TABLE OF CONTENTS - ADA, ACCORD

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1 TABLE OF CONTENTS Practice Guideline Updates - ADA, Immunization, and Perioperative Beta-Blockade 1-4 Literature Update - ACCORD and JUPITER 4-6 P&T Committee Formulary Actions 7 American Diabetes Association 2010 Clinical Practice Recommendation Each January the American Diabetes Association (ADA) publishes clinical practice recommendations for the medical care of diabetes. The 2010 ADA clinical practice recommendations include the following changes: a new section on cystic fibrosis-related diabetes, inclusion of A1C as a criteria for diagnosis of diabetes and a predictor of risk for future diabetes, and revisions to sections on gestational diabetes, diabetes self-management education, antiplatelet therapy, retinopathy screening, inpatient glycemic control, and diabetes care strategies. The summary below addresses the 2010 ADA standards for glycosylated hemoglobin (A1C) criteria for diabetes diagnosis, antiplatelet therapy, and inpatient glycemic control. Diabetes diagnosis The diagnosis of diabetes traditionally is made when 1 of 3 of the following criteria are met on 2 separate days: fasting plasma glucose (FPG) 126 mg/dl, a 2-hour plasma glucose 200 mg/dl with an oral glucose tolerance test (OGTT), or a casual plasma glucose 200 mg/dl with symptoms of diabetes. Added to the criteria in this year s practice recommendations is A1C. A diagnosis of diabetes can be established when the A1C is 6.5% and it is confirmed on a separate day with a repeat A1C, a FPG, or an OGTT. Advantages of the A1C test include easier collection compared to FPG and less susceptibility to daily variations in glucose levels and acute illness. Previous recommendations have not included A1C as a diagnostic option due to the lack of standardization of the assay. However, assays are now considered highly standardized and only those that are certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized to the Diabetes Control and Complication Trial reference assay should be used to determine A1C. The A1C should not be used as a diagnostic tool for patients with hemolytic anemia and iron deficiency due to abnormal red cell turnover that renders the test inaccurate. On the other hand, specific A1C assays can be used for patients with hemoglobin variants such as HbS (sickle cell trait). A list of assays with information regarding interference from various hemoglobin variants can be found at Impaired fasting glucose (IFG), defined as FPG between mg/dl, and impaired glucose tolerance (IGT), defined as an OGTT between mg/dl, have been identified as risk factors for the development of diabetes. In addition to IFG and IGT, an A1C level between 5.7% to 6.4% is now considered a risk factor for future diabetes. Antiplatelet therapy Historically, aspirin has been used for primary prevention of cardiovascular disease (CVD) for patients with diabetes over the age of 40 or with other CVD risk factors, such as smoking, hypertension, family history of CVD, hyperlipidemia, and albuminuria. However, recent studies, such as the Anti-Thrombotic Trialists (ATT) collaboration s meta analysis, the prevention of progression of arterial disease and diabetes (POPADAD) trial and the primary prevention project (PPP), have brought this practice into question. Overall, these studies did not demonstrate a significant primary preventive effect of aspirin on atherosclerotic events in all patients with diabetes. The ADA recommends low dose aspirin (75 to 162 mg/ day) for men > 50 years old and women > 60 years old who have type 1 or type 2 diabetes and a minimum of 1 other cardiovascular risk factor (smoking, dyslipidemia, hypertension, albuminuria, family history of CVD). These patients are estimated to have a 10-year risk of CVD of >10%. Aspirin 75 to 162 mg/day should continue to be used as secondary prevention in patients with a previous cardiovascular event. After an acute coronary syndrome, the use of aspirin in combination with clopidogrel is also supported by the ADA. The use of aspirin in men < 50 years old and women < 60 years old without other risk factors is not currently supported by clinical evidence 1

2 and therefore, is not recommended. Clinical judgment is advised in choosing antiplatelet therapy for patients of this younger age group with CVD risk factors. Inpatient Glycemic Control Both hyperglycemia and hypoglycemia in critically ill and non-critically ill patients, in the presence or absence of diabetes, are known to lead to poor outcomes. The intensity or level to which hyperglycemia should be controlled, however, has been controversial due to conflicting evidence of the impact on mortality for patients in the intensive care unit (ICU). Although early studies indicated improved patient outcomes, more recent and larger controlled studies have demonstrated either no improvement or an increase in mortality, and a higher risk of hypoglycemia with intensive glycemic control. The largest of these trials was the Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study that demonstrated an increase in mortality in over 6000 ICU patients with glycemic targets between 81 to 108 mg/dl compared to less intense control that targeted levels <180 mg/dl. Based on current evidence, the ADA supports controlling hyperglycemia in hospitalized patients within certain targets. Policies for inpatient glycemic targets can vary among institutions. However, glucose targets <110 mg/ dl are not recommended. For non-critically ill patients, the recommendations, based primarily on expert clinical judgment, are to target premeal glucose levels to <140 mg/dl and random glucose levels <180 mg/dl. For both populations, avoidance of hypoglycemia is of prime importance. Intravenous insulin for ICU patients and subcutaneous insulin for non-critically ill patients are recommended to help achieve these targets. For non-critically ill patients, scheduled use of basal and prandial insulin should be instituted with use of supplemental insulin to decrease premeal hyperglycemia. The use of sliding scale insulin as the sole treatment strategy to control hyperglycemia is not recommended due to lack of evidence demonstrating its efficacy and the potential for severe hypoglycemia or hyperglycemia in patients with type 1 diabetes. Other recommendations for management of hyperglycemia in the inpatient setting include: scheduled glucose monitoring for patients receiving therapies known to increase blood glucose including high-dose glucocorticoids, enteral or parenteral nutrition, octreotide, and immunosuppressants established action plans for treatment of hypoglycemic events tracking of hypoglycemic events follow-up care for patients identified with diabetes during hospitalization The addition of a laboratory test, A1C, to aid in the diagnosis of diabetes, the use of aspirin in select patients with diabetes, and less stringent glycemic targets for hospitalized patients with hyperglycemia are among the revisions to the 2010 ADA clinical practice recommendations for diabetes management. For a review of other revisions, the full practice recommendation can be viewed at Supplement_1. Immunization Schedules 2010 The Centers for Disease Control and Prevention (CDC) s Advisory Committee on Immunization Practices (ACIP) updates the recommendations for adult and childhood immunizations in January of each year. This year the document states that combination vaccines are preferred over giving injections separately. Changes to the schedules for children include: Inactivated poliovirus - the final dose of inactivated poliovirus should be administered on or after the fourth birthday (at least 6 months following the previous dose). Children who have received all 4 doses before age 4 should receive a fifth dose at age 4 through 6 years. Hepatitis A - the vaccine can be given to children older than 23 months who are at increased risk for infection or for whom immunity is desired. Meningococcal conjugate vaccine - revaccination is recommended for children who remain at increased risk for disease after 3 to 5 years depending on when the first dose was given. Human papillomavirus - quadrivalent vaccine can be given to boys aged 9 to 18 years to reduce their chance for contracting genital warts. The availability of the bivalent vaccine and recommendations for its use in girls are also included. The full document including the charts (ages 0 to 6 and 7 to 18) is available at: schedules/default.htm#child. The adult schedule has also been updated, specifically: Hepatitis A - unvaccinated persons who anticipate contact with an international adoptee should consider getting vaccinated. Meningococcal - the meningococcal conjugate vaccine is preferred for patients aged 55 years or younger, while the meningococcal polysaccharide vaccine is recommended for patients aged 56 and above. Human papillomavirus - quadrivalent vaccine can be given to males aged 9 to 26 years to reduce their chances for contracting genital warts (most effective prior to HPV exposure through sexual contact). The availability of the bivalent vaccine and recommendations for its use in women are also included (aged 19 through 26 years). Haemophilus influenza type b - this vaccine is generally not administered after age 5; however, it is acceptable to give 1 dose in patients 2

3 with sickle cell disease, leukemia, human immunodeficiency virus, or those who have had a splenectomy who have not previously received the vaccine. Hepatitis B - 3 dose schedule, second dose should be 1 month after the first, and third dose at least 2 months after second. Measles, mumps, rubella - unvaccinated healthcare workers born before 1957 who lack laboratory evidence of immunity or disease confirmation should be vaccinated with 2 doses; if an outbreak occurs, these workers should receive 2 doses (measles or mumps outbreak) or 1 dose (rubella outbreak). The full document including the chart is available at: Based on their recent committee meeting, ACIP will recommend annual influenza vaccination for everyone aged 6 months and above for the season. This would represent near universal vaccination of the population. These recommendations are typically published in July or August prior to the start of influenza season. The World Health Organization has recommended inclusion of the 2009 H1N1 strain in vaccines for next season. Update on Perioperative Beta-Blockade In November 2009, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) released a focused update on the perioperative use of beta-blockers. This update was released as a result of new data on the use of beta-blockers for patients undergoing surgery. The primary article that prompted this update was the POISE (PeriOperative ISchemic Evaluation) trial, the largest trial to date to evaluate the use of beta-blockers perioperatively for patients undergoing non-cardiac surgery. POISE Data The POISE study was a controlled trial that randomized 8351 patients who were undergoing noncardiac surgery to extended-release metoprolol succinate 100 mg (n=4174), started 2 to 4 hours before scheduled surgery, or placebo (n=4177). A second dose was given within 6 hours after surgery and, 12 hours after the first postoperative dose, patients began taking extended-release metoprolol succinate 200 mg daily or placebo for 30 days. Eligible patients had atherosclerotic disease (coronary artery disease [CAD], peripheral vascular disease, stroke), a heart failure hospitalization within the previous 3 years, or 3 of the following 7 risk criteria: undergoing intrathoracic or intraperitoneal surgery, history of heart failure, transient ischemic attack, diabetes, elevated serum creatinine, age >70 years, or undergoing emergent or urgent surgery. In addition, patients were undergoing major vascular surgery except arteriovenous shunt, vein stripping procedures, or carotid endarterectomies. Atherosclerotic cardiovascular disease was common with 83% of patients in the metoprolol group and 82% of patients in the placebo group having a history of CAD, peripheral vascular disease, or stroke. At the 30-day follow-up period, significantly fewer patients in the metoprolol group met the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal cardiac arrest (5.8% vs. 6.9%, p=0.04); this was primarily attributed to significantly fewer patients in the metoprolol group having an MI (4.2% vs. 5.7%, p=0.0017). Unfortunately, the investigators noted that there were more deaths (3.1% vs. 2.3%, p=0.0317) and stroke (1.0% vs. 0.5%, p=0.0053) in the metoprolol group than the placebo group. The use of metoprolol was also associated with more cases of clinically significant hypotension and bradycardia. The investigators concluded that use of perioperative beta-blockade is associated with benefits and risks and that practice guidelines that recommend beta-blocker therapy for patients undergoing non-cardiac surgery should reconsider their recommendations based on this new data. Revised recommendations The results of POISE and other recently published data prompted ACCF/AHA to release the following recommendations: Beta-blockers should be continued in patients undergoing surgery who were already receiving these agents for the treatment of conditions/indications advocated by the ACCF/AHA. Beta-blockers titrated to heart rate and blood pressure are probably recommended for patients undergoing vascular surgery (e.g., aortic surgery, peripheral vascular surgery) who are at high cardiac risk because they have CAD or have ischemia on perioperative testing. Beta-blockers titrated to heart rate and blood pressure are reasonable for patients who are going to have vascular surgery and have more than 1 clinical risk factor such as history of ischemic heart disease, heart failure, or cerebrovascular disease, diabetes, or renal impairment (serum creatinine of >2 mg/dl preoperatively). Beta-blockers titrated to heart rate and blood pressure are reasonable for patients who are going to have intermediate-risk surgery, defined as surgeries with a 1% to 5% cardiac risk such as head and neck surgeries, orthopedic surgeries, and prostate surgeries, and in whom perioperative assessment identifies CAD or the presence of more than 1 clinical risk factor as described above. For patients who are undergoing immediate-risk procedures or vascular surgery with a single clinical risk factor and no documented CAD, the usefulness of beta-blockers is uncertain. For patients who are undergoing vascular surgery with no clinical risk factors, the usefulness of beta- 3

4 blockers is uncertain. Patients with absolute contraindications to betablockers should not receive them perioperatively. Based on the results of POISE, routine administration of high-dose beta-blockers in the absence of dose titration is not useful and may be harmful for patients not currently taking betablockers who are undergoing noncardiac surgery. Literature Update Intensive glucose lowering in type 2 diabetes retrospective analyses of the ACCORD study In 2008, results of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study were published. The ACCORD study was designed to evaluate the effects of intensive glycemic control on cardiovascular events and mortality in patients with type 2 diabetes. A total of 10,251 patients with type 2 diabetes and A1C of 7.5% or more were randomly assigned to intensive glycemic control therapy (target A1C < 6%) or standard therapy (target A1C 7 to 7.9%). The planned follow-up of the study was 5.6 years. However, the trial was stopped after a mean of 3.5 years due to a higher mortality rate in the intensive therapy group compared with standard therapy (257 vs. 203 patient deaths; hazard ratio [HR] 1.22, p=0.04). To further assess this effect of increased mortality with intensive glycemic control, 2 retrospective analyses were conducted on data from the ACCORD trial one to evaluate the association between severe hypoglycemia and mortality, and the second to identify characteristics associated with severe hypoglycemia. Retrospective analyses The first analysis, conducted by Bonds and colleagues, evaluated the association between 2 outcomes, all cause mortality and episodes of symptomatic, severe hypoglycemia. In the ACCORD study, hypoglycemia was classified as symptomatic, severe hypoglycemia requiring medical assistance (abbreviated HMA, defined as blood glucose < 50 mg/dl or symptoms that resolved with glucose or glucagon) and symptomatic, severe hypoglycemia requiring any assistance, medical or nonmedical (abbreviated HA; defined as blood glucose < 50 mg/dl or symptoms that resolved with carbohydrate treatment). Mortality was then assessed based on occurrence of hypoglycemic episodes. At least one HA occurred in 1071 patients; 256 in the standard therapy group and 816 in the intensive therapy group. Among 74 patients who died and had at least one HA event, no difference was seen in mortality between the 2 treatment groups 21 patients in the standard therapy group (8.20%) and 53 in the intensive therapy group (6.49%). Similarly, among patients with one HA event to up to 3 or more events, no significant differences were seen in the rates of mortality between the standard and intensive therapy groups. However, rates of mortality among patients with hypoglycemia were consistently higher among the standard treatment group compared to intensive therapy (7.39 to 13.79% vs to 6.90%). The results were similar among the 703 patients experiencing at least one to up to 3 or more HMA events, with nonsignificantly higher rates seen with standard therapy compared with intensive therapy. The authors also assessed the differences in mortality within each treatment group, comparing patients with no previous hypoglycemic events and those with at least one HA or HMA. For both the intensive therapy and standard therapy groups, mortality was higher among patients who had experienced at least one hypoglycemic event. However, mortality rates were higher in the standard therapy group compared with the intensive therapy group. For patients experiencing at least one HA event, mortality was 2.8% a year in the intensive therapy group (vs. 1.2% with no events) compared with 3.7% a year with standard therapy (vs. 1.0% with no events). For patients experiencing at least one HMA event, mortality was 2.8% a year with intensive therapy (vs. 1.3% with no events) and 4.9% a year with standard therapy (vs. 1.0% with no events). The authors concluded that, based on these results, symptomatic, severe hypoglycemia alone cannot account for mortality seen with intensive control in the ACCORD study; only one death in the study was determined to be a result of hypoglycemia. Rather, severe hypoglycemia may be a marker for increased mortality due to other causes, whether intensive or standard glycemic control is used in patients with type 2 diabetes. The second analysis conducted on ACCORD data was to assess baseline characteristics on the risk of symptomatic, severe hypoglycemia. The same definitions of hypoglycemia were used in the analysis as in the ACCORD study. Hypoglycemic events (HA or HMA) occurred more frequently among the intensive therapy group 7.9% of patients had at least one HMA event compared with 2.6% in the standard therapy group. For HA events, the corresponding percentages were 10.5% and 3.5%. The overall rates of HA were calculated as 8.25 and 2.31 per 100 person-years for intensive and standard therapies, respectively, and 4.28 and 1.37 per 100 person-years for HMA, respectively, when all episodes were considered. The authors then determined hazard ratios for HMA events based on selected patient characteristics. The following patient variables were found to be significant independent predictors of an HMA for both intensive and standard therapies: female gender (HR 1.21), African-American race (HR 1.43), history of peripheral neuropathy (HR 1.19), long-standing (16+ years) diabetes (HR 1.37), body mass index >30 (HR 0.65), albumin:creatinine ratio ( HR 1.20; >300 HR 1.74), elevated serum creatinine (1 to 1.3 mg/dl HR 1.21, >1.3 HR 1.66), and age (per 1 year increase, HR 1.03). Among patients in the standard therapy group, other significant predictors for an HMA event included education (<high school, high school, and 4

5 some college vs. college graduate or more, HR 1.62 to 2.31), low levels of low density lipoprotein cholesterol (HR 0.59), any insulin use (HR 4.08), and baseline A1C (for every 1% increase HR 1.30). For the intensive therapy group, only education less than high school (HR 1.38 vs. college graduate) and any use of insulin (HR 1.95) were significant predictors of an HMA event. When the predictive effects of A1C were further evaluated, for the standard therapy group, the risk of an HMA event was 76% for every 1% higher updated (within 4 months of therapy) A1C. For the intensive therapy group increased A1C was also significant, but to a lesser degree (15% higher risk for every 1% higher updated A1C level); baseline A1C did not reach significance as a predictor of an HMA event in the intensive group. For declines in A1C within 4 months of initiating therapy, lower risks for episodes of HMA were seen in both groups for every 1% A1C decrease, a 28% and 14% reduction in risk in the standard and intensive therapy groups, respectively. The authors concluded that these findings would assist clinicians identifying individuals at risk for symptomatic, severe episodes of hypoglycemia, including women, African-Americans, older patients, those on insulin, and those with lower educational levels. In addition, patients given an intensive therapy regimen who do not have a prompt reduction in A1C may also be at risk for severe hypoglycemia. According to the results of the ACCORD study, intensive glycemic therapy in patients with type 2 diabetes was associated with increased mortality and no significant cardiovascular benefit. Two retrospective analyses were conducted to identify risk factors associated with severe hypoglycemia (a potential result of intensive glycemic control) and the risk of mortality with severe hypoglycemia. Identification of individuals at increased risk of hypoglycemia may help to guide therapy to avoid this complication. In addition, severe, symptomatic hypoglycemia and poor glycemic control, regardless of the approach to therapy (intensive or standard), may indicate an increased risk of mortality among patients with type 2 diabetes. Based on these analyses, hypoglycemia does not appear to be the driving force behind the increased mortality in patients treated with intensive control. Clinical implications of JUPITER Elevated high sensitivity C-reactive protein (hscrp), a marker of inflammation, has been associated with an increased risk of cardiovascular disease (CVD). HMG-CoA reductase inhibitors (statins) have been shown to reduce hscrp levels which may, in part, explain some of their nonlipid effects in reducing CVD risk. Current treatment guidelines recommend the use of statins as secondary prevention in patients with CVD and primary prevention for patients with elevated cholesterol and multiple risk factors. In addition, the CDC and the AHA suggest using hscrp testing to help determine whether to initiate therapy in patients with intermediate CVD risk. The use of statin therapy in low risk patients without hyperlipidemia, but with elevated hscrp levels, has been evaluated in the JUPITER trial. JUPITER JUPITER (Justification for the Use of statins in primary Prevention: an Interventional Trial Evaluating Rosuvastatin) was a randomized, double-blind, placebo-controlled, multicenter study designed to determine whether the rate of a first cardiovascular (CV) event could be reduced with rosuvastatin 20 mg in healthy patients with increased hscrp ( 2 mg/l) and normal low-density lipoprotein (LDL) cholesterol levels (< 130 mg/dl). Men 50 years-of-age and women 60 years-of age who did not have a history of CVD, met the hscrp and LDL criteria, and had triglyceride levels < 500 mg/dl were included in the trial. Diabetes, uncontrolled hypertension, hypothyroidism, and chronic inflammatory conditions were among the conditions that led to exclusion. The primary outcome measure was the occurrence of a first major CV event, which included nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for unstable angina, arterial revascularization, or death from CV causes. Components of the primary outcome were evaluated individually as secondary outcomes. Over 17,000 patients were randomized to receive either rosuvastatin 20 mg or placebo with a planned duration of 5 years. The trial; however, was terminated after the first interim analysis due to benefits of treatment and differences in death rates between groups. The median duration of follow up was 1.9 years. A review of the baseline characteristics demonstrates a relatively healthy population with respect to family CHD history, cholesterol, and glucose levels. Patients on rosuvastatin achieved a median LDL of 55 mg/dl and median hscrp of 2.2 mg/l at 12 months, which represented a 50% lower LDL and a 37% lower hscrp compared to the placebo group. With the exception of hospitalization for unstable angina, the primary and other secondary outcome measures were significantly reduced with rosuvastatin compared to placebo. Although the relative risk reduction in the incidence of a major CV event was 43%, the absolute risk reduction was only 1.2%. Therefore, in order to prevent 1 major CV event, 95 patients would need to be treated with rosuvastatin for almost 2 years. Upon subgroup analysis, the benefits of rosuvastatin over placebo were evident in higher and lower risk groups such as those who were smokers or non smokers, those who were normal weight or overweight, those with Framingham risk scores of greater than or less than 10%, those with hypertension or normal blood pressure, those with or without metabolic syndrome, and those with at least 1 risk factor or no risk factors. Clinical implications of JUPITER Ridker and colleagues conducted a prospective subanalysis of JUPITER to assess the effect of reductions in hscrp and LDL cholesterol in healthy patients randomized to rosuvastatin 20 mg versus placebo on the predefined endpoints specified in JUPITER during a maximum follow-up of 5 years (median 1.9 years). The baseline and 1-year values 5

6 for hscrp and LDL concentrations for 15,548 patients were collected and all CV events that occurred after randomization were recorded. Baseline hscrp and LDL cholesterol were lower in patients who received rosuvastatin. Compared with placebo, median LDL cholesterol was reduced by 50% and median hscrp was reduced by 37% in the rosuvastatin group (p<0.001 for both comparisons). Patients in the rosuvastatin group who achieved an LDL cholesterol of < 70 mg/ dl had a 55% reduction in CV events (hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.34 to 0.6; p<0.001), whereas a significant reduction in CV events was not seen in patients who did not achieve this LDL goal (HR 0.89, 95% CI 0.63 to 1.25; p=0.49). Patients in the rosuvastatin group who achieved an hscrp target of <2 mg/l had a 62% reduction in CV events (HR 0.38, 95% CI 0.26 to 0.56; p<0.001) versus a 31% reduction in CV events in patients that did not reach the hscrp target (HR 0.69, 95% CI 0.53 to 0.91; p=0.007). The lowest risk of CV events occurred in patients who received rosuvastatin and met both the LDL and hscrp targets; better clinical outcomes were associated with LDL cholesterol <70 mg/dl and hscrp <2 mg/l. The authors concluded that reduction in both LDL cholesterol and hscrp are indicators of successful treatment with rosuvastatin. The clinical implications of JUPITER were evaluated in the ARIC (Arthrosclerosis Risk in Communities) study, a prospective, observational study of CV disease involving over 15,000 patients who were between the ages of 45 and 64 years at the initial visit in the late 1980s. Yang and colleagues used data from ARIC to compare the long-term effects of JUPITER based on patient characteristics, predicted 10-year coronary heart disease, and CV event rates. Over 8900 patients were evaluated, 5513 of whom were eligible for primary prevention. The primary outcome was the first major CV event (similar to JUPITER). Patients were stratified into 4 groups: hscrp 2 mg/l, LDL <130 mg/dl ( JUPITER-eligible ); hscrp <2 mg/l and LDL <130 mg/dl; hscrp <2 mg/l and LDL 130 mg/dl; hscrp 2 mg/l and LDL 130 mg/dl. After a mean follow-up of 6.9 years, the JUPITER-eligible group experienced CV events/1000 person-years (adjusted for age, race, and gender). The highest rate of CV events was 21.96/1000 person-years, which was seen in the group that had hscrp 2 mg/l and LDL 130 mg/ dl. The reduction rates of CV events in the JUPITEReligible group that received rosuvastatin were similar to those seen in JUPITER. The ARIC trial showed that the JUPITER-eligible group had an absolute CV risk of ~10.9% over a mean follow-up of 6.9 years. The authors determined that the number of individuals needed-totreat to prevent 1 first CV event was approximately 38 over 5 years and 26 over 6.9 years, suggesting long-term benefits of treating patients with rosuvastatin. The authors concluded that patients with an hscrp 2 mg/l and low LDL cholesterol are still at risk for CV events; therefore, individuals that may be at higher risk can be identified by using hscrp and age, which could lead to the initiation of pharmacotherapy. On February 9, 2010, the Food and Drug Administration (FDA) announced the approval of a new indication for rosuvastation based on the results of JUPITER. In addition to lowering cholesterol and triglycerides in patients with dyslipidemia, rosuvastatin is now indicated for the primary prevention of CVD to reduce the risk of stroke, heart attack, and the risk of arterial revascularization procedures in individuals who have no clinically evident heart disease but are at increased risk of heart disease due to the combined effect of the following risk factors: Age (> 50 years in men; > 60 years in women); an elevated hscrp level (> 2 mg/l); and presence of at least 1 additional CV risk factor (e.g., high blood pressure, low HDL-C, smoking, or a family history of premature heart disease). The FDA posted a summary of questions and answers for healthcare professionals regarding the new indication for rosuvastatin. The document can be accessed at PostmarketDrugSafetyInformationforPatientsandProviders/ ucm htm. The results of JUPITER and the 2 subanalyses summarized above strengthen the evidence that CVD is associated with an inflammatory component. The majority of statins are indicated for primary prevention of CVD; however, the new FDA-approved indication for rosuvastatin is unique in that it specifically targets patients with an elevated hscrp (>2 mg/l). As a result, the frequency of hscrp testing, as well as rosuvastatin prescribing patterns are likely to increase. The National Cholesterol Education Program Adult Treatment Panel III (NCEP III) guidelines remain the standard for the treatment of dyslipidemia. The impact of the JUPITER trial, subanalyses, and clinical utility of hscrp testing continues to be controversial. Additional literature does not support the role of hscrp as a definitive risk factor of CVD. Since it was not assessed in these trials, clinicians should continue to use hscrp testing as it is currently recommended in intermediate risk patients to help determine whether primary prevention with pharmacologic therapy is required. The NCEP III guidelines should be followed for all other patients. Furthermore, the cost-effectiveness of this approach considering the generic availability of other statins, as well as the long-term safety profile of rosuvastatin, needs further evaluation. 6

7 P & T Committee Formulary Action Additions: - Dronedarone: Restricted to patient on therapy prior to admission or initiation by Cardiology - Prasugrel: Restricted to Cardiology for initiation in ACS - Topiramate Deletions: - Cromolyn - Daclizumab - Prednisolone / gentamicin ophthalmic Authors: Carissa E. Mancuso, PharmD Rita Soni, PharmD, BCPS Joan Stachnik, PharmD, BCPS Maria G. Tanzi, PharmD Editor: Amy E. Lodolce, PharmD, BCPS 7