Dabigatran Reversal Agent Looks Good in Real-World Clinical Testing

June 22, 2015

TORONTO, ON — A real-world clinical test of idarucizumab (Boehringer Ingelheim) shows the agent safely and effectively reverses the anticoagulant effect of the direct oral thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) in a group of high-risk patients undergoing emergency surgery or suffering from life-threatening bleeding[1].

"Based on these data, what idarucizumab does is very predictably and very effectively take anticoagulation off the list of concerns of the treating physician," lead investigator Dr Charles Pollack (Pennsylvania Hospital, Philadelphia) told heartwire from Medscape. "It doesn't close up holes in vessels, it doesn't stop hematomas in the head from expanding, but it does remove any concern the provider might have about dabigatran so he/she can move forward and deal with the underlying issues."

Known as RE-VERSE AD, the study is an ongoing, international open-label trial with an expected enrollment of 250 to 300 patients. Today, here at the International Society for Thrombosis and Haemostasis (ISTH) 2015 Congress, investigators presented data from their preplanned interim analysis of the first 90 patients enrolled. The interim analysis, which is now published online in the New England Journal of Medicine, specifically examines the maximum reversal capacity of idarucizumab in a clinical setting.

In an editorial[2], Dr Kenneth Bauer (Beth Israel Deaconess Medical Center, Boston, MA) calls the emergence of antidotes for the novel oral anticoagulants (NOACs) an important advance, especially since some physicians and patients have been unwilling to use the new drugs without an established means to reverse anticoagulation.

He points out there are already various reversal agents and/or strategies, nonspecific to dabigatran and the factor Xa inhibitors, available to physicians, including prothrombin complex concentrates, activated prothrombin complex concentrates, or recombinant factor VIIa. While these reversal strategies have been shown effective in vitro, in animal models, and in healthy volunteers, they have yet to be shown effective in "improving hemostasis in patients with bleeding related to direct oral anticoagulant use," writes Bauer.

Regarding the unmet clinical need for a reversal agent for dabigatran, as well as the other NOACs, Pollack said, "It is often more psychological than clinical because physicians tend to be insecure about not having a specific reversal strategy for a NOAC." In an emergency setting, for the vast majority of NOAC-related bleeding concerns, there are already documented reversal and management strategies in place for patients, he agreed, but these aren't specific to dabigatran. At present, there is a gap in treatment and physicians wanted it filled, said Pollack.

Study to Reflect Real-World Use of Dabigatran

The RE-VERSE AD study investigators are enrolling two types of dabigatran-treated patients in the clinical trial: patients who experience life-threatening or uncontrolled bleeding (group A) and patients who require an emergency surgery or procedure (group B). So far, 90% of patients have atrial fibrillation and were prescribed dabigatran for stroke/systemic embolism prophylaxis. Investigators have signed up approximately 400 sites worldwide to enroll the planned 300 patients, recognizing how uncommon it is for emergency centers to need to stop dabigatran and treat such patients.

"We recognize that this is not that common an occurrence, but when it does occur, physicians want something that has been battle-tested," said Pollack.

RE-VERSE AD was designed to reflect real-world clinical practice and included bleeding patients in "real dire straits," said Pollack. There are no age restrictions for entry nor any cutoffs based on life expectancy, he said. In the group B arm, the emergency surgery or procedure had to take place within 8 hours. The primary end point of RE-VERSE AD is the maximum percentage reversal of the anticoagulant effect of dabigatran. The reason for selecting a laboratory outcome, said Pollack, is that enrolled patients are the typical older atrial-fibrillation patient with multiple comorbidities. Comparing clinical outcomes across the heterogeneous group would have been difficult.

In 51 group A patients, the median maximum percentage reversal in anticoagulation measured at 4 hours was 100%. In the 39 group B patients, median maximum percentage reversal in anticoagulation was also 100%. For the group B patients, 36 underwent emergency surgery while one patient avoided surgery after the administration of idarucizumab. Two other patients had complete reversal of anticoagulation but were too unstable for surgery. In the 36 patients who underwent surgery, 33 had normal intraoperative hemostasis as reported by the surgeon onsite, two had mildly abnormal hemostasis, and one patient had moderately abnormal hemostasis.

In his editorial, Bauer says the data are convincing that idarucizumab neutralizes the activity of dabigatran, but it is difficult to gauge the true clinical benefit of idarucizumab in RE-VERSE AD, as the study did not include a control arm. He also points out the half-life of dabigatran is 12 to 14 hours in patients with normal renal function and questions just how important it is to reverse the anticoagulant on top of providing other supportive measures.

"Major bleeding events in patients taking anticoagulants originate from anatomical lesions, and anticoagulation can lead to a rapid loss of blood from these sites," writes Bauer. "Thus, the location and size of the lesion along with the coexisting conditions of the patient may have a greater effect on prognosis than the ability to rapidly neutralize an anticoagulant that the patient is taking."

Other End Points and Safety

To heartwire , Pollack said they are investigating other more clinically relevant end points, such as how much did patients bleed and how much blood was transfused, and these data will be presented and published when the trial is completed. He noted that every patient, regardless of weight and renal function, receives 5 g of intravenous idarucizumab in two 2.5-g doses and that the reversal of anticoagulation is evident after the first 2.5-g dose, or "literally within minutes."

In terms of safety, investigators observed no signal, including no reported cases of hypotension, abnormal liver tests, injection-site reactions, or rashes. From a patient-outcome standpoint, there were 18 deaths in the first 90 patients. Deaths within the first 96 hours were related to the index event, including two patients who died from septic shock and three patients who died from intracranial hemorrhage.

"These are patients who, even in the absence of anticoagulation, have a very poor outcome," said Pollack. "We put no limits on enrollment—some of these patients are being given this drug on the verge of being coded. This drug has never been put forward as a lifesaver. It's there to reverse anticoagulation, which it does very effectively."

In the editorial, Bauer points out that nearly 25% of patients tested in the trial had a normal diluted thrombin time, which is a marker of dabigatran concentration. With a normal level, indicative of little to no circulating anticoagulant in the blood, these patients would not be expected to benefit from idarucizumab. Given this, Bauer suggests it will be useful to have laboratory activity measurements for dabigatran, as well as other NOACs, available in real time "to help guide the treatment of such patients and to prevent overutilization of what will surely be a costly medication."

Boehringer Ingelheim sponsors RE-VERSE AD. Pollack reports receiving payment for consulting from Boehringer Ingelheim, Janssen, Daiichi-Sankyo, and Bristol-Myers Squibb/Pfizer. Disclosures for the coauthors are listed on the journal's website. Bauer reports receiving personal fees from Boehringer Ingelheim, Janssen Pharmaceuticals, Bristol-Myers Squibb, Pfizer, Bayer Healthcare, Daiichi-Sankyo, Portola Pharmaceuticals, and Instrumentation Laboratory.


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