COMPASS Charts New Course for Rivaroxaban in Stable Vascular Disease

(UPDATED) BARCELONA, Spain—Combining low doses of rivaroxaban and aspirin seems to be a winning approach to improving outcomes for patients with stable atherosclerotic vascular disease, the prematurely halted COMPASS trial shows.

Compared with low-dose aspirin alone, the combination reduced the risk of a composite of cardiovascular death, MI, or stroke through an average follow-up of about 2 years (4.1% vs 5.4%; HR 0.76; 95% CI 0.66-0.86), John Eikelboom, MBBS (Population Health Research Institute, Hamilton, Canada), reported here at the European Society of Cardiology Congress 2017.

That represents the “overwhelming efficacy” on the primary outcome touted in the previously reported top-line results used to justify stopping the trial early in February.

The addition of rivaroxaban (Xarelto; Bayer/Janssen) came at the cost of increased major bleeding (3.1% vs 1.9%; HR 1.70; 95% CI 1.40-2.05), although a composite net clinical benefit endpoint incorporating risks of the most serious bleeds still favored the anticoagulant-aspirin combination.

The findings were published simultaneously online today in the New England Journal of Medicine.

“COMPASS has very important implications, because there’s a huge number of patients who have established coronary disease or peripheral arterial disease,” Christopher Granger, MD (Duke University, Durham, NC), who was not involved in the trial, told TCTMD.

Although the size of the reduction in vascular events is comparable to the size of the increase in major bleeding, it is important to look at the aggregate effect, he said. All-cause mortality is a good measure of that effect, he added, pointing out that rivaroxaban plus aspirin carried a lower risk versus aspirin alone.

The trial is compelling, so I’m sure the guidelines will change, but how exactly it’ll be positioned we’ll have to wait and see. Christopher Granger

“There is more bleeding, not surprisingly, but it’s a modest increase in bleeding that’s more than counterbalanced by the benefits,” Granger said.

The results are likely enough to get the 2.5-mg twice daily rivaroxaban dose used in the study approved for use in the United States, and to change guidelines, although data from this trial alone might not be enough to get a class I recommendation, he added. “I do think the trial is compelling, so I’m sure the guidelines will change, but how exactly it’ll be positioned we’ll have to wait and see.”

Although aspirin has been shown to reduce the risk of recurrent events in patients with stable CAD or PAD, residual risk remains, and the medical community continues to search for more effective alternatives. Trials involving warfarin have demonstrated the potential for an anticoagulant to add benefit to aspirin, but concerns with warfarin include increased serious bleeding and inconvenience, Eikelboom said.

Non-vitamin K antagonist oral anticoagulants might have a role to play. In the ATLAS ACS 2-TIMI 51 trial involving patients with ACS on standard medical therapy, rivaroxaban 2.5 or 5.0 mg twice daily reduced the risk of a composite of CV death, MI, or stroke compared with placebo, with a mortality benefit seen at the lower dose. As expected, major bleeding was increased.

COMPASS, conducted at 602 centers in 33 countries, extends those findings to patients with stable ischemic coronary disease, peripheral disease, or both. After a run-in phase, 27,395 patients (90.6% with CAD and 27.3% with PAD) were randomized to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily, rivaroxaban 5.0 mg twice-daily alone, or aspirin 100 mg once-daily alone. Patients not taking a proton pump inhibitor were also randomized to pantoprazole or placebo, and that part of the trial is ongoing.

In addition to lowering the risk of the primary efficacy outcome, the combination of rivaroxaban and aspirin reduced risks of several secondary outcomes, including a composite of ischemic stroke, MI, acute limb ischemia, or death from coronary heart disease (3.6% vs 4.9%; HR 0.72; 95% CI 0.63-0.83) and a composite of ischemic stroke, MI, acute limb ischemia, or cardiovascular death (4.3% vs 5.7%; HR 0.74; 95% CI 0.65-0.85).

All-cause death also occurred at a lower rate with the combination (3.4% vs 4.1%; HR 0.82; 95% CI 0.71-0.96), although that fell short of formal statistical significance when taking into account the multiple comparisons.

“I think that’s more a technicality,” Granger noted, saying that the mortality reduction appeared “pretty robust.”

Rivaroxaban monotherapy, on the other hand, did not have any advantage over aspirin alone.

COMPASS is a large, rigorously conducted trial with unambiguous results. Eugene Braunwald

A separate presentation at the meeting by Sonia Anand, MD, PhD (Population Health Research Institute), included results in the subgroup of patients with peripheral or carotid artery disease. As in the main analysis, rivaroxaban plus aspirin lowered the risk of cardiovascular death, MI, or stroke versus aspirin alone (5.1% vs 6.9%; HR 0.72; 95% CI 0.57-0.90).

The combination additionally reduced risks of major adverse limb events (1.2% vs 2.2%; HR 0.54; 95% CI 0.35-0.84), major amputation (0.2% vs 0.7%; HR 0.30; 95% CI 0.11-0.80), and an endpoint combining the major adverse cardiovascular and limb events (6.3% vs 9.0%; HR 0.69; 95% CI 0.56-0.85). Rivaroxaban monotherapy demonstrated an advantage over aspirin for major adverse limb events only.

As seen in the larger trial, rivaroxaban either alone or combined with aspirin increased major bleeding in the PAD subgroup.

An Important Step Forward in Thrombocardiology

Serving as a discussant following Eikelboom’s presentation, Eugene Braunwald, MD (Brigham and Women’s Hospital, Boston, MA), called COMPASS an important step forward in the field of thrombocardiology, noting that clinical investigators have been studying the use of various antithrombotic agents in patients with ischemic heart disease for more than 7 decades.

“COMPASS is a large, rigorously conducted trial with unambiguous results which I believe should change guidelines for the management of chronic stable coronary artery disease,” he said.

But, he added, there’s more research to be done in this field. The combination of a factor Xa inhibitor like rivaroxaban and aspirin should be compared with dual antiplatelet therapy and with the combination of a factor Xa inhibitor and a P2Y12 inhibitor. It would be logical to do so in a single trial, which would have to be very large, he added.

Granger agreed that a study comparing a combination of rivaroxaban and aspirin with dual antiplatelet therapy would be valuable for practicing clinicians.

Regarding the current results, Granger said that even though the findings are compelling, it remains to be seen how they will be integrated into clinical practice, citing slow uptake to some prior major trial findings. “I think for the high-risk patients it’s going to be a really important additional treatment, but it’s going to take time to get it implemented,” he said, noting that cost and concerns about bleeding could be obstacles.

Bleeding is a valid concern, Granger said, “but I think that when we make decisions as healthcare providers we tend to overweight bleeding and we tend to withhold overall beneficial treatments because of being overly concerned about bleeding.”