Jatin Patel, PharmD Candidate 2016, Mercer University College of Pharmacy
Per the Package insert, Pradaxa® (dabigatran) is indicated to reduce the risk of recurrence and the treatment of deep vein thrombosis and pulmonary embolism. The package insert also states dabigatran is prescribed to reduce the risk of strokes or blood clots in patients who have nonvalvular atrial fibrillation. According to package insert dabigatran is a reversible, direct thrombin inhibitor that binds both free and fibrin-bound thrombin.1 It is also an activator of factors V, VIII, XI, and XII, and inhibits thrombin-induced platelet aggregation.2
According to Micromedex, idarucizumab is humanized antibody fragment that is design to reverse the anticoagulant effect of dabigatran. Miromedex states that idarucizumab is under a new drug application status.3
|Title: Idarucizumab for Dabigatran Reversal|
|Design||Multicenter, prospective cohort study|
|Objective||To determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B)|
|Study Groups||Group A: Patients with overt, uncontrollable, or life-threatening bleeding that required a reversal agent based on clinician judgment.
Group B: Patient who required surgery or other invasive procedures which could be delayed for at least 8 hours and required normal hemostasis.
|Methods||Only 90 patients were included in the study. All patients received 5 g of IV idarucizumab which was administered as two 50 ml bolus infusions for no more than 15 minutes apart, each containing 2.5 g of idarucizumab. Blood samples were obtained at baseline, after first infusion of idarucizumab, between 10 to 30 minutes after first infusion, and 1, 2, 4, 12, and 24 hours after the second infusion. Clotting tests were conducted at the central laboratory and the activated partial-thromboplastin time was assessed locally in parallel expect at 1, 2, 4, and 24 hours.|
|Duration||June 2014 through February 2015|
|Primary Outcome Measure||The maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab|
|Results||The study included 90 patients who received idarucizumab. Out of 90 patients 68 patients were assessed by means of the dilute-thrombin time and 81 of 90 patients were assessed by the means of the ecarin clotting time for the percentage reversal. The median maximum percentage reversal in the patients in group A and in those in group B was 100% (95% confidence interval, 100 to 100). The dilute thrombin time was normalized in 98% for patient in group A and 93% in group B for patients who could be evaluated in both groups. In addition, the ecarin clotting time was normalized in 89% in group A and 88% in group B who could be evaluated. Similar results were obtained for activated partial-thromboplastin time and thrombin time.
After the first bolus of idarucizumab was administered, the concentration of unbound dabigatran was less than 20 ng/ml where little or no anticoagulant effects were produce in all expect one patient. At 4 hours after treatment, 83 of the 86 patients had a concentration of unbound dabigatran near the lower limit of quantification.
|Adverse Events||Common Adverse Events: N/A|
|Serious Adverse Events: Intracranial bleeding (18 patients), trauma-related (9 patients), gastrointestinal (20 patients), septic shock (2 patients), multiorgan failure (1 patient), hemodynamic collapse (1 patient), respiratory failure (1 patient), cardiac arrest (1 patient), deep-vein thrombosis (1 patient), pulmonary embolism (1 patient), left atrial thrombus (1 patient), non-ST-segment elevation (1 patient), myocardial infarction (1 patient), and ischemic stroke (1 patient)|
|Percentage that Discontinued due to Adverse Events: N/A|
|Study Author Conclusions||Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes.|
Idarucizumab reversed the anticoagulant activity of dabigatran in 88 – 98% of patients. The study had broad inclusion criteria, a simple study design, and confirmation that normalization of coagulation tests results by measuring unbound dabigatran concentration to limit bias. Even though the study lacked a control group, it is not ideal to provide patients a placebo to manage their current conditions due to malpractice.4
- Paradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; Revised January 2015.
- Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. https://online-lexi-com.proxy-s.mercer.edu/lco/action/doc/retrieve/docid/patch_f/1200582. Accessed June 24,2015.
- Investigational Drugs – New Drug Application (NDA) Status. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com.proxy-s.mercer.edu/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/04B19B/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/E4563C/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/evidencexpert.IntermediateToDocumentLink?docId=1034&contentSetId=50&title=INVESTIGATIONAL+DRUGS+-+NEW+DRUG+APPLICATION+%28NDA%29+STATUS&servicesTitle=INVESTIGATIONAL+DRUGS+-+NEW+DRUG+APPLICATION+%28NDA%29+STATUS. Accessed June 24, 2015.
- Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015.