‘Less Is More’ for Patients With AF and Stable CAD: AFIRE Analysis

Among patients with stable CAD and atrial fibrillation (AF), using rivaroxaban (Xarelto; Bayer/Janssen) alone rather than in combination with antiplatelet therapy reduces total thrombotic and bleeding events, including mortality, according to a post hoc analysis of the AFIRE trial.

Over a median follow-up of about 2 years, the rate of death, bleeding, and thrombotic events—encompassing both first and subsequent events—was 12.2% with rivaroxaban monotherapy and 19.2% with rivaroxaban plus antiplatelets. Rivaroxaban monotherapy was independently associated with a lower risk after accounting for potential confounders (HR 0.62; 95% CI 0.48-0.80).

Typically, the primary endpoints of randomized trials are based on first events, and AFIRE was no different. The main results, reported at the European Society of Cardiology Congress 2019, showed that rivaroxaban monotherapy was noninferior to rivaroxaban plus antiplatelet therapy when it came to first stroke, systemic embolism, MI, unstable angina requiring revascularization, or all-cause death (4.14% vs 5.75% per patient-year; P < 0.001 for noninferiority), and superior in terms of first ISTH-defined major bleed (1.62% vs 2.76% per patient-year; P = 0.01 for superiority). Monotherapy also lowered the risk of all-cause death.

But looking only at first events doesn’t capture the complete clinical picture of a patient, Ryo Naito, MD (Juntendo University Graduate School of Medicine, Tokyo, Japan), lead author of the new post hoc analysis, told TCTMD. He noted that elderly patients with multiple health problems, such as those enrolled in AFIRE, often are taking several medications and are more likely to have associated adverse effects, like bleeding.

Thus, in the context of a world population that is growing older, “we have to consider tapering medication regimens for those people in this aging society,” Naito said. “The very simple message is: less is more.”

The analysis was published online this week in JAMA Cardiology.

Balancing Bleeding, Thrombotic Risks

How to manage antithrombotic treatment in patients who have indications for both antiplatelet therapy and anticoagulation remains a dilemma for clinicians concerned with balancing thrombotic and bleeding risks. In recent years, numerous trials have explored various combinations of antiplatelets and anticoagulants in patients with stable coronary disease and AF, and groups have begun issuing recommendations.

A North American consensus statement last updated in 2021, for instance, recommends triple therapy with a direct oral anticoagulant, a P2Y12 inhibitor, and aspirin during the peri-PCI period in patients with AF undergoing the procedure, after which aspirin should be discontinued. The authors advise stopping antiplatelet therapy altogether at 1 year, with the possibility of earlier discontinuation among patients deemed to have low ischemic risk or high bleeding risk as well as extended treatment among select patients at high risk for recurrent ischemic events and low bleeding risk.

AFIRE, conducted at 294 Japanese centers, focused on patients with AF and stable CAD—defined as being at least a year out from PCI or CABG or having angiographically confirmed coronary disease that did not require revascularization. This post hoc analysis examining total events included 2,215 patients (mean age 74 years; 79.1% men) who had 348 total events (death, bleeding, or thrombotic) over a median follow-up of 24.1 months. After a first event, subsequent events were more likely to be related to bleeding than thrombosis.

Rivaroxaban monotherapy reduced risks of both first events (by a relative 31%) and subsequent events (by a relative 54%) compared with rivaroxaban plus antiplatelet therapy. The mortality rate was lowered, too (HR 0.57 or 0.61 depending on whether the time-dependent variable was a first nonfatal bleed or a first thrombotic event).

Of those who had a first nonfatal event and subsequently died, mortality risk was higher after a bleed (75% with rivaroxaban monotherapy and 62% with combination therapy) than after a thrombotic event (25% and 38%, respectively), “indicating that bleeding events are clinically more impactful than thrombotic events in patients with AF and stable CAD receiving antithrombotic agents,” Naito et al write.

They note that prior research has shown that major bleeding is a primary cause of in-hospital mortality and is associated with a long-term risk of death. “Thus, reducing bleeding events may be a key factor in improving the prognosis in patients with AF and stable CAD, which was one of the rationales for the AFIRE study,” the investigators say.

A ‘Dynamic Assessment’

Ying Gue, MBChB, PhD (Liverpool Heart & Chest Hospital, University of Liverpool, England), who co-wrote an invited commentary accompanying the study, told TCTMD that this post hoc analysis “confirms a well-known view that we have . . . that the bleeding events are actually very, very impactful.” And that highlights, he said, a dilemma clinicians face when deciding how to respond to a bleed—whether they should pull back on antithrombotic therapy to lessen bleeding risk, keep it the same, or even increase the intensity due to high thrombotic risk.

Whatever decision is made, it’s important to realize that this is “a dynamic assessment,” Gue said, with the balance of thrombotic and bleeding risks shifting over time as patients gain new comorbidities and diseases.

“The collection of total events highlights that as clinicians we need to be quite involved with the patient from the start to the end, and that means a regular reassessment,” particularly for patients on the cusp of being at high risk for either bleeding or thrombotic complications, he said.

In a general sense, though, Gue agreed with the study authors that when it comes to antithrombotic therapy in patients with complex diseases, “less might mean more.”

Moving forward, Naito said, there’s a need for more research examining which variables are most important for assessing bleeding and thrombotic risks in elderly patients on antithrombotic therapy, as existing scoring systems have not been well validated in older age groups.