Case for rivaroxaban and aspirin for pad gets stronger

Combination treatment with aspirin and low dosage of the anticoagulant rivaroxaban has a broader benefit for reducing adverse events in patients with peripheral artery disease than initially reported from the COMPASS trial, which included more than 7,000 patients whose primary diagnosis at study entry was stable PAD.

Secondary analysis of data from the PAD patients enrolled in the COMPASS (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary Peripheral Artery Disease) trial showed that, compared with aspirin alone, treatment with 100 mg aspirin daily plus a low dosage of the anticoagulant rivaroxaban (2.5 mg b.i.d.) resulted in a statistically significant, 24% relative cut in the combined rate of vascular interventions: acute or chronic limb ischemia, vascular amputation, peripheral vascular bypass or percutaneous intervention, and vascular hospitalization. This finding, plus the results in prior report from COMPASS that rivaroxaban plus aspirin cut major adverse limb events (MALE) by 33%, compared with aspirin alone, together show that rivaroxaban plus aspirin represent a new, effective regimen for a majority of PAD patients (in addition to treating with a statin and an ACE inhibitors) to cut adverse outcomes on a high-risk but historically undertreated patients population. Additional analysis showed that patients with PAD who had an index MALE during follow-up had a very high rate of subsequent event.

Among the 128 PAD patients in COMPASS who had an index MALE (major vascular amputation or severe limb ischemia that resulted in an intervention) and, compared with PAD patients who did not have a MALE, the rate of subsequent death was more than three times higher, the rate of hospitalization increased more than seven-fold and the rate of amputation increased nearly 200-fold.

“The most important message [from the study] is that patients with PAD who have limb events are at incredibly high risk for everything else.”

The analysis of post-MALE outcomes, as well as the expanded vascular-outcomes analysis, focused on 6,391 of the COMPASS patients who had lower-extremity PAD and were randomized to either 100 mg aspirin daily or the low-dosage rivaroxaban plus aspirin regimen. COMPASS also randomized patients to a higher-dosage rivaroxaban-only regimen administered at 5 mg b.i.d., but this arm did not perform as well as the lower-dosage regimen, with an efficacy that equaled aspirin only and with more bleeding.

Also reported on a comparison of the clinical and demographic profiles of the 128 PAD patients who developed MALE during follow-up and the 6,263 who did not, a 2% incidence during almost 2 years. Multivariate analysis identified four significant factors that closely linked with MALE incidence: a history of peripheral surgery or angioplasty, prior limb amputation, baseline Fontaine classification of stage III or IV, and treatment in COMPASS with aspirin alone and not with rivaroxaban plus aspirin.

The new, additional analyses reported also showed total peripheral vascular outcomes during follow-up in COMPASS in 8.0% of patients on aspirin only and 6.2% of patients on aspirin plus low-dosage rivaroxaban, a 24% relative risk reduction, and vascular intervention in 7.1% of aspirin-only patients and in 5.5% of the combined-regimen patients, also a 24% relative risk reduction. MALE occurred in 2.6% of the aspirin only patients and in 1.5% of patients on both drugs, a 33% relative risk reduction. All three of this relative risk reductions were statistically significant.

She estimated that about two-thirds of the PAD patients she sees in routine practice would qualify for treatment with aspirin plus low-dosage rivaroxaban once the 2.5-mg formulation becomes approved by regulators. The companies that jointly market rivaroxaban have an application pending with the Food and Drug Administration to market a 2.5-mg pill based on the COMPASS results.

Patients with stable PAD who are not good candidates for the COMPASS regimen are those with a history of a major bleed, those who require full-dose anticoagulation for a co-morbidity such as a trial fibrillation or mechanical heart valve, and patients with newly diagnosed, stable PAD without concurrent coronary artery disease who might receive adequate protection from aspirin alone.