COMPASS - aspirin plus rivaroxaban for preventing atherothrombotic events in people with coronary or peripheral artery disease

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Cardiovascular Outcomes for People Using Anticoagulation Strategies - COMPASS

COMPASS is a double-blind randomised clinical trial comparing rivaroxaban plus aspirin against aspirin alone in people with stable coronary artery disease or peripheral artery disease who are at high risk of ischaemic events (1,2,3,4,5,6)

  • COMPASS trial showed that rivaroxaban plus aspirin was associated with fewer adverse cardiovascular events, but more major bleeding events vs. aspirin alone.

Description: The goal of the trial was to evaluate anticoagulation strategies with rivaroxaban among patients with stable atherosclerosis.

Study Design

  • Randomized
  • Parallel
  • Blinded

Patients with stable atherosclerosis were randomized to rivaroxaban 2.5 mg twice daily plus aspirin (n = 9,152) vs. rivaroxaban 5 mg twice daily alone (n = 9,117) vs. aspirin alone (n = 9,126).

  • Total number of enrollees: 27,395
  • Duration of follow-up: mean 23 months
  • Mean patient age: 68 years
  • Percentage female: 23%
  • Percentage with diabetes: 38%

Inclusion criteria:

  • Atherosclerosis in >= 2 vascular beds or two additional risk factors (current smoking, diabetes, renal insufficiency, heart failure, or nonlacunar ischemic stroke >= 1 month)

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

Principal Findings:

  • primary outcome, incidence of cardiovascular death, myocardial infarction, or stroke, occurred in 4.1% of the rivaroxaban plus aspirin group vs. 4.9% of the rivaroxaban alone group vs. 5.4% of the aspirin alone group (p < 0.001 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.12 for rivaroxaban alone vs. aspirin alone). The primary efficacy outcome was the same in all tested subgroups
    • Number needed to treat (NNT) for primary income for a rivaroxban plus aspirin versus aspirin alone was 77
    • the mean study follow-up was 23 months (after early termination of the trial due to achievement of the interim efficacy threshold)
    • NICE noted that (1) rivaroxaban plus aspirin showed a statistically significant relative risk reduction of 24% in major cardiovascular events compared with aspirin (HR 0.76, 95% confidence interval [CI] 0.66 to 0.86; p<0.001)
      • two of the individual components of the primary composite outcome also showed statistically significant relative risk reductions in the treatment arm: 42% for ischaemic stroke (HR 0.58, 95% CI 0.44 to 0.76; p<0.001) and 22% for cardiovascular death (HR 0.78, 95% CI 0.64 to 0.96; p=0.02)
      • concluded that rivaroxaban plus aspirin reduces the risk of cardiovascular events compared with aspirin alone, and that the greatest effect is for ischaemic stroke.

Secondary outcomes:

  • all-cause mortality: 3.4% for rivaroxaban plus aspirin, 4.0% for rivaroxaban alone, vs. 4.1% for aspirin alone (p = 0.01 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.67 for rivaroxaban alone vs. aspirin alone)
  • all stroke: 0.9% for rivaroxaban plus aspirin, 1.3% for rivaroxaban alone, vs. 1.6% for aspirin alone (p < 0.001 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.12 for rivaroxaban alone vs. aspirin alone)
  • ischaemic stroke: 0.7% for rivaroxaban plus aspirin, 0.9% for rivaroxaban alone, vs. 1.4% for aspirin alone (p < 0.001 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.004 for rivaroxaban alone vs. aspirin alone)
  • haemorrhagic stroke: 0.2% for rivaroxaban plus aspirin, 0.3% for rivaroxaban alone, vs. 0.1% for aspirin alone (p = 0.33 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.005 for rivaroxaban alone vs. aspirin alone)

  • Major bleeding: 3.1% for rivaroxaban plus aspirin, 2.8% for rivaroxaban alone, vs. 1.9% for aspirin alone (p < 0.001 for rivaroxaban plus aspirin vs. aspirin alone, p < 0.001 for rivaroxaban alone vs. aspirin alone)
    • Number needed to harm (NNH) for major bleeding for rivaroxaban + aspirin versus aspirin for 83
    • NICE noted that rivaroxaban plus aspirin increases the risk of major bleeding
      • primary safety outcome in COMPASS was major bleeding based on a modification of the International Society on Thrombosis and Haemostasis (ISTH) criteria
        • Major bleeding was defined as a composite of fatal bleeding, and/or symptomatic bleeding in a critical area or organ (such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, intramuscular with compartment syndrome, or bleeding into the surgical site requiring re-operation), and/or bleeding leading to hospitalisation (with or without an overnight stay)
        • risk of major bleeding, as defined by the modified ISTH criteria, increased by 70% in the rivaroxaban plus aspirin group compared with aspirin alone (HR 1.70, 95% CI 1.40 to 2.05; p<0.001)

  • Cancer diagnosis: 4.0% for rivaroxaban plus aspirin, 4.0% for rivaroxaban alone vs. 3.8% for aspirin alone
    • note that in 77.1%, the timing of gastrointestinal (GI) cancer was within 6 months of a GI bleeding event, while in 88.7%, the timing of genitourinary (GU) cancer was within 6 months of a GU bleeding event.

COMPASS PAD: Among 7,470 participants with peripheral arterial disease (PAD), 4,129 had symptomatic PAD, 1,919 had carotid disease, and 1,422 had coronary artery disease plus ankle-brachial index <0.9.

  • Major adverse cardiac events (MACE): 5.0% for rivaroxaban plus aspirin, 6.0% for rivaroxaban alone, vs. 7.0% for aspirin alone (p = 0.005 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.19 for rivaroxaban alone vs. aspirin alone)
  • Major adverse limb events (MALE): 1.5% for rivaroxaban plus aspirin, 1.9% for rivaroxaban alone, vs. 2.6% for aspirin alone (p = 0.01 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.07 for rivaroxaban alone vs. aspirin alone)
  • Major bleeding: 3.0% for rivaroxaban plus aspirin, 3.0% for rivaroxaban alone, vs. 2.0% for aspirin alone (p = 0.009 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.004 for rivaroxaban alone vs. aspirin alone)

COMPASS CAD: There were 24,824 subjects with coronary artery disease (CAD).

  • MACE: 4.0% for rivaroxaban plus aspirin, 5.0% for rivaroxaban alone, vs. 6.0% for aspirin alone (p < 0.0001 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.094 for rivaroxaban alone vs. aspirin alone)
  • Major bleeding: 3.0% for rivaroxaban plus aspirin, 3.0% for rivaroxaban alone, vs. 2.0% for aspirin alone (p < 0.0001 for rivaroxaban plus aspirin vs. aspirin alone; p < 0.0001 for rivaroxaban alone vs. aspirin alone)

COMPASS-CABG: This substudy randomized 1,448 COMPASS trial patients 4-14 days after CABG.

  • Graft failure: 9.1% for rivaroxaban plus aspirin, 7.8% for rivaroxaban alone, vs. 8.0% for aspirin alone (p = 0.45 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.75 for rivaroxaban alone vs. aspirin alone)

COMPASS Heart Failure: There were 5,902 subjects with a history of heart failure and CAD or PAD.

  • MACE: 5.5% for rivaroxaban plus aspirin, 6.3% for rivaroxaban alone, vs. 7.9% for aspirin alone; rivaroxaban plus aspirin vs. aspirin alone (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53-0.86), rivaroxaban alone vs. aspirin alone (HR 0.80, 95% CI 0.63-1.01)
  • Hospitalization for heart failure: Rivaroxaban plus aspirin vs. aspirin alone was associated with greater benefit among those with heart failure vs. those without heart failure (p for interaction = 0.05)
  • All-cause mortality: Rivaroxaban plus aspirin vs. aspirin alone was associated with greater benefit among those with heart failure vs. those without heart failure (p for interaction = 0.05)

COMPASS Vascular Risk: In this analysis, subjects were classified as high-risk according to REACH scoring (2 or more vascular beds affected, history of heart failure, or renal insufficiency) or CART scoring (2 or more vascular beds affected, history of heart failure, or diabetes).

  • High-risk features-REACH, MACE, acute limb ischemia, or total vascular amputation: 5.8% with rivaroxaban plus aspirin vs. 8.0% with aspirin (events prevented per 1,000 patients treated [95% CI] = 36 [21-52])
  • High-risk features-CART, MACE, acute limb ischemia, or total vascular amputation: 5.6% with rivaroxaban plus aspirin vs. 7.5% with aspirin (events prevented per 1,000 patients treated [95% CI] = 33 [19-47])
  • High-risk features-REACH, severe bleeding: 1.1% with rivaroxaban plus aspirin vs. 0.8% with aspirin (events caused per 1,000 patients treated [95% CI] = 3 [-4 to 9])
  • High-risk features-CART, severe bleeding: 1.0% with rivaroxaban plus aspirin versus 0.8% with aspirin (events caused per 1,000 patients treated [95% CI] = 1 [-4 to 6])

COMPASS Sex Differences: 22% of subjects were women and 78% were men.

  • For cardiovascular death, myocardial infarction, or stroke:
    • Hazard ratio for rivaroxaban plus aspirin vs. aspirin alone for women = 0.72
    • Hazard ratio for rivaroxaban plus aspirin vs. aspirin alone for men = 0.76 (p for interaction = 0.75)
  • Major Bleeding:
    • Hazard ratio for rivaroxaban plus aspirin vs. aspirin alone for women = 2.22
    • Hazard ratio for rivaroxaban plus aspirin vs. aspirin alone for men = 1.60 (p for interaction = 0.19)

NICE suggest (1):

  • clopidogrel is not a relevant comparator for the overall COMPASS population
    • clinical experts explained that clopidogrel is the preferred antiplatelet treatment for people with peripheral artery disease (based on NICE's technology appraisal guidance for the prevention of occlusive vascular events), but it is not a relevant comparator for the whole COMPASS population. This is because aspirin is the preferred treatment for secondary prevention of cardiovascular disease in people with stable coronary artery disease, and clopidogrel is only recommended when aspirin is unsuitable because of contraindication or hypersensitivity
  • indirect comparison of rivaroxaban against ticagrelor does not provide reliable estimates of relative effectiveness or risk of bleeding
    • concluded that COMPASS and PEGASUS have too many differences to allow a reliable estimate of the relative efficacy or bleeding risk of rivaroxaban plus aspirin compared with ticagrelor plus aspirin

Interpretation:

  • in patients with stable atherosclerosis, rivaroxaban plus aspirin was associated with fewer adverse cardiovascular events, but more major bleeding events compared with aspirin alone
  • net clinical benefit appears favourable for high-risk patients
    • Anand et al (2) note
      • use of low-dose rivaroxaban twice a day, together with aspirin 100 mg once a day, reduces cardiovascular death, myocardial infarction, stroke, and acute limb ischaemia and amputation, compared with aspirin alone. Although there is an increase in bleeding leading to more hospital admissions, there is no excess of fatal bleeding, intracranial bleeding, or bleeding into critical organs. Thus, the net clinical benefit favours the use of low-dose rivaroxaban plus aspirin..the combination of low dose rivaroxaban twice a day with aspirin could replace aspirin alone as standard of care in patients with stable peripheral artery disease who are not at high risk for bleeding
  • rivaroxaban alone was not more effective than aspirin alone
  • rivaroxaban plus aspirin compared with aspirin alone was associated with a reduction in all strokes and ischaemic strokes
  • rivaroxaban alone compared with aspirin alone was not associated with a reduction in all strokes
  • haemorrhagic strokes were very low in all treatment groups; however, there was a nonsignificant increase in this outcome for rivaroxaban plus aspirin compared with aspirin alone, and a significant increase in this outcome for rivaroxaban alone compared with aspirin alone. Findings were the same among those with PAD, CAD, heart failure, and women.

Rivaroxaban plus aspirin was effective at preventing both MACE and MALE among those with PAD

  • bleeding is an important outcome; therefore, net clinical benefit will needs to be carefully considered with this strategy
    • GI and GU bleeding should stimulate a search for a new cancer diagnosis in the same organ
  • rivaroxaban plus aspirin (or rivaroxaban alone) was ineffective at improving bypass graft patency rates.

A further analysis of the COMPASS trial in the 1 year following the study (8):

  • analysis found that in those that discontinued rivaroxaban and aspirin to non-study aspirin had a similar rate of CV death, and a higher risk of stroke vs those allocated aspirin alone
  • discontinuing study rivaroxaban and aspirin to non-study aspirin was associated with the loss of cardiovascular benefits and a stroke excess

GPnotebook Commentary (7):

  • "Upon reading the details of the COMPASS trial last year, I thought that the risk of Major Bleeding would make the combination a difficult clinical paradigm to adopt. The NNT to for the MACE for aspirin + rivaroxaban versus aspirin alone is 78 based on the 2 year study. This though is very similar to the NNH for the increased risk of major bleeding for the combined therapies versus aspirin at 83.

    Study authors note that there were no fatal incidences of major bleeding, but this is based on a study arm population of 9,152 and there may well be fatal major bleeds on the combination when used in clinical practice. There may be benefit for using a PPI or H2 antagonist when patients are on this combination - but this is not based on the trial data and just the art of clinical medicine ("guessology").

    There are also other questions relating to the implementation of the study:

  • exclusion of 2,320 participants after run-in period (due to failure to adhere/tolerate) leads to questions of possibility of selection bias and decreased ability to generalise the study results
  • the termination of the study early due to efficacy of rivaroxaban plus aspirin versus aspirin alone has led to concerns that this may mean that the study may overestimate the degree of benefit of rivaroxaban plus aspirin and potentially underestimate the degree of increased bleeding with this therapy

    In conclusion, I suspect that this combination will be initiated from secondary care - in my experience it could easily be for an admission non related to coronary heart disease and just because the patient was on aspirin. If the combination is commenced, then there needs to be an informed discussion with the patient about the risks and benefits of this NICE recommended therapeutic intervention. "

Reduction in thromboembolism risk (8)

  • secondary analysis of the COMPASS trial (27,395) and data review from the VOYAGER PAD study found the vascular benefits of adding rivaroxaban 2.5mg twice daily to aspirin were consistent across age, cancer status number of vascular beds involved and renal function

Reference:

Last edited 06/2022

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