Dabigatran-Reversal Agent Fast, Effective in RE-VERSE AD, but Now What?

November 17, 2016

NEW ORLEANS, LA —An agent that reverses the anticoagulation effect of dabigatran (Pradaxa, Boehringer Ingelheim) worked almost right away after infusion, with an effect lasting 2 days, in an analysis including almost 500 patients on the oral direct thrombin inhibitor when they developed severe bleeding or needed urgent surgery[1].

The patients in the cohort, said to be a broad reflection of "real-world" clinical practice, achieved hemostasis within about 4 hours after administration of the reversal agent, idarucizumab (Praxbind, Boehringer Ingelheim), with normalization of coagulation metrics in virtually every case. And most patients went back on oral anticoagulation within days, usually with dabigatran.

Dr Charles V Pollack

"When you give idarucizumab, literally within seconds you see reversal. It's almost instantaneous," Dr Charles V Pollack (Thomas Jefferson University, Philadelphia, PA), principal investigator of the Reversal Effects of Idarucizumab in Patients on Active Dabigatran (RE-VERSE AD) study, told heartwire from Medscape. Two bolus doses are given one after the other, and reversal is fully achieved within about 10 minutes, the effect still evident after 48 hours, he said.

Pollack presented the RE-VERSE AD analysis, an update in nearly all of the trial's patients that was consistent with earlier reports in far fewer of them, here at the American Heart Association 2016 Scientific Sessions.

Idarucizumab was approved in the US and Europe last year; approval of andexanet alfa (AndexXa, Portola Pharmaceuticals), a reversal agent for direct oral anticoagulants (DOACs) other than dabigatran—that is, the factor Xa inhibitors, is expected soon. Those agents include apixaban (Eliquis, Bristol-Myers Squibb), edoxaban (Savaysa/Lixiana, Daiichi Sankyo), and rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals).

"Generalizable to Real-World Practice"

The results of RE-VERSE AD "are overwhelmingly convincing," discussant Dr Christian T Ruff (Brigham and Women's Hospital, Boston, MA) said after Pollack's formal presentation of the study. And idarucizumab "is certainly safe, which is very reassuring," he said.

"In my opinion, this really places it first line in the management of patients taking dabigatran who present with life-threatening emergencies, either serious bleeding or a patient who is not bleeding who requires urgent procedures or surgeries."

Ruff said the study's entry criteria were broad within those two categories of patients; "this is important, because I think the results are therefore generalizable to real-world practice, clinical practice in general."

The trial included two patient groups reflecting the likeliest indications for the agent: 298 in "group A" (with uncontrolled bleeding) and 196 in "group B" (requiring an emergency surgery or procedure). Nearly all had atrial fibrillation as their DOAC indication. The median time since their last dose was 14.2 hours and 18 hours, respectively. About 62% in each group had been on dabigatran at the 110-mg twice-daily dosage, virtually all the rest at 150 mg twice daily.

Serious bleeds in group A were gastrointestinal in 135 cases and intracranial in 97, with a variety of sites making up the rest. The emergent-surgery indication included acute abdomen in 45 patients, bone fracture in 30, infections in 20, and pacemaker implantation in 10.

How It Might Be Used in Practice

Questions remain about what kinds of patients with bleeds or need for emergent surgery with dabigatran on board would actually need to receive a reversal agent for effective management.

"I think it is useful, [but] I think we need a little more experience to know how useful it is in usual clinical practice," emergency physician Dr Graham Nichol (University of Washington, Seattle), who isn't connected to the study, told heartwire .

"A challenge is that the medication is somewhat expensive, but I would use it in someone with major trauma or with an intracranial bleed," Nichol said. "We are seeing more of these patients over time as they switch from warfarin to the oral anticoagulants."

Dr Gordon F Tomaselli (Johns Hopkins University, Baltimore, MD) said, "When there's surgery to correct active bleeding, I guess that's a problem, in a very vascular space. I think that's probably at least a reason to consider using a reversal agent."

Some of the urgent surgeries the RE-VERSE AD patients underwent "probably do require reversal," but "we put in pacemakers all the time with people fully anticoagulated, so we don't really need to do that," Tomaselli, who was not part of the trial, observed for heartwire .

"The serious clinical problem, in my mind, is intracranial bleeds. I don't care how fast the reversal agent is, if it's a serious intracranial bleed, then the difficulty is I don't think any reversal agent is going to make that much difference. You have very little time to fix that problem."

Still, Tomaselli said, idarucizumab will likely "be used as first-line treatment for people who are on dabigatran who have bleeds or who need surgery. The question then becomes, the other [DOACs] don't have a reversal agent yet, but will. Are people going to be moved from some of those other agents to dabigatran now, in this interim, now that there's a reversal agent? Maybe."

More importantly, "Knowing there's a reversal agent, are we going to be using [DOACs] in patients less well selected, therefore increasing the risk of bleeding overall in patients who are on these drugs because there's a reversal agent? That's a practice-pattern change that one could anticipate would occur."

Ruff predicted that "one of the biggest impacts" of reversal-agent availability will be reassurance. Perhaps, he said, "We can finally tap into those unprotected patients, the 30% to 40% for whom we're not even trying anticoagulation because we think they're too frail."

On the other hand, he cautioned, "You can remove the anticoagulant from the equation, and certainly there's an imperative to do that, but that doesn't address vessel integrity in a bleeding patient or the substantial comorbid conditions that exist in these patients who present with life-threatening emergencies."

Open Label and Without Controls

The patients from 173 sites in 39 countries received 5-g idarucizumab in two sequential open-label IV bolus administrations and were followed for 90 days, without a control group, which the investigators said would have been unethical to include.

Reversal of anticoagulation was measured in two ways and evaluated at a core laboratory. The diluted thrombin time (dTT) normalized within 4 hours in 98.7% of patients in group A and 98.6% of patients in group B. Ecarin clotting time normalized within 4 hours in 81.5% and 83.5%, respectively. The time to hemostasis as judged by the clinicians averaged 3.5 hours and 4.5 hours, respectively.

Resumption of oral anticoagulation after the reversal period, using dabigatran in two-thirds of cases, occurred in 72% of group A patients after a median of 5.3 days from receiving the reversal agent; the rate was 90% in the surgical group B after a "remarkable" median of 1.2 days, said Pollack.

Adjudicated Thrombotic Events After Idarucizumab in RE-VERSE AD

End points Group A, n=298 (%) Group B, n=196 (%)
Thrombotic events
30 d 4.4 4.6
90 d 6.0 6.6
Mortality
30 d 12.3 12.4
90 d 18.7 18.5
Group A=uncontrolled bleeding
Group B=Emergency surgery

The adjudicated 30-day rate of thrombotic events was about 4.5%; most events were in the period after idarucizumab administration and before restart of anticoagulation. They included eight ischemic strokes, seven cases of deep-vein thrombosis (DVT), seven MIs, four pulmonary embolisms (PE), and four cases of both PE and DVT.

Studies of andexanet alfa, the investigational factor Xa inhibitor antidote, have not included presurgical patients, although they are likely to in the future, Pollack observed when interviewed.

"They don't have our equivalent of a group B," he said, so approval may not at first include the urgent-surgery indication. For the time being at least, "ours is a little more 'one size fits all.' "

The study was funded by Boehringer Ingelheim. Pollack discloses consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, and Janssen and receiving research support from AstraZeneca. Ruff reports receiving research grants from Daiichi Sankyo and honoraria from Daiichi Sankyo, Bayer, and Boehringer Ingelheim. Nichol discloses research grants from Zoll Medical and Sotera Wireless and consulting or serving on an advisory board for Remedy Pharmaceuticals and Zoll. Tomaselli reported no relevant financial relationships.

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