How To Compare Warfarin To Dabigatran

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1 Page 1 WOMEN AT RISK Anticoagulation Issues In Atrial Fibrillation WOMEN AT RISK Anticoagulation Issues In Atrial Fibrillation J E A N N A P P I, P H A R M. D., F C C P, B C P S Accreditation: Pharmacists: L01-P Nurses: N-722 CE Credits: 1.0 contact hour Target Audience: Pharmacists & Nurses This webcast has been supported by an educational grant from Boehringer Ingelheim Program Overview: This program will provide a brief overview of the pathophysiology, signs and symptoms of heart failure. The pharmacologic basis for the commonly used drugs used to manage patients with heart failure will be discussed. The ACC/AHA guidelines as well as the EMPHASIS-HF trail will be reviewed Objectives: Identify the under-recognized risk of strokes in women diagnosed with atrial fibrillation, and the associated morbidity, mortality, and cost burdens Provide an update on the efficacy, safety, and role of the available treatments for anticoagulation therapy in atrial fibrillation Outline the compliance communication strategies between pharmacists and their patients about the benefits and risks of anticoagulation therapy, especially with women. PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education Legal Disclaimer: The material presented here does not necessarily reflect the views of Pharmaceutical Education Consultants (PharmCon) or the companies that support educational programming. A qualified healthcare professional should always be consulted before using any therapeutic product discussed. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity. This webcast has been supported by an educational grant from Boehringer Ingelheim 2 WOMEN AT RISK Anticoagulation Issues In Atrial Fibrillation Learning Objectives Speaker: Dr. Jean Nappi received her BS in Pharmacy from the State University of NY at Buffalo. She completed her Doctor of Pharmacy degree and residency in internal medicine from the University of Texas at Austin / UT Health Science Center at San Antonio. Dr. Nappi has been on the faculty at the Universities of Wisconsin, Utah, and Houston prior to her current position. She is now Professor of Clinical Pharmacy and Outcome Sciences in the South Carolina College of Pharmacy-MUSC Campus and Professor of Medicine (Cardiology) at the Medical University of South Carolina. Speaker Disclosure: Dr. Nappi has no actual or potential conflicts of interest in relation to this program This webcast has been supported by an educational grant from Boehringer Ingelheim PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education Legal Disclaimer: The material presented here does not necessarily reflect the views of Pharmaceutical Education Consultants (PharmCon) or the companies that support educational programming. A qualified healthcare professional should always be consulted before using any therapeutic product discussed. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity. 3 At the completion of this activity, the participant will be able to: 1. Identify the under-recognized risk of strokes in women diagnosed with atrial fibrillation, and the associated morbidity, mortality, and cost burdens. 2. Provide an update on the efficacy, safety, and role of available treatments for anticoagulation therapy in atrial fibrillation. 3. Outline compliance communication strategies between pharmacists and their patients about the benefits and risks of anticoagulation therapy, especially with women. 4

2 Page 2 Atrial Fibrillation Prevalence of Stroke by Age and Gender Atrial fibrillation is a very common arrhythmia The lifetime risk for developing AF is 1 in 4 for both men and women Atrial fibrillation is a powerful risk factor stroke 5 fold increase in risk for stroke in patients with AF Strokes due to AF increases with age (~24% at age 80-89) Heart Disease and Stroke Statistics 2012 Update 5 Heart Disease and Stroke Statistics 2012 Update 6 Gender Differences In the Canadian Registry of Atrial Fibrillation compared to men, women were older than men at presentation (65 vs 60 yrs) had higher heart rates (126 vs 119) and more symptomatic older women were less likely to receive warfarin than older men 3.35 times more likely to have a major bleed while receiving warfarin Gender Differences Risk of TE and/or ischemic stroke in women with AF compared to men Study N (% women) Risk Randomized AF Investigators 3,432 (34) 1.2 ATRIA 13,559 (43) 1.5 SPAF 2,012 (28) 1.6 Observational Framingham 2,844(48) 1.92 Euro Heart Study 5,333 (42) 1.83 Copenhagen 29,310 (40) 2.6 Women more likely to have stroke when not taking warfarin compared to men. They were not more likely to have a major bleed when INR was controlled. Humphries et al. Circulation 2001;103: Lane et al. Thromb Haemost 2009;101:

3 Page 3 CHADS 2 Score CHA 2 Ds 2 VASc Score Cardiac failure: Hypertension: Age> 75: Diabetes: Stroke or TIA: 1 pt 1 pt 1 pt 1 pt 2 pts Congestive heart failure 1 Congestive heart failure/lvd 1 Hypertension 1 Hypertension 1 Age 75 years 1 Age 75 years 2 Diabetes mellitus 1 Diabetes mellitus 1 Stroke/TIA/ TE 2 Stroke/TIA/ TE 2 Maximum score 6 Vascular disease (MI, PAD, aortic plaque) 1 ACC/AHA/HRS Age years 1 Sex category (female gender) 1 Maximum score 9 European Society of Cardiology Aspirin 0 Aspirin or no antithrombotic therapy (preferred) Aspirin or anticoagulant 1 Aspirin or oral anticoagulant (preferred) Oral anticoagulant 2 Oral anticoagulant Eur Heart J 2010;31: Circulation 2011; 123:e269-e Cost of Stroke In 2008, the direct and indirect cost of stroke was $34.3 billion Direct medical costs $18.8 billion Mean lifetime costs for ischemic stroke is $140,048 Anticoagulation In Atrial Fibrillation One in six strokes is cardioembolic in origin RE-LY vs warfarin Rocket-AF Rivaroxaban vs warfarin Aristotle Apixaban vs warfarin Heart Disease and Stroke Statistics 2012 Update 11 12

4 Page 4 W Factor IX Rivaroxaban Apixaban MECHANISMS OF ACTION Factor IXa W Factor X Factor Xa Prothrombin (Factor II) W W Factor VII Factor VIIa Distribution Rivaroxaban Apixaban Vitamin K Antagonist Direct thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor Affects the synthesis of Vitamin K dependent factors ( II, VII, IX, X ) 99% bound Vd = 0.14 L/kg Requires conversion to active form by a serum esterase, reversible 35% bound Vd = L Half-life hours hours 34 hours in ESRD Elimination Drug interactions Metabolized via CYP 2C9, 2C19, 2C8, 2C18, 1A2, 3A4 YES Metabolized to active metabolites; 80% excreted renally P-gp inducers AUC (rifampin), P-gp inhibitors Dose-dependent inhibition of Factor Xa 92-95% bound Vd = 50 L 5-9 hours in elderly 50% metabolized, 36% excreted renally P-gp and strong CYP3A4 inhibitors/inducers Direct acting reversible Factor Xa inhibitor 87% bound 9-14 hours Metabolized via CYP3A4 and 3A5 25% excreted renally CYP3A4 inhibitors/inducers? Monitoring PT/INR None (ECT Ecarin Clotting Time used) Clin Pharmacokinet. 2009;48(1):1-22 Fibrinogen Thrombin (Factor IIa) Fibrin Antidote Vitamin K, FFP Dialysis, antifibrinolytics, rfviia? Other S entantiomer 2-5x more potent, 2C9, VKOR polymorphisms Keep in original container, do not open capsules Dosing Highly individualized 150 mg bid (CrCl>30) 75 mg bid (CrCl 15-30) PCC (prothrombin complex concentrate) Japanese and elderly: 50% higher exposure 20 mg daily 15 mg (CrCl 15-50) 5 mg bid (2.5 mg bid) Anticoagulation In Atrial Fibrillation versus warfarin in patients with atrial fibrillation (RE-LY) Connolly SJ et al New England Journal of Medicine 2009;361: RE-LY THE RANDOMIZED EVALUATION OF LONG-TERM ANTICOAGULATION THERAPY Randomized to adjusted-dose warfarin (open-label) or fixed dose dabigatran 110 mg or 150 mg BID (blinded) Non-inferiority trial of >18,000 patients Sponsored by Boehringer Ingelheim Patient enrollment: December 05-December 07 Final follow up: December 08-March 09 Population Health Research Institute of Canada independently managed the database and performed the primary data analysis 15 16

5 Page 5 RE-LY ENDPOINTS RE-LY POPULATION Primary- stroke or systemic embolism Safety- major hemorrhage Secondary- stroke, systemic embolism, and death Other MI, PE, TIA, hospitalization Primary net clinical benefit (composite of stroke, systemic embolism, PE, MI, death or major hemorrhage) Included Atrial fibrillation at screening or within last 6 months and one of the following: Previous stroke, EF < 40% NYHA II or higher Age >75 Age DM, HTN, CAD Excluded Severe valvular disease Stroke within 14 days Severe stroke within 6 months Risk for hemorrhage Creatinine clearance <30 ml/min Active liver disease Pregnancy RE-LY DEMOGRAPHICS 18,113 patients enrolled, well-matched Mean age 71.5 years, 35% female One-third in each group had persistent, paroxysmal and permanent AF 20% had previous stroke or TIA 32% had HF, 23% DM, 79% HTN Mean CHADs score was % were on vitamin K antagonist at baseline RE-LY RESULTS Primary End Point - stroke or systemic embolism 110 mg bid 150 mg bid Primary End Point % per year Relative risk for 1 End Point compared to warfarin 0.91 ( ) 0.66 ( ) Hemorrhagic stroke % per year Relative risk for hemorrhagic stroke compared to warfarin 0.31 ( ) 0.26 ( ) P value < both doses non-inferior higher dose superior <

6 Page 6 RE-LY SECONDARY OUTCOMES 110 mg bid 150 mg bid Death from any cause % per year Relative risk for death compared to warfarin Myocardial infarction % per year Relative risk for myocardial infarction 0.91 ( ) P= ( ) P= ( ) P= ( ) P= RE-LY ADVERSE EVENTS 110 mg bid 150 mg bid Major bleeding % per year Relative risk for: Life threatening bleed Intracranial bleed Major or minor bleed Net clinical benefit % per year (vascular events, major bleeding, death) 0.68 ( ) 0.31 ( ) 0.78 ( ) 7.09 RR = 0.92 ( ) P= ( ) 0.40 ( ) 0.91 ( ) 6.91 RR = 0.91 ( ) P= RE-LY Anticoagulation In Atrial Fibrillation Other noteworthy points More discontinuations in dabigatran groups (21% vs 17% at 2 years) Two fold increase in dyspepsia (11.5%) Increase in MI Also seen with ximelagatran INRs were therapeutic 64% of time Recommended dose CrCl >30 ml/min, dose dabigatran 150 mg twice daily, CrCl ml/min, dose dabigatran 75 mg twice daily No recommendations for patients with a CrCl <15 ml/min or on dialysis Drug interactions P-glycoprotein inhibitors (verapamil, amiodarone, quinidine) raise dabigatran serum concentrations but do not require dose adjustment P-glycoprotein inducers (rifampin) reduce dabigatran serum concentrations and should be avoided 23 Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (Rocket AF) Patel MR et al New England Journal of Medicine 2011;365:

7 Page 7 ROCKET AF ROCKET-AF ENDPOINTS Randomized, double-blind, double dummy non-inferiority trial of rivaroxaban vs warfarin Sponsored by Johnson & Johnson and Bayer ~14,000 patients with atrial fibrillation 2 risk factors (CHF, HTN, age >75, DM) or Stroke, TIA or systemic embolism Rivaroxaban 20 mg daily 15 mg daily for Cr Cl ml/min adjusted to INR 2-3 Primary endpoint: stroke or non-cns embolism 25 Primary Efficacy Endpoint Composite of stroke and systemic embolism Primary Safety Endpoint Composite of major and non-major bleeding events Secondary Endpoints Composite of stroke, systemic embolism, or death from cardiovascular causes Composite of stroke, systemic embolism, death from cardiovascular causes, or MI Individual components of composite endpoints New Engl J Med (10): ROCKET-AF POPULATION ROCKET AF DEMOGRAPHICS Included Nonvalvular atrial fibrillation Moderate-to-high risk of stroke History of stroke or TIA History of systemic embolism At least 2 of the following: Heart failure or LVEF < 35% Hypertension Age 75 years Diabetes Mellitus Excluded Significant mitral valve stenosis Prosthetic heart valve Creatinine Clearance <30 ml/min Increased bleeding risk ASA > 100 mg daily Stroke within past 14 days Or severe, disabling stroke within past 3 months Uncontrolled HTN ( 180/100) Pregnancy 14,171 patients enrolled, well-matched Median age 73 years, 40% female 55% had previous stroke, TIA, embolism 62% had HF, 40% DM, 90% HTN Mean CHADs score was 3.5 (median = 3.0) 62% prior vitamin K antagonist use New Engl J Med (10):

8 Page 8 ROCKET AF RESULTS Primary End Point - stroke or systemic embolism Rivaroxaban Hazard ratio (95% CI) P value ROCKET AF ADVERSE BLEEDING EVENTS Rivaroxaban (n=7111) Events # (%) Rate #/100 pt-yr Events # (%) (n=7125) Rate #/100 pt-yr Hazard ratio (95% CI) P value On treatment per protocol ITT After Discont ( ) ( ) 1.1 <0.001 for noninferiority <0.001 for noninferiority 0.12 for superiority 0.58 Major & non-major clinically relevant bleeding Intracranial hemorrhage Non-major clinically relevant bleeding 1475 (20.7) 55 (0.8) 1185 (16.7) (20.3) (1.2) Any major bleeding More in Hgb >2 and need for transfusion (16.2) More critical and fatal bleeding ( ) ( ) ( ) 1.04 ( ) Event rate expressed as percent / year Other noteworthy points ROCKET AF INRs were therapeutic 55% of time Less than 50% achieved the TTR threshold of >58-60% The efficacy of rivaroxaban, as compared to warfarin, was as favorable in centers with the best INR control as in those with poorer control 31 Pros ROCKET AF SUMMARY Appears to be a reasonable alternative to warfarin with easy dosing No INR monitoring Cons By intention to treat analysis, rivaroxaban was non-inferior to warfarin, but did not achieve superiority despite rather poor achievement of target INR 32

9 Page 9 Anticoagulation In Atrial Fibrillation Apixaban versus warfarin in patients with atrial fibrillation ARISTOTLE Granger CB et al New England Journal of Medicine 2011;365: ARISTOTLE Randomized, double-blind, double-dummy trial of apixaban 5 mg bid to adjusted warfarin Sponsored by Bristol-MyersSquibb and Pfizer ~18,000 patients with atrial fibrillation and 1 risk factor of stroke Apixaban 5 mg bid 2.5 mg bid for: age 80 yo, wgt 60 kg, or serum cr >1.5 mg/dl adjusted to INR 2-3 Primary endpoint: stroke or non-cns embolism ARISTOTLE ENDPOINTS Primary Efficacy Endpoint Composite of stroke and systemic embolism (noninferiority) Primary Safety Endpoint Major bleeding events (ISTH criteria) Secondary Endpoints Superiority relative to the primary outcome Superiority relative to warfarin in rates of major bleeding Death from any cause N Engl J Med (10): ARISTOTLE POPULATION Included Nonvalvular atrial fibrillation 2 or more episodes of AF within last 12 months 1 additional risk factor Age 75 Previous stroke, TIA, systemic embolism Symptomatic HF or EF 40% DM HTN Excluded Moderate-severe mitral stenosis Prosthetic heart valve Stroke within previous 7 days Creatinine 2.5 mg/dl Creatinine Cl < 25 ml/min Increased bleeding risk ASA > 165 mg daily Dual antiplatelet therapy New Engl J Med (10):

10 Page 10 ARISTOTLE DEMOGRAPHICS ARISTOTLE RESULTS 18,201 patients enrolled, well-matched Median age 70 years, 35% female 19% had previous stroke, TIA, embolism 35% had HF, 25% DM, 88% HTN Mean CHADS score End Point stroke/systemic embolism Stroke Ischemic,uncertain Hemorrhagic Systemic embolism Apixaban (n=9120) (n=9081) Hazard ratio (95% CI) ( ) ( ) 0.92 ( ) 0.51 ( ) 0.87 ( ) P value < Event rate expressed as percent / year 38 ARISTOTLE SECONDARY EVENTS ARISTOTLE ADVERSE BLEEDING EVENTS Apixaban (n=9120) (n=9081) Hazard ratio (95% CI) P value Apixaban (n=9120) (n=9081) Hazard ratio (95% CI) P value Rate Rate Rate Rate Death from any cause ( ) Stroke, embolism, or death ( ) ISTH Major bleeding ( ) Intracranial hemorrhage ( ) <0.001 <0.001 Myocardial infarction ( ) Stroke, embolism, MI, or death ( ) GUSTO severe bleeding ( Any bleeding ( ) <0.001 <0.001 Event rate expressed as percent / year 39 Event rate expressed as percent / year 40

11 Page 11 ARISTOTLE Pros 21% RRR in stroke or systemic embolism 31% RRR in major bleeding 11% RRR in death No monitoring TTR 66% Cons Sponsor on steering committee and authorship BID vs daily dosing 41 Trial RE-LY ROCKET-AF ARISTOTLE Drug Trial design, randomized 18,113 (3 arms) 14,264 18, mg bid 110 mg bid Open label Rivaroxaban 20 mg (15 mg) daily Double blind, double dummy Apixaban 5 mg (2.5 mg) bid Double blind, double dummy Mean Age (yrs) Male 63.6% 60.1% 65.3% Previous CVA 20% 54.7% 18.9% CHADS score % 0-1 % 2 % 3 Efficacy: % vs warfarin (CVA or Systemic Embolism) % 35% 33% 1.11 v p<0.001 NNT = 172 Major Bleeding % 3.11 vs 3.36 p=0.31 Conclusion vs. warfarin Superior efficacy for high dose, similar bleeding 3.5 0% 13% 87% 2.1 vs 2.4 p<0.001 non-inferiority p=0.12 superiority 3.4 vs 3.6 p=0.58 Non-inferior on efficacy and safety measures (ITT) % 36% 30% 1.27 vs 1.60 p < NNT = vs 3.09 p<0.001 Superior efficacy, less major bleeding, lower mortality Summary What Next? All 3 agents reduce hemorrhagic stroke vs warfarin High dose superior to warfarin, similar bleeding Reduces ischemic and hemorrhage stroke Rivaroxaban Non-inferior to warfarin (some sub-analysis showed superiority) Higher risk population Apixaban Compared to aspirin (AVERROES), superior efficacy, similar bleeding Superior to warfarin, less bleeding, reduced mortality Cost-effectiveness? What is the role of TTR (time in therapeutic range) for warfarin Patient selection Renal insufficiency Elderly Dose adjustment Concomitant CAD and antiplatelet agents Rebound with drug discontinuation? Drug interactions 43 44

12 Page 12 (Coumadin) VKA Many drug-drug interactions, especially amiodarone Drug-food interactions INR for routine monitoring Use in Atrial Fibrillation (Pradaxa) DTI Consider dose reduction to 75 mg bid if dronedarone or ketoconazole used in patients with Cr Cl Avoid with rifampin. Do not open the capsules Routine monitoring not needed Rivaroxaban (Xarelto) Xa Inhibitor Avoid with strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir) and inducers (carbamazepine, phenytoin, rifampin, St Johns wort) Routine monitoring not needed Vitamin K is an antidote No antidote for bleeding Prothrombin complex concentrate has been used No dose adjustment with renal insufficiency 150 mg bid if Cr Cl >30 75 mg bid if CrCl Dyspepsia is common 20 mg daily if Cr Cl>50 15 mg daily if CrCl Patient Counseling Female gender has been identified in some studies as a risk factor for bleeding with anticoagulation. The benefit of anticoagulation outweighs the risk in the vast majority of cases. Women more likely to have stroke when not taking warfarin compared to men. Inform the patient to watch for signs and symptoms of bleeding but also subtle signs of blood loss (fatigue, orthostatic hypotension) 46 Notes Notes 47 48