In such patients with or without a history of revascularization, use of a novel oral anticoagulant (NOAC) alone was “noninferior” to the NOAC plus an antiplatelet agent for a composite clinical primary endpoint over 2 years in a randomized trial conducted in Japan.
At the same time, the risk for major bleeding fell by about 40% among patients on NOAC monotherapy with rivaroxaban (Xarelto, Janssen/Bayer) compared with those who took the anticoagulant with an antiplatelet, which could be aspirin or a P2Y12 inhibitor such as clopidogrel.
More than 80% of the patients in the trial, called Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients With Stable Coronary Artery Disease (AFIRE), had undergone percutaneous coronary intervention (PCI) or coronary bypass grafting (CABG) at least a year previously. The rest of the trial’s patients had angiographically documented CAD without a history of intervention.
Based on AFIRE, patients with AF who have PCI or CABG should take both a NOAC and an antiplatelet agent for the first 12 months after the intervention, lead investigator Satoshi Yasuda, MD, PhD, National Cerebral and Cardiovascular Center, Suita, Japan, told theheart.org | Medscape Cardiology. After that first year, they could drop the antiplatelet and go with NOAC monotherapy.
“For stable patients with no history of revascularization, monotherapy would be appropriate, on the basis of our study.”
That recommendation, consistent with guidelines, nonetheless strengthens what has been a thin evidence base for guiding therapy in a group that historically has been a bit of a conundrum, with their two distinct antithrombotic indications.
Guidelines in both Europe and North America recommend stopping antiplatelet therapy 12 months after revascularization in patients with AF, but that isn’t based on “firm data in the literature,” Freek W.A. Verheugt, MD, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands, said as an invited discussant following Yasuda’s presentation of AFIRE here at the European Society of Cardiology (ESC) Congress 2019.
“The AFIRE results confirm the European and US guidelines to quit antiplatelet therapy 1 year after PCI in atrial-fib patients who are anticoagulated. Stopping at 1 year is safer and more effective than continuation, and most of all, it saves lives.”
AFIRE was published September 2 in the New England Journal of Medicine to coincide with its live presentation by Yasuda, who is first author on the report.
In an accompanying editorial, Richard C. Becker, MD, University of Cincinnati College of Medicine, Ohio, describes previous trials of antithrombotic therapy in patients with “active” CAD, such as acute coronary syndromes or recent revascularization, but notes there are “few trials to go by for patients with AF and stable coronary disease.
One such trial was OAC-ALONE, which allowed a vitamin K antagonist or a NOAC as the monotherapy. It was halted for slow enrollment after achieving just over a third of its patient target, and so on its own has little to contribute to practice.
But, Becker asks, “Do the collective data from the AFIRE and OAC-ALONE trials provide definitive guidance for clinicians who are treating patients in this population?”
“In my judgment, they do add an element of support for current guidelines and underscore the potential effect of direct oral anticoagulants on the pathobiology of coronary artery disease and cardioembolic events in patients with atrial fibrillation, but they fall short of securing level 1 and class A evidence,” he writes.
Currently in practice, most AFIRE-like patients “are still on double therapy, a NOAC plus an antiplatelet,” Frank Ruschitzka, MD, University Heart Center, Zurich, Switzerland, who was not associated with the trial, told theheart.org | Medscape Cardiology. That’s recommended for “most of the year” after a revascularization, “but the question is open: What are we going to do after 12 months?”
In patients whose PCI involved complex lesions or involved other high-risk considerations, “I’d be somewhat reluctant to remove the antiplatelet,” he said. “But for the majority of patients, I think AFIRE is reinforcing the concept that you may do well with a NOAC alone.”
Further research on the concept is called for, including on whether it applies to NOACs besides rivaroxaban and to clopidogrel at dosages used outside Japan, Ruschitzka said.
Indeed, one quirk in AFIRE was that rivaroxaban was given at the dosage level approved uniquely in Japan, 10 to 15 mg/day, rather than the 20 mg/day used in much of the rest of the world.
Yasuda said pharmacokinetic studies suggest that blood levels of the NOAC in Japanese patients taking 10 to 15 mg/day are “similar” to that in white patients taking 20 mg/day.
But Verheugt and Ruschitzka both commented that the rivaroxaban dosage level used in AFIRE limits broader applicability of its results and that the issue should be explored further.
AFIRE randomly assigned 2236 patients with AF and established CAD, 79% of whom were men, to receive rivaroxaban monotherapy or the rivaroxaban-antiplatelet combination at 294 centers in Japan.
Of the 1107 assigned to monotherapy and 1108 to combination antithrombotic therapy, 70.6% had undergone PCI and 11.4%, CABG at least a year earlier; the rest had angiographic CAD but no history of revascularization.
Antiplatelet therapy consisted of aspirin at 81 mg/day or 100 mg/day in 72%, or a P2Y12 inhibitor — overwhelmingly clopidogrel — in the remainder of the combination therapy arm.
Follow-up was planned to last at least 24 months and up to 45 months; however, after meeting its stipulated enrollment goal and a median follow-up of 24.1 months, the trial was halted on the basis of the interim observation of a significant increase in all-cause mortality in the combination therapy group.
Monotherapy was noninferior to combination therapy for the primary efficacy endpoint of stroke, systemic embolism, myocardial infarction (MI), unstable angina requiring revascularization, or death from any cause. The rates were 4.14% and 5.75% per patient-year respectively (hazard ratio [HR], 0.72 [95% CI, 0.55 – 0.95] by modified intention-to-treat; P < .001 for noninferiority).
In an analysis that was not prospectively defined, the primary efficacy endpoint difference was significant at P = .02 for superiority.
Rivaroxaban monotherapy bested combination therapy for the primary safety endpoint of major bleeding by International Society for Thrombosis and Hemostasis criteria. The rates were 1.62% and 2.76% per patient-year, respectively (HR, 0.59 [95% CI, 0.39 – 0.89]; P = .01 for superiority).
Table. Secondary Outcomes, Rivaroxaban Monotherapy vs Rivaroxaban-Antiplatelet Combination
|Endpoints||Monotherapy (% per Patient-Year)||Combination Therapy (% per Patient-Year)||HR (95% CI)|
|Death from any cause||1.85||3.37||0.55 (0.38 – 0.81)|
|Ischemic cardiovascular events or death||5.37||6.77||0.80 (0.62 – 1.02)|
|Nonmajor bleeding||5.89||10.31||0.58 (0.46 – 0.72)|
|Net adverse clinical eventsa||3.90||6.28||0.62 (0.47 – 0.82)|
|aDeath from any cause, MI, stroke, or major bleeding.|
The jump in all-cause mortality in the combination therapy arm that triggered the trial’s termination, which Yasuda said “was a surprise to us,” was driven about equally by cardiovascular (CV) and non-CV deaths.
“The extra mortality with combination therapy was a totally unanticipated finding. It was hard to explain,” he said when interviewed.
“It’s the bleeding,” Verheugt speculated. “We know from many trials and registries that bleeding is correlated with mortality.”
Yasuda reports receiving grants from Takeda and personal fees from Daiichi-Sankyo and Bristol-Meyers Squibb and having a nonspecified relationship with Abbott; disclosures for the other authors are at NEJM.org. Becker reports receiving personal fees from Janssen, Akcea, Portola, and Mercator “outside the submitted work.” Verheugt discloses consulting, receiving royalties, or holding stock or other ownership interest in Bayer Healthcare, Bristol-Myers Squibb/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo. Ruschitzka has previously disclosed receiving research grants from St Jude Medical and Novartis; personal fees for lectures from St Jude Medical, Servier, Zoll, Novartis, Bayer, and Abbott; and personal fees for advisory board or steering committee meetings from AstraZeneca, Sanofi, Cardiorentis, Amgen, BMS, Pfizer, Fresenius, Vifor, and Roche.