Are Two Antithrombotic Agents Better Than Three?

Dual antithrombotic therapy with dabigatran and a P2Y12 inhibitor (eg, clopidogrel or ticagrelor) is associated with a lower risk of bleeding, compared with standard triple antithrombotic therapy, after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, according to research published online ahead of print August 27 in the New England Journal of Medicine. Dual therapy also is noninferior to triple therapy regarding the risk of thromboembolic events.

“Patients who received two anticlotting medications—including one of a newer class of drug—had fewer bleeding events without being more at risk for a stroke or other cardiac events,” said Christopher P. Cannon, MD, Professor of Medicine at Harvard Medical School and a cardiovascular medicine specialist at Brigham and Women’s Hospital in Boston, and colleagues.

Christopher P. Cannon, MD

Standard triple antithrombotic therapy (ie, warfarin plus two antiplatelet agents) has been associated with a high risk of bleeding, thus prompting researchers to seek a better approach to treatment. One emerging therapy omits aspirin from the standard regimen and uses a single P2Y₁₂ inhibitor in combination with an oral anticoagulant. A moderate-sized trial found that this form of dual-therapy lowered the risk of bleeding, compared with standard triple therapy. Another trial supported standard triple therapy for a shorter duration. Finally, a recent trial found that the risk of bleeding was lower with a regimen of reduced-dose rivaroxaban plus a P2Y₁₂ inhibitor than with standard triple therapy.

Dual Therapy Versus Triple Therapy

To compare two regimens of dual antithrombotic therapy that include dabigatran with a regimen of triple antithrombotic therapy that includes warfarin, Dr. Cannon and colleagues conducted the RE-DUAL PCI trial. Eligible participants were 18 or older, had nonvalvular atrial fibrillation, and had successfully undergone PCI with a bare-metal or drug-eluting stent within the previous 120 hours. Patients with bioprosthetic or mechanical heart valves, severe renal insufficiency, or other major coexisting conditions were excluded.

All patients in the United States and nonelderly patients in other countries were randomized 1:1:1 to receive triple therapy with warfarin plus a PSY₁₂ inhibitor and aspirin for one to three months, or to receive dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y₁₂ inhibitor and no aspirin. Outside the US, elderly patients (ie, 70 or older in Japan and 80 or older elsewhere) were randomized 1:1 to receive 110 mg of dual therapy or triple therapy.

The primary end point was the first major or clinically relevant nonmajor bleeding event. A major secondary end point was the composite of thromboembolic events (ie, myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization. Other secondary end points included a composite of thromboembolic events or death, as well as the individual thromboembolic events and definite stent thrombosis.

No Significant Difference in Serious Adverse Events Between Groups

Between July 21, 2014, and October 31, 2016, 2,725 participants underwent randomization at 414 sites in 41 countries. The mean age of participants was 70.8. The mean duration of treatment with the trial anticoagulant was 12.3 months, and the mean duration of follow-up was 14 months. Six patients were lost to follow-up. Most patients received clopidogrel as their P2Y₁₂ inhibitor, and 12% received ticagrelor.

The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group, compared with 26.9% in the triple-therapy group, and 20.2% in the 150-mg dual-therapy group, compared with 25.7% in the corresponding triple-therapy group. The incidence of the composite efficacy end point was 13.7% in both dual-therapy groups combined, compared with 13.4% in the triple-therapy group.

Researchers found no significant difference between groups in the rate of serious adverse events. Fatal serious adverse events occurred during treatment in 38 patients in the 100-mg dual-therapy group, 24 patients in the 150-mg dual-therapy group, and 41 patients in the triple-therapy group.

“We now have new information to help select the right treatment for individual patients,” said Dr. Cannon. “With respect to the results for both the bleeding and thromboembolic-event end points, we may only speculate on the relative contributions of the omission of aspirin and the type of oral anticoagulant in the dual-therapy groups and the triple-therapy group. A trial conducted with a formal two-by-two factorial design would be able to discern these contributions, and one such trial is ongoing.”

One limitation of this trial was that researchers enrolled a smaller number of patients than initially planned. The power of the trial to examine efficacy according to dabigatran dose consequently was limited, said the authors.

This study was supported by Boehringer Ingelheim.

—Erica Tricarico

Suggested Reading

Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017 Aug 27 [Epub ahead of print].