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New Oral Anticoagulants for the Prevention of Thromboembolic Events in Patients with Atrial Fibrillation [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2012.

SUMMARY OF FINDINGS

Summary of Evidence

No clinical evidence was retrieved pertaining to the clinical effectiveness or cost of strategies to identify over-anticoagulation states for patients taking dabigatran, rivaroxaban, or apixaban. Limited evidence with uncertain applicability to clinical practice was retrieved regarding strategies to manage over-anticoagulation and bleeding associated with the use of dabigatran and rivaroxaban. No evidence was identified that evaluated the cost of strategies to manage bleeding associated with the use of these oral anticoagulants.

Studies

There was no evidence regarding approaches to identify over-anticoagulation states for patients taking dabigatran, rivaroxaban, or apixaban. No studies were identified that evaluated interventions to treat clinical bleeding; however, two studies were identified that evaluated strategies to reverse anticoagulation. One randomized controlled trial (RCT)13 examined the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of rivaroxaban and dabigatran. In addition, one cohort study14 sought to identify the fraction of dabigatran in blood removed by hemodialysis in a study of the pharmacokinetics and pharmacodynamics of dabigatran in patients with renal impairment or end-stage renal disease on hemodialysis. No evidence was found on antidotes for reversal of the anticoagulant effect of dabigatran, rivaroxaban, or apixaban.

The RCT13 compared PCC with placebo (saline infusion) in 12 healthy male subjects who received rivaroxaban or dabigatran in a crossover design. The 12 volunteers in this study received either 150 mg dabigatran twice daily (recommended dose for the prevention of stroke and systemic embolism with atrial fibrillation)5 or 20 mg rivaroxaban twice daily (twice the recommended dose for the prevention of stroke and systemic embolism with atrial fibrillation)15 for two and a half days. Following the last dose of the anticoagulant on the third day, study subjects received either non-activated PCC (Cofact; 50 U/kg) or placebo (saline solution). Blood was collected at various time points during the study and up to 24 hours post-infusion of PCC or saline. Following a washout period of 11 days, the study subjects received the other anticoagulant drug according to the same protocol.

Administration of PCC reversed the anticoagulant effect of rivaroxaban, as assessed using blood coagulation tests that measure prothrombin time and endogenous thrombin potential (summarized in Table 1). Blood coagulation tests measuring activated partial thromboplastin time, endogenous thrombin potential lag time, thrombin time, and ecarin clotting time were not reversed by PCC infusion in individuals who received dabigatran (summarized in Table 2). No major or clinically relevant bleeding complications occurred during the study; accordingly, the clinical effect of PCC on bleeding reversal was not examined in this study. Because this small RCT measured the effect of PCC on surrogate markers (blood coagulation tests) without assessing the clinical effect of PCC, it did not provide any information related to the effectiveness of PCC in patients experiencing bleeding in clinical practice while being treated with an oral anticoagulant.

Table 1. Summary of Laboratory Assay Results for Subjects Who Received Rivaroxaban.

Table 1

Summary of Laboratory Assay Results for Subjects Who Received Rivaroxaban.

Table 2. Summary of Laboratory Assay Results for Subjects Who Received Dabigatran.

Table 2

Summary of Laboratory Assay Results for Subjects Who Received Dabigatran.

The cohort study14 examined the amount of dabigatran that could be removed from the blood by hemodialysis in patients with end-stage renal disease on maintenance hemodialysis. The plasma concentration of dabigatran was evaluated in the dialyzer inlet and outlet lines following oral administration of dabigatran etexilate 50 mg (lower than the recommended dose for the prevention of stroke and systemic embolism with atrial fibrillation) in six patients with end-stage renal disease. The mean plasma concentration of dabigatran was lower in the dialyzer outlet line than in the inlet line (measured both at two hours [4.4 ng/mL versus 12.5 ng/mL] and at four hours [3.4 ng/mL versus 8.9 ng/mL]). The study found the mean fractions of dabigatran removed by hemodialysis were 62% at two hours and 68% at four hours.

Limited data and statistics were reported for this cohort study. Although this study demonstrated that a fraction of dabigatran can be removed from the blood by hemodialysis, whether this method might be suitable for patients experiencing major bleeding is unclear.

Evidence-Based Guidelines

The Institute for Clinical Systems Improvement (ICSI) has published an antithrombotic therapy guideline supplement16 and a consensus-based statement17 regarding the emergency care of bleeding for adult patients taking dabigatran. In these guidelines, it was stated that very little data were identified to support the guidelines. However, available evidence was included in the form of a summary and consensus-based protocol for bleeding management (summarized in Table 3). No evidence was identified for an antidote for reversing the anticoagulant effect of dabigatran. There was also no evidence identified regarding the relationship between plasma dabigatran levels and the risk of hemorrhage.

Table 3. Direct ICSI Statements on Bleeding Management for Patients Taking Dabigatran.

Table 3

Direct ICSI Statements on Bleeding Management for Patients Taking Dabigatran.

Copyright © 2012 CADTH.
Cover of New Oral Anticoagulants for the Prevention of Thromboembolic Events in Patients with Atrial Fibrillation
New Oral Anticoagulants for the Prevention of Thromboembolic Events in Patients with Atrial Fibrillation [Internet].

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