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Reference: COMPASS trial - stable coronary artery disease substudy (Lancet 2017 Nov 10 early online) (level 1 [likely reliable] evidence)
- The addition of anti-coagulation drugs such as rivaroxaban to aspirin therapy may offer some benefits to patients with stable coronary artery disease (CAD), but evidence in these patients is limited.
- The recent COMPASS trial randomized 24,824 adults with stable CAD to combination rivaroxaban plus aspirin vs. rivaroxaban alone vs. aspirin alone for mean 2 years.
- Combination rivaroxaban plus aspirin had modestly lower rates of all-cause mortality and major cardiovascular events compared to aspirin alone. However, rivaroxaban, with or without aspirin, had a greater risk of major bleeding, mostly in the gastrointestinal tract.
Aspirin or other antiplatelet drugs are recommended for patients with stable CAD to reduce the risk of a clotting-mediated occlusive thrombus following atherosclerotic plaque rupture or erosion. Adding drugs that target other steps of the clotting process may further reduce the risk, but more research is needed to determine regimens that best balance reduced clotting with increased bleeding. The direct factor Xa inhibitor rivaroxaban has been shown to have some benefits in patients with acute coronary syndrome (N Engl J Med 2012). To evaluate rivaroxaban in patients with stable CAD, the recent COMPASS trial randomized 24,824 adults (mean age 68 years, 80% men) with stable CAD to 1 of 3 groups: combination low-dose rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily) vs. high-dose rivaroxaban alone (5 mg twice daily with aspirin placebo) vs. aspirin alone (100 mg once daily with rivaroxaban placebo). Other prescription medications were allowed. Patients not already taking proton pump inhibitors were also randomized to pantoprazole vs. placebo to evaluate other hypotheses (analysis ongoing). Almost all patients (94%) participated in a pre-randomization 30-day run-in period with rivaroxaban placebo twice daily plus aspirin once daily; those with < 80% adherence were excluded. The other 6% of patients had coronary artery bypass surgery 4-14 days before randomization. The primary efficacy outcome was the composite of cardiovascular death, myocardial infarction, or first-ever stroke.
Patients were followed for a mean of 2 years before the trial was stopped due to pre-specified criteria demonstrating efficacy at the first interim analysis. Patients on combination rivaroxaban plus aspirin had significantly lower rates of the composite outcome compared to aspirin alone (4.2% vs. 5.6%, p < 0.0001, NNT 72), as well as death by any cause (3.2% vs. 4.1%, p = 0.0012, NNT 112), cardiovascular death (1.7% vs. 2.2%, p = 0.01, NNT 200), non-cardiovascular death (1.5% vs. 1.9%, p = 0.048, NNT 250), and stroke (0.9% vs. 1.6%, p < 0.0001, NNT 143). The rates of these outcomes with rivaroxaban alone were not significantly different than rates with aspirin alone. As expected, rates of major bleeding with rivaroxaban plus aspirin (3.2%) and rivaroxaban alone (2.9%) were higher than rates with aspirin alone (1.9%, p < 0.0001 vs. each, NNH 77 for rivaroxaban plus aspirin and NNH 100 for rivaroxaban alone), with gastrointestinal bleeding as the most common type of bleeding in each group. The rates of fatal bleeding, non-fatal symptomatic intracerebral hemorrhage, and non-fatal symptomatic hemorrhage in other critical organs were each < 1% and not significantly different between groups.
The COMPASS trial demonstrated that, in adults with stable CAD, combination rivaroxaban plus aspirin reduced the risks of death and major cardiovascular events compared to aspirin alone. However, rivaroxaban, with or without aspirin, increased the risk of major bleeding, mostly in the gastrointestinal tract. The lower all-cause mortality with combination rivaroxaban plus aspirin suggests that it has a favorable balance between reduced clotting and increased bleeding in these patients. The absolute differences in rates are not dramatic but may be important in terms of total numbers given the high prevalence of CAD. The patients analyzed in this study are a pre-specified subgroup of a larger population that also included patients with stable peripheral or carotid artery disease; consistent results were found in analyses of the other subgroup (Lancet 2017b Nov 10 early online) and the entire cohort (N Engl J Med 2017). The exclusion of patients with < 80% adherence during the run-in period raises some questions regarding applicability to the general population. In summary, combination rivaroxaban plus aspirin has a modest overall benefit compared to aspirin alone, but there are significant bleeding risks as well and these should be carefully considered and discussed with the patient.
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