What was found for the primary efficacy endpoint, of cardiovascular death, myocardial infarction, or stroke, was a significant reduction in that important triple ischemic composite. In fact, it was so significant that the data safety monitoring board stopped the trial early because they felt that the data showed overwhelming efficacy. In fact, that's what the company-issued press release said when the trial was stopped. In addition to seeing a benefit in that triple ischemic endpoint, they also saw a lower rate of mortality, of all-cause mortality. So that combination of findings made them say, "stop the trial," which is what the COMPASS investigators then did.

The efficacy results, I think, are quite robust. In terms of bleeding, there's always a downside with potent antithrombotic therapy. There was a significant excess in major bleeding. Fortunately, there was no, at least, statistically significant excess in fatal bleeding or intercrancial bleeding. So overall, a very good net clinical benefit—about a 20% or so reduction in that endpoint.

Overall, I would then say that it was a very positive trial. How exactly to integrate it into the practice of stable CAD, stable PAD versus other therapies, that is going to be a topic of discussion, I'm sure.

In the clip, Deepak Bhatt, MD, discusses the results of the COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS) trial, presented at the European Society of Cardiology Congress 2017, held August 26-30 in Barcelona, Spain. 

The results of the international, double-blind, randomized controlled trial, which tested how to improve on aspirin to protect against heart attack and stroke, were also published in the New England Journal of Medicine. John Eilkelboom, MBBS, MSc, FRCPC, associate professor at McMaster University, presented the primary results.

Rivaroxaban plus aspirin has significant benefits for patients with peripheral artery disease (PAD) and stable coronary artery disease, according to the trial results. The study found that rivaroxaban plus aspirin reduced cardiovascular death, stroke, or heart attack by 24% and improved survival by 18%. However, the combination increased bleeding, most commonly in the stomach or lower bowel, but there were no significant increase in fatal or brain bleeding.

“Many of these bleeds were not serious and, despite the increase in bleeding, the results clearly show a net benefit for patients, as highlighted by the 18% reduction in mortality,” Stuart J. Connolly, FRCPC, co-principal investigator and professor of medicine at McMaster University, said in a statement.
Eikelboom added that “this is no time for complacency about bleeding.” Further efforts to reduce bleeding are still needed, and he identified the use of proton pump inhibitors as one possible solution that is still being investigated.

The trial included more than 27,000 patients from 33 countries, and the treatments tested were rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily or rivaroxaban 5 mg twice daily against standard therapy with aspirin 100 mg once daily. The rivaroxaban plus aspirin arm was stopped early because there was a clear superiority over the arm receiving aspirin alone. The rivaroxaban 5 mg arm was not found to be superior to aspirin alone.

“The substantial benefits seen with rivaroxaban and aspirin support the approach of using low doses of the 2 treatments in combination,” Eikelboom said.

In his review of the study, Eugene Braunwald, MD, of Brigham and Women’s Hospital and Harvard Medical School, said that the trial results are “unambiguous” and he believes that they should lead to a “change [of] guidelines for the treatment of coronary artery disease.”
The COMPASS study also tested ways to improve on aspirin to protect against major adverse cardiovascular and limb events, such as severe limb ischemia and amputation, in patients with PAD. The results were presented by Sonia Anand, MD, PhD, FRCPC, professor of Medicine at McMaster University.
The trial included 7470 patients with PAD of the lower extremities and carotid artery disease from 33 countries in North and South America, and it tested using a combination of rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily and rivaroxaban 5 mg twice daily. Both treatments were compared with standard therapy with aspirin 100 mg once daily. One-third of the participants were current smokers and 44% had diabetes.
The combination of rivaroxaban with aspirin reduced cardiovascular death, stroke, or heart attack by 28%, and limb-threatening ischemia, including amputation, by 46%. Overall, rivaroxaban plus aspirin reduced major adverse cardiovascular or limb events by 31%.
“To now have a therapy that reduces major adverse cardiovascular events and major adverse limb events by one-third is going to be a great benefit for these high-risk patients,” Anand said.
Similar to the overall COMPASS study, the combination therapy increased the risk of major bleeding. Most major bleedings were reversible.
“Although there was an increase in major bleeding, there was no significant increase in fatal or critical organ bleeding,” Anand said.
In his review of the study, Lars Wallentin, MD, PhD, of Uppsala University, noted that there were some concerns around bleeding, namely that bleeding risk patients had been excluded from the trial and he wondered which treatment should be used when there is bleeding. However, he congratulated the patients with PAD and healthcare providers treating them.
“Now, we have an effective treatment in PAD, when we rarely had new or effective treatments over the last few years,” he said.