Utilizing Anticoagulants for Atrial Fibrillation Related Stroke Prevention

Utilizing Anticoagulants for Atrial Fibrillation Related Stroke Prevention Rajat Deo, MD, MTR Assistant Professor of Medicine Division of Cardiology, Electrophysiology Section University of Pennsylvania April 25, 2014 Disclosures None 1

Objectives Identify individualized anticoagulant therapy using risk stratification for patients with atrial fibrillation Evaluate the latest clinical data on current and novel anticoagulants Assess the guideline recommendations for anticoagulant and antiplatelet therapy Examine management strategies to improve adherence to anticoagulation therapies Atrial fibrillation Most common arrhythmia in clinical practice Affects >3 million Americans and estimated to reach 16 million by 2050 Responsible for 1 in 5 strokes in US 90% of thromboembolism in AF originates in the left atrial appendage 2

CHADS 2 scores establish risk of stroke CHADS 2, developed and validated by Gage et al, is a system for establishing the risk of stroke in patients with non rheumatic atrial fibrillation 1 Patients are awarded points based on comorbidities Condition Points C Congestive heart failure 1 H Hypertension 1 A Age 75 years 1 D Diabetes mellitus 1 S 2 Previous stroke or TIA 2 European Society of Cardiology Guidelines 2 CHADS 2 Score Treatment 0 Aspirin 1 Aspirin or warfarin* 2 Warfarin Risk of Stroke 20% 18% 15% 13% 10% 8% 5% 3% 0% Annual Risk of Stroke 18.2% 12.5% 8.5% 5.9% 4.0% 2.8% 1.9% 0 1 2 3 4 5 6 CHADS 2 Score * Use of aspirin or warfarin is based on additional patient characteristics such as age, number of risk factors, etc. 1 Gage BF et al, JAMA 2001;285:2864 2870 2 Camm AJ et al, Eur Heart J 2010;31:2369 2429 CHA 2 DS 2 VASc is a newer scoring system CHA 2 DS 2 VASc, developed by Lip et al, is a refinement of the older CHADS 2 Score which includes additional stroke risk factors and puts greater emphasis on age as a risk factor 1 Condition/Risk Factor Points C Congestive heart failure 1 H Hypertension 1 A Age 75 years 2 D Diabetes mellitus 1 S 2 Previous stroke or TIA 2 V Vascular disease 1 A Age 65-74 years 1 Sc Sex (female gender) 1 European Society of Cardiology Guidelines 2 Risk of Stroke 18% 15% 12% 9% 6% 3% 0% CHA 2 DS 2 -VASc Score Treatment 0 No treatment 1 Aspirin or warfarin or dabigatran 2 Warfarin or dabigatran Annual Risk of Stroke 15.2% 9.8% 9.6% 6.7% 6.7% 3.2% 4.0% 2.2% 1.3% 0.0% 0 1 2 3 4 5 6 7 8 9 CHA 2 DS 2 VASc Score 1 Lip GY et al, Chest. 2010;137(2):263-72 2 Camm AJ et al, Eur Heart J. 2010;31:2369 2429 3

How do they Compare? Generally, they result in similar treatment recommendations Where they are the same: Both CHADS systems assign 1 point each for presence of congestive heart failure (any), hypertension and diabetes Both CHADS systems assign 2 points for prior TIA or stroke Where they differ: CHA 2 DS 2 VASc puts greater emphasis on age, assigning 1 point for age between 65-74 years, and 2 points for age >75 years. CHADS 2 only assigns one point for age >75 years CHA 2 DS 2 VASc adds 1 point each for presence of any vascular disease and female gender, which are not included in the CHADS 2 score The Coagulation Cascade Antiplatelet agents: Aspirin, clopidogrel, NSAIDS, dipyridamole Rivaroxaban, Apixaban Dabigatran 4

Warfarin effective but limitations exist When taken appropriately, warfarin is effective Monitoring required to ensure therapeutic range (INR) Many foods and medicines interact with warfarin Despite efficacy, warfarin exposes patients to risks (e.g. intracranial hemorrhage and hemorrhagic stroke) Warfarin use represents a challenge to surgeries High rates of discontinuation and non adherence to therapy Warfarin tops the list for emergency hospitalizations for adverse drug events in older Americans 1 1 Budnitz DS, et al. NEJM 2011, 365: 2002-2012 Novel Oral Anticoagulants 5

Dabigatran RE LY: Randomized Evaluation of Long Term Anticoagulation Therapy Comparison: Stroke or systemic embolism (efficacy) and Major bleeding (safety) Dabigatran 110 mg bid vs Dabigatran 150 mg bid vs Warfarin (INR 2 3) Patients: N = 18,113 with nonvalvular AF + age 75 yrs, previous stroke/tia, LVEF <40%, or Class II-IV CHF; or Age 65 74 yrs with DM, HTN, or CAD Design: Blinded dabigatran/open-label warfarin Parallel-group, RCT, 1:1:1 randomized Designed as non-inferiority trial Connolly SJ et al. N Engl J Med. 2009;36:1139-51. 6

RE-LY Trial Reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation Dabigatran 110 mg PO BID or 150 mg PO BID (blinded) to open-label warfarin 1, 3, or 5 mg (goal INR 2-3) in patients with non-valvular Afib and one or more of the following risk factors: Previous stroke, TIA, or systemic embolism LVEF<40% Symptomatic heart failure, NYHA class >2 Age >75 years Age >65 years with DM, CAD, or HTN 18,113 patients randomized and followed for a median of 2 years Time in Therapeutic Range (TTR) for warfarin: 64% (mean) Dabigatran 150 mg bid compared to warfarin had an approximate 35% decreased risk (RR 0.66, 95% CI 0.53-0.82, p<0.001) in the primary efficacy event of stroke or systemic embolism Dabigatran 150 mg bid had a trend towards increased risk of bleeding compared to warfarin in major bleeding (not statistically significant) and showed a greater risk for life-threatening bleeding (RR 0.81, 95% CI 0.66-0.99, p = 0.04) and for GI bleeding (RR 1.50, 95% CI 1.19-1.89, p<0.001) Design of RE LY: A Non inferiority Trial Randomized Evaluation of Long-Term Anticoagulation Therapy Atrial fibrillation 1 Stroke risk factors Absence of contraindications Blinded event adjudication R Primary outcome: Stroke or systemic embolism Open Blinded Warfarin (Adjusted INR 2.0 3.0) n = 6022 Dabigatran 110 mg bid n = 6015 Dabigatran 150 mg bid n = 6076 Follow up: 1-yr minimum, 2-yr median, 3-yr maximum Connolly SJ et al. N Engl J Med. 2009;361:1139-51. 7

RE LY: Stroke or Systemic Embolism 1.0 0.05 Cumulative hazard rate 0.8 0.6 0.4 0.2 0.04 0.03 0.02 0.01 0.00 0 6 12 18 24 30 34% P < 0.001 0.0 0 Warfarin 6 12 18 24 30 Months Dabigatran 110 Dabigatran 150 Connolly SJ et al. N Engl J Med. 2009;361:1139-51. RE LY: Bleeding and Net Clinical Benefit Net clinical benefit = Composite of stroke, systemic embolism, MI, pulmonary embolism, death, or major bleeding D 110 mg D 150 mg Warfarin D 110 mg vs warfarin D 150 mg vs warfarin Annual rate Annual rate Annual rate RR (95% CI) P RR (95% CI) P Major bleeding 2.71% 3.11% 3.36% 0.80 (0.69 0.93) 0.003 0.93 (0.81 1.07) 0.31 Minor bleeding 13.16% 14.84% 16.37% 0.79 (0.74 0.84) <0.001 0.91 (0.85 0.97) 0.005 Intracranial bleeding 0.23% 0.30% 0.74% 0.31 (0.20 0.47) <0.001 0.40 (0.27 0.60) <0.001 Net clinical benefit 7.09% 6.91% 7.64% 0.92 (0.84 1.02) 0.10 0.91 (0.82 1.00) 0.04 D = dabigatran Connolly SJ et al. N Engl J Med. 2009;361:1139-51. 8

Dabigatran (Pradaxa) Class: Direct thrombin inhibitor Dose: 150 mg PO bid 75 mg PO bid for CrCl < 30 ml/min (dose not studied) FDA indications: Prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation Pharmacokinetics: Absorption: absolute oral bioavailability 3-7%; rapid absorption Metabolism: Rapidly and completely converted to dabigatran by esterase-catalyzed hydrolysis; not a CYP450 substrate, inducer, or inhibitor. P-glycoprotein substrate: Avoid use with P-gp inducers (i.e. rifampin); may use with concominant p-gp inhibitors (i.e. ketoconazole, verapamil, amiodarone, clarithromycin) but bioavailability of dabigatran is decreased. Elimination: t 1/2 = 12-17 hours; 80% renally eliminated Dabigatran (Pradaxa) Monitoring: - aptt: a value 2.5 x normal may indicate overanticoagulation For efficacy, median peak for 150 mg bid dose was ~2x control and was ~1.5x control measured 12 hours after the last dose. Median trough in trial of patients receiving 150 mg bid dose was 52 (40 to 76) seconds. -Ecarin Clotting Time (ECT): median trough in trial of patients receiving the 150 mg bid dose was 64 (44 to 103) seconds Reversal: Maintain adequate diuresis; 60% is dialyzable Fresh frozen plasma PRBC (packed red blood cells) Prothrombin complex concentrates Recombinant Factor VIIa Contraindications: Active bleeding or hypersensitivity to dabigatran 9

Dabigatran (Pradaxa) Considerations for surgery: CrCl>50mL/min: D/C drug 1-2 days before procedure CrCl<50mL/min: D/C drug 3-5 days before procedure If major surgery, spinal puncture, or epidural catheter or port is scheduled, consider discontinuing dabigatran for longer times Assess bleeding risk with ECT or aptt Storage Requirements: Both blister packs and bottles must be stored at 77 F. Capsules need to be kept in their original containers until they are used to protect from moisture and avoid potency loss. The product should be used within 4 months of opening the bottle. Conversion from and to Warfarin Converting from warfarin to dabigatran: Discontinue warfarin and start dabigatran when INR <2 Converting to warfarin from dabigatran, recommended start times based on renal function. If CrCl: >50 ml/min, start warfarin 3 days before stopping dabigatran 31 50 ml/min, start warfarin 2 days before stopping dabigatran 15 30 ml/min, start warfarin 1 day before stopping dabigatran <15 ml/min, no recommendation made Source: http://bidocs.boehringeringelheim.com/biwebaccess/viewservlet.ser?docbase=renetnt&fo lderpath=/prescribing%20information/pis/pradaxa/pradaxa.pdf 10

Rivaroxoban ROCKET AF: Protocol Schema Atrial fibrillation Rivaroxaban 20 mg daily 15 mg for CrCl 30 49 Randomize Double-blind; Double dummy (N ~ 14,000) Warfarin INR target - 2.5 (2.0 3.0 inclusive) 2 of: CHF Hypertension Age 75 Diabetes AND/OR Stroke, TIA, or systemic embolus Monthly monitoring and adherence to standard of care guidelines Primary endpoint: Stroke or non-cns systemic embolism Statistics: Non-inferiority, >95% power, 2.3% warfarin event rate ROCKET AF Investigators. Am Heart J. 2010;159:340-7. 11

Rivaroxaban vs Warfarin Efficacy outcomes Stroke/Systemic embolism Hemorrhagic stroke Myocardial infarction Safety outcomes ICH Major bleeding 0 0.50 1.00 1.50 2.00 Rivaroxaban better Warfarin better Patel MR et al. N Engl J Med. 2011;365:883-91; Fox KAA et al. Eur Heart J. 2011;32: 2387-94 12

ROCKET AF Prevention of stroke or systemic embolism in atrial fibrillation ROCKET AF Rivaroxaban 20 mg PO once daily vs. adjusted dose warfarin (target INR of 2-3) Patients with CrCl 30-49 ml/min use rivaroxaban 15 mg PO once daily Primary efficacy endpoint: composite of ischemic or hemorrhagic stroke and systemic embolism Rivaroxaban demonstrated non-inferiority in primary endpoint HR (hazard ratio) 0.79 (95% CI 0.66-0.96) in the per-protocol population and in the intent-to-treat population (p<0.001). Rivaroxaban did NOT demonstrate superiority in the intent-to-treat population» HR 0.88 (95% CI 0.75-1.03) statistically NOT significant (p=0.12) Primary safety endpoint: composite of major and clinically relevant nonmajor bleeding events Major and nonmajor bleeding events remained similar between 2 groups HR 1.03 (95% CI 0.96-1.11) statistically NOT significant Increased incidence of GI bleeding (3.2%) vs. warfarin (2.2%, p<0.001). ROCKET AF Limitations: Exclusion criteria:» Patients with mechanical valves» Patients taking aspirin >100 mg/day, and aspirin in combination w/ thienopyridine» Concomitant medications (i.e. CYP3A4 inhibitors, inducers, chronic use of NSAIDs) Possible violation of constancy assumption for non-inferiority margin» Study population had higher risk patients CHADS2 score 3.47» Lower mean time-in-therapeutic range (TTR) of 55% compared to other studies (62 to 73%) 13

Prescribing information Dabigatran Rivaroxaban Indication To reduce the risk of stroke and systemic embolism in patients with non-valvular AF Dosage CrCl >30 ml/min: 150 mg bid CrCl 15 30 ml/min: 75 mg bid CrCl >50 ml/min: 20 mg qd CrCl 15 50 ml/min: 15 mg qd http://bidocs.boehringeringelheim.com/biwebaccess/viewservlet.s er?docbase=renetnt&folderpath=/prescribi ng%20information/pis/pradaxa/pradaxa.pdf http://www.xareltohcp.co m/sites/default/files/pdf/xa relto_0.pdf#zoom=100 Rivaroxaban (Xarelto) Class: Direct Factor Xa inhibitor Non-FDA Indications: Prevention of stroke or systemic embolism in patients with atrial fibrillation Pharmacokinetics: Absorption: bioavailability of 80-100%, take with or without food Metabolism: P-glycoprotein, CYP3A4 substrate Concomitant use of inhibitors will anticoagulant effect Inducers will anticoagulant response If use is unavoidable, can give 20 mg once daily taken with food. Avoid use in patients with moderate or severe hepatic impairment (Child-Pugh B or C). Elimination: half-life of 5-9 h, 11-13 h (elderly); 66% (renal), 34% (feces) Avoid use in patients with CrCl < 30 ml/min. Caution in patients with CrCl 30 to 50 ml/min monitoring recommended 14

Rivaroxaban (Xarelto) Contraindications/Warnings: Black Box Warning: Epidural or spinal hematomas can occur in patients who are anticoagulated and are receiving neuraxial anesthesia or undergoing spinal puncture Hepatic disease Bleeding Concomitant strong CYP3A4, P-glycoprotein inhibitors and inducers Pregnancy Breastfeeding Monitoring: bleeding complications (incidence: 5.8%) Routine monitoring not required Anti-factor Xa assays Most reliable Assays are not standardized and no therapeutic level has been established Prothrombin time (PT)/ INR Dose dependent with PT No standardized assay; INR is standardized for warfarin only Activated partial thromboplastin time (aptt) Not very effective since prolongation only seen at peak drug levels Rivaroxaban (Xarelto) Reversal: No standard antidote Factor VIIa (theoretical due to benefit with fondaparinux(arixtra)) Cost: ~$10,000 for single 90 µg/kg dose in 80 kg patient Prothrombin complex concentrate (PCC) (theoretical) Usefulness in clinical settings not yet established Fresh frozen plasma Short-term reversal, short half-life of 3-5 hours Activated charcoal Considerations for surgery: No exact guidelines established Timing for stopping rivaroxaban will be dependent on half-life 15

Apixaban (Eliquis) 16

Hemorrhagic stroke 49% lower Ischemic Stroke 8% lower Fatal/Disabling stroke 0.5% per year vs 0.71% Bleeding 327 patients in the apixaban group (2.13% per year as compared with 462 patients in the warfarin group (3.09% per year). Intracranial hemorrhage 0.33% per year with apixaban and 0.8% per year with warfarin Rate of any bleeding was 25.8% per year in the warfarin group and 18.1% in the apixaban group. Absolute reduction of 7.7 percentage points. Fatal bleeding occurred in 34 patients in the apixaban group & 55 patients in the warfarin group 17

Class: Factor Xa inhibitor Apixaban(Eliquis) MOA: Direct-acting, reversible factor Xa inhibitor. Inhibits the conversion of prothrombin to thrombin. Dose: 5 mg po BID for patients with non-valvular AF. Decrease to 2.5 mg po BID w/ 2 of the following (age >80, <60 kg, Creat>1.5 Pharmacokinetics: Absorption: rapidly absorbed, reach Cmax within 1-3 hours; 66% bioavailability Metabolism: CYP3A4 substrate to inactive metabolite O- demethyl-apixaban. Drug interactions: Potent 3A4 inhibitors Elimination: t 1/2 12 hours; 25% renally and 55% fecally eliminated. Apixaban(Eliquis) ADRs: Bleeding (6%), nausea (7%), vomiting (5%), constipation (5%) in ADVANCE trials. Elevation of LFTs (the incidence rate was no different from the comparator groups) ALT >3X ULN (~1.1% in ADVANCE-I and ARISTOTLE trials) Monitoring: No routine monitoring is required Anti factor Xa assay Linear relationship between apixaban plasma concentration and factor Xa inhibition No standardized assay Prothrombin time/inr Reversal agent: No standard antidote investigational agent PRT064445: designed to reverse the actions factor Xa inhibitors. preclinical study results demonstrated reversal effects of anticoagulation by enoxaparin, fondaparinux, both factor Xa inhibitors in an animal model. Prothrombin complex concentrates (theoretical) Recombinant factor VII (theoretical) Activated charcoal (preclinical study- reduced apixaban exposure) 18

The Bottom Line on Alternatives to Warfarin Dabigatran, rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials However, real world and long term efficacy and safety and drug interactions have yet to be investigated While new oral anticoagulants may avoid the burden of regular INR monitoring, bleeding risks and high rates of non adherence are still a problem A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long term patient adherence Edoxaban 19

Inclusion criteria: ENGAGE AF TIMI 21 years of age AF documented within 12 months of randomization CHADS 2 risk assessment 2 Anticoagulation therapy planned for duration of trial Exclusion criteria AF due to reversible disorder Estimated CrCl < 30mL/min High risk of bleeding Use of dual antiplatelet therapy Moderate to severe mitral stenosis Acute coronary syndrome Coronary revascularization stroke within 30 days before randomization Non-compliance to study procedure Design of ENGAGE AF TIMI 48 Patients with moderate to high risk AF Randomize Double-blind; Double dummy (N =21,105) Edoxaban High dose: 60 mg OR Low dose: 30 mg (CrCl 30 50) Warfarin INR 2 3 Study visits on days 8, 15, 29, 60, 3 months and every 3 months thereafter for duration of study 20

ENGAGE AF TIMI 48 Primary efficacy end point: stroke or systemic embolism Intent-to-treat analysis found favoring trend high dose Edoxaban vs. warfarin (HR, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08). Intent-to-treat analysis found unfavorable trend with low dose Edoxaban vs. warfarin (HR, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). Principal safety end point: major bleeding Annualized bleeding events higher with warfarin, 3.43% as compared to high dose Edoxaban at 2.75% (HR, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and low dose Edoxaban at 1.61% (HR, 0.47; 95% CI, 0.41 to 0.55; P<0.001) Major GI bleeding was higher with high dose Edoxaban (1.51%) vs. warfarin (1.23%), and lowest with low dose Edoxaban (0.82%). ENGAGE AF TIMI 48: Primary Efficacy 21

Principal Safety Endpoint Conclusions of ENGAGE AF TIMI 48 Low dose and high dose Edoxaban were noninferior to warfarin for prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. High dose Edoxaban resulted in more GI bleeding versus warfarin and low dose Edoxaban. 22

Summary of the 4 NOACs PK/PD of 4 Novel Oral Agents Target Dabigatran Apixaban Rivaroxaban IIa (thrombin) Edoxaban (DU-176b) Xa Xa Xa Hrs to Cmax 2 1-3 2-4 1-2 CYP Metabolism None 15% 32% NR Half-Life 12-14h 8-15h 9-13h 8-10h Renal Elimination 80% 25% 66% 35% CYP = cytochrome P450; NR = not reported Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010; 4: 7-14 Ericksson BI et al. Clin Pharmacokinet 2009; 48: 1-22 Ruff CR et al. Am Heart J 2010; 160: 635-41 23

Phase III AF trials RE-LY ROCKET AF ARISTOTLE ENGAGE AF-TIMI 48 Drug Dabigatran Rivaroxaban Apixaban Edoxaban Dose (mg) Freq 150, 110 BID 20 (15*) QD 5 (2.5*) BID 60*, 30* QD N 18,113 14,266 18,206 >21,000 Design PROBE 2 x blind 2 x blind 2 x blind AF criteria AF x 1 <6 mths AF x 2 ( 1 in <30d) AF or AFI x 2 <12 mths AF x 1 <12 mths % VKA naive 50% 38% 43% 40% goal *Dose adjusted in patients with drug clearance. **Max of 10% with CHADS-2 score = 2 and no stroke/tia/see PROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist RE-LY Dabigatran 110 mg Dabigatran 150 mg Warfarin CHADS 2 Mean 0-1 (%) 2 (%) 3+ (%) 2.1 32.6 34.7 32.7 2.2 32.2 35.2 32.6 2.1 30.9 37.0 32.1 ROCKET AF Rivaroxaban Warfarin CHADS 2 Mean 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) 3.5 13 43 29 13 2 3.5 13 44 28 12 2 3+ 87% ARISTOTLE Apixaban Warfarin CHADS 2 Mean 0-1 (%) 2 (%) 3+ (%) 2.1 34 35.8 30.2 2.1 34 35.8 30.2 ENGAGE AF-TIMI 48 Edoxaban 60 mg Edoxaban 30 mg Warfarin CHADS 2 Mean 3 (%) 4-6 (%) 2.8 77.4 22.6 2.8 77.1 22.9 2.8 77.8 22.2 24

Comparison of Trial Metrics Time in Therapeut ic Range (TTR) RE-LY ROCKET AF ARISTOTLE ENGAGE AF 64% 58% 62% 68% 25

Summary of recommendations Summary of Recommendations 26

Dosing Recommendations Conclusions PROTECT THE BRAIN! PROTECT THE BRAIN! PROTECT THE BRAIN! Many AF patients, who should be anticoagulated, are not being treated Variety of anticoagulants that can be used to protect against thromboembolic risk in AF Provides the clinician a greater opportunity to select AN anticoagulant 27