BARCELONA, SPAIN — The combination of low-dose (2.5 mg twice daily) rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals) plus aspirin 100 mg daily showed significant reductions in both major cardiovascular and limb events, including amputations, in patients with peripheral arterial disease (PAD) in the COMPASS trial[1].
Presenting the results from the PAD subgroup at the European Society of Cardiology (ESC) 2017 Congress, Dr Sonia Anand (McMaster University, Hamilton, ON), said: “Until now we haven’t had a pharmaceutical therapy that has shown a clear reduction in both cardiovascular and limb events. So this is a major step forward.”
To theheart.org / Medscape Cardiology she elaborated: “The results in PAD patients from COMPASS with the combination of rivaroxaban and aspirin are so dramatic because we see a reduction in major amputation as well as all types of amputation, which is what patients care most about. They know they are at a high risk of heart attack but what they worry most about is whether they will lose a limb. Amputation is one of those end points like death—it either happens or it doesn’t, so it is a very robust end point, and it’s very exciting to show such a large and significant reduction.”
The COMPASS trial included 7470 PAD patients—4129 with symptomatic PAD limbs, 1919 with carotid disease, and 1422 with CAD and low ankle-brachial index (<0.90).
They were randomized to one of three groups: rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily; rivaroxaban 5 mg twice daily alone; or aspirin 100 mg daily alone. The trial was stopped for superiority of the rivaroxaban-plus-aspirin group at 23 months in the overall population, which also included patients with stable coronary disease.
Results in the PAD subgroup showed significant benefits of the combination arm on both major adverse cardiovascular events (MACE) and major adverse limb events (MALE).
The combination also increased the risk of major bleeding but did not increase the risk of fatal or critical organ bleeding, and most major bleeds were reversible, Anand reported.
The rivaroxaban-alone arm did reduce MALE vs aspirin but did not show a significant reduction in MACE.
COMPASS PAD Results: Combination Therapy vs Aspirin Alone
| Outcome | Rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily), n=2492 (%) | Aspirin (100 mg once daily) alone, n=2504 (%) | HR (95% CI) | P |
|---|---|---|---|---|
| Primary outcome: CV death/stroke/MI | 5.1 | 6.9 | 0.72 (0.57–0.90) | 0.005 |
| Major adverse limb events | 1.2 | 2.2 | 0.54 (0.34–0.84) | 0.005 |
| Major amputation | 0.2 | 0.7 | 0.30 (0.11–0.80) | 0.01 |
| Composite of MACE/MALE/major amputation | 6.3 | 9.0 | 0.69 (0.56–0.85) | 0.0003 |
| Major bleeding | 3.1 | 1.9 | 1.61 (1.12–2.31) | 0.009 |
Referring to the combination group, Anand stated: “In terms of drug treatment for PAD, these are the most robust results we have ever seen.
“The results indicate that for every 1000 PAD patients treated for an average of 21 months, rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily prevents 27 patients from having a serious cardiovascular event at a cost of 12 major bleeds, most of which were readily treatable,” she added.
The results indicate that for every 1000 PAD patients treated for an average of 21 months, rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily prevents 27 patients from having a serious cardiovascular event at a cost of 12 major bleeds, most of which were readily treatable. She noted that there have been some smaller subanalyses of larger trials that have shown some promise, but “the risk/benefit profile of low-dose rivaroxaban in combination with aspirin is the most favorable yet.”
She explained that single antiplatelet therapy is the currently recommended mainstay of therapy for PAD patients. “Meta-analyses of studies of aspirin or clopidogrel as single therapy have shown a 20% or so reduction in major adverse cardiovascular events, and there have been some suggestions that these drugs may reduce limb outcomes, but these are not so clear-cut as the results from COMPASS.
“COMPASS is the first trial to show a definite effect in both these types of end points.”
Interestingly, Anand noted that her group have previously studied a combination of warfarin plus aspirin (in the WAVE trial) vs aspirin alone, but there was no reduction in MACE or MALE outcomes and an excess of life-threatening bleeding. “MACE was not reduced because of the excess of life-threating bleeds, and death due to bleeding was counted as a cardiovascular outcome. Why the warfarin/aspirin combination didn’t reduce limb outcomes I don’t know, but I think we can say the low-dose rivaroxaban looks much safer than warfarin when used in combination with aspirin in PAD patients.”
“Uniquely Striking Results”
Discussant of the PAD results from COMPASS, Dr Lars Wallentin (Uppsala University, Sweden), said: “We now have a demonstration of a truly effective treatment for PAD that we have not had before. These are uniquely striking results showing not only a reduction in cardiovascular events but also a reduction in limb events.”
He noted that other agents have shown suggestions of either MACE or MALE reductions but not both.
He pointed some cautions about the trial, such as the exclusion of patients intolerant of aspirin and those at high bleeding risk. He also pointed out that as the trial was conducted in a stable population, “we don’t really know when to start treatment,” and “if bleeding occurs which agent do we stop?”
But he concluded: “The combination of rivaroxaban plus aspirin is definitely a new treatment alternative in PAD.”
He added: “Decisions will have to be made on how to select different treatment strategies when trying to balance bleeding risk and benefits, and we eagerly await the cost-effectiveness analysis.”
The PAD subgroup analysis was part of the larger COMPASS trial in patients with stable atherosclerotic disease. Results of the overall trial were presented at the same session at the ESC meeting and also showed benefits of the combination therapy on the total population.
Dr Magnus Ohman (Duke University Medical Center, Durham, NC) suggested that the PAD patients may be considered one of the first priorities for treatment with the combination regimen as “they have very high event rates, where treatment effects can clearly be justified.”
The overall COMPASS trial has been published online today in the New England Journal of Medicine. The PAD subgroup results will be published separately as a paper in the Lancet in due course, Anand said.
Anand has received speaking and consulting fees from Bayer and Novartis. Wallentin reports having received institutional research grants from AstraZeneca, Bristol-Myers Squibb, MS Pharma, Boehringer-Ingelheim, GlaxoSmithKline, Pfizer, and Roche Diagnostics.
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