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Idarucizumab for Reversal of Dabigatran-Associated Bleeding: Misnomer or Miracle?
The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–7, 2016 Ó 2016 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2016.08.023
Pharmacology in Emergency Medicine IDARUCIZUMAB FOR REVERSAL OF DABIGATRAN-ASSOCIATED BLEEDING: MISNOMER OR MIRACLE? Luke Miller, PHARMD, BCPS,* Jason A. Ferreira, PHARMD, BCPS, BCCCP,† and Calvin Tucker, PHARMD, BCPS, BCCCP* *St. Vincent’s Medical Center Riverside, Jacksonville, Florida and †University of Florida Health Jacksonville, Jacksonville, Florida Corresponding Address: Luke Miller, PHARMD, BCPS, St. Vincent’s Medical Center Riverside, 1 Shircliff Way, Jacksonville, FL 32204
, Keywords—bleeding; dabigatran; idarucizumab; oral anticoagulation; reversal strategies; toxicology
, Abstract—Background: The development of novel oral anticoagulants (NOACs) has revolutionized oral anticoagulation. Rapid incorporation of NOACs into general practice has heightened the demand for directed reversal agents. Idarucizumab is a targeted reversal agent that is approved for the urgent reversal of the anticoagulant effects of dabigatran. While it is a welcome addition to reversal strategies of dabigatran, a number of clinical questions exist regarding its place in therapy. Objective: We describe controversies regarding the use of idarucizumab therapy in patients with dabigatran-associated bleeding. Discussion: Although existing clinical studies show a rapid reversal of coagulation assays, these studies did not describe a corresponding improvement in mortality or rapid cessation of hemorrhage. It is questionable how heavily clinicians can rely upon the use of the surrogate endpoints in clinical studies, such as ecarin clotting time and dilute thrombin time. Another issue is whether patients exhibiting re-elevation of coagulation assays would benefit from an additional dose of idarucizumab, because this has not been studied. It is currently unclear if blood products must be given in addition to idarucizumab can be used as monotherapy. Conclusions: The initial data suggest a definite role for idarucizumab in treatment of bleeding associated with dabigatran. As more clinical practice experience is gained with the agent and the remaining data on its use are released, clinicians can better guide the clinical use of idarucizumab. At present, there is currently not enough evidence for idarucizumab to be used as monotherapy. Ó 2016 Elsevier Inc. All rights reserved.
INTRODUCTION The development of novel oral anticoagulants (NOACs) in the last decade has revolutionized anticoagulation. For decades, warfarin was the only available oral anticoagulant and presented a number of issues, including interpatient variability, complex dosing, drug and diet interactions, and the need for routine monitoring. With the development and approval of dabigatran, shortly followed by rivaroxaban, apixaban, and edoxaban, health care providers were quickly offered therapeutic alternatives where previously only one option existed. Dabigatran is the first and only direct thrombin inhibitor; rivaroxaban, apixaban, and edoxaban are factor Xa inhibitors. These therapies have been incorporated into practice, and while they have not completely replaced the use of vitamin K antagonists (VKAs), they have, in many circumstances, provided a safer and more effective alternative. However, NOACs are not without risk and still provide a challenge to providers who manage complications when they arise. DISCUSSION NOAC-Associated Bleeding While bleeding continues to be the primary concern with regard to oral anticoagulation, NOACs have improved
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RECEIVED: 14 April 2016; FINAL SUBMISSION RECEIVED: 28 July 2016; ACCEPTED: 23 August 2016 1
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upon this overall risk. Several trials have identified a lower risk of bleeding when comparing NOACs to VKAs. Early literature in atrial fibrillation (AF) identified a lower risk of bleeding when using NOACs. The Randomized Evaluation of Long-Term Anticoagulation Therapy trial identified a substantially lower rate of life-threatening bleed (relative risk [RR] 0.81 [95% confidence interval {CI} 0.66–0.99]) and minor bleeding (RR 0.91 [95% CI 0.85–0.97]), with a higher risk of gastrointestinal bleeding (RR 1.50 [95% CI 1.19–1.89]) with dabigatran, a similar risk has been noted with other NOACs (1,2). These early trials showed promise not only to provide therapeutic anticoagulation but with the benefit of reducing bleeding risk. These results continued when NOACs were evaluated in the therapy of venous thromboembolism, such as in the Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism trial, in which dabigatran reduced major bleeding by more than half (dabigatranassociated major or clinically relevant bleeding: HR 0.63 [95% CI 0.47–0.84]), a finding mirrored by other NOACs (3,4). van der Hulle et al. showed a number needed to treat of 149 patients with NOAC therapy in order to prevent one major bleed, and 56 patients to prevent one clinically relevant bleed (5). While the literature appears robust, the protective attributes of the NOACs may not be generalized to all patient populations or types of bleeds. This is highlighted by such findings as the increased risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and edoxaban (1,2,6). Drug interactions and organ dysfunction also place patients at a substantially higher risk of bleeding. The concomitant use of antiplatelets and the safety of the NOACs in patients with renal dysfunction have conflicting opinions (7,8). Some suggest that these agents can be safely used if properly dose-adjusted for renal dysfunction; others claim that patients with elevated creatinine levels are at an increased risk for bleeding regardless of dose (9,10). In addition, all agents may not be created equal in all populations. Sharma et al. identified a higher risk of major bleeding in the elderly population when using dabigatran, but failed to identify this difference with any other NOAC (11). Interpretation of the information to date supports a lower risk of bleeding in most uses of NOACs. However, they were brought to market with one significant drawback: the lack of an effective and reliable reversal agent. While VKAs are cumbersome and carry a higher risk of bleeding, to many there is comfort in the fact that an antidote is available for rapid reversal with vitamin K and factor replacement. Little clinical evidence exists on outcomes of patients experiencing a bleed while receiving a NOAC. When evaluating safety data from a majority of
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the large randomized dabigatran trials, Majeed et al. suggested that patients who bled from dabigatran had a less complicated hospital stay. Patients were less likely to die (odds ratio 0.66 [95% CI 0.44–1.00]) and had shorter stays in the intensive care unit (1.6 days for patients taking dabigatran vs. 2.7 days for those with VKAs; p = 0.01) when compared to patients receiving VKA therapy (10). A larger meta-analysis similarly showed a reduced rate of death in patients experiencing major bleeds while anticoagulated with NOACs when compared to VKAs. The higher mortality was likely caused by a higher rate of intracranial bleed, with only 18% of bleeds being intracranial, yet these accounted for 78% of fatal bleeds. Skaistis et al. emphasized the tendency of VKAs to cause bleeding in sites with higher mortality risk (12). The currently recommended reversal strategies have minimal literature supporting their use. Professional opinion recommends the use of clotting factor products (e.g., prothrombin complex concentrate, recombinant factor VII, or activated prothrombin complex concentrate), assumed to overcome inhibition of the active moiety, in the event of severe bleeds. However, these recommendations come on the back of scant clinical data and primarily in healthy individuals, in vitro, and animal models (13–21). Outcomes from these studies have inherent issues, including primarily using surrogate endpoints involving the reversal of nonvalidated coagulation parameters. While animal models have provided data on attenuating bleeding, use in humans requires the assumption of similar coagulation, because there appears to be a substantial difference across species (14–17). Extracorporeal approaches have been advocated for based on pharmacokinetic trials conducted in nonbleeding patients who are undergoing dialysis, specifically with dabigatran (22). Similarly, this practice has been shown to be ineffective for other agents, such as edoxaban (23). This approach to bleeding during NOAC therapy, to this point, remains highly controversial, with little evidence to suggest clinical efficacy. While rates of overall bleeding appear to be lower with NOAC therapy than with VKA, when bleeding does occur its outcomes stand to be just as devastating. The rapid incorporation of NOACs into practice has heightened the need for directed reversal agents. This review seeks to evaluate the role of idarucizumab in the care of critically ill or bleeding patients and addresses the impact this agent may have on the safe use of NOACs. Idarucizumab The first targeted reversal agent to be approved in the United States was idarucizumab, approved in October
Idarucizumab for Reversal of Dabigatran-Associated Bleeding
2015. Idarucizumab is a humanized monoclonal antibody fragment used for the urgent reversal of the anticoagulant effects of dabigatran. Idarucizumab was granted ‘‘breakthrough therapy’’ designation to expedite the approval process in order to meet the unmet need of urgent reversal of dabigatran. The approval of idarucizumab was largely the result of an interim analysis of a phase III multicenter prospective cohort study. The Reversal Effects of Idarucizumab in Patients on Active Dabigatran (RE-VERSE AD) interim analysis included 90 patients (expected enrollment of 300) (24). The study was designed as a cohort study because there is currently not an agreed upon standard of care for treatment of dabigatranassociated bleeding (25). While a welcomed addition to the arsenal of anticoagulant reversal agents, a number of clinical questions exist regarding its place in therapy. Pharmacokinetics/Pharmacodynamics Idarucizumab is a recombinant immunoglobulin G1 isotype molecule that binds specifically to the thrombin binding site of dabigatran and its metabolites with an affinity that is approximately 350 times greater than the affinity of dabigatran to thrombin, resulting in the inability of dabigatran to bind thrombin (26). However, idarucizumab does not bind substrates of thrombin nor does it possess thrombin-like enzymatic activity (27). Idarucizumab exhibits a volume of distribution at steady state of 8.9 L with limited extravascular distribution because of its large molecular size (47,776 Daltons). The recommended dose of idarucizumab is 5 g, clinically delivered as two consecutive intravenous infusions, producing an average serum concentration of 14,900 nmol/ L after the initial 2.5-g infusion and 25,500 nmol/L after the subsequent 2.5-g infusion. Given the volume of distribution and primary intravascular distribution, there appears to be a linear rise in serum concentrations with repeated dosing. It has been supported by phase I trials that idarucizumab 2 g is the predicted equimolar dose required to neutralize 100% of standard therapeutic serum concentrations (180 ng/mL) (28). The mean unbound serum dabigatran concentration in which idarucizumab has been clinically studied to neutralize was 83.5 ng/mL among both groups. The average total concentrations of serum dabigatran varied greatly from 3 to 3600 ng/mL, with medians of 132 and 114 ng/mL among the two groups, respectively. These concentrations reflect those considered therapeutic in patients who are receiving dabigatran for anticoagulation in atrial fibrillation, averaging between 90 to 180 ng/mL (29). While monitoring for dabigatran is not routine, dabigatran has been shown to increase thrombin time (TT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), ecarin clotting time
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(ECT), and dilute thrombin time (dTT). These coagulation parameters respond differently to dabigatran, affecting their use to evaluate the effectiveness of idarucizumab. The aPTT displays a curvilinear dose response to increasing plasma concentrations of dabigatran and may be used to show that a patient is anticoagulated with dabigatran. However, it is best used as a negative indicator for dabigatran. TT provides a linear time response to increasing plasma concentrations of dabigatran. It is very sensitive to the presence of dabigatran, but TT is not routinely performed and may not be readily available in hospitals. In addition, samples may be unclottable at therapeutic levels, making quantitative assays unsuitable. dTT, also known as the commercially available Hemoclot, is not as sensitive as TT, allowing for it to be used to measure the anticoagulant activity of dabigatran. Finally, ECT has a linear relationship and strong correlation with plasma dabigatran concentrations (30). dTT and ECT can accurately identify therapeutic and supratherapeutic levels. In the research setting, laboratory tests are available to evaluate patients with severe bleeding associated with dabigatran use and monitor the use of idarucizumab. However, these laboratory assays are not routinely available in the clinical setting (31). CLINICAL TRIALS RE-VERSE AD included two distinct groups: patients in group A had uncontrollable or life-threatening bleeding; group B included patients who required an urgent surgery or invasive procedure that could not be delayed for $8 h. The primary endpoint was the maximum percentage reversal of the effects of dabigatran from the time of completion of the initial infusion to any time within 4 h after the second infusion of idarucizumab as assessed by ECT. The median maximum percentage reversal was deemed to be 100% (95% CI 100–100) in both groups. However, this endpoint could not be assessed in 22% of patients in group A and in 28% of patients in group B because baseline coagulation assays were normal. Reversal of dTT was seen in 93% of patients in group A and 98% of patients in group B, while ECT was normalized in 89% and 88% of patients, respectively. The plasma level of unbound dabigatran was near or below the lower limit of quantification (20 ng/mL) in all but one patient after the completion of the first infusion and remained near this level at 24 h in 79% of patients. The median time to cessation of bleeding was 11.4 h. In group A, assessment of hemostasis was only performed in 69% of patients. Patients in group B had normal intraoperative hemostasis in 92% of cases. It is important to note that in group B, 10% of patients received their last dose of dabigatran >48 h earlier. Overall, there were 18 deaths (9 in each group), with five patients experiencing a thrombotic
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event (i.e., 3 venous thromboembolisms, 1 myocardial infarction, and 1 ischemic stroke) (24). CLINICAL CONSIDERATIONS There are several important unanswered questions that arise with the use of idarucizumab. There is currently not a routinely available coagulation assay to detect the presence of dabigatran. ECT and dTT are not routinely used outside of the research setting. In the clinical environment, aPTT and TT are currently the best available options for detecting the presence of dabigatran and possibly idarucizumab response; however, these data were not used for the study and at best remain surrogate endpoints (32). While a rapid reversal of coagulation assays was demonstrated in the RE-VERSE AD trial, the pharmacodynamic effects were markedly delayed in the patients with life-threatening bleeding compared to the pharmacokinetic effects, because the median time to cessation of bleeding was 11.4 h. With a rapid reversal of these coagulation parameters, one would expect a corresponding rapid cessation of bleeding. The patients requiring urgent procedures did not experience abnormal intraoperative bleeding. Mild or moderate abnormal bleeding was observed in only 8% of patients. The effectiveness of idarucizumab might vary in its ability to cause cessation versus prevention of bleeding. While the argument can be made that clinically relevant endpoints have been demonstrated in the RE-VERSE AD trial, the question then becomes with only 30% of anticipated enrollment and 17% of patients having a nearly undetectable unbound dabigatran level (<20 ng/mL) at baseline, can we rely upon the endpoints seen in this interim analysis? The normalization of these coagulation parameters may not correlate with cessation of bleeding but may identify that dabigatran is no longer propagating its anticoagulation effects. There is a lack of evidence that shows a reduction of dabigatran concentrations already bound to thrombin. Dabigatran exhibits highly selective, rapid, yet reversible binding to thrombin; however, the duration of dabigatran’s ability to bind thrombin is unknown. If dabigatran demonstrates an on-off phenomenon, reversal will occur. If dabigatran is bound for an extended duration, idarucizumab will not reverse the activity of drug already bound to thrombin. This may account for the delay in bleeding cessation observed in the RE-VERSE AD trial. After the administration of idarucizumab, a redistribution phenomenon can occur in which re-elevations of dabigatran concentrations have been noted, producing an average total serum concentration, or total drug burden, of roughly 500 ng/mL (250–2000 ng/mL). This re-elevation is theorized to be caused by the redistribution of extravascular dabigatran into the intravascular compartment. It is un-
certain whether patients with such a response would benefit from an additional dose of idarucizumab. Perhaps the use of aPTT could guide this clinical scenario, because a patient with re-elevation of aPTT and continued bleeding may be an ideal candidate for an additional dose of idarucizumab. Currently, this has not been specifically studied and remains an unknown area, because the patient may only require an additional 2.5-g infusion. Another interesting question is the role of blood products in the RE-VERSE AD trial—most notably, fresh frozen plasma and factor-based products. Fresh frozen plasma was used in 25.5% of patients, while activated prothrombin complex concentrate was used in four patients (24). While exclusion of these products from the study may not have been appropriate because they are considered life-saving therapies by many clinicians, it does raise some interesting clinical questions. While there is little doubt that idarucizumab specifically and robustly binds to dabigatran, the critical question is if the binding of dabigatran is responsible for cessation of bleeding in these patients. Perhaps factor supplementation is responsible for bleeding cessation while idarucizumab simply prevents further anticoagulant activity of dabigatran. This could offer a potential explanation for the rapid normalization of coagulation assays while bleeding continued. It is unclear if blood products, such as fresh frozen plasma, must be given in addition to idarucizumab or if monotherapy with idarucizumab would suffice. A potential necessary role of idarucizumab may be in the setting of toxic ingestion of dabigatran. The dose of idarucizumab used in the RE-VERSE AD trial was calculated to reverse the effects of dabigatran measured from the 99th percentile in the Randomized Evaluation of Long-Term Anticoagulation Therapy trial (24). Two patients in group B had plasma concentrations of total dabigatran of >1000 ng/mL, with one being defined as a toxic ingestion. At 4 h after the second infusion, two patients still had high concentrations of 848 ng/mL and 1510 ng/mL, respectively. The authors did note that dialysis was prevented in the patient who presented with a toxic ingestion. It is unclear, however, if the patient also received activated charcoal, a therapy that may be effective in dabigatran ingestion. While another dose of idarucizumab was not administered to these patients, there is potential that this could be a strategy applied in the clinical setting for these patients. When comparing the therapeutic concentrations of dabigatran studied to the potential concentrations that may be produced by a toxic ingestion, the therapeutic concentrations may appear miniscule. If current dosing is recommended to reverse in an equiosmolar fashion roughly 200% of therapeutic concentrations, does this signify the need for additional or higher dosing in those patients with exponentially
Idarucizumab for Reversal of Dabigatran-Associated Bleeding
larger exposures (28)? For these circumstances, a dose to drug neutralization equation would be useful, similar to that seen with other monoclonal agents, such as digoxin-specific antibody (33). Finally, the requirement or even ability to use extracorporeal elimination requires additional analysis. While complex duration is significant, staying bound for up to 260 h, elimination may be significantly delayed in the event of acute renal failure. However, the molecular weight of this agent may preclude its elimination via most dialysis modalities, given that the molecular weight threshold of some filters peak at 15,000 Da. Knowledge of filter capacity would therefore be important, because super high flux membranes have cutoffs closer to 65,000 Da (34). Institutions lacking these higher capacity filters may consider plasmapheresis modalities, because this extends molecular weight capabilities well above that of idarucizumab (970,000 Da) and therefore may be an extracorporeal option in the event that it is required (35). Additional research will be required in this arena to provide further insight into therapeutic options. A substantial number of questions still circulate around the best use of idarucizumab—and its efficacy, for that matter. With the absence of data to support displacement of dabigatran from its molecular binding site, no evidence currently supports the conclusion that idarucizumab as monotherapy is capable of reversing the anticoagulation effects of dabigatran. While idarucizumab consistently showed a profound reduction in unbound dabigatran concentrations, as the literature stands this agent may be more appropriately referred to as a neutralizing agent—calling it a reversal agent may in fact be a misnomer. This is substantiated by the delay in time to cessation of bleeding in relation to the decline in unbound serum concentrations observed in the REVERSE AD trial. Once more, this calls into question the true impact of product supplementation used in this trial. In theory, if idarucizumab is only capable of neutralizing unbound drug, removing free drug from circulation, potentially a multimodal approach would be optimal. Supplementing thrombin in these patients may replace thrombin rendered ineffective by dabigatran, thereby hastening hemostasis. The lack of the RE-VERSE AD trial authors reporting differences in time to bleeding cessation with regard to blood products unfortunately prevents this analysis from being performed. While this would still result in idarucizumab providing a therapeutic benefit, it may prove to be a component of a multiple agent reversal strategy as opposed to the misleading reversal agent terminology label it currently carries. If this is the case, the potential false sense of security associated with idarucizumab as monotherapy must be dispelled. The potential widespread use of idarucizumab may help elucidate many of these questions (24).
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CONCLUSION While many questions about the use of idarucizumab remain unanswered, the initial data suggest a definite role of this agent for treatment of bleeding associated with dabigatran. As more clinical experience is gained with the agent and the remaining data on its use are released, a more specific role for idarucizumab may be carved out. At present, there is not enough evidence for idarucizumab to be used as monotherapy. It is important moving forward as a medical profession that these new agents fast-tracked through the approval process are critically and continually evaluated until many years of practice can help dictate their use.
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6 15. Pragst I, Zeitler SH, Doerr B, et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (beriplex P/N) in a rabbit model. J Thromb Haemost 2012;10:1841–8. 16. Perzborn E, Gruber A, Tinel H, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost 2013;110:162–72. 17. Martin AC, Le Bonniec B, Fischer AM, et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol 2013;168:4228–33. 18. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573–9. 19. Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108:217–24. 20. Khoo TL, Weatherburn C, Kershaw G, Reddel CJ, Curnow J, Dunkley S. The use of FEIBA(R) in the correction of coagulation abnormalities induced by dabigatran. Int J Lab Hematol 2013;35: 222–4. 21. Korber MK, Langer E, Ziemer S, Perzborn E, Gericke C, Heymann C. Measurement and reversal of prophylactic and therapeutic peak levels of rivaroxaban: an in vitro study. Clin Appl Thromb Hemost 2014;20:735–40. 22. Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013;109: 596–605. 23. Parasrampuria DA, Marbury T, Matsushima N, et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost 2015; 113:719–27. 24. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511–20.
L. Miller et al. 25. Pollack CV Jr, Reilly PA, Bernstein R, et al. Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost 2015;114:198–205. 26. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121: 3554–62. 27. Das A, Liu D. Novel antidotes for target specific oral anticoagulants. Exp Hematol Oncol 2015;4:25. 28. Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: A randomised, placebo-controlled, double-blind phase 1 trial. Lancet 2015;386: 680–90. 29. Okubo K, Kuwahara T, Takagi K, et al. Relation between dabigatran concentration, as assessed using the direct thrombin inhibitor assay, and activated clotting time/activated partial thromboplastin time in patients with atrial fibrillation. Am J Cardiol 2015;115:1696–9. 30. Hawes EM, Deal AM, Funk-Adcock D, et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a crosssectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 2013;11:1493–502. 31. Alikhan R, Rayment R, Keeling D, et al. The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran. Emerg Med J 2014;31:163–8. 32. Dager WE, Gosselin RC, Kitchen S, Dwyre D. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother 2012;46:1627–36. 33. Chan BS, Buckley NA. Digoxin-specific antibody fragments in the treatment of digoxin toxicity. Clin Toxicol (Phila) 2014;52:824–36. 34. Karkar A. Advances in hemodialysis techniques. In: Carpi A, Donadio C, Tramonti G, eds. Progress in hemodialysis—from emergent biotechnology to clinical practice. Rijeka, Croatia: InTech; 2013:409–38. 35. Ward DM. Conventional apheresis therapies: a review. J Clin Apher 2011;26:230–8.
Idarucizumab for Reversal of Dabigatran-Associated Bleeding
ARTICLE SUMMARY 1. Why is this topic important? The rapid incorporation of novel oral anticoagulants into general practice has heightened the demand for directed reversal agents. Idarucizumab is a humanized monoclonal antibody fragment that was recently approved for the urgent reversal of the anticoagulant effects of dabigatran. 2. What does this review attempt to show? This review seeks to evaluate the role of idarucizumab in the care of critically ill or bleeding patients addressing important questions pertaining to the use of this agent. 3. What are the key findings? While many questions remain unanswered with the use of idarucizumab, the initial data suggest a definite role of this agent for treatment of bleeding associated with dabigatran. 4. How is patient care impacted? As more clinical experience is gained with the agent and the remaining data on its use are released, clinicians will be able to appropriately use idarucizumab for dabigatran-associated bleeding.
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http://dx.doi.org/10.1016/j.jemermed.2016.08.023
Pharmacology in Emergency Medicine IDARUCIZUMAB FOR REVERSAL OF DABIGATRAN-ASSOCIATED BLEEDING: MISNOMER OR MIRACLE? Luke Miller, PHARMD, BCPS,* Jason A. Ferreira, PHARMD, BCPS, BCCCP,† and Calvin Tucker, PHARMD, BCPS, BCCCP* *St. Vincent’s Medical Center Riverside, Jacksonville, Florida and †University of Florida Health Jacksonville, Jacksonville, Florida Corresponding Address: Luke Miller, PHARMD, BCPS, St. Vincent’s Medical Center Riverside, 1 Shircliff Way, Jacksonville, FL 32204
, Keywords—bleeding; dabigatran; idarucizumab; oral anticoagulation; reversal strategies; toxicology
, Abstract—Background: The development of novel oral anticoagulants (NOACs) has revolutionized oral anticoagulation. Rapid incorporation of NOACs into general practice has heightened the demand for directed reversal agents. Idarucizumab is a targeted reversal agent that is approved for the urgent reversal of the anticoagulant effects of dabigatran. While it is a welcome addition to reversal strategies of dabigatran, a number of clinical questions exist regarding its place in therapy. Objective: We describe controversies regarding the use of idarucizumab therapy in patients with dabigatran-associated bleeding. Discussion: Although existing clinical studies show a rapid reversal of coagulation assays, these studies did not describe a corresponding improvement in mortality or rapid cessation of hemorrhage. It is questionable how heavily clinicians can rely upon the use of the surrogate endpoints in clinical studies, such as ecarin clotting time and dilute thrombin time. Another issue is whether patients exhibiting re-elevation of coagulation assays would benefit from an additional dose of idarucizumab, because this has not been studied. It is currently unclear if blood products must be given in addition to idarucizumab can be used as monotherapy. Conclusions: The initial data suggest a definite role for idarucizumab in treatment of bleeding associated with dabigatran. As more clinical practice experience is gained with the agent and the remaining data on its use are released, clinicians can better guide the clinical use of idarucizumab. At present, there is currently not enough evidence for idarucizumab to be used as monotherapy. Ó 2016 Elsevier Inc. All rights reserved.
INTRODUCTION The development of novel oral anticoagulants (NOACs) in the last decade has revolutionized anticoagulation. For decades, warfarin was the only available oral anticoagulant and presented a number of issues, including interpatient variability, complex dosing, drug and diet interactions, and the need for routine monitoring. With the development and approval of dabigatran, shortly followed by rivaroxaban, apixaban, and edoxaban, health care providers were quickly offered therapeutic alternatives where previously only one option existed. Dabigatran is the first and only direct thrombin inhibitor; rivaroxaban, apixaban, and edoxaban are factor Xa inhibitors. These therapies have been incorporated into practice, and while they have not completely replaced the use of vitamin K antagonists (VKAs), they have, in many circumstances, provided a safer and more effective alternative. However, NOACs are not without risk and still provide a challenge to providers who manage complications when they arise. DISCUSSION NOAC-Associated Bleeding While bleeding continues to be the primary concern with regard to oral anticoagulation, NOACs have improved
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RECEIVED: 14 April 2016; FINAL SUBMISSION RECEIVED: 28 July 2016; ACCEPTED: 23 August 2016 1
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upon this overall risk. Several trials have identified a lower risk of bleeding when comparing NOACs to VKAs. Early literature in atrial fibrillation (AF) identified a lower risk of bleeding when using NOACs. The Randomized Evaluation of Long-Term Anticoagulation Therapy trial identified a substantially lower rate of life-threatening bleed (relative risk [RR] 0.81 [95% confidence interval {CI} 0.66–0.99]) and minor bleeding (RR 0.91 [95% CI 0.85–0.97]), with a higher risk of gastrointestinal bleeding (RR 1.50 [95% CI 1.19–1.89]) with dabigatran, a similar risk has been noted with other NOACs (1,2). These early trials showed promise not only to provide therapeutic anticoagulation but with the benefit of reducing bleeding risk. These results continued when NOACs were evaluated in the therapy of venous thromboembolism, such as in the Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism trial, in which dabigatran reduced major bleeding by more than half (dabigatranassociated major or clinically relevant bleeding: HR 0.63 [95% CI 0.47–0.84]), a finding mirrored by other NOACs (3,4). van der Hulle et al. showed a number needed to treat of 149 patients with NOAC therapy in order to prevent one major bleed, and 56 patients to prevent one clinically relevant bleed (5). While the literature appears robust, the protective attributes of the NOACs may not be generalized to all patient populations or types of bleeds. This is highlighted by such findings as the increased risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and edoxaban (1,2,6). Drug interactions and organ dysfunction also place patients at a substantially higher risk of bleeding. The concomitant use of antiplatelets and the safety of the NOACs in patients with renal dysfunction have conflicting opinions (7,8). Some suggest that these agents can be safely used if properly dose-adjusted for renal dysfunction; others claim that patients with elevated creatinine levels are at an increased risk for bleeding regardless of dose (9,10). In addition, all agents may not be created equal in all populations. Sharma et al. identified a higher risk of major bleeding in the elderly population when using dabigatran, but failed to identify this difference with any other NOAC (11). Interpretation of the information to date supports a lower risk of bleeding in most uses of NOACs. However, they were brought to market with one significant drawback: the lack of an effective and reliable reversal agent. While VKAs are cumbersome and carry a higher risk of bleeding, to many there is comfort in the fact that an antidote is available for rapid reversal with vitamin K and factor replacement. Little clinical evidence exists on outcomes of patients experiencing a bleed while receiving a NOAC. When evaluating safety data from a majority of
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the large randomized dabigatran trials, Majeed et al. suggested that patients who bled from dabigatran had a less complicated hospital stay. Patients were less likely to die (odds ratio 0.66 [95% CI 0.44–1.00]) and had shorter stays in the intensive care unit (1.6 days for patients taking dabigatran vs. 2.7 days for those with VKAs; p = 0.01) when compared to patients receiving VKA therapy (10). A larger meta-analysis similarly showed a reduced rate of death in patients experiencing major bleeds while anticoagulated with NOACs when compared to VKAs. The higher mortality was likely caused by a higher rate of intracranial bleed, with only 18% of bleeds being intracranial, yet these accounted for 78% of fatal bleeds. Skaistis et al. emphasized the tendency of VKAs to cause bleeding in sites with higher mortality risk (12). The currently recommended reversal strategies have minimal literature supporting their use. Professional opinion recommends the use of clotting factor products (e.g., prothrombin complex concentrate, recombinant factor VII, or activated prothrombin complex concentrate), assumed to overcome inhibition of the active moiety, in the event of severe bleeds. However, these recommendations come on the back of scant clinical data and primarily in healthy individuals, in vitro, and animal models (13–21). Outcomes from these studies have inherent issues, including primarily using surrogate endpoints involving the reversal of nonvalidated coagulation parameters. While animal models have provided data on attenuating bleeding, use in humans requires the assumption of similar coagulation, because there appears to be a substantial difference across species (14–17). Extracorporeal approaches have been advocated for based on pharmacokinetic trials conducted in nonbleeding patients who are undergoing dialysis, specifically with dabigatran (22). Similarly, this practice has been shown to be ineffective for other agents, such as edoxaban (23). This approach to bleeding during NOAC therapy, to this point, remains highly controversial, with little evidence to suggest clinical efficacy. While rates of overall bleeding appear to be lower with NOAC therapy than with VKA, when bleeding does occur its outcomes stand to be just as devastating. The rapid incorporation of NOACs into practice has heightened the need for directed reversal agents. This review seeks to evaluate the role of idarucizumab in the care of critically ill or bleeding patients and addresses the impact this agent may have on the safe use of NOACs. Idarucizumab The first targeted reversal agent to be approved in the United States was idarucizumab, approved in October
Idarucizumab for Reversal of Dabigatran-Associated Bleeding
2015. Idarucizumab is a humanized monoclonal antibody fragment used for the urgent reversal of the anticoagulant effects of dabigatran. Idarucizumab was granted ‘‘breakthrough therapy’’ designation to expedite the approval process in order to meet the unmet need of urgent reversal of dabigatran. The approval of idarucizumab was largely the result of an interim analysis of a phase III multicenter prospective cohort study. The Reversal Effects of Idarucizumab in Patients on Active Dabigatran (RE-VERSE AD) interim analysis included 90 patients (expected enrollment of 300) (24). The study was designed as a cohort study because there is currently not an agreed upon standard of care for treatment of dabigatranassociated bleeding (25). While a welcomed addition to the arsenal of anticoagulant reversal agents, a number of clinical questions exist regarding its place in therapy. Pharmacokinetics/Pharmacodynamics Idarucizumab is a recombinant immunoglobulin G1 isotype molecule that binds specifically to the thrombin binding site of dabigatran and its metabolites with an affinity that is approximately 350 times greater than the affinity of dabigatran to thrombin, resulting in the inability of dabigatran to bind thrombin (26). However, idarucizumab does not bind substrates of thrombin nor does it possess thrombin-like enzymatic activity (27). Idarucizumab exhibits a volume of distribution at steady state of 8.9 L with limited extravascular distribution because of its large molecular size (47,776 Daltons). The recommended dose of idarucizumab is 5 g, clinically delivered as two consecutive intravenous infusions, producing an average serum concentration of 14,900 nmol/ L after the initial 2.5-g infusion and 25,500 nmol/L after the subsequent 2.5-g infusion. Given the volume of distribution and primary intravascular distribution, there appears to be a linear rise in serum concentrations with repeated dosing. It has been supported by phase I trials that idarucizumab 2 g is the predicted equimolar dose required to neutralize 100% of standard therapeutic serum concentrations (180 ng/mL) (28). The mean unbound serum dabigatran concentration in which idarucizumab has been clinically studied to neutralize was 83.5 ng/mL among both groups. The average total concentrations of serum dabigatran varied greatly from 3 to 3600 ng/mL, with medians of 132 and 114 ng/mL among the two groups, respectively. These concentrations reflect those considered therapeutic in patients who are receiving dabigatran for anticoagulation in atrial fibrillation, averaging between 90 to 180 ng/mL (29). While monitoring for dabigatran is not routine, dabigatran has been shown to increase thrombin time (TT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), ecarin clotting time
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(ECT), and dilute thrombin time (dTT). These coagulation parameters respond differently to dabigatran, affecting their use to evaluate the effectiveness of idarucizumab. The aPTT displays a curvilinear dose response to increasing plasma concentrations of dabigatran and may be used to show that a patient is anticoagulated with dabigatran. However, it is best used as a negative indicator for dabigatran. TT provides a linear time response to increasing plasma concentrations of dabigatran. It is very sensitive to the presence of dabigatran, but TT is not routinely performed and may not be readily available in hospitals. In addition, samples may be unclottable at therapeutic levels, making quantitative assays unsuitable. dTT, also known as the commercially available Hemoclot, is not as sensitive as TT, allowing for it to be used to measure the anticoagulant activity of dabigatran. Finally, ECT has a linear relationship and strong correlation with plasma dabigatran concentrations (30). dTT and ECT can accurately identify therapeutic and supratherapeutic levels. In the research setting, laboratory tests are available to evaluate patients with severe bleeding associated with dabigatran use and monitor the use of idarucizumab. However, these laboratory assays are not routinely available in the clinical setting (31). CLINICAL TRIALS RE-VERSE AD included two distinct groups: patients in group A had uncontrollable or life-threatening bleeding; group B included patients who required an urgent surgery or invasive procedure that could not be delayed for $8 h. The primary endpoint was the maximum percentage reversal of the effects of dabigatran from the time of completion of the initial infusion to any time within 4 h after the second infusion of idarucizumab as assessed by ECT. The median maximum percentage reversal was deemed to be 100% (95% CI 100–100) in both groups. However, this endpoint could not be assessed in 22% of patients in group A and in 28% of patients in group B because baseline coagulation assays were normal. Reversal of dTT was seen in 93% of patients in group A and 98% of patients in group B, while ECT was normalized in 89% and 88% of patients, respectively. The plasma level of unbound dabigatran was near or below the lower limit of quantification (20 ng/mL) in all but one patient after the completion of the first infusion and remained near this level at 24 h in 79% of patients. The median time to cessation of bleeding was 11.4 h. In group A, assessment of hemostasis was only performed in 69% of patients. Patients in group B had normal intraoperative hemostasis in 92% of cases. It is important to note that in group B, 10% of patients received their last dose of dabigatran >48 h earlier. Overall, there were 18 deaths (9 in each group), with five patients experiencing a thrombotic
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event (i.e., 3 venous thromboembolisms, 1 myocardial infarction, and 1 ischemic stroke) (24). CLINICAL CONSIDERATIONS There are several important unanswered questions that arise with the use of idarucizumab. There is currently not a routinely available coagulation assay to detect the presence of dabigatran. ECT and dTT are not routinely used outside of the research setting. In the clinical environment, aPTT and TT are currently the best available options for detecting the presence of dabigatran and possibly idarucizumab response; however, these data were not used for the study and at best remain surrogate endpoints (32). While a rapid reversal of coagulation assays was demonstrated in the RE-VERSE AD trial, the pharmacodynamic effects were markedly delayed in the patients with life-threatening bleeding compared to the pharmacokinetic effects, because the median time to cessation of bleeding was 11.4 h. With a rapid reversal of these coagulation parameters, one would expect a corresponding rapid cessation of bleeding. The patients requiring urgent procedures did not experience abnormal intraoperative bleeding. Mild or moderate abnormal bleeding was observed in only 8% of patients. The effectiveness of idarucizumab might vary in its ability to cause cessation versus prevention of bleeding. While the argument can be made that clinically relevant endpoints have been demonstrated in the RE-VERSE AD trial, the question then becomes with only 30% of anticipated enrollment and 17% of patients having a nearly undetectable unbound dabigatran level (<20 ng/mL) at baseline, can we rely upon the endpoints seen in this interim analysis? The normalization of these coagulation parameters may not correlate with cessation of bleeding but may identify that dabigatran is no longer propagating its anticoagulation effects. There is a lack of evidence that shows a reduction of dabigatran concentrations already bound to thrombin. Dabigatran exhibits highly selective, rapid, yet reversible binding to thrombin; however, the duration of dabigatran’s ability to bind thrombin is unknown. If dabigatran demonstrates an on-off phenomenon, reversal will occur. If dabigatran is bound for an extended duration, idarucizumab will not reverse the activity of drug already bound to thrombin. This may account for the delay in bleeding cessation observed in the RE-VERSE AD trial. After the administration of idarucizumab, a redistribution phenomenon can occur in which re-elevations of dabigatran concentrations have been noted, producing an average total serum concentration, or total drug burden, of roughly 500 ng/mL (250–2000 ng/mL). This re-elevation is theorized to be caused by the redistribution of extravascular dabigatran into the intravascular compartment. It is un-
certain whether patients with such a response would benefit from an additional dose of idarucizumab. Perhaps the use of aPTT could guide this clinical scenario, because a patient with re-elevation of aPTT and continued bleeding may be an ideal candidate for an additional dose of idarucizumab. Currently, this has not been specifically studied and remains an unknown area, because the patient may only require an additional 2.5-g infusion. Another interesting question is the role of blood products in the RE-VERSE AD trial—most notably, fresh frozen plasma and factor-based products. Fresh frozen plasma was used in 25.5% of patients, while activated prothrombin complex concentrate was used in four patients (24). While exclusion of these products from the study may not have been appropriate because they are considered life-saving therapies by many clinicians, it does raise some interesting clinical questions. While there is little doubt that idarucizumab specifically and robustly binds to dabigatran, the critical question is if the binding of dabigatran is responsible for cessation of bleeding in these patients. Perhaps factor supplementation is responsible for bleeding cessation while idarucizumab simply prevents further anticoagulant activity of dabigatran. This could offer a potential explanation for the rapid normalization of coagulation assays while bleeding continued. It is unclear if blood products, such as fresh frozen plasma, must be given in addition to idarucizumab or if monotherapy with idarucizumab would suffice. A potential necessary role of idarucizumab may be in the setting of toxic ingestion of dabigatran. The dose of idarucizumab used in the RE-VERSE AD trial was calculated to reverse the effects of dabigatran measured from the 99th percentile in the Randomized Evaluation of Long-Term Anticoagulation Therapy trial (24). Two patients in group B had plasma concentrations of total dabigatran of >1000 ng/mL, with one being defined as a toxic ingestion. At 4 h after the second infusion, two patients still had high concentrations of 848 ng/mL and 1510 ng/mL, respectively. The authors did note that dialysis was prevented in the patient who presented with a toxic ingestion. It is unclear, however, if the patient also received activated charcoal, a therapy that may be effective in dabigatran ingestion. While another dose of idarucizumab was not administered to these patients, there is potential that this could be a strategy applied in the clinical setting for these patients. When comparing the therapeutic concentrations of dabigatran studied to the potential concentrations that may be produced by a toxic ingestion, the therapeutic concentrations may appear miniscule. If current dosing is recommended to reverse in an equiosmolar fashion roughly 200% of therapeutic concentrations, does this signify the need for additional or higher dosing in those patients with exponentially
Idarucizumab for Reversal of Dabigatran-Associated Bleeding
larger exposures (28)? For these circumstances, a dose to drug neutralization equation would be useful, similar to that seen with other monoclonal agents, such as digoxin-specific antibody (33). Finally, the requirement or even ability to use extracorporeal elimination requires additional analysis. While complex duration is significant, staying bound for up to 260 h, elimination may be significantly delayed in the event of acute renal failure. However, the molecular weight of this agent may preclude its elimination via most dialysis modalities, given that the molecular weight threshold of some filters peak at 15,000 Da. Knowledge of filter capacity would therefore be important, because super high flux membranes have cutoffs closer to 65,000 Da (34). Institutions lacking these higher capacity filters may consider plasmapheresis modalities, because this extends molecular weight capabilities well above that of idarucizumab (970,000 Da) and therefore may be an extracorporeal option in the event that it is required (35). Additional research will be required in this arena to provide further insight into therapeutic options. A substantial number of questions still circulate around the best use of idarucizumab—and its efficacy, for that matter. With the absence of data to support displacement of dabigatran from its molecular binding site, no evidence currently supports the conclusion that idarucizumab as monotherapy is capable of reversing the anticoagulation effects of dabigatran. While idarucizumab consistently showed a profound reduction in unbound dabigatran concentrations, as the literature stands this agent may be more appropriately referred to as a neutralizing agent—calling it a reversal agent may in fact be a misnomer. This is substantiated by the delay in time to cessation of bleeding in relation to the decline in unbound serum concentrations observed in the REVERSE AD trial. Once more, this calls into question the true impact of product supplementation used in this trial. In theory, if idarucizumab is only capable of neutralizing unbound drug, removing free drug from circulation, potentially a multimodal approach would be optimal. Supplementing thrombin in these patients may replace thrombin rendered ineffective by dabigatran, thereby hastening hemostasis. The lack of the RE-VERSE AD trial authors reporting differences in time to bleeding cessation with regard to blood products unfortunately prevents this analysis from being performed. While this would still result in idarucizumab providing a therapeutic benefit, it may prove to be a component of a multiple agent reversal strategy as opposed to the misleading reversal agent terminology label it currently carries. If this is the case, the potential false sense of security associated with idarucizumab as monotherapy must be dispelled. The potential widespread use of idarucizumab may help elucidate many of these questions (24).
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CONCLUSION While many questions about the use of idarucizumab remain unanswered, the initial data suggest a definite role of this agent for treatment of bleeding associated with dabigatran. As more clinical experience is gained with the agent and the remaining data on its use are released, a more specific role for idarucizumab may be carved out. At present, there is not enough evidence for idarucizumab to be used as monotherapy. It is important moving forward as a medical profession that these new agents fast-tracked through the approval process are critically and continually evaluated until many years of practice can help dictate their use.
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6 15. Pragst I, Zeitler SH, Doerr B, et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (beriplex P/N) in a rabbit model. J Thromb Haemost 2012;10:1841–8. 16. Perzborn E, Gruber A, Tinel H, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost 2013;110:162–72. 17. Martin AC, Le Bonniec B, Fischer AM, et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol 2013;168:4228–33. 18. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573–9. 19. Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108:217–24. 20. Khoo TL, Weatherburn C, Kershaw G, Reddel CJ, Curnow J, Dunkley S. The use of FEIBA(R) in the correction of coagulation abnormalities induced by dabigatran. Int J Lab Hematol 2013;35: 222–4. 21. Korber MK, Langer E, Ziemer S, Perzborn E, Gericke C, Heymann C. Measurement and reversal of prophylactic and therapeutic peak levels of rivaroxaban: an in vitro study. Clin Appl Thromb Hemost 2014;20:735–40. 22. Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013;109: 596–605. 23. Parasrampuria DA, Marbury T, Matsushima N, et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost 2015; 113:719–27. 24. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511–20.
L. Miller et al. 25. Pollack CV Jr, Reilly PA, Bernstein R, et al. Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost 2015;114:198–205. 26. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121: 3554–62. 27. Das A, Liu D. Novel antidotes for target specific oral anticoagulants. Exp Hematol Oncol 2015;4:25. 28. Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: A randomised, placebo-controlled, double-blind phase 1 trial. Lancet 2015;386: 680–90. 29. Okubo K, Kuwahara T, Takagi K, et al. Relation between dabigatran concentration, as assessed using the direct thrombin inhibitor assay, and activated clotting time/activated partial thromboplastin time in patients with atrial fibrillation. Am J Cardiol 2015;115:1696–9. 30. Hawes EM, Deal AM, Funk-Adcock D, et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a crosssectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 2013;11:1493–502. 31. Alikhan R, Rayment R, Keeling D, et al. The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran. Emerg Med J 2014;31:163–8. 32. Dager WE, Gosselin RC, Kitchen S, Dwyre D. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother 2012;46:1627–36. 33. Chan BS, Buckley NA. Digoxin-specific antibody fragments in the treatment of digoxin toxicity. Clin Toxicol (Phila) 2014;52:824–36. 34. Karkar A. Advances in hemodialysis techniques. In: Carpi A, Donadio C, Tramonti G, eds. Progress in hemodialysis—from emergent biotechnology to clinical practice. Rijeka, Croatia: InTech; 2013:409–38. 35. Ward DM. Conventional apheresis therapies: a review. J Clin Apher 2011;26:230–8.
Idarucizumab for Reversal of Dabigatran-Associated Bleeding
ARTICLE SUMMARY 1. Why is this topic important? The rapid incorporation of novel oral anticoagulants into general practice has heightened the demand for directed reversal agents. Idarucizumab is a humanized monoclonal antibody fragment that was recently approved for the urgent reversal of the anticoagulant effects of dabigatran. 2. What does this review attempt to show? This review seeks to evaluate the role of idarucizumab in the care of critically ill or bleeding patients addressing important questions pertaining to the use of this agent. 3. What are the key findings? While many questions remain unanswered with the use of idarucizumab, the initial data suggest a definite role of this agent for treatment of bleeding associated with dabigatran. 4. How is patient care impacted? As more clinical experience is gained with the agent and the remaining data on its use are released, clinicians will be able to appropriately use idarucizumab for dabigatran-associated bleeding.
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