Anticoagulation Versus Antiplatelet Therapy: The Emerging Role for Fixed Low-dose Anticoagulants in Arterial Disease

The secondary prevention of atherosclerotic cardiovascular events (ischemic stroke, myocardial infarction, peripheral arterial embolization) with antithrombotic agents in various combinations has been investigated for decades (Table). A common theme in this debate has been the role of antiplatelet agents compared to or in addition to anticoagulants. Until recently, there was no clear role for anticoagulants, but this ongoing debate has seen new attention after the success of direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) and stroke prevention in atrial fibrillation. The ability to use DOACs at fixed low doses has begun to shape a different future for antithrombotic regimens, and hematologists and oncologists who prescribe anticoagulation should take note.

The VOYAGER-PAD trial¹  was a double-blind, randomized, control trial of patients with peripheral arterial disease having undergone lower extremity revascularization within 10 days. Subjects 50 years or older were randomized to either rivaroxaban (2.5 mg twice daily) plus aspirin or placebo plus aspirin. Additional administration of clopidogrel was allowed for up to six months after revascularization per investigator discretion but could not be used for long-term treatment. The primary efficacy outcome was analyzed as intention to treat and was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. The principle safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding with secondary safety outcomes examining International Society on Thrombosis and Haemostasis (ISTH) and Bleeding Academic Research Consortium (BARC) major bleeding.

This was a large, event-driven endpoint study. In total, 6,564 patients were randomized in 34 countries and 542 sites. After a median follow-up of 28 months, 508 patients randomized to rivaroxaban and 584 randomized to placebo had a primary composite outcome (HR, 0.85; 95% CI, 0.76-0.96), a significant benefit to the DOAC and aspirin arm. Multiple composite secondary efficacy outcomes also showed lower event rates with rivaroxaban, including a lower risk for acute limb ischemia (HR, 0.67; 95% CI, 0.76-0.96). Notably, death from cardiovascular causes or all-cause mortality was not significantly lower with rivaroxaban. Interestingly, there was a trend toward lower VTE rates in the rivaroxaban arm (HR, 0.61; 95% CI, 0.37-1.00), despite the intervention being half the daily dose of currently approved rivaroxaban prevention doses. The principal safety outcome of TIMI major bleeding occurred in 62 subjects treated with rivaroxaban compared to 44 with placebo (HR, 1.43; 95% CI, 0.97-2.10). The secondary safety outcome examining ISTH major bleeding did occur more frequently with rivaroxaban (HR, 1.42; 95% CI, 1.10-1.84) but was not statistically different from BARC major bleeding. Similar numbers in both groups were treated with clopidogrel at time of randomization (50.5% in each). The results from this important study build on a paradigm established in the COMPASS trial that evaluated rivaroxaban at 2.5 mg twice daily alone, with aspirin once daily or aspirin alone in 27,395 patients with stable cardiovascular disease.²  The COMPASS study demonstrated that the combination of rivaroxaban and aspirin was superior to aspirin alone for the primary composite outcome of cardiovascular death, stroke, or myocardial infarction. It also specifically reduced cardiovascular death and death from any cause, but at the expense of increased ISTH major bleeding. Rivaroxaban alone compared with aspirin did not result in a significant reduction of the primary composite outcome. A lack of reduction in cardiovascular events with rivaroxaban 2.5 mg twice daily alone versus aspirin alone was also demonstrated in the COMMANDER HR trial, studying patients with chronic left heart failure with coronary arterial disease who were in sinus rhythm.³ 

These two trials with low-dose rivaroxaban in different settings and with high-risk patients demonstrate the ability to lower adverse cardiovascular outcomes in combination with aspirin in a way no anticoagulant has before. Warfarin in combination with aspirin versus aspirin alone in patients with peripheral arterial disease (WAVE trial) failed to reduce cardiovascular events and led to increased fatal, life-threatening, and intracranial bleeding.⁴  Similarly, in the WARS study, warfarin, at an international normalized ratio goal ranging between 1.4 and 2.8, failed to reduce recurrent ischemic strokes compared to aspirin.⁵  Rivaroxaban has also been studied in the NAVIGATE-ESUS trial comparing rivaroxaban (15 mg once daily) to aspirin in patients with embolic stroke of unknown source (ESUS) and was stopped early due to excess bleeding and lack of efficacy.⁶  Similarly, dabigatran could not be proven superior to aspirin in patients with ESUS.⁷ 

While results from a clinical trial with apixaban versus aspirin in patients with cryptogenic stroke are ongoing (NCT03192215), the combination of low-dose DOACs with aspirin or other antiplatelet agents is likely to be an ongoing area of interest for cardiovascular disease prevention. For now, rivaroxaban 2.5 mg twice daily in combination with aspirin is the only antithrombotic regimen in atherosclerotic disease secondary prevention (excluding post-acute myocardial infarction regimens) proven to reduce cardiovascular and all-cause mortality when compared to aspirin.