The oral anticoagulant dabigatran plus a P2Y12 inhibitor was found to “markedly” reduce the risk of early bleeding in patients with nonvalvular atrial fibrillation undergoing percutaneous coronary intervention (PCI) compared to warfarin triple therapy, according to a new post hoc analysis funded by dabigatran manufacturer Boehringer Ingelheim.
The dabigatran 110-mg regimen was also found to have a lower bleeding risk after 30 days and after aspirin was discontinued, and in its 150-mg regimen had a similar bleeding-risk profile to warfarin dual therapy.
The findings were published online Monday and appear in the April 12 issue of JACC: Cardiovascular Interventions, with Harvard Medical School’s Benjamin E. Peterson, MD, MPH, as lead author.
Atrial fibrillation patients who undergo PCI are at an increased risk of both bleeding and thrombotic events, the researchers noted, adding that, for many years, antiplatelet and anticoagulation therapy for this group has consisted of warfarin plus low-dose aspirin plus a P2Y12 inhibitor.
More recently, randomized clinical trials have shown improvements in bleeding with different antithrombotic strategies, leading to the hypothesis that “triple-antithrombotic therapy may be unnecessary and even harmful for many patients in an era of newer generation stents and direct oral anticoagulants (DOACs).”
The researchers, therefore, set out to explore the early versus late benefits and risks of dabigatran dual therapy versus warfarin triple therapy in the RE-DUAL PCI trial (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention).
A total of 2,725 atrial fibrillation patients were randomized to receive either 110 mg of dabigatran twice daily (804 patients), or 150 mg of dabigatran twice daily (621 patients) plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and no aspirin, or warfarin plus one of the same P2Y12 inhibitors and aspirin (826 patients). Of the whole cohort, 2,251 (82.6%) had undergone stenting with a drug-eluting stent.
In the triple-therapy group, aspirin was discontinued after 90 days in those who received a drug-eluting stent and in 30 days for the 404 patients given a bare metal stent.
Landmark analyses were carried out at 30 and 90 days.
At baseline, 1,966 patients (84%) had not yet experienced International Society on Thrombosis and Haemostasis (ISTH) major bleeding or clinically relevant nonmajor (CRNM) bleeding.
The researchers noted a “consistent and large reduction” in major or CRNM bleeding in patients given the dabigatran dual therapy vs. the warfarin triple therapy during the first 30 days (110 mg: hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.31 to 0.66; p < 0.0001; 150 mg: HR, 0.46; 95% CI: 0.30 to 0.72; p = 0.0006).
Both dabigatran regimens also had significantly lower rates of recurrent bleeding events based on recurrent-events analysis conducted using the Prentice, Williams, and Peterson gap time model for the whole study period (110 mg: HR, 0.61; 95% CI, 0.51 to 0.72; p < 0.0001; 150 mg: HR, 0.77; 95% CI, 0.64 to 0.93; p = 0.0056).
However, in the first 30 days after randomization, the dabigatran 110-mg group had a higher number of death or thrombotic or unplanned revascularization events than the warfarin triple therapy group (28 [2.9%] vs. (20 [2.0%]; HR: 1.39; 95% CI: 0.79 to 2.47; p = 0.26).
The dabigatran 150-mg group had no difference in early risk for thrombotic events compared with warfarin (12 [1.6%] vs. 17 [2.2%]; HR: 0.70; 95% CI: 0.33 to 1.46; p = 0.34).
In a landmark analysis at 90 days among patients who had received drug-eluting stents, there was a reduction in the primary endpoint of ISTH major bleeding or CRNM bleeding in those given dabigatran.
These events occurred for 6.8% of patients on dabigatran 110-mg dual therapy compared with 16.3% of those on warfarin triple therapy (HR: 0.40; 95% CI: 0.29 to 0.54; p < 0.0001) and in 9% of those on dabigatran 150-mg dual therapy compared with 15.7% on warfarin triple therapy (9.0% vs. 15.7%; HR: 0.54; 95% CI: 0.39 to 0.75; p = 0.0003).
There was an early net clinical benefit in both dabigatran groups versus warfarin (110 mg: HR, 0.65; 95% CI, 0.47 to 0.88; p = 0.0062; 150 mg: HR, 0.54; 95% CI, 0.37 to 0.79; p = 0.0015), due to larger reductions in bleeding than increased thrombotic events for dabigatran 110 mg and bleeding reduction without increased thrombotic risk for dabigatran 150 mg dual therapy versus warfarin triple therapy.
“After the removal of aspirin in the warfarin group, bleeding remained lower with dabigatran 110 mg and was similar with dabigatran 150 mg versus warfarin,” the researchers noted.
“On the basis of this exploratory analysis, either combination could be a safe substitution for warfarin when combined with a P2Y12 inhibitor, without the need for aspirin at any point after the doses received peri-PCI, except in select cases,” the researchers said.
‘DOAC doses matter’
In an accompanying editorial, Davide Capodanno, MD, PhD, from the University of Catania, Italy, said the results overall suggest that “DOAC doses matter.”
He expanded: “Modulation of anticoagulation intensity deserves more consideration as a way to personalize antithrombotic treatment over the course of time according to individual thrombotic and bleeding risk profiles.
“For example, on the basis of the results of this RE-DUAL sub-study, one may think of using dabigatran 150 mg TAT [triple-antithrombotic therapy] in the peri-PCI period (i.e., stopping aspirin after 1 day), then continuing with dabigatran 150 mg DAT [dual-antithrombotic therapy] up to 30 days (i.e., to lower the risk for thrombotic complications), and finally de-escalating to dabigatran 110 mg DAT up to 1 year (i.e., to lower the risk for bleeding complications).”
He added that guidelines and expert consensus across Europe and the U.S. are now “relatively aligned” when it comes to antithrombotic therapy in atrial fibrillation patients undergoing PCI; recommending oral anticoagulation preferably with a DOAC, P2Y12 inhibition – “preferably clopidogrel” – for 6 to 12 months, and aspirin for 1 to 7 days or to hospital discharge.
“When different therapeutic dosing options are available, as for dabigatran, modulation of anticoagulation intensity, with de-escalation on the basis of the time from PCI and individual thrombotic and bleeding risk considerations, is an emerging concept that warrants further investigation,” Capodanno concluded.
Peterson BE, Bhatt DL, Steg G, et al. Evaluation of Dual Versus Triple Therapy by Landmark Analysis in the RE-DUAL PCI Trial. JACC: Cardiovasc Interv 2021;14:768-80.
Capodanno D. Triple Therapy, Dual Therapy, and Modulation of Anticoagulation Intensity. JACC: Cardiovasc Interv 2021;14:781-4.