Cardiovascular New Drug Update

1. Cardiovascular New Drug Update C. Wayne Weart, Pharm D, FASHP, FAPhA, BCPS Professor of Clinical Pharmacy and Outcome Sciences South Carolina College of Pharmacy Professor of Family Medicine Medical University of South Carolina Charleston, South Carolina weartcw@musc.edu

2. Disclosure • I am a consultant for Merck in the area of outcomes research. • I served on a formulary advisory board for BMS and Pfizer for apixaban – Eliquis FDA approved on 12-28-2012.

3. FDA Safety Update on Statins • March 2, 2012 Monitoring Liver Enzymes • Labels have been revised to remove the need for routine periodic monitoring of liver enzymes in patients taking statins. The labels now recommend that liver enzyme tests should be performed before starting statin therapy and as clinically indicated thereafter. FDA has concluded that serious liver injury with statins is rare.

4. FDA Safety Update on Statins • March 2, 2012 Adverse Event Information: • Rare post-marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These reported symptoms are generally not serious and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

5. FDA Safety Update on Statins • March 2, 2012 Increases in glycosylated hemoglobin (HbA1c) and fasting plasma glucose • FDA’s review of the results from the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) reported a 27% increase in investigator-reported diabetes mellitus in rosuvastatin-treated patients compared to placebo-treated patients. High-dose atorvastatin had also been associated with worsening glycemic control in the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22) sub study. • FDA also reviewed the published medical literature. A meta-analysis by Sattar et al. which included 13 statin trials with 91,140 participants, reported that statin therapy was associated with a 9% increased risk for incident diabetes (Absolute risk is about 1 in 100-150 patients) • FDA continues to believe that the cardiovascular benefits of statins outweigh these small increased risks. • Cause and effect has not been established

6. Citalopram hydrobromide (Celexa)FDA Safety Alert • Patients at particular risk for developing prolongation of the QT interval include those with underlying heart conditions and those who are predisposed to low levels of potassium and magnesium in the blood. • Studies have not shown a benefit in the treatment of depression at doses higher than 40 mg per day. • Citalopram and sertraline are the recommended agents of choice for patients with depression and CVD according to the AHA/APA • Circulation 2008;118:1768-75

7. Citalopram hydrobromide (Celexa)FDA Safety Alert Additional Recommendations: 3-28-2012 • Citalopram is not recommended for use in patients with congenital long QT syndrome, bradycardia, hypokalemia, or hypomagnesaemia, recent acute myocardial infarction, or uncompensated heart failure. • Citalopram use is also not recommended in patients who are taking other drugs that prolong the QT interval. • The maximum recommended dose of citalopram is 20 mg per day for patients with hepatic impairment, patients who are older than 60 years of age, patients who are CYP 2C19 poor metabolizers, or patients who are taking concomitant cimetidine (Tagamet) or another CYP2C19 inhibitor, because these factors lead to increased blood levels of citalopram, increasing the risk of QT interval prolongation and Torsade de Pointes.

8. Aliskiren (Tekturna) Safety Update • December 20, 2011 - Novartis announced that following the seventh interim review of data from the ALTITUDE study with Rasilez®/Tekturna® (aliskiren), a decision to terminate the trial has been taken on the recommendation of the independent Data Monitoring Committee (DMC) overseeing the trial. The trial involved 8606 patients with type 2 diabetes and renal impairment who are at high risk of cardiovascular and renal events • The DMC concluded that patients were unlikely to benefit from treatment added on top of standard anti-hypertensives (ACEI or ARB), and identified higher adverse events in patients receiving Rasilez/Tekturna in addition to standard of care in the trial. Specifically, in the trial arm in which Rasilez/Tekturna was added to the standard of care there was an increased incidence after 18-24 months of non-fatal stroke, renal complications, hyperkalemia and hypotension in this high-risk study population.

9. Aliskiren (Tekturna) Safety Update Continued… • As a precautionary measure, Novartis will no longer promote Rasilez / Tekturna-based medicines for use in combination with a therapy in the ACE or ARB classes. Novartis is having discussions with the FDA about these findings and the FDA has not taken any specific action to date.

10. Aliskiren-containing Medications: Drug Safety Communication - New Warning and Contraindication • 4/20/2012 RECOMMENDATION: Concomitant use of aliskiren with ARBs or ACEIs in patients with diabetes is contraindicated because of the risk of renal impairment, hypotension, and hyperkalemia. Avoid use of aliskiren with ARBs or ACEIs in patients with renal impairment where GFR < 60 mL/min. Patients should not stop taking aliskiren without talking to your healthcare professional. Stopping aliskiren suddenly can cause problems if your high blood pressure (hypertension) is not treated.

11. Generic Clopidogrel is here FDA Approvals May 17, 2012 • clopidogrel bisulfate • Apotex Inc • Aurobindo Pharma Ltd • Dr Reddys Labs Ltd • Gate Pharma • Mylan Pharma Inc • Roxane • Sun Pharma Global • Teva • Torrent Pharma Ltd • Brand Plavix $185.49/30 • Generic wholesale cost • $3.48 - $6.00/30 WAC as of 10/16/2012

12. Generic Atorvastatin–The price is falling! • May 29. 2012 we now have 5 new manufacturers with FDA approval joining Dr Reddy’s and Watson with more to come: • Apotex, Mylan, Ranbaxy, Sandoz, Teva Atorvastatin (Lipitor) Brand Generic 10mg -39% LDL $113.70 $4.35-5.66 20mg -43% $162.30 $6-7.66 40mg -50% $162.30 $6-7.66 80mg -60% $162.30 $6-7.66 • Cost is per 30 day supply WAC 10-16-2012

13. Dabigatran - Pradaxa A direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation 75 mg and 150 mg capsules BID $253.00/60 No need to monitor INR Not reversible with vitamin K or FFP (consider factor concentrates or dialysis)

14. Dabigatran- Pradaxa RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy), a randomized trial comparing two blinded doses of dabigatran (110 mg twice daily and 150 mg twice daily) with open-label warfarin (dosed to target INR of 2 to 3) in 18,113 patients with non-valvular, persistent, paroxysmal, or permanent atrial fibrillation and one or more of the following additional risk factors: (Mean CHADS2 Score 2.1) • Previous stroke, transient ischemic attack (TIA), or systemic embolism • Left ventricular ejection fraction <40% • Symptomatic heart failure, ≥ New York Heart Association Class 2 • Age ≥75 years • Age ≥65 years and one of the following: diabetes mellitus, coronary artery disease (CAD), or HBP • The primary objective of this study was to determine if dabigatran was non-inferior to warfarin in reducing the occurrence of the composite endpoint, stroke (ischemic and hemorrhagic) and systemic embolism.

15. Dabigatran- Pradaxa

16. Dabigatran- Pradaxa Risk of extracranial and intracranial bleeding (% per year) by age Circulation 2011;123:2363-2372

17. Dabigatran- Pradaxa • The rates of adverse reactions leading to treatment discontinuation in RE-LY were 21% for dabigatran 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of dabigatran were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea). • NNH 20 patients • Drug Interactions • The concomitant use of dabigatran 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

18. Dabigatran- Pradaxa ACCF/AHA/HRS 2011 Focused Update Recommendation Class I “Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance <15 mL/min), or advanced liver disease.” (Level of Evidence: B) • (Circulation. 2011;123:00-00 – on-line but in print 3-15-2011)

19. AT-9 Chest Guidelines • For patients with AF, including those with paroxysmal AF, who are at high risk of stroke (e.g., CHADS 2 score >/= 2), we recommend: • oral anticoagulation rather than no therapy (Grade 1A) , aspirin (75 mg to 325 mg once daily) (Grade 1B) , or combination therapy with aspirin and clopidogrel (Grade 1B). • we suggest dabigatran 150 mg twice daily rather than adjusted-dose VKA therapy (target INR range, 2.0-3.0) (Grade 2B) Chest AT-9 (2/2012)

20. Dabigatran- Pradaxa • AHA/ASA advisory on stroke prevention in atrial fibrillation (Stroke 2012; DOI:10.1161/STR.0b013e318266722a. Available at: http://stroke.ahajournals.org) • Warfarin, dabigatran, apixaban, and rivaroxaban are all indicated for the prevention of first and recurrent stroke in patients with non valvular AF. "The selection of an agent should be individualized on the basis of risk factors, cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including time in INR therapeutic range if the patient has been taking warfarin."

21. Dabigatran- Pradaxa • AHA/ASA advisory on stroke prevention in atrial fibrillation (Stroke 2012) • Dabigatran 150 mg twice daily is an "efficacious alternative" to warfarin for the prevention of first and recurrent stroke in patients with non valvular AF and at least one additional risk factor who have creatinine clearance (CrCl) >30 mL/min. • Use of dabigatran 75 mg twice daily may be considered in patients with AF and at least one additional risk factor who have a low CrCl, in the range of 15 to 30 mL/min. Dabigatran is not recommended in patients with more severe renal failure (CrCl <15 mL/min).

22. Dabigatran- Pradaxa • Converting from warfarin • When converting patients from warfarin therapy to dabigatran, discontinue warfarin and start dabigatran when the international normalized ratio (INR) is below 2.0. • Converting from dabigatran to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows: • For CrCl >50 mL/min, start warfarin 3 days before discontinuing dabigatran. • For CrCl 31-50 mL/min, start warfarin 2 days before discontinuing dabigatran. • For CrCl 15-30 mL/min, start warfarin 1 day before discontinuing dabigatran.

23. Dabigatran- Pradaxa • Management prior to surgery: • CrCl ≥ 50 mL/min: Discontinue dabigatran 1 to 2 days before procedure • CrCl < 50 mL/min: Discontinue dabigatran 3 to 5 days before procedure. • Major procedures, spinal puncture, spinal or epidural catheter placement may require discontinuation for a longer period of time.

24. Dabigatran- Pradaxa • DOSING: Recommended Dose for patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of dabigatran is 150 mg taken orally, twice daily, with or without food. For patients with CrCl 15-30 mL/min, or patients 75 years of age or older the recommended dose is 75 mg twice daily • Instruct patients to swallow the capsules whole. Breaking, chewing, or emptying the contents of the capsule can result in increased exposure. • Pradaxa capsules will hydrolyze over time when exposed to humidity, causing a breakdown of active ingredient, and rendering the medication less effective. Pradaxa is packaged in a 30-day supply bottle with a desiccant cap or in unit-of-use blister packaging to minimize product breakdown from moisture. • (Use within 4 months of opening and keep in original container)

25. Don't use dabigatran off-label with mechanical valves • Primary-care practitioners may be putting the lives of patients with prosthetic heart valves at risk by switching their anticoagulation from warfarin to newer agents such as dabigatran (Pradaxa, Boehringer Ingelheim), say Canadian researchers. Dr Joel Price (University of Ottawa Heart Institute, ON) and colleagues report the cases of two women who had undergone valve replacement some years before and had been faring well on warfarin; they were switched to dabigatran and subsequently suffered valve thromboses. • RE-ALIGN—a phase 2 dose-finding trial with dabigatran in patients with mechanical valves—is now under way, employing doses ranging from 150 to 330 mg twice daily, adjusted based on renal function and the results of the Hemoclot (Aniara, West Chester, OH) assay. • http://content.onlinejacc.org/article.aspx?articleID=1361772

26. Rivaroxaban exhibits a linear pharmacokinetic relationship with a rapid onset of action, resulting in maximal factor Xa inhibition in approximately 3 hours. Maintenance of the anti–factor Xa effect lasted 8 to 12 hours, depending on the dose of rivaroxaban. Terminal half-life of rivaroxaban is approximately 9 hours in adults and 12 hours in elderly patients (older than 65 years of age). Elimination of rivaroxaban occurs by multiple routes: renal (one-third is excreted unchanged), biliary/fecal, and hepatic (through CYP-450 3A4). Renal function impairment may influence elevated plasma concentrations and increased anti-Xa activity; therefore, dose adjustments may be required Rivaroxaban – Xarelto by Bayer HealthCare AG and Janssen Pharmaceuticals

27. Rivaroxaban - Xarelto • July 5, 2011 The FDA approved rivaroxaban a factor Xa inhibitor indicated for the prophylaxis of deep vein thrombosis (DVT) which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement. • The recommended dose of is 10 mg taken orally once daily with or without food. The initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been established. • For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended. • For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.

28. Rivaroxaban - Xarelto • RECORD 1 (Hip) R=1.1% vs. E=3.9%, RRR 71%, ARR 2.8%, NNT=36 • RECORD 2 (Hip) R=2.0% vs. E=8.4%, RRR 76%, ARR 6.4%, NNT=16 • RECORD 3 (Knee) R=9.7% vs. E=18.8%, RRR 48%, ARR 9.1%, NNT=11 • RECORD 4 (Knee) US approved dosing R=6.9% vs. E=10.1%, RRR 31%, ARR 3.19%, NNT=32

29. AT-9 Chest Guidelines • In patients undergoing THA or TKA, irrespective of the concomitant use of an IPCD or length of treatment, we suggest the use of LMWH in preference to the other agents we have recommended as alternatives: fondaparinux, apixaban, dabigatran, rivaroxaban, LDUH (all Grade 2B), adjusted-dose VKA, or aspirin (all Grade 2C). • AT-9 Chest Guidelines 2-2012

30. AT-9 Chest Guidelines • “The best estimates suggest that five fewer symptomatic DVT per 1,000 achieved with rivaroxaban over LMWH will be offset by nine more major bleeding events. • In summary, based on moderate-quality evidence, both the possibility of increased major bleeding events and the availability of long-term safety data for LMWH makes LMWH more appealing than rivaroxaban in spite of the inconvenience of subcutaneous administration.” • AT-9 Chest Guidelines 2-2012

31. Rivaroxaban - Xarelto • Avoid concomitant administration of rivaroxaban with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) which cause significant increases in rivaroxaban exposure that may increase bleeding risk. • When clinical data suggest a change in exposure is unlikely to affect bleeding risk (e.g., clarithromycin, erythromycin), no precautions are necessary during co administration with drugs that are combined P-gp and CYP3A4 inhibitors.

32. ROCKET-AF Trial • The ROCKET AF study was a multicenter, double-blind, randomized trial of once-daily oral rivaroxaban 20 mg or 15 mg daily in patients with a creatinine clearance of 30 to 49 ml per minute) compared with dose-adjusted warfarin (INR 2-3) in moderate-to-high-risk patients with non valvular AF. The authors hypothesized that rivaroxaban is non inferior to warfarin at preventing the composite of stroke (ischemic and hemorrhagic) and systemic embolism. The 14,264 enrolled patients (median age, 73; 40% women) had a mean CHADS2 score of 3.5; about half had a CHADS2 score of 4. • N Engl J Med 2011;365:883-91.

33. ROCKET-AF Trial • Median follow-up was 707 days. • In the warfarin group, the overall mean proportion of time in therapeutic international normalized ratio range was 55%. -N Engl J Med 2011;365:883-91. • On Sept 9, 2011 the FDA Cardiovascular and Renal Drugs Advisory Committee recommended approval of rivaroxaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) by a 9-2 vote. • The FDA had expressed concern over the low rate of desired INR’s)

34. ROCKET-AF Trial N Egl J Med 2011;365:883-91.

35. ROCKET-AF Trial N Engl J Med 2011;365:883-91.

36. Rivaroxaban - Xarelto • Nonvalvular Atrial Fibrillation: • For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal • For patients with CrCl 15 - 50 mL/min: 15 mg orally, once daily with the evening meal • Avoid use in patients with CrCl <15 mL/min • The absolute bioavailability of rivaroxaban at a dose of 20 mg in the fasted state is approximately 66%. Co administration of XARELTO with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). XARELTO 15 mg and 20 mg tablets should be taken with the evening meal

37. Rivaroxaban - Xarelto • Box Warning: “Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant” • Rocket AF did not have a protocol for what to do after the trial ended and the results were not good

38. Switching Anticoagulants? • Switching to XARELTO® from warfarin • Discontinue warfarin and start XARELTO® as soon as the INR is below 3.0 to avoid periods of inadequate anticoagulation • Switching from XARELTO® to warfarin • No clinical trial data are available to guide converting patients from XARELTO® to warfarin. XARELTO® affects INR, so INR measurements made during co administration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue XARELTO® and begin both a parenteral anticoagulant and warfarin at the time the next dose of XARELTO® would have been taken

39. Rivaroxaban - Xarelto • Management prior to surgery • Discontinue rivaroxaban at least 24 hours before surgery.

40. Canadian CardiovascularSociety Atrial Fibrillation Guidelines • We recommend that all patients with AF or AFL (paroxysmal, persistent, or permanent), should be stratified using a predictive index for stroke risk (e.g., CHADS2) and for the risk of bleeding (e.g., HAS-BLED), and that most patients should receive either an OAC or ASA (Strong Recommendation, High-Quality Evidence). • We suggest, that when OAC therapy is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban in preference to warfarin (Conditional Recommendation, High-Quality Evidence). • Practical tip. Among patients > 75 years and certainly those > 80 years, dose reduction of the new OACs, especially dabigatran, should be considered. • Canadian Journal of Cardiology 28 (2012) 125–136

41. Canadian CardiovascularSociety Atrial Fibrillation Guidelines • For antithrombotic therapy of CKD patients, therapy should relate to eGFR as follows: • eGFR > 30 mL per minute: We recommend that such patients receive antithrombotic therapy according to their CHADS2 score as detailed in recommendations for patients for patients with normal renal function (Strong Recommendation, High-Quality Evidence). • eGFR 15-30 mL per minute and not on dialysis: We suggest that such patients receive antithrombotic therapy according to their CHADS2 score as for patients with normal renal function. The preferred agent for these patients is warfarin (Conditional Recommendation, Low- Quality Evidence). -Canadian Journal of Cardiology 28 (2012) 125–136

42. Rivaroxaban - Xarelto • AHA/ASA advisory on stroke prevention in atrial fibrillation (Stroke 2012; DOI:10.1161/STR.0b013e318266722a. Available at: http://stroke.ahajournals.org) • In patients with non valvular AF who are at moderate to high risk of stroke (prior history of transient ischemic attack [TIA], stroke, or systemic embolization or more than two additional risk factors), rivaroxaban 20 mg/day "is reasonable" as an alternative to warfarin. • In patients with renal impairment and non valvular AF who are at moderate to high risk of stroke (prior history of TIA, stroke, or systemic embolization or more than two additional risk factors), with a CrCl of 15 to 50 mL/min, 15 mg of rivaroxaban daily may be considered, but its safety and efficacy have not been established. Rivaroxaban should not be used if the CrCl is <15 mL/min.

43. Rivaroxaban for Symptomatic VenousThromboembolism: Einstein DVT • Open-label, randomized, event-driven, non inferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3 (12%), 6 (63%), or 12 (25%) months in patients with acute, symptomatic DVT. • Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study • In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. • N Engl J Med 2010;363:2499-510.

44. * Intent to treat population N Engl J Med 2010;363:2499-510.

45. EINSTEIN DVT Trial Intent to treat population N Engl J Med 2010;363:2499-510.

46. Rivaroxaban for Symptomatic VenousThromboembolism: Einstein DVT • In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. • In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). N Engl J Med 2010;363:2499-510

47. Rivaroxaban for Symptomatic VenousThromboembolism: Einstein DVT • The principal safety outcome was major bleeding or clinically relevant non major bleeding in the initial-treatment study • The principal safety outcome occurred in 8.1% of the patients in each group. • In the long term follow=up period, Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P = 0.11). N Engl J Med 2010;363:2499-510

48. Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism • A randomized, open-label, event-driven, non inferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3 (5%), 6 (57%), or 12 (37%) months. • Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 60% in EINSTEIN PE study. N Engl J Med 2012; 366:1287-1297

49. EINSTEIN PE Trial Intent to treat population N Engl J Med 2012; 366:1287-1297

50. N Engl J Med 2012; 366:1287-129