Rivaroxaban With or Without Aspirin for the Secondary Prevention of Cardiovascular Disease

Clinical Implications of the COMPASS Trial

Stephen J. Nicholls; Adam J. Nelson


Am J Cardiovasc Drugs. 2019;19(4):343-348. 

In This Article

Evidence for Anticoagulant Therapy in Atherosclerosis

Beyond patients with clearly established indications for use of anticoagulation therapy, the potential utility of empirical anticoagulant use in patients with atherosclerotic disease has never been satisfactorily resolved. Administration of long-term vitamin K antagonists has been demonstrated to be clinically efficacious in patients following a myocardial infarction, whether as monotherapy or in combination with aspirin, compared with aspirin alone.[14–19] A number of recent studies have investigated the impact of combined antiplatelet and anticoagulant therapy in patients with a clinical indication for an anticoagulant agent undergoing percutaneous coronary intervention.[7–10] However, these benefits are accompanied by an increase in the risk of bleeding. The most compelling findings, albeit from an open-label study with a modest sample size, suggested that combination therapy with warfarin and clopidogrel could be useful.[9] However, warfarin continues to be a challenging agent to use in clinical practice, with the need for frequent blood tests and potential changes in dosage.

The evolution of the direct oral anticoagulants (DOACs) ushered in a new era in the management of thrombotic risk in patients with cardiovascular disease. The ability to achieve more stable therapeutic levels without the requirement for blood tests presents an attractive alternative for patients requiring long-term therapy. Rivaroxaban is a selective direct factor Xa inhibitor with good clinical evidence for use in the prevention and treatment of venous thromboembolism (VTE)[20] and in the prevention of stroke in patients with AF.[21] In a dose-ranging phase II study of patients following acute coronary syndrome (ACS), rivaroxaban at the low and very low doses of 5 mg twice daily (BID) and 2.5 mg BID, respectively, had a directionally favorable net clinical benefit compared with the conventional 15 mg once daily (OD) and 20 mg OD regimens used in VTE and AF—potentially a pharmacokinetic phenomenon of higher troughs and lower peaks.[22] In the phase III ATLAS ACS 2 study of low (5 mg BID) and very low (2.5 mg BID) doses in patients following ACS, the combined rivaroxaban arms resulted in a 16% reduction (hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.74–0.96; p < 0.008) in the composite of cardiovascular death, myocardial infarction, and stroke (8.9 vs. 10.7%; p < 0.002).[23] This was associated with a greater risk of major bleeding (2.1 vs. 0.6%; p < 0.001) and intracranial hemorrhage (0.6 vs. 0.2%; p = 0.009). While these findings suggested a potential benefit in cardiovascular event reduction with the use of very low-dose rivaroxaban in combination with potent antiplatelet therapy following an ACS, the trial was criticized for its loss to follow-up of approximately 10% of patients who did not have primary endpoint data.[24] Safety concerns from missing data as well as anticipated excess bleeding have hindered US FDA regulatory approval, despite it being listed by European drug regulators. In similar post-ACS trials of DOACs, a signal for excess bleeding was observed in both the APPRAISE-2 trial[25] of full-dose apixaban (two- and fourfold the equivalent dose of low and very low-dose rivaroxaban) as well as the dose-ranging RE-DEEM trial of dabigatran.[26] While meta-analyses suggest net excess bleeding alongside dual antiplatelet therapy with full-dose anticoagulant,[27] it remains to be seen whether substitution of the aspirin for very low-dose rivaroxaban (2.5 mg BID) alongside a P2Y12 inhibitor, recently shown to be safe in the phase II GEMINI-ACS-I trial,[28] can find the "sweet spot" of cardiovascular event reduction and tolerable bleeding.