COMPASS Approach Helps With Leg Complications in Patients With PAD

ORLANDO, FL—Using the combination of low-dose rivaroxaban (Xarelto; Bayer/Janssen) and aspirin in patients with stable lower-extremity PAD pays dividends not only in preventing major adverse limb events (MALE) but in mitigating the poor outcomes that follow such events, an analysis of the COMPASS trial shows.

Over the roughly 2 years of follow-up in the trial, occurrence of MALE was associated with substantially increased risks of subsequent death (HR 3.23), hospitalization (HR 7.21), a composite of MACE or amputations (HR 7.56), and amputations (HR 197.5; P < 0.0001 for all), Sonia Anand, MD, PhD (Population Health Research Institute, Hamilton, Canada), reported at the American College of Cardiology 2018 Scientific Session here.

“We’re alerting clinicians to what a high-risk outcome suffering a MALE is,” Anand told TCTMD.

However, prognosis after having a MALE was significantly better in patients who received the rivaroxaban-aspirin combo than in those who received aspirin alone, according to the results, which were published simultaneously online in the Journal of the American College of Cardiology.

Commenting for TCTMD, Joshua Beckman, MD (Vanderbilt University, Nashville, TN), said the new analysis highlights how serious limb events can be, noting that they are a strong predictor for adverse cardiovascular outcomes.

It’s good that the study is being presented at a large cardiology meeting, he added, “because I think that limb events are as much a cardiovascular problem as they are anything else and that cardiologists really need to pay close attention to what happens to the leg. It’s another window into the whole-body experience of atherosclerosis.”

I think that limb events are as much a cardiovascular problem as they are anything else and that cardiologists really need to pay close attention to what happens to the leg. Joshua Beckman

Beckman said that he expected the rivaroxaban dose used in COMPASS (2.5 mg twice daily) to be approved in the United States—it’s already available in Europe—and to be welcomed by clinicians treating patients with PAD because of the lack of available options. No medications have a labeled indication for reducing MALE and only a few drugs—vorapaxar (Zontivity; Aralez) and evolocumab (Repatha; Amgen)—have been shown to modify limb outcomes, he said.

There are, therefore, few obstacles to implementation of the approach in the PAD population, particularly because it simplifies the message given to patients about the whole-body effects of atherosclerosis, Beckman said.

“This makes the case far more directly,” he said. “The disease is here in your legs. [This treatment is] going to reduce heart attacks and strokes, but it’s also going to help your legs. So I think that the barriers will be fewer and the change in practice will be something that clinicians who treat patients with peripheral artery disease are looking for.”

Heterogeneous Treatment After MALE

MALE are not frequently seen in PAD, affecting about 1% of patients each year, but when they do occur they carry potentially serious consequences, Anand said during her presentation, in which she delved into data on the 6,391 patients with lower-extremity PAD enrolled in COMPASS. As previously reported, the trial, which included a total of 27,395 patients with stable CAD, PAD, or both, showed that the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily reduced risks of both MACE and MALE through an average follow-up of 23 months.

During the trial, 128 of the patients with lower-extremity PAD (2.0%) had a MALE, defined as severe limb ischemia requiring an intervention or major vascular amputation. Predictors included severe ischemia symptoms at baseline (Fontaine classification 3 or 4), prior limb or foot amputation at baseline, prior history of peripheral revascularization surgery or angioplasty, and randomization to the aspirin arm of the trial.

Interventions used in response to the events varied, with the most common being angioplasty (35.9%), amputation (23.4%), bypass (21.1%), and thrombectomy/embolectomy (7.8%).

Medical therapy administered after MALE was “all over the map,” Anand said. Most patients (63%) remained on their randomized study drug, but 13% received single antiplatelet therapy, 10% dual antiplatelet therapy, 2% oral anticoagulation, and 12% no therapy at all. That heterogeneity speaks to the dearth of evidence for how to treat patients with MALE acutely and underscores the need for further studies in this area, Anand said.

Compared with patients taking aspirin alone, those taking the combination of rivaroxaban and aspirin had lower rates of MALE (1.5% vs 2.6%), total vascular amputations (0.5% vs 1.2%), peripheral vascular interventions (5.5% vs 7.1%), and all peripheral vascular outcomes (6.2% vs 8.0%; P < 0.05 for all).

Moreover, when patients did experience MALE, patients treated with the combination fared better. Risks of death and of a composite of MACE and total amputations were not significantly higher after MALE in those patients, whereas aspirin-treated patients had sixfold and tenfold greater risks, respectively, of those outcomes before versus after MALE.

‘No Free Lunch’

Anand noted that there is an increase in major bleeding with the rivaroxaban-aspirin combination compared with aspirin alone (3.2% vs 2.0%; HR 1.61; 95% CI 1.09-2.36), but pointed out that the rate of severe bleeding was not significantly elevated (1.1% vs 0.8%; HR 1.32; 95% CI 0.71-2.42).

Anand said she’s advocating this treatment approach for all patients with PAD because of the lack of options and because the benefit will likely outweigh the bleeding risk. “But certainly if you have a patient who has a history of severe bleeding this may make you think twice about putting them on an anticoagulant,” she commented.

“If we select our patients carefully, essentially weeding out the patients that COMPASS excluded from entering the trial, we will be in pretty good shape to use this therapy,” Anand added.

When asked about his concern about the risk of bleeding, Beckman responded, “There’s no free lunch.”

But even so, he said, “When you take a look at the cardiovascular events and limb events that are prevented compared with the permanent bleeding events that can occur, the net clinical benefit clearly lines up on the side of treating the patients.”