Rivaroxaban Plus Aspirin in Patients With and Without Heart Failure and Chronic Coronary or Peripheral Artery Disease: The COMPASS Trial Kelley Branch, MD, MSc, on behalf of the COMPASS Steering Committee and Investigators

Background Heart failure (HF) affects over 26 million people worldwide and the incidence is expected to increase dramatically over the next decade HF with atherosclerotic coronary artery disease (CAD) and/or peripheral artery disease (PAD) leads to increased cardiovascular events compared to those without CAD or PAD Ambrosy AP, et al. J Am Coll Cardiol 2014;63:1123-33. Shah KS, et al. J Am Coll Cardiol 2017;70:2476-2486. Jones WS, et al. Am J Cardiol;2011;108:380-384.

27,325 patients with stable CAD or PAD COMPASS Design Cardiovascular Outcomes for People Using Anticoagulation Strategies 27,325 patients with stable CAD or PAD 1,323 with a primary outcome event Randomized, placebo controlled, double blinded trial Ongoing arm testing proton pump inhibitor pantoprazole versus placebo (PPI arm) Rivaroxaban 5 mg bid R Rivaroxaban 2.5 mg bid + aspirin 100 mg daily Aspirin 100 mg daily Run-in (aspirin) Median Follow Up: 23 months (1.9 years) Eikelboom JW, et al. NEJM 2017;377:1319-1330.

COMPASS Main Trial Outcomes Primary Outcome: MACE (CV death, stroke or MI) Median 23 month follow up Riva+ASA vs ASA: ↓MACE 24% ↑Net benefit 20% ↓ Mortality 18% ASA Riva Riva+ASA Cumulative Hazard No benefit for Riva alone ASA = aspirin; CV = cardiovascular; MACE = major adverse cardiovascular events; MI = myocardial infarction; Riva = rivaroxaban. Time (years) Eikelboom JW, et al. NEJM 2017;377:1319-1330.

COMPASS HF Substudy Outcomes Purpose: To explore the effects of combination rivaroxaban + aspirin compared with aspirin alone in chronic CAD and PAD patients with or without HF Primary Outcome MACE: Cardiovascular death, stroke or myocardial infarction Safety Outcome ISTH major bleeding (modified) Net Clinical Benefit Primary MACE plus severe bleeding (fatal or critical organ bleeding)

COMPASS HF Methods COMPASS exclusion criteria included severe heart failure with known left ventricular ejection fraction (LVEF) <30% or New York Heart Association (NYHA) class III or IV symptoms HF status was site reported (history or current) at baseline LVEF was recorded for trial participants, if available. Primary and safety outcomes compared by HF status Cox proportional hazard ratio calculated for each primary outcome Log rank tests for interaction for HF groups were stratified by PPI arm Bosch J, et al. Can J Cardiol. 2017 Aug;33(8):1027-1035.

Baseline Characteristics   Overall (N=27395) No HF (N=21493) HF (N=5902) P value Age (yr) 68.2±7.9 69.0±7.5 65.5±9.0 <0.0001 Female sex 6020 (22.0) 4653 (21.6) 1367 (23.2) 0.01 Current smoker 5867 (21.4) 4114 (19.1) 1753 (29.7) Hypertension 20632 (75.3) 15632 (72.7) 5000 (84.7) Diabetes 10341 (37.7) 7915 (36.8) 2426 (41.1) Previous MI 17028 (62.2) 12497 (58.1) 4531 (76.8) White race 17027 (62.2) 13354 (62.1) 3673 (62.2) 0.89 PAD 7470 (27.3) 6079 (28.3) 1391 (23.6) NYHA Class I/II/III - 36%/64%/0.1% eGFR <60 ml/min 6276 (23%) 4760 (22%) 1516 (26%) ACE inhibitor or ARB 19518 (71.2) 14866 (69.2) 4652 (78.8) Calcium-channel blocker 7269 (26.5) 5854 (27.2) 1415 (24.0) Diuretic 8139 (29.7) 5427 (25.3) 2712 (46.0) Beta blocker 19184 (70.0) 14382 (66.9) 4802 (81.4) Lipid-lowering agent 24601 (89.8) 19203 (89.3) 5398 (91.5) NSAID 1470 (5.4) 1193 (5.6) 277 (4.7)

Primary MACE Outcome by HF Status (CV death, stroke, MI) Riva + ASA N=9,152 ASA N=9,126 Rivaroxaban + aspirin vs. aspirin n/N (%) HR (95% CI) P No HF 271/7189 (3.8%) 339/7147 (4.7%) 0.79 (0.68-0.93) 0.28 HF 108/1963 (5.5%) 157/1979 (7.9%) 0.68 (0.53-0.86) P = p value for interaction by log-rank test by HF category

Primary MACE Outcome by HF Status P=0.28 for interaction HF, ASA HR 0.68 (95% CI 0.53-0.86) ARR 2.4% NNT 42 No HF, ASA Cumulative Hazard HF, Riva+ASA HR 0.79 (95% CI 0.68-0.93) ARR 0.9% NNT 111 No HF, Riva+ASA Time (months)

Major (modified ISTH) bleeding Riva + ASA N=9,152 ASA N=9,126 Rivaroxaban + Aspirin vs. Aspirin n/N (%) HR (95% CI) P No HF 239/7189 (3.3) 134/7147 (1.9) 1.79 (1.45-2.21) 0.26 HF 49/1963 (2.5) 36/1979 (1.8) 1.36 (0.88-2.09) P = p value for interaction by log-rank test by HF category

Net Clinical Benefit (Primary outcome + Severe bleeding events) Riva + ASA N=9,152 ASA N=9,126 Rivaroxaban + aspirin vs. aspirin n/N (%) HR (95% CI) P No HF 315/7189 (4.4) 369/7147 (5.2) 0.85 (0.73-0.99) 0.15 HF 116/1963 (5.9) 165/1979 (8.3) 0.69 (0.55-0.88) P = p value for interaction by log-rank test by HF category

Net Clinical Benefit: Hazard Ratios (Primary outcome + Severe bleeding events) 0.85 (0.73-0.99) 0.69 (0.55-0.88) 0.76 (0.66-0.86) No HF HF Overall P=0.15 Net clinical benefit of patients with HF and no HF are consistent with overall trial Higher absolute risk reduction for patients with HF

Limitations HF status was not explicitly defined or adjudicated at baseline Restricted to mild to moderate HF at baseline Baseline LVEF was incompletely collected (55% of patients) Cannot define HFpEF and HFrEF Planned analysis after additional LVEF ascertainment

COMPASS HF Substudy: Conclusions Patients with chronic CAD and PAD with HF have higher event rates than those without HF Rivaroxaban + aspirin had consistent effects on primary MACE outcome and net clinical benefit in those with HF and without HF Absolute risk benefits are greatest in those with HF Primary Outcome: HF - absolute risk reduction (ARR) 2.4% (NNT 42) No HF – ARR 0.9% (NNT 111) Net clinical benefit: HF – ARR 2.4% (NNT 42) No HF – ARR 0.8% (NNT 125) Efficacy of rivaroxaban 2.5 mg bid + aspirin in HFrEF with CAD will be reported with recently completed COMMANDER HF trial

We sincerely thank all investigators, study coordinators Acknowledgments Steering Committee: S. Yusuf (Chair), K. Fox (Co-Chair), S. Connolly (Co-PI), JW. Eikelboom (Co-PI), J. Bosch (Study Director), V. Aboyans, M. Alings, S. Anand, A. Avezum, D. Bhatt, K. Branch, P. Commerford, N. Cook-Bruns, G. Dagenais, A. Dans, R. Diaz, G. Ertl, C. Felix, , T. Guzik, J. Ha, R. Hart, M. Hori, A. Kakkar, K. Keltai, M. Keltai, J. Kim, A. Lamy, F. Lanas, B. Lewis, Y. Liang, L. Liu, E. Lonn, P. Lopez-Jaramillo, A. Maggioni, K. Metsarinne, P. Moayyedi, M. O'Donnell, A. Parkhomenko, L. Piegas, N. Pogosova, J. Probstfield, L. Ryden, M. Sharma, P.G. Steg, S. Stoerk, A. Tonkin, C. Torp-Pedersen, J. Varigos, P. Verhamme, D. Vinereanu, P. Widimsky, K. Yusoff, J. Zhu We sincerely thank all investigators, study coordinators and participants