John H. Alexander, MD, MHS Associate Professor of Medicine Director, Cardiovascular Research Duke Clinical Research Institute Duke Medicine Update on antithrombotics in acute coronary syndromes Oral Anti-Xa Agents A new opportunity?

Disclosure n I am on the faculty of the Duke University School of Medicine and Duke Clinical Research Institute. I conduct research on antithrombotic therapies in patients with atrial fibrillation and acute coronary syndromes. n Research Support: Bristol-Myers Squibb, CSL Behring, U.S. NIH, Pfizer, Phyxius Pharmaceuticals, Regado Biosciences n Consultant: Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Jannsen, Orexigen, Pfizer, U.S. VA CSP, Xoma Conflict of interest disclosures available at

op·por·tu·ni·ty Definitions n n a favorable juncture of circumstances n n a good chance for advancement or progress Oral Anti-Xa Agents post ACS, a new opportunity?

Primary Efficacy Endpoint CV Death, MI, Stroke Days after randomisation Cumulative incidence (%) 11.7 Clopidogrel Wallentin NEJM 2009;361: % per year Post-Acute Acute

Combination Better Trials Aspirin Better Odds Ratio & 95% CI N All studies 1425, Bleeding14 25, Extracranial1012, Intracranial 1012, Death/MI/Stroke107, Bleeding107, Extracranial73, Intracranial73, ComboAspirin % Andreotti EHJ 2006;27: Warfarin After Acute Coronary Syndrome * non-fatal thromboembolic 50.2 Death/MI/Stroke* Studies with INR 2-3

Antithrombotic Therapy Post-ACS Where Are We Now? Dose? Duration? Familiar Drugs Aspirin Clopidogrel New Drugs Prasugrel Ticagrelor Vorapaxar* Apixaban* Rivaroxaban* Bleeding Common Clinically important Individualization Weight Renal function Regional Genetic polymorphisms Drug interactions Insurance *Not approved in US

Tissue factor Plasma clotting cascade * Prothrombin * Thrombin * FibrinogenFibrin Thrombus Platelet aggregation Conformational activation of GPIIb/IIIa Collagen Thrombin Tx A 2 ADP Aspirin Clopidogrel Prasugrel Ticagrelor Ximeligatran Dabigatran Factor Xa * Rivaroxaban Apixaban Darexaban PAR1 Vorapaxar Atopaxar Warfarin * Post-ACS Antithrombotic Therapy Multiple Targets

New Oral Anticoagulants in ACS Phase 2 DrugTrialTargetPhase 2 ACS Published XimeligatranESTEEMFIIa2003 ApixabanAPPRAISEFXa2009 RivaroxabanATLAS-ACSFXa2009 DabigatranREDEEMFIIa2011 DarexabanRUBY-1FXa2011

Study Design Phase 2 Clinical Trials of New Anticoagulants Post-ACS NOAC Dose A Safety Outcome: Major or CRNM Bleeding Efficacy Outcome: Ischemic Event Composite Randomize Aspirin Clopidogrel Placebo Recent (≤7days) Acute Coronary Syndrome (STEMI or NSTE-ACS) NOAC Dose B NOAC Dose C NOAC Dose D Revasc 6 Month Treatment Period Parallel or Dose escalation

Phase 2 Conclusions n Adding an anticoagulant to dual antiplatelet therapy post-ACS consistently results in a dose related 2 to 4 fold increase in bleeding ● ESTEEM, REDEEM (IIa); APPRAISE, ATLAS, RUBY (Xa) ■ Suggestion of a potential reduction in ischemic events in some (ESTEEM, APPRAISE, ATLAS) but not other (REDEEM, RUBY) phase 2 clinical trials ● Benefits less apparent with dual antiplatelet therapy ■ Adequately powered phase 3 trial are needed ■ What is the right dose(s) to take forward in phase 3? ● Higher (more efficacy/more bleeding?) ● Lower (less efficacy/less bleeding?)

Apixaban 5 mg BID CrCl<40 ml/min 2.5 mg BID Primary Outcome: CV Death, MI, Ischemic Stroke Safety: TIMI Major Bleeding Randomize 1:1 Double blind Aspirin Other antiplatelet therapy N=10,800 Placebo Recent (≤7days) Acute Coronary Syndrome (STEMI or NSTE-ACS) At Least 2 Additional Risk-Factors Design Alexander NEJM 2011;365:

Index ACS Event Characteristic Apixaban (n=3705) Placebo (n=3687) Time from index ACS event to rand, days 6.0 (4.0, 7.0) Elevated biomarkers (CKMB or Troponin)81.2 Index ACS event type ST-elevation MI Non-ST-elevation MI Unstable angina Index event ACS management Coronary angiography PCI Medical therapy only Dual antiplatelet therapy Alexander NEJM 2011;365:

Trial Stopped Prematurely On November 15, 2010 the Data Monitoring Committee recommended that the trial be stopped due to an excess of clinically important bleeding in the apixaban arm without a counterbalancing reduction in ischemic events. Patients = 7048 Median f/u = 3.5 months Primary Events = 412 (44%) Alexander NEJM 2011;365:

Primary Outcome CV Death, MI, Ischemic Stroke Apixaban279 (7.5%) Placebo293 (7.9%) HR 0.95; 95% CI ; p=0.509 Alexander NEJM 2011;365:

Other Efficacy Outcomes Apixaban N=3705 Placebo N=3687 p-value CV death, MI, ischemic stroke CV death, MI, ischemic stroke, UA Death CV death Myocardial infarction Ischemic stroke Unstable angina Definite stent thrombosis Alexander NEJM 2011;365:

Primary Outcome CV Death, MI, Stroke — Subgroups *HR not calculated for subgroups with ≤10 events Alexander NEJM 2011;365:

TIMI Major Bleeding Apixaban 48 (1.3%) Placebo 18 (0.5%) HR 2.59; 95% CI 1.50–4.46; p=0.001 Alexander NEJM 2011;365:

TIMI Major Bleeding Subgroups *HR not calculated for subgroups with ≤10 events Alexander NEJM 2011;365:

Recent ACS: STEMI, NSTEMI, UA Stabilized 1-7 Days Post-Index Event Exclusions: increased bleeding risk, warfarin use, ICH, prior stroke if on ASA + thienopyridine PRIMARY ENDPOINTS: EFFICACY: CV Death, MI, Stroke (Ischemic, Hemorrhagic, or Uncertain Origin) SAFETY: TIMI major bleeding not associated with CABG Rivaroxaban 5.0 mg BID n=5,176 Stratified by Thienopyridine Use at MD Discretion ASA 75 to 100 mg/day Placebo n=5,176 Rivaroxaban 2.5 mg BID n=5,174 Event driven trial with 1,002 primary efficacy events Mega NEJM 2012;366:9-19

Months After Randomization Primary Efficacy Endpoint CV DeathMI/Stroke Rivaroxaban (both doses) HR 0.84 ( ) mITT p = ITT p = ARR 1.8% NNT = % 8.9% Estimated Cumulative Incidence (%) Placebo Placebo Rivaroxaban 2 Yr KM Estimate No. at Risk Mega NEJM 2012;366:9-19

Months Estimated Cumulative Incidence (%) Placebo Rivaroxaban 5 mg BID 0 8.8% 10.7% “Low Dose” Rivaroxaban 5.0 mg BID 24 Cardiovascular Death CV Death / MI / Stroke HR 0.94 mITT p=0.63 ITT p=0.57 Months % 4.1% Placebo Rivaroxaban 5 mg BID HR 0.85 mITT p=0.028 ITT p=0.010 NNT=53 Mega NEJM 2012;366:9-19

“Very Low Dose” Rivaroxaban 2.5 mg BID 0 24 Cardiovascular Death Months CV Death / MI / Stroke Estimated Cumulative incidence (%) HR 0.84 mITT p=0.020 ITT p=0.007 HR 0.66 mITT p=0.002 ITT p= % 9.1% 0 24 Placebo Months 4.1% 2.7% Rivaroxaban 2.5 mg BID Rivaroxaban 2.5 mg BID Placebo NNT = 71NNT = % 5% Mega NEJM 2012;366:9-19

Primary Efficacy Endpoint - Subgroups CV Death / MI / Stroke Consistent Benefit Mono / Dual Age Sex Weight Renal function Prior MI Prior Stroke Diabetes STEMI / NSTEMI Region Mega NEJM 2012;366:9-19

TIMI Major Bleeding Overall HR=3.96 ( ) P<0.001 Riva 5 BID HR=4.47 ( ) P<0.001 Riva 2.5 BID HR=3.46 ( ) P< Mega NEJM 2012;366:9-19 Intracranial Hemorrhage Riva 2.5 BID: HR 2.8 ( ) Riva 5.0 BID: HR 3.7 ( )

TIMI Major Bleeding - Subgroups Consistent Risk Mono / Dual Age Sex Weight Renal function Prior MI Prior Stroke Diabetes STEMI / NSTEMI Region Mega NEJM 2012;366:9-19

APPRAISE-2 and ATLAS-2 Comparing Efficacy Results n Different drugs l apixaban vs. rivaroxaban n Different doses l 5.0 bid vs. 2.5 bid / 5.0 bid n Different populations l High-risk vs. broad inclusive n Duration of treatment / follow-up l Mean 8 months vs. 13 months n Chance l Bias introduced by early study discontinuation

Apixaban279 (7.5%) Placebo293 (7.9%) HR 0.95; 95% CI p=0.509 Efficacy event rate higher in APPRAISE-2 at 6 months; similar treatment effect

Development of Oral Anti-Thrombotic Therapy Post-ACS Reduction in Ischemic Events ASA Prasugrel Ticagrelor No Tx Clopidogrel Vorapaxar Anticoagulant Increases in Bleeding

DoseDose CombinationsCombinations DurationDuration The Sweet Spot for Post-ACS Antithrombotics PatientFactorsPatientFactors Ischemic Events Ischemic stroke Myocardial infarction Unstable angina CV death Revascularization Bleeding Intracranial Major bleeding Transfusion Minor bleeding

op·por·tu·ni·ty Definitions n n a favorable juncture of circumstances n n a good chance for advancement or progress Oral Anti-Xa Agents post ACS, a new opportunity? My answer: certainly yes.

Summing it Up n Adding an oral fXa inhibitor to dual antiplatelet therapy post-ACS… l A definite ~3-4 fold (1.5% absolute) increase in major bleeding, including ICH. l A less certain ~15% (2.0% absolute) decrease in important ischemic events, including total mortality. n These findings (risks & benefits) appear consistent across a wide spectrum of patients. n Whether similar risks and benefits would be observed in patients taking new P2Y12 antagonists is unknown. n Whether and how factor Xa inhibitors are integrated into post-ACS care will depend largely on the relative importance given to ischemic events and bleeding.

“Humanity’s greatest advances are not in its discoveries – but in how those discoveries are applied…” Harvard

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