Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial
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The COMPASS trial investigated the efficacy of rivaroxaban combined with aspirin compared to aspirin alone in patients with stable peripheral or carotid artery disease, showing a 1.3% absolute risk reduction in major cardiovascular events. The study was a double-blind, randomized control trial involving 27,395 participants across 33 countries. Results indicated that while rivaroxaban plus aspirin reduced thrombotic outcomes, concerns about selection bias and early termination raise questions about the magnitude of benefits observed.
Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial
- 1. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo- controlled trial John Eikelboom, on behalf of the COMPASS Steering Committee and Investigators Independently conducted by PHRI, Sponsored by Bayer AG Journal club: LANCET- JOURNAL OF MEDICINE (November 10, 2017 )
- 2. • Patients with carotid artery disease or with peripheral artery disease(PAD) of the lower extremities are at high risk for major adverse cardiovascular events, and patients with PAD of the lower extremities are also at high risk for major adverse limb events such as severe limb ischemia and amputation • Anticoagulant therapies have NOT been shown to be superior to antiplatelet therapy in peripheral artery disease and have unacceptably high rates of major bleeding
- 3. • In patients with established stable atherosclerotic disease, is rivaroxaban plus aspirin more effective than aspirin alone in reducing cardiovascular death, stroke, or nonfatal MI?
- 4. Back ground • Despite effective secondary prevention strategies in patients with established stable atherosclerotic disease, the risk of recurrent events remains in the range of 5-10% per year. • CV disease affects 4% of world population (300 million persons) and causes 18 million deaths each year • Aspirin is widely used for secondary prevention but is only modestly effective • Warfarin trial results demonstrate the potential of anticoagulation to provide benefit • Rivaroxaban reduced mortality post acute coronary syndrome (ATLAS ACS- 2 TIMI 51).
- 5. Study design • Study type - Double-blind, randomised placebo-controlled trial • Study population – 27,395 from 558 centres • Randomization - Randomly assigned in a 1:1:1 ratio • Study centre – Multicentric, patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents • Duration of study – March 12, 2013, and May 10, 2016 • Study funded by - Bayer AG
- 8. Population • Inclusion Criteria: • Presence of CAD or PAD • CAD defined as any of: 1. Myocardial infarction within the last 20 years 2. Multivessel coronary disease with symptoms or with history of stable or unstable angina 3. Multivessel PCI 4. Multivessel CABG
- 9. • PAD defined as any of: 1. Previous aorto-femoral bypass surgery, limb bypass surgery, or PTCA of the iliac, infra-inguinal arteries 2. Previous limb or foot amputation for arterial vascular disease 3. History of claudication (peripheral extremity pain with either of ABI < 0.90 or ≥ 50% stenosis of peripheral artery by angiography or duplex ultrasound) 4. Previous carotid revascularization or asymptomatic carotid stenosis ≥ 50% by either angiography or duplex ultrasound
- 10. • If included for CAD, also requires either of: • Age ≥ 65 years • Age < 65 years with documented atherosclerosis or revascularization involving at least 1 additional vascular bed or presence of at least 2 of: • Current smoker • Diabetes • Renal dysfunction with eGFR < 60mL/min • Heart failure • Non-lacunar stroke ≥ 1 month prior to randomization
- 11. Exclusion Criteria • High risk of bleeding • Stroke within 1 month or any history of hemorrhagic or lacunar stroke • Severe heart failure with known LVEF < 30% or NYHA III or IV • Estimated GFR < 15mL/min • Need for dual antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral anticoagulant therapy • Known non-cardiovascular disease associated with poor prognosis or increases risk of adverse effect from study medications
- 12. • History of hypersensitivity or known contraindication to rivaroxaban, aspirin, pantoprazole, or excipients or study procedures • Systemic treatment with strong inhibitors of CYP3A4 • Any known hepatic disease with coagulopathy • Subject who are pregnant, breastfeeding, or are of childbearing potential and sexually active without contraception
- 13. Methodology • Eligible patients entered a 30-day run-in phase during which time they received rivaroxaban placebo twice a day and aspirin 100 mg once a day, both administered orally. • After the run-in period, participants who adhered to the assigned regimen and who did not have any adverse events, were randomly assigned to receive either rivaroxaban 2·5 mg twice a day with aspirin 100 mg once a day, rivaroxaban 5 mg twice a day (with aspirin placebo once a day), or aspirin 100 mg once a day (with rivaroxaban placebo twice a day).
- 14. • At the randomization visit, patients were assessed for eligibility, adherence to run-in medications, had physical measurements taken including blood pressure and ankle brachial index, and answered questionnaires to obtain data on the participants’ health and quality of life. • Participants were seen at 1 and 6 months after randomization and 6 month intervals thereafter. Patients were assessed at follow-up visits to record outcomes and adverse events, and to enhance adherence. Additional follow-up visits were done via telephone at 3 and 9 months.
- 15. Follow up, adherence • On February 6, 2017 the Data and Safety Monitoring Board recommended discontinuation of rivaroxaban/aspirin arms for clear evidence of efficacy (combination: Z= -4.59, P<0.00001; rivaroxaban: Z= -2.44, P=0.01) • Close-out between March and June 2017 • Mean follow up 23 months • Follow up 99.8% complete
- 19. Outcomes • PRIMARY – CV death, stroke or myocardial infarction • SECONDARY • CHD death, ischemic stroke, myocardial infarction, or acute limb ischemia, • CV death, ischemic stroke, myocardial infarction, or acute limb ischemia, • Mortality
- 21. • • SAFETY AND NET CLINICAL BENEFIT • – International Society on Thrombosis and Hemostasis (ISTH) major bleeding (modified) • – Primary plus fatal or critical organ bleeding
- 24. Results
- 28. Criticisms • Exclusion of 2320 participants after run-in period (due to failure to adhere/tolerate) raises possibility of selection bias and decreased generalizability • Study terminated early due to efficacy of rivaroxaban plus aspirin versus aspirin alone. As a result, the study may overestimate the degree of benefit of rivaroxaban plus aspirin and potentially underestimate the degree of increased bleeding with this therapy • The lack of statistical significance of the observed trend towards improved mortality with combination rivaroxaban plus aspirin may be due to under powering for this outcome
- 29. CONCLUSION • Rivaroxaban plus aspirin was associated with a 1.3% absolute risk reduction in the primary outcome when compared to aspirin alone. • The relative risk reduction in the primary outcome was 24% • COMPASS trial provides further evidence that use of rivaroxaban in addition to background aspirin is effective in reducing thrombotic outcomes in patients with established atherosclerotic disease
- 30. • Based on the results of COMPASS the addition of rivaroxaban to background aspirin in patients with established stable atherosclerotic disease is now a legitimate consideration that will need to be made on a case-by-case basis particularly in patients whose high thrombotic risk is felt to substantially outweigh bleeding risk.
- 31. Thank you
Editor's Notes
- #3: In addition to smoking cessation and exercise, statins, angiotensin converting enzyme (ACE) inhibitors, and antiplatelet agents (aspirin or a P2Y12 inhibitor) are used to reduce vascular complications.
- #5: Previous studies investigating whether therapeutic anticoagulation with warfarin in addition to standard-of-care low-dose aspirin have largely demonstrated modestly improved event rates but with substantially increased risk of bleeding (including intracranial bleeding) Whether the newer direct-acting oral anticoagulants (e.g., rivaroxaban), which demonstrate similar antithrombotic efficacy as warfarin but with lower risk of bleeding, may provide a safer means of more effective thrombotic protection is unclear. However, the ATLAS trial has been criticized for missing data leading to uncertainty regarding its results. Dual antiplatelet therapy is not consistently superior to single antiplatelet therapy in reducing major adverse cardiovascular events or major adverse limb events in patients with peripheral artery disease. Vorapaxar, a platelet receptor modulator, did not reduce major adverse cardiovascular events in patients with peripheral artery disease but acute limb ischaemia was significantly reduced, and there was an increase in moderate and severe bleeding.12
- #6: Study was designed by the Steering Committee and the sponsor, Bayer AG. Site management, data collection, and data analysis were coordinated at the Population Health Research Institute, which is affliated with Hamilton Health Sciences and McMaster University in ON, Canada. A computer-generated randomisation schedule was generated by the Population Health Research Institute. Each treatment group was double dummy, and the patient, investigators, and central study sta were masked to treatment allocation.
- #20: Acute limb ischaemia was defined as limb threatening ischaemia with evidence of acute arterial obstruction by radiological criteria or a new pulse deficit leading to an intervention (ie, surgery, thrombolysis, peripheral angioplasty, or amputation) within 30 days of symptoms onset Chronic limb ischaemia was defined as severe limb ischaemia leading to a vascular intervention. Major amputation was defined as amputations due to a vascular event above the forefoot, or defined as minor amputation if involving the forefoot and digits
- #21: Efficacy of rivaroxaban compared with aspirin in patients with peripheral artery disease
- #22: (ISTH) criteria for major bleeding, defined as the composite of bleeding that was fatal, symptomatic bleeding into a critical organ, surgical site requiring reoperation, or requiring hospitalization (including presentation to an acute care facility without an overnight stay)