Advances in the Management of Peripheral Arterial Disease - Episode 14

Interpreting Data From the COMPASS and ATLAS ACS 2-TIMI 51 Trials

April 28, 2020

Transcript: Deepak L. Bhatt, MD, MPH: We can pivot now and talk about some of the newest data from the COMPASS and VOYAGER PAD trials. I’ll make a few comments about COMPASS. The overall results of the COMPASS trial, of course, have been presented and published. That included 27,000 patients with coronary artery disease and/or peripheral artery disease [PAD] randomized to aspirin plus low-dose rivaroxaban, sometimes called a vascular dosage, of 2.5 mg twice a day; or to low-dose aspirin plus placebo; or to rivaroxaban alone at 5 mg twice a day. This was to see which was best: an antiplatelet, an antiplatelet plus a low dose of an anticoagulant or a dual-pathway inhibition, or an anticoagulant alone.

The winner was aspirin plus a vascular dose of rivaroxaban. Aspirin at a low dose plus rivaroxaban at 2.5 mg twice a day significantly reduced cardiovascular events, including a significant reduction in all-cause mortality and certainly in CV [cardiovascular] mortality. For all-cause mortality, the P value was less than .05. One can perhaps debate that P value. It wasn’t quite what we prespecified in the protocol, but that was because the Data and Safety Monitoring Board ended the trial early because of what they thought was overwhelming efficacy. They saw a significant primary end point. They saw significantly lower mortality. There was the trial that Mike led, ATLAS ACS 2-TIMI 51, which also showed a mortality reduction with that dose. They said, “Enough is enough. We’re not going to continue this experiment just for the sake of science.” That’s the overall trial.

What’s been presented more recently at the American Heart Association Scientific Sessions meeting as a late breaker and published in Circulation by Kevin Bainey was COMPASS-PCI. We specifically looked at patients with a history of PCI [percutaneous coronary intervention] in the past. These weren’t only patients receiving PCI, but if you were on dual-antiplatelet therapy or should have been, that was an exclusion criterion in COMPASS. In those patients with a history of PCI, the drug performed very well.

Most recently, as a late breaker at the American College of Cardiology Scientific Session meeting a few days ago, I presented COMPASS-Diabetes. That was published in Circulation simultaneously. That showed a consistent benefit for this vascular dose of rivaroxaban plus aspirin. Those with diabetes, as in those without diabetes, saw similar degrees of relative risk reduction. But given their higher baseline absolute risk, we saw larger numerical risk reductions in an absolute sense for those with diabetes versus those without diabetes, including a 3-fold higher reduction in all-cause mortality in those with diabetes with this regimen of dual-pathway inhibition. We’ve identified another subgroup from the overall COMPASS trial that looks particularly good, not just in terms of relative risk reductions but absolute risk reductions. Other subgroups include, pertinent to today’s talk, those with polyvascular disease, atherothrombosis involving 2 or 3 different arterial beds.

That was the COMPASS trial’s story and updates. Mike, in a sense, you started it all with ATLAS ACS 2-TIMI 51. That’s what led to the COMPASS trial and that specific dosage being tested. What are your thoughts now, reflecting on both ATLAS ACS 2-TIMI 51 and COMPASS, which was a stable, albeit high-ischemic risk, low-bleeding-risk population?

C. Michael Gibson, MS, MD: As I said before, Deepak, COMPASS included “a stable population,” but in many cases, about 70% of the time, these were ACS patients who grew up and were enrolled in COMPASS several years later. I’d like to emphasize that the magnitude of the primary end point reduction was homogenous between the 2 studies, very consistent. There was no real-time dependency. It didn’t matter whether you start acutely or chronically. There was a similar magnitude of event reduction in the 2 trials. They call them acute and chronic, but it’s all part of a continuum of atherothrombosis. You’re never really out of the woods. Thrombin is the new cholesterol; acutely and chronically, it’s there. The consistent results in the acute setting and chronic setting point to the fact that it’s a modifiable target for treatment.

Deepak L. Bhatt, MD, MPH: That’s a clever way of looking at things. Thrombin is the new cholesterol. There is 1 difference, though, because with LDL [low-density lipoprotein], lower is better unequivocally in high-risk patients. But with thrombin, lower is better, but there is a risk of bleeding that can’t be avoided. That is across every trial we’ve mentioned, every strategy we’ve mentioned, whether it’s dual-antiplatelet therapy or adding thrombin inhibition into the mix. It increases major bleeding and, in some cases, intracranial or fatal bleeding depending on the exact trial compound and population. All these regimens have that potential, even if the trials with select patients didn’t demonstrate it.

Transcript Edited for Clarity