WASHINGTON, DC — Anticoagulation with uninterrupted dabigatran was associated with fewer bleeding complications than uninterrupted warfarin in patients undergoing pulmonary vein ablation for atrial fibrillation (AF), according to results of the RE-CIRCUIT trial presented at the 66th Annual Scientific Session & Expo of the American College of Cardiology (ACC).1
RE-CIRCUIT (Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Anticoagulation Strategy; Clinicaltrials.gov identifier: NCT02348723) was a randomized open-label multicenter controlled trial with blinded end point assessments, conducted by a group of international researchers. The findings were simultaneously published in the New England Journal of Medicine.2
A total of 704 patients from 104 sites were enrolled in the trial, 635 of whom underwent ablation. The primary end point was the incidence of major bleeding events (as defined by the International Society on Thrombosis and Hemostasis); secondary end points included a composite of stroke, systemic embolism, or transient ischemic attack (TIA); minor bleeding events; and a composite of major bleeding events and thromboembolic events (stroke, systemic embolism, or TIA).
Up to 8 weeks after ablation, the incidence of major bleeding events was lower with dabigatran than with warfarin (1.6% vs 6.9%; absolute risk difference, −5.3 percentage points; 95% CI, −8.4 to −2.2; P <.001). Compared with warfarin, the relative risk reduction was 77.2%. Cox proportional hazards analysis reinforced the robustness of the primary end point by demonstrating a hazard ratio (HR) of 0.22 for dabigatran vs warfarin (95% CI, 0.08-0.59).
In terms of minor bleeding events, both groups had similar incidence rates (18.6% vs 17.0% in the dabigatran and warfarin groups, respectively). However, the composite incidence of major bleeding events and thromboembolic events was lower in the dabigatran group than in the warfarin group (1.6% vs 7.2%).
The Cardiology Advisor (TCA) caught up with Jagmeet P. Singh, MD, PhD, a late-breaking clinical trial discussant at ACC in Washington to learn more about the potential effect of these results.
Dr Singh is the associate chief of the Cardiology Division at Massachusetts General Hospital in Boston.
TCA: What are the biggest takeaways for clinicians from the RE-CIRCUIT trial?
Dr Singh: I think there are 2 large takeaways: [first,] this trial reinforces the concept that uninterrupted anticoagulation periprocedurally in AF is a very reasonable approach because it potentially reduces the risk for thromboembolic events and reduces the postprocedural complication risk related to bleeding (eg, major bleeding).
The other takeaway, the main takeaway, is that this study compared dabigatran with warfarin, and it actually did better. In another smaller study, VENTURE-AF (A Randomized, Open-Label, Active-Controlled Multi-Center Study to Assess Safety of Uninterrupted Rivaroxaban vs Usual Care in Subjects Undergoing Catheter Ablation Therapy for Atrial Fibrillation; ClinicalTrials.gov identifier: NCT01729871), results showed that you can use an uninterrupted NOAC [new oral anticoagulant] periprocedurally, but those results were pretty comparable. This actually shows that dabigatran is better.
TCA: Do you think the study limitations are problematic (eg, small sample, low numbers of bleeding and thromboembolic events)? Do we need to replicate these findings in larger trials?
Dr Singh: So the limitations for VENTURE-AF were that the population was small and the events were low, which is why the investigators did not see a difference between the treatments. But in the RE-CIRCUIT study, the numbers were larger all around. As a result, they had statistically significant differences between the 2 arms.
RE-CIRCUIT had a difference in the primary end point of major bleeding events. There were 1.6% in the dabigatran arm and 5.9% in the warfarin arm. Overall, there was a 77.2% relative risk reduction with the use of dabigatran in major bleeding events.
The interesting thing is that the patients in the vitamin K antagonist arm had a disproportionally large number of cardiac tamponades and groin hematomas. I don’t know how to explain that, because these are not common complications to start with, but the fact that the vitamin K antagonist arm had fairly high numbers contributed to the difference between the 2 treatment groups.
The resistance to using dabigatran in the past was mostly related to [gastrointestinal (GI)] issues or bleeding. In this trial, there were no differences in GI bleeding between the 2 treatment groups, but almost 5.6% of patients actually had to stop using dabigatran because of GI-related issues. These were mostly mild GI issues (eg, abdominal discomfort). I think it’s just a noteworthy point that some patients may not want to take [dabigatran] long-term. However, the risk-benefit ratio is pretty clear.
TCA: Is it significant that all bleeding events in the dabigatran group were managed without the need for dabigatran reversal?
Dr Singh: Absolutely. It is always comforting to know that you have a reversal agent out there, but interestingly enough, the bleeding events were markedly smaller and lower in the dabigatran arm anyway, and the researchers did not need the reversal agent. I do not think that in any way impacted the outcome, but having an antidote at hand makes an even more compelling argument to use a thrombin inhibitor. On the safety and efficacy end, this study showed dabigatran works well.
TCA: Is this trial another win for NOACs and another nail in the coffin for warfarin?
Dr Singh: I think vitamin K antagonists will still have a role in a certain subset of patients. NOACs are useful in nonvalvular AF on, but in in other situations, for example, patients who have prosthetic or mechanical valves, etc, vitamin K antagonists still have their place. They are progressively becoming niche, especially as clinicians become more comfortable with NOACs, and now with an antidote in the market, I think that will further enhance the comfort level. [These study results] may potentially contract the vitamin K antagonist market, but they will always have a niche area.
Note: this interview was edited for clarity.
- Calkins H, Willems S, Gerstenfeld EP, et al; for the RE-CIRCUIT Investigators. RE-CIRCUIT: Safety and efficacy of uninterrupted anticoagulation with dabigatran etexilate vs warfarin in patients undergoing catheter ablation of atrial fibrillation: the RE-CIRCUIT study. Late-Breakers V. Presented at: The 66th Annual Scientific Session & Expo of the American College of Cardiology. March 17-19, 2017; Washington, DC.
- Calkins H, Willems S, Gerstenfeld EP, et al; for the RE-CIRCUIT Investigators. Uninterrupted dabigatran vs warfarin for ablation in atrial fibrillation [published online March 19, 2017]. N Engl J Med. doi:10.1056/NEJMoa1701005