COMPASS

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Eikelboom JW et al. "Rivaroxaban with or without aspirin in stable cardiovascular disease". The New England Journal of Medicine. 2017. 377(14):1319-1330.
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Clinical Question

In patients with established stable atherosclerotic disease, is rivaroxaban plus aspirin more effective than aspirin alone in reducing cardiovascular death, stroke, or nonfatal MI?

Bottom Line

In patients with established stable atherosclerotic disease, rivaroxaban plus aspirin resulted in a modest 1.3% absolute risk reduction in cardiovascular death, stroke, or nonfatal MI, with a trend toward improved mortality. This benefit was offset by a 1.2% increased absolute risk in major bleeding.

Major Points

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. 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).[1] 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. Furthermore, the ATLAS ACS-2, TIMI 51 trial demonstrated that in patients with recent acute coronary syndrome, low-dose rivaroxaban in addition to background dual-antiplatelet therapy reduced recurrent thrombosis rates without increasing bleeding rates. However, the ATLAS trial has been criticized for missing data leading to uncertainty regarding its results. A randomized trial of rivaroxaban in addition to aspirin in patients with stable atherosclerotic disease was needed.

The 2017 Cardiovascular Outcomes for People Using Anticoagulation Stratgies (COMPASS) trial randomized 27,395 patients to three treatments: a) rivaroxaban 2.5MG twice daily with aspirin, b) rivaroxaban 5MG twice daily alone, and c) aspirin alone, and assessed for a primary outcome of cardiovascular death, stroke, or nonfatal MI. At mean follow-up of 23 months (after early termination of the trial due to achievement of the interim efficacy threshold), 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%. This was driven by largely symmetric reductions in each component of the primary outcome although none of the individual component differences reached statistical significance after adjustment for multiple comparisons (although the absolute rate of all-cause mortality was reduced by 0.7% with marginal significance). Of note, a separate publication documented a reduction in major cardiac and limb events among adults with stable PAD or carotid artery disease.[2]

Use of rivaroxaban plus aspirin was also associated with a 1.2% absolute increase in major bleeding compared to aspirin alone although the rate of intracranial hemorrhage was similar. The majority of the bleeding sites was gastrointestinal. Of note, the modified ISTH bleeding by definition used in in COMPASS was broader; all bleeding that led to presentation to an acute care facility or hospitalization was considered major.

A net clinical benefit outcome attempting to incorporate both thrombotic and bleeding outcomes demonstrated a 1.2% absolute reduction in events with the rivaroxaban plus aspirin group when compared to aspirin alone. When rivaroxaban alone was compared to aspirin alone, essentially all thrombotic endpoints were similar but with a higher bleeding risk associated with rivaroxaban use.

In summary, the 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. However, further evidence of increased major bleeding with this approach will necessitate careful consideration and further study. At this point, 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.

Guidelines

As of August 2017, no guidelines have been published that reflect the results of this trial.

Design

  • Prospective, multi-center, double-blind, 3-by-2 partial factorial design, randomized controlled trial
  • N=27,395
    • Rivaroxaban and aspirin (n=9152)
    • Rivaroxaban alone (n=9117)
    • Aspirin alone (n=9126)
  • Setting: 602 centers in 33 countries
  • Enrollment: March 2013 to May 2016
  • Mean follow-up: 23 months
  • Analysis: Intention-to-treat
  • Primary outcome: Cardiovascular death, stroke, or nonfatal MI

Population

Inclusion Criteria

  • Presence of CAD or PAD
    • CAD defined as any of:
      • Myocardial infarction within the last 20 years
      • Multivessel coronary disease with symptoms or with history of stable or unstable angina
      • Multivessel PCI
      • Multivessel CABG
    • PAD defined as any of:
      • Previous aorto-femoral bypass surgery, limb bypass surgery, or PTCA of the iliac, infra-inguinal arteries
      • Previous limb or foot amputation for arterial vascular disease
      • History of claudication (peripheral extremity pain with either of ABI < 0.90 or ≥ 50% stenosis of peripheral artery by angiography or duplex ultrasound)
      • Previous carotid revascularization or asymptomatic carotid stenosis ≥ 50% by either angiography or duplex ultrasound
  • 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

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
  • 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

Baseline Characteristics

From the aspirin only group

  • Demographics: age 68.2, female 21.8%, BMI 28.4, white 62.3%
  • Cardiovascular: Total cholesterol 4.2 mmol/L, tobacco 21.6%, HTN 75.4%, diabetes 38.1%, stroke 3.7%, previous MI 62.7%, heart failure 21.7%, CAD 90.5%, PAD 27.4%, eGFR < 30mL/min 0.9%, eGFR 30 to < 60 mL/min 22.2%
  • Medications: ACE/ARB 70.8%, CCB 27.2%, diuretic 30.1%, beta blocker 70.1%, anti-lipid 89.4%, NSAID 5.2%, PPI 35.8%

Interventions

  • Randomized 1:1:1 to rivaroxaban plus aspirin, rivaroxaban alone, or aspirin alone
    • Rivaroxaban 2.5MG twice daily with aspirin 100MG daily
    • Rivaroxaban 5MG twice daily (with aspirin-matched placebo)
    • Aspirin 100MG daily (with rivaroxaban-matched placebo)
  • Prior to randomization, patients entered a run-in phase during which they received a rivaroxaban-matched placebo twice daily and aspirin 100MG daily
  • Randomization stratified by center and use of PPI therapy at baseline
  • Patients eligible for PPI also randomized to PPI or matching placebo (for separate trial)
  • After randomization, patients were seen at 1 and 6 months and then every 6 months thereafter

Outcomes

Comparisons are rivaroxaban plus aspirin vs. rivaroaxaban alone vs. aspirin alone

Hazard ratios presented as rivaroxaban plus aspirin vs. rivaroxaban alone and rivaroxaban alone vs. aspirin alone

Primary Outcomes

Cardiovascular death, stroke, nonfatal MI
379 (4.1%) vs. 448 (4.9%) vs. 496 (5.4%) [HR 0.76 (95% CI 0.66-0.86) p<0.001, HR 0.90 (95% CI 0.79-1.03) p=0.12]

Secondary Outcomes

Threshold p<0.0025 due to correction for multiple comparisons

Ischemic stroke, nonfatal MI, ALI, or cardiovascular death
329 (3.6%) vs. 397 (4.4%) vs. 450 (4.9%) [HR 0.72 (95% CI 0.63-0.83) p<0.001, HR 0.88 (95% CI 0.77-1.01) p=0.06]
Ischemic stroke, nonfatal MI, ALI, or death from coronary disease
329 (3.6%) vs. 397 (4.4%) vs. 450 (4.9%) [HR 0.72 (95% CI 0.63-0.83) p<0.001, HR 0.88 (95% CI 0.77-1.01) p=0.06]
All-cause mortality
313 (3.4%) vs. 366 (4.0%) vs. 378 (4.1%) [HR 0.82 (95% CI 0.71-0.96) p=0.01, HR 0.97 (95% CI 0.84-1.12) p=0.67]
Stroke (ischemic or uncertain)
68 (0.7%) vs. 91 (1.0%) vs. 132 (1.4) [HR 0.51 (95% CI 0.38-0.68) p<0.001, HR 0.69 (95% CI 0.53-0.90) p=0.006]
Stroke (hemorrhagic)
15 (0.2%) vs. 27 (0.3%) vs. 10 (0.1%) [HR 1.49 (95% CI 0.67-3.31) p=0.33, HR 2.70 (95% CI 1.31-5.58) p=0.005]

Subgroup Analysis

The effects of rivaroxaban plus aspirin as compared with aspirin alone on the primary outcome and on major bleeding was consistent among subgroups that were defined according to age, sex, geographic region, race or ethnic group, body weight, renal function, and history of cardiovascular risk factors

Adverse Events

Major bleeding
288 (3.1%) vs. 255 (2.8%) vs. 170 (1.9%) [HR 1.70 (95% CI 1.40-2.05) p<0.001, HR 1.51 (95% CI 1.25-1.84) p<0.001]
Nonfatal symptomatic intracranial hemorrhage
21 (0.2%) vs. 32 (0.4%) vs. 19 (0.2%) [HR 1.10 (95% CI 0.59-2.04) p=0.77, HR 1.69 (95% CI 0.96-2.98) p=0.07]

Net Clinical Benefit Outcome

CV death, stroke, nonfatal MI, fatal bleeding, or symptomatic bleeding into critical organ
431 (4.7%) vs. 504 (5.5%) vs. 534 (5.9%) [HR 0.80 (95% CI 0.70-0.91) p<0.001, HR 0.94 (95% CI 0.84-1.07) p=0.36]

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 underpowering for this outcome

Funding

  • Trial sponsor (Bayer) involved in development of the study protocol as well as conduct and oversight of the study
  • Authors with multiple ties to industry

Further Reading

  1. Anand SS & Yusuf S Oral anticoagulants in patients with coronary artery disease. J. Am. Coll. Cardiol. 2003. 41:62S-69S.
  2. Anand SS et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2017. :.