OPTIMIZING CLINICAL OUTCOMES MANAGING GI RISK IN THE ARTHRITIS PATIENT ON CHRONIC NSAID THERAPY

OPTIMIZING CLINICAL OUTCOMES MANAGING GI RISK IN THE ARTHRITIS PATIENT ON CHRONIC NSAID THERAPY pmicme Updates November, Rosemont, IL Faculty: Allan Gibofsky, MD, JD David A. Peura, MD Educational Partner: Innovations Consulting Group, LLC

Session : Optimizing Clinical Outcomes: Managing GI Risk in the Arthritis Patient on Chronic NSAID Therapy Learning Objectives. Discuss the importance of gastroprotection for at-risk patients who require nonsteroidal anti-inflammatory drug (NSAID) treatment for the relief of signs and symptoms of rheumatoid arthritis (RA) and osteoarthritis (OA).. Summarize current treatment guidelines for gastroprotection in patients receiving NSAIDs/selective cyclooxygenase- inhibitors (coxibs).. Describe the risks and benefits of different gastroprotective strategies.. Summarize the latest clinical trial results supporting the effectiveness of the combination therapies naproxen plus esomeprazole and ibuprofen plus famotidine.. Review case studies addressing important challenges in the management of patients who require NSAIDs and gastroprotection. Faculty Allan Gibofsky, MD, JD Professor of Medicine and Public Health Weill Medical College of Cornell University New York Dr Allan Gibofsky is professor of medicine and public health at the Weill Medical College of Cornell University, professor of law at Fordham University. He is an attending physician and rheumatologist at the Hospital for Special Surgery. Dr Gibofsky has authored or co-authored numerous papers and text chapters, primarily on rheumatic diseases and legal aspects of medical practice. Currently secretary-treasurer of the New York Rheumatism Association, Dr Gibofsky is past chair of the Medical and Scientific Committee of the New York Chapter of the Arthritis Foundation and is a recipient of their Physicians Leadership Award. He also served as a member of the local and national Arthritis Foundation Board of Trustees, and was chair for professional education. In, Dr Gibofsky served as president of the American College of Rheumatology. He is a member of the Health and Public Policy Committee of the American College of Physicians, past president of the American College of Legal Medicine, past chair of the American Board of Legal Medicine, and past chair of the Arthritis Advisory Committee of the Food and Drug Administration. David A. Peura, MD Emeritus Professor Department of Medicine, Division of Gastroenterology and Hepatology University of Virginia School of Medicine Charlottesville Dr David A. Peura is emeritus professor of medicine in the division of gastroenterology and hepatology at the University of Virginia School of Medicine in Charlottesville, Virginia. Throughout his career he has been actively involved in clinical investigation relating to acid peptic disorders, particularly peptic ulcer disease. He serves as a reviewer for most of the major medicine and gastroenterology subspecialty journals and has authored or co-authored more than original articles, book chapters, and reviews. Over the years, Dr Peura has held leadership positions in the major national gastroenterology organizations and received numerous commendations and awards for his contributions, including being selected as a master of the American College of Gastroenterology in, and fellow of the American Gastroenterologic Association (AGA) in. Dr Peura served as the th president of the AGA from to. He is an internationally recognized clinician and educator and a popular speaker in the area of upper gastrointestinal disease. Session

Faculty Financial Disclosure Statement The presenting faculty report the following: Allan Gibofsky, MD, JD, has received honoraria as an advisor from Horizon Pharma and AstraZeneca. He has received honoraria as an advisor and a speaker from Abbott, Amgen, UCB, and Genentech. David A. Peura, MD, has received consulting fees from Horizon Pharma and AstraZeneca. He has received consulting and speaker fees from Takeda. Education Partner Financial Disclosure Statement The content collaborators at Innovations Consulting Group, LLC report the following: Robert Rhoades, PhD, Medical Director, has no financial relationships to disclose. Valorie J. Thompson, President, has no financial relationships to disclose. Acronym List Acronym Definition Acronym Definition NSAID nonsteroidal anti-inflammatory drug OTC over the counter OA osteoarthritis UGI upper gastrointestinal coxib selective cyclo-oxygenase- inhibitor ASA aspirin PPI proton pump inhibitor H RA histamine- receptor ns non-specific antagonist PUB perforation, obstruction, bleeding CV cardiovascular GI gastrointestinal BID twice a day MTX methotrexate TID three times a day MI myocardial infarction RA rheumatoid arthritis PCI percutaneous coronary intervention Hgb hemoglobin SSRI selective serotonin reuptake inhibitor Suggested Reading List Lanas A, Tornero J, Zamorano JL. Assessment of gastrointestinal and cardiovascular risk in patients with osteoarthritis who require NSAIDs: the LOGICA study. Ann Rheum Dis. ;9(8):-8. Stockl K, Cyprien L, Chang EY. Gastrointestinal rates among managed care patients newly started on cox- inhibitors or non-selective NSAIDs. J Manag Care Pharm. ;(7):-8. Taha AS, Hudson N, Hawkey CJ, et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med. 99;():-9. vansoest EM, Valkhoff VE, Mazzaglia G, et al. Suboptimal gastroprotective coverage of NSAID use and the risk of upper gastrointestinal bleeding and ulcers: an observational study using three European databases. Gut. June (Epub ahead of print). Weinblatt ME, Schiff M, Genovese M, et al. Significant reduction in upper gastrointestinal (UGI) ulcers with HZT-, a single-tablet combination of ibuprofen-famotidine, the REDUCE and Trials. Ann Rheum Dis. 9;8(Suppl ):7. Session

Faculty Optimizing Clinical Outcomes Managing GI Risk in the Arthritis Patient on Chronic NSAID Therapy Allan Gibofsky, MD, JD Professor of Medicine and Public Health Weill Medical College of Cornell University Attending Rheumatologist Hospital for Special Surgery New York, NY David A. Peura, MD Emeritus Professor Department of Medicine Division of Gastroenterology and Hepatology University of Virginia School of Medicine Charlottesville, VA Faculty Disclosures Drug List The presenting faculty has reported the following: - Allan Gibofsky, MD, JD has received honoraria as an advisor from Horizon Pharma, Astra Zeneca; advisor and speaker fees from Abbott, Amgen, UCB, Genentech - David A. Peura, MD has received consulting fees from Horizon Pharma and Astra Zeneca; consulting and speaker fees from Takeda Generic Name acetaminophen aspirin/asa celecoxib cimetidine clopidogrel diclofenac esomeprazole etodolac etoricoxib famotidine fenbufen flurbiprofen ibuprofen ibuprofen + famotidine indomethacin ketoprofen lansoprazole Trade Name Tylenol various Celebrex Tagamet Plavix Voltaren, various Nexium Lodine Arcoxia (not available in US) Pepcid Lederfen, various Ansaid Motrin, various Duexis Indocin Orudis, various Prevacid Drug List Objectives Generic Name mefenamic meloxicam misoprostol nabumatone naproxen naproxen + esomeprazole magnesium nizatidine omeprazole pantoprazole piroxicam rabeprazole ranitidine sulindac tenoxicam tiaprofenic acid tramadol Trade Name Ponstel Mobic Cytotec Relafen Anaprox, various Vimovo Axid Prilosec, Losec Protonix Feldene Aciphex Zantac Clinoril Mobiflex (available in UK) Tiaprofen, Surgam Ultram. Discuss the importance of gastroprotection for at-risk patients who require nonsteroidal anti-inflammatory drug (NSAID) treatment for the relief of signs and symptoms of rheumatoid arthritis (RA) and osteoarthritis (OA). Summarize current treatment guidelines for gastroprotection in patients receiving NSAIDs/selective cyclo-oxygenase- inhibitors (coxibs). Describe the risks and benefits of different gastroprotective strategies. Summarize the latest clinical trial results supporting the effectiveness of the combination therapies, naproxen plus esomeprazole and ibuprofen plus famotidine. Review case studies addressing important challenges in the management of patients who require NSAIDs and gastroprotection

Question Pre-?/Post-? Question Pre-? / Post-? Which of the following is/are effective ways to reduce risk of NSAID associated ulcers?. Buffer the NSAID or give with an antacid. Give NSAID with a high-dose H RA. Give NSAID with a PPI. and are effective. All are effective. Unsure A number of factors have been identified as increasing the risk for NSAID-associated ulcer complications. Which of the following has NOT been confirmed as a risk factor:. Age > 7 y. Past history of uncomplicated ulcer. H pylori infection. SSRI use. Clostridium difficile infection. None of the above they are all risk factors 7. Unsure Question Pre-?/Post-? Question Pre-?/Post-? In a patient who takes aspirin for cardiovascular (CV) prophylaxis, which strategy is best to reduce the risk for an NSAID related upper gastrointestinal (UGI) complication?. Use celecoxib with a buffered aspirin. Use an NSAID and a high-dose H RA. Use an NSAID and a PPI. Both and. All are appropriate. Unsure The benefit of proton pump inhibitors (PPIs) in the prevention of NSAID induced gastric ulcers has been confirmed; however, PPIs have also been associated with the following risks:. Hip fracture. Community acquired pneumonia. Community acquired clostridium difficile. and. All of the above. Unsure Prevalence of Selected Musculoskeletal Conditions in the United States The Size of the Problem Prevalence Rate per, Osteoarthritis Arthritis and other musculoskeletal conditions affect more than 9,, people in the United States 8 Rheumatoid Arthritis 89 Ankylosing Spondylitis Psoriatic Arthropathy Sacks JJ, et al. Arthritis Care & Res. ;:-.

GI and CV Risk Factors Are Common in Patients With Arthritis Use of Nonsteroidal Anti-inflammatory Drugs in the US CV disease Coronary heart disease Stroke Heart failure High blood pressure Hypercholesterolemia Diabetes 8 8 Baseline CV-GI risk factors in patients with osteoarthritis and rheumatoid arthritis in the United States In, individuals in the United States spent >$. billion on over-the-counter (OTC) NSAIDs and filled > million NSAID prescriptions Most commonly used OTC analgesics: - Aspirin - Acetaminophen - Ibuprofen Smoking Peptic ulcer Prevalence (%) NHANES III. Available at: http://www.cdc.gov/nchs/about/major/nhanes/nhdata.htm. Accessed 8//. Gaziano JM. Am J Cardiol. ;97:-. Ulcers in Patients Taking NSAIDs The Severity of the Problem Endoscopically-demonstrable ulcers develop in -% of regular NSAID users and the annual rate of upper GI (UGI) clinical events is approximately.-.%: - Only a minority of patients who have serious gastrointestinal complications report any antecedent dyspepsia - In a study of patients with serious gastrointestinal complications, the proportion of patients with prior symptoms was.7% versus.% for those with no symptoms. Laine L. J Cardiovasc Pharmacol. ;7 (Suppl ):S-S.. Wolfe MM, et al. N Engl J Med. 999;:888-899.. Singh G, et al. Arch Intern Med. 99;:-. GI Bleeding in NSAID Users Estimated Mortality Attributable to NSAID/aspirin-associated GI Complications Inpatient Hospitalization or Primary Diagnosis for GI Bleed on Medical Claims (per,) 8 NSAID Coxib 9. Total Population (N=,7).8 7.7 Low Risk (N=,).7.8 High Risk (N=,7) Mortality Rate per Million People. Spain.7 United Kingdom Entire Country Population 9..8 United States Spain United Kingdom NSAID/aspirin Users United States Stockl K, et al. J Manag Care Pharm. ;:-8. Lanas A, et al. Am J Gastroenterol. ;:8-9.

Lack of Symptoms Does Not Mean Patients Are Safe What Are the Risk Factors for NSAID-Associated Ulcer Complications? Results for consecutive patients with a life threatening complication of peptic ulceration, who either died or required emergency surgery: - 78 patients died ( at home, 9 in hospital without surgery, and postoperatively) - 98 patients had bleeding ulcers - had perforated ulcers - had both bleeding and perforated ulcers of the patients (%) were taking an NSAID: - Nearly 8% of all ulcer related deaths occurred in patients using an antiinflammatory agent - The first sign of an ulcer was a life threatening complication in 8.% of patients taking a NSAID Armstrong CP, et al.. Gut. 987;8:7-. Other Patient/ Treatment Characteristics NSAID Dose Low Medium High Anticoagulants Corticosteroids Previous Ulcer w/ Complication Previous Ulcer w/o Complication Age 7-8 -9-9 -9. Hernandez-Diaz S, et al. Arch Intern Med. ;:9-99.. Garcia-Rodriguez LA, Jick H. Lancet. 99;:79-77..... (Reference)....9. Relative Risk for Upper GI Bleeding Risk Stratification for NSAID-related GI Toxicity GI Risk Varies According to Type and Dose of NSAID High Risk History of a previously complicated ulcer, especially a recent flare-up More than risk factors Moderate risk (- risk factors) Age > years High-dose NSAID therapy History of uncomplicated ulcer Concurrent use of aspirin (including low dose), corticosteroids, or anticoagulants Low risk No risk factors Helicobacter pylori is an independent risk factor and needs to be addressed separately Relative risk (current use vs. nonuse) 7 Risk of ulcer complications. Naproxen > Aspirin > Ibuprofen > Acetaminophen (a non-nsaid)* Dose related....8.......7...9.. Lanza FL, et al. Am J Gastroenterol. 9;:78-78. García-Rodríguez LA, et al. Epidemiology. ;:7-7. Hernández-Díaz S, et al. Arch Intern Med. ;:9-99. de Abajo FJ, et al. BMC Clin Pharmacol. ;:. * Statistical significance was not reported Substitute Acetaminophen Approaches to the Problem: Risk Reduction

Risk for Upper GI Complications With Acetaminophen Acetaminophen Versus NSAIDs: Efficacy and Patient Preferences Relative Relative Risk Risk for Upper GI GI Complication Non-Use.7*.9*.*.9 Current Use < g/day g/day g/day (all) Acetaminophen Use Meta-analysis: randomized, controlled trials in osteoarthritis - Acetaminophen less effective overall vs. NSAIDs for Pain reduction Stiffness Function Patient and investigator global assessments Patient preferences considering side effects and effectiveness % Acetaminophen % No preference NSAIDs % N = 799 patients with OA, RA, and fibromyalgia *P <. vs reference based on 9% CI. Garcia Rodríguez LA, Hernández-Díaz S. Arthritis Res. ;:98-. Towheed TE, et al. Cochrane Database Syst Rev. ;. Wolfe F, et al. Arthritis Rheum. ;:78-8. Adding a Gastroprotective Agent Prevention of NSAID Gastric and Duodenal Ulcers: Addition of PPI -week Ulcer Incidence (%). * *. Placebo (n=) Misoprostol µg (n=) * * * 7. Lansoprazole mg (n=) *. Lansoprazole mg (n=) *P<. vs placebo Graham DY, et al. Arch Intern Med. ;:9-7. PPI Outcomes Prevention: Recurrent Ulcer Bleeding in High-risk Patients Adding an H RA to a Conventional NSAID Non-ASA Ulcers* ASA ulcers* 8.8.8 8 8 8.. Control Omeprazole Control Lansoprazole P=. P=.8 *Helicobacter pylori eradicated. Chan FK, et al. N Engl J Med. ;:97-97.. Lai KC, et al. N Engl J Med. ;:-8. Percent of Patients Percent of Patients Cumulative Ulcer Incidence (%) 9 P=. P=. Gastric + Duodenal Ulcer Taha A, et al. N Engl J Med. 99;:-9. NSAID + Placebo (n=9) NSAID + Famotidine mg bid (n=9) NSAID + Famotidine mg bid (n=97) P=. P=. P=. 8 P=. Gastric Ulcer Duodenal Ulcer

Fracture Risk with PPIs and H RAs Pneumonia Risk with PPI and H RA Adjusted Odds Ratio for Hip Fracture........... (9% CI=.-.9) PPI. (9% CI=.-.9) H RA Relative Risk for Communityacquired Pneumonia...9.8.7... (9% CI=.-.) PPI (9% CI=.8-.).98 H RA Yang Y-X, et al. JAMA. ;9:97-9. Rodriguez LA, et al. Epidemiology. 9;:8-8. Clostridium difficile Infection with PPI and H RA Substituting a Coxib for a Conventional NSAID Rate Ratio for Cases Versus Controls.8....8....9 (9% CI=.-.) (9% CI=.-.7). (9% CI=.-.) NSAID H RA PPI Dial S, et al. JAMA. ;989-99. MEDAL Study Perforation, Symptomatic Ulcer, Bleed CLASS Trial: Upper GI Complications Alone and With Symptomatic Ulcers (-month results) Cumulative Incidence, % (9% CI)..8.....8.....8... Etoricoxib and 9 mg pooled (7 events) Diclofenac mg ( events) Etoricoxib vs diclofenac HR=.9 (9% CI:.7,.8) 8 Months Patients at risk Etoricoxib 7,,7,97 8 9 8 Diclofenac 7,89,9,9 87 87 8 GI = gastrointestinal; PUB = perforation, symptomatic ulcer, bleeds; mitt = modified intention-to-treat; CI = confidence interval; HR = hazard ratio Cannon CP, et al. Lancet. ; 8: 77 8 P<. Annualized Incidence % All Patients P=.9..7 Patients Not Taking Aspirin P=....7 Patients Taking Aspirin. Ulcer Complications Silverstein FE, et al. JAMA. ; 8:7-. NSAIDs (ibuprofen + diclofenac) P=.9 Celecoxib P=...8. P=..9 P=.9.9.7 Symptomatic Ulcers and Ulcer Complications

Update on GI Safety of Coxibs High-risk Patients with Recent NSAID Ulcer Bleed: Comparison of Coxib vs nsnsaid Plus PPI Cochrane Systematic Review Relative Risk (9% CI) COX- inhibitors vs nsnsaids Endoscopically detected ulcers ( studies). (.,.) Clinically important PUBs (8 studies).9 (.,.) COX- inhibitors + concomitant aspirin vs nsnsaids ( studies) Clinically important PUBs.89 (.,.) Percent of Patients Single Trial, RR =.77 (.-.).9 Celecoxib Diclofenac + Omeprazole. RR =.7 (.-.8) 9.. ns = nonselective, PUBs = perforation, obstruction, bleeding, or the presence of symptomatic ulcers. Bleeding ulcers Endoscopic ulcers Rostom A, et al. Clin Gastroenterol Hepatol. 7;:88-88.. Chan FK, et al. Gastroenterology. ;7:8-.. Chan FK, et al. N Engl J Med. ;7:-. Recurrent Ulcer Bleeding with Coxib plus PPI vs Coxib Alone Results of a single center RCT comparing esomeprazole mg BID vs placebo added to celecoxib mg BID in high-risk patients Recurrent Ulcer Bleeding During Treatment or Within Month of The End of Treatment 9 8 7 8.9 Celecoxib P=. Celecoxib + PPI Current Guidelines: What the Experts Suggest Chan FK, et al. Lancet. 7;9:-. American College of Rheumatology Osteoarthritis Society International 8 Exercise, weight-loss, self-management programs, aids Acetaminophen NSAIDs: oral (age <7 years) or topical (age 7 years) - If GI risk, selective COX- inhibitor or nonselective NSAID+PPI or selective COX- inhibitor + PPI - If low dose aspirin, nonselective NSAID+PPI Suggest not to use oral NSAIDs if patient 7 years of age Tramadol Intra-articular steroid or hyaluronate Acetaminophen (up to g/d) NSAIDs should be used at the lowest effective dose but their long-term use should be avoided if possible - in patients with increased GI risk, either a COX- selective agent or a nonselective NSAID with co-prescription of a PPI or misoprostol for gastroprotection may be considered - NSAIDs, including both nonselective and COX- selective agents, should be used with caution in patients with CV risk factors Weak opioids and narcotic analgesics can be considered - stronger opioids should only be used for the management of severe pain in exceptional circumstances - nonpharmacologic therapies should be continued in such patients and surgical treatments should be considered ACR. Arthritis Care Res ; (as reported at annual ACR 9) Zhang W, et al. Osteoarthritis Cartilage 8;:7 Evidence update Zhang W et al. Osteoarthritis Cartilage ;8:7 7

Management Algorithm for OA Patients with Comorbidities (American College of Gastroenterology) Case Study NSAID alone the least ulcerogenic at the lowest effective dose Assess for CV Risk Low CV Risk NSAID + PPI/ misoprostol Assessment Education Information Nonpharmacologic Core Therapies Acetaminophen Consider Topical NSAID Assess for GI risk Low Moderate High Low Moderate Alternative therapy if possible or COX- + PPI/ misoprostol Naproxen + PPI/ misoprostol *Low-dose aspirin required; GI risk is stratified into low (no risk factors), moderate (presence of or risk factors), and high (multiple risk factors, or previous ulcer complications, or concomitant use of corticosteroids or anticoagulants). High CV Risk* Naproxen + PPI/ misoprostol High Avoid NSAIDs or COX-; use alternative therapy -year-old white woman with OA of both knees and chronic pain ( on a -point visual analog scale) that is not effectively managed with up to g/day acetaminophen. The patient has no history of cardiovascular disease, but is taking a bisphosphonate for osteoporosis. She self-manages her pain with over-the-counter ibuprofen or naproxen but continues to have joint pain. She presents to her primary care physician with abdominal pain and dyspepsia. Adapted from Lanza FL, et al. Am J Gastroenterol. 9;:78-7. Question? Case Study (cont d) What is the next step?. Switch OTC NSAID to Rx dose. Switch to opiate until her dyspepsia improves. Test her for H. pylori. Add an H RA and stop her NSAIDs. Add a PPI and continue her NSAIDs. Refer her for endoscopy The patient is referred to a gastroenterologist for endoscopy. This evaluation reveals several gastric ulcers ranging from - mm in diameter. Biopsies for H pylori are negative. Question? What are your treatment options for her?. Heal the ulcer with a PPI and avoid future NSAIDs. Heal ulcer with a PPI and restart NSAID with gastroprotective therapy (H RA, PPI or misoprostol) to prevent ulcer recurrence. Switch to coxib since ulcer will heal by itself on this safer class of NSAIDs. Switch to opiate since ulcer will heal when NSAID is discontinued Addressing Adherence with Risk Reduction 8

Adherence to Guidelines for Prescribing NSAIDs According to GI Risk Adherence to Gastroprotective Therapy in Patients Prescribed NSAIDs Adherent (%) < % of patients at GI risk are optimally managed 7 At least risk factor (n =,787) At least risk factors (n =,) or more risk factors (n = ) Risk factors: Age years Concomitant corticosteroid use Concomitant anticoagulant use History of upper GI events High average daily dose Percent of Patients Nonadherent to Gastroprotective Treatment* 9 8 7..8 7.9 9..7. *Nonadherence was defined as lack of co-therapy for gastroprotection on <7% of days on which NSAIDs were prescribed 7 Abraham NS, et al. Gastroenterology. ;9:7-78. Sturkenboom MCJM, et al. Aliment Pharmacol Ther. ;8:7-7. Number of Medications Negatively Affects Adherence Combination Naproxen-Esomeprazole Odds Ratio for Adherence to Antihypertensive and Lipid-lowering Therapy..8... P<..9 P<.... - Number of Additional Prescription Medications Chapman RH, et al. Arch Intern Med. ;:7-. P<. P<. (Reference) Overview of Two Pivotal Trials Approximately subjects entered into each trial and randomized to receive either combination naproxen-esomeprazole or entericcoated naproxen mg BID Subjects underwent upper endoscopies at baseline and at,, and months Primary endpoint: cumulative incidence of gastric ulcers* through months Results showed that significantly fewer subjects taking the combination naproxen-esomeprazole experienced endoscopically confirmed gastric ulcers compared to subjects receiving naproxen alone * mm in diameter with depth Pozen Inc. http://www.pozen.com/product/pn.asp. Goldstein JL, et al. Ann Rheum Dis ;9(Suppl):87 Combination Naproxen-Esomeprazole: Study Results Combination Ibuprofen-Famotidine vs Ibuprofen Alone: REDUCE- and REDUCE- Percent with Gastric Ulcers* P<.. Naproxen-Esomeprazole. P<.. 7. Naproxen n= n= n=8 n=9 Study Study * mm in diameter with depth Goldstein JL, et al. Ann Rheum Dis ;9(Suppl):87 Objective: to determine if a single-tablet combination of ibuprofen (8 mg) and famotidine (. mg) will significantly decrease ulcers compared to ibuprofen alone REDUCE- and REDUCE- randomized 8 and 7 patients, respectively, in a : ratio to single tablet combination of ibuprofen-famotidine or identicalappearing ibuprofen 8 mg tablets TID Endoscopies were done at 8,, and weeks Primary endpoint: incidence of gastric and duodenal ulcers* at weeks * mm in diameter with significant depth Laine LA, et al. Oral presentation at Digestive Disease Week, 9. Laine LA, et al. Oral presentation at: Digestive Disease Week; May -June, 9; Chicago, Illinois. 9

Combination Ibuprofen-Famotidine vs Ibuprofen Alone: Results of REDUCE- and REDUCE- Patients (%) 9.8* Gastric Ulcers..* Duodenal Ulcers 9.7 HZT- (n=8) Ibuprofen TID (n=7) 7.9* Gastric Ulcers.8.7* Duodenal Ulcers REDUCE- (N = 8) REDUCE- (N = 7) Ulcers were defined as being mm in diameter with significant depth Laine LA, et al. Oral presentation at: Digestive Disease Week; May -June, 9; Chicago, Illinois. *P<. Reduction in Upper GI Ulcers with Combination Ibuprofen-Famotidine in Patients Using Low-dose Aspirin (LDA) Incidence of Upper GI Ulcers From Ibuprofen in Patients Using LDA Patients (%) The use of aspirin and the combination of ibuprofen-famotidine may increase the risk of adverse events. With concomitant use of LDA and ibuprofen, it is recommended that aspirin be taken at least minutes before ibuprofen. Catella-Lawson F, et al. N Engl J Med. ;:89. MacDonald T, et al. Lancet. ;:7. Weinblatt ME, et al. Poster [9] presented at ACR. Ibuprofen (n=79) Ibuprofen-Famotidine (n=) Safety Information: Combination Naproxen-Esomeprazole and Combination Ibuprofen-Famotidine Warning: Cardiovascular and Gastrointestinal Risks - Cardiovascular Risk Naproxen, a component of the combination tablet of naproxen-esomeprazole, and, ibuprofen, a component of the combination tablet of ibuprofen-famotidine, may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. The combination products of naproxen-esomeprazole and ibuprofen-famotidine are contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Product labeling; www.fda.gov Safety Information: Combination Naproxen-Esomeprazole and Combination Ibuprofen-Famotidine Warning: Cardiovascular and Gastrointestinal Risks - Gastrointestinal Risk NSAIDs, including naproxen, a component of the combination tablet of naproxen-esomeprazole, and, ibuprofen, a component of the combination tablet of ibuprofen-famotidine, may cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events. Product labeling; www.fda.gov Case Study Question? 7-year-old black man with RA being treated with methotrexate (MTX) and etanercept. The patient has a history of MI with PCI and stenting and is taking aspirin ( mg/day) plus clopidogrel (7 mg/day). The patient is currently taking naproxen ( mg bid) for management of pain associated with RA. He has been prescribed lansoprazole for protection against UGI events, but often forgets to take it if he does not have any GI symptoms. He also has intermittent diarrhea believed to be related to treatment with MTX and etanercept. He presents to his rheumatologist for routine follow up and is noted to have a Hgb of 7. g/dl. What is the next step?. Check stools for occult blood. Start iron and see how his Hgb responds. Barium small bowel x-rays to exclude Crohn s disease in view of his diarrhea. Refer for colonoscopy to evaluate anemia. Refer for both endoscopy and colonoscopy. Refer for upper endoscopy only

Case Study (cont d) Question? The patient is referred for both endoscopy and colonoscopy. The colonoscopy is normal but the endoscopy shows a large deep pre-pyloric ulcer ( mm in diameter). Biopsies for H pylori are negative. How do you manage him now?. Heal the ulcer and avoid future NSAIDs. Heal the ulcer and start a coxib. Heal the ulcer and restart therapy with either individual tablets of PPI and NSAID or a single tablet combination product of PPI-NSAID product to reduce ulcer recurrence. Heal the ulcer and restart therapy with either individual tablets of H RA and NSAID or a single tablet combination H RA- NSAID product to reduce ulcer recurrence. Heal the ulcer and restart NSAID with a combination misoprostol NSAID product to reduce ulcer recurrence Risk of AMI and SCD With Current Use of COX- Selective and Nonselective NSAIDs Risk Reduction: Cardiovascular Implications Adjusted Odds Ratio (9% CI)........ P<.. (.-8.7) P=..9 P=. (.97-.9) P=..9 P<...8..8.9 (.9-.79). (.9-.) (.-.) (reference) (.9-.7) (.99-.) (.-.) Control Celecoxib Ibuprofen Naproxen Rofecoxib Rofecoxib Other Indomethacin Diclofenac (remote use) mg > mg NSAIDs AMI = acute myocardial infarction, SCD = sudden cardiac death Adjusted for age, sex, health plan region, medical history, smoking, and medication use Graham DJ, et al. Lancet. ;:7-8. Cardiovascular Risk with Higher Dose Celecoxib ( mg bid) Factors Associated with Increased Risk for CV Events during Treatment with NSAIDs/coxibs 8 years of age Any CV Event CV Death, nonfatal MI, stroke, HF, TE, angina, CV Procedure CV Death, nonfatal MI, stroke, HF, TE, angina CV Death, nonfatal MI, Stroke, HF, TE CV Death, Nonfatal MI, Stroke, HF CV Death, Nonfatal MI, Stroke CV Death or Nonfatal MI.......9* Hypertension Prior myocardial infarction Prior cardiovascular disease Rheumatoid arthritis Chronic obstructive pulmonary disease Chronic renal disease CV Death.7 * P<. based on 9% CI. CV = cardiovascular, MI = myocardial infarction, HF = heart failure, TE = thromboembolic event Hazard Ratio Solomon SD, et al. Circ. 8;7:-. Beaulieu M, et al. Am J Manage Care. ;:9-7. Solomon DH, et al. Arthritis Rheum. 8;9:97-.

Ibuprofen: Cardiovascular Data Interaction with Aspirin Interaction Between NSAIDs/coxibs and Aspirin January Ibuprofen reported to block aspirin from binding to platelets in vitro potentially reducing cardioprotective effects February Retrospective analysis of 77 patients showed patients taking ibuprofen + ASA had higher mortality than those taking ASA alone or aspirin plus other NSAIDs (adjusted hazard ratio.9, 9% CI.-.87, P=.) Recommend separating dosing of aspirin and NSAID if combination must be used NSAID/Coxib Ibuprofen Indomethacin Naproxen Tiaprofenic acid Sulindac Celecoxib Interference with Antiplatelet Effects of Aspirin Yes Yes Yes Yes No No Catella-Lawson F, et al. N Engl J Med. ;:89. MacDonald T, et al. Lancet. ;:7. Gladding PA, et al. Am J Cardiol. 8;:-. PPI-Clopidogrel Interaction: Platelet Aggregation PPI-Clopidogrel Interaction: Clinical Consequences Mean Maximal Platelet Aggregation Clopidogrel P<..8 Siriswangvat S, et al. Circ J. ;7:87-9..7 Omeprazole Clopidogrel + PPI P=. 8.. Rabeprazole Cumulative Risk of All-Cause Mortality and Recurrent ACS Among Patients Taking Clopidogrel After Hospital Discharge for ACS and Prescribed a PPI at Hospital Discharge or During Follow-up (n=) Proportion of Deaths or Recurrent ACS.7...... 9 Ho M, et al. JAMA. 9;:97-9. Neither clopidogrel nor PPI PPI without clopidogrel Clopidogrel + PPI Clopidogrel without PPI 8 7 7 8 9 99 8 Period Since Discharge, d PPI-Clopidogrel Interaction: Clinical Consequences Analysis Association between acid-reducing therapies and recurrent MI within 9 days after hospital discharge for acute MI Cases n/n Controls n/n Odds Ratio for Recurrent MI (9% CI) PPI + Clopidogrel Recurrent MI (<9 days) Current PPI 9/7 /7.7 (.-.7) Risk Reduction and Cardiovascular Implications: What the Experts Say Previous PPI /7 9/7.8 (.-.9) Remote PPI 7/7 8/7.8 (-.) PPI without Clopidogrel 8/7 /7,9. (.7-.7) H RA 7/7 /7.9 (.-.) Juurlink DN, et al. CMAJ. 9;8:7-78.

Balancing GI and Cardiovascular Risks of NSAID Therapy First International Working Party on Gastrointestinal and Cardiovascular Effects of Nonsteroidal Anti-inflammatory Drugs and Anti-platelet Agents Cardiovascular Risk Low (no aspirin) GI Risk Low Medium High Nonselective NSAID alone High (aspirin) Naproxen + PPI/misoprostol Nonselective NSAID + PPI/misoprostol Naproxen + PPI/misoprostol Coxib + PPI/misoprostol Avoid NSAID or Coxib if possible Average Cardiovascular Risk High Cardiovascular Risk Average GI Risk High GI Risk Nonselective NSAID alone Nonselective NSAID + PPI/misoprostol or Coxib + PPI/misoprostol Naproxen (if not on aspirin) Naproxen + PPI/misoprostol (if on aspirin) Avoid NSAIDs if possible Naproxen + PPI/misoprostol (irrespective of concomitant aspirin use) High GI risk was defined as age 7 years, prior upper GI event, and concomitant use of concomitant aspirin, corticosteroids, or anticoagulants High cardiovascular (CV) risk was defined as established coronary artery disease, any CV disease that required prophylactic low-dose aspirin, or an estimated -year CV risk >% Graham DY, Chan FK. Gastroenterology. 8;:-. Chan FKL, et al. Am J Gastrointerol. 8;:98-98. Question Pre-?/Post-? Question Pre-? / Post-? Which of the following is/are effective ways to reduce risk of NSAID associated ulcers?. Buffer the NSAID or give with an antacid. Give NSAID with a high-dose H RA. Give NSAID with a PPI. and are effective. All are effective. Unsure A number of factors have been identified as increasing the risk for NSAID-associated ulcer complications. Which of the following has NOT been confirmed as a risk factor:. Age > 7 y. Past history of uncomplicated ulcer. H pylori infection. SSRI use. Clostridium difficile infection. None of the above they are all risk factors 7. Unsure Question Pre-?/Post-? Question Pre-?/Post-? In a patient who takes aspirin for cardiovascular (CV) prophylaxis, which strategy is best to reduce the risk for an NSAID related upper gastrointestinal (UGI) complication?. Use celecoxib with a buffered aspirin. Use an NSAID and a high-dose H RA. Use an NSAID and a PPI. Both and. All are appropriate. Unsure The benefit of proton pump inhibitors (PPIs) in the prevention of NSAID induced gastric ulcers has been confirmed; however, PPIs have also been associated with the following risks:. Hip fracture. Community acquired pneumonia. Community acquired clostridium difficile. and. All of the above. Unsure

Conclusion NSAIDs are used extensively for treatment of chronic pain, including that associated with OA and rheumatoid arthritis NSAIDs increase risk for ulcers, but this risk can be decreased by gastroprotective strategies, including H RAs, PPIs, or misoprostol Research has confirmed that < % of patients at risk for NSAID induced ulcers are optimally managed with gastroprotective therapy. Fixed-dose combinations of NSAIDs and gastroprotective agents may theoretically improve adherence and decrease ulcer risk NSAID/coxib treatment may increase risk for cardiovascular events, and this risk should influence treatment decisions