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1 NOACS or Not? When to Use -- and Not Use The Novel Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation 6 th Annual New York State Stroke Conference Tarrytown, NY May 29, 2014 Jonathan L. Halperin, M.D. The Cardiovascular Institute Disclosure Relationships with Industry Consulting fees from the following companies involved in developing anticoagulant drugs and device-based strategies for thromboembolism prevention: Bayer HealthCare Biotronik Boehringer Ingelheim Boston Scientific Daiichi Sankyo Janssen Johnson & Johnson Medtronic Sanofi-Aventis Anticoagulation in Atrial Fibrillation Stroke Risk Reductions AFASAK SPAF BAATAF CAFA SPINAF EAFT Aggregate Warfarin Better Control Better 100% 50% 0-50% -100% Hart R, et al. Ann Intern Med 2007;146:857. 1

2 Anticoagulation in Atrial Fibrillation The Standard of Care for Stroke Prevention Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF Unblinded Unblinded Unblinded Double-blind; Men only Terminated early EAFT 2 o prevention; Unblinded Aggregate 100% 50% 0-50% -100% Hart R, et al. Ann Intern Med 2007;146:857. The CHADS 2 Index Stroke Risk in Patients with Atrial Fibrillation Approximate Risk threshold for Anticoagulation Score (points) Risk of Stroke (%/year) %/year Van Walraven C, et al. Arch Intern Med 2003; 163:936. Go A, et al. JAMA 2003; 290: Gage BF, et al. Circulation 2004; 110: The CHA 2 DS 2 VASc Index Stroke Risk Score for Atrial Fibrillation Weight (points) Congestive heart failure or LVEF < 35% 1 Hypertension 1 Age >75 years 2 Diabetes mellitus 1 Stroke/TIA/systemic embolism 2 Vascular Disease (MI/PAD/Aortic plaque) 1 Age years 1 Sex category (female) 1 Moderate-High risk > 2 Low risk 0-1 Lip GYH, Halperin JL. Am J Med 2010; 123:

3 The HAS-BLED Score Risk Score to Predict Major Bleeding in Anticoagulated Patients with Atrial Fibrillation Weight (points) Hypertension (>160 mmhg systolic) 1 Abnormal renal or hepatic function 1-2 Stroke 1 Bleeding history or anemia 1 Labile INR (TTR <60%) 1 Elderly (age >75 years) 1 Drugs (antiplatelets, NSAIDs) & alcohol 1-2 High risk (>4%/year) > 4 Moderate risk (2-4%/year) 2-3 Low risk (<2%.year) 0-1 Pisters R, et al Chest 2010 (online) Risk Factors for ICH During Anticoagulation Established or likely factors Age >75 years Hypertension (systolic BP >160 mmhg) Cerebrovascular disease (prior stroke) Intensity of anticoagulation Initial period of anticoagulation Concomitant antiplatelet therapy Amyloid cerebral angiopathy Leukoaraiosis Ethnicity Tobacco and alcohol Hart RG, et al. Stroke 1995;26:1471. Sjöblom L, et al. Stroke 2001; 32: 2567 Shen AY, et al. J Am Coll Cardiol 2007; 50: 309. Target-Specific Oral Anticoagulants The NOACs 3

4 Targets for New Anticoagulants Oral TTP889 Apixaban Betrixaban Darexaban LY TAK-442 Ximelagatran Dabigatran X Fibrinogen TF/VIIa IXa VIIIa Va Xa IIa IX II (thrombin) AT Fibrin Adapted from Weitz JI, Bates SM. J Thromb Haemost 2005; 3:1843 Turpie AGG. Eur Heart J 2007; 29,155 Guertin KR, Choi YM. Curr Med Chem 2007; 14:2471 APC AT stm TF FPI Parenteral TFPI (tifacogin) APC (drotrecogin alfa) stm (ART-123) Idra(biota)parinux DX-9065a Otamixaban activated protein C antithrombin soluble thrombomodulin tissue factor tissue factor pathway inhibitor Novel Oral Anticoagulants Pharmacological Properties Feature Dabigatran Apixaban Target IIa Xa Xa Xa Molecular Weight (g/mol) Prodrug Yes No No No Bioavailability (%) Time to peak (h) Half-life (h) Renal excretion (%) CYP Metabolism (%) None 32 <32 <4 Antidote None None None None Ogata, et al. J Clin Pharmacol 2010;50:743. Mendell, et al. Am J Cardiovasc Drugs 2013;13:331. Bathala, et al. Drug Metab Dispos 2012;40:2250. New Oral Anticoagulants Phase III Trials for Stroke Prevention in Patients with AF Trial Acronym RE-LY Drug Dabigatran Dose (mg) 150 bid 110 bid Design n Risk Dose Factors adjustment (#) PROBE 18,113 1 None ROCKET-AF 20 qd 15 qd* Blinded 14, % at baseline ARISTOTLE Apixaban 5 bid 2.5 bid* Blinded 18, % at baseline ENGAGE-AF 60 qd 30 qd* Blinded 21, % at baseline >9% after * Adjusted based on renal function or other factors associated with reduced drug clearance 4

5 Trials of NOACs for AF Distribution of Stroke Risk Factors CHADS 2 Scores RE-LY (Dabigatran) Connolly SJ, et al. N Engl J Med 2009;361:1139. Patel MR, et al. N Engl J Med 2011; 365:883. Granger CB et al. N Eng J Med 2011; 365. Giugliano RP, et al. N Engl J Med 2013; 369: ROCKET-AF () ARISTOTLE (Apixaban) ENGAGE AF () # Randomized 18,113 14,264 18,201 21,105 Age, years 72 ± 9 73 [65-78] 70 [63-76] 72 [64-78] Female, % Paroxysmal AF VKA naive Aspirin use CHADS Relative Risks of Stroke and Systemic Embolism Meta-Analysis Warfarin vs. Placebo/control Warfarin vs. low-dose warfarin + ASA Warfarin vs. ASA VKA vs. ASA + clopidogrel Warfarin vs. ximelagatran Warfarin vs. dabigatran 110 mg bid Warfarin vs. dabigatran 150 mg bid Favors warfarin Favors alternative Camm AJ. European Society of Cardiology, Barcelona, August ROCKET-AF Trial Stroke and Systemic Embolism On Treatment N= 14,143 ITT N= 14,171 Warfarin Event Rates (%/year) HR (95% CI) 0.79 (0.65,0.95) 0.88 (0.74,1.03) p* better Warfarin better * p-values for superiority Patel MR, et al. N Engl J Med 2011; 365:883. 5

6 ROCKET-AF Trial Efficacy for Secondary Stroke Prevention 7 Prior stroke No Prior stroke 6 Cumulative event rate (%) Warfarin Warfarin 2 o 1 o Months from randomization *Safety population, on-treatment. Hankey GJ, et al. Lancet Neurol 2012; 11: 315. ARISTOTLE Trial Primary Outcome: All Stroke or Systemic Embolism Non-inferiority p < % RRR Apixaban 212 patients, 1.27%/year Warfarin 265 patients, 1.60%/year HR 0.79 (95% CI, ); Superiority p = No. at Risk Warfarin Apixaban Granger CB et al. N Engl J Med 2011; 365 ARISTOTLE Trial Major Bleeding Events 31% RRR Apixaban 327 patients, 2.13%/year Warfarin 462 patients, 3.09%/year HR 0.69 (95% CI, ); p <0.001 No. at Risk Warfarin Apixaban Granger CB et al. N Engl J Med 2011; 365 6

7 Apixaban vs. Aspirin: The AVERROES Trial Efficacy and Safety Event Rates Event Rate (% / y) p< p = 0.57 Apixaban Aspirin Stroke/Systemic Embolism Major Bleeding Connolly S. N Engl J Med 2011; 364: 806. ENGAGE AF TIMI-48 Trial Primary Endpoint Stroke + Systemic Embolism 60* mg QD vs warfarin 30* mg QD vs warfarin Warfarin TTR 68.4% Hazard ratio (97.5% CI) edoxaban noninferior Non-inferiority (mitt, on-treatment) p < p = * mg QD vs warfarin 30* mg QD vs warfarin edoxaban superior edoxaban inferior Superiority (ITT, Overall) p = 0.08 p = 0.10 Giugliano RP, et al. N Engl J Med 2113; 369: * mg ENGAGE AF TIMI-48 Trial Safety Outcome: Bleeding On Treatment ISTH Major Bleeding 30* mg Warfarin TTR 68.4% HR (95% CI) p <0.001 p <0.001 Fatal Bleeding p = p <0.001 ICH GI Bleeding p <0.001 p <0.001 p = 0.03 p <0.001 Giugliano RP, et al. N Engl J Med 2113; 369: edoxaban superior edoxaban inferior 7

8 Nonvalvular Atrial Fibrillation A Moving Target? Original warfarin trials excluded: Rheumatic heart disease (mitral stenosis) Prosthetic heart valves (mechanical or biological) Valve repair (rare, not considered) Thyrotoxicosis Self-limited AF due to acute illness or surgery Identifying Patients with Nonvalvular AF Valvular Disease Exclusion Criteria in Trials of NOACS Trial SPORTIF III & V RE-LY ROCKET AF AVERROES ARISTOTLE ENGAGE AF Excluded Valvular Diseases Mitral stenosis or previous valvular heart surgery Hemodynamically relevant valve disease or prosthetic valve Mitral stenosis or prosthetic heart valve Valvular disease requiring surgery or mechanical prosthetic heart valve Moderate or severe mitral stenosis or prosthetic heart valve requiring anticoagulation Moderate or severe mitral stenosis or mechanical heart valve. (Patients with bioprosthetic heart valves or valve repair could be included.) AVR or MVR Dabigatran vs. Warfarin in Patients with Mechanical Heart Valves RE-ALIGN Trial Kaplan-Meier Analysis First Thromboembolic Event <7 days 3 months Dabigatran dose 150, 220 or 300 mg bid, based on kidney function and blood levels 252 patients Trial terminated b/o excess thromboembolism and bleeding Probability of No event Probability of No event Warfarin Dabigatran Extension phase of the trial p=0.24 Days First Bleeding Event Warfarin Dabigatran Extension phase of trial p=0.01 Eikelboom JW, et al. N Engl J Med 2013; 369:1206. Days 8

9 Meta-analysis of NOACs vs. Warfarin in Non-valvular AF All Stroke + Systemic Embolism 71,683 patients enrolled in RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE-AF TIMI 48 42,411 patients randomized to a NOAC 29,272 patients randomized to warfarin NOAC (events) Warfarin (events) RR (95% CI) p Favors NOAC Favors warfarin Ruff CT, et al. Lancet 2014; 383; 955. Meta-analysis of NOACs vs. Warfarin in Non-valvular AF Secondary Efficacy and Safety Outcomes Favors NOAC Favors warfarin Ruff CT, et al. Lancet 2014; 383; 955. Meta-analysis of NOACs vs. Warfarin in Non-valvular AF Major Bleeding Favors NOAC Favors warfarin Ruff CT, et al. Lancet 2014; 383;

10 Newer Oral Anticoagulants for AF Key Similarities All are noninferior to warfarin for prevention of total stroke and systemic embolism All reduce the risk of intracerebral hemorrhage Outcomes of major bleeding are generally better than with warfarin Reductions in mortality are comparable, ~10%/year, mainly related to lower rates of cardiovascular death and fatal bleeding. Newer Anticoagulants for AF Inferences from the Pivotal Trials Differences in outcomes may be due to variations in study design, sample size, intrinsic risk, concurrent treatment and other factors, rather than the drugs themselves. In the doses approved for use in the U.S., factor Xa inhibitors may have less efficacy against ischemic stroke than dabigatran but also less toxicity. Factor Xa inhibitors are less dependent on renal elimination and have fewer GI side effects than dabigatran. NOACs for Venous Thromboembolism Prophylaxis and Therapy Trials (Partial list) ODIXa-HIP ODIXa-Knee RECORD 1,2,3,4 EINSTEIN-DVT EINSTEIN-PE EINSTEIN Extension Dabigatran RE-MODEL RE-MOBILIZE RE-NOVATE RE-COVER RE-MEDY RE-SOLVE HOKUSAI-VTE STARS-S STARS-E Apixaban ADVANCE 1,2,3 AMPLIFY AMPLIFY-EXT APROPOS ADAPT APPRAISE BOTTICELLI 10

11 NOACs for VTE Prevention and Treatment U.S. Regulatory Approval Status (Approved) VTE prophylaxis (orthopaedic surgery) DVT treatment PE treatment Apixaban (Approved) VTE prophylaxis (orthopaedic surgery) Dabigatran (Approved) DVT treatment PE treatment Dabigatran (Filed) VTE prophylaxis (orthopaedic surgery) Apixaban (Filed) DVT treatment PE treatment (Filed) VTE prophylaxis DVT treatment PE treatment Novel Oral Anticoagulants for AF Areas of Uncertainty Requiring Further Study Patients with AF undergoing PCI or CABG Cardioversion of AF Catheter ablation, Maze or intra-operative cryoablation Device-detected AF Bioprosthetic heart valves Valve repair Prior hemorrhagic stroke Resuming NOACs After Surgery or Invasive Procedures Timing and Dosing Considerations Depends on postoperative risk of bleeding Risks of bleeding and VTE postoperatively usually outweigh the risk of embolic stroke For major abdominal or urologic surgery: delay NOAC until drainage or active bleeding cease. For procedures with good hemostasis, resume NOAC >4-6 hours postoperatively. When bowel paralysis is present, bridging with a parenteral anticoagulant may be necessary. Dabigatran: Resume 75 mg first dose, then maintenance dose. : Resume 10 mg first dose, then maintenance dose. Apixaban: Resume 2.5 mg first dose, then maintenance dose. :? Resume 30 mg first dose, then maintenance dose. Adapted from Schulman S, et al. Blood 2012; 119:

12 Outcomes of Major Bleeding During Treatment with Dabigatran or Warfarin 1,034 Patients, 1,121 Major Bleeds in 5 Phase III Trials Majeed A, et al. Circulation (published online September 30, 2013) Development of a Specific Dabigatran Antidote adabi-fab Binding and Reversal of the Anticoagulant Effect Millar CM, Lane DA. Blood 2013; 121:3543. Schiele F, et al. Blood 2013; 121:3554. Reversal of the Anticoagulant Effect of Factor Xa Inhibitors Dose-Dependent Action of Recombinant Andexanet alfa (PRT064445) On fxa Suppression by Betrixaban, or Apixaban Lu G, et al. Nature Med 2013: 19:

13 Common Concerns about the NOACs How to choose between VKA and NOAC which NOAC to select? Lack of monitoring insecurity about dosing and adherence No simple spot-checks need-to-know occasions Short half-lives concern about missed doses No antidotes yet how to manage major bleeding? Drug-drug interactions under- and over-dosing Clinical development incomplete e.g., cardioversion, ablation, PCI Contraindications valvular AF Need to monitor renal and hepatic function Expense for health care systems and patients Modified from Camm AJ, American Heart Association Scientific Sessions, Dallas, TX, November 2013 Antithrombotic Therapy for Atrial Fibrillation ACC/AHA/HRS Guidelines, 2014 January CT, et al. Circulation 2014; (E-published March 28). Antithrombotic Therapy for Atrial Fibrillation ACC/AHA/HRS Guidelines, 2014 January CT, et al. Circulation 2014; (E-published March 28). 13

14 Summary of Phase III NOAC Trial Results Dabigatran Outcomes vs. warfarin Apixaban 150 mg bid 60 mg qd Stroke/systemic embolism Superiority Non-inferiority Superiority Non-inferiority Stroke Yes No Yes Yes Ischemic or unspecified Stroke Yes No No No Hemorrhagic stroke Yes Yes Yes Yes Disabling or fatal stroke Yes No Yes Yes Vascular death Yes No No Yes All-cause mortality No No Yes No Major bleeding No No Yes Yes ICH Yes Yes Yes Yes GI bleeding Yes Yes No No Treatment discontinuation No No Yes Yes Modified from Camm AJ, American Heart Association Scientific Sessions, Dallas, TX, November 2013 Considerations in NOAC Selection for AF High risk of bleeding HAS-BLED 3 Consider agent / dose with the lowest incidence of bleeding Apixaban Specific patient characteristics Previous GI bleeding or high-risk High risk of ischemic stroke, low bleeding risk Previous stroke (secondary prevention) CAD, previous MI or highrisk for ACS/MI Renal impairment GI upset / disorders Consider agent with the lowest reported incidence of GI bleed Consider agent / dose with the best reduction of ischemic stroke Consider best investigated agent or greatest reduction of 2 0 stroke Consider agent with positive effect in ACS Consider agent least dependent on renal function Consider agent / dose with fewer GI effects Apixaban Dabigatran 150 Apixaban Apixaban Patient preference Consider once daily formulation Modified after Savalieva I, Camm AJ. Clin Cardiol 2014; 37: 32 Alternatives to Anticoagulation Left Atrial Appendage Occlusion 14

15 PROTECT-AF Trial Primary Efficacy Events Stroke, Systemic Embolism and Cardiovascular Mortality Reddy VY, et al, Heart Rhythm Society Scientific Sessions, May 2013 Ischemic Stroke in PROTECT-AF Trial Mechanistic Inferences Patients with Ischemic Stroke (%) Procedure related Not Procedurerelated Reddy VY, et al, Heart Rhythm Society Scientific Sessions, May 2013 From Fermented Sweet Clover to Molecular Targeting of Thrombosis The Promise of New Oral Anticoagulants The Goal: To bring effective stroke prevention therapy to more patients. 15

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