In patients with stable atherosclerotic vascular disease, the combination of aspirin and a low dose of an anticoagulant is associated with a lower rate of cardiovascular outcomes but more major bleeding events than aspirin alone. This finding from the COMPASS trial was presented at the ESC Congress in Barcelona, Spain, in 2017 and published in The New England Journal of Medicine.
The double-blind COMPASS trial involved 27,395 patients with stable atherosclerotic vascular disease: 90.6% with a history of coronary artery disease (CAD) and 27.3% with a history of peripheral artery disease (PAD). Participants were randomly assigned to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). Of note, both doses of rivaroxaban were lower than the 10 mg dose approved for stroke prevention in patients with atrial fibrillation. The independent data and safety monitoring board recommended early termination of this part of the trial (mean follow-up 23 months) because of superiority of the combined treatment.
The rate of the primary outcome (a composite of cardiovascular death, stroke, or myocardial infarction) was significantly lower in the rivaroxaban plus aspirin group than in the aspirin-only group (4.1% versus 5.4%; HR 0.76, 95% CI 0.66–0.86, P < 0.001), but was not significantly different with rivaroxaban only compared with aspirin only (4.9% versus 5.4%; HR 0.90, 95% CI 0.79–1.03, P = 0.12). All-cause death occurred in 3.4%, 4.0%, and 4.1% of patients in the rivaroxaban plus aspirin, rivaroxaban-only, and aspirin-only groups, respectively.
The rate of major bleeding was higher in patients receiving rivaroxaban and aspirin than in patients receiving aspirin only (3.1% versus 1.9%; HR 1.70, 95% CI 1.40–2.05, P < 0.001), and higher in patients receiving rivaroxaban only compared with aspirin only (2.8% versus 1.9%; HR 1.51, 95% CI 1.25–1.84, P < 0.001). Most of the excess bleeding in the rivaroxaban plus aspirin group was in the gastrointestinal tract.
In The Lancet, the investigators subsequently published separate analyses in patients with stable CAD and those with PAD. In 24,824 patients with stable CAD, the combination of rivaroxaban plus aspirin reduced the rate of the primary outcome more than aspirin alone (HR 0.74, 95% CI 0.65–0.86, P < 0.0001), and also reduced mortality (HR 0.77, 95% CI 0.65–0.90, P = 0.0012). However, combined treatment resulted in a higher risk of major bleeding than use of aspirin alone (HR 1.66, 95% CI 1.37–2.03, P < 0.0001), mainly in the gastrointestinal tract. Rivaroxaban alone did not significantly improve the primary outcome versus aspirin alone, but increased the risk of major bleeding.
The COMPASS investigators ... hit the sweet spot with the dose of rivaroxaban
Similarly, in 7,470 patients with PAD, the combination of rivaroxaban plus aspirin compared with aspirin only reduced the occurrence of the primary outcome (HR 0.72, 95% CI 0.57–0.90, P = 0.0047), and also major adverse limb events including major amputation (HR 0.54, 95% CI 0.35–0.82, P = 0.0037). Again, this benefit was at the expense of an increased risk of major bleeding (HR 1.61, 95% CI 1.12–2.31, P = 0.0089), mainly gastrointestinal. Rivaroxaban only compared with aspirin only did not reduce the primary outcome, but did reduce major adverse limb events, also with an increase in major bleeding events.
“The COMPASS investigators ... hit the sweet spot with the dose of rivaroxaban, thereby maximizing the efficacy of the combination while minimizing the bleeding risk,” comments Jack Hirsh (McMaster University, Ontario, Canada), who was not involved in the trial. “The findings are likely to change clinical practice, because the combination not only increased net clinical benefit, but also reduced total mortality,” he adds.
John Eikelboom, lead author on the initial trial report, anticipates that the results will “lead to widespread regulatory approval for long-term secondary prevention in patients with coronary or peripheral artery disease. I suspect that this regimen will become the standard of care in the future.” Nevertheless, “bleeding is always an issue ... We are currently testing whether pantoprazole can reduce the risk of gastrointestinal bleeding in patients receiving antithrombotic therapy for secondary prevention.” The pharmacological balancing act between clotting and bleeding continues.
Eikelboom, J. W. et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N. Engl. J. Med. 377, 1319–1330 (2017)
Connolly, S. J. et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet http://dx.doi.org/10.1016/S0140-6736(17)32458-3 (2017)
Anand, S. S. 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 http://dx.doi.org/10.1016/S0140-6736(17)32409-1 (2017)
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Lim, G. COMPASS-guided secondary prevention. Nat Rev Cardiol (2017). https://doi.org/10.1038/nrcardio.2017.184