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

Country Death, stroke, MI % per year* Death % per year* Sweden 11.4% 9.0% USA 12.1% 10.1% England 10.8% 6.5% France 8.7% 7.4%

Rapsomaniki E, et al. Eur Heart J Qual Care Clin Outcomes 2016; 2: 172–183.

*Crude rates (unadjusted for baseline characteristics)

ATLAS Trial: clear benefit of rivaroxaban

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1

0 30 90 180 270 360 450 540 630 720 810

Riva 2.5 mg BID Riva 5 mg BID Placebo

Cumulative Event Rate (%)

Subjects at Risk Riva 2.5 mg BID Riva 5 mg BID Placebo 4765 4767 4760 4143 4082 4152 3687 3590 3720 2995 2920 3056 2448 2363 2503 1883 1834 1935 1333 1308 1369 822 816 830 389 390 397 82 77 82

2 - Year Cumulative Risk Rate: 2.5 mg BID vs Placebo: 9.0 vs 10.4 5.0 mg BID vs Placebo: 8.6 vs 10.4 Comparison Riva vs. Placebo HR (95% CI) Log Rank p-value Riva 2.5 mg BID vs Placebo 0.85 (0.72, 0.99) 0.039 Riva 5 mg BID vs Placebo 0.87 (0.74, 1.01) 0.075

Days from Randomization Composite of CV Death, Stroke and MI

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

R

Rivaroxaban 2.5 mg bid + Aspirin 100 mg od Aspirin 100 mg od Rivaroxaban 5 mg bid Expected mean follow up: 3-4 years Run-in (aspirin plus rivaroxaban placebo)

Stable CAD or PAD 2,200 participants with a primary outcome event

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

Canada N=2443 United States N=1475 Brazil N=1515 Argentina N=2789 Netherlands N=2522 Italy N=1014 Czech Rep N=1553 Russia N=682 China N=1086 Japan N=1556

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 N=9,152 Rivaroxaban N=9,117 Aspirin 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 N=9,152 Rivaroxaban N=9,117 Aspirin N=9,126 Lipid-lowering 90% 90% 89% ACE-I/ARB 71% 72% 71% Beta blocker 70% 70% 70% Aspirin* 87% 87% 87%

Eikelboom J, et al. N Engl J Med 2017; 377: 1319-1330.

*Excluding patients randomized 4-14 days post CABG

Primary Outcome CV death, stroke, MI

Outcome R + A N=9,152 Riva N=9,117 Aspirin N=9,126 Riva + aspirin

• vs. aspirin

Rivaroxaban

• vs. aspirin

N (%) N (%) N (%) HR (95% CI) p HR (95% CI) p CV death, stroke, MI 379 (4.1) 448 (4.9) 496 (5.4) 0.76 (0.66-0.86) <0.0001 0.90 (0.79-1.03) 0.12

Eikelboom J, et al. N Engl J Med 2017; 377: 1319-1330.

CAD, PAD: CV death, stroke, MI

Participant group R + A N=2,492 Aspirin N=2,504 Rivaroxaban + aspirin

• vs. aspirin

N (%) N (%) HR (95% CI) P CAD 347 (4.2) 460 (5.6) 0.74 (0.65-0.86) <0.0001 PAD 126 (5.1) 174 (6.9) 0.72 (0.57-0.90) 0.005

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

Rankin score at 7 days or discharge R + A N=9,152 Aspirin N=9,126 Rivaroxaban + aspirin

• vs. aspirin

N (%) N (%) HR (95% CI) P 0 (nil) 15 (0.2) 30 (0.3) 0.50 (0.27-0.92) 0.02 1-2 (mild) 36 (0.4) 63 (0.7) 0.57 (0.38-0.85) 0.006 3 (moderate) 11 (0.1) 17 (0.2) 0.64 (0.30-1.37) 0.25 4-5 (severe) 9 (<0.1) 26 (0.3) 0.34 (0.16-0.73) 0.004 6 (fatal) 12 (0.1) 13 (0.1) 0.92 (0.42-2.02) 0.84

Peripheral limb outcomes

Outcome R + A N=9,152 Aspirin N=9,126 Rivaroxaban + aspirin

• vs. aspirin

N (%) N (%) HR (95% CI) p MALE 34 (0.4) 64 (0.7) 0.53 (0.35-0.80) 0.002 MALE + major amputation 36 (0.4) 68 (0.7) 0.53 (0.35-0.79) 0.002 Any amputation 15 (0.2) 31 (0.3) 0.48 (0.26-0.89) 0.02

Major Bleeding

Outcome R + A N=9,152 Aspirin N=9,126 Rivaroxaban + aspirin

• vs. aspirin

N (%) N (%) HR (95% CI) p Major Bleed 288 (3.1%) 170 (1.9%) 1.70 (1.40-2.05) <0.0001 Non-Critical 210 (2.3%) 112 (1.2%) 1.88 (1.49-2.36) <0.0001 Critical 87 (1.0%) 64 (0.7) 1.35 (0.98-1.87) 0.07

Rivaroxaban + aspirin vs aspirin Balance between benefit and risk

Net clinical benefit Riva + aspirin N=9,152 Aspirin N=9,126 Rivaroxaban + Aspirin

• vs. Aspirin

N (%) N (%) HR (95% CI) P Pre-specified Primary + critical bleeding 431 (4.7) 534 (5.9) 0.80 (0.70-0.91) 0.0005 Death 313 (3.4) 378 (4.1) 0.82 (0.71-0.96) 0.01 Other Primary + MALE + critical bleeding 461 (5.0) 588 (6.4) 0.78 (0.69-0.88) <0.0001

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

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

COMPASS in context

Proven secondary prevention therapies

COMPASS Rivaroxaban + aspirin Beta- blockers Lipid lowering (1mmol/L) BP Lowering (10mm Hg) ACE (HOPE) PCSK9 inhibitor (Evolucumab) Triple

• utcome
• 24%
• 21%
• 20%
• 18%
• 15%

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

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