New RE-DUAL PCI Data: Dabigatran Dual Therapy Benefit Consistent

Patrice Wendling

November 17, 2017

ANAHEIM, CA — Dual antithrombotic therapy with dabigatran (Pradaxa, Boehringer Ingelheim) and a P2Y12 inhibitor reduces the risk of bleeding better than triple therapy with warfarin in a range of patients with atrial fibrillation (AF) undergoing PCI, according to subgroup analysis from the RE-DUAL PCI study[1].

The benefit of dabigatran dual therapy was consistent with the main results in:

  • Patients with and without acute coronary syndrome (ACS) as the index event.

  • Those receiving drug-eluting stents (DES) or bare-metal stents.

  • Patients treated with either P2Y12 inhibitor, clopidogrel or ticagrelor (Brilinta/Brilique, AstraZeneca).

"I think it's reassuring that for the majority of patients we can use the higher dose of dabigatran in a dual therapy setting, which is better compared with warfarin triple therapy, which is standard guidelines care," study author Dr Jonas Oldgren (Uppsala University, Sweden) said in an interview. "For higher-risk, frail patients, we can use the lower dose."

The results were reported here at the American Heart Association (AHA) 2017 Scientific Sessions.

Earlier this year, the RE-DUAL PCI study showed absolute risk reductions in ISTH major or clinically relevant nonmajor bleeding of 11.5% and 5.5% with twice-daily 110-mg and 150-mg dabigatran dual therapy, respectively, compared with triple therapy with warfarin, clopidogrel or ticagrelor, and aspirin.

Dabigatran dual therapy also met the noninferiority threshold for the composite efficacy outcome of death, thromboembolic events, or unplanned revascularization.

RE-DUAL PCI took aim at difficult clinical scenario because anticoagulation is recommended for AF and dual antiplatelet therapy for PCI, but triple therapy is associated with excess bleeding.

Notably, aspirin therapy duration was just 1 to 3 months in the study and ACS was the index indication for PCI in 50% of patients. DES were used in 83% of patients and at similar rates in ACS and non-ACS patients.

ACS vs Non-ACS

In the new analysis, rates of ISTH major or clinically relevant nonmajor bleeding were lower in ACS patients treated with 110-mg (14.7% vs 27.8%) and 150-mg (20.5% vs 27.1%) dabigatran dual therapy than in those treated with triple therapy.

Similar reductions in these events were observed among non-ACS patients in the 110-mg (16.1% vs 26.1%) and 150-mg (19.9% vs 24.4%) dabigatran groups vs triple therapy.

ISTH and TIMI major bleeding was also lower in both ACS and non-ACS patients with dual therapy than with triple therapy.

There was a "weak trend," however, for a higher risk of MI in ACS patients treated with lower-dose dabigatran dual therapy vs triple therapy (6.3% vs 3.4%), but "again, it's a nonsignificant interaction [P=0.20]," Oldgren said.

"We didn't present data on age, but we have looked at patients above the age of 80 and we don't see any signal on myocardial infarctions with the lower dose," he added.

ACS patients on the higher dabigatran 150-mg dose had roughly the same risk of MI as those receiving warfarin triple therapy (3.3% vs 3.0%; P for interaction=0.82).

Bare-Metal Stents vs DES

Among 404 patients receiving bare-metal stents, rates of ISTH major or clinically relevant nonmajor bleeding fell from 26.3% with triple therapy to 12.8% with 110-mg dabigatran dual therapyand from 25.2% with triple therapy to 14.6% with 150-mg dabigatran dual therapy.

For the 2251 patients receiving DES, rates of this bleeding outcome fell from 27.6% to 15.8% and from 26.3% to 21.4%, respectively.

"The risk of bleeding events was consistent with the overall results of the study for both dabigatran dosages," Oldgren said.

The composite of death, thromboembolic events, or unplanned revascularization was more common among bare-metal-stent patients treated with either 110-mg (16.9% vs 12.8%) or 150-mg (13.0% vs 11.2%) dabigatran dual therapy than with triple therapy.

This was also true for DES patients treated with lower-dose (14.7% vs 13.1%) but not with higher-dose (11.8% vs 12.7%) dabigatran dual therapy .

None of the interactions were significant, and the study was not powered to examine differences in the individual thromboembolic end points, Oldgren said.

In the main study, higher event rates were seen in the 110-mg dabigatran dual therapy arm vs triple therapy for all-cause death (55 vs 48 events) and MI (44 vs 29 events).

Clopidogrel vs Ticagrelor

Finally, the investigators looked at ticagrelor vs clopidogrel, which was given at investigator discretion. About 12% of patients received ticagrelor as part of dual therapy, but, "at least to my surprise," so did 12% of those in the warfarin triple-therapy arm, Oldgren remarked.

Patients receiving ticagrelor were more likely than those receiving clopidogrel to have ACS as the index reason for PCI, to be oral anticoagulation naïve, and to have dual-antiplatelet clinical complexity factors.

The risk of ISTH major/clinically relevant nonmajor bleeding events was lower with ticagrelor in the 110-mg (21.2% vs 37.4%) and 150-mg (23.1% vs 34.2%) dabigatran groups than in the warfarin triple-therapy group.

Still, the risk of these bleeding events was consistently lower with clopidogrel combined with 110-mg dabigatran vs triple therapy (14.5% vs 25.8%) or 150-mg dabigatran vs triple therapy (19.7% vs 24.7%).

"There were no significant interactions in any of the presented outcomes for any of the presented subgroups," Oldgren concluded.

Discussant Dr Mark Hlatky (Stanford University School of Medicine, Stanford, CA) said "I do think subgroups are worth examining, but don't overinterpret the findings."

He reminded physicians to look for significant interactions and that absolute benefits and risks may vary, even if relative risks don't.

"In particular, there was more bleeding in this study in patients who were treated with ticagrelor vs clopidogrel, but the randomized dual vs triple therapy had the same relative risk reductions [and] somewhat larger absolute risk differences for bleeding between the groups, because the people on ticagrelor had a higher risk of bleeding," Hlatky said.

"I do want to emphasize that the ticagrelor vs clopidogrel comparison is not randomized; there were big differences between these groups in terms of their clinical characteristics, and the comparison was not adjusted for those things," he added.

Hlatky observed that stroke and bleeding share many of the same risk factors, so both risks tend to go up or down together. The balance of risk and benefits, however, may be tipped in patients with a low risk of bleeding and high risk of thromboembolism, or the other way around.

"I didn't see very clear evidence for that in RE-DUAL, but any group that has really high risk of bleeding would have a balance of risk and benefit that would favor the dual [therapy]," he said.

The study was funded by Boehringer Ingelheim. Oldgren reports consultant and lecture fees to his institution from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, and Sanofi. Disclosures for the coauthors are listed in the abstract. Hlatky reports no relevant financial relationships.

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