Idarucizumab May Quickly Reverse Dabigatran Effects Before Emergency Surgery

Deborah Brauser

September 10, 2015

LONDON, UK — Idarucizumab (Boehringer Ingelheim) is safe and effective in rapidly reversing effects from an anticoagulation agent in patients with atrial fibrillation (AF) who need emergency surgery or intervention, suggests preliminary results from the RE-VERSE AD study[1].

Investigators found that, among 39 patients who had been receiving dabigatran (Pradaxa, Boehringer Ingelheim) and were then given idarucizumab, 36 underwent their urgent procedure—with 33 (92%) having normal hemostasis during the event. Two of the remaining patients had mildly abnormal bleeding (with slight oozing), while just one had moderately abnormal yet controlled bleeding.

None of the patients had any bleeding complications 24 hours after undergoing surgery. Although eight patients later experienced serious adverse events, none were determined to be related to use of idarucizumab.

The findings were presented at the European Society of Cardiology (ESC) 2015 Congress.

Dr Charles_Pollack

Principal investigator Dr Charles Pollack (Thomas Jefferson University, Philadelphia, PA) told heartwire from Medscape that, at least for this patient population, idarucizumab "has the potential to streamline management" through its rapid reversal process.

"From the laboratory end points of the study, all of these patients experienced very prompt reversal of dabigatran effect within minutes," said Pollack. "They went from being presumably anticoagulated in an urgent-care setting to having their procedure without any active anticoagulation. The results were pretty striking."

Dabigatran Binder, Neutralizer

Dabigatran is an oral thrombin inhibitor and is commonly used to prevent stroke in nonvalvular-AF patients, as well as to prevent and treat venous thromboembolism.

The agent has a half-life of approximately 12 hours, which is adequate for interruptions before elective surgery. However, emergency surgery or other invasive procedures require a much quicker reversal.

"Our surgical colleagues, radiology colleagues, and other invasive-practice colleagues are often hesitant to do procedures on patients who are anticoagulated because they know the risk of bleeding that can complicate their procedure or outcomes from the procedure is very high," said Pollack.

The humanized Fab fragment idarucizumab "binds dabigatran . . . and thereby neutralizes its activity," he noted.

The ongoing, multicenter, phase 3 RE-VERSE AD trial was created to assess the anticoagulant reversal effects of idarucizumab on patients treated with dabigatran. It hopes to recruit a total of 300 patients from 38 countries.

As reported by heartwire , a presentation at ISTH 2015 discussed initial results from two patients groups: the first 51 enrolled who presented with serious bleeding (Group A), and the first 39 enrolled who required urgent surgery or intervention that could not be delayed for more than 8 hours (Group B).

In their ESC poster, the investigators focused specifically on the Group B patients (54% women; mean age 76 years), all of whom had AF and were receiving dabigatran at either 110 mg (n=24) or 150 mg (n=15) twice daily for stroke prevention. The most common reasons for needing emergency surgery were because of bone fractures (n=8) or acute cholecystitis (n=5).

All 39 group members, who were enrolled between June 2014 and February 2015, received 5 g of intravenous idarucizumab given in two separate bolus infusions spaced less than 15 minutes apart.

Dilute thrombin time (dTT) or ecarin clotting time (ECT) was used to assess the maximum percentage of dabigatran anticoagulant reversal within 4 hours of receiving idarucizumab—the primary end point. Secondary end points included hemostasis classified as normal, mildly abnormal, moderately abnormal, or severely abnormal.

Fast Reversal

Out of the 39 total patients, 36 underwent emergency surgery or procedures. One patient who overdosed on dabigatran didn't end up needing emergency dialysis after receiving idarucizumab. The other two were successfully reversed but deemed still too unstable for surgery.

The median time was 1.7 hours between first administration of the reversal agent and surgery. "And that's a median. So half of them were faster than that," said Pollack.

"Median maximum percentage reversal was 100%, as assessed by both the dTT and ECT, with reversal evident on the sample taken after the first infusion," he reported.

At baseline, the median dabigatran plasma concentration was 76 ng/mL. After administration of the first vial of idarucizumab, only one patient did not have a median unbound dabigatran concentration less than 20 ng/mL. It was determined that this patient had "vascular disorders/circulatory collapse and a possible clinically significant abnormality in coagulation."

In addition, the 4-hour postadministration point showed that 26 of the 28 patients assessed by dTT were normalized, as were 30 of the 34 assessed by ECT. In these assessed patients at 12 hours, 81% had dTT below the upper limit of the normal (ULN) and 54% had ECT below the ULN.

Of those who had normal hemostasis during their emergency procedure, "this was determined at the scene by the physician who had hands on the patient," said Pollack.

Although one patient had deep vein thrombosis 7 days after treatment and another experienced an ischemic stroke 26 days after treatment, neither were receiving antithrombotic therapy at time of occurrence. In addition, nine patients died—two within 2 days of the procedure and three within 90 days postprocedure. However, all deaths were judged to be due to the original reason for the needed surgery or to comorbidities.

"The drug is behaving in real-life bleeding or preprocedure patients exactly the way it did in human volunteers and animal studies," said Pollack. "I think the results are truly groundbreaking because it advances the whole idea of using [novel oral anticoagulants] NOACs instead of warfarin in appropriate patients."

He added that, if they continue this way in the study, the results could be potentially practice changing. "For dabigatran patients, this gives providers a sense of security that should something untoward happens, we've got a specific approach to dealing with it," said Pollack.

"In terms of managing these patients, we can, sort of on demand, remove the effect of dabigatran."

"Great Impact"

After its presentation at an oral session at the ESC meeting, comoderator Dr Antonio Fernandez-Ortiz (San Carolos University Hospital, Madrid, Spain) told heartwire that these issues are important from a clinical point of view.

"This study could have a great impact on clinical practice. This is especially important for those who are going to undergo urgent surgery," he said.

Ortiz added, however, that he doesn't think idarucizumab would be very useful in those who need normal procedures. "You can delay 24 or 48 hours. But in serious situations, where you really need a quick antidote to anticoagulation, which we really don't have right now, it's going to be very useful."

The study was funded by Boehringer Ingelheim. Pollack reports receiving consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, and Janssen and receiving research support from AstraZeneca. Fernandez-Ortiz reported no relevant financial disclosures.

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