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

7. COMPASS DESIGN

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