Clinical judgment is the key to the appropriate use of idarucizumab (‘Praxbind’) to specifically reverse dabigatran in patients who need an urgent procedure or have serious bleeding, according to the lead author of the pivotal RE-VERSE AD study.1
Dr Charles Pollack, an emergency physician at Thomas Jefferson University Hospital in Philadelphia, told the limbic that the study had a very pragmatic trial design, reflecting how idarucizumab would be used in practice.
“In RE-VERSE AD we used idarucizumab in truly emergent situations,” he says. “We enrolled patients taking dabigatran whose bleeding could not be controlled, was immediately life-threatening or was occurring in a critical space (such as an intracranial bleed), or when a procedure could not wait and could not be safely performed without effective haemostasis.
“We had strictly clinical enrolment criteria and no central screening,” he says. “The decision was made by the investigator at the point of care. As we continue to enrol further patients into the study, it’s increasingly clear that they would meet any rational clinician’s definition of a true emergency.”
Dr Pollack, who is also Director of the Institute for Emerging Health Professions at the Thomas Jefferson University, explained that regulatory authorities in the United States and Europe requested an early interim analysis of RE-VERSE AD in the light of preclinical data showing consistent efficacy and safety.
In August 2015 the outcomes of the first 90 patients were published in the New England Journal of Medicine, confirming that idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes in emergency patients.
Idarucizumab is a humanised monoclonal antibody fragment that binds to dabigatran 350 times more avidly than dabigatran binds to thrombin.1 Idarucizumab neutralises its activity, whether dabigatran is circulating freely or already bound to thrombin.
Preclinical studies in volunteers1, including elderly individuals (65 to 80 years of age) and people with mild or moderate renal impairment, showed idarucizumab immediately and completely reversed the anticoagulant effects of dabigatran, without pro-coagulant effects.
What the RE-VERSE AD study1 showed
RE-VERSE AD plans to recruit up to 500 patients in 38 countries. The first report described 51 patients who had serious bleeding and another 39 who required an urgent procedure.
Their median age was 76.5 years and the median creatinine clearance was 58 mL/min. All but four of the patients were taking dabigatran because of atrial fibrillation. The median time since the last dose of dabigatran, as reported by patients, was 15.4 hours.
Clotting tests were performed on blood taken at baseline, 10 and 30 minutes, and then at 1, 2, 4, 12 and 24 hours, but the results were not available to clinicians when they made the decision to treat.
Among patients with clotting tests suggestive of active dabigatran, idarucizumab normalised the results in 88-98% of cases, and the effect was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng/mL at 24 hours in 79% of patients.
Patients with bleeding included 18 with intracranial haemorrhage, 20 with gastrointestinal bleeding, and nine with bleeding from trauma.
The most common indication for urgent procedures was bone fractures (eight patients) , followed by acute cholecystitis (five patients) and catheter placement for acute renal insufficiency (four patients). Normal intraoperative haemostasis was reported in 33 of 36 patients in whom a procedure was actually performed. It was classified as mildly abnormal in two, and moderately abnormal in one.
Thrombotic events occurred in five patients, ranging from 2 to 26 days after treatment1. None of the patients were receiving antithrombotic therapy when the events occurred.
Use in practice
Dr Pollack emphasises that a decision to use idarucizumab is a clinical one. A review of its role in practice noted that the management of bleeding complications in patients receiving dabigatran should always be individualised according to the location and severity of the haemorrhage.2
“It is important to point out that coexisting medical conditions may have a greater effect on prognosis than the ability to rapidly neutralise the anticoagulant effect of dabigatran,” he said.
“I can tell you as an emergency physician that if I have a patient with a big intracranial bleed on anticoagulant, I know that the mortality is quite high,” Dr Pollack says. “To have the ability to reverse the anticoagulant within moments, and at least have that part of the patient’s critical condition taken care of, is nonetheless promising to me.”
It will usually be impractical to perform clotting tests such as diluted thrombin time or activated partial thromboplastin time, indicative of active dabigatran, before making a decision to treat, Dr Pollack says.
“If I have a patient taking warfarin, for example, who presents obtunded with a sudden change in consciousness, when I see the first cut of a CT scan that reveals a haemorrhage I will give prothrombin complex concentrate,” he says. “At that point I probably won’t know the INR, but I have a patient who I believe is anticoagulated and is acutely compromised by something I can try to reverse.”
“We need to apply the same thinking to a patient taking a NOAC. If you have reason to believe that the patient is taking dabigatran, and the patient is bleeding, or has a closed space haemorrhage, or needs immediate surgery that could be disastrous if the patient is truly anticoagulated, then we need to take urgent action.”
“Idarucizumab appears to have a robust safety profile and it’s unlikely that harm will be done if the patient in fact does not have active dabigatran.”
Coagulation tests might have a role in the follow-up of some patients. “For example, a rare patient taking dabigatran who is treated with idarucizumab will require a second dose or have a coagulopathy, such as a dilutional coagulopathy from a massive transfusion regimen after trauma,” Dr Pollack says. “You might need to look at other strategies in these cases.”
“Presumably the patient was anticoagulated with dabigatran for a good reason, so we want to restore protection as soon as it is safe to do so,” he says. “In the case of a surgical patient, dabigatran can be re-commenced as soon as operative haemostasis is attained. In patients presenting with a haemorrhage, there may be a little more uncertainty about when haemostasis can be assured, particularly in the case of intracranial haemorrhage when you are worried about a re-bleed, and a little more caution is required.
“In a patient with normal renal function, idarucizumab is cleared within 24 hours and it would not interfere with re-initiation of dabigatran.”
Because idarucizumab is specific for dabigatran, the anticoagulant activity of other anticoagulants will not be affected.2
Implications for prescribers
“I think we can agree that non-vitamin K antagonist oral anticoagulants, including dabigatran, represent a pharmacological advance over the vitamin K antagonists,” Dr Pollack says.
“There are rare occasions when such patients need reversal of anticoagulation because of major bleeding or for an urgent procedure. The availability of idaruzicumab to reverse dabigatran reliably and quickly in these settings should give physicians prescribing anticoagulation reason to think of dabigatran very favourably.”
Related articles: TGA approves first NOAC reversal agent
- New England Journal of Medicine 2015; 373: 511-520.
- Eikelboom JW et al. Circulation 2015; 132: 2412-2422.