Should I consider low-dose rivaroxaban (2.5 mg) for my patient with peripheral artery disease?

VARIOUS ANTITHROMBOTIC STRATEGIES TESTED

Several antithrombotic strategies have been tested to see if they reduce the risk of atherosclerotic events.

Aspirin inhibits cyclooxygenase, thereby inhibiting platelet aggregation and thrombosis.

Vitamin K antagonists, with a target international normalized ratio of 2 to 3, when added to low-dose aspirin, have been demonstrated to reduce the risk of major adverse cardiovascular events, at the cost of higher risk of bleeding.³

Dual antiplatelet therapy with a P2Y₁₂ inhibitor such as clopidogrel plus aspirin has also been shown to reduce the risk of major adverse cardiovascular events, with some increased bleeding risks in patients with atherosclerosis or multiple atherosclerotic risk factors.⁴

Full-dose factor-Xa inhibition with apixaban,⁵ rivaroxaban,⁶ or edoxaban⁷ has been investigated in patients who had experienced an acute coronary syndrome or undergone endovascular therapy for peripheral artery disease, but it has yielded unpromising results, causing more bleeding.

Dual-pathway inhibition, ie, low-dose rivaroxaban plus low-dose aspirin, is the newest strategy to be considered in patients at high atherothrombotic risk. Other factor Xa inhibitors have not been tested at low doses for this indication.

EVIDENCE BEHIND LOW-DOSE RIVAROXABAN FOR ATHEROSCLEROSIS

Low-dose rivaroxaban plus aspirin was tested in 2 large trials: COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies)¹ and VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD [peripheral artery disease]).²

The COMPASS trial¹ enrolled patients with stable coronary, carotid, or lower-extremity artery disease. Those randomized to receive the combination of rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily had a lower incidence of major adverse cardiovascular events than those who received aspirin alone (absolute risk reduction 1.3%, number needed to treat 77). Although bleeding risk was higher with the combination than with aspirin alone, the net clinical benefit (measured as the composite of major adverse cardiovascular events plus fatal or critical organ bleeding) favored rivaroxaban (hazard ratio 0.80, 95% confidence interval 0.70–0.91) over 23 months.¹

Of note, a third treatment group, who received rivaroxaban 5 mg twice daily without aspirin, did not experience a lower incidence of major adverse cardiovascular events and had a higher risk of bleeding.

In the subgroup of patients who had only symptomatic peripheral artery disease, dual-pathway inhibition (ie, low-dose rivaroxaban plus low-dose aspirin) was even more effective, with an absolute risk reduction in major adverse limb events of 2.2% (number needed to treat 45) and absolute risk reduction in major adverse cardiovascular events of 3.9% (number needed to treat 30) over 30 months.⁸

The VOYAGER trial² enrolled patients who had undergone revascularization for lower-extremity artery disease and randomized them to receive either low-dose rivaroxaban or placebo, in addition to low-dose aspirin. In 3 years of follow-up, patients on low-dose rivaroxaban had a lower risk of major adverse cardiovascular events and major adverse limb events (absolute risk reduction 2.6%, number needed to treat 38). Rates of major bleeding were modestly increased (an absolute increase of 1.2% by the International Society on Thrombosis and Haemostasis criteria, but no difference by the Bleeding Academic Research Consortium and Thrombolysis in Myocardial Infarction criteria).

BALANCING ATHEROTHROMBOTIC AND BLEEDING RISKS

Considering these data, it is important to identify patients most likely to benefit from this therapy—those at high risk of atherothrombosis, low risk of bleeding, or both.^9,10

WHAT DO GUIDELINES RECOMMEND?

The 2024 American College of Cardiology and American Heart Association guideline¹⁵ for the management of lower-extremity peripheral artery disease gave a class 1 recommendation for low-dose rivaroxaban along with low-dose aspirin in patients with symptomatic peripheral artery disease or after lower-extremity revascularization.

The 2024 European Society of Cardiology guideline¹⁶ for the management of peripheral artery disease and aortic diseases gave this combination a class 2a recommendation (ie, it should be considered) for patients with “high ischemic risk” and “non-high bleeding-risk.”

Both the American¹⁷ and the European¹⁸ guidelines for chronic coronary disease give a class 2a recommendation for low-dose rivaroxaban along with low-dose aspirin for patients with no indication for full-dose anticoagulation.

OTHER PATIENTS WHO SHOULD NOT GET LOW-DOSE RIVAROXABAN

Low-dose rivaroxaban should not be considered in several other groups of patients besides those at high bleeding risk:

• Patients with indications for “full-dose” anticoagulation such as atrial fibrillation, history of venous thromboembolism with an indication for long-term anticoagulation, and mechanical valve replacement

• Those taking reduced-dose apixaban (2.5 mg twice daily) or rivaroxaban (10 mg daily) for “extended duration” venous thromboembolism prophylaxis

• Those with advanced renal disease (creatinine clearance < 15 mL/min/1.73 m²) or liver disease (defined as “any known hepatic disease with coagulopathy” in the trials)—these patients were excluded from the clinical trials.

Other subsets of patients in which low-dose rivaroxaban has not been studied are patients with recent percutaneous coronary intervention (< 1 year) or concomitantly receiving a P2Y₁₂ inhibitor. Decisions to start low-dose rivaroxaban in patients on P2Y₁₂ inhibitors should be individualized based on their bleeding and thrombotic risks. For example, in patients with prior aspirin allergy, gastrointestinal bleeding on aspirin, or thrombotic events on aspirin, this strategy can be considered, understanding there are limited data behind this strategy.

THE BOTTOM LINE

For patients with high ischemic risk such as those with polyvascular disease or lower-extremity artery disease, rivaroxaban 2.5 mg twice daily with aspirin 81 or 100 mg daily is a proven strategy to reduce major cardiovascular and limb events. It is crucial to assess bleeding risk when considering escalating antithrombotic regimens.

DISCLOSURES

The authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.