Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease - PowerPoint PPT Presentation

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease (COMPASS Trial) Thursday, February 8, 12:00 ET Speaker: John Eikelboom, M.B., B.S. Panelists: Jack Ansell, MD; Tracy Minichiello, MD; Sara Vazquez, PharmD; Diane Wirth, ANP, CACP

Cardio-protection in chronic atherosclerosis: Is COMPASS a new paradigm?

Disclosures • Relationships with commercial interests: – Grants/Research Support: Bayer, BI, BMS, Daiichi-Sankyo, Janssen, Pfizer – Speakers Bureau/Honoraria: Bayer, BI, BMS, Daiichi-Sankyo, Janssen, Pfizer • Employment: – Hamilton Health Sciences and McMaster University; I work at an anticoagulation clinic • Government grants: – CIHR, HSF, NIF, NHMRC

Burden of disease • Cardiovascular disease affects 4% of world population (300 million persons) • Accounts for more than 300,000 deaths each week (18 million deaths each year) Benjamin EJ, et al. Circulation 2017; 135: e146-e603.

FDA-approved pharmacological therapies for cardiovascular prevention • Beta-blockers • Blood pressure-lowering • Glucose-lowering • LDL cholesterol-lowering • Statins • PCSK9 inhibitors • Other lipid-lowering therapies • Renin-angiotensin blockers (ACE-I/ARB) • Antithrombotic therapies

High event rates despite proven therapies Death, stroke, MI Death Country % per year* % per year* Sweden 11.4% 9.0% USA 12.1% 10.1% England 10.8% 6.5% France 8.7% 7.4% *Crude rates (unadjusted for baseline characteristics) Rapsomaniki E, et al. Eur Heart J Qual Care Clin Outcomes 2016; 2: 172–183.

ATLAS Trial: clear benefit of rivaroxaban Riva 2.5 mg BID Riva 5 mg BID Riva vs. Placebo Log Rank 15 Comparison Placebo HR (95% CI) p-value 14 13 Riva 2.5 mg BID vs Placebo 0.85 (0.72, 0.99) 0.039 12 Cumulative Event Rate (%) Riva 5 mg BID vs Placebo 0.87 (0.74, 1.01) 0.075 11 Composite of CV Death, 10 Stroke and MI 9 8 7 6 5 4 2 - Year Cumulative Risk Rate: 3 2.5 mg BID vs Placebo: 9.0 vs 10.4 2 5.0 mg BID vs Placebo: 8.6 vs 10.4 1 0 0 30 90 180 270 360 450 540 630 720 810 Days from Randomization Subjects at Risk 4765 4143 3687 2995 2448 1883 1333 822 389 82 Riva 2.5 mg 4767 4082 3590 2920 2363 1834 1308 816 390 77 BID 4760 4152 3720 3056 2503 1935 1369 830 397 82 Riva 5 mg BID Placebo

Antithrombotic comparisons in COMPASS • Low doses of an antiplatelet and anticoagulant agent • targets two mechanisms • hypothesized to produce superior efficacy with minimal increase in bleeding • Moderate dose of an anticoagulant alone • targets one mechanism • hypothesized to produce superior efficacy without increasing bleeding compared with aspirin • No dual antiplatelet therapy to avoid excess bleeding

COMPASS objectives • To determine in stable CAD or PAD whether: • Rivaroxaban 2.5mg bid + aspirin 100mg od, or • Rivaroxaban 5mg bid • reduces the risk of CV death, stroke or MI compared with aspirin 100 mg od • Pantoprazole 40mg od vs. placebo reduces the risk of upper GI complications Bosch J, et al. Can J Cardiol 2017; 33: 1027-1035.

Design Stable CAD or PAD 2,200 participants with a primary outcome event Rivaroxaban 2.5 mg bid + Aspirin 100 mg od Rivaroxaban 5 mg bid R Run-in Aspirin 100 mg od (aspirin plus rivaroxaban placebo) Expected mean follow up: 3-4 years Bosch J, et al. Can J Cardiol 2017; 33: 1027-1035.

Efficacy outcomes • Primary • CV death, stroke, or MI • Secondary • CHD death, ischemic stroke, MI, or acute limb ischemia • CV death, ischemic stroke, MI, or acute limb ischemia • Mortality Bosch J, et al. Can J Cardiol 2017; 33: 1027-1035.

Efficacy outcomes • Peripheral limb outcomes • Major adverse limb events (MALE) • severe limb ischemia leading to an intervention (angioplasty, bypass surgery, amputation, thrombolysis) • Major amputation due to vascular insufficiency above forefoot Anand SS, et al. Lancet. 2017 Nov 10. pii: S0140-6736(17)32409-1. doi: 10.1016/S0140-6736(17)32409-1. [Epub ahead of print]

Bleeding outcome • Major bleeding (ISTH modification) • Critical bleeding • Fatal – bleeding leading to death • Critical – symptomatic into a critical organ • Surgical site – bleeding requiring reoperation • Other (non-critical) major bleeding • Any bleeding leading to hospitalization (includes presentation to an acute care facility without overnight stay) Bosch J, et al. Can J Cardiol 2017; 33: 1027-1035.

COMPASS involved most major regions North America: N=3,918; Western Europe: N=8,555 Russia Canada N=682 Netherlands N=2443 N=2522 United States Italy N=1475 China N=1014 N=1086 Japan N=1556 Czech Rep N=1553 Brazil N=1515 Argentina N=2789

Interim analysis • On February 6, 2017 the DSMB recommended discontinuation of rivaroxaban and aspirin arms for efficacy (combination: Z= -4.59, 0.000004; rivaroxaban: Z= -2.44, P=0.01) Eikelboom J, et al. N Engl J Med 2017; 377: 1319-1330.

COMPASS: baseline characteristics Good baseline blood pressure & cholesterol control R + A Rivaroxaban Aspirin N=9,152 N=9,117 N=9,126 Age, yr* 68 68 68 Female 23% 22% 22% Diabetes 38% 38% 38% CAD 91% 90% 91% PAD 27% 27% 27% SBP/DBP, mmHg* 136/77 136/78 136/78 Cholesterol, mmol/L* 4.2 4.2 4.2 *Mean Eikelboom J, et al. N Engl J Med 2017; 377: 1319-1330.

COMPASS: a well-treated population R + A Rivaroxaban Aspirin N=9,152 N=9,117 N=9,126 Lipid-lowering 90% 90% 89% ACE-I/ARB 71% 72% 71% Beta blocker 70% 70% 70% Aspirin* 87% 87% 87% *Excluding patients randomized 4-14 days post CABG Eikelboom J, et al. N Engl J Med 2017; 377: 1319-1330.

Primary Outcome CV death, stroke, MI R + A Riva Aspirin Riva + aspirin Rivaroxaban N=9,152 N =9,117 N=9,126 vs. aspirin vs. aspirin Outcome N N N HR HR p p (%) (%) (%) (95% CI) (95% CI) CV death, 379 448 496 0.76 0.90 <0.0001 0.12 stroke, MI (4.1) (4.9) (5.4) (0.66-0.86) (0.79-1.03) Eikelboom J, et al. N Engl J Med 2017; 377: 1319-1330.

CAD, PAD: CV death, stroke, MI R + A Aspirin Rivaroxaban + aspirin N=2,492 N=2,504 vs. aspirin Participant group N N HR P (%) (%) (95% CI) 347 460 0.74 CAD <0.0001 (4.2) (5.6) (0.65-0.86) 126 174 0.72 PAD 0.005 (5.1) (6.9) (0.57-0.90) Connolly S, et al. Lancet 2017 Nov 10. pii: S0140-6736(17)32458-3. doi: 10.1016/S0140-6736(17)32458-3. [Epub ahead of print] Anand SS, et al. Lancet. 2017 Nov 10. pii: S0140-6736(17)32409-1. doi: 10.1016/S0140-6736(17)32409-1. [Epub ahead of print]

Stroke severity R + A Aspirin Rivaroxaban + aspirin N=9,152 N=9,126 vs. aspirin Rankin score at 7 days or discharge N N HR P (%) (%) (95% CI) 15 30 0.50 0 (nil) 0.02 (0.2) (0.3) (0.27-0.92) 36 63 0.57 1-2 (mild) 0.006 (0.4) (0.7) (0.38-0.85) 11 17 0.64 3 (moderate) 0.25 (0.1) (0.2) (0.30-1.37) 9 26 0.34 4-5 (severe) 0.004 (<0.1) (0.3) (0.16-0.73) 12 13 0.92 6 (fatal) 0.84 (0.1) (0.1) (0.42-2.02)

Peripheral limb outcomes Aspirin Rivaroxaban + aspirin R + A N=9,152 N=9,126 vs. aspirin Outcome N N HR p (%) (%) (95% CI) 34 64 0.53 MALE 0.002 (0.4) (0.7) (0.35-0.80) MALE + major 36 68 0.53 0.002 amputation (0.4) (0.7) (0.35-0.79) 15 31 0.48 Any amputation 0.02 (0.2) (0.3) (0.26-0.89)

Major Bleeding R + A Aspirin Rivaroxaban + aspirin N=9,152 N=9,126 vs. aspirin Outcome N N HR p (%) (%) (95% CI) 288 170 1.70 Major Bleed <0.0001 (3.1%) (1.9%) (1.40-2.05) 210 112 1.88 Non-Critical <0.0001 (2.3%) (1.2%) (1.49-2.36) 87 64 1.35 Critical 0.07 (1.0%) (0.7) (0.98-1.87)

Rivaroxaban + aspirin vs aspirin Balance between benefit and risk Riva + aspirin Aspirin Rivaroxaban + Aspirin N=9,152 N=9,126 vs. Aspirin Net clinical benefit N N HR P (%) (%) (95% CI) Pre-specified 431 534 0.80 Primary + critical bleeding 0.0005 (4.7) (5.9) (0.70-0.91) 313 378 0.82 Death 0.01 (3.4) (4.1) (0.71-0.96) Other 461 588 0.78 Primary + MALE + critical bleeding <0.0001 (5.0) (6.4) (0.69-0.88)

CV death, stroke, MI vs bleeding: landmark analysis

In patients with stable CAD or PAD • Rivaroxaban 2.5 mg twice daily + aspirin 100 mg once daily vs. aspirin 100 mg once daily: • Reduces CV death, stroke, or MI • Reduces mortality • Reduces acute limb ischemia and amputation • Increases major bleeding but does not increase critical bleeding • Is associated with a clear net clinical benefit

COMPASS in context Proven secondary prevention therapies COMPASS BP Beta- Lipid lowering ACE PCSK9 inhibitor Rivaroxaban Lowering blockers (1mmol/L) (HOPE) (Evolucumab) + aspirin (10mm Hg) Triple -24% - -21% -20% -18% -15% outcome Death -18% -23% -9% -13% -14% +4%* Stroke -42% - -15% -27% -23% -21% MI -14%* -26% -24% -17% -18% -27% MALE -46% - - - -11%* -42% *Not significant Eikelboom J, et al. N Engl J Med 2017; 377: 1319-1330. Yusuf S, et al. Prog Cardiovasc Dis 1985; 27: 335-71. Ettehad D, et al. Lancet 2016;387:957- 67. CTT Collaboration. Lancet 2015;385:1397-1405; Collins R, et al. Lancet 2016;388:2532-61. Dagenais GR, et al. Lancet. 2006; 368:581-8. HOPE Investigators. N Engl J Med 2000;342:145-53. Sabatine MS, et al. N Engl J Med 2017; 376:1713-22. Bonaca MP, et al. https://doi.org/10.1161/CIRCULATIONAHA.117.032235

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