RE-LY: Dabigatran Shortens Drug Interruption with No Increased Bleeding

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Periprocedural bleeding in patients with nonvalvular atrial fibrillation (A-fib) who need to halt anticoagulation for a surgical procedure is similar whether they are on warfarin or the oral direct thrombin inhibitor dabigatran. And according to results of a subanalysis of the RE-LY trial, published online June 14, 2012, ahead of print in Circulation, the required window for anticoagulation interruption is smaller with the newer drug.

For the noninferiority RE-LY (Randomized Evaluation of Long-term anticoagulant therapY) trial, published in the New England Journal of Medicine (Connolly SJ, et al. NEJM. 2009;361:1139-1151), researchers compared 2 doses of dabigatran (110 or 150 mg twice daily) with warfarin in 18,113 patients at risk of stroke from nonvalvular A-fib

After a median follow-up of 2 years, both doses of dabigatran proved noninferior to warfarin with regard to the primary endpoint of stroke or systemic embolism, with the higher dose showing superiority over warfarin. Based on RE-LY, dabigatran (Pradaxa, Boehringer-Ingelhiem Pharmaceuticals, Ridgfield, CT) 150 mg was approved by the US Food and Drug Administration for stroke risk reduction in patients with nonvalvular A-fib in October 2010.

Subanalysis: Invasive Procedures Not Uncommon

For the subanalysis, Jeff S. Healey, MD, MSc, of McMaster University (Hamilton, Canada), and colleagues looked at the 4,591 patients from RE-LY who had their oral anticoagulant therapy interrupted at least once for surgery or another invasive procedure. This occurred in one-fourth of patients in each of the 3 arms. In the 2 dabigatran arms, the last dose was given an average of 49 hours prior to the procedure, while warfarin patients had their last dose 114 hours before (P < 0.001).

The most common surgeries and procedures were:

  • Pacemaker or defibrillator insertion (10.3%)
  • Dental procedures (10.0%)
  • Diagnostic procedures (10.0%)
  • Cataract removal (9.3%)
  • Colonoscopy (8.6%)
  • Joint replacement (6.2%)

When considering only initial surgeries and procedures, there were no differences in perioperative bleeding or thrombotic events between dabigatran and warfarin patients (table 1).

Table 1. Perioperative Bleeding/Thrombotic Eventsa


Dabigatran 110 mg
(n = 1,487)

Dabigatran 150 mg
(n = 1,546)

(n = 1,558)

Major Bleeding




Fatal Bleeding








Systemic Embolism








a P = NS for all outcomes for dabigatran 110 mg, 150 mg vs. warfarin.

When the analysis was repeated to include first and all subsequent procedures during the RE-LY trial, the results for major bleeding remained similar for both dabigatran 110 mg (OR 0.88; 95% CI 0.63-1.12; P = 0.23) and dabigatran 150 mg (OR 0.92; 95% CI 0.70-1.22; P = 0.57) compared with warfarin. Major bleeding was also similar between treatment groups when divided into elective or urgent procedures.

Overall, dabigatran patients were 4 times more likely to have their procedure or surgery within 48 hours of interrupting anticoagulation compared with warfarin patients. Rates of discontinuation within that time frame were 46% for both dabigatran groups, compared with 11% of patients receiving warfarin (P < 0.001). Compared with warfarin, both doses of dabigatran were associated with a lower risk of perioperative bleeding when discontinued within 48 hours (table 2).

Table 2. Risk of Major Bleeding by Timing of Preoperative Study Drug Discontinuation


Dabigatran 110 mg

Dabigatran 150 mg


< 24 hours




24-48 hours




a P < 0.001 vs. warfarin.
b P = 0.027 vs. warfarin.
c P = 0.01 vs. warfarin.

“This is a very important analysis because it helps translate the RE-LY trial into clinical practice,” study coauthor Michael D. Ezekowitz, MD, PhD, of Thomas Jefferson Medical College (Philadelphia, PA), told TCTMD in a telephone interview. “Patients with atrial fibrillation are an aging population. As you can see from the list of invasive procedures, these are the kind of things that happen to patients at this age, so we’re not surprised by the number that require temporary interruption of anticoagulation.” The average age in the subanalysis was about 72 years.

Dr. Ezekowitz stressed that because of the stroke risk, “you want to keep the period of time [A-fib patients are] off anticoagulation as short as possible. When dabigatran was synthesized, one of the criteria was that it needed to be a short-acting drug for that reason, so it would be easier to use than warfarin in this setting.”

No Antidote? No Problem

A fear, however, has been that while dabigatran is easier to use, there is no direct antidote and no routine way of measuring the drug’s anticoagulant effect. “So this study was important in that without an antidote and without an ability to measure anticoagulation effect, the bleeding rates were practically identical and there was no difference between the 2 doses,” Dr. Ezekowitz said, adding that dabigatran’s fast-acting nature also enables quick resumption of anticoagulant protection. “When you give it by mouth, the patients are therapeutically anticoagulated within an hour or two, and that’s a huge advantage over warfarin.”

In an accompanying editorial, David A. Garcia, MD, of the University of New Mexico (Albuquerque, NM), and Christopher B. Granger, MD, of the Duke Clinical Research Institute (Durham, NC), praise the potential for new oral anticoagulants like dabigatran to be stopped and started within a short window around an invasive procedure. “The ability to resume these medicines after hemostasis and rapidly reestablish effective anticoagulation without an overlapping parenteral agent is potentially a major advantage, both clinically and logistically,” they write.

Two other rapid-acting anticoagulants—rivaroxaban (Xarelto, Johnson & Johnson/Bayer), already approved, and apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), not yet approved—show similar potential, though data comparable to the dabigatran subanalysis have not been seen yet, Dr. Ezekowitz noted.

“We’re just scratching the surface of understanding these drugs,” Dr. Ezekowitz said. “There’s a steep learning curve and now that the trials are over, the major challenge is to translate the results into clinical practice. All the drugs are different and my sense is in aggregate, they’re better than warfarin, so our patients will benefit by having more user-friendly agents, and in the case of dabigatran, a drug that is superior to warfarin in terms of ischemic stroke reduction.”

Note: Dr. Ezekowitz is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.


1. Healey JS, Eikelboom J, Douketis J, et al. Peri-procedural bleeding and thromboembolic events with dabigatran compared to warfarin: Results from the RE-LY randomized trial. Circulation. 2012;Epub ahead of print.

2. Garcia DA, Granger CB. Anticoagulation, novel agents, and procedures: Can we “pardon the interruption?” Circulation. 2012;Epub ahead of print.



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  • Dr. Healey reports receiving consulting fees, lecture fees, and grant support from AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, and St. Jude Medical.
  • Dr. Ezekowitz reports receiving consulting fees, lecture fees, and grant support from Aryx Pharmaceuticals and Boehringer-Ingelheim, consulting fees from Sanofi-Aventis, and lecture fees and grant support from Portola Pharmaceuticals.
  • Dr. Garcia reports receiving modest compensation for occasional service as an advisor to Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo.
  • Dr. Granger reports receiving compensation for research grants and consulting/honoraria from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Sanofi-Aventis.