NEW ORLEANS – The puzzle of how to safely prevent thrombotic events in patients with atrial fibrillation who receive a coronary stent now has a little more clarity in the era of new oral anticoagulants.
The first randomized trial to compare the safety of a new oral anticoagulant (NOAC, in this case rivaroxaban) against warfarin when paired with one or more antiplatelet drugs showed that the NOAC edged out warfarin for safety by cutting the rate of clinically significant bleeding events while preventing thrombotic events roughly as well as warfarin.
Mitchel L. Zoler/Frontline Medical News
Dr. C. Michael Gibson
Despite that, the incidence of all major adverse coronary events during the 1-year follow-up was virtually identical in the three groups, ranging from 5.6% to 6.5%, with very low rates of stroke in the three treatment arms, ranging from 1.2%-1.5%, said Dr. Gibson, a professor of medicine at Harvard Medical School and an interventional cardiologist at Beth Israel Deaconess Medical Center, both in Boston.
These results “are a huge step forward and will change practice,” commented Philippe Gabriel Steg, MD, discussant for the report and director of the coronary care unit of Bichat Hospital in Paris. “We’ve gone from having no evidence to having some evidence” for using a NOAC in this setting. “It was a difficult but very important study that truly advances the field.”
Mitchel L. Zoler/Frontline Medical News
Dr. Philippe Steg
The trial randomized patients to any of three main treatment regimens: 2.5 mg rivaroxaban b.i.d., 15 mg rivaroxaban once daily, or warfarin taken to maintain an international normalized ratio of 2.0-3.0. During the study, patients in the warfarin arm were in this therapeutic range 65% of the time.
The trial’s design instructed physicians to treat patients who received the lower rivaroxaban dosage to also administer aspirin (75-100 mg daily) plus a thienopyridine of their choice. Patients on the higher rivaroxaban dosage received monotherapy with a thienopyridine of the physician’s choosing, while patients assigned to receive warfarin were also to get aspirin (75-100 mg daily) and a thienopyridine. It turned out that in each of the three treatment arms, 95% of patients received clopidogrel, 4% received ticagrelor (Brilinta), and 1% received prasugrel (Effient).
The trial also left it up to each physician to decide how long each patient should remain on dual antiplatelet therapy. In each of the two treatment arms that used dual therapy, 49% received 12 months of dual treatment, 35% received it for 6 months, and 16% received it for 1 month. Once the period of dual therapy ended, patients continued to receive aspirin (at 75-100 mg/day) for the balance of the 12-month study.
Leaving the choice of thienopyridine and duration of dual therapy up to each physician helped make this a “real world study,” Dr. Gibson said.
The trial was fully powered to prove a difference in safety based on rates of clinically significant bleeding events. The 1-year rates were 17% in patients who received 15 mg of rivaroxaban daily, 18% in those who received 2.5 mg rivaroxaban b.i.d., and 27% in the patients on warfarin: statistically significant differences between the warfarin arm and each of the two rivaroxaban arms. The study was not powered to prove noninferiority of the rivaroxaban regimens for efficacy at preventing stroke or major adverse events (cardiovascular death, MI, or stroke). To do that would require a trial with more than 30,000 patients, Dr. Gibson noted.
Also concurrently with Dr. Gibson’s report, a second article was published online with a post-hoc efficacy analysis that used as an efficacy endpoint the combined 1-year rate of death and all-cause hospitalization for an adverse event (Circulation. 2016 Nov 14. doi: 10.1161/CIRCULATIONAHA.116.025783). In this analysis, each of the two rivaroxaban arms cut the rate of this outcome by about 25% relative to the patients treated with warfarin, statistically significant differences. Both of the rivaroxaban regimens led to significant reductions in hospitalizations both for cardiovascular events and for bleeding events, Dr. Gibson reported.
He speculated that the vast majority of patients in the study wound up receiving clopidogrel because of cost consideration, because many physicians weren’t comfortable pairing a more potent thienopyridine with an anticoagulant, and because clopidogrel remains the most commonly used agent from this class in many parts of the world.
Dr. Gibson suggested that physicians who use these rivaroxaban-based regimens in routine practice tailor their thienopyridine selection and the duration of dual therapy to each patient based on these factors as well as whether the individual patient appears to face a greater danger from bleeding or from an ischemic event. The same approach should also guide choosing between the two rivaroxaban regimens tested. The 2.5-mg b.i.d. dosage used in a triple-therapy strategy that combines it with aspirin and a thienopyridine is better suited to patients at higher risk for ischemic events, while the 15-mg once daily dosage coupled with a thienopyridine but without aspirin is better suited to patients with a high bleeding risk, he said in an interview. Because the 2.5-mg formulation is not currently available for U.S. sales, most American physicians will be limited to only prescribing 15 mg of rivaroxaban daily. And for patients with very poor renal function, with a creatinine clearance rate of less than 15 mL/min, warfarin remains the best option, Dr. Gibson said.
PIONEER AF-PCI was sponsored by Johnson & Johnson (Janssen) and Bayer, the two companies that market rivaroxaban (Xarelto) worldwide. Dr. Gibson has received research support from and has been a consultant to Johnson & Johnson and Bayer and has also received research support and consulted for several other drug companies. Dr. Steg has been a consultant to Bayer and Janssen, and has received research support from or has been a consultant to several other drug companies.
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