patients with diabetes. Diabetes patients receiving 6 months of dual-antiplatelet therapy had a TVF rate of 8.9%, vs. 2.9% with 12 months of treatment. There were no other significant subgroup differences.

12 12 INTERVENTIONAL CARDIOLOGY JUNE 2011 CARDIOLOGY NEWS DES Boosted Survival in Primary PCI Patients Higher 5-year survival with drug-eluting stents shows safety in setting of myocardial infarction. BY MITCHEL L. ZOLER FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY NEW ORLEANS Acute myocardial infarction patients treated with a drugeluting coronary stent during a primary percutaneous coronary intervention had significantly better 5-year survival, compared with myocardial infarction patients who received a bare-metal stent, in a review of more than 12,000 patients treated in New Jersey during Although this analysis could not take into account selection biases that might have determined whether patients received drug-eluting or bare-metal stents, the findings in general provide reassurance about the safety of drug-eluting coronary stents for patients with an acute MI, Dr. Tudor D. Vagaonescu said at the meeting. These data are consistent with the idea that using drug-eluting stents in the setting of an acute MI is safe, said Dr. Vagaonescu, a cardiologist at the Robert Wood Johnson Medical School, New Brunswick, N.J. Our data show that preventing the need for revascularization by using drugeluting stents [DES] helped with survival, although improved survival was Adjusted HRs for Drug-Eluting Stents Vs. Bare-Metal Stents in Primary PCI 0.80 All-cause death All MIs ST-elevation MI likely due to a combination of things, including selection bias and the type of index event, he said in an interview. The study used data collected in the Myocardial Infarction Data Acquisition System (MIDAS) registry and included all patients who underwent primary PCI for an acute MI at a nonfederal hospital in New Jersey during The group included 6,172 patients treated with one or more drug-eluting coronary stents only, and 5,833 patients treated with one or more bare-metal stents only. The analysis excluded patients who received both stent types. Based on New Jersey death registration files, during the 5 years following stent placement, cumulative all-cause mortality in the DES recipients was 16% and was 20% in the bare-metal stent recipients, a statistically significant difference. The rate of cardiovascular death was 8% and 10% in the drug-eluting and bare-metal stent groups, respectively, also a statistically significant difference. Similar, statistically significant differences in favor of improved 5-year total survival and reduced cardiovascular deaths with DES also occurred in both the subset of patients with ST-elevation myocardial infarction and in patients with non STelevation myocardial infarction, Dr. Vagaonescu reported. Cardiovascular death Non STelevation MI Notes: Based on 5-year follow-up of 12,005 patients treated with percutaneous coronary intervention. All hazard ratios are statistically significant, compared with bare-metal stents. Source: Dr. Vagaonescu ELSEVIER GLOBAL MEDICAL NEWS He and his associates also performed multivariate analyses of mortality rates adjusted by age, sex, race, diabetes, hypertension, renal disease, anemia, cancer, cerebrovascular disease, prior MI, and treatment with a glycoprotein IIb/IIIa inhibitor. All of these multi- VIEW ON THE NEWS VITALS variate analyses showed statistically significant survival advantages for the patients who received drug-eluting stents (see graph). Another aspect of the analysis showed the dramatic shift toward use of DES for primary PCI during the period studied, which covered the time when the first sirolimus-eluting stent received Food and Drug Administration approval in April 2003, and when the first paclitaxel-eluting coronary stent received FDA approval in March In 2003, 73% of the 6,027 patients who received a single type of coronary stent for primary PCI in New Jersey received a bare-metal stent. By 2004, this pattern flipped, and 76% of the 5,978 patients who received a single type of coronary stent for primary PCI received a drug-eluting stent. Both years predated the reports in 2006 that first raised awareness of the risk for stent thrombosis in patients who received a DES, especially patients who prematurely stopped dual-antiplatelet therapy. Jury Out on First-Generation DES Amajor concern when using drug-eluting coronary stents to treat acute myocardial infarction is the risk of late stent thrombosis, especially with the first-generation drug-eluting stents, the sirolimuseluting Cypher and the paclitaxeleluting Taxus stents. For several years, since evidence established a link between long-term dual-antiplatelet therapy and reduced stent thrombosis, the issue has been can an acute myocardial infarction patient reliably remain on dual-antiplatelet therapy for at least 1 year. This information is often difficult to know in the emergency department at the time of primary percutaneous coronary intervention. This concern has been balanced by the very respectable performance of bare-metal stents when placed in acute myocardial infarction patients. Experience has taught us that when you have doubt about a patient s willingness or ability to remain on dual-antiplatelet therapy, there is nothing wrong with using a baremetal stent. What s unclear is the potential role for the second-generation drug Major Finding: Acute myocardial infarction patients treated with drug-eluting coronary stents had a 16% mortality rate during 5 years of follow-up, significantly better than the 20% mortality rate in patients treated with bare-metal stents. Data Source: Review of 12,005 New Jersey patients treated with primary percutaneous coronary intervention during Disclosures: Dr. Vagaonescu said that he had no disclosures. eluting stents for primary percutaneous coronary interventions. The everolimus-eluting stents seem to have a reduced risk for late thrombosis, compared with the first-generation stents in patients without an acute myocardial infarction. We d like to know the performance of second-generation drug-eluting stents in myocardial infarction patients, but we currently have no evidence about this. The data presented by Dr. Vagaonescu do not provide a solid case for using first-generation drug-eluting stents in myocardial infarction patients. These data came from a retrospective review, and the patients involved were very heterogeneous. It s just a first step toward understanding, in a broad group of patients, how drug-eluting and baremetal stents perform in myocardial infarction patients. DAVID G. RIZK, M.D., is an interventional cardiologist and director of the division of heart and vascular medicine at the Scottsdale (Ariz.) Healthcare Hospital. His comments were made in an interview. He said that he had no disclosures. FDA Expands Carotid Stent Indication to Standard-Risk Patients BY MARY ELLEN SCHNEIDER The Food and Drug Administration expanded the indication for the RX Acculink carotid stent, allowing it to be marketed for use in patients with carotid artery disease who do not face an increased risk of complications from surgery. The RX Acculink stent, which is marketed by Abbott Vascular, a subsidiary of Abbott Laboratories, was originally approved by the FDA in At that time, the stent was approved for patients at high risk of complications from carotid endarterectomy. The company sought an expanded approval based on the results of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST), a randomized, multicenter, noninferiority study sponsored by the National Institutes of Health and funded in part by the manufacturer. The study of more than 2,500 patients in the United States and Canada showed that at 1 year, patients who were treated with RX Acculink had a combined 30-day rate of death, stroke, and myocardial infarction, and a 31 to 365-day rate of ipsilateral stroke, of 7.1%, compared with 6.6% among those who underwent endarterectomy, a difference that met the prespecified criteria for noninferiority. As a condition of the expanded approval, the FDA is requiring Abbott Vascular to conduct a postapproval study. The study would follow new patients treated with RX Acculink for at least 3 years to confirm the results from the CREST study. The FDA has also asked the manufacturer to look at how patients aged 80 years and older respond to treatment and whether patients who show symptoms prior to treatment experience different outcomes than those who don t exhibit symptoms. The FDA s action follows a recommendation from the Circulatory System Devices Panel. In January, a majority of those experts voted that the benefits of using the RX Acculink stent outweighed the risks when used in patients at standard risk for surgery.

13 BYSTOLIC. Helping patients get the blood pressure reductions they need. NOW with even wider formulary availability

14 BYSTOLIC. Significant blood pressure reductions with a low incidence of side effects. Effective as monotherapy or in combination 1,2 * DBP/SBP reductions of up to -15.3/-29.0 mm Hg for BYSTOLIC when used in combination with HCTZ 25 mg (vs -1.4/-0.2 mm Hg for placebo) DBP/SBP reductions of -9.3/-16.7 and -13.8/-17.6 for BYSTOLIC monotherapy 5 mg and 10 mg, respectively (vs -1.4/-0.2 for placebo) Low incidence of side effects and overall low discontinuation rate 3 Discontinuation rate due to adverse events was 2.8% for BYSTOLIC vs 2.2% for placebo 3 * Results from a 3-month, multicenter, randomized, double-blind, parallel-group, placebo-controlled, multifactorial-design study of BYSTOLIC and hydrochlorothiazide, alone or in combination, for the treatment of mild to moderate hypertension. Primary endpoint was sitting DBP at trough. Mean values at baseline: sitting DBP at trough, mm Hg; sitting SBP at trough, mm Hg (N=240; n=100). Primary endpoint was sitting DBP at trough. Mean values at baseline: sitting DBP at trough, mm Hg; sitting SBP at trough, mm Hg (N=240; n=59). BYSTOLIC is indicated for the treatment of hypertension. BYSTOLIC may be used alone or in combination with other antihypertensive agents. Important Safety Information Adverse Reactions The most common adverse events with BYSTOLIC versus placebo (approximately 1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema. The most common adverse events that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%), and bradycardia (0.2%). Contraindications BYSTOLIC is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product. Warnings and Precautions Do not abruptly discontinue BYSTOLIC therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction, and ventricular arrhythmias have been reported following the abrupt discontinuation of therapy with beta blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other beta blockers, when discontinuation of BYSTOLIC is planned, carefully observe and advise patients to minimize physical activity. Taper BYSTOLIC over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, restart BYSTOLIC promptly, at least temporarily. BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI. In general, patients with bronchospastic diseases should not receive beta blockers. Because beta blocker withdrawal has been associated with an increased risk of MI and chest pain, patients already on beta blockers should generally continue treatment throughout the perioperative period. If BYSTOLIC is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene are used. If beta-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The beta-blocking effects of BYSTOLIC can be reversed by beta agonists, eg, dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with beta blockers. Beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities. Beta blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta blockers in these patients may be followed by an exacerbation of symptoms or may precipitate a thyroid storm. Beta blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Because of significant negative inotropic and chronotropic effects in patients treated with beta blockers and calcium channel blockers of the verapamil and diltiazem type, monitor the ECG and blood pressure of patients treated concomitantly with these agents Forest Laboratories, Inc /10

15 BYSTOLIC. Widely available on managed care formularies. 87% COMMERCIAL MEDICARE PART D 78% unrestricted access 4 unrestricted access 4 NEW Medco NEW Medco Part D NEW ESI UnitedHealthcare Aetna CIGNA Humana MedImpact CVS Caremark UnitedHealthcare Part D Aetna Part D CIGNA Part D Humana Part D SilverScript MemberHealth/CCRx Health Net Part D WellPoint Part D Formulary status information is valid as of October Coverage is subject to change. Warnings and Precautions (continued) Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc). When BYSTOLIC is co-administered with an inhibitor or an inducer of CYP2D6, monitor patients closely and adjust the nebivolol dose according to blood pressure response. The dose of BYSTOLIC may need to be reduced. When BYSTOLIC is administered with fluoxetine, significant increases in d-nebivolol may be observed (ie, an 8-fold increase in AUC and a 3-fold increase in Cmax for d-nebivolol). Renal clearance of nebivolol is decreased in patients with severe renal impairment. In patients with severe renal impairment (ClCr less than 30 ml/min) the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients receiving dialysis. Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients with severe hepatic impairment and therefore it is not recommended in that population. Patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine while taking beta blockers. In patients with known or suspected pheochromocytoma, initiate an alpha blocker prior to the use of any beta blocker. Drug Interactions Do not use BYSTOLIC with other beta blockers. Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. BYSTOLIC can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide. Use in Specific Populations Use BYSTOLIC during pregnancy only if the potential benefit justifies the potential risk to the fetus. BYSTOLIC is not recommended during nursing. The safety and effectiveness of BYSTOLIC have not been established in pediatric patients. In a placebo-controlled trial of 2128 patients (1067 BYSTOLIC, 1061 placebo) over 70 years of age with chronic heart failure receiving a maximum dose of 10 mg per day for a median of 20 months, no worsening of heart failure was reported with nebivolol compared to placebo. However, if heart failure worsens, consider discontinuation of BYSTOLIC. Please see brief summary of full Prescribing Information on last page of this advertisement. References: 1. Lacourcière Y, Lefebvre J, Poirier L, Archambault F, Arnott W. Treatment of ambulatory hypertensives with nebivolol or hydrochlorothiazide alone and in combination: a randomized, double-blind, placebo-controlled, factorial-design trial. Am J Hypertens. 1994;7: Data on file. Forest Laboratories, Inc. 3. BYSTOLIC [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; MediMedia Information Technologies, LLC, as of October Data is subject to change.

16 16 ARRHYTHMIAS & ELECTROPHYSIOLOGY JUNE 2011 CARDIOLOGY NEWS Asymptomatic AF Increases After Ablation BY BRUCE JANCIN FROM THE ANNUAL MEETING OF THE HEART RHYTHM SOCIETY SAN FRANCISCO Declaring a patient cured of atrial fibrillation on the basis of a lack of symptoms following atrial fibrillation ablation is definitely jumping the gun, the DISCERN AF study indicates. Implantable loop recorders used in DIS- BYSTOLIC (nebivolol) tablets Brief Summary of full Prescribing Information Initial U.S. Approval: 2007 Rx Only INDICATIONS AND USAGE: Hypertension - BYSTOLIC is indicated for the treatment of hypertension [see Clinical Studies (14.1)]. BYSTOLIC may be used alone or in combination with other antihypertensive agents [see Drug Interactions (7)]. CONTRAINDICATIONS: BYSTOLIC is contraindicated in the following conditions: Severe bradycardia; Heart block greater than first degree; Patients with cardiogenic shock; Decompensated cardiac failure; Sick sinus syndrome (unless a permanent pacemaker is in place); Patients with severe hepatic impairment (Child-Pugh >B); Patients who are hypersensitive to any component of this product. WARNINGS AND PRECAUTIONS: Abrupt Cessation of Therapy - Do not abruptly discontinue BYSTOLIC therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of BYSTOLIC is planned, carefully observe and advise patients to minimize physical activity. Taper BYSTOLIC over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, restart BYSTOLIC promptly, at least temporarily. Angina and Acute Myocardial Infarction - BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI. Bronchospastic Diseases - In general, patients with bronchospastic diseases should not receive β-blockers. Anesthesia and Major Surgery - Because beta-blocker withdrawal has been associated with an increased risk of MI and chest pain, patients already on beta-blockers should generally continue treatment throughout the perioperative period. If BYSTOLIC is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of BYSTOLIC can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with β-blockers. Diabetes and Hypoglycemia - β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities. Thyrotoxicosis - β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm. Peripheral Vascular Disease - β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Non-dihydropyridine Calcium Channel Blockers - Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, monitor the ECG and blood pressure in patients treated concomitantly with these agents. Use with CYP2D6 Inhibitors - Nebivolol exposure increases with inhibition of CYP2D6 [see Drug Interactions (7)]. The dose of BYSTOLIC may need to be reduced. Impaired Renal Function - Renal clearance of nebivolol is decreased in patients with severe renal impairment. BYSTOLIC has not been studied in patients receiving dialysis [see Clinical Pharmacology (12.4) and Dosage and Administration (2.1)]. Impaired Hepatic Function - Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. BYSTOLIC has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.4) and Dosage and Administration (2.1)]. Risk of Anaphylactic Reactions - While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. Pheochromocytoma - In patients with known or suspected pheochromocytoma, initiate an α-blocker prior to the use of any β-blocker. ADVERSE REACTIONS: Clinical Studies Experience - BYSTOLIC has been evaluated for safety in patients with hypertension and in patients with heart failure. The observed adverse reaction profile was consistent with the pharmacology of the drug and the health status of the patients in the clinical trials. Adverse reactions reported for each of these patient populations are provided below. Excluded are adverse reactions considered too general to be informative and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. The data described below reflect worldwide clinical trial exposure to BYSTOLIC in 6545 patients, including 5038 patients treated for hypertension and the remaining 1507 subjects treated for other cardiovascular diseases. Doses ranged from 0.5 mg to 40 mg. Patients received BYSTOLIC for up to 24 months, with over 1900 patients treated for at least 6 months, and approximately 1300 patients for more than one year. HYPER- TENSION: In placebo-controlled clinical trials comparing BYSTOLIC with placebo, discontinuation of therapy due to adverse reactions was reported in 2.8% of patients treated with nebivolol and 2.2% of patients given placebo. The most common adverse reactions that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%) and bradycardia (0.2%). Table 1 lists treatment-emergent adverse reactions that were reported in three 12-week, placebo-controlled monotherapy trials involving 1597 hypertensive patients treated with either 5 mg, 10 mg, or mg of BYSTOLIC and 205 patients given placebo and for which the rate of occurrence was at least 1% of patients treated with nebivolol and greater than the rate for those treated with placebo in at least one dose group. Table 1. Treatment-Emergent Adverse Reactions with an Incidence (over 6 weeks) 1% in BYSTOLIC-Treated Patients and at a Higher Frequency than Placebo- Treated Patients are listed below in the following order: System Organ Class Preferred Term [Placebo (n = 205), Nebivolol 5 mg (n = 459), Nebivolol 10 mg (n = 461), Nebivolol mg (n = 677)] Cardiac Disorders: Bradycardia (0, 0, 0, 1); Gastrointestinal Disorders: Diarrhea (2, 2, 2, 3); Nausea (0, 1, 3, 2); General Disorders: Fatigue (1, 2, 2, 5); Chest pain (0, 0, 1, 1); Peripheral edema (0, 1, 1, 1); Nervous System Disorders: Headache (6, 9, 6, 7); Dizziness ( 2, 2, 3, 4); Psychiatric Disorders: Insomnia (0, 1, 1, 1); Respiratory Disorders: Dyspnea (0, 0, 1, 1); Skin and Subcutaneous Tissue Disorders: Rash (0, 0, 1, 1). Listed below are other reported adverse reactions with an incidence of at least 1% in the more than 4300 patients treated with BYSTOLIC in controlled or open-label trials except for those already appearing in Table 1, terms too general to be informative, minor symptoms, or adverse reactions unlikely to be attributable to drug because they are common in the population. These adverse reactions were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies. Body as a Whole: asthenia. Gastrointestinal System Disorders: abdominal pain. Metabolic and Nutritional Disorders: hypercholesterolemia. Nervous System Disorders: paraesthesia. Laboratory Abnormalities - In controlled monotherapy trials of hypertensive patients, BYSTOLIC was associated with an increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count. Postmarketing Experience - The following adverse reactions have been identified from spontaneous reports of BYSTOLIC received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to BYSTOLIC. Adverse reactions common in the population have generally been omitted. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to BYSTOLIC exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonary edema, acute renal failure, atrioventricular block (both second- and third-degree), bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergic vasculitis and rare reports of angioedema), myocardial infarction, pruritus, psoriasis, Raynaud s phenomenon, peripheral ischemia/claudication, somnolence, syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting. DRUG INTERACTIONS: CYP2D6 Inhibitors - Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) [see Clinical Pharmacology (12.5)]. Hypotensive Agents - Do not use BYSTOLIC with other β-blockers. Closely monitor patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, because the added β-blocking action of BYSTOLIC may produce excessive reduction of sympathetic activity. In patients who are receiving BYSTOLIC and clonidine, discontinue BYSTOLIC for several days before the gradual tapering of clonidine. Digitalis Glycosides - Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Calcium Channel Blockers - BYSTOLIC can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide. USE IN SPECIFIC POPULATIONS: Pregnancy: Teratogenic Effects, Category C - Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period (late gestation, parturition and lactation). At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup survival. Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance. In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD). Labor and Delivery - Nebivolol caused prolonged gestation and dystocia at doses 5 mg/kg in rats (1.2 times the MRHD). These effects were associated with increased fetal deaths and stillborn pups, and decreased birth weight, live litter size and pup survival rate, events that occurred only when nebivolol was given during the perinatal period (late gestation, parturition and lactation). No studies of nebivolol were conducted in pregnant women. Use BYSTOLIC during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers - Studies in rats have shown that nebivolol or its metabolites cross the placental barrier and are excreted in breast milk. It is not known whether this drug is excreted in human milk. Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, BYSTOLIC is not recommended during nursing. Pediatric Use - Safety and effectiveness in pediatric patients have not been established. Pediatric studies in ages newborn to 18 years old have not been conducted because of incomplete characterization of developmental toxicity and possible adverse effects on long-term fertility [see Nonclinical Toxicology (13.1)]. Geriatric Use - Of the 2800 patients in the U.S.- sponsored placebo-controlled clinical hypertension studies, 478 patients were 65 years of age or older. No overall differences in efficacy or in the incidence of adverse events were observed between older and younger patients. Heart Failure - In a placebo-controlled trial of 2128 patients (1067 BYSTOLIC, 1061 placebo) over 70 years of age with chronic heart failure receiving a maximum dose of 10 mg per day for a median of 20 months, no worsening of heart failure was reported with nebivolol compared to placebo. However, if heart failure worsens consider discontinuation of BYSTOLIC. OVERDOSAGE: In clinical trials and worldwide postmarketing experience there were reports of BYSTOLIC overdose. The most common signs and symptoms associated with BYSTOLIC overdosage are bradycardia and hypotension. Other important adverse reactions reported with BYSTOLIC overdose include cardiac failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse reactions associated with β-blocker overdose include bronchospasm and heart block. The largest known ingestion of BYSTOLIC worldwide involved a patient who ingested up to 500 mg of BYSTOLIC along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhidrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure, and vomiting. The patient recovered. Because of extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance. If overdose occurs, provide general supportive and specific symptomatic treatment. Based on expected pharmacologic actions and recommendations for other β-blockers, consider the following general measures, including stopping BYSTOLIC, when clinically warranted: Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful. Heart Block (second- or third-degree): Monitor and treat with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Congestive Heart Failure: Initiate therapy with digitalis glycosides and diuretics. In certain cases, consider the use of inotropic and vasodilating agents. Bronchospasm: Administer bronchodilator therapy such as a short-acting inhaled β 2 -agonist and/or aminophylline. Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required. Supportive measures should continue until clinical stability is achieved. The half-life of low doses of nebivolol is hours. Call the National Poison Control Center ( ) for the most current information on β-blocker overdose treatment. Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA Licensed from Mylan Laboratories, Inc. Under license from Janssen Pharmaceutica N.V., Beerse, Belgium Rev. 02/ Forest Laboratories, Inc. CERN AF (Discerning the Incidence of Symptomatic and Asymptomatic Episodes Post Radiofrequency Ablation of AF) clearly documented that the proportion of AF episodes that are asymptomatic markedly increases after ablation, Dr. Atul Verma reported at the meeting. There is something about the postablation state that is making patients less able to detect their arrhythmia, observed Dr. Verma, DISCERN AF principal investigator and an electrophysiologist at Southlake Regional Health Center in Newmarket, Ont. DISCERN AF was an eight-center, prospective Canadian study in which 50 patients with symptomatic AF received a Medtronic Reveal XT insertable cardiac monitor at least 3 months before they underwent a standard first-time AF ablation procedure. Eighty percent of participants had paroxysmal AF. The subjects mean left atrial size was 41 mm. Dr. Verma presented the study results through 18 months of postablation follow-up, but there will be a subsequent report, because the devices will be left in place for a total of 30 months post ablation. Patients kept a detailed standardized diary to record the exact times of onset and end of their arrhythmic symptoms. Every 3 months the implantable loop recorder data were downloaded, and all recorded episodes were blindly adjudicated and compared to entries in the symptom diaries. Radiofrequency ablation effectively reduced total AF burden. Indeed, the total AF/atrial flutter burden decreased from a mean of 2 hours per day per patient preablation to 0.3 hours per day per patient post ablation, an 86% reduction. But while 52% of all AF/flutter episodes preablation were asymptomatic, that There is something about the postablation state that is making patients less able to detect their arrhythmia. DR. VERMA proportion climbed to 79% post ablation. The ratio of asymptomatic-to-symptomatic AF episodes preablation was 1.1:1; post ablation, it jumped to 3.7:1. Similarly, 36% of the total AF/flutter burden patients shouldered preablation consisted of asymptomatic arrhythmias, while post ablation 68% of the burden was asymptomatic. The ratio of asymptomatic-to-symptomatic AF/flutter burden preablation was 0.6:1; post ablation, it was 2:1. Patient self-reports corresponded to an implantable loop recorder documented episode of AF only 47% of the time. On the basis of self-reported symptoms only, 58% of patients were free of AF postablation. However, the implantable monitor data showed that the true figure was 46%. In other words, after AF ablation 12% of study participants had AF recurrences that were exclusively asymptomatic, Dr. Verma continued. Asymptomatic episodes were shorter than symptomatic ones, lasting 4 and 6 hours, respectively. They also involved a significantly lower heart rate and less heart rate variability. In a multivariate analysis, all three of these factors were independent predictors of asymptomatic AF recurrences. But postablation recurrences were a threefold more powerful predictor of lack of symptoms than any of the other three predictors. One plausible explanation for the increased proportion of asymptomatic AF episodes postablation is that the procedure results in denervation, although this hypothesis requires further investigation, according to the cardiologist. Discussant Dr. Michael R. Gold called Continued on following page

17 JUNE ARRHYTHMIAS & ELECTROPHYSIOLOGY 17 AF Boosts Nonaccidental Fall Risk in Elderly BY BRUCE JANCIN FROM THE ANNUAL MEETING OF THE HEART RHYTHM SOCIETY SAN FRANCISCO A history of atrial fibrillation independently more than triples the risk of a nonaccidental fall in the elderly, an emergency department study has shown. Of 459 consecutive elderly patients who presented to a large emergency department with a chief complaint of a fall, 225 had a fall deemed to be nonaccidental that is, a fall not explained by mitigating circumstances such as a loose paving stone or a collision with a skateboarder. A history of atrial fibrillation (AF) was present in 20.4% of those with a nonaccidental fall, compared with 10.6% of the 234 elderly patients who presented with an accidental fall, Dr. Joya A. Ganguly reported at the meeting. The study population had a median age of 81 years. Patients not older than that who had a nonaccidental fall were 3.36-fold more likely to have a history of AF, compared with those who had an accidental fall. However, among patients Continued from previous page the finding that the proportion of asymptomatic episodes increases following AF ablation very intriguing. In addition, DISCERN AF made a point very similar to the key message of the Catheter Ablation vs. Antiarrhythmic Drug Therapy for AF (CABANA) pilot study presented at the 2010 annual meeting of the American College of Cardiology in Atlanta: We re not as good as we thought we were in terms of ablating AF, observed Dr. Gold, professor of medicine, chief of cardiology, and medical director of the heart and vascular center at the Medical University of South Carolina, Charleston. Dr. Gold noted that in the CABANA pilot study, 66% of patients had experienced asymptomatic and/or symptomatic recurrences of AF, atrial flutter, or tachycardia at 12 months of follow-up post ablation. That wasn t significantly different from the 72% recurrence rate in patients assigned to drug therapy. The harder you look, the more arrhythmias you find, Dr. Gold observed. Clearly, DISCERN AF and the CA- BANA pilot study point to the need for large-scale studies with long-term follow-up to help us understand the best long-term clinical strategies, such as anticoagulation, as well as how well we re doing with ablation. One such study is the full-scale CA- BANA trial, sponsored by the National Heart, Lung, and Blood Institute; St. Jude Medical; and Biosense Webster. It will involve 3,000 patients and 5 years of follow-up. The DISCERN AF study was supported by Medtronic. Dr. Verma serves as an adviser to Medtronic and half a dozen other medical device and pharmaceutical companies. AVAILABLE NOW! older than 81 years, a history of AF was only 1.3-fold more frequent in those with a nonaccidental fall, compared with an accidental fall, and this difference was not significant, according to Dr. Ganguly of the University of Utah, Salt Lake City. Patients with a nonaccidental fall were an average of 4 years older than those who presented with an accidental fall. In addition to being more likely to have a history of AF, patients with a nonaccidental fall were also more likely to have a neurologic disorder and to be on three or more medications. In contrast, there were no differences between patients in the nonaccidental and accidental fall groups in terms of blood pressure, heart rate, orthostatic hypotension, prior pacemaker placement, a history of heart failure, or the prevalence of AF at presentation, which was about 8% in both groups. Cardiology News NETWORK Visit for the latest advances from key symposia at the 60 th Annual Scientific Session and Innovation in Intervention: i2 Summit New Orleans, LA April 2-5, CARDIOLOGY NEWS NETWORK Custom Conference Coverage provides onsite coverage of selected key sessions from the 60 th Annual Scientific Session and Innovation in Intervention: i2 Summit. Stay up-to-date on the latest developments in the field by reading about key clinical findings and watching interviews with some of the top researchers and clinicians who presented at this year s meeting. This news site is brought to you by the Custom Conference Coverage Department of CARDIOLOGY NEWS NETWORK, and is not an official site of the Foundation nor its sponsor, the American College of Cardiology Foundation (ACC). Dr. Ganguly concluded that these study findings suggest elderly patients with a history of AF might be good candidates for a fall prevention education program along the lines of the national program recently proposed by investigators at the University of Southern California as a cost-effective intervention (Clin. Geriatr. Med. 2010;26:751-66). She said she had no relevant financial disclosures.

18 18 ARRHYTHMIAS & ELECTROPHYSIOLOGY JUNE 2011 CARDIOLOGY NEWS AF Linked to Systemic Inflammatory Diseases BY BRUCE JANCIN FROM THE ANNUAL MEETING OF THE HEART RHYTHM SOCIETY SAN FRANCISCO What do individuals with rheumatoid arthritis and inflammatory bowel disease have in common? They all have debilitating chronic diseases that throw off high levels of systemic inflammation. And what s more, they share a newly recognized predisposition to atrial fibrillation compared with the general population, VITALS Major Finding: First study: Patients with AF were 65% more likely to have rheumatoid arthritis than were controls without AF, but were 35% less likely to have SLE. Second study: Patients with IBD had an 11-fold increased prevalence of AF compared with controls without IBD. Data Source: 86,497 patients with the diagnosis of AF and 100,000 randomly selected control patients from the Nationwide Inpatient Sample database; 142 patients with IBD from Metro Health Medical Center in Cleveland and a large population of control patients without IBD from a Kaiser Permanente database. Disclosures: Dr. Hebbar and Dr. Pattanshetty declared having no financial conflicts of interest. according to two studies presented at the meeting. Dr. Prabhat Hebbar and his coworkers used the Nationwide Inpatient Sample database for 2008, which contains discharge diagnoses for roughly 1,000 U.S. hospitals in 40 states, to identify 86,497 patients with the diagnosis of atrial fibrillation (AF) and 100,000 randomly selected controls from the rest of the database. The frequency of rheumatoid arthritis among patients with AF was 0.28%, compared with 0.13% in controls not having AF. The frequency of SLE in the AF population was 0.05%, compared with 0.12% in controls. However, after adjusting for demographic factors for example, patients with SLE were skewed considerably younger than were those with AF, and the AF group had significantly higher rates of comorbidities including hypertension, diabetes, and chronic obstructive pulmonary disease the adjusted odds ratio for rheumatoid arthritis in patients with AF was Conversely, an OR of 0.65 was found for SLE in AF patients, according to Dr. Hebbar of the University of Arkansas for Health Sciences, Little Rock. The explanation for this association lies in the likely pathogenic role inflammation plays in AF. This inflammation can result from the physical handling of the heart during cardiac surgery, with the consequence of postoperative new-onset AF. Or the trigger can be the systemic inflammation that s a key part of a chronic rheumatologic or gut disease. This point was underscored by Dr. Deepak J. Pattanshetty in a separate retrospective cohort study. He and his coworkers reviewed the records of 142 patients with inflammatory bowel disease (IBD) at Metro Health Medical Center in Cleveland, and compared them with a large general population described in the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study of 1.89 million enrollees in Kaiser Permanente Northern California (JAMA 2001;285: ). The prevalence of AF in the IBD patients was 11%, compared with 0.95% in the Kaiser Permanente controls without IBD. This disparity is all the more striking given that the IBD patients were significantly younger, with a mean age of 57 years, compared with 71 years for controls. Atrial fibrillation is the most common sustained arrhythmia. Its prevalence in the general population is strongly age-dependent, with a rate of less than 1.7% in individuals under age 65, rising to 4%-9% in 65- to 80-year-olds, and to 10% or more after age 80, noted Dr. Pattanshetty. There were no significant differences between the IBD cohort and the controls in terms of hypertension, diabetes, and other conventional risk factors for AF. The explanation for the 11-fold increased prevalence of AF seen in patients with IBD probably is that recurrent flares of the gut disease are known to lead to increased systemic levels of C-reactive protein and inflammatory cytokines including interleukin-6. These could predispose to the atrial arrhythmia, said Dr. Pattanshetty. The associations between AF and rheumatologic and gastrointestinal diseases not only provide insight into the pathogenesis of the arrhythmia, but also have a practical implication for patient care. Patients with these systemic diseases need to understand that they are at elevated risk for the arrhythmia, and that if they feel symptoms such as a rapid or irregular heart beat they should seek medical attention so that if they do have AF their stroke risk can be managed appropriately. More Than Half of Atrial Fib Cases Appear Preventable BY DENISE NAPOLI FROM CIRCULATION VITALS Major Finding: Having one or more elevated risk factor levels (including high blood pressure, high BMI, or smoking) explained 50% of AF occurring over 17 years of follow-up among four American communities, according to population-attributable fraction estimates (95% CI, 37.5%-58.5%). Data Source: The ARIC study. Disclosures: The study was funded by the National Heart, Lung, and Blood Institute, as well as the American Heart Association. The investigators reported having no other disclosures related to this study. More than half of atrial fibrillation is likely attributable to modifiable risk factors, including high blood pressure, obesity, and smoking, according to an analysis of the Atherosclerosis Risk in Communities Study. The finding, which was based on a cohort of middle-aged American adults from communities in the ARIC study, highlights the need for primary prevention among this population. Moreover, because improvement in these behaviors would also favorably affect other AF risk factors, such as diabetes mellitus and impaired glucose tolerance, the reduction in the incidence of AF would be even greater than expected through BP lowering alone, wrote Rachel R. Huxley, D.Phil. Dr. Huxley, an epidemiologist at the University of Minnesota, Minneapolis, and colleagues looked at nearly 20 years of follow-up from the ARIC survey, a prospective cohort study of atherosclerotic diseases in Forsyth County, N.C.; Jackson, Miss.; Washington County, Md.; and the suburbs of Minneapolis. At baseline in , it included 15,792 men and women aged years, selected by area probability sampling. All patients underwent three triennial visits, and in the present study, AF cases were counted as those diagnosed at an incident study visit (not baseline assessment) by 12-lead ECG, or during followup with an ICD code for AF in a hospital discharge, or when AF was listed as any cause of death on a death certificate. Those with baseline AF on electrocardiogram or history of AF were excluded, as were those with missing data. The researchers characterized participants into one of three risk profiles. An optimal group had no history of cardiac disease, systolic BP less than 120 mm Hg and diastolic less than 80 mm Hg without antihypertensive drugs; a body mass index less than 25 kg/m 2 ; fasting serum glucose less than 100 mg/dl without antidiabetic drugs or history of diabetes; and no history of smoking. Borderline participants had any of the following criteria: systolic BP and/or diastolic BP mm Hg without antihypertensives; BMI 25-30; fasting glucose mg/dl without use of antidiabetics and no history of diabetes; and former smoker status. Finally, participants regarded as having elevated risk profiles had any of the following: history of cardiac disease (heart failure or coronary heart disease); systolic BP at least 140 mm Hg, diastolic BP at least 90 mm Hg, or use of antihypertensives; BMI greater than 30; fasting serum glucose greater than or equal to 126, or use of antidiabetic drugs; history of diabetes; or current smoker status. Among the 14,598 subjects (55% women; 25% black; mean age, 54.2 years) over a mean 17.1 years of follow-up who were included in the current analysis, there were 1,520 cases of incident AF. Compared with those with no risk factors, the age-adjusted incidence rates were three times higher in those with one or more elevated risk factors (2.19 vs per 1,000 person-years, respectively), wrote the authors (relative hazard for optimal patient group, 0.33). For the borderline group, the incidence rate was 3.68, for a relative hazard of 0.50, compared with participants who had one or more elevated risk factors. Overall, the [population-attributable fraction] estimates indicated that having [one or more] elevated risk factor levels could explain 50%... of AF events, added the authors (Circulation 2011: /CIRCULATIONAHA ). Adding elevated and borderline levels together, that number jumped to 57%. The authors also sought to determine which of the relevant risk factors played the biggest role in incident AF. Elevated blood pressure, experienced by 39% of the entire cohort, accounted for roughly one in five cases of AF (21.6%). This rose to 24.5% if borderline levels of BP, which affected another 22.7% of the cohort, were also included, wrote the authors. Obesity and overweight explained 17.9% of all AF cases, and diabetes mellitus and impaired glucose tolerance combined accounted for the smallest fraction [3.9%] of the AF burden in this cohort, they added. According to the authors, this study is the second to look at the relationship between modifiable risk factors and atrial fibrillation. A 1994 analysis, using data from the Framingham cohort, found that smoking, diabetes, hypertension, and prevalent coronary heart disease combined explained 44% of the AF burden in men and 58% in women, a conclusion that Dr. Huxley called broadly comparable to that of the current study. They added that the study was limited by its inability to differentiate subtypes of AF, as well as by its reliance on hospital discharge codes to ascertain AF cases. However, if anything, this fact likely led to the underascertainment of cases that perhaps were not severe enough to warrant hospitalization.

19 JUNE ARRHYTHMIAS & ELECTROPHYSIOLOGY 19 Totally Subcutaneous ICD Viable Alternative BY BRUCE JANCIN FROM THE ANNUAL MEETING OF THE HEART RHYTHM SOCIETY VITALS SAN FRANCISCO An entirely subcutaneous implantable cardioverter defibrillator accurately detected and successfully converted all episodes of ventricular fibrillation in a multicenter Dutch study. For us, so far, it has been a viable alternative to conventional ICD systems in selected patients, Dr. Lara Dabiri Abkenari said in presenting the study results at the meeting. Session cochair Dr. Luc Jordaens, who was Dr. Abkenari s senior coinvestigator in the study, went further: He said that viable alternative is too conservative an assessment now that a software upgrade has improved the detection algorithm and greatly reduced inappropriate shocks. We often see the subcutaneous ICD as the first choice, said Dr. Jordaens, professor of cardiology at Erasmus University, Rotterdam, the Netherlands. The subcutaneous ICD has generated Nearly Half of ICDs in Massachusetts Placed Off Label BY MITCHEL L. ZOLER FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY NEW ORLEANS Nearly half of patients who received an implantable cardioverter defibrillator in Massachusetts during had at least one clinical factor that categorized them as an off-label recipient, based on the exclusion criteria used in the clinical trials that established the efficacy of these devices. The most common off-label use occurred in patients aged either 75 or older or 19 or younger, which in both cases put them outside of the age enrollment criteria for the implantable cardioverter defibrillator (ICD) trials, Dr. Norman S. Kato reported while presenting a poster at the meeting. ICDs given to patients outside the age range that was tested in trials accounted for well over a quarter of all ICD use in Massachusetts during the period studied, and more than half of all off-label use. Other common offlabel ICD uses occurred in patients with renal insufficiency or a recent acute MI, reported Dr. Kato, a cardiothoracic surgeon in Encino, Calif., and his associates. Their analysis, which included 15,724 ICD recipients during the 11-year period studied, represents the first analysis [of ICD use] to encompass all patients who have received this technology in a single state, he said in an interview. The key finding from our study was that patients over age 65 represent a significant portion of the population receiving these devices. Our research revealed that about 45% of all patients receiving the devices in the Medicare age group were age 75 or older, and 15% considerable interest among cardiologists and patients because unlike conventional transvenous ICDs it is easily implanted without fluoroscopy, it requires no vascular access, and the lead is simple to remove if necessary. A smaller experience with the subcutaneous system that was reported last year attracted a great deal of attention (N. Engl. J. Med. 2010;363:36-44). The system, by Cameron Health Inc., is approved for the European market and is under review at the Food and Drug Administration. Major Finding: Over 9 months of follow-up in 98 patients, a subcutaneous ICD identified 14 nonsustained ventricular arrhythmia episodes in 5 patients and treated 28 sustained episodes in 4 patients. The system also delivered 22 inappropriate shocks to eight patients because of oversensing. Data Source: An observational study of 98 ICD candidates who were treated with an entirely subcutaneous ICD. Disclosures: Dr. Abkenari had no relevant financial interests. Dr. Jordaens is a consultant to Cameron Health, which makes the subcutaneous ICD. The system comprises a pulse generator, a subcutaneous lead that has two sensing electrodes, and about 8 cm of shock coil. It has no pacing or resynchronization capabilities. This is for patients who need defibrillation. It s restricted to patients who would not benefit from antitachycardia pacing.... In a nutshell, it s a shock box, explained Dr. Abkenari, an electrophysiology fellow and PhD candidate at Erasmus. She reported on 98 patients (mean age, 56 years) who received the subcutaneous ICD and have been followed for a median of 9 months, during which the system identified 14 nonsustained ventricular arrhythmia episodes in 5 patients and treated 28 sustained episodes in 4 patients. The mean time to treatment with an 80-J shock was 13.9 seconds. The system also delivered 22 inappropriate shocks to eight patients because of oversensing. Since the software upgrade, however, there have been no further inappropriate shocks. In addition to inappropriate shocks, other major complications included infections requiring explantation in five patients, hematomas not requiring device removal in three patients, and lead migration or dislodgment in three patients. The pulse generator box is placed in a left lateral thoracic subcutaneous pocket. The lead is tunneled from the pocket to the xiphoid process, where the tip of the electrode is sutured to a sleeve attached to the xiphoid fascia. The generator box is substantially larger than those used in conventional transvenous ICDs. On a thin patient, the box is very obvious under the skin. The lateral position results in arm contact with movement, albeit with no pain. Because the subcutaneous ICD preserves the vasculature, Dr. Abkenari sees the device as particularly attractive for relatively young, active patients who may need surgery later, such as individuals with hypertrophic cardiomyopathy who may one day need myomectomy or a heart transplant. The subcutaneous device has been placed in several children VITALS Major Finding: During , off-label placement of ICDs in Massachusetts occurred in 28%-50% of patients who received devices for primary prevention, and in 35%-58% of patients treated for secondary prevention. Data Source: Hospital case mix and charge data collected by the Massachusetts DHHS for 15,724 patients receiving an ICD during Disclosures: Dr. Kato and his associates said that they had no disclosures. of recipients were age 85 or older. ICDs may have been implanted when there was little empirical evidence to support their use. Because subjects over age 75 were specifically excluded from the randomized clinical trials [of ICDs,] there is no scientific evidence to support the notion that ICDs are safe or effective in this group, Dr. Kato said. Off-label use does not necessarily mean that the use was without benefit or was unsafe, he noted. Off-label use is simply the use of the device for conditions that were not tested during the randomized clinical trials. The Centers for Medicare and Medicaid Services, in a 2005 decision memo on ICD use, noted that only 10% of patients who were enrolled in the two largest ICD trials were aged 75 or older, and as a consequence the implantation of a defibrillator in the most elderly patients should be carefully considered and not routinely recommended, the memo said (CAG-00157R3). Dr. Kato s study of Massachusetts ICD usage also This is for patients who would not benefit from antitachycardia pacing.... In a nutshell, it s a shock box. DR. ABKENARI in the Dutch study with favorable results. Discussant Dr. Bruce L. Wilkoff expressed reservations about the current iteration of the subcutaneous ICD. The 5% infection rate that resulted in device removal in the Dutch study is most disturbing, observed Dr. Wilkoff, director of cardiac pacing and tachyarrhythmia devices at the Cleveland Clinic and professor of medicine at Case Western Reserve University, Cleveland. The hope was that infection would be more easily managed with this system, noted Dr. Wilkoff. He also zeroed in on the four patients who required shocks for 28 sustained ventricular arrhythmic episodes. It s hard to imagine that those patients wouldn t have benefited a little bit from ATP [antitachycardia pacing]. It seems to me that ATP may be an important component of what s needed in a device. That being said, he cautioned that important new medical technologies rarely spring up full grown. Refinements made along the way can make all the difference betweesuccess and failure. showed disproportionate placement of ICDs in men. During , men received ICDs three- to eightfold more often than did women for primary prevention indications, and three- to ninefold more often for secondary prevention. These findings raise issues of a sex bias or a disease bias that favored men over women for ICD placement, he said. In general, men have a higher risk for and greater rates of heart attack and coronary artery disease than women, hence men should probably be more likely to receive an ICD. But this merits consideration since results from other studies have also identified the same frequency differences by gender, said Dr. Kato. The analyses used data compiled by the Massachusetts Department of Health and Human Services on hospital case mix and charge, as well as population estimates from the National Center for Health Statistics. During the 11-year period studied, the rate of offlabel ICD use for primary prevention indications ranged from 28% to 50%, depending on the year. In 2008, about 45% of Massachusetts patients who received an ICD had at least one off-label clinical feature, with age being an off-label factor for about 28% of all recipients. Primary-prevention use, which totaled 13,801 patients over the 11 years studied, occurred in patients with a diagnosis of heart failure or cardiomyopathy. In 2008, about 45% of patients who received an ICD for secondary prevention had an off-label feature. Secondary-prevention use, which occurred in 1,923 patients in the 11 years studied, included the indications of a history of cardiac arrest or ventricular arrhythmia during the year prior to ICD placement in patients who did not have a primary-prevention indication.

20 20 CAD & ATHEROSCLEROSIS JUNE 2011 CARDIOLOGY NEWS Add-On ApoB Synthesis Inhibitor Cut LDL Levels BY CAROLINE HELWICK FROM THE ANNUAL SCIENTIFIC SESSIONS OF THE AMERICAN COLLEGE OF CARDIOLOGY Benefits of Lipid-Lowering Agents Persist After Trials End NEW ORLEANS In patients with hypercholesterolemia and high cardiovascular risk, the novel agent mipomersen administered as add-on therapy led to robust reductions in LDL cholesterol, based on the results of a double-blind, phase III study. In high-risk patients refractory to maximally tolerated statin therapy, the addition of mipomersen significantly reduced LDL-C and other atherogenic lipids and lipoproteins, said Dr. William C. Cromwell of the Presbyterian Cardiovascular Institute in Charlotte, N.C. Mipomersen is the first of a new class of agents called apolipoprotein B (apob) synthesis inhibitors. In the study, the drug was administered subcutaneously once a week. Among its side effects were injection site reactions, increases in ALT levels, and steatosis. The study included 158 patients at high risk for cardiovascular events who were unable to achieve target LDL-C levels with statins, bile-acid sequestrants, and niacin. At baseline, all patients were on maximally tolerated doses of a statin; 63 were on the maximal approved dose, and 25 were also receiving ezetimibe. All subjects had LDL-C levels of at least 100 mg/dl and triglycerides below 200 mg/dl. They were randomized 2:1 to 200 mg subcutaneous mipomersen or placebo weekly for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28 or 2 weeks after the last dose if treatment was not completed. LDL-C levels of less than 100 mg/dl were achieved by 77 (76%) mipomersen-treated patients, compared with 19 (38%) placebo-treated patients. LDL-C levels of less than 70 mg/dl were achieved by 51 (50%) and 4 (8%), respectively. The percent reduction in LDL cholesterol from baseline to the primary efficacy time point was a 37% drop in the mipomersen arm and a 5% drop in the placebo arm, a significant difference. LDL-C levels decreased through the first 17 weeks of treatment and remained relatively low through week 28, Dr. Cromwell observed. Mipomersen s VITALS Major Finding: LDL-C levels of less than 100 mg/dl were achieved by 76% of mipomersen-treated patients, compared with 38% of placebo-treated patients. LDL-C levels of less than 70 mg/dl were achieved by 50% and 8%, respectively. Data Source: The double-blind study included 158 high-risk patients who were unable to achieve target LDL-C levels on optimal therapy and were randomized 2:1 to 200 mg subcutaneous mipomersen or placebo weekly for 26 weeks. Disclosures: The study was sponsored by Isis Pharmaceuticals and Genzyme Corporation. Dr. Cromwell has received consultant fees or honoraria from Isis. Dr. Moriarty has participated in clinical trials of mipomersen. lipid-lowering effects were independent of baseline LDL-C or race, and were similar for patients with and without diabetes. The effect of the drug in the diabetic subset was robust. In the diabetes cohort, the mean decline in LDL-C from baseline was 51% for the 56 patients on mipomersen and 32% for the 29 on placebo. Dr. Cromwell noted that the drug had a more pronounced effect in females and in patients whose age was above the median. However, mipomersen s effects in males and in younger persons were still statistically significant and clinically meaningful. Mipomersen also was associated with significant reductions from baseline values in apob (38%), total cholesterol (26%), non-hdl cholesterol (36%), and lipoprotein(a) (24%). HDL-C levels did not change significantly from baseline. Sixty of the 105 mipomersen-treated patients (57%) and 44 of 52 placebo patients (85%) completed treatment. A total of 26 mipomersen-treated patients and 2 placebo-treated patients discontinued due to on-treatment adverse events. Of the mipomersen noncompleters, seven discontinued due to a liver enzyme-related adverse event, and seven stopped because of an injection site reaction. Injection site reactions were the most common adverse event, occurring in 78% of the mipomersen group and 31% of the placebo group. Flu-like symptoms occurred in 34% and 21%, respectively. ALT elevations at least 3 times the upper limit of normal were observed in 14% of patients on mipomersen, versus none receiving placebo, but this occurred without concomitant significant bilirubin elevations, he said. For 10% of patients, ALT elevations occurred on consecutive measurements at least 7 days apart. One patient had an ALT of at least 10 times the upper limit of normal. Approximately one-third of patients had an increase in steatosis, defined as liver fat increasing by at least 5%; median percent change from baseline was 15%. This does not represent a huge accumulation of fat. Instead, it is a signal that it s there at 28 weeks, and it is not particularly worrying. In a series of patients with much longer exposures, there is a plateau in this increase. Dr. Patrick Moriarty, a lipid specialist who is assistant professor of medicine at the University of Kansas, Kansas City, commented, We treat many refractory patients, and I can tell you that a drug of this class is very much needed in this patient population. It will help get their lipid numbers down. The fact that patients achieve good LDL-C reductions on top of statin therapy is very encouraging, he said. New Insights Into SLE s Cardiovascular Pathogenesis BY CAROLINE HELWICK FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY NEW ORLEANS In major clinical trials of lipid-lowering drugs, the mortality benefit from medical therapy persists long after the studies end, according to a meta-analysis presented at the meeting. Furthermore, placebo recipients who cross over to lipid-lowering therapy in the open-label phases of the studies show VITALS Major Finding: During the open-label phase of randomized trials studied, the lower mortality in those who initially received active therapy persisted (OR, 0.90) as did the reduction in cardiovascular mortality (OR, 0.82). Data Source: A meta-analysis involving 44,255 patients in eight clinical trials of lipid-lowering therapy. All trials involved an open-label treatment phase after the randomized treatment period ended. Disclosures: Dr. Kostis reported having no relevant conflicts of interest. survival benefits as well, but never attain the protection achieved by being randomized to active treatment earlier on, according to Dr. William J. Kostis of Massachusetts General Hospital, Boston. Persons with risk factors for coronary artery disease should be treated early, Dr. Kostis said in an interview. The sooner you treat, the better. He and his colleagues identified randomized trials of lipid-lowering therapies that also contained an analysis of patient outcomes after the randomized portion of the trials had ended and an open-label phase had begun. Active treatment in the trials involved statins, niacin, cholestyramine, or gemfibrozil. The analysis included eight clinical trials involving 44,255 patients, of whom 8,144 died during follow-up. During the randomized phase of the trials, the mean all-cause mortality was significantly lower for the active treatment group (odds ratio, 0.84, as was cardiovascular mortality (0.72). The lower mortality in those initially receiving active therapy persisted during the open-label follow-up phase (OR, 0.90, as did the reduction in cardiovascular mortality (OR, 0.82). BY BRUCE JANCIN EXPERT ANALYSIS FROM A SYMPOSIUM SPONSORED BY THE AMERICAN COLLEGE OF RHEUMATOLOGY SNOWMASS, COLO. A distinct subset of proinflammatory activated neutrophils may play a pivotal role in the accelerated atherosclerosis of systemic lupus erythematosus. The aberrant neutrophils (known as low-density granulocytes [LDGs]) synthesize increased amounts of interferon-alpha and other type I interferons in levels sufficient to kill vascular endothelial cells while at the same time disrupting the capacity of endothelial progenitor cells to differentiate into mature endothelial cells, Dr. W. Joseph McCune explained at the symposium. The role of LDGs in patients with SLE was unclear until Dr. McCune and his colleagues developed a laboratory technique that isolated LDGs from peripheral blood mononuclear cells. In earlier studies, Dr. McCune, professor of rheumatic diseases at the University of Michigan, Ann Arbor, and his colleagues showed that the number of circulating apoptotic endothelial cells is at least several-fold greater in SLE patients, than in controls, and is higher still in those with highly active lupus. The researchers also showed that lupus patients had a significantly impaired capacity for endothelial progenitor cells to differentiate into mature endothelial cells available for vascular repair. Dr. McCune and coworkers recently isolated LDGs and normal-density neutrophils from 190 SLE patients and neutrophils from 110 healthy controls. These in vitro studies pinned down LDG function: namely, increased synthesis of type I interferons and induction of vascular damage ( J. Immunol. 2010;184: ). In vitro, the depletion of LDGs restored the capacity of endothelial progenitor cells to properly differentiate into mature endothelial cells. In another study in 120 SLE patients, serial measurement of carotid intimal medial thickness during 1.5 years of follow-up indicated that carotid narrowing progressed significantly more quickly in patients who produced high levels of type I interferon, independent of Framingham risk score, systolic blood pressure, and other predictors. Dr. McCune declared having no relevant financial interests.

21 JUNE CAD & ATHEROSCLEROSIS 21 CIMT Predicts Coronary Events in RA Patients BY AMY ROTHMAN SCHONFELD FROM A RHEUMATOLOGY MEETING SPONSORED BY NEW YORK UNIVERSITY NEW YORK Ð Imaging seems to be the sine qua non of determining cardiovascular disease risk in patients with rheumatoid arthritis. Dr. Jeffrey D. Greenberg noted that, over the last years, epidemiologic studies have shown patients with rheumatoid arthritis (RA) have a doubled risk of MI and stroke and an increase in cardiovascular-related deaths. ÒAn important issue we face is how can we risk had 66 ACS events, with an incidence of 2.1 ACS/100 person-years. Multivariate analysis of baseline factors associated with incident or recurrent ACS revealed that two markers of atherosclerosis were independent predictors of a subsequent coronary event. Having a past cardiovascular event raised the risk almost threefold (hazard ratio, 2.87) and CIMT also raised the risk significantly (HR, 1.61). After substituting carotid plaque for intimalmedial thickness, the investigators found a 2.5-fold increase in risk for unilateral plaque and almost a 6-fold increase in risk for bilateral plaque. The findings confirmed that traditional demographic and cardiovascular risk factors also significantly predict coronary events as would be expected. These include male gender (HR, 1.94), diabetes (HR, 2.24), and hypertension (HR, 1.56). Measures of RA severity, such as swollen joint counts and cumulative prednisone dose of 20 g also had predictive value. Dr. Greenberg, who is director of the Arthritis Translational Registry and Biorepository at NYU Hospital for Joint Diseases, is involved in ongoing studies using advanced MRI and PET techniques to visualize and quantify some of key histologic features of plaque that are most likely to rupture. VITALS Major Finding: Carotid intimal medial thickness is an independent predictor of coronary events in patients with RA. Unilateral plaque more than doubled the risk and bilateral plaque increased the risk more than fourfold. Data Source: Prospective study of 636 patients with RA. Disclosures: Dr. Greenberg receives consulting fees from Genentech. stratify our patients to predict who will develop cardiovascular disease? Imaging is a promising area that may help us develop biomarkers of risk or better understand pathophysiological mechanisms of RA.Ó The need for precise tools with which to predict risk has become more urgent with the recently published findings that carotid ultrasound measurement of carotid intimal medial thickness (CIMT) has been found to predict coronary events in patients with RA, independent of traditional cardiovascular risk factors and manifestations of RA. The study, conducted by Dr. Matthew R. Evans and his associates at Brooke Army Medical Center, Fort Sam Houston, Tex., found that there appears to be a dose-dependent relationship between plaque and risk, with a 2.5-fold increase with unilateral plaque and 4.3-fold increase with bilateral carotid plaque, suggesting that atherosclerosis plays a significant role in acute coronary events in patients with RA (Arthritis Rheum [doi: /art.30265]). In discussing Dr. EvansÕs research at his presentation at the meeting, Dr. Greenberg said that this is the first study to show the predictive value of measuring CIMT and plaque for cardiovascular events in RA patients. In the Evans study, carotid ultrasounds were performed on 636 RA patients as part of the prospective ORALE (Outcome of Rheumatoid Arthritis Longitudinal Evaluation) study. These patients were followed for 3,402 person-years and, during that time, 84 patients experienced 121 new or recurrent acute coronary syndrome events. The rate of ACS events was 3.5/100 patient-years for this group. If only those without a prior history of ACS were analyzed, this group A Critical Measure of Patient Health

22 22 CAD & ATHEROSCLEROSIS JUNE 2011 CARDIOLOGY NEWS Heart Involvement Missed in Systemic Sclerosis BY BRUCE JANCIN FROM A SYMPOSIUM SPONSORED BY THE AMERICAN COLLEGE OF RHEUMATOLOGY SNOWMASS, COLO. Cardiac abnormalities were detected by magnetic resonance imaging in three-quarters of an unselected consecutive series of systemic sclerosis patients, underscoring the impressive frequency of heart involvement in this collagen vascular disease. The heart is something we often forget in scleroderma. The heart disease is underestimated, Dr. Fredrick M. Wigley said at the symposium. The hallmark of cardiac involvement in systemic sclerosis (SSc) is fibrosis and inflammation. Cardiac MRI is unequaled at visualizing these features, he said. You can see fibrosis of the myocardium, pericardium, coronary circulation, and conduction system. Arrhythmias are common. Coronary vasospasm is thought to occur, particularly with cold conduction the so-called Raynaud s of the heart leading to ischemic reperfusion injury and fibrosis of the heart, said Dr. Wigley, professor of medicine and director of the scleroderma center at Johns Hopkins University, Baltimore. A resting tachycardia in patients with The hallmark of cardiac involvement in systemic sclerosis is fibrosis and inflammation. Cardiac MRI is unequaled at visualizing these features. systemic sclerosis is a common clinical manifestation of cardiac involvement. Clinically evident heart disease carries an unfavorable prognosis, as do cardiac abnormalities detected via right heart catheterization or other invasive methods. The prognostic significance of asymptomatic abnormalities that are detected only on cardiac MRI and that are not evident at the bedside remains to be established. The noninvasive imaging technique has only recently been applied in systemic sclerosis. Scleroderma patients at greatest risk for clinically severe cardiac involvement are those with myopathy and rapidly progressing skin disease, according to the rheumatologist. Dr. Wigley highlighted a recent study by investigators at Lille 2 (France) University that effectively demonstrated the power of cardiac MRI in detecting heart involvement in SSc. The French investigators examined 52 consecutive unselected scleroderma patients with both Doppler echocardiography and cardiac MRI. One or more cardiac abnormalities were found on cardiac MRI in 75% of the patients, while Doppler detected the abnormalities in only 48% of the patients. Moreover, only cardiac MRI permitted precise analysis of the patterns of cardiac involvement in SSc, as it was able to distinguish between the fibrotic, inflammatory, and microvascular components. Interestingly, patients with limited cutaneous SSc had cardiac MRI abnormalities that were similar to those with diffuse cutaneous disease. Seven of the 40 patients without pulmonary arterial hypertension were found to have right ventricular dilation on cardiac MRI, underscoring the point that right ventricular dilation is not specific for this common respiratory manifestation of SSc. Study participants had a mean year disease history since developing Raynaud s phenomenon. The longer a patient s disease duration, the greater the number of cardiac segments with kinetic abnormalities and delayed contrast enhancement on MRI (Ann. Rheum. Dis. 2009;68: ). Dr. Wigley said that while to date no Effient (prasugrel) is indicated to reduce the rate of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as follows: [1] patients with unstable angina (UA) or non ST-elevation myocardial infarction (NSTEMI); [2] patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI. The loading dose of Effient is 60 mg and the maintenance dose is 10 mg once daily. Effient is available in 5-mg and 10-mg tablets. EFFIENT IS INCLUDED IN THE GUIDELINES FOR UA/NSTEMI AND STEMI PATIENTS UNDERGOING PCI 2011 ACCF/AHA Update for UA/NSTEMI 1, ACC/AHA/SCAI Update for PCI 3, ACC/AHA Update for STEMI 3,4 therapy has been shown to alter the natural course of cardiac disease in patients with scleroderma, French investigators strongly believe calcium channel blockers are cardioprotective, and they have documented increased myocardial perfusion in nifedipine-treated SSc patients. He receives consulting fees and/or research grants from Actelion, Amira, Kinemed, Medimmune, Novartis, Orion, Pfizer, and United Therapeutics. IMPORTANT SAFETY INFORMATION WARNING: BLEEDING RISK Effient (prasugrel) can cause significant, sometimes fatal, bleeding. Do not use Effient in patients with active pathological bleeding or a history of transient ischemic attack or stroke. In patients 75 years of age, Effient is generally not recommended, because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior myocardial infarction [MI]) where its effect appears to be greater and its use may be considered. Do not start Effient in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue Effient at least 7 days prior to any surgery. Additional risk factors for bleeding include: body weight <60 kg propensity to bleed concomitant use of medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytic therapy, chronic use of nonsteroidal anti-inflammatory drugs [NSAIDs]) Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of Effient. If possible, manage bleeding without discontinuing Effient. Discontinuing Effient, particularly in the first few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular events. References: 1. Wright RS, Anderson JL, Adams CD, et al. Circulation. 2011;123: Wright RS, Anderson JL, Adams CD, et al. J Am Coll Cardiol. 2011;57: Kushner FG, Hand M, Smith SC Jr, et al. Circulation. 2009;120: Kushner FG, Hand M, Smith SC Jr, et al. J Am Coll Cardiol. 2009;54: Effient and the Effient logo are registered trademarks of Eli Lilly and Company. Copyright 2011 Daiichi Sankyo, Inc. and Lilly USA, LLC. All Rights Reserved. PG PGHCPISI10Dec2010. Printed in USA. June 2011.

23 JUNE CAD & ATHEROSCLEROSIS 23 CABG Relieves Angina Better Than PCI BY MARY ANN MOON FROM THE NEW ENGLAND JOURNAL OF MEDICINE In patients with complicated coronary artery disease, coronary artery bypass graft surgery provided greater relief from angina at 6 and 12 months after revascularization than did PCI with paclitaxel-eluting stents. This benefit with CABG was consistent across a broad range of patient characteristics, said Dr. David J. Cohen of the University of Missouri Kansas City and his associates in the randomized SYN- TAX) trial, in which 1,800 patients with three-vessel or left main coronary artery disease underwent either CABG or PCI with paclitaxel-eluting stents. The rate of the primary efficacy end point of death, MI, stroke, or repeat revascularization was significantly lower with CABG at 1 year. The current analysis was a quality of life substudy of SYNTAX that included 903 patients who had been assigned to PCI and 897 who received CABG. At baseline, 12% of the subjects had daily angina and 20% had no angina; the remaining subjects had occasional angina. The primary quality of life end point was the score on the Seattle Angina Questionnaire angina frequency subscale. The improvement in this score was slightly but significantly greater with CABG than with PCI at 6 and 12 months. There were marked benefits with PCI as compared with CABG in general health-related quality of life as assessed by the SF-36 as well as EQ-SD [European Quality of Life 5-Dimensions instrument] at 1 month, but these differences had largely disappeared by 6 months, Dr. Cohen and his colleagues reported (N. Engl. J. Med. 2011:364: ). CONTRAINDICATIONS Effient is contraindicated in patients with active pathological bleeding, such as from a peptic ulcer or intracranial hemorrhage (ICH), or a history of transient ischemic attack (TIA) or stroke, and in patients with hypersensitivity to prasugrel or any component of the product WARNINGS AND PRECAUTIONS Patients who experience a stroke or TIA while on Effient generally should have therapy discontinued. Effient should also be discontinued for active bleeding and elective surgery Premature discontinuation of Effient increases risk of stent thrombosis, MI, and death Thrombotic thrombocytopenic purpura (TTP), a rare but serious condition that can be fatal, has been reported with Effient, sometimes after a brief exposure (<2 weeks), and requires urgent treatment, including plasmapheresis ADVERSE REACTIONS Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction Please see Brief Summary of Prescribing Information on subsequent pages. FOR MORE INFORMATION, PLEASE VISIT EFFIENTHCP.COM

24 24 SURGERY JUNE 2011 CARDIOLOGY NEWS RAPS: Radial Artery Tops Saphenous Vein Graft BY PATRICE WENDLING FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY NEW ORLEANS Long-term data from the Radial Artery Patency Study show that radial arteries, compared with saphenous veins, are associated with reduced rates of functional and complete graft occlusion in patients undergoing coronary artery bypass surgery. Radial arteries also are associated with lower rates of graft disease, lead author Dr. Stephen E. Fremes said during a latebreaking trial session at the meeting. The issue of which conduit provides the best long-term graft outcomes has been a subject of debate. Several trials have indicated that radial artery grafts are no better than saphenous vein grafts, including a Veterans Affairs study showing similar 1-year graft patency among 757 patients undergoing first-time, elective coronary artery bypass grafting ( JAMA 2011;305:167-74). One-year data from the Radial Artery Patency Study (RAPS) showed that complete graft occlusion was significantly reduced in radial artery grafts compared with saphenous vein grafts (8.2% vs. 13.6%), but that partial graft occlusion was similar (12.3% vs. 14.3%) between the two conduits (N. Engl. J. Med. 2004;351:2302-9). When Dr. Fremes was asked how to reconcile the results of RAPS with those from the VA study, he replied that the VA study was conducted almost exclusively in men (99%), vein grafts performed better than predicted, and there were very high rates of evidence-based medicine. Adherence to evidence-based medicine was good in RAPS, but the trial accrued much earlier, from November 1996 to January The mean age of the 269 Effient (prasugrel) tablets Brief Summary of Prescribing Information BRIEF SUMMARY: Please see Full Prescribing Information for additional information about Effient. WARNING: BLEEDING RISK Effient can cause significant, sometimes fatal, bleeding [see Warnings and Precautions (5.1 and 5.2) and Adverse Reactions (6.1)]. Do not use Effient in patients with active pathological bleeding or a history of transient ischemic attack or stroke [see Contraindications (4.1 and 4.2)]. In patients 75 years of age, Effient is generally not recommended, because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in highrisk situations (patients with diabetes or a history of prior MI) where its effect appears to be greater and its use may be considered [see Use in Specific Populations (8.5)]. Do not start Effient in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue Effient at least 7 days prior to any surgery. Additional risk factors for bleeding include: tcpezxfjhiu<60 kg tqspqfotjuzupcmffe tdpodpnjubouvtfpgnfejdbujpotuibujodsfbtfuifsjtlpg bleeding (e.g., warfarin, heparin, fibrinolytic therapy, chronic use of non-steroidal anti-inflammatory drugs [NSAIDs]) Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of Effient. If possible, manage bleeding without discontinuing Effient. Discontinuing Effient, particularly in the first few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular events [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Acute Coronary Syndrome: Effient is indicated to reduce the rate of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as follows: t1bujfoutxjuivotubcmfbohjob 6"PSOPO45FMFWBUJPONZPDBSEJBM JOGBSDUJPO /45&.* t1bujfoutxjui45fmfwbujponzpdbsejbmjogbsdujpo 45&.*XIFO managed with primary or delayed PCI. Effient has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal TUSPLFDPNQBSFEUPDMPQJEPHSFM5IFEJGGFSFODFCFUXFFOUSFBUNFOUT was driven predominantly by MI, with no difference on strokes and little difference on CV death [see Clinical Studies (14)]. It is generally recommended that antiplatelet therapy be administered promptly in the management of ACS because many cardiovascular events occur within hours of initial presentation. In the clinical trial that established the efficacy of Effient, Effient and the control drug were OPUBENJOJTUFSFEUP6"/45&.*QBUJFOUTVOUJMDPSPOBSZBOBUPNZXBT established. For the small fraction of patients that required urgent CABG after treatment with Effient, the risk of significant bleeding was substantial [see Warnings and Precautions (5.2)]. Because the large majority of patients are managed without CABG, however, treatment can be considered before determining coronary anatomy if need for $"#(JTDPOTJEFSFEVOMJLFMZ5IFBEWBOUBHFTPGFBSMJFSUSFBUNFOUXJUI Effient must then be balanced against the increased rate of bleeding in patients who do need to undergo urgent CABG. 2 DOSAGE AND ADMINISTRATION Initiate Effient treatment as a single 60 mg oral loading dose and then continue at 10 mg orally once daily. Patients taking Effient should also take aspirin (75 mg to 325 mg) daily [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Effient may be administered with or without food [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. Dosing in Low Weight Patients: Compared to patients weighing 60 kg, patients weighing <60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10 mg once daily maintenance dose. Consider lowering the maintenance dose to 5 mg in patients <LH5IFFGGFDUJWFOFTTBOE safety of the 5 mg dose have not been prospectively studied. 4 CONTRAINDICATIONS 4.1 Active Bleeding: Effient is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. 4.2 Prior Transient Ischemic Attack or Stroke: Effient is contraindicated in patients with a history of prior transient ischemic BUUBDL 5*"PSTUSPLF*O53*50/5*.* 53ial to Assess Improvement in 5IFSBQFVUJD 0VUDPNFT CZ 0ptimizing Platelet InhibitioN with 1SBTVHSFM QBUJFOUT XJUI B IJTUPSZ PG 5*" PS JTDIFNJD TUSPLF >3 months prior to enrollment) had a higher rate of stroke on Effient (6.5%; of which 4.2% were thrombotic stroke and 2.3% were intracranial hemorrhage [ICH]) than on clopidogrel (1.2%; all thrombotic). In patients without such a history, the incidence of stroke was 0.9% (0.2% ICH) and 1.0% (0.3% ICH) with Effient and clopidogrel, respectively. Patients with a history of ischemic stroke within 3 months of screening and patients with a history of IFNPSSIBHJDTUSPLFBUBOZUJNFXFSFFYDMVEFEGSPN53*50/5*.* 1BUJFOUTXIPFYQFSJFODFBTUSPLFPS5*"XIJMFPO&GýFOUHFOFSBMMZ should have therapy discontinued [see Adverse Reactions (6.1) and Clinical Studies (14)]. 4.3 Hypersensitivity: Effient is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product [see Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 General Risk of Bleeding:5IJFOPQZSJEJOFT JODMVEJOH &GýFOU increase the risk of bleeding. With the dosing regimens used in 53*50/5*.*5*.* 5ISPNCPMZTJTJO.ZPDBSEJBM*OGBSDUJPO.BKPS (clinically overt bleeding associated with a fall in hemoglobin 5 g/dl, PSJOUSBDSBOJBMIFNPSSIBHFBOE5*.*.JOPS PWFSUCMFFEJOHBTTPDJBUFE with a fall in hemoglobin of 3 g/dl but <5 g/dl) bleeding events were more common on Effient than on clopidogrel [see Adverse Reactions (6.1)]5IF CMFFEJOH SJTL JT IJHIFTU JOJUJBMMZ BT TIPXO JO 'JHVSF (events through 450 days; inset shows events through 7 days). Figure 1: Non-CABG-Related TIMI Major or Minor Bleeding Events Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures even if the patient does not have overt signs of bleeding. %POPUVTF&GýFOUJOQBUJFOUTXJUIBDUJWFCMFFEJOHQSJPS5*"PSTUSPLF [see Contraindications (4.1 and 4.2)]. 0UIFSSJTLGBDUPSTGPSCMFFEJOHBSF t"hf 75 years. Because of the risk of bleeding (including fatal bleeding) and uncertain effectiveness in patients 75 years of age, use of Effient is generally not recommended in these patients, FYDFQUJOIJHISJTLTJUVBUJPOT QBUJFOUTXJUIEJBCFUFTPSIJTUPSZPG myocardial infarction) where its effect appears to be greater and its use may be considered [see Adverse Reactions (6.1), Use in Specific Populations (8.5), Clinical Pharmacology (12.3), and Clinical Trials (14)]. t$"#( PS PUIFS TVSHJDBM QSPDFEVSF [see Warnings and Precautions (5.2)]. t#pezxfjhiulh$potjefsbmpxfs NHNBJOUFOBODFEPTF [see Dosage and Administration (2), Adverse Reactions (6.1), Use in Specific Populations (8.6)]. t1spqfotjuzupcmffe FHSFDFOUUSBVNBSFDFOUTVSHFSZSFDFOUPS recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, or severe hepatic impairment) [see Adverse Reactions (6.1) and Use in Specific Populations (8.8)]. t.fejdbujpot UIBU JODSFBTF UIF SJTL PG CMFFEJOH e.g., oral BOUJDPBHVMBOUT DISPOJD VTF PG OPOTUFSPJEBM BOUJJOþBNNBUPSZ drugs [NSAIDs], and fibrinolytic agents). Aspirin and heparin were DPNNPOMZ VTFE JO53*50/5*.* [see Drug Interactions (7), Clinical Studies (14)]. 5IJFOPQZSJEJOFT JOIJCJU QMBUFMFU BHHSFHBUJPO GPS UIF MJGFUJNF PG UIF QMBUFMFU EBZT TP XJUIIPMEJOH B EPTF XJMM OPU CF VTFGVM JO managing a bleeding event or the risk of bleeding associated with an JOWBTJWF QSPDFEVSF #FDBVTF UIF IBMGMJGF PG QSBTVHSFMT BDUJWF metabolite is short relative to the lifetime of the platelet, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective. 5.2 Coronary Artery Bypass Graft Surgery-Related Bleeding:5IF risk of bleeding is increased in patients receiving Effient who undergo CABG. If possible, Effient should be discontinued at least 7 days prior to CABG. 0GUIFQBUJFOUTXIPVOEFSXFOU$"#(EVSJOH53*50/5*.*UIF SBUFTPG$"#(SFMBUFE5*.*.BKPSPS.JOPSCMFFEJOHXFSFJOUIF Effient group and 4.5% in the clopidogrel group [see Adverse Reactions (6.1)]5IFIJHIFSSJTLGPSCMFFEJOHFWFOUTJOQBUJFOUTUSFBUFE with Effient persisted up to 7 days from the most recent dose of study drug. For patients receiving a thienopyridine within 3 days prior to $"#(UIFGSFRVFODJFTPG5*.*.BKPSPS.JOPSCMFFEJOHXFSF (12 of 45 patients) in the Effient group, compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies EFDSFBTFEUP PGQBUJFOUTJOUIFQSBTVHSFMHSPVQBOE PGQBUJFOUTJOUIFDMPQJEPHSFMHSPVQ %POPUTUBSU&GýFOUJOQBUJFOUTMJLFMZUPVOEFSHPVSHFOU$"#($"#( related bleeding may be treated with transfusion of blood products, including packed red blood cells and platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective. 5.3 Discontinuation of Effient: Discontinue thienopyridines, including &GýFOUGPSBDUJWFCMFFEJOHFMFDUJWFTVSHFSZTUSPLFPS5*"5IFPQUJNBM duration of thienopyridine therapy is unknown. In patients who are managed with PCI and stent placement, premature discontinuation of any antiplatelet medication, including thienopyridines, conveys an increased risk of stent thrombosis, myocardial infarction, and death. Patients who require premature discontinuation of a thienopyridine will be at increased risk for cardiac events. Lapses in therapy should be avoided, and if thienopyridines must be temporarily discontinued because of an adverse event(s), they should be restarted as soon as possible [see Contraindications (4.1 and 4.2) and Warnings and Precautions (5.1)]. 5.4 Thrombotic Thrombocytopenic Purpura: 5ISPNCPUJD UISPNCPDZUPQFOJDQVSQVSB 551IBTCFFOSFQPSUFEXJUIUIFVTF PG&GýFOU551DBOPDDVSBGUFSBCSJFGFYQPTVSF XFFLT551 is a serious condition that can be fatal and requires urgent USFBUNFOUJODMVEJOHQMBTNBQIFSFTJT QMBTNBFYDIBOHF551JT characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragment red blood cells] seen on peripheral smear), neurological findings, renal dysfunction, and fever [see Adverse Reactions (6.2)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: 5IF GPMMPXJOH TFSJPVT BEWFSTF reactions are also discussed elsewhere in the labeling: t #MFFEJOH [see Boxed Warning and Warnings and Precautions (5.1, 5.2)] t 5ISPNCPUJD UISPNCPDZUPQFOJD QVSQVSB [see Warnings and Precautions (5.4)] Safety in patients with ACS undergoing PCI was evaluated in a DMPQJEPHSFMDPOUSPMMFETUVEZ53*50/5*.*JOXIJDIQBUJFOUT were treated with Effient (60 mg loading dose and 10 mg once daily) GPSBNFEJBOPGNPOUIT QBUJFOUTXFSFUSFBUFEGPSPWFS NPOUIT QBUJFOUT XFSF USFBUFE GPS NPSF UIBO ZFBS5IF population treated with Effient was 27 to 96 years of age, 25% GFNBMFBOE$BVDBTJBO"MMQBUJFOUTJOUIF53*50/5*.*TUVEZ XFSFUPSFDFJWFBTQJSJO5IFEPTFPGDMPQJEPHSFMJOUIJTTUVEZXBTB 300 mg loading dose and 75 mg once daily. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials cannot be directly compared with the rates observed in other clinical trials of another ESVHBOENBZOPUSFþFDUUIFSBUFTPCTFSWFEJOQSBDUJDF Drug Discontinuation5IFSBUFPGTUVEZESVHEJTDPOUJOVBUJPOCFDBVTF of adverse reactions was 7.2% for Effient and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for Effient and 1.4% for clopidogrel). Bleeding: Bleeding Unrelated to CABG Surgery*O53*50/5*.* PWFSBMM SBUFT PG 5*.*.BKPS PS.JOPS CMFFEJOH BEWFSTF SFBDUJPOT unrelated to coronary artery bypass graft surgery (CABG) were TJHOJýDBOUMZIJHIFSPO&GýFOUUIBOPODMPQJEPHSFMBTTIPXOJO5BCMF Table 1: Non-CABG-Related Bleeding a (TRITON-TIMI 38) Effient (%) Clopidogrel (%) (N=6741) (N=6716) p-value 5*.*.BKPSPS.JOPSCMFFEJOH p= *.*.BKPSCMFFEJOH b p= JGFUISFBUFOJOH 1.3 p=0.015 Fatal Symptomatic intracranial hemorrhage (ICH) Requiring inotropes Requiring surgical intervention Requiring transfusion ( 4 units) *.*.JOPSCMFFEJOH b p=0.022 a Patients may be counted in more than one row. b See 5.1 for definition. 'JHVSF EFNPOTUSBUFT OPO$"#( SFMBUFE 5*.*.BKPS PS.JOPS CMFFEJOH5IFCMFFEJOHSBUFJTIJHIFTUJOJUJBMMZBTTIPXOJO'JHVSF (inset: Days 0 to 7) [see Warnings and Precautions (5.1)].

25 JUNE SURGERY 25 VITALS Major Finding: Functional graft occlusion at 5 years was 12% in radial artery grafts and nearly 19% in saphenous vein grafts. Data Source: Multicenter, randomized Radial Artery Patency Study in 269 patients. Disclosures: The Canadian Institutes of Health Research funded the study. Dr. Fremes reported no conflicts. patients in the current analysis was 60 years, and 15% were women. RAPS enrolled 561 patients with isolated triple-vessel disease and a left ventricular fraction of more than 35% from 12 Canadian centers and 1 in New Bleeding rates in patients with the risk factors of age 75 years and weight <LHBSFTIPXOJO5BCMF Table 2: Bleeding Rates for Non-CABG-Related Bleeding by Weight and Age (TRITON-TIMI 38) Major/Minor Fatal Effient (%) Clopidogrel (%) Effient (%) Clopidogrel (%) Weight <LH / Effient, N=356 clopidogrel) Weight 60kg (N=6373 Effient, N=6299 clopidogrel) Age <ZFBST / &GýFOU/DMPQJEPHSFM Age ZFBST / &GýFOU/DMPQJEPHSFM Bleeding Related to CABG *O53*50/5*.* QBUJFOUT XIP received a thienopyridine underwent CABG during the course of the TUVEZ 5IF SBUF PG $"#(SFMBUFE 5*.*.BKPS PS.JOPS CMFFEJOH XBT GPSUIF&GýFOUHSPVQBOEJOUIFDMPQJEPHSFMHSPVQ 5BCMF 5IFIJHIFSSJTLGPSCMFFEJOHBEWFSTFSFBDUJPOTJOQBUJFOUTUSFBUFEXJUI Effient persisted up to 7 days from the most recent dose of study drug. Table 3: CABG-Related Bleeding a (TRITON-TIMI 38) Effient (%) Clopidogrel (%) (N=213) (N=224) 5*.*.BKPSPS.JOPSCMFFEJOH *.*.BKPSCMFFEJOH Fatal Reoperation 0.5 5SBOTGVTJPOPG 5 units Intracranial hemorrhage 0 0 5*.*.JOPSCMFFEJOH 0.9 a Patients may be counted in more than one row. Bleeding Reported as Adverse Reactions)FNPSSIBHJDFWFOUT SFQPSUFE BT BEWFSTF SFBDUJPOT JO 53*50/5*.* XFSF GPS Effient and clopidogrel, respectively: epistaxis (6.2%, 3.3%), gastrointestinal hemorrhage (1.5%, 1.0%), hemoptysis (0.6%, TVCDVUBOFPVTIFNBUPNB QPTUQSPDFEVSBM hemorrhage (0.5%, 0.2%), retroperitoneal hemorrhage (0.3%, 0.2%), pericardial effusion/hemorrhage/tamponade (0.3%, 0.2%), and retinal hemorrhage (0.0%, 0.1%). Malignancies%VSJOH53*50/5*.*OFXMZEJBHOPTFENBMJHOBODJFT were reported in 1.6% and 1.2% of patients treated with prasugrel BOEDMPQJEPHSFMSFTQFDUJWFMZ5IFTJUFTDPOUSJCVUJOHUPUIFEJGGFSFODFT were primarily colon and lung. It is unclear if these observations are DBVTBMMZSFMBUFEPSBSFSBOEPNPDDVSSFODFT 0UIFS"EWFSTF&WFOUT*O53*50/5*.*DPNNPOBOEPUIFSJNQPSUBOU OPOIFNPSSIBHJD BEWFSTF FWFOUT XFSF GPS &GýFOU BOE DMPQJEPHSFM respectively: severe thrombocytopenia (0.06%, 0.04%), anemia (2.2%, 2.0%), abnormal hepatic function (0.22%, 0.27%), allergic reactions BOEBOHJPFEFNB 5BCMFTVNNBSJ[FT the adverse events reported by at least 2.5% of patients. Table 4: Non-Hemorrhagic Treatment Emergent Adverse Events Reported by at Least 2.5% of Patients in Either Group Effient (%) Clopidogrel (%) (N=6741) (N=6716) Hypertension Hypercholesterolemia/Hyperlipidemia Headache Back pain Dyspnea Nausea Dizziness Cough Hypotension 3.9 Fatigue 3.7 /PODBSEJBDDIFTUQBJO Atrial fibrillation Bradycardia Leukopenia (<4 x 10 9 WBC/L) 3.5 Rash 2.4 Pyrexia Peripheral edema Pain in extremity Diarrhea Postmarketing Experience: 5IF GPMMPXJOH BEWFSTF reactions have been identified during post approval use of Effient. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible Zealand. Randomization was unique in that it was performed within patients and not between patients, said Dr. Fremes, head of the cardiovascular surgery division at Sunnybrook Health Sciences Centre and research director at to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders 5ISPNCPDZUPQFOJB 5ISPNCPUJDUISPNCPDZUPQFOJDQVSQVSB 551[see Warnings and Precautions (5.4) and Patient Counseling Information (17.3)] Immune system disorders Hypersensitivity reactions including anaphylaxis [see Contraindications (4.3)] 7 DRUG INTERACTIONS 7.1 Warfarin: Coadministration of Effient and warfarin increases the risk of bleeding [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 7.2 Non-Steroidal Anti-Inflammatory Drugs: Coadministration of Effient and NSAIDs (used chronically) may increase the risk of bleeding [see Warnings and Precautions (5.1)]. 7.3 Other Concomitant Medications: Effient can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes [see Clinical Pharmacology (12.3)]. Effient can be administered with aspirin (75 mg to 325 mg per day), heparin, GPIIb/IIIa inhibitors, statins, digoxin, and drugs that elevate gastric ph, including proton pump inhibitors and H 2 blockers [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category B5IFSFBSFOPBEFRVBUFBOE well controlled studies of Effient use in pregnant women. Reproductive and developmental toxicology studies in rats and rabbits at doses of up to 30 times the recommended therapeutic exposures in humans (based on plasma exposures to the major circulating human metabolite) revealed no evidence of fetal harm; however, animal studies are not always predictive of a human response. Effient should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. In embryo fetal developmental toxicology studies, pregnant rats and rabbits received prasugrel at maternally toxic oral doses equivalent to more than 40 times the human exposure. A slight decrease in pup body weight was observed; but, there were no structural malformations in either species. In prenatal and postnatal rat studies, maternal treatment with prasugrel had no effect on the behavioral or reproductive development of the offspring at doses greater than 150 times the human exposure [see Nonclinical Toxicology (13.1)]. 8.3 Nursing Mothers: It is not known whether Effient is excreted in human milk; however, metabolites of Effient were found in rat milk. Because many drugs are excreted in human milk, prasugrel should be used during nursing only if the potential benefit to the mother justifies the potential risk to the nursing infant. 8.4 Pediatric Use: Safety and effectiveness in pediatric patients have not been established [see Clinical Pharmacology (12.3)]. 8.5 Geriatric Use:*O53*50/5*.*PGQBUJFOUTXFSF 65 years of age and 13.2% were ZFBSTPGBHF5IFSJTLPGCMFFEJOH increased with advancing age in both treatment groups, although the relative risk of bleeding (Effient compared with clopidogrel) was similar across age groups. Patients 75 years of age who received Effient had an increased risk of fatal bleeding events (1.0%) compared to patients who received clopidogrel (0.1%). In patients 75 years of age, symptomatic JOUSBDSBOJBMIFNPSSIBHFPDDVSSFEJOQBUJFOUT XIPSFDFJWFE Effient and in 3 patients (0.3%) who received clopidogrel. Because of the risk of bleeding, and because effectiveness is uncertain in patients 75 years of age [see Clinical Studies (14)], use of Effient is generally OPU SFDPNNFOEFE JO UIFTF QBUJFOUT FYDFQU JO IJHISJTL TJUVBUJPOT (diabetes and past history of myocardial infarction) where its effect appears to be greater and its use may be considered [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. 8.6 Low Body Weight:*O53*50/5*.*PGQBUJFOUTUSFBUFE with Effient had body weight <60 kg. Individuals with body weight <60 kg had an increased risk of bleeding and an increased exposure to the active metabolite of prasugrel [see Dosage and Administration (2), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]. $POTJEFSMPXFSJOHUIFNBJOUFOBODFEPTFUPNHJOQBUJFOUTLH 5IF FGGFDUJWFOFTT BOE TBGFUZ PG UIF NH EPTF IBWF OPU CFFO prospectively studied. 8.7 Renal Impairment: No dosage adjustment is necessary for QBUJFOUTXJUISFOBMJNQBJSNFOU5IFSFJTMJNJUFEFYQFSJFODFJOQBUJFOUT XJUIFOETUBHFSFOBMEJTFBTF[see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment: No dosage adjustment is necessary in QBUJFOUTXJUINJMEUPNPEFSBUFIFQBUJDJNQBJSNFOU $IJME1VHI$MBTT "BOE#5IFQIBSNBDPLJOFUJDTBOEQIBSNBDPEZOBNJDTPGQSBTVHSFM in patients with severe hepatic disease have not been studied, but such patients are generally at higher risk of bleeding [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 8.9 Metabolic Status: In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving prasugrel, there was the Schulich Heart Centre at Sunnybrook, Toronto. Patients were randomized to receive either a radial artery to the right coronary territory and a saphenous vein to the circumflex territory or a saphenous vein to the right coronary territory and a radial artery to the circumflex territory. Late angiography was performed on 440 patients at 1 year and on 269 patients at a mean of 7.6 years after surgery. Grafts were considered occluded if they had a TIMI (Thrombolysis in Myocardial Infarction) score of 0-2, and were considered patent with a TIMI score of 3. no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, PS$:1"POUIFQIBSNBDPLJOFUJDTPGQSBTVHSFMTBDUJWFNFUBCPMJUF or its inhibition of platelet aggregation. 10 OVERDOSAGE 10.1 Signs and Symptoms: Platelet inhibition by prasugrel is rapid and irreversible, lasting for the life of the platelet, and is unlikely to be increased in the event of an overdose. In rats, lethality was observed after administration of 2000 mg/kg. Symptoms of acute toxicity in dogs included emesis, increased serum alkaline phosphatase, and hepatocellular atrophy. Symptoms of acute toxicity in rats included mydriasis, irregular respiration, decreased locomotor activity, ptosis, staggering gait, and lacrimation Recommendations about Specific Treatment: Platelet USBOTGVTJPONBZSFTUPSFDMPUUJOHBCJMJUZ5IFQSBTVHSFMBDUJWFNFUBCPMJUF is not likely to be removed by dialysis. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis/PDPNQPVOESFMBUFEUVNPSTXFSFPCTFSWFEJOB ZFBSSBUTUVEZXJUIQSBTVHSFMBUPSBMEPTFTVQUPNHLHEBZ (>100 times the recommended therapeutic exposures in humans (based on plasma exposures to the major circulating human NFUBCPMJUF 5IFSF XBT BO JODSFBTFE JODJEFODF PG UVNPST (hepatocellular adenomas) in mice exposed for 2 years to high doses (>250 times the human metabolite exposure). Mutagenesis1SBTVHSFMXBTOPUHFOPUPYJDJOUXPin vitro tests (Ames bacterial gene mutation test, clastogenicity assay in Chinese hamster fibroblasts) and in one in vivo test (micronucleus test by intraperitoneal route in mice). Impairment of Fertility1SBTVHSFMIBEOPFGGFDUPOGFSUJMJUZPGNBMFBOE GFNBMFSBUTBUPSBMEPTFTVQUPNHLHEBZ UJNFTUIFIVNBO major metabolite exposure at daily dose of 10 mg prasugrel). 17 PATIENT COUNSELING INFORMATION See Medication Guide 17.1 Benefits and Risks t4vnnbsj[fuiffggfdujwfofttgfbuvsftboeqpufoujbmtjeffggfdut of Effient. t5fmmqbujfoutupublf&gýfoufybdumzbtqsftdsjcfe t3fnjoeqbujfoutopuupejtdpoujovf&gýfouxjuipvuýstuejtdvttjoh it with the physician who prescribed Effient. t3fdpnnfoeuibuqbujfoutsfbeuif.fejdbujpo(vjef 17.2 Bleeding: Inform patients that they: txjmmcsvjtfboecmffenpsffbtjmz txjmmublfmpohfsuibovtvbmuptupqcmffejoh ttipvmesfqpsubozvoboujdjqbufeqspmpohfepsfydfttjwfcmffejoh or blood in their stool or urine Other Signs and Symptoms Requiring Medical Attention t*ogpsnqbujfoutuibu551jtbsbsfcvutfsjpvtdpoejujpouibu has been reported with Effient. t*otusvduqbujfoutuphfuqspnqunfejdbmbuufoujpojguifzfyqfsjfodf any of the following symptoms that cannot otherwise be explained: fever, weakness, extreme skin paleness, purple skin patches, yellowing of the skin or eyes, or neurological changes Invasive Procedures: Instruct patients to: tjogpsnqiztjdjbotboeefoujtutuibuuifzbsfubljoh&gýfoucfgpsf any invasive procedure is scheduled. tufmmuifepdupsqfsgpsnjohuifjowbtjwfqspdfevsfupubmlupuif prescribing health care professional before stopping Effient Concomitant Medications: Ask patients to list all prescription NFEJDBUJPOTPWFSUIFDPVOUFSNFEJDBUJPOTPSEJFUBSZTVQQMFNFOUT they are taking or plan to take so the physician knows about other treatments that may affect bleeding risk (e.g., warfarin and NSAIDs). Literature revised: December 6, 2010 Manufactured by Eli Lilly and Company, Indianapolis, IN, Marketed by Daiichi Sankyo, Inc. and Eli Lilly and Company Copyright 2009, 2010, Daiichi Sankyo, Inc. and Eli Lilly and Company. All rights reserved. 1(1()$1#4%FD PV 7311 AMP 13*/5&%*/64" At 5 years, the primary end point of functional graft occlusion was significantly decreased in radial artery grafts at 12%, compared with saphenous vein grafts at 18.8% (odds ratio, 0.64), Dr. Fremes said. Significantly fewer radial artery grafts also became completely occluded at 9%, compared with saphenous-vein grafts at 18% (OR, 0.50). Among 164 patients who had completely patent grafts at follow-up, graft stenosis was similar for both conduits for proximal and distal anastomotic lesions. There were fewer graft-body lesions at 6.7% in radial arteries, vs. saphenous veins at 15.2% (OR, 0.42). Consequently, radial artery grafts were significantly less likely to be either stenotic or completely occluded at 22%, compared with saphenous vein grafts at 34% (OR, 0.58), he said. Target vessel stenosis, an important risk factor for graft occlusion at 1 year, was evaluated in a subgroup analysis. Target vessels with stenosis were classified a priori as those with 70%-89% narrowing and those with at least 90% narrowing. Although graft occlusion was reduced almost 50% for either graft in target vessels with at least 90% narrowing, radial artery grafts had much lower functional (8.8%) and complete (6.3%) occlusion rates, as did saphenous vein grafts (14.6% and 14.5%, respectively), in the more severely narrowed vessels. The incidence of cardiac death beyond 1 year was 5%, of nonfatal myocardial infarction was 1.5%, and of major adverse cardiac events was 15%. Dr. Fremes pointed out that the clinical event findings were descriptive rather than explanatory since each patient received both graft types. Overall survival in the entire cohort was 96% at 5 years, 91% at 7.5 years, and 78% at 10 years. Event-free survival was 95%, 90%, and 78%, respectively. This [study] lends credence to utilizing the radial artery, with obvious caveats that it is important to place it in highly obstructed vessels so there is not competitive flow and to maintain patency for the longest period of time, Dr. James McClurken, professor and vice-chair of surgery at Temple University, Philadelphia, said in a panel discussion. This is not quite as good as internal mammary artery patency data, but certainly better than vein-graft data. Fellow discussant Dr. Steven Bolling, a thoracic surgeon at the University of Michigan, Ann Arbor, said he expects the data will shift practice and increase utilization of the radial artery graft. When asked about this point at a press conference, Dr. Fremes said that radial artery utilization varies by jurisdiction at about 20%, compared with more than 95% for the internal mammary artery. He noted that the evidence to date on radial artery grafts has been mixed and comes mainly from observational studies. The study we presented is the first multi-institutional, longitudinal, randomized comparison, so this is fairly unique data, he said. Hopefully, it will be persuasive.

26 26 SURGERY JUNE 2011 CARDIOLOGY NEWS Use of Hearts From High-Risk Donors Waning BY SUSAN LONDON FROM THE ANNUAL MEETING OF THE INTERNATIONAL SOCIETY FOR HEART AND LUNG TRANSPLANTATION SAN DIEGO Transplantation physicians may be increasingly avoiding the use of hearts from donors who have high-risk characteristics, even as demand for transplantable hearts continues to outstrip supply, suggests a retrospective study of more than 42,000 heart transplant recipients. The percentages of transplanted hearts from donors who have characteristics that are associated with an elevated risk of poor outcomes for the recipient (such as older age or hypertension) initially increased during the recent 2-decade study period. But thereafter, they plateaued or fell in some cases to levels seen at the start of the period. There are two possible explanations for the declining use of hearts from high-risk donors, lead investigator Dr. Jose N. Nativi told attendees of the meeting. One hypothesis is that there is a concern about adverse outcomes for recipients who would be given these hearts, in the wake of publications describing actual experience with their use, he explained. The second hypothesis is that, probably, we have another option to offer these patients, that is, the increasing utilization of left ventricular assist devices, Dr. Nativi said. So for a patient who is critically ill, instead of offering them a high-risk donor, now we have the luxury in some centers to offer them an alternative, that is, mechanical support, he added. There have been several key milestones in efforts to make more organs available for transplantation in the United States, according to Dr. Nativi, a fellow in cardiology with the University of Utah and the UTAH (Utah Transplantation Affiliated Hospitals) Cardiac Transplant Program in Salt Lake City. The Crystal City Conference in 2001 resulted in a formal recommendation to expand the use of hearts from high-risk donors (Circulation 2002;106:836-41). In addition, the Organ Donation Breakthrough Collaborative in 2003 encouraged increased consent and donation by individuals with high-risk features (Crit. Care Nurs. Q. 2008;31: ). These efforts are resulting in the expansion of acceptable donor criteria toward high-risk donors, he said. But the highrisk donor still remains a matter of controversy. In the year after the collaborative, there was an increase in the number of all types of organs donated with the sole exception of hearts. So we are still struggling to find donors for heart recipients, Dr. Nativi commented. To assess temporal patterns in the use of hearts from high-risk donors, the investigators analyzed data from the U.S. Scientific Registry of Transplant Recipients, identifying adult patients who underwent single-organ heart transplantation in They were divided into three eras by transplantation date: era 1 ( ), when standard donor criteria were used; era 2 ( ), when there was increasing acceptance of the high-risk donor, and reports about the use of organs from such donors increased; and era 3 ( ), after the collaborative was established. Results were based on 42,023 patients who underwent transplantation during the study period (42% in era 1, 32% in era 2, and 26% in era 3), Dr. Nativi reported. In multivariate analyses that included more than 40 donor characteristics as well as a transplant center s patient volume, recipients were We can now offer a critically ill patient a left ventricular assist device rather than a high-risk donor heart. DR. NATIVI more likely to die in the first year post transplantation if their donor was older than 40 years of age (hazard ratio, 1.2), was female (HR, 1.2), had a cerebrovascular cause of death (HR, 1.6), or had a history of hypertension (HR, 1.3). Temporal trends showed a biphasic pattern for three of these high-risk characteristics, with the percentage of hearts having the characteristic increasing significantly between era 1 and era 2, but then decreasing significantly between era 2 and era 3. For example, the percentage of hearts from donors older than 40 years averaged 21%, 30%, and 28% in eras 1, 2, and 3, respectively. The pattern was similar for hearts from donors who were female (29%, 31%, and 27%) and those having a cerebrovascular cause of death (26%, 29%, and 23%). The percentage of hearts from donors having hypertension increased from 4% to 11% between eras 1 and 2, and again from 11% to 13% between eras 2 and 3. But in clinical terms, the latter change was really more of a plateau, according to Dr. Nativi. Survival Data Show Viability of Transplants in Older Patients BY SUSAN LONDON FROM THE ANNUAL MEETING OF THE INTERNATIONAL SOCIETY FOR HEART AND LUNG TRANSPLANTATION SAN DIEGO Heart transplant recipients in their 70s have outcomes that are generally similar to those of their counterparts in their 60s, new data show. In a retrospective study of 18,534 waitlisted older adults, the rates of posttransplantation complications in septuagenarians were much the same as those VIEW ON THE NEWS in sexagenarians, except that the former were in fact less likely to experience rejection. And on average, the septuagenarians lived roughly 8 years after getting their new heart, which is not much shorter than the 9.8 years seen in sexagenarians, according to results reported at the meeting. Selected septuagenarians and I underscore the word selected with advanced heart failure derive great benefit from heart transplantation, said lead investigator Dr. Daniel Goldstein. This Consider Ethics, Consequences The boundaries of reasonable medical care are being pushed daily, and it now appears that heart transplantation can be done safely with acceptable survival in septuagenerians. Do these recipients receive the same posttransplant survival benefit as sexagenerians? Not quite, but it s pretty close. The small survival differences between the septuagenarians and sexagenerians suggest that age (and perhaps selection bias) should allow for older patients to be considered, in certain circumstances, as candidates. What sets organ transplantation apart from other heroic interventions (e.g., experimental chemotherapy for patients with metastatic cancer) is that donor organs are an exquisitely limited commodity. The ethics of increasing the recipient pool by including older patients must be considered, and this change may have significant consequences for younger patients on the wait list. DR. SUDISH MURTHY is an ACS fellow and surgical director of the Center for Major Airway Disease at the Cleveland Clinic. VITALS Major Finding: Relative to sexagenarians, septuagenarians had both shorter unadjusted median survival (8.5 vs. 9.8 years) and predicted median adjusted survival (8.15 vs years), although most of the difference between groups appeared to result from a difference in the first year. Data Source: A retrospective cohort study of 18,534 patients aged 60 years or older who were on the waiting list for heart transplantation. Disclosures: Dr. Goldstein reported that he had no relevant financial disclosures. is not every 70-year-old [who is] going to walk into your office. The findings raise the thorny ethical issue of expanding age limits on eligibility for heart transplantation, as organs are scarce and every heart given to an older adult is one that is not given to a young person, he noted. One approach would be to limit transplantation to those septuagenarians who have the best risk profile. Another would be to use an alternative list, as first tested by the University of California, Los Angeles, whereby older recipients are given hearts that are typically rejected by transplant centers. I don t see being able to do this without having an alternative list situation. UCLA is the perfect model, asserted Dr. Goldstein, a cardiothoracic surgeon at the Montefiore Einstein Center for Heart and Vascular Care at Montefiore Medical Center in the Bronx, N.Y. It would be hard to get an 18-year-old donor and give the heart to a 70-year-old, but if you take in a heart that nobody else wants, I think it s a little more palatable. With the aging of the population and the epidemic of heart failure among older adults, this dilemma is likely to intensify, he noted. Centers generally use an age cutoff of 65 years for cardiac transplantation eligibility. But an informal survey of centers in the New York City and New Jersey areas suggests that there is great variability in who we think is too old for transplantation, he said. It s clear that more centers are doing away with chronological age criteria. In the study, the investigators analyzed data from the UNOS (United Network for Organ Sharing) database for , first looking at trends among 18,534 adults aged 60 years or older put on the waiting list for a primary, singleorgan heart transplantation. Results showed that in the current era, septuagenarians are being transplanted more frequently, without a doubt, Dr. Goldstein said. The number undergoing transplantation increased almost every year, and their median age was 71 years. Continued on page 28

27 When diet and nonpharmacological measures alone have been inadequate... FIGHT BACK, FIGHT PLAQUE with NIASPAN Multiple indications brought to you by NIASPAN In patients with a history of CAD and hyperlipidemia, niacin, in combination with a bile acid binding resin, is indicated to slow progression or promote regression of atherosclerotic disease 1 In patients with a history of MI and hyperlipidemia, niacin is indicated to reduce the risk of recurrent nonfatal MI 1 In patients with primary hyperlipidemia and mixed dyslipidemia, NIASPAN is indicated to reduce elevated TC, LDL-C, Apo B and TG levels, and to increase HDL-C 1 The effect of NIASPAN plus colestipol on cardiovascular morbidity and mortality is not known. NIASPAN Safety Information 1 : Contraindicated in patients with active liver disease or unexplained persistent hepatic transaminase elevations, active peptic ulcer disease or arterial bleeding Severe hepatic toxicity, including fulminant hepatic necrosis, has occurred when sustained-release niacin is substituted for equivalent doses of immediate-release niacin Associated with myopathy, rhabdomyolysis and elevations in liver enzymes, serum uric acid and glucose levels Should be used with caution in patients who consume large quantities of alcohol The most common adverse reactions are flushing, diarrhea, nausea, vomiting, increased cough and pruritus Fight Back. Fight Plaque. Please see brief summary of full Prescribing Information on adjacent pages. Reference: 1. NIASPAN [package insert]. North Chicago, IL: Abbott Laboratories Abbott Laboratories Abbott Park, IL January 2011

28 28 SURGERY JUNE 2011 CARDIOLOGY NEWS Continued from page 26 For age-group comparisons, the investigators restricted analyses to the years , a period when the data became robust and contemporary medical and surgical practices were in use, he explained. Relative to the 5,807 sexagenarians who underwent transplantation during this period, the 332 septuagenarians who did were generally similar in terms of a wide range of comorbidities and risk factors, with a few exceptions. Patients in the older group were more likely to be male and nondiabetic and, in terms of acuity, were less likely to be on a ventricular assist device and more likely to have the lower status 2 priority at transplantation. With respect to recipient-donor matching, the septuagenarians were more likely to have a donor who was not an identical ABO match and who died from intracranial hemorrhage. Also, their donors were older. In findings that Dr. Goldstein called quite eye opening, there were no differences between septuagenarians and sexagenarians in most posttransplantation complications (rejection during hospitalization, stroke, length of hospital stay, and receipt of a pacemaker) or in cause of death. The former were less likely to be treated for graft rejection in the first year (19% vs. 32%). In a multivariate analysis, an age of 70 years or older was a significant risk factor for death (hazard ratio, 1.29). Relative to sexagenarians, septuagenarians had both shorter unadjusted median survival (8.5 vs. 9.8 years) and predicted median adjusted survival (8.15 vs years), although most of the difference between groups appeared to result from a difference in the first year. I was rather surprised by the 8-year value for the septuagenarians. That s a very important number, commented Dr. Goldstein. While survival is comparatively reduced, it still exceeds by a lot what we currently see with mechanical support therapy, he said. In a final analysis that was restricted to patients who survived the first year post transplantation, patients aged 70 years or older no longer had an increased risk of death, compared with their counterparts aged years. NIASPAN (niacin extended-release tablets) INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at signiű cantly increased risk for atherosclerotic vascular disease due to hyperlipidemia. Niacin therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. 1. NIASPAN is indicated to reduce elevated TC, LDL-C, Apo B and TG levels, and to increase HDL-C in patients with primary hyperlipidemia and mixed dyslipidemia. 2. NIASPAN in combination with simvastatin or lovastatin is indicated for the treatment of primary hyperlipidemia and mixed dyslipidemia when treatment with NIASPAN, simvastatin, or lovastatin monotherapy is considered inadequate. 3. In patients with a history of myocardial infarction and hyperlipidemia, niacin is indicated to reduce the risk of recurrent nonfatal myocardial infarction. 4. In patients with a history of coronary artery disease (CAD) and hyperlipidemia, niacin, in combination with a bile acid binding resin, is indicated to slow progression or promote regression of atherosclerotic disease. Limitations of Use No incremental beneű t of NIASPAN coadministered with simvastatin or lovastatin on cardiovascular morbidity and mortality over and above that demonstrated for niacin, simvastatin, or lovastatin monotherapy has been established. CONTRAINDICATIONS NIASPAN is contraindicated in the following conditions: Active liver disease or unexplained persistent elevations in hepatic transaminases [see Warnings and Precautions] Patients with active peptic ulcer disease Patients with arterial bleeding Hypersensitivity to niacin or any component of this medication [see Adverse Reactions] WARNINGS AND PRECAUTIONS NIASPAN preparations should not be substituted for equivalent doses of immediate-release (crystalline) niacin. For patients switching from immediate-release niacin to NIASPAN, therapy with NIASPAN should be initiated with low doses (i.e., 500 mg at bedtime) and the NIASPAN dose should then be titrated to the desired therapeutic response. C aution should also be used when NIASPAN is used in patients with unstable angina or in the acute phase of an MI, particularly when such patients are also receiving vasoactive drugs such as nitrates, calcium channel blockers, or adrenergic blocking agents. Niacin is rapidly metabolized by the liver, and excreted through the kidneys. NIASPAN is contraindicated in patients with signiű cant or unexplained hepatic impairment [see Contraindications and Warnings and Precautions] and should be used with caution in patients with renal impairment. Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during NIASPAN therapy. Skeletal Muscle Cases of rhabdomyolysis have been associated with concomitant administration of lipid-altering doses (ū1 g/day) of niacin and statins. Physicians contemplating combined therapy with statins and NIASPAN should carefully weigh the potential beneű ts and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Periodic serum creatine phosphokinase (CPK) and potassium determinations should be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. The risk for myopathy and rhabdomyolysis are increased when lovastatin or simvastatin are coadministered with NIASPAN, particularly in elderly patients and patients with diabetes, renal failure, or uncontrolled hypothyroidism. Liver Dysfunction Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release (modiğed-release, timed-release) niacin products for immediate-release (crystalline) niacin at equivalent doses. NIASPAN should be used with caution in patients who consume substantial quantities of alcohol and/ or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of NIASPAN. Niacin preparations have been associated with abnormal liver tests. In three placebo-controlled clinical trials involving titration to Ű nal daily NIASPAN doses ranging from 500 to 3000 mg, 245 patients received NIASPAN for a mean duration of 17 weeks. No patient with normal serum transaminase levels (AST, ALT) at baseline experienced elevations to more than 3 times the upper limit of normal (ULN) during treatment with NIASPAN. In these studies, fewer than 1% (2/245) of NIASPAN patients discontinued due to transaminase elevations greater than 2 times the ULN. In three safety and efű cacy studies with a combination tablet of NIASPAN and lovastatin involving titration to Ű nal daily doses (expressed as mg of niacin/ mg of lovastatin) 500 mg/10 mg to 2500 mg/40 mg, ten of 1028 patients (1.0%) experienced reversible elevations in AST/ALT to more than 3 times the ULN. Three of ten elevations occurred at doses outside the recommended dosing limit of 2000 mg/40 mg; no patient receiving 1000 mg/20 mg had 3-fold elevations in AST/ALT. Ni acin extended-release and simvastatin can cause abnormal liver tests. In a simvastatin-controlled, 24 week study with a Ű xed dose combination of NIASPAN and simvastatin in 641 patients, there were no persistent increases (more than 3x the ULN) in serum transaminases. In three placebo-controlled clinical studies of extended-release niacin there were no patients with normal serum transaminase levels at baseline who experienced elevations to more than 3x the ULN. Persistent increases (more than 3x the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminases levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. In the placebo-controlled clinical trials and the long-term extension study, elevations in transaminases did not appear to be related to treatment duration; elevations in AST levels did appear to be dose related. Transaminase elevations were reversible upon discontinuation of NIASPAN. Li ver function tests should be performed on all patients during therapy with NIASPAN. Serum transaminase levels, including AST and ALT (SGOT and SGPT), should be monitored before treatment begins, every 6 to 12 weeks for the Ű rst year, and periodically thereafter (e.g., at approximately 6-month intervals). Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 times ULN and are persistent, or if they are associated with symptoms of nausea, fever, and/or malaise, the drug should be discontinued. La boratory Abnormalities Increase in Blood Glucose: Niacin treatment can increase fasting blood glucose. Frequent monitoring of blood glucose should be performed to ascertain that the drug is producing no adverse effects. Diabetic patients may experience a dose-related increase in glucose intolerance. Diabetic or potentially diabetic patients should be observed closely during treatment with NIASPAN, particularly during the Ű rst few months of use or dose adjustment; adjustment of diet and/or hypoglycemic therapy may be necessary. Reduction in platelet count: NIASPAN has been associated with small but statistically signiű cant dose-related reductions in platelet count (mean of -11% with 2000 mg). Caution should be observed when NIASPAN is administered concomitantly with anticoagulants; platelet counts should be monitored closely in such patients. Increase in Prothrombin Time (PT): NIASPAN has been associated with small but statistically signiű cant increases in prothrombin time (mean of approximately +4%); accordingly, patients undergoing surgery should be carefully evaluated. Caution should be observed when NIASPAN is administered concomitantly with anticoagulants; prothrombin time should be monitored closely in such patients. Increase in Uric Acid: Elevated uric acid levels have occurred with niacin therapy, therefore use with caution in patients predisposed to gout. Decrease in Phosphorus: In placebo-controlled trials, NIASPAN has been associated with small but statistically signiű cant, dose-related reductions in phosphorus levels (mean of -13% with 2000 mg). Although these reductions were transient, phosphorus levels should be monitored periodically in patients at risk for hypophosphatemia. ADVERSE REACTIONS Be cause clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reű ect the rates observed in practice. Clinical Studies Experience In the placebo-controlled clinical trials database of 402 patients (age range years, 33% women, 89% Caucasians, 7% Blacks, 3% Hispanics, 1% Asians) with a median treatment duration of 16 weeks, 16% of patients on NIASPAN and 4% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with NIASPAN that led to treatment discontinuation and occurred at a rate greater than placebo were ű ushing (6% vs. 0%), rash (2% vs. 0%), diarrhea (2% vs. 0%), nausea (1% vs. 0%), and vomiting (1% vs. 0%). The most commonly reported adverse reactions (incidence >5% and greater than placebo) in the NIASPAN controlled clinical trial database of 402 patients were ű ushing, diarrhea, nausea, vomiting, increased cough and pruritus. In the placebo-controlled clinical trials, ű ushing episodes (i.e., warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse reactions (reported by as many as 88% of patients) for NIASPAN. Spontaneous reports suggest that ű ushing may also be accompanied by symptoms of dizziness, tachycardia, palpitations, shortness of breath, sweating, burning sensation/skin burning sensation, chills, and/or edema, which in rare cases may lead to syncope. In pivotal studies, 6% (14/245) of NIASPAN patients discontinued due to ű ushing. In comparisons of immediate-release (IR) niacin and NIASPAN, although the proportion of patients who ű ushed was similar, fewer ű ushing episodes were reported by patients who received NIASPAN. Following 4 weeks of maintenance therapy at daily doses of 1500 mg, the incidence of ű ushing over the 4-week period averaged 8.6 events per patient for IR niacin versus 1.9 following NIASPAN. Other adverse reactions occurring in ū5% of patients treated with NIASPAN and at an incidence greater than placebo are shown in 1 below. Table 1. Treatment-Emergent Adverse Reactions by Dose Level in Ű 5% of Patients and at an Incidence Greater than Placebo; Regardless of Causality Assessment in Placebo-Controlled Clinical Trials b Placebo-Controlled Studies NIASPAN b b Recommended Daily Maintenance Doses b Placebo 500 mg 1000 mg 1500 mg 2000 mg b (n = 157) (n = 87) (n = 110) (n = 136) (n = 95) b % % % % % Gastrointestinal Disorders b b b b b Diarrhea Nausea Vomiting Respiratory b b b b b Cough, Increased < 2 8 Skin and Subcutaneous Tissue Disorders b b b b b Pruritus Rash Vascular Disorders b b b b b Flushing & Note: Percentages are calculated from the total number of patients in each column. Adverse reactions are reported at the initial dose where they Pooled results from placebo-controlled studies; for NIASPAN, n = 245 and median treatment duration = 16 weeks. Number of NIASPAN patients (n) are not additive across doses. The 500 mg/day dose is outside the recommended daily maintenance dosing range. & 10 patients discontinued before receiving 500 mg, therefore they were not included. In general, the incidence of adverse events was highe r in women compared to men. Postmarketing Experience Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse reactions have been identiű ed during post-approval use of NIASPAN: Hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, ű ushing, dyspnea, tongue edema, larynx edema, face edema, peripheral edema, laryngismus, and vesiculobullous rash; maculopapular rash; dry skin; tachycardia; palpitations; atrial Ű brillation; other cardiac arrhythmias; syncope; hypotension; postural hypotension; blurred vision; macular edema; peptic ulcers; eructation; ű atulence; hepatitis; jaundice; decreased glucose tolerance; gout; myalgia; myopathy; dizziness; insomnia; asthenia; nervousness; paresthesia; dyspnea; sweating; burning sensation/skin burning sensation; skin discoloration, and migraine. Clinical Laboratory Abnormalities Chemistry: Elevations in serum transaminases [see Warnings and Precautions], LDH, fasting glucose, uric acid, total bilirubin, amylase and creatine kinase, and reduction in phosphorus. Hematology: Slight reductions in platelet counts and prolongation in prothrombin time [see Warnings and Precautions]. DRUG INTERACTIONS Statins Caution should be used when prescribing niac in (ū1 gm/day) with statins as these drugs can increase risk of myopathy/rhabdomyolysis. Combination therapy with NIASPAN and lovastatin or NIASPAN and simvastatin should not exceed doses of 2000 mg NIASPAN and 40 mg lovastatin or simvastatin daily. [see Warnings and Precautions ]. Bile Acid Sequestrants An in vitro study results suggest that the bile acid-b inding resins have high niacin binding capacity. Therefore, 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acidbinding resins and the administration of NIASPAN. Aspirin Concomitant aspirin may decrease the metabolic clearance of nicotinic acid. The clinical relevance of this Ű nding is unclear. Antihypertensive Therapy Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension. Other Vitamins or other nutritional supplements containing large doses of niacin or related compounds such as nicotinamide may potentiate the adverse effects of NIASPAN. Laboratory Test Interactions Niacin may produce false elevations in some ű uorometric determinations of plasma or urinary catecholamines. Niacin may also give false-positive reactions with cupric sulfate solution (Benedict s reagent) in urine glucose tests. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Cate gory C. Animal reproduction studies have not been conducted with niacin or with NIASPAN. It is also not known whether niacin at doses typically used for lipid disorders can cause fetal harm when administered to pregnant women or whether it can affect reproductive capacity. If a woman receiving niacin for primary hyperlipidemia becomes pregnant, the drug should be discontinued. If a woman being treated with niacin for hypertriglyceridemia conceives, the beneű ts and risks of continued therapy should be assessed on an individual basis. All statins are contraindicated in pregnant and nursing women. When NIASPAN is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin. Nursing Mothers Niacin is excreted into human milk but the actual infant dose or infant dose as a percent of the maternal dose is not known. Because of the potential for serious adverse reactions in nursing infants from lipid-altering doses of nicotinic acid, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. No studies have been conducted with NIASPAN in nursing mothers. Pediatric Use Safety and effectiveness of niacin therapy in pediatric patients (Ū16 years) have not been established. PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION Geriatric Use Of 979 patients in clinical studies of NIASPAN, 21% of the patients were age 65 and over. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identiű ed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment No studies have been performed in this population. NIASPAN should be used with caution in patients with renal impairment [see Warnings and Precautions]. Hepatic Impairment No studies have been performed in this population. NIASPAN should be used with caution in patients with a past history of liver disease and/or who consume substantial quantities of alcohol. Active liver disease, unexplained transaminase elevations and signiű cant or unexplained hepatic dysfunction are contraindications to the use of NIASPAN [see Contraindications and Warnings and Precautions]. Gender Data from the clinical trials suggest that wome n have a greater hypolipidemic response than men at equivalent doses of NIASPAN. OVERDOSAGE Supportive measures should be undertaken in the event o f an overdose. PATIENT COUNSELING INFORMATION Patient Counseling Patients should be advised to adher e to their National Cholesterol Education Program (NCEP) recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel. Patients should be advised to inform other healthcare professionals prescribing a new medication that they are taking NIASPAN. The patient should be informed of the following: Dosing Time NIASPAN tablets should be taken at bedtime, after a low -fat snack. Administration on an empty stomach is not recommended. Tablet Integrity NIASPAN tablets should not be broken, crushed or chewed, but should be swallowed whole. Dosing Interruption If dosing is interrupted for any length of time, their physician should be contacted prior to restarting therapy; re-titration is recommended. Muscle Pain Notify their physician of any unexplained m uscle pain, tenderness, or weakness promptly. They should discuss all medication, both prescription and over the counter, with their physician. Flushing Flushing (warmth, redness, itching and/or tingling of the skin) is a common side effect of niacin therapy that may subside after several weeks of consistent NIASPAN use. Flushing may vary in severity and is more likely to occur with initiation of therapy, or during dose increases. By dosing at bedtime, ű ushing will most likely occur during sleep. However, if awakened by ű ushing at night, the patient should get up slowly, especially if feeling dizzy, feeling faint, or taking blood pressure medications. Advise patients of the symptoms of ű ushing and how they differ from the symptoms of a myocardial infarction. Use of Aspirin Medication Taking aspirin (up to the recommended dose of 325 mg) approximately 30 minutes before dosing can minimize ű ushing. Diet Avoid ingestion of alcohol, hot beverages and spic y foods around the time of taking NIASPAN to minimize ű ushing. Supplements Notify their physician if they are taking vitamins or other nutritional supplements containing niacin or nicotinamide. Dizziness Notify their physician if symptoms of dizziness occur. Diabetics If diabetic, to notify their physician of changes in bl ood glucose. Pregnancy Discuss future pregnancy plans with your patients, and discuss when to stop NIASPAN if they are trying to conceive. Patients should be advised that if they become pregnant, they should stop taking NIASPAN and call their healthcare professional. Breastfeeding Women who are breastfeeding should be advised to not us e NIASPAN. Patients, who have a lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional Abbott Laboratories Manufactured for Abbott Laboratories, North Chicago, IL 60064, U.S.A. 500 mg tablets by Norwich Pharmaceuticals, Inc., Norwich, NY or 500 mg, 750 mg and 1000 mg tablets by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR Ref: 03-A432-Revised December, MASTER

29 JUNE SURGERY 29 LVH in Donor Does Not Raise Risk of Death BY SUSAN LONDON FROM THE ANNUAL MEETING OF THE INTERNATIONAL SOCIETY FOR HEART AND LUNG TRANSPLANTATION SAN DIEGO Cardiac transplant recipients who are given hearts from donors with left ventricular hypertrophy are not at increased risk of death, Dr. Omar Wever Pinzon reported at the meeting. In a retrospective, nationwide study of VITALS Major Finding: Donor-heart left ventricular hypertrophy did not increase recipients risk of death overall. However, LVH did increase mortality risk when combined with either of two other high-risk characteristics: older donor age and longer graft ischemic time. Data Source: A retrospective study of 2,626 adult patients who underwent heart transplantation between 2006 and Disclosures: Dr. Pinzon reported that he had no relevant conflicts of interest. more than 2,500 adults who underwent cardiac transplantation during , nearly half of the donor hearts had LVH. Recipients who had been given hearts with LVH did not have poorer survival overall than did their counterparts who had been given hearts without this highrisk characteristic. But getting a heart with LVH did reduce survival if, in addition, the donor was older than 55 years or the graft had a longer ischemic time. Overall survival of recipients of donor hearts with LVH is similar to those without LVH, which indicates that the current donor selection and allocation algorithms successfully mitigate the risk that donor LVH could pose to recipient survival, Dr. Pinzon said. However, the combination of donor LVH with certain other high-risk characteristics can result in excess mortality. Because few donor hearts had moderate or severe LVH, I think we have to be very cautious when using those hearts, he added. But hearts having an interventricular septum and posterior wall thickness up to 1.3 cm may be safe in the absence of other high-risk characteristics. The scarcity of donor hearts coupled with growing knowledge about the impact of various donor characteristics on recipient outcomes has led to strategies to make more hearts available for transplantation, according to Dr. Pinzon. Thanks to these strategies, patients with left ventricular hypertrophy, considered a high-risk characteristic, are more likely now to become donors, he commented. However, some studies have raised concerns that such hearts are more susceptible to ischemic graft injury, which could translate into poorer outcomes for the recipients. Using data from the United Network for Organ Sharing and the Organ Procurement and Transplantation Network, the investigators studied 2,626 adult patients who underwent a first, single-organ heart transplantation in On the basis of the thickness of the interventricular septum and posterior wall, donor hearts were classified as having no LVH (less than 1.1 cm) or LVH that was mild ( cm), moderate ( cm), or severe (1.7 cm or greater). The transplant recipients were 52 years old on average, and 78% were men. The donors were 33 years old on average, and 72% were men. Fully 44% of the donor hearts had some degree of LVH, reported Dr. Pinzon of the UTAH (Utah Transplantation Affiliated Hospitals) Cardiac Transplant Program in Salt Lake City. The LVH was mild in most cases (38%) but occasionally moderate (5%) or severe (1%). Relative to their peers who had been given donor hearts without LVH, recipients who had been given donor hearts with LVH had a higher body mass index and a higher ratio of donor-to-recipient BMI, had been on the waiting list for a shorter time, and were more likely to have a graft ischemic time exceeding 4 hours. During a follow-up period of 3.3 years post transplantation, 13% of the recipients died or underwent retransplantation. In univariate and multivariate analyses, neither recipients of donor hearts with mild LVH nor recipients of donor hearts with moderate or severe LVH were more likely to die than their counterparts whose donor hearts did not have any LVH, Dr. Pinzon reported. However, recipients risk of death increased with the age of their donor (hazard ratio, 1.01) and with their own serum creatinine level (HR, 1.31) and mean pulmonary artery pressure (HR, 1.01). Also, they were more likely to die if their donor had used tobacco (HR, 1.32), or if they themselves were older than 55 years of age (HR, 1.30) or had been on extracorporeal membrane oxygenation support (HR, 6.0). Further analyses revealed an interaction between donor heart LVH and donor age. Of recipients whose donor was older than 55 years, those getting a heart with any LVH had roughly six times the risk of death. But there was no such association in recipients from younger donors. There was also an interaction between donor heart LVH and graft ischemic time. Of recipients whose graft had an ischemic time of 4 hours or longer, those receiving a heart with moderate or severe LVH had twice the risk of death. Men Receiving Women s Hearts Have Higher Mortality BY SUSAN LONDON FROM THE ANNUAL MEETING OF THE INTERNATIONAL SOCIETY FOR HEART AND LUNG TRANSPLANTATION SAN DIEGO For men undergoing heart transplantation, the sex of their donor may mean the difference between life and death, according to a pair of large retrospective cohort studies The studies, which were reported at the meeting, each analyzed data from more than 60,000 recipients over periods spanning several decades. Their conclusion: Men were more likely to die if they received a heart from a female donor vs. a male donor, with the elevation in risk largely resulting from excess deaths in the first year. Overall mortality was 13% higher for these men after potential confounders were taken into account. In contrast, women undergoing heart transplantation had a similar risk of death regardless of whether their donor was male or female. A possible explanation for this finding, according to Dr. Ingo Kaczmarek, a cardiac surgeon at the Transplantation Center Munich of Ludwig-Maximilians University of Munich and the lead investigator of one of the studies, is that women s hearts are smaller than men s, even given the same body height and weight (J. Am. Coll. Cardiol. 2002;39: ). Additionally, medication nonadherence may play a part. In our population I can tell you that females take their medication and males don t, he said. And that might be a big confounder that you can t measure. Although her study took donor characteristics into account, it is still possible that the smaller size of female hearts played a role, agreed Dr. Kiran K. Khush, lead investigator of the other study. But I think there are probably also some immunological processes involved and sex differences that we don t completely understand, she added. This new information helps explain why some patients fare better than others after heart transplantation, The fact that women s hearts are smaller than men s even given the same body height and weight, may be a factor. DR. KACZMAREK but it would not necessarily alter her practice, said Dr. Khush, a cardiologist and instructor in cardiovascular medicine at Stanford (Calif.) University. I would worry about it clinically, but I m not sure that would preclude me from accepting a female graft for a male recipient, because as we all know when you have a very sick recipient who is in imminent danger of dying, you just want to have a heart for that patient, she commented. However, she added, perhaps given a situation wherein several highest-priority patients on the waiting list were otherwise similar, sex matching might be something to consider. Dr. Khush and her colleagues analyzed data from the International Society of Heart and Lung Transplantation (ISHLT) database for the years , restricting analyses to 60,584 adult recipients having at least 2 years of follow-up post transplantation. Fully 79% of the heart transplant recipients were men. On average, the men were 52 years old and the women were 49 years old at the time of transplantation. Men s odds of acute rejection within 2 years of transplantation were higher if their donor was female vs. male before adjustment for more than a dozen potential confounders (odds ratio, 1.22), although not afterward. Women s odds of this outcome did not differ by the sex of their donor. The donor s sex did not affect the likelihood of cardiac allograft vasculopathy for either group before adjustment. But afterward, men actually had a lower risk of this outcome if their donor was female (OR, 0.77). In terms of the hard end point of death, results showed that men were more likely to die after transplantation if their donor was female vs. male, both before statistical adjustment (hazard ratio, 1.18) and afterward (HR, 1.13). The donor s sex had no influence on this outcome in women. Dr. Kaczmarek and his coinvestigators similarly analyzed data from the ISHLT database, but for a wider range of years ( ). Their analyses were based on 67,833 heart transplant recipients. Overall, 80% were men. On average, the men were 53 years old and the women were 51 years old. Onequarter of men received a female donor heart, and slightly fewer than one-half of women received a male donor heart. The 15-year survival rate was best for women who were given a female heart and worst for men who were given a female heart. The curves divide in the first year, Dr. Kaczmarek pointed out. In the long run, they seem to be parallel, but women with female hearts do a bit better. The 1-year rate of survival ranged from a low of 78% among men who were given a female heart to a high of 84% among men who were given a male heart. This [latter] effect lasts for a few years, and then the better combination is female donor, female recipient, he said. Dr. Khush had no relevant conflicts of interest. Dr. Kaczmarek reported receiving travel or research grants from Novartis, Astellas, Roche, Orion Pharma, and Berlin Heart.

30 30 EPIDEMIOLOGY & PREVENTION JUNE 2011 CARDIOLOGY NEWS Psoriasis Boosts Framingham Risk Score 6% BY MITCHEL L. ZOLER FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY NEW ORLEANS Patients with severe psoriasis face a 6% higher 10-year risk for a cardiovascular event than do comparable people without psoriasis, according to the findings of a prospective cohort study of nearly 18,000 people. This added CV risk can have substantial implications, as it can move psoriasis patients into a higher Framingham Risk Score category and shift the way physicians need to think about CV risk management of these patients, Dr. Nehal N. Mehta said at the meeting. Dr. Mehta implements aggressive lifestyle interventions for these patients, and also suggests the consumption of fiber, red yeast rice, soy, phytoestrogens, fish oil, and niacin. If a patient s LDL cholesterol or BP remains at a questionably high level, he discusses the option of starting treatment with a statin or an antihypertensive medication, making clear that these steps have not yet been endorsed by most society management guidelines. Ultimately, about 5% of my psoriasis patients end up on a statin, said Dr. Mehta, a cardiologist and director of the inflammatory risk clinic in preventive cardiology at the University of Pennsylvania, Philadelphia. Dr. Mehta and his associates derived an estimate of CV disease risk attributable to psoriasis by reviewing follow-up data maintained on 3,603 patients with severe psoriasis and 14,330 control participants without psoriasis enrolled in the General Practice Research Database, a collection of records from more than 5 million people seen by U.K. general practice physicians. The researchers excluded people with a history of CV events. The average age of all the people in the analysis was about 50 years and, on average, people were followed for about 3 years. In a multivariable analysis that controlled for diabetes, hypertension, hyperlipidemia, age, gender, body mass index, and smoking status, the risk for a MI, stroke, or death from a CV cause was 53% higher in the psoriasis patients than in the controls, a statistically significant difference. This higher CV risk in patients with psoriasis matched the 50% increased risk proposed last year for patients with rheumatoid arthritis and other forms of inflammatory arthritis including psoriatic arthritis (Ann. Rheum. Dis. 2010;69:325-31). To translate the 1.53 relative risk into an attributable risk, Dr. Mehta and his associates multiplied that factor against the background CV risk for someone in the general population of the study to derive an adjusted risk. They then subtracted the background risk from the adjusted risk. Over a 10-year period, this translated into an excess risk for a cardiovascular event of 6.2%. To illustrate the potential impact of this estimate, the researchers then applied this to a consecutive sample of 103 psoriasis patients seen in Dr. Mehta s psoriasis clinic at the Penn Heart and Vascular Center, including nine patients with psoriatic arthritis. (See graph.) Dr. Mehta had no disclosures. Enormous Complexity of CV Meds Impairs Adherence BY MARY ANN MOON FROM ARCHIVES OF INTERNAL MEDICINE Patients in Category 100% 80% 60% 40% 20% Patients with cardiovascular disease face enormous complexity in managing their prescriptions, and it directly interferes with their adherence to medication, a study has shown. Streamlining this complexity may improve adherence, and thus morbidity and mortality, in this patient group, said Dr. Niteesh K. Choudhry of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women s Hospital and Harvard Medical School, Boston, and his associates. Using prescription claims data from CVS Caremark during a 1-year period, the investigators assembled a nationally representative cohort of patients taking longterm cardiovascular medications. They chose patients taking a statin, an angiotensin-converting enzyme inhibitor or a renin angiotensin receptor blocker (ACEI/ARB), or both, because these agents represent the two most widely sold therapeutic classes to treat cardiovascular disease in the United States. Therapeutic complexity was assessed by measuring the total number of prescriptions filled, the number of fills for medications in different drug classes, the number of physicians who wrote prescriptions, the number of pharmacies used, the number of pharmacy visits the patients made, and the number of daily medication doses that were prescribed. The researchers also estimated patient adherence by calculating the number of days the medication was available. The statin cohort comprised 1,827,395 patients and the ACEI/ARB cohort comprised 1,480,304 patients. A total of 20% of the total sample took both classes of drugs. The mean patient age was 63 years, and the cohort was evenly divided between men and women. Mean income was greater than $50,000 per year, and most patients received drug coverage directly through employer-sponsored insurance or a health plan. Thus, the 0 Psoriasis Shifts Patients Into Intermediate Cardiovascular Risk Category Men Women Low CV Risk study findings may not apply to uninsured patients. During a 3-month complexity assessment period, patients filled a mean of 11 medications in six different drug classes at five visits to a pharmacy, from prescriptions written by an average of two physicians. More striking, during this same time frame, 10% of patients filled prescriptions for 23 or more medications, 12 or more unique medications, and 11 or more different drug classes; had prescriptions written by four or more prescribers; filled them at two or more pharmacies; and made 11 or more visits to a pharmacy, the researchers wrote (Arch. Intern. Med. 2011;171:814-22). Overall, mean medication adherence was 69% with statins and 66% with ACEI/ARBs. After adjustment for demographic factors, comorbidities, and copayments, patients who visited more pharmacies and those who filled fewer medications per visit were found to be substantially less adherent to their prescribed therapy. For example, each additional pharmacy at which a patient filled a prescription was associated with a nearly 2% reduction in statin adherence. Patients who filled the fewest prescriptions per pharmacy visit those who had the least refill consolidation had adherence rates that were 8% lower than adherence rates of patients who had the highest refill consolidation. The magnitude of Men Women Intermediate CV Risk VIEW ON THE NEWS Before psoriasis risk adjustment After psoriasis risk adjustment Men Women High CV Risk Note: 103 patients with psoriasis were assessed for their 10-year Framingham Risk Score based on LDL cholesterol before and after upward adjustment by 6.2% for psoriasis. Source: Dr. Mehta these effects [was] particularly large for patients who had newly initiated therapy and who filled their prescriptions at both retail pharmacies and via mail order, the investigators wrote. These results highlight an essential aspect of the therapeutic cascade that may be particularly burdensome and which few clinicians likely consider when making prescribing decisions. As such, our findings highlight the potential benefit of efforts to reduce prescribing and filling complexity by encouraging filling by mail order and/or reducing the frequency with which they must fill (e.g., by providing 90-day supplies of medications), Dr. Choudhry and his colleagues said. A Valuable Step Forward Despite its limitations, this study provides a valuable step forward in measuring the complexity of prescription medication management and its effect on adherence. Previous research has focused on the number of medications, the number of doses, and the times of administration, failing to take into account that many patients have multiple prescribers, shop around for lower prices, use both mail order and retail pharmacies, and have refills due on different dates, said Dr. Amanda H. Salanitro and Dr. Sunil Kripalani. To improve adherence, physicians can encourage patients to simplify their pattern of filling medications by using a single pharmacy or synchronizing refill dates. Having a ELSEVIER GLOBAL MEDICAL NEWS pharmacy home... might also be helpful for maintaining an accurate medication list and avoiding drugdrug interactions. Though the present study does not provide direct evidence for these practices, their potential to improve adherence is intriguing, Dr. Salanitro and Dr. Kripalani said. DR. SALANITRO and DR. KRIPALANI are at Vanderbilt University, Nashville, Tenn. Dr. Kripalani reported ties to PictureRx, Pfizer, and Bristol-Myers Squibb/Sanofi-Aventis. Dr. Salanitro reported she did not have any relevant financial disclosures. These remarks were taken from their editorial accompanying Dr. Choudhry s report (Arch. Intern. Med. 2011;171:822-3).

31 PRADAXA 150 MG TWICE DAILY REDUCES THE RISK OF STROKE IN NON-VALVULAR ATRIAL FIBRILLATION (AF) 1 DABIGATRAN NOW RECOMMENDED IN AF GUIDELINES 2 Stroke in non-valvular AF RISK REDUCED Image is a patient portrayal. Indications and Usage PRADAXA (dabigatran etexilate mesylate) capsules is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. IMPORTANT SAFETY INFORMATION ABOUT PRADAXA CONTRAINDICATIONS PRADAXA is contraindicated in patients with active pathological bleeding and patients with a known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA. WARNINGS AND PRECAUTIONS Risk of Bleeding PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Risk factors for bleeding include: Medications that increase the risk of bleeding in general (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs) Labor and delivery Promptly evaluate any signs or symptoms of blood loss, such as a drop in hemoglobin and/or hematocrit or hypotension. Discontinue PRADAXA in patients with active pathological bleeding. Please see additional Important Safety Information about PRADAXA and brief summary of full Prescribing Information on the following pages.

32 PRADAXA 150 MG TWICE DAILY In non-valvular atrial fibrillation Significant risk reduction of stroke vs warfarin 1 Effects of PRADAXA compared to warfarin were more apparent in patients with lower levels of INR control. Statistically significant reduction in stroke/systemic embolism Efficacy of PRADAXA was generally consistent across major subgroups* Patients With Events P-value for superiority= Hazard Ratio: % CI (0.52, 0.81) CI=confidence interval N=18,113 warfarin N=6022 PRADAXA 150 mg N=6076 IMPORTANT SAFETY INFORMATION ABOUT PRADAXA (continued from previous page) Temporary Discontinuation of PRADAXA Discontinuing PRADAXA for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Lapses in therapy should be avoided, and if PRADAXA must be temporarily discontinued for any reason, therapy should be restarted as soon as possible. Effect of P-gp Inducers and Inhibitors on PRADAXA Exposure The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces dabigatran exposure and should generally be avoided. P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin, do not require dose adjustments. These results should not be extrapolated to other P-gp inhibitors. ADVERSE REACTIONS In the pivotal trial comparing PRADAXA to warfarin, the most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal (GI) events. PRADAXA 150 mg resulted in a higher rate of major GI bleeds and any GI bleeds compared to warfarin. In patients 75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin. Patients on PRADAXA 150 mg had an increased incidence of GI adverse reactions. These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer). Drug hypersensitivity reactions were reported in <0.1% of patients receiving PRADAXA. Other Measures Evaluated The risk of myocardial infarction was numerically greater in patients who received PRADAXA 150 mg than in those who received warfarin. * Major subgroups were prespecified and included age (<65, 65 and <75, 75), previous stroke/systemic embolism/tia (no or yes), heart failure (no or yes), diabetes (no or yes), hypertension (no or yes), warfarin use at entry (naïve or experienced). References: 1. Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; Wann LS, Curtis AB, Ellenbogen KA, et al, writing on behalf of the 2006 ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation Writing Committee ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;57: Data on file. Boehringer Ingelheim Pharmaceuticals, Inc. PRADAXA is a registered trademark of Boehringer Ingelheim Pharma GmbH and Co. KG and used under license. COPYRIGHT 2011 BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.

33 Lower total bleed rate vs warfarin 1 Higher rate of major gastrointestinal (GI) bleeds (1.6% vs 1.1%) Fewer intracranial hemorrhages (0.3% vs 0.8%) Hazard Ratio: % CI (0.85, 0.96) Bleeding Events (per 100 Patient-Years) % % % warfarin (N=6022) PRADAXA 150 mg (N=6076) Hazard Ratio: 0.80 Hazard Ratio: % CI (0.66, 0.98) 95% CI (1.2,1.9) Hazard Ratio: % CI (0.28, 0.60) % % % % % Total Bleeds Life-Threatening Bleeds Major GI Bleeds 1,3 Intracranial Hemorrhage PRADAXA can cause serious and, sometimes, fatal bleeding Number of total GI bleeds was 681 vs 452 for warfarin (6.1% vs 4.0% for warfarin) 1,3 Number of major bleeds was 399 vs 421 for warfarin (3.3% vs 3.6% for warfarin, Hazard Ratio: 0.93, 95% CI [0.81, 1.07]) Trend toward a higher incidence of major bleeding on PRADAXA for patients 75 years of age (Hazard ratio: 1.2, 95% Cl [1.0 to 1.4]) Risk of stroke and bleeding increase with age, but risk-benefit profile is favorable in all age groups Patients contributed multiple events and events were counted in multiple categories. Major bleeds fulfilled 1 or more of the following criteria: bleeding associated with a reduction in hemoglobin of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal, or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding). Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. A life-threatening bleed met 1 or more of the following criteria: fatal, symptomatic intracranial bleed, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention. Please see brief summary of full Prescribing Information for PRADAXA on following page. For more information, visit ALL RIGHTS RESERVED. [03/11] PX91306PROF Significant Risk Reduction of Stroke

34 34 HYPERTENSION JUNE 2011 CARDIOLOGY NEWS Incidence of Negative Outcomes in LIFE Patients without LVH (n = 252) Patients with LVH (n = 211) 7.0% HR 3.3% 2.65 MI 8.5% HR % Stroke PRADAXA (dabigatran etexilate mesylate) capsules for oral use BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information. INDICATIONS AND USAGE PRADAXA is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. CONTRAINDICATIONS PRADAXA is contraindicated in patients with: s Active pathological bleeding [see Warnings and Precautions and Adverse Reactions]. s History of a serious hypersensitivity reaction to PRADAXA (e.g., anaphylactic reaction or anaphylactic shock) [see Adverse Reactions]. WARNINGS AND PRECAUTIONS Risk of Bleeding: PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Risk factors for bleeding include the use of drugs that increase the risk of bleeding in general (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs) and labor and delivery. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding. In the RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study, a life-threatening bleed (bleeding that met one or more of the following criteria: fatal, symptomatic intracranial, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention) occurred at an annualized rate of 1.5% and 1.8% for PRADAXA 150 mg and warfarin, respectively [see Adverse Reactions]. Temporary Discontinuation of PRADAXA: Discontinuing anticoagulants, including PRADAXA, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Lapses in therapy should be avoided, and if anticoagulation with PRADAXA must be temporarily discontinued for any reason, therapy should be restarted as soon as possible. Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure: The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin do not require dose adjustments. These results should not be extrapolated to other P-gp inhibitors. ADVERSE REACTIONS Clinical Trials Experience: The RE-LY study provided safety information on the use of two doses of PRADAXA and warfarin. The numbers of patients and their exposures are described in Table 1. Limited information is presented on the 110 mg dosing arm because this dose is not approved. Table 1 Summary of Treatment Exposure in RE-LY PRADAXA 110 mg twice daily PRADAXA 150 mg twice daily Warfarin Total number treated Exposure > 12 months > 24 months Mean exposure (months) Total patient-years 10,242 10,261 10,659 Because clinical studies are conducted under widely varying conditions and over varying lengths of time, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Drug Discontinuation in RE-LY: The rates of adverse reactions leading to treatment discontinuation were 21% for PRADAXA 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea). Bleeding [see Warnings and Precautions]: Table 2 shows the number of patients experiencing serious bleeding during the treatment period in the RE-LY study, with the bleeding rate per 100 patient-years (%). Major bleeds fulfilled one or more of the following criteria: bleeding associated with a reduction in hemoglobin of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding or pericardial bleeding). A life-threatening bleed met one or more of the following criteria: fatal, symptomatic intracranial bleed, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. Table 2 Bleeding Events* (per 100 Patient-Years) PRADAXA 150 mg twice daily N (%) 8.9% HR 3.4% 3.07 Warfarin N (%) 7.0% Hazard Ratio (95% CI**) 20.0% HR 3.1 Cardiovascular MI, stroke, or death CV death composite Randomized patients Patient-years 12,033 11,794 Intracranial hemorrhage 38 (0.3) 90 (0.8) 0.41 (0.28, 0.60) 14.9% HR 10.0% 1.73 All-cause death Notes: Based on data for patients who achieved a systolic blood pressure of <130 mm Hg; LVH = left ventricular hypertrophy, HR = adjusted hazard ratio. Source: Dr. Okin (Table 2, Cont d.) PRADAXA 150 mg twice daily N (%) Warfarin N (%) Hazard Ratio (95% CI**) Life-threatening 179 (1.5) 218 (1.9) 0.80 (0.66, 0.98) bleed Major bleed 399 (3.3) 421 (3.6) 0.93 (0.81, 1.07) Any bleed 1993 (16.6) 2166 (18.4) 0.91 (0.85, 0.96) *Patients contributed multiple events and events were counted in multiple categories. **Confidence interval The risk of major bleeds was similar with PRADAXA 150 mg and warfarin across major subgroups defined by baseline characteristics, with the exception of age, where there was a trend towards a higher incidence of major bleeding on PRADAXA (hazard ratio 1.2, 95% CI: 1.0 to 1.4) for patients *75 years of age. There was a higher rate of major gastrointestinal bleeds in patients receiving PRADAXA 150 mg than in patients receiving warfarin (1.6% vs. 1.1%, respectively, with a hazard ratio vs. warfarin of 1.5, 95% CI, 1.2 to 1.9), and a higher rate of any gastrointestinal bleeds (6.1% vs. 4.0%, respectively). Gastrointestinal Adverse Reactions: Patients on PRADAXA 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs. 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer). Hypersensitivity Reactions: In the RE-LY study, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in <0.1% of patients receiving PRADAXA. The risk of myocardial infarction was numerically greater in patients who received PRADAXA (1.5% for 150 mg dose) than in those who received warfarin (1.1%). DRUG INTERACTIONS The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin do not require dose adjustments. These results should not be extrapolated to other P-gp inhibitors. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times the human exposure at maximum recommended human dose [MRHD] of 300 mg/day based on area under the curve [AUC] comparisons) prior to mating and up to implantation (gestation Day 6). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition. Although dabigatran increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat, it did not induce major malformations in rats or rabbits. Labor and Delivery: Safety and effectiveness of PRADAXA during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using PRADAXA in this setting [see Warnings and Precautions]. Death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the human exposure at MRHD of 300 mg/day based on AUC comparisons). Nursing Mothers: It is not known whether dabigatran is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRADAXA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of PRADAXA in pediatric patients has not been established. Geriatric Use: Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups [see Warnings and Precautions and Adverse Reactions]. Renal Impairment: No dose adjustment of PRADAXA is recommended in patients with mild or moderate renal impairment. Reduce the dose of PRADAXA in patients with severe renal impairment (CrCl ml/min). Dosing recommendations for patients with CrCl <15 ml/min or on dialysis cannot be provided. OVERDOSAGE Accidental overdose may lead to hemorrhagic complications. There is no antidote to dabigatran etexilate or dabigatran. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with PRADAXA, and investigate the source of bleeding. Dabigatran is primarily excreted in the urine; therefore, maintain adequate diuresis. Dabigatran can be dialyzed (protein binding is low), with the removal of about 60% of drug over 2 to 3 hours; however, data supporting this approach are limited. Consider surgical hemostasis or the transfusion of fresh frozen plasma or red blood cells. There is some experimental evidence to support the role of activated prothrombin complex concentrates (e.g., FEIBA), or recombinant Factor VIIa, or concentrates of coagulation factors II, IX or X; however, their usefulness in clinical settings has not been established. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used. Measurement of aptt or ECT may help guide therapy. Copyright 2011 Boehringer Ingelheim Pharmaceuticals, Inc. ALL RIGHTS RESERVED ELSEVIER GLOBAL MEDICAL NEWS Persistent LVH Worsens Outcomes in Hypertensives BY MITCHEL L. ZOLER FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY NEW ORLEANS Hypertensive patients with persistent left ventricular hypertrophy despite normalized BP faced a substantially higher risk for death and cardiovascular events, compared with Revised: March 2011 PX-BS (3-11) PX91425PROF Persistence of LVH in certain patients with lower achieved BP may explain the lack of benefit of treatment. DR. OKIN patients without hypertrophy on antihypertensive treatment, according to a study involving 463 patients. These results suggest that persistence of left ventricular hypertrophy [LVH] in a subset of patients with lower achieved blood pressure during treatment may in part explain the lack of benefit seen in hypertensive patients, despite treatment to lower systolic blood pressure, Dr. Peter M. Okin said at the meeting. Based on these results, it may be necessary to track end-organ damage in addition to BP to fully assess response to treatment in hypertensive patients, said Dr. Okin, professor of medicine at Cornell University in New York. The analysis Dr. Okin reported came from a subset of participants in the LIFE (Losartan Intervention for End Point Reduction in Hypertension) study, which enrolled 9,193 patients aged years with a BP of 160/95 mm Hg to 200/115 mm Hg. The study randomized patients to two different antihypertensive treatment arms, one based primarily on losartan and the control based primarily on atenolol, with a target BP of 140/90 mm Hg or less (Lancet 2002;359: ). The subgroup used for the new analysis included the 463 patients in the study who achieved a systolic BP of 130 mm Hg or less. During an average follow-up of more than 4 years, the combined rate of cardiovascular death, MI, or stroke was 15%. The researchers used data from the 12- lead ECG recordings of these patients, as analyzed to calculate left ventricular size. They considered any patient with a Cornell product greater than 2440 mm x msec to have residual LVH. This identified 211 patients (46%) with persistent hypertrophy despite their low achieved systolic BP, and 252 patients without LVH. Patients with persistent LVH were significantly older (66 years) than were those without LVH (64 years), and were significantly more likely to be women (53%) compared with the 40% rate of women in the group without LVH. During the average 4.4 years of followup, patients with residual hypertrophy had significantly higher rates of MI, strokes, cardiovascular death, and allcause mortality, as well as a significantly higher rate of the combined end point of MI, stroke, or cardiovascular death, compared with the patients without hypertrophy. (See box.) Dr. Okin said that he receives a financial benefit from GE Medical Systems. The LIFE trial was sponsored by Merck, which markets losartan (Cozaar).

35 JUNE HYPERTENSION 35 Maximize Stroke Risk Reduction in Elderly Studies show benefits of calcium channel blockers and diuretics. BY BRUCE JANCIN EXPERT ANALYSIS FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY NEW ORLEANS Calcium channel blockers and diuretics are the best drugs for treating hypertension in the elderly because they are the most effective at reducing the risk of what elderly patients fear most: stroke, Dr. Norman M. Kaplan asserted at the meeting. Coronary disease remains by far the most common cause of mortality [in the United States], but stroke poses the greatest threat to the elderly, not coronary disease, said Dr. Kaplan, professor of internal medicine at the University of Texas, Dallas. He presented a state-of-the-art perspective on antihypertensive therapy in the elderly from the unique vantage point of having served as a member of the third, fourth, fifth, and sixth Joint National Committees on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Dr. Kaplan noted that a British meta-analysis of 46 randomized trials comparing each of the five major classes of antihypertensive drugs with any other class showed that all of the classes were similarly effective in preventing both coronary disease events and strokes, with one exception: calcium channel blockers had a significantly greater preventive effect on stroke than other agents. Diuretics showed a trend in the same direction that did not reach statistical significance (BMJ 2009;338:b1665 [doi: /bmj.b1665]). A secondary analysis of the 19,257-subject ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) demonstrated that calcium channel blocker based antihypertensive therapy was particularly effective against stroke in the population most in need of such protection: the elderly. Although there was no significant difference in strokes between amlodipine- and atenolol-based therapy in patients younger than age 65 years, there was a highly significant 30% relative risk reduction with amlodipine in the over- 65 group (J. Hypertens. 2011;29:583-91). The latest thinking regarding mechanism of benefit is that calcium channel blockers and diuretics are more effective at reducing stroke risk because they decrease within-individual variation in systolic blood pressure, unlike ACE inhibitors, angiotensin receptor blockers, and beta-blockers, all of which significantly increase it. In a meta-analysis of 389 randomized, controlled trials of antihypertensive therapy, stroke risk proved strongly related to this interindividual variation in blood pressure (Lancet 2010;375:906-15). Calcium channel blockers may also have a neuroprotective effect. A French study of 378 elderly, nondemented, hypertensive patients with the complaint of memory loss showed that memory scores were significantly better in those on a calcium channel blocker than on any other class of antihypertensive medication (J. Hypertens. 2010;28: ). Although that s an intriguing finding, this was an observational study and needs confirmation, in Dr. Kaplan s view. Elderly hypertensives predominantly have isolated systolic hypertension. Because of the extensive body of evidence showing that such patients have a good response rate to diuretic monotherapy, he recommends using a diuretic as the first-line drug. I would start chlorthalidone now having a resurgence as the diuretic of choice at 12.5 mg/day, and add a calcium channel blocker if additional therapy is needed to reach 150/70 mm Hg, which I think is a rational goal to aim for in the elderly, he said. Indeed, although the 7th Joint National Committee calls 140 mm Hg the upper limit of normal systolic blood pressure at all ages, nearly all the randomized trials that have shown a protective value for antihypertensive therapy in the elderly enrolled patients with a baseline systolic pressure in excess of 160 mm Hg, and achieved an on-treatment systolic pressure in the 150s or 160s. I do not think the evidence we have to date shows protective value for treatment in patients with a baseline systolic blood pressure below 160 mm Hg. There is evidence to suggest that if we lower the elderly patient s systolic blood pressure more than mm Hg, we may be invoking additional trouble rather than protecting the patient, said Dr. Kaplan. These are old people who obviously have atherosclerotic vascular disease, even if they don t show it. Reduction in diastolic blood pressure to 65 mm Hg or lower may reduce their coronary perfusion which occurs only during diastole to a degree that could invoke a cardiovascular catastrophe, he continued. Other important aspects of treating elderly hypertensive patients include identifying and overcoming postural hypotension, encouraging the consumption of one or two alcoholic drinks per day for the well-documented health benefits, starting a statin, and measuring home blood pressures to ensure that an individual really is being treated adequately, Dr. Kaplan said. The risks posed by orthostatic hypotension were highlighted in a study of 374 unselected ambulatory adults with an average age of 70 years and no known cardiovascular disease or other comorbidities. An orthostatic decrease in systolic blood pressure greater than 20 mm Hg was present 2 minutes after standing in 12% of them. Over roughly 1 year of follow-up, cardiovascular events were 2.4-fold more frequent in that patient subset (Hypertension 2010;56:56-61). Dr. Kaplan disclosed that he is on the speakers bureaus for Pfizer, AstraZeneca, Merck, Novartis, and Bayer. Moderate Hypertension Linked to Adverse Brain Changes BY MITCHEL L. ZOLER FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF CARDIOLOGY NEW ORLEANS Elderly people with modestly elevated systolic blood pressures showed significant declines in their mobility and cognition, and concurrent significant increases in brain damage, during 2 years of follow-up in a small study. These correlations suggest a possible new reason to control blood pressure in the elderly, Dr. William B. White said at the meeting. These data support an interventional trial evaluating different thresholds of ambulatory systolic blood pressure for preventing white matter progression and functional decline in older people, said Dr. White, professor of medicine and chief of the division of hypertension and clinical pharmacology at the University of Connecticut in Farmington. He plans to compare target systolic blood pressures of 145 and 130 mm Hg, he said in an interview. If you can intervene in patients with early-onset white matter disease and prevent progression, then you will do these people a big favor. I don t think we will see regression [of white matter damage], just prevention of it getting worse. This is the first study I know of to longitudinally compare ambulatory blood pressure VITALS Major Finding: A significant correlation was found between 24-hour ambulatory systolic hypertension, brain damage, and functional and cognitive impairment in elderly people. Each 1 mm Hg rise in systolic pressure over a 2-year period linked with an average 0.04% increased brain volume of white matter hyperintensity. Data Source: Two-year follow-up study of 72 people aged years (average age, 82 at baseline) who were normotensive or mildly hypertensive at entry. Disclosures: Dr. White said that he has been a consultant to the Forest Research Institute and has received research grants from Novartis. with both white matter hyperintensity and functional decline in older people. Blood pressure turned out to be the most important determinant of declines in cognition and mobility and in an MRI measure of brain damage, and blood pressure is something where we can intervene, he said. Hypertension specialists think about the burden [of hypertension] on the heart and the kidney, but they don t think about the chronic burden on the brain, said Dr. C. Venkata S. Ram, professor of medicine at the University of Texas Southwestern Medical Center in Dallas. Chronic hypertension can lead to significant morphologic and physiologic dysfunction. Many patients diagnosed with Alzheimer s disease probably had poorly controlled hypertension over their lifetime. Dr. White and his associates enrolled 72 people aged with various degrees of mobility and cognitive impairment who underwent blood pressure, cognitive, mobility, and MRI brain assessments at entry and 24 months later. At baseline, their age averaged 82 years, their 24-hour ambulatory blood pressure averaged 126/66 mm Hg, and their average amount of brain white matter hyperintensity, a marker of brain damage, was 1% of their total brain volume. Two years later, their average ambulatory blood pressure stood at 131/67 mm Hg. At both times, about 70% of patients received antihypertensive medication. When the researchers compared the findings at the two measurement times, they found that for each 1% increase in the volume of white matter hyperintensity, subjects showed an average 0.31-second decrease in their walk time and a 33-millisecond increase in their simple reaction time on cognitive testing. In addition, for each 1 mm Hg increase in 24-hour systolic blood pressure over the 2-year period between measurements, the subjects had an average 0.04% increase in their volume of white matter hypertrophy. In a different analysis, Dr. White and his associates divided the 72 people into tertiles based on their 24-hour systolic Blood pressure was the most important determinant of declines in cognition and mobility. DR. WHITE blood pressure at their 2-year assessment. The top and bottom tertiles had average systolic pressures of 144 and 117 mm Hg. The top tertile showed a significantly larger increase in white matter hyperintensity volume over the 2 years of follow-up, a significantly longer 8-foot walk time, a significantly slower walking speed, and nonsignificant trend toward poorer results on cognition tests. Also notable in the findings was that a modest level of systolic hypertension in the highest tertile linked with significant changes over the 2-year period. The people only averaged 144 mm Hg. That s not so bad, but they had progression, Dr. White said.

36 In chronic angina Superior clinical effects Ranexa 1000 mg twice daily with standard treatments* EXERCISE TREADMILL TEST PERFORMANCE Mean results over 12 weeks, trough plasma concentrations (CARISA) 1,2 Change from baseline (seconds) Δ 24 sec P = Δ 26 sec P = Placebo + standard treatments (n = 258) Ranexa 1000 mg twice daily + standard treatments (n = 261) Δ21 sec P = Exercise duration (modified Bruce treadmill test) Time to angina Time to 1-mm ST depression TRIAL DESCRIPTION CARISA (Combination Assessment of Ranolazine In Stable Angina) was a double-blind, randomized, placebo-controlled clinical trial of 823 patients with chronic angina who received Ranexa 750 mg twice daily, Ranexa 1000 mg twice daily, or placebo for 12 weeks. Patients also received daily doses of atenolol 50 mg, amlodipine 5 mg, or diltiazem CD 180 mg as standard treatment. The primary endpoint was exercise duration on the modified Bruce treadmill test at trough drug levels (12 hours after dosing). Secondary endpoints included exercise duration at peak drug levels, time to angina, time to 1-mm ST-segment depression, angina frequency, and weekly nitroglycerin use. Sublingual nitrates were used as needed. 1 Indication Ranexa is indicated for the treatment of chronic angina. Ranexa may be used with beta-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. IMPORTANT SAFETY INFORMATION Contraindications Ranexa is contraindicated in patients: Taking strong inhibitors of CYP3A (eg, ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir) Taking inducers of CYP3A (eg, rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St John s wort) With clinically significant hepatic impairment Warnings and Precautions Ranexa blocks I Kr and prolongs the QTc interval in a dose-related manner. Clinical experience did not show an increased risk of proarrhythmia or sudden death. There is little experience with high doses (> 1000 mg twice daily) or exposure, other QT-prolonging drugs, or potassium channel variants resulting in a long QT interval. Adverse Reactions The most common adverse reactions (> 4% and more common than with placebo) during treatment with Ranexa were dizziness, headache, constipation, and nausea.

37 wassuperiorcomparedwithstandardtreatmentsalone 26% increase in exercise duration (P =.03) 1 23% increase in time to angina (P =.03) 1 36% relative reduction in angina frequency (P <.001) 1 In the CARISA trial, patients receiving placebo experienced a mean of 3.3 angina attacks per week (compared with 4.6 at baseline), whereas patients receiving Ranexa 1000 mg twice daily experienced a mean of 2.1 angina attacks per week (compared with 4.5 at baseline). Effects on exercise tolerance and angina frequency were considerably smaller in women than in men. The improvement in exercise duration in women was about 33% of that in men at the 1000-mg twice-daily dose level. 2 For patient case studies, visit RanexaCases.com. *Patients in the CARISA trial also received standard doses of atenolol, amlodipine, or diltiazem, and sublingual nitrates as needed. Dosage and Administration Begin treatment with 500 mg twice daily and increase to the maximum recommended dose of 1000 mg twice daily, based on clinical symptoms. Limit the dose of Ranexa to 500 mg twice daily in patients on moderate CYP3A inhibitors (eg, diltiazem, verapamil, aprepitant, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products). Ranexa tablets should be taken whole and not crushed, broken, or chewed. FDA approved as a first-line agent for treatment of patients with chronic angina Drug Interactions Do not use Ranexa with CYP3A inducers or strong CYP3A inhibitors (see Contraindications); modify the dose of Ranexa with moderate CYP3A inhibitors (see Dosage and Administration). P-gp inhibitors (eg, cyclosporine): may need to lower the dose of Ranexa based on clinical response. Doses of drugs transported by P-gp (eg, digoxin) or metabolized by CYP2D6 (eg, metoprolol, tricyclic antidepressants, and antipsychotics) may need to be reduced. Please see brief summary of prescribing information on adjacent page. 1. Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004;291: Ranexa (ranolazine extended-release tablets) [package insert]. Palo Alto, CA; Sept Ranexa is a registered trademark of Gilead Palo Alto, Inc Gilead Sciences, Inc. All rights reserved. RAN9096 4/11

38 38 PRACTICE TRENDS JUNE 2011 CARDIOLOGY NEWS Medicare Proposes 2012 Pay Cut for Hospitals These highlights do not include all the information needed to use Ranexa safely and effectively. See full prescribing information for Ranexa. Ranexa (ranolazine) extended-release tablets 1. INDICATIONS AND USAGE Ranexa is indicated for the treatment of chronic angina. Ranexa may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. 2. DOSAGE AND ADMINISTRATION 2.1 Dosing Information Initiate Ranexa dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. Take Ranexa with or without meals. Swallow Ranexa tablets whole; do not crush, break, or chew. The maximum recommended daily dose of Ranexa is 1000 mg twice daily. If a dose of Ranexa is missed, take the prescribed dose at the next scheduled time; do not double the next dose. 2.2 Dose Modification Dose adjustments may be needed when Ranexa is taken in combination with certain other drugs [see Drug Interactions (7.1)]. Limit the maximum dose of Ranexa to 500 mg twice daily in patients on diltiazem, verapamil, and other moderate CYP3A inhibitors. Downtitrate Ranexa based on clinical response in patients concomitantly treated with P-gp inhibitors, such as cyclosporine. 3. DOSAGE FORMS AND STRENGTHS Ranexa is supplied as film-coated, oblong-shaped, extendedrelease tablets in the following strengths: 500 mg tablets are light orange, with GSI500 on one side 1000 mg tablets are pale yellow, with GSI1000 on one side 4. CONTRAINDICATIONS Ranexa is contraindicated in patients: Taking strong inhibitors of CYP3A [see Drug Interactions (7.1)] Taking inducers of CYP3A [see Drug Interactions (7.1)] With clinically significant hepatic impairment [see Use in Specific Populations (8.6)] 5. WARNINGS AND PRECAUTIONS 5.1 QT Interval Prolongation: Ranolazine blocks I Kr and prolongs the QTc interval in a dose-related manner. Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death. However, there is little experience with high doses (> 1000 mg twice daily) or exposure, other QT-prolonging drugs, or potassium channel variants resulting in a long QT interval. 6. ADVERSE REACTIONS BY ALICIA AULT The Centers for Medicare and Medicaid Services is proposing to reduce payments for hospitals by $498 million, or 0.55%, in fiscal The proposals under the Inpatient Prospective Payment System and the Long-Term Care Hospital Prospective Payment System continue a flat-to-downward trend in Medicare reimbursement Brief Summary of Prescribing Information 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 2,018 patients with chronic angina were treated with ranolazine in controlled clinical trials. Of the patients treated with Ranexa, 1,026 were enrolled in three double-blind, placebocontrolled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks duration. In addition, upon study completion, 1,251 patients received treatment with Ranexa in open-label, long-term studies; 1,227 patients were exposed to Ranexa for more than 1 year, 613 patients for more than 2 years, 531 patients for more than 3 years, and 326 patients for more than 4 years. At recommended doses, about 6% of patients discontinued treatment with Ranexa because of an adverse event in controlled studies in angina patients compared to about 3% on placebo. The most common adverse events that led to discontinuation more frequently on Ranexa than placebo were dizziness (1.3% versus 0.1%), nausea (1% versus 0%), asthenia, constipation, and headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily are poorly tolerated. over the past few years. A big reason for the reduction: The agency is adjusting for overpayments made for coding errors in the previous fiscal years, according to Ira Loss and his colleagues at Washington Analysis, a company that monitors policy developments for investor clients. The cuts will will maintain pressure on makers and suppliers of certain device categories, like orthopedics, general surgery, routine lab tests, and medical supplies, for In controlled clinical trials of angina patients, the most frequently reported treatment-emergent adverse reactions (> 4% and more common on Ranexa than on placebo) were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). Dizziness may be dose-related. In open-label, long-term treatment studies, a similar adverse reaction profile was observed. The following additional adverse reactions occurred at an incidence of 0.5 to 2.0% in patients treated with Ranexa and were more frequent than the incidence observed in placebo-treated patients: Cardiac Disorders bradycardia, palpitations Ear and Labyrinth Disorders tinnitus, vertigo Gastrointestinal Disorders abdominal pain, dry mouth, vomiting General Disorders and Administrative Site Adverse Events peripheral edema Respiratory, Thoracic, and Mediastinal Disorders dyspnea Vascular Disorders hypotension, orthostatic hypotension Other (< 0.5%) but potentially medically important adverse reactions observed more frequently with Ranexa than placebo treatment in all controlled studies included: angioedema, renal failure, eosinophilia, blurred vision, confusional state, hematuria, hypoesthesia, paresthesia, tremor, pulmonary fibrosis, thrombocytopenia, leukopenia, and pancytopenia. A large clinical trial in acute coronary syndrome patients was unsuccessful in demonstrating a benefit for Ranexa, but there was no apparent proarrhythmic effect in these high-risk patients. Laboratory Abnormalities Ranexa produces small reductions in hemoglobin A1c. Ranexa is not a treatment for diabetes. Ranexa produces elevations of serum creatinine by 0.1 mg/dl, regardless of previous renal function. The elevation has a rapid onset, shows no signs of progression during long-term therapy, is reversible after discontinuation of Ranexa, and is not accompanied by changes in BUN. In healthy volunteers, Ranexa 1000 mg twice daily had no effect upon the glomerular filtration rate. The elevated creatinine levels are likely due to a blockage of creatinine s tubular secretion by ranolazine or one of its metabolites. 7. DRUG INTERACTIONS 7.1 Effects of Other Drugs on Ranolazine: Ranolazine is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp). CYP3A Inhibitors Do not use Ranexa with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir. Ketoconazole (200 mg twice daily) increases average steady-state plasma concentrations of ranolazine 3.2-fold [see Contraindications (4)]. Limit the dose of Ranexa to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, aprepitant, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products. Diltiazem ( mg daily) and verapamil (120 mg three times daily) increase ranolazine steady-state plasma concentrations about 2-fold [see Dosage and Administration (2.2)]. Weak CYP3A inhibitors such as simvastatin (20 mg once daily) and cimetidine (400 mg three times daily) do not increase the exposure to ranolazine in healthy volunteers. P-gp Inhibitors Down-titrate Ranexa based on clinical response in patients concomitantly treated with P-gp inhibitors, such as cyclosporine [see Dosage and Administration (2.2)]. CYP3A and P-gp Inducers Avoid co-administration of Ranexa and CYP3A inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John s wort. Rifampin (600 mg once daily) decreases the plasma concentration of ranolazine (1000 mg twice daily) by approximately 95% by induction of CYP3A and, probably, P-gp. 7.2 Effects of Ranolazine on Other Drugs: In vitro studies indicate that ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A, moderate inhibitors of CYP2D6 and moderate P-gp inhibitors. Drugs Transported by P-gp Ranexa (1000 mg twice daily) causes a 1.5-fold elevation of digoxin plasma concentrations. The dose of digoxin may have to be adjusted. Drugs Metabolized by CYP2D6 Ranexa 750 mg twice daily increased the plasma concentrations of a single dose of immediate-release metoprolol (100 mg), a CYP2D6 substrate, by 1.8-fold. The exposure to other CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with Ranexa, and lower doses of these drugs may be required. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: In animal studies, ranolazine at exposures 1.5 (rabbit) to 2 (rat) times the usual human exposure caused maternal toxicity and misshapen sternebrae and reduced ossification in offspring. These doses in rats and rabbits were associated with an increased maternal mortality rate. There the foreseeable future, said Mr. Loss. The April 19 announcement included new quality improvement proposals. The proposals... reflect an underlying premise that we can improve the quality of and access to care while at the same time slowing the growth in health care spending, CMS Administrator Donald Berwick said in a statement. The rule will encourage support of Partnerships for Patients, a joint effort by are no adequate well-controlled studies in pregnant women. Ranexa should be used during pregnancy only when the potential benefit to the patient justifies the potential risk to the fetus. 8.3 Nursing Mothers: It is not known whether ranolazine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ranolazine in nursing infants, decide whether to discontinue nursing or to discontinue Ranexa, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use: Of the chronic angina patients treated with Ranexa in controlled studies, 496 (48%) were 65 years of age, and 114 (11%) were 75 years of age. No overall differences in efficacy were observed between older and younger patients. There were no differences in safety for patients 65 years compared to younger patients, but patients 75 years of age on ranolazine, compared to placebo, had a higher incidence of adverse events, serious adverse events, and drug discontinuations due to adverse events. In general, dose selection for an elderly patient should usually start at the low end of the dosing range, refl ecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease, or other drug therapy. 8.6 Use in Patients with Hepatic Impairment: Ranexa is contraindicated in patients with clinically significant hepatic impairment. Plasma concentrations of ranolazine were increased by 30% in patients with mild (Child-Pugh Class A) and by 60% in patients with moderate (Child-Pugh Class B) hepatic impairment. This was not enough to account for the 3-fold increase in QT prolongation seen in patients with mild to severe hepatic impairment [see Contraindications (4)]. 8.7 Use in Patients with Renal Impairment: In patients with varying degrees of renal impairment, ranolazine plasma levels increased up to 50%. The pharmacokinetics of ranolazine has not been assessed in patients on dialysis. 8.8 Use in Patients with Heart Failure: Heart failure (NYHA Class I to IV) had no significant effect on ranolazine pharmacokinetics. Ranexa had minimal effects on heart rate and blood pressure in patients with angina and heart failure NYHA Class I to IV. No dose adjustment of Ranexa is required in patients with heart failure. 8.9 Use in Patients with Diabetes Mellitus: A population pharmacokinetic evaluation of data from angina patients and healthy subjects showed no effect of diabetes on ranolazine pharmacokinetics. No dose adjustment is required in patients with diabetes. Ranexa produces small reductions in HbA1c in patients with diabetes, the clinical significance of which is unknown. Ranexa should not be considered a treatment for diabetes. 10. OVERDOSAGE High oral doses of ranolazine produce dose-related increases in dizziness, nausea, and vomiting. High intravenous exposure also produces diplopia, paresthesia, confusion, and syncope. In addition to general supportive measures, continuous ECG monitoring may be warranted in the event of overdose. Since ranolazine is about 62% bound to plasma proteins, hemodialysis is unlikely to be effective in clearing ranolazine. Please see full prescribing information at To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc, at GILEAD-5, or FDA at FDA-1088 or Rx only Manufactured for: Gilead Sciences, Inc, Foster City, CA USA Ranexa Prescribing Information, September GS-008 SEP10 Ranexa is a registered US trademark of Gilead, Palo Alto, Inc Gilead Sciences, Inc. RAN /10 the Department of Health and Human Services and private entities to improve patient safety and quality. Beginning in fiscal 2013, the agency is to start reducing payments to hospitals that have excess readmissions for certain conditions. The proposed rule lays the groundwork for that by publishing rates of readmissions for three conditions: acute myocardial infarction, heart failure, and pneumonia. The proposal also would add one category to the list of hospital-acquired conditions that the CMS will not pay for at a higher rate, if the condition occurred during the hospital stay. That category is acute renal failure after contrast Heart transplants and heart assist systems will have about a 9% pay reduction. Defibrillator implantation will range from a decrease of 2.1% to an increase of 4.5%. administration (also known as contrastinduced acute kidney injury, or CI-AKI). The new rule contains provisions that will support the hospital value-based purchasing regulation when that final rule is issued in the near future. One of those proposals is to adopt a Medicare Spending per Beneficiary Measure for the value-based purchasing program. The CMS also proposes to reduce the reporting burden for physicians and hospitals by retiring some quality measures, introducing others that will more closely align with measures collected for other purposes, and streamlining the submissions process, said the agency. On the reimbursement side, cardiac and orthopedic procedures will see an overall slight reduction in payment, according to Washington Analysis. Heart transplants and heart assist systems will have about a 9% pay reduction. Defibrillator implantation will range from a decrease of 2.1% to an increase of 4.5%, depending on the patient s status, the analysts said. Deep brain stimulation, vagus nerve stimulation for epilepsy, and spinal cord stimulation will see a small increase. The rule is open for comment until June 20. The final rule is to be issued by Aug. 1. Can't Find Your Last Issue? You have FREE access to articles from this issue and past issues of CARDIOLOGY NEWS at

39 JUNE PRACTICE TRENDS 39 House Hears SGR Alternatives, Vows Action BY FRANCES CORREA FROM A HEARING OF THE HOUSE ENERGY AND COMMERCE COMMITTEE S SUBCOMMITTEE ON HEALTH WASHINGTON A plan to finally replace Medicare s much maligned Sustainable Growth Rate payment formula could be unveiled by this summer, federal lawmakers predicted at a committee hearing. Here s the bottom line: If we get to December and we re doing an extension, that s a failure on our part, Rep. Michael Burgess (R-Tex.) said at the hearing. We need a permanent solution that s predictable, updatable, and reasonable for this year and nothing else will do. Whatever virtues the SGR had when it was created 14 years ago, it s clear that they have vanished, noted Rep. Henry A. Waxman (D-Calif.). He added that in the past 2 years, Congress has had to pass legislation six times, blocking fee cuts of up to 21% or more. About 30 medical associations responded to the House subcommittee s request for suggestions and proposals in developing a new system. Speaking with a five-person panel of experts from medical associations and health policy organizations, House subcommittee members considered alternatives to the current SGR formula. One Size Won t Fit All While the details of the plans vary, they do show a consensus on several fronts: repealing the SGR, moving away from the traditional fee-for-services payment model, and providing a 4- to 5-year transition period in which providers can experiment with a variety of payment systems. The expert panel also stressed the importance of avoiding a one size fits all solution. I think we should also have a realization that what will work in one part of the country will not work in another part of the country, and that s why we have continued to talk about a variety of options, said Dr. Cecil Wilson, president of the American Medical Association. Dr. Wilson pointed to the provisions in the Affordable Care Act that allow for a variety of models of accountable care organizations, embodying the concept of options in the medical system. In that spirit, he said that the AMA has formed a physician leadership group to evaluate the effectiveness of alternative payment methods. To strengthen primary care s role in Medicare, the American Academy of Family Physicians backs payment reforms that would boost primary care reimbursement and support the concept of the patient-centered medical home (PCMH). AAFP President Roland A. Goertz noted in written testimony to the committee that the proposal would create a blended reimbursement system for primary care delivered within a PCMH: fee-for-service payments and pay for performance, plus care management fees for PCMHrelated activities that don t involve direct patient care. Dr. David Hoyt, executive director of the American College of Surgeons, said the college is analyzing the use of bundled payments for surgery. Dr. M. Todd Williamson, of the Coalition of State Medical and National Specialty Societies, introduced the option of private contracting, in which patients would be free to apply their benefits to a doctor of their choice, who would be free to opt out on a per-patient basis. Harold Miller, executive director of the Center for Healthcare Quality and Payment Reform, suggested an episode-of-care payment plan through which hospitals and physicians jointly charge one price for all services included in a hospitalization. The model would also include a warranty stating that any infections or complications What will work in one part of the country will not work in another, said Dr. Cecil Wilson (center). COURTESY AMERICAN MEDICAL ASSOCIATION would be treated at no additional cost. Also, a physician practice would receive one payment for all patient needs associated with chronic diseases or other conditions. Rep. Burgess, who is also a doctor, said organizations should focus on ways to address patients with chronic conditions, adding that 80% of Medicare funding is spent by 20% of beneficiaries with chronic illnesses. Is IPAB the New SGR? Rep. Fred Upton (R-Mich.) raised concerns about the Independent Payment Advisory Board (IPAB), created by the Affordable Care Act. The board sets expenditure targets, on which it bases spending cuts. In 2018, targets will be based on the gross domestic product. Sounds a lot like SGR, which we re trying to get rid of, Mr. Upton said. Since hospitals are exempt from IPAB cuts through the rest of the decade, it seems that the IPAB has the potential to undermine any serious efforts at physician payment reform. Some panelists agreed. It s not impossible that [the IPAB] could serve a function, Dr. Wilson said, but as presently constituted, we see it [as] basically another target for physicians to meet potential double jeopardy, with an SGR as well as the pronouncements from this body. The panelists also asserted their belief that whatever plan chosen should be physician led, with financial support of the government. It would be helpful if physicians could get better financial support in their own payment system to enable them to lead all of those efforts, said Dr. Mark B. McClellan, director of the Engelberg Center for Health care Reform and former administrator of the Centers for Medicare and Medicaid Services. Electronic Health Records Deemed Good for the Earth BY FRANCES CORREA FROM HEALTH AFFAIRS Greater use of electronic health records would cut greenhouse gas emissions, energy use, waste and toxic chemical production, and water consumption, according to a study by Marianne C. Turley, Ph.D., and her associates at Kaiser Permanente. Even after factoring in the additional energy consumption from the increased use of personal computers, the overall net effect on the environment would be favorable, the re- VITALS searchers concluded based on an analysis of the impact of the Kaiser Permanente EHR system, which covers 8.7 million beneficiaries. Annually, the use of the Kaiser EHR system eliminated the use of 1,373 tons of paper by discontinuing the use of paper medical charts, x-ray jackets, and administrative forms. The system also decreased annual gas consumption by an estimated million gallons by cutting the number of visits by 4-13 million. Patients who were registered online could correspond with their providers about nonemergency concerns through secure messages, the investigators reported (Health Aff. 2011;30:938-46). Switching from desktop to laptop computers saved 89,300 megawatt hours and digitizing x-rays eliminated the Major Finding: The use of electronic health records cut Kaiser Permanente s use of paper by 1,373 tons annually. The system also decreased energy use by million gallons of gasoline by reducing medical visits. Data Source: Based on a 2011 internal analysis. Disclosures: All seven researchers are employees of Kaiser Permanente. waste of 203 tons of plastic and 79 tons of toxic chemicals. Using the Environmental Protection Agency s greenhouse gas equivalencies calculator, Dr. Turley and her associates estimated that Kaiser s efforts reduced greenhouse gas emissions by 9,200 tons. Results were based on data from regional operational reports, paper-purchasing records, and internal pharmaceutical reports. Travel distance was estimated by calculating the distance from patient addresses to Kaiser-participating primary care buildings and aggregating them by region. With a growing emphasis on health technology, the Kaiser study showed that the use of electronic health records can both change the face of health care and help reduce its environmental footprint, the researchers wrote. Despite these findings, Dr. Turley and her associates said that the environmental impact of switching to electronic health records will vary from system to system. As the Affordable Care Act calls for implementation of electronic systems, they said further analysis is necessary to determine the impacts of widespread implementation. Although 51% of office-based physicians are currently using an electronic system, only 10% of practices reported their systems as being fully functioning, according to the most recent evaluation from the Centers for Disease Control and Prevention. Regardless, implementation of electronic systems will probably increase as provisions in the American Recovery and Reinvestment Act of 2009 create incentives for providers who invest in electronic systems. Public and private investment in these systems is ex- pected to reach $40 billion in the next several years, according to the investigators. INDEX OF ADVERTISERS Abbott Laboratories Niaspan Accumetrics VerifyNow 5 Bayer HealthCare LLC Aspirin 3 Boehringer Ingelheim Pharmaceuticals, Inc. Pradaxa Daiichi Sankyo, Inc. Welchol 10a-10b, 11 Daiichi Sankyo, Inc. and Lilly USA, LLC Effient Forest Laboratories, Inc. Bystolic Gilead Sciences, Inc. Ranexa LipoScience Inc. Corporate 34a-34b Pfizer Inc. Revatio sanofi-aventis U.S. LLC Multaq 6-9 Verathon Inc. AortaScan 21

40 40 JUNE 2011 CARDIOLOGY NEWS CLASSIFIEDS iolog ynews.com BOARD REVIEW ATTORNEYS KEEP UP-TO-DATE Watch our Classified Notices for Postgraduate Course information. Our law firm represents medical and business professionals who are either preparing to file or have been denied benefits under their insurance policy. We also handle lump-sum buyouts. Established in 1979, our litigation experience and disability claim handling knowledge has allowed us to help our clients receive disability benefits. Visit our website at: DiAttorney.com Moving? Look to Classified Notices for practices available in your area. Call to learn how we can help you with your disability claim. Hollywood 2011 CLASSIFIEDS Disclaimer CARDIOLOGY NEWS assumes the statements made in classified advertisements are accurate, but cannot investigate the statements and assumes no responsibility or liability concerning their content. Classified advertising in OB.GYN. NEWS should avoid the use of language that imparts bias against persons or groups on the basis of sex, race or ethnicity, age, physical or mental disability, or sexual orientation. The Publisher reserves the right to decline, withdraw, or edit advertisements. Every effort will be made to avoid mistakes, but responsibility cannot be accepted for clerical or printer errors. Recycle Life Donate Blood Cardiology News Rates 4 Column Classified Ads From 1 to 12 Sizes from 1/48th of a page to a full page For Deadlines and More Information Contact: Andrea LaMonica 60 Columbia Road, Building B Morristown, NJ Tel: or fax your ad to: ad to: a.lamonica@elsevier.com Also availab le at med job s.com

41 JUNE PRACTICE TRENDS 41 New Initiatives Aim to Encourage Move to ACOs The Pioneer ACO Model and other initiatives are the result of feedback from medical associations. BY FRANCES CORREA FROM THE CENTERS FOR MEDICARE AND MEDICAID SERVICES Three new initiatives aim to help physicians make the jump to becoming part of an Accountable Care Organization, officials from the Centers for Medicare and Medicaid services announced May 17. The Pioneer ACO Model would accelerate the process for ACOs that already have the infrastructure in place to coordinate care for patients. Under this model, private payers would offer provider incentives and would function on a separate contract from the Medicare Shared Savings Program. About 30 integrated health systems are expected to participate in the Pioneer ACO Model project this summer, making a full transition to ACO by September or October, according to Jonathan Blum, director of the Center for Medicare Management, a part of the CMS. Use of the pioneer model could result in $430 million in Medicare savings over 3 years, according to the CMS Office of the Actuary. The pioneer model will follow the same 65 quality measurements and regulations already assigned to ACOs. The second initiative is a series of free accelerated development learning sessions to educate providers on becoming an ACO and implementing a coordinated care model. The first of the four learning sessions offered in 2011 will be available June in Minneapolis. All materials from the sessions, including webcast sessions, will be publicly available. Finally, the CMS is requesting public comment on the proposal for providing upfront payments to providers who are interested in becoming ACOs but lack the resources. The accelerated payment program would allow providers who lack the capital to invest in the necessary infrastructure and staffing, Mr. Blum said, adding that the CMS plans to CLASSIFIEDS iolog ynews.com We re very conscious of the fact that we have to create payment policies and other requirements that provide an attractive model. determine how much funding might be provided after evaluating public comments. These initiatives came as a result of feedback from medical associations during the comment period of the ACO regulations, according to Dr. Donald Berwick, CMS administrator, who added that the challenge to implementing the best model is striking a balance between patient and provider needs. This includes balancing an ACO s need for data with patient privacy, the need for better coordinated care without overburdening providers with regulations, and the need for creating provider incentives without allowing them to avoid methods of care that might threaten those incentives. Regardless, Mr. Blum said the CMS is devising a model that will greatly improve care. We think that the ACO model, both the base model but also the Pioneer [model], is one of the best ways for us to improve care and so we re very conscious of the fact that we have to create payment policies and other requirements that provide an attractive model. The comment period on accountable care organization regulation was scheduled to close on June 6. PRODUCTS PROFESSIONAL OPPORTUNITIES THE OHIO STATE UNIVERSITY HEART AND VASCULAR CENTER Third Annual Contemporary Multidisciplinary Cardiovascular Medicine A Disease-Based Learning Experience for the Practitioner October 7-9, 2011 New Location! Marriott Orlando World Center Orlando, Florida Have questions on classifieds? Call Andrea LaMonica (914) (800) for more information. Disclaimer CARDIOLOGY NEWS assumes the statements made in classified advertisements are accurate, but cannot investigate the statements and assumes no responsibility or liability concerning their content. The Publisher reserves the right to decline, withdraw, or edit advertisements. Every effort will be made to avoid mistakes, but responsibility cannot be accepted for clerical or printer errors. Project HOPE Improving Health Through Education Give to Dept. A, Washington, D.C Join experts from Ohio State s Heart and Vascular Center and distinguished guest speakers for this unique teaching symposium for all practicing cardiologists, cardiologists-in-training, physicians and allied health professionals who care for patients with heart disease. This twoand-a-half day course will highlight the latest advances and clinical hotbutton issues in cardiovascular medicine, including targeted segments for: Coronary Artery Disease Preventive Cardiology Heart Failure Electrophysiology Valvular Heart Disease Ohio State Course Faculty Includes: William Abraham, MD Martha Gulati, MD Robert Higgins, MD Laxmi Mehta, MD Thomas Ryan, MD For a full course agenda and registration information, visit bit.ly/orlando2011. Guest Faculty: Michael Blazing, MD Steven Bolling, MD Blase Carabello, MD Kim A. Eagle, MD Angel Leon, MD Jeffrey Popma, MD Also availab le at med job s.com

42 42 PRACTICE TRENDS JUNE 2011 CARDIOLOGY NEWS POLICY & PRACTICE WANT MORE HEALTH REFORM NEWS? SUBSCRIBE TO OUR PODCAST SEARCH POLICY & PRACTICE IN THE ITUNES STORE Cardiologists Top E-Prescribers Cardiologists appear to be adopting electronic prescribing more readily than colleagues in other specialties, according to a report by the Surescripts e-prescribing network. The 49% of cardiologists using e-prescribing is ahead of family practitioners (47%) and internists (45%). Behind them, 38% of gastroenterologists and 36% of pediatricians are e-prescribing. About 36% of all office-based physicians were e-prescribing in 2010, and 1 in 10 prescriptions was delivered electronically in 2010, up from 1 in 18 in E- prescribing is being driven primarily by federal legislation, including health care reform, according to Surescripts. Bill Would Protect Device Makers A tort-reform bill that was passed by the House Energy and Commerce Committee in mid-may would exempt medical device makers from paying punitive damages in product liability suits, according to the Gray Sheet, which reports on the medical-device industry. The committee passed the Help Efficient, Accessible, Low-Cost, Timely Healthcare (HEALTH) Act of 2011 (H.R. 5) by a vote of 30-20, largely along party lines. The bill was introduced in January by Rep. Phil Gingrey (R-Ga.), who is a physician. Although Republicans and physicians organizations have generally favored the bill, Democrats have objected to the exemptions for medical device and pharmaceutical manufacturers. The bill would place a $250,000 cap on noneconomic damages in malpractice cases and would require that most medical liability suits be filed within 3 years of an injury. Heart Admissions Declined Hospital admissions for top cardiovascular conditions declined among Medicare beneficiaries from 1998 to 2008, researchers at New York University and Yale University found. While overall Medicare admissions climbed from 11 million to 13 million during the decade, hospitalizations for heart failure, ischemic heart disease, and acute myocardial infarction went down 7%, 24%, and 13%, respectively. In contrast, admissions for cardiac arrhythmia increased 28%. The study was presented as a poster at an American Heart Association meeting in Washington. Some Pacemakers Okay With MRI Medicare has proposed ending its blanket ban on MRI in patients with implantable pacemakers. Device maker Medtronic had asked the agency to alter the policy after the company in February won Food and Drug Administration approval of a pacemaker that was designed for use with MRI. In a Proposed Decision Memo, the Centers for Medicare and Medicaid services said that the evidence is adequate to conclude that magnetic resonance imaging (MRI) improves health outcomes for Medicare beneficiaries with implanted permanent pacemakers (PMs) when the PMs are used according to the FDA-approved labeling for use in an MRI environment. Heart Failure Certification Begins The Joint Commission and the American Heart Association announced that their advanced certification program in heart failure will start next month. The program will focus on safe, successful transitions of care from inpatient to outpatient settings, according to an AHA statement. Programs seeking certification must have a hospital-based or outpatient heart failure clinic, a collaborative relationship with a cardiology practice, and proof of adherence to the AHA American College of Cardiology guidelines on diagnosis and management of heart failure. By achieving advanced certification in heart failure, programs will have demonstrated their commitment to consistently delivering REVATIO (SILDENAFIL) Brief Summary of Prescribing Information INDICATIONS AND USAGE: REVATIO is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise ability and delay clinical worsening. Delay in clinical worsening was demonstrated when REVATIO was added to background epoprostenol therapy. Studies establishing effectiveness included predominantly patients with NYHA Functional Class II-III symptoms and etiologies of primary pulmonary hypertension (71%) or pulmonary hypertension associated with connective tissue disease (25%). The efficacy of REVATIO has not been adequately evaluated in patients taking bosentan concurrently. DOSAGE AND ADMINISTRATION Pulmonary Arterial Hypertension (PAH) REVATIO Tablets The recommended dose of REVATIO is 20 mg three times a day (TID). REVATIO tablets should be taken approximately 4-6 hours apart, with or without food. In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg TID is not recommended. Dosages lower than 20 mg TID were not tested. Whether dosages lower than 20 mg TID are effective is not known. REVATIO Injection REVATIO injection is for the continued treatment of patients with pulmonary arterial hypertension (PAH) who are currently prescribed oral REVATIO and who are temporarily unable to take oral medication. The recommended dose is 10 mg (corresponding to 12.5 ml) administered as an intravenous bolus injection three times a day. The dose of REVATIO injection does not need to be adjusted for body weight. A 10 mg dose of REVATIO injection is predicted to provide pharmacological effect of sildenafil and its N-desmethyl metabolite equivalent to that of a 20 mg oral dose. CONTRAINDICATIONS Use with Organic Nitrates Do not use REVATIO in patients taking organic nitrates in any form, either regularly or intermittently. Consistent with its known effects on the nitric oxide/cgmp pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates. Hypersensitivity Reactions REVATIO is contraindicated in patients with a known hypersensitivity to sildenafil or any component of the tablet. Rare cases of hypersensitivity have been reported in association with the use of sildenafil including anaphylactic reaction/shock events and anaphylactoid reaction. The majority of reported events were non-serious hypersensitivity reactions. WARNINGS AND PRECAUTIONS Cardiovascular Effects REVATIO has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing REVATIO, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients with resting hypotension [BP < 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of REVATIO to patients with veno-occlusive disease, administration of REVATIO to such patients is not recommended. Should signs of pulmonary edema occur when REVATIO is administered, consider the possibility of associated PVOD. As there are no controlled clinical data on the safety or efficacy of REVATIO in the following groups, prescribe with caution for: Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months; Patients with coronary artery disease causing unstable angina; Patients with hypertension (BP > 170/110); Patients currently on bosentan therapy. Use with Alpha-blockers PDE5 inhibitors, including sildenafil, and alpha-adrenergic blocking agents are both vasodilators with blood pressure-lowering effects.when vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly, leading to symptomatic hypotension. In the sildenafil interaction studies with alpha-blockers, cases of symptomatic hypotension consisting of dizziness and lightheadedness were reported [see Drug Interactions]. No cases of syncope or fainting were reported during these interaction studies. The safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and concomitant use of anti-hypertensive drugs. Effects on Bleeding In humans, sildenafil has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide donor).the combination of heparin and sildenafil had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans. The incidence of epistaxis was 13% in patients taking sildenafil with PAH secondary to connective tissue disease (CTD). This effect was not seen in primary pulmonary hypertension (PPH) (sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of REVATIO is unknown in patients with bleeding disorders or active peptic ulceration. Use with Ritonavir and Other Potent CYP3A Inhibitors The concomitant administration of the protease inhibitor ritonavir (a highly potent CYP3A inhibitor) substantially increases serum concentrations of sildenafil; therefore, co-administration of ritonavir or other potent CYP3A inhibitors with REVATIO is not recommended. Effects on the Eye Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE5 inhibitors, including REVATIO. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, that has been reported postmarketing in temporal association with the use of all PDE5 inhibitors, including sildenafil, when used in the treatment of erectile dysfunction. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE5 inhibitors [see Adverse Reactions]. There are no controlled clinical data on the safety or efficacy of REVATIO in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe REVATIO with caution in these patients. Hearing Impairment Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE5 inhibitors, including REVATIO.These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including REVATIO. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions]. Combination with other PDE5 inhibitors Sildenafil is also marketed as VIAGRA. The safety and efficacy of combinations of REVATIO with VIAGRA or other PDE5 inhibitors have not been studied. Inform patients taking REVATIO not to take VIAGRA or other PDE5 inhibitors. Prolonged Erection Use REVATIO with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie s disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result. Pulmonary Hypertension Secondary to Sickle Cell Anemia In a small, prematurely terminated study of patients with PH secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received REVATIO than by those randomized to placebo. The effectiveness of REVATIO in pulmonary hypertension (PH) secondary to sickle cell anemia has not been established. ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Hypotension [see Warnings and Precautions] Vision loss [see Warnings and Precautions] Hearing loss [see Warnings and Precautions] Priapism [see Warnings and Precautions] Vaso-occlusive crisis [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety data were obtained from the 12 week, placebo-controlled clinical study and an open-label extension study in 277 treated patients with pulmonary arterial hypertension. Doses up to 80 mg TID were studied. The overall frequency of discontinuation in REVATIO-treated patients at the recommended dose of 20 mg TID was 3% and was the same for the placebo group. In the placebo-controlled trial in pulmonary arterial hypertension, the adverse drug reactions that were reported by at least 3% of REVATIO patients treated at the recommended dosage (20 mg TID) and were more frequent in REVATIO patients than placebo patients, are shown in Table 1. Adverse events were generally transient and mild to moderate in nature. Table 1. REVATIO All Causality Adverse Events in 3% of Patients and More Frequent (> 1%) than Placebo ADVERSE EVENTS % Epistaxis Headache Dyspepsia Flushing Insomnia Erythema Dyspnea exacerbated Rhinitis nos Diarrhea nos Myalgia Pyrexia Gastritis nos Sinusitis Paresthesia nos: Not otherwise specified reliable, effective and high quality care to their heart failure patients, said Dr. Gregg C. Fonarow, who led the AHA s guidelines committee. CME-Funding Dilemma Persists Although physicians and other medical professionals say they re concerned that commercial funding of continuing medical education may bias the information provided, most are not willing to pay more to offset or eliminate such funding, a study in Archives of Internal Medicine shows. Researchers surveyed 770 physicians, nurses, nurse practitioners, Placebo (n=70) Revatio 20 mg TID (n=69) Placebo- Subtracted

43 JUNE PRACTICE TRENDS 43 and physician assistants at CME sessions and found that the vast majority (88%) said that commercial support of CME introduces bias. They also said that the greater the financial support, the greater the bias. However, only 15% would eliminate commercial support from CME activities and only 42% said they were willing to pay more in an effort to cut industry financial involvement. Most CME participants also significantly underestimated the amount of commercial funding for their courses, the authors wrote, adding that the dilemma remains of how to provide quality CME either with [alternative funding] or at reduced cost. Uninsured Can t Afford Hospitals Few families that lack health insurance hold the financial assets that would be necessary to pay potential hospital bills, according to a report from the DHHS. Each year, nearly 2 million uninsured Americans are hospitalized, and 58% of the resulting bills total more than $10,000 each. On average, uninsured families can afford to pay only about 12% of potential hospital stays in full, and even families of four making up to $89,400 per year four times the federal poverty level would be unable to pay for most hospitalizations, HHS found. About 50 million Americans are uninsured, and their median family financial assets are about $20, the report said. State Smoke-Free Laws Jump More than half the states now prohibit smoking in indoor work areas, restaurants, and bars, an increase from zero states in 2000, according to the Centers for Disease Control and Prevention. However, regional disparities persist, especially in the South, where no state has adopted a law that prohibits smoking in all three venues, the CDC said. It s still possible for the United States to reach the Healthy People 2000 target of smoke-free indoor work sites in all 50 states by 2020, the report said. Tremendous progress has been made during the past decade to protect workers and patrons from the hazardous effects of secondhand smoke, the American Cancer Society Cancer Action Network said in a statement, but the organization called for more states to act quickly. Alicia Ault At doses higher than the recommended 20 mg TID, there was a greater incidence of some adverse events including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately colortinge to vision, but also increased sensitivity to light or blurred vision. The incidence of retinal hemorrhage at the recommended sildenafil 20 mg TID dose was 1.4% versus 0% placebo and for all sildenafil doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both the recommended dose and at all doses studied was 1.4% for sildenafil versus 1.4% for placebo. The patients experiencing these events had risk factors for hemorrhage including concurrent anticoagulant therapy. In a placebo-controlled fixed dose titration study of REVATIO (starting with recommended dose of 20 mg TID and increased to 40 mg TID and then 80 mg TID) as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, the adverse events that were reported were more frequent than in the placebo arm (>6% difference) are shown in Table 2. Table 2. REVATIO-Epoprostenol Adverse Events More Frequent (> 6%) than Placebo ADVERSE EVENTS % Headache Edema^ Dyspepsia Pain in extremity Diarrhea Nausea Nasal congestion ^includes peripheral edema Placebo Epoprostenol (n=70) Revatio 20 mg TID Epoprostenol (n=69) Placebo- Subtracted REVATIO Injection REVATIO injection was studied in a 66-patient, placebo-controlled study at doses targeting plasma concentrations between 10 and 500 ng/ml (up to 8 times the exposure of the recommended dose). Adverse events in PAH patients were similar to those seen with oral tablets. Postmarketing Experience The following adverse reactions have been identified during postapproval use of sildenafil (marketed for both PAH and erectile dysfunction). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Events In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient s underlying cardiovascular disease, or to a combination of these or other factors. Decreases in and Loss of Vision When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio ( crowded disc ), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors [see Warnings and Precautions]. Loss of Hearing Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including REVATIO. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of REVATIO, to the patient s underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions]. Other Events The following list includes other adverse events that have been identified during postmarketing use of REVATIO. The list does not include adverse events that are reported from clinical trials and that are listed elsewhere in this section. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous system: Seizure, seizure recurrence DRUG INTERACTIONS Nitrates Concomitant use of REVATIO with nitrates in any form is contraindicated [see Contraindications]. Ritonavir and other Potent CYP3A Inhibitors Concomitant use of REVATIO with ritonavir and other potent CYP3A inhibitors is not recommended [see Warnings and Precautions]. Alpha-blockers Use caution when co-administering alpha-blockers with REVATIO because of additive blood pressure-lowering effects [see Warnings and Precautions]. In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmhg, 9/5 mmhg, and 8/4 mmhg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmhg, 11/4 mmhg, and 4/5 mmhg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope. Amlodipine When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmhg systolic and 7 mmhg diastolic. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 68-times, respectively, the recommended human dose (RHD) of 20 mg TID. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis).there are, however, no adequate and well-controlled studies of sildenafil in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery The safety and efficacy of REVATIO during labor and delivery has not been studied. Nursing Mothers It is not known if sildenafil or its metabolites are excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when REVATIO is administered to a nursing woman. Pediatric Use Safety and effectiveness of sildenafil in pediatric pulmonary hypertension patients have not been established. Geriatric Use Clinical studies of REVATIO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied. Renal Impairment No dose adjustment is required (including severe impairment CLcr < 30 ml/min). OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and female rats respectively, the human exposure at the RHD of 20 mg TID. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19 and 38 times for males and females, respectively, the human exposure at the RHD of 20 mg TID. PATIENT COUNSELING INFORMATION Inform patients of contraindication of REVATIO with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise patients taking REVATIO not to take VIAGRA or other PDE5 inhibitors. Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking REVATIO. Such an event may be a sign of NAION. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking REVATIO. These events may be accompanied by tinnitus and dizziness. RX only Revised: March 2011 RVU00253/ Pfizer Inc All rights reserved. Printed in USA/March 2011

44 Did you know REVATIO samples are just a phone call away? Order REVATIO Starter Samples by phone Contact the REVATIO Sample Fulfillment Program by calling Important Safety Information Do not use REVATIO in patients taking organic nitrates in any form, either regularly or intermittently. Consistent with its known effects on the nitric oxide/cgmp pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates. Before starting REVATIO, physicians should carefully consider whether their patients with underlying conditions could be adversely affected by the mild and transient vasodilatory effects of REVATIO on blood pressure. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary venoocclusive disease (PVOD) and administration of REVATIO to these patients is not recommended. Should signs of pulmonary edema occur when sildenafil is administered, the possibility of associated PVOD should be considered. Caution is advised when PDE5 inhibitors, such as REVATIO, are administered with α-blockers as both are vasodilators with blood pressure lowering effects. In PAH patients, the concomitant use of vitamin K antagonists and REVATIO resulted in a greater incidence of reports of bleeding (primarily epistaxis) versus placebo. The incidence of epistaxis was higher in patients with PAH secondary to CTD (sildenafil 13%, placebo 0%) than in PPH patients (sildenafil 3%, placebo 2%). Co-administration of REVATIO with potent CYP3A4 inhibitors, eg, ketoconazole, itraconazole, and ritonavir, is not recommended as serum concentrations of sildenafil substantially increase. Co-administration of REVATIO with CYP3A4 inducers, including bosentan; and more potent inducers such as barbiturates, carbamazepine, phenytoin, efavirenz, nevirapine, rifampin, and rifabutin, may alter plasma levels of either or both medications. Dosage adjustment may be necessary. Non-arteritic anterior ischemic optic neuropathy (NAION) has been reported post-marketing in temporal association with the use of PDE5 inhibitors for the treatment of erectile dysfunction, including sildenafil. It is not possible to determine if these events are related to PDE5 inhibitors or to other factors. Physicians should advise patients to seek immediate medical attention in the event of sudden loss of vision while taking PDE5 inhibitors, including REVATIO. Sudden decrease or loss of hearing has been reported in temporal association with the intake of PDE5 inhibitors, including REVATIO. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE5 inhibitors, including REVATIO. REVATIO should be used with caution in patients with anatomical deformation of the penis or patients who have conditions which may predispose them to priapism. The effectiveness of REVATIO in pulmonary hypertension (PH) secondary to sickle cell anemia has not been established. In a small, prematurely terminated study of patients with PH secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received REVATIO than by those randomized to placebo. REVATIO contains sildenafil, the same active ingredient found in VIAGRA. Combinations of REVATIO with VIAGRA or other PDE5 inhibitors have not been studied. Patients taking REVATIO should not take VIAGRA or other PDE5 inhibitors. Patients with the following characteristics did not participate in the preapproval clinical trial: patients who have suffered a myocardial infarction, stroke, or lifethreatening arrhythmia within the last 6 months, unstable angina, hypertension (BP >170/110), retinitis pigmentosa, or patients on bosentan. The safety of REVATIO is unknown in patients with bleeding disorders and patients with active peptic ulceration. In these patients, physicians should prescribe REVATIO with caution. The most common side effects of REVATIO (placebo-subtracted) were epistaxis (8%), headache (7%), dyspepsia (6%), flushing (6%), and insomnia (6%). Adverse events of REVATIO injection were similar to those seen with oral tablets. The most common side effects of REVATIO (placebo-subtracted) as an adjunct to intravenous epoprostenol were headache (23%), edema (14%), dyspepsia (14%), pain in extremity (11%), diarrhea (7%), nausea (7%), and nasal congestion (7%). Indication REVATIO is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise ability and delay clinical worsening. Delay in clinical worsening was demonstrated when REVATIO was added to background epoprostenol therapy. Studies establishing effectiveness included predominantly patients with NYHA Functional Class II-III symptoms and etiologies of primary pulmonary hypertension (71%) or pulmonary hypertension associated with connective tissue disease (25%). The efficacy of REVATIO has not been adequately evaluated in patients taking bosentan concurrently. Please see Brief Summary of Prescribing Information on the following pages. RVU00243A 2011 Pfizer Inc. All rights reserved. Printed in USA/March 2011