COMPASS: Prognosis 'Dire' in PAD With Major Limb Events

March 16, 2018

A new analysis from the peripheral arterial disease (PAD) subgroup of the large-scale COMPASS trial show that development of a major adverse limb event — the primary endpoint of the study — is associated with a dire longer-term prognosis, including a 7-fold increased risk for hospitalization, a 200-fold increased risk for an amputation, and a 3-fold increased risk for death over the following year.

"Our results highlight the utmost importance of preventing major adverse limb events in patients with PAD," COMPASS investigator, Sonia Anand, MD, Population Health Research Institute, Hamilton, Ontario, Canada, told theheart.org | Medscape Cardiology.     

The main results of the PAD subgroup in the COMPASS trial, reported last year, showed a 46% reduction in major adverse limb events (defined as severe limb ischemia necessitating hospitalization for an intervention such as bypass, angioplasty, amputation, or thrombolysis) in patients receiving low-dose rivaroxaban (2.5 mg twice daily) plus aspirin compared with those receiving aspirin alone.  

In the current analysis, the COMPASS researchers looked at the longer-term prognosis of the 128 patients who developed a major adverse limb event in the trial, the baseline factors that predicted the development of a major adverse limb event, and the impact of the low-dose rivaroxaban and aspirin combination on long-term outcomes.

This new analysis was presented by Anand earlier this week at the American College of Cardiology (ACC) 2018 Annual Scientific Session. It was also simultaneously published online in Journal of the American College of Cardiology.

Anand reported that the independent predictors of a major adverse limb event included severe ischemia symptoms at baseline (Fontaine classification 3 or 4), prior limb or foot amputation at baseline, and history of peripheral revascularization surgery or angioplasty.

Over the next year, the 128 (2%) patients who experienced a major adverse limb event in the trial had a 95.4% risk for a subsequent hospitalization, a 22.9% risk for a vascular amputation, and an 8.7% risk for death. 

Compared with patients with PAD who had not experienced a major adverse limb event, those who did had hazard ratios for subsequent hospitalization of 7.21, for vascular amputations of 197.5, and for death of 3.23.

In terms of treatment, compared with those receiving aspirin alone, patients who had been randomly assigned to low-dose rivaroxaban plus aspirin had a 58% reduction in total amputations, a 67% reduction of major amputations and a 24% reduction in vascular interventions.

"The combination of rivaroxaban 2.5 mg twice daily and aspirin significantly lowers the incidence of major adverse limb events and their related complications and should be considered as an important therapy for patients with PAD," Anand concluded.

She added: "We did not know much about the prognosis for these patients suffering a major adverse limb event before.  These results show that having such an event is a very important marker of adverse prognosis and anything that reduces these events is likely to have a major effect on longer-term outcomes."

Experts in the field asked to comment for theheart.org | Medscape Cardiology were encouraged by these latest results.

Leslie Cooper, MD, Mayo Clinic, Jacksonville, Florida, pointed out that although a small minority of patients with PAD and claudication progress to critical limb ischemia, those that do have a high rate of amputation at 1 year.

"The combination of rivaroxaban 2.5 mg twice daily and aspirin is a major new advance in the management of PAD because it demonstrates that inhibiting a new pathway, factor Xa inhibition, can impact clinically meaningful outcomes with acceptable risk in this population," Cooper said. "As with any substudy, caution is required in interpretation, but the large sample size and rigorous methodology of the parent trial add credibility to these data."

Lars Wallentin, MD, PhD, Uppsala Clinical Research Center, Sweden, added that these new data further emphasize the importance of PAD as a risk factor for both limb events and cardiac events in patients with vascular disease.

"The new results further strengthen the previously published findings that the combination of rivaroxaban at a very low dose of 2.5 mg per day in combination with low-dose aspirin provides a clinically very meaningful protection against both new limb events and coronary events," Wallentin said. "As the treatment is associated with only a modest increase in major bleeding, and no difference in severe bleeding, this treatment strategy is an appealing alternative for many patients with PAD."

Joseph Ladapo, MD, PhD, associate professor of medicine at David Geffen School of Medicine at the University of California Los Angeles and a health policy researcher, called this an "important study because it highlights a condition — PAD with limb complications — that can cause a tremendous amount of suffering for patients."

"Physicians know that outcomes are worse for patients with limb ischemia, but these authors quantify their risk in a large cohort, which I have not seen before," Lapado said. The hazard ratio for subsequent amputation is about 200 among patients with a prior major adverse limb event, he noted.

"We all knew it was a risk factor, but it's beneficial to see how much of a profound risk factor it is," he said. "The other major takeaway is that aspirin plus rivaroxaban is effective, but we have shown previously that patients with PAD are undertreated. There are evidence-based therapies that improve outcomes in these patients, but they're just not being prescribed."

Despite describing the reduction in major adverse limb events with rivaroxaban plus aspirin as "eye popping," Lapado said that translating this into a reduction in outcomes in the real world would depend on addressing the inertia that physicians currently demonstrate. 

"There is slow adoption of evidence-based therapy in this population," he stressed.   

The COMPASS trial was funded by Bayer.  A nand has received honoraria and consulting fees from Bayer and Novartis.

American College of Cardiology (ACC) 2018 Annual Scientific Session. Presentation 407-16. Presented March 11, 2018.

J Am Coll Cardiol. Published online March 11, 2018.  Abstract

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