Apixaban Plus Mono vs. Dual Antiplatelet Therapy in Acute Coronary Syndromes: Insights from the APPRAISE-2 Trial

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1 Apixaban Plus Mono vs. Dual Antiplatelet Therapy in Acute Coronary Syndromes: Insights from the APPRAISE-2 Trial Connie N. Hess, MD, MHS, Stefan James, MD, PhD, Renato D. Lopes, MD, PhD, Daniel M. Wojdyla, MSc, Megan L. Neely, PhD, Danny Liaw, MD, PhD, Emil Hagstrom, MD, PhD, Deepak L. Bhatt, MD, MPH, Steen Husted, MD, DSc, Shaun G. Goodman, MD, MSc, Basil S. Lewis, MD, Freek W.A. Verheugt, MD, Raffaele De Caterina, MD, PhD, Hisao Ogawa, MD, Lars Wallentin, MD, PhD, John H. Alexander, MD, MHS

2 Disclosures None

3 Background Risk of repeat cardiovascular events after acute coronary syndrome (ACS) may be due to persistent thrombin generation Mixed results for efficacy w/ oral anticoagulation plus antiplatelet therapy post-acs Warfarin 1 & rivaroxaban 2 reduce ischemic events No efficacy of dabigatran 3 or apixaban 4 versus placebo Consistent increase in bleeding with oral anticoagulation plus antiplatelet therapy after ACS Rivaroxaban approved in Europe for secondary prevention post-acs (based on ATLAS ACS-2 TIMI 51) 1 Rothberg, 2005 Ann Intern Med 2 Mega, 2012 N Engl J Med 3 Oldgren, 2011 Eur Heart J 4 Alexander, 2011 N Engl J Med

4 Mono vs dual antiplatelet therapy? Bleeding Ischemia Anticoagulation with Xa inhibitors may have different efficacy / bleeding balance on top of mono vs. dual antiplatelet therapy In ATLAS-2, only 7% of patients were on mono antiplatelet therapy In APPRAISE-2, 19% of patients on mono antiplatelet therapy

5 Objectives To describe overall patterns of mono and dual antiplatelet therapy use over time To examine rates of ischemic and bleeding events among patients randomized to apixaban vs. placebo on top of ASA alone vs. ASA plus clopidogrel

6 Methods - Data Source Data from the Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2) trial Double-blind, placebo-controlled randomized trial Patients w/ ACS w/in 7 days + at least 2 additional risk factors: Age >65 yrs, diabetes, myocardial infarction w/in 5 yrs, cerebrovascular disease, PAD, CHF, CrCl<60 ml/min, no revascularization after index event Randomized to apixaban (5 mg bid or 2.5 mg bid for CrCl <40 ml/min) or placebo Trial stopped early due to increased bleeding with apixaban without a reduction in ischemic events

7 Methods - Definitions Description of overall antiplatelet therapy Mono = any antiplatelet agent alone (ASA, clopidogrel, prasugrel, ticlopidine) Dual = ASA + thienopyridine Main analysis population ASA alone ASA + clopidogrel Daily medication records were summarized to reflect weekly use Patients considered to be on a specific regimen if >50% of the week

8 Methods - Outcomes Efficacy Primary: Composite of cardiovascular death, myocardial infarction (MI), and ischemic stroke Secondary: Cardiovascular death, all-cause mortality Safety Primary: Thrombolysis in Myocardial Infarction (TIMI) major bleeding Secondary: TIMI major or minor bleeding

9 Methods - Statistical Analysis Overall population Mono vs. dual antiplatelet therapy use assessed over time Main analysis population Patients examined according to ASA vs. ASA + clopidogrel Simple model : Cox proportional hazards model adjusted for baseline clinical variables Marginal Structural Model : Cox model with antiplatelet therapy as a time-dependent covariate Patients re-weighted weekly based on their propensity to take ASA or ASA + clopidogrel to account for actual antiplatelet therapy taken Tested for interaction between antiplatelet therapy and apixaban vs. placebo

10 Results - Patient Selection Patients randomized in APPRAISE-2 (n=7,392) Excluded (n=28): No antiplatelet therapy (n=23) No information on antiplatelet therapy (n=5) Patients on baseline antiplatelet therapy (n=7,364) Mono antiplatelet therapy (n=1,369) Dual antiplatelet therapy (n=5,995) Aspirin (n=1,202) Clopidogrel (n=162) Prasugrel (n=4) Ticlopidine (n=1) Clopidogrel (n=5,826) Prasugrel (n=155) Ticlopidine (n=26)

11 Antiplatelet Therapy Use Mono (N=1369) Dual (N=5995) Switching during course of trial None 1108 (80.9) 4826 (80.7) Any 261 (19.1) 1154 (19.3) Median days to 1st switch (25 th, 75 th ) 19 (4, 97) 41 (12, 109) Number of switches (56.7) 728 (63.1) 2 75 (28.7) 252 (21.8) (14.6) 174 (15.1)

12 Baseline Characteristics ASA only (N=1202) ASA + Clopidogrel (N=5814) Median age (25 th, 75 th ), yrs 67 (58, 73) 67 (59, 74) Female sex 493 (41.0) 1750 (30.1) Diabetes 468 (38.9) 2860 (49.2) History of MI 276 (23.0) 1544 (26.6) History of cerebrovascular disease 116 (9.7) 592 (10.2) History of PAD 165 (13.7) 1,105 (19.0) HF or LVEF <40% during index event 538 (44.8) 2279 (39.2) History of renal insufficiency 320 (26.6) 1708 (29.4) Prior coronary revascularization 176 (14.6) 1771 (30.5) Index ACS event ST-segment elevation MI 383 (31.9) 2386 (41.0) Non-ST-segment elevation MI 503 (41.9) 2434 (41.9) Unstable angina 314 (26.1) 946 (16.3)

13 Rate per 100 patient-years ASA vs. ASA + Clopidogrel HR 1.07 ( ) HR 0.77 ( ) ASA ASA + clopidogrel *Adjusted HR (95% CI) HR 0.81 ( ) HR 1.47 ( ) HR 2.06 ( ) 0 CV death, MI, and ischemic stroke CV death All-cause death TIMI major bleeding TIMI major or minor bleeding

14 Apixaban Effect According to Antiplatelet Therapy (Simple Model) ASA ASA + clopidogrel Similar results obtained with Marginal Structural Model

15 Limitations Subgroup analysis- antiplatelet therapy use not randomized Potential bias as APPRAISE-2 was terminated early Study may have been underpowered to detect true interaction between apixaban vs. placebo and ASA vs. ASA + clopidogrel antiplatelet therapy No data on dosing of concomitant antiplatelet agents Insufficient numbers to examine clopidogrel or newer P2Y12 inhibitors as mono antiplatelet therapy

16 Conclusions In high-risk ACS patients enrolled in APPRAISE-2, 1 in 5 patients changed antiplatelet therapy at least once over 8 month median follow-up Compared with ASA + clopidogrel, apixaban added to ASA alone caused a smaller absolute increase in bleeding without an apparent increase in ischemic events Use of oral anticoagulation post-acs on a background of mono antiplatelet therapy (vs. dual antiplatelet therapy) may improve safety without increasing thrombotic risk and deserves further prospective study

17 Thank you