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Paul A Reilly - One of the best experts on this subject based on the ideXlab platform.
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Dabigatran Reversal With Idarucizumab in Patients With Renal Impairment
Journal of the American College of Cardiology, 2019Co-Authors: John W Eikelboom, Paul A Reilly, Elaine M. Hylek, Joanne Van Ryn, Amelie Elsaesser, Stephan Glund, Charles V. Pollack, Jeffrey I. WeitzAbstract:Abstract Background Dabigatran and idarucizumab, its reversal agent, are renally cleared. Objectives The purpose of this study was to determine the extent of reversal and outcomes according to baseline renal function in Dabigatran-treated nondialysis patients receiving idarucizumab. Methods In 503 patients in RE-VERSE AD (Reversal of Effects of Idarucizumab in Patients on Active Dabigatran), the extent of Dabigatran reversal and clinical outcomes were compared according to baseline renal function (creatinine clearance: normal ≥80, mild 50 to Results Compared with patients with normal renal function, those with impaired renal function were older, were more often women, and had lower body mass indexes, more comorbidities, higher CHADS2 scores, and higher Dabigatran plasma levels despite more frequent use of lower-dose Dabigatran regimens. Regardless of renal function, median reversal measured by dilute thrombin time was 100% within 4 h of idarucizumab administration, and over 98% of patients achieved this with corresponding undetectable levels of unbound Dabigatran. By 12 or 24 h, 56% of patients with severe, 29.1% with moderate, and 9.2% with mild renal impairment had Dabigatran levels >20 ng/ml compared with 8.3% of patients with normal renal function at baseline. Time to cessation of bleeding and the proportion with normal hemostasis with procedures were similar regardless of renal function, but patients with severe renal impairment had higher 30- and 90-day mortality rates. Conclusions Idarucizumab completely reverses Dabigatran in >98% of patients regardless of renal function. Although re-elevation of Dabigatran levels within 12 to 24 h is more common with renal impairment, the time to bleeding cessation and the extent of hemostasis during procedures are similar. (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab; NCT02104947 )
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Idarucizumab for Dabigatran overdose.
Clinical toxicology (Philadelphia Pa.), 2016Co-Authors: Marijke Peetermans, Jeffrey I. Weitz, Paul A Reilly, Jerrold H. Levy, Charles V. Pollack, Marc Jacquemin, Laurens Liesenborghs, Peter VerhammeAbstract:AbstractContext: An overdose of oral anticoagulants represents a challenging scenario for emergency physicians. Dabigatran, an oral direct thrombin inhibitor, is increasingly used in place of warfarin. The lack of an antidote is a concern in patients who overdose on Dabigatran, even though the drug can be eliminated with hemodialysis. Idarucizumab is an antibody fragment that binds Dabigatran with high affinity. It reverses the anticoagulant effect of Dabigatran within minutes and is approved for the reversal of Dabigatran during emergency situations.Case details: We describe the use of idarucizumab in the management of a 68-year-old woman who was taking Dabigatran 150 mg twice daily and ingested 125 capsules. Despite gastric lavage and administration of activated charcoal within two hours of drug intake, the activated partial thromboplastin time (aPTT) and prothrombin time (PT) remained prolonged. The administration of 5 g of intravenous idarucizumab promptly and completely reversed the anticoagulant act...
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Letter to the Editor: Managing Dabigatran-Related Bleeding
Journal of intensive care medicine, 2015Co-Authors: Jerrold H. Levy, Jeffrey I. Weitz, Paul A Reilly, John W Eikelboom, Richard A. Bernstein, Elaine M. Hylek, Menno V. Huisman, Thorsten Steiner, Pieter W. Kamphuisen, Chak Wah KamAbstract:Kumar et al report their experience (n 1⁄4 7) and present a thoughtful set of recommendations for managing lifethreatening, Dabigatran-associated hemorrhage. Randomized trials have shown the overall frequency of bleeding complications with Dabigatran and warfarin to be similar, although intracranial bleeding events are lower with Dabigatran. Furthermore, all anticoagulants have the potential to cause bleeding, and the benefit-to-risk profile of each agent needs to be considered when making treatment decisions. The authors state that ‘‘there is no quick method to assess plasma Dabigatran activity or a specific antidote for its reversal.’’ As members of the study leadership for the Reversal of Active Dabigatran (RE-VERSE AD) study, we would like to make several comments. First, the thrombin clotting time (TCT) and activated partial thromboplastin time (aPTT) provide qualitative measures of the anticoagulant activity of Dabigatran, whereas the dilute thrombin time and chromogenic ecarin assay with Dabigatran calibrators can be used for quantitative assessment of Dabigatran concentrations in plasma. These tests, together with information about the timing of the last dose and current renal function, can be helpful to determine the expected duration of anticoagulation in Dabigatran-treated patients who require urgent surgery or interventions. Completely normal aPTT or TCT provides reassurance that very little anticoagulant activity attributable to Dabigatran is in effect. Likewise, in Dabigatran-treated patients who present with serious bleeding, the potential contribution of Dabigatran to the bleeding can be assessed by considering coagulation assay values, renal status, and time since last dose. Second, the authors point out that there is no specific antidote for Dabigatran. However, idarucizumab, a monoclonal antibody fragment against Dabigatran, has been developed and shown to completely reverse Dabigatran effects in healthy volunteers, and a study evaluating its utility for reversal of the anticoagulant effects of Dabigatran in patients with serious bleeding or in those requiring urgent surgery is currently underway (clinicaltrials.gov NCT02104947). Idarucizumab almost instantaneously shortens the clotting times in animals and healthy human volunteers treated with Dabigatran. We believe that the availability of an effective antidote will enhance the safety profile of Dabigatran, as its use expands into new indications besides stroke prevention in nonvalvular atrial fibrillation, such as treatment of venous thromboembolism. Third, until idarucizumab is available for clinical use, it is important to point out that repletion strategies, such as recombinant factor VIIa and prothrombin complex concentrate (PCC), which are suggested by Kumar and colleagues, as well as fresh frozen plasma, have not been definitively shown to be of benefit in managing Dabigatran-associated bleeding. Nonetheless, because PCC reduces Dabigatran-induced bleeding in various animal models, it can be considered in patients with life-threatening hemorrhage. Finally, we wish to point out that despite logistical challenges, hemodialysis is an effective method for reducing plasma concentrations of Dabigatran. Until the results of the RE-VERSE AD study are known, our best guidance for the evaluation and management of
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Dabigatran etexilate and reduction in serum apolipoprotein B
Heart (British Cardiac Society), 2015Co-Authors: Philip Joseph, John W Eikelboom, Lars Wallentin, Michael D Ezekowitz, Salim Yusuf, Stuart J Connolly, Jia Wang, Guillaume Paré, Agneta Siegbahn, Paul A ReillyAbstract:Objective Carboxylesterases, which convert Dabigatran etexilate to its active form, Dabigatran, have also been shown to influence lipoprotein metabolism, although any pleotropic effects of the drug based on this possible mechanism has not been evaluated. We examined the effects of Dabigatran etexilate on serum lipoprotein markers in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study. Methods 2513 participants from the RE-LY randomised control trial with baseline and 3-month apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) measurements were included. We prospectively compared the effects of Dabigatran 110 mg twice daily, Dabigatran 150 mg twice daily and warfarin on changes in ApoB and ApoA1 concentrations using a mixed model analysis. Results From baseline to 3 months, a significant reduction in ApoB concentration was observed with low-dose Dabigatran (−0.057 (95% CI −0.069 to −0.044) g/L, p Conclusions Dabigatran is associated with a significant (∼7%) reduction in ApoB concentration, suggesting a novel effect of this drug on lipoprotein metabolism. Further studies are needed to determine the mechanism of this observed effect, and its impact on clinical outcomes.
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decrease in the oral bioavailability of Dabigatran etexilate after co medication with rifampicin
British Journal of Clinical Pharmacology, 2012Co-Authors: S Hartter, Michael Koenenbergmann, Ashish Sharma, Gerhard Nehmiz, Ute Lemke, Wolfgang Timmer, Paul A ReillyAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Dabigatran etexilate is an oral prodrug that is rapidly converted to Dabigatran, a direct and reversible thrombin inhibitor. • Dabigatran etexilate and Dabigatran are not metabolized by the cytochrome P450 system, and Dabigatran does not affect the metabolism of other drugs that utilize this system, leading to a low potential for drug–drug interactions. • Dabigatran etexilate, but not Dabigatran, is a P-glycoprotein (P-gp) substrate, and the bioavailability of Dabigatran may be altered by P-gp inhibitors or inducers. WHAT THIS STUDY ADDS • Administration of rifampicin (a strong P-gp inducer) for 7 days before a single dose of Dabigatran etexilate resulted in a significant reduction in the bioavailability of Dabigatran compared with administration of Dabigatran etexilate alone. • Within 7 days following the cessation of rifampicin administration, the bioavailability of Dabigatran returned almost to baseline values. • Rifampicin is not recommended for use with Dabigatran etexilate because of the potential for reduced systemic exposure to Dabigatran. AIMS This study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of Dabigatran following oral administration of the prodrug, Dabigatran etexilate. METHODS This was an open-label, fixed-sequence, four-period study in healthy volunteers. Subjects received a single dose of Dabigatran etexilate 150 mg on day 1, rifampicin 600 mg once daily on days 2–8, and single doses of Dabigatran etexilate on days 9, 16 and 23. RESULTS Twenty-four subjects were treated, of whom 22 received all treatments. Relative to the reference (single dose of Dabigatran etexilate alone; treatment A), administration of Dabigatran etexilate following 7 days of rifampicin (treatment B) decreased the geometric mean (gMean) area under the concentration–time curve (AUC0–∞) and maximal plasma concentration (Cmax) of total Dabigatran by 67 and 65.5%, respectively. The time to peak and the terminal half-life were not affected. The gMean ratio for the primary comparison (treatment B vs. treatment A) was 33.0% (90% confidence interval 26.5, 41.2%) for AUC0–∞ and 34.5% (90% confidence interval 26.9, 44.1%) for Cmax, indicating a significant effect on total Dabigatran exposure (total pharmacologically active Dabigatran represents the sum of nonconjugated Dabigatran and Dabigatran glucuronide). After a 7 day (treatment C) or 14 day washout (treatment D), the AUC0–∞ and Cmax of Dabigatran were reduced by 18 and 20%, and by 15 and 20%, respectively, compared with treatment A, which was considered not clinically relevant. The overall safety profile of all treatments was good. CONCLUSIONS Administration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of Dabigatran, which returned almost to baseline after 7 days washout.
Jeffrey I. Weitz - One of the best experts on this subject based on the ideXlab platform.
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Dabigatran Reversal With Idarucizumab in Patients With Renal Impairment
Journal of the American College of Cardiology, 2019Co-Authors: John W Eikelboom, Paul A Reilly, Elaine M. Hylek, Joanne Van Ryn, Amelie Elsaesser, Stephan Glund, Charles V. Pollack, Jeffrey I. WeitzAbstract:Abstract Background Dabigatran and idarucizumab, its reversal agent, are renally cleared. Objectives The purpose of this study was to determine the extent of reversal and outcomes according to baseline renal function in Dabigatran-treated nondialysis patients receiving idarucizumab. Methods In 503 patients in RE-VERSE AD (Reversal of Effects of Idarucizumab in Patients on Active Dabigatran), the extent of Dabigatran reversal and clinical outcomes were compared according to baseline renal function (creatinine clearance: normal ≥80, mild 50 to Results Compared with patients with normal renal function, those with impaired renal function were older, were more often women, and had lower body mass indexes, more comorbidities, higher CHADS2 scores, and higher Dabigatran plasma levels despite more frequent use of lower-dose Dabigatran regimens. Regardless of renal function, median reversal measured by dilute thrombin time was 100% within 4 h of idarucizumab administration, and over 98% of patients achieved this with corresponding undetectable levels of unbound Dabigatran. By 12 or 24 h, 56% of patients with severe, 29.1% with moderate, and 9.2% with mild renal impairment had Dabigatran levels >20 ng/ml compared with 8.3% of patients with normal renal function at baseline. Time to cessation of bleeding and the proportion with normal hemostasis with procedures were similar regardless of renal function, but patients with severe renal impairment had higher 30- and 90-day mortality rates. Conclusions Idarucizumab completely reverses Dabigatran in >98% of patients regardless of renal function. Although re-elevation of Dabigatran levels within 12 to 24 h is more common with renal impairment, the time to bleeding cessation and the extent of hemostasis during procedures are similar. (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab; NCT02104947 )
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Idarucizumab for Dabigatran overdose.
Clinical toxicology (Philadelphia Pa.), 2016Co-Authors: Marijke Peetermans, Jeffrey I. Weitz, Paul A Reilly, Jerrold H. Levy, Charles V. Pollack, Marc Jacquemin, Laurens Liesenborghs, Peter VerhammeAbstract:AbstractContext: An overdose of oral anticoagulants represents a challenging scenario for emergency physicians. Dabigatran, an oral direct thrombin inhibitor, is increasingly used in place of warfarin. The lack of an antidote is a concern in patients who overdose on Dabigatran, even though the drug can be eliminated with hemodialysis. Idarucizumab is an antibody fragment that binds Dabigatran with high affinity. It reverses the anticoagulant effect of Dabigatran within minutes and is approved for the reversal of Dabigatran during emergency situations.Case details: We describe the use of idarucizumab in the management of a 68-year-old woman who was taking Dabigatran 150 mg twice daily and ingested 125 capsules. Despite gastric lavage and administration of activated charcoal within two hours of drug intake, the activated partial thromboplastin time (aPTT) and prothrombin time (PT) remained prolonged. The administration of 5 g of intravenous idarucizumab promptly and completely reversed the anticoagulant act...
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Letter to the Editor: Managing Dabigatran-Related Bleeding
Journal of intensive care medicine, 2015Co-Authors: Jerrold H. Levy, Jeffrey I. Weitz, Paul A Reilly, John W Eikelboom, Richard A. Bernstein, Elaine M. Hylek, Menno V. Huisman, Thorsten Steiner, Pieter W. Kamphuisen, Chak Wah KamAbstract:Kumar et al report their experience (n 1⁄4 7) and present a thoughtful set of recommendations for managing lifethreatening, Dabigatran-associated hemorrhage. Randomized trials have shown the overall frequency of bleeding complications with Dabigatran and warfarin to be similar, although intracranial bleeding events are lower with Dabigatran. Furthermore, all anticoagulants have the potential to cause bleeding, and the benefit-to-risk profile of each agent needs to be considered when making treatment decisions. The authors state that ‘‘there is no quick method to assess plasma Dabigatran activity or a specific antidote for its reversal.’’ As members of the study leadership for the Reversal of Active Dabigatran (RE-VERSE AD) study, we would like to make several comments. First, the thrombin clotting time (TCT) and activated partial thromboplastin time (aPTT) provide qualitative measures of the anticoagulant activity of Dabigatran, whereas the dilute thrombin time and chromogenic ecarin assay with Dabigatran calibrators can be used for quantitative assessment of Dabigatran concentrations in plasma. These tests, together with information about the timing of the last dose and current renal function, can be helpful to determine the expected duration of anticoagulation in Dabigatran-treated patients who require urgent surgery or interventions. Completely normal aPTT or TCT provides reassurance that very little anticoagulant activity attributable to Dabigatran is in effect. Likewise, in Dabigatran-treated patients who present with serious bleeding, the potential contribution of Dabigatran to the bleeding can be assessed by considering coagulation assay values, renal status, and time since last dose. Second, the authors point out that there is no specific antidote for Dabigatran. However, idarucizumab, a monoclonal antibody fragment against Dabigatran, has been developed and shown to completely reverse Dabigatran effects in healthy volunteers, and a study evaluating its utility for reversal of the anticoagulant effects of Dabigatran in patients with serious bleeding or in those requiring urgent surgery is currently underway (clinicaltrials.gov NCT02104947). Idarucizumab almost instantaneously shortens the clotting times in animals and healthy human volunteers treated with Dabigatran. We believe that the availability of an effective antidote will enhance the safety profile of Dabigatran, as its use expands into new indications besides stroke prevention in nonvalvular atrial fibrillation, such as treatment of venous thromboembolism. Third, until idarucizumab is available for clinical use, it is important to point out that repletion strategies, such as recombinant factor VIIa and prothrombin complex concentrate (PCC), which are suggested by Kumar and colleagues, as well as fresh frozen plasma, have not been definitively shown to be of benefit in managing Dabigatran-associated bleeding. Nonetheless, because PCC reduces Dabigatran-induced bleeding in various animal models, it can be considered in patients with life-threatening hemorrhage. Finally, we wish to point out that despite logistical challenges, hemodialysis is an effective method for reducing plasma concentrations of Dabigatran. Until the results of the RE-VERSE AD study are known, our best guidance for the evaluation and management of
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Only high levels of Dabigatran attenuate catheter thrombosis in vitro and in rabbits
Thrombosis and haemostasis, 2014Co-Authors: Jonathan W. Yau, Peng Liao, James C. Fredenburgh, Robin S Roberts, Jeffrey I. WeitzAbstract:In patients with mechanical heart valves, thromboembolic events were more frequent with Dabigatran, an oral thrombin inhibitor, than with warfarin. This observation raises the possibility that Dabigatran may be less effective than conventional anticoagulants in patients with other blood-contacting devices, such as catheters. To address this, we compared the capacity of Dabigatran and/or heparin to inhibit catheter-induced thrombin generation in vitro and to attenuate catheter occlusion in rabbits. Using a catheter-induced thrombin generation assay, concentrations of Dabigatran over 100 ng/ml prolonged the lag time and time to peak thrombin, and reduced the peak thrombin concentration and endogenous thrombin potential in a concentration-dependent fashion. Compared with saline in a rabbit model of catheter thrombosis, Dabigatran prolonged the mean time to catheter occlusion by 2.9– and 1.9-fold when plasma levels were 173 and 140 ng/ml, respectively; values comparable to median peak levels in humans given Dabigatran 150 mg twice daily. In contrast, low-dose Dabigatran, which produced a level of 60 ng/ml; a value comparable to the trough level of Dabigatran in humans, did not prolong the time to occlusion. Whereas a 70 U/kg bolus of heparin prolonged the mean time to occlusion by 3.4-fold, a 15 U/kg bolus had no effect. When low-dose Dabigatran was given in combination with 15 U/kg heparin, the mean time to occlusion was prolonged by 2.7-fold. These findings suggest that only peak levels of Dabigatran are sufficient to prevent catheter-induced clotting unless supplemented heparin is given.
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Dabigatran monitoring made simple
Thrombosis and haemostasis, 2013Co-Authors: J. W. Eikelboom, Jeffrey I. WeitzAbstract:Haemost 2013; 110: 308-315. Dabigatran, an oral thrombin inhibitor, is licensed as an alternative to warfarin for stroke prevention in patients with atrial fibrillation. As the first of the new oral anticoagulants (NOACs) to gain approval for this indication, its use is increasing now that its safety has been confirmed using real-world data (1, 2), and clinical guidelines have given preference to NOACs over warfarin for stroke prevention in patients with atrial fibrillation (3-5). Although Dabigatran was designed to be given in fixed doses without monitoring, there are situations where assessment of its anticoagulant activity can be helpful (6). For example, detection of little or no Dabigatran activity in plasma may identify patients who can safely undergo surgery, or receive thrombolytic therapy for management of acute ischaemic stroke. Conversely, excessive anticoagulant activity may indicate Dabigatran accumulation in patients with deteriorating renal function, or may influence therapy in those with serious bleeding; common concerns in everyday clinical practice (6, 7). These scenarios highlight the need for simple, rapid and widely available monitoring tests for Dabigatran. How can the anticoagulant activity of Dabigatran be assessed? Dabigatran prolongs the activated partial thromboplastin time (aPTT) more than the prothrombin time (▶ Table 1). Although the effect of Dabigatran on the aPTT is concentrationdependent, the aPTT begins to plateau with plasma Dabigatran concentrations above 200 ng/ml (8-12). The thrombin time is very sensitive to Dabigatran and even low concentrations of Dabigatran produce a marked prolongation in the thrombin time. Dilution of the plasma prior to thrombin time determination renders the test less sensitive to Dabigatran. The Hemoclot assay capitalises on this phenomenon; to perform this test, patient plasma is diluted eight-fold prior to thrombin time determination (13). The plasma Dabigatran concentration is then calculated by reference to a standard curve constructed using Dabigatran calibrators. Although the test is rapid and simple, the Hemoclot assay is only available in specialised coagulation laboratories, and the test is not licensed for patient use in the United States. The ecarin clotting time can also be used to determine plasma Dabigatran concentrations, but this test is even less widely available than the Hemoclot assay. How do these coagulation tests perform in the real world setting? This is the focus of the study by Hapgood et al. (14) in a recent issue of Thrombosis and Haemostasis. These investigators used the Hemoclot assay to determine drug concentrations in 75 plasma samples collected from 45 patients taking Dabigatran. Dabigatran levels were then correlated with the aPTT, which was performed with four different reagents. Using linear regression analysis, they determined the aPTT range with each reagent that corresponded to Dabigatran levels of 90 to 180 ng/ml; the range that the authors designated as therapeutic for Dabigatran. The thrombin time also was correlated with Dabigatran concentrations. Dabigatran concentrations over 60 ng/ml were associated with marked prolongation of the thrombin time; a finding that highlights the responsiveness of this test to Dabigatran. Although the study design is straightforward, do plasma concentrations of 90 to 180 ng/ml really represent the therapeutic range for Dabigatran? As outlined by the authors, these values reflect the median trough and peak concentrations of Dabigatran determined in subjects given the drug at a dose of 150 mg twice daily (15). However, the corresponding values in those taking 110 mg twice daily -the Dabigatran dose used in at least 50% of patients in most countries -are about 65 and 130 ng/ml, respectively (16). Furthermore, even if the median trough and peak levels with the 150 mg dose of Dabigatran are 90 and 180 ng/ml, respectively, this means that half of the patients will have Dabigatran levels lower or higher than these values at trough and peak, respectively; findings that will complicate interpretation of aPTT results calibrated to this range. Therefore, 90 to 180 ng/ml cannot be considered the therapeutic range for Dabigatran. What can we learn from this study? The authors show that the aPTT values obtained with Dabigatran concentrations ranging from 90 to 180 ng/ml differ with each of the aPTT reagents examined; a finding consistent with previous reports that aPTT reagents vary in their responsiveness to the anticoagulant effects of Dabigatran (9-12). In addition to confirming this finding in samples collected from patients taking Dabigatran, the results of this study suggest that each laboratory will need to determine the sensitivity of its aPTT reagent to Dabigatran; a process analogous to determining the aPTT range that corresponds to therapeutic anti-Xa levels for heparin whenever the aPTT reagent lot number changes. It is uncertain whether
John W Eikelboom - One of the best experts on this subject based on the ideXlab platform.
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Dabigatran Reversal With Idarucizumab in Patients With Renal Impairment
Journal of the American College of Cardiology, 2019Co-Authors: John W Eikelboom, Paul A Reilly, Elaine M. Hylek, Joanne Van Ryn, Amelie Elsaesser, Stephan Glund, Charles V. Pollack, Jeffrey I. WeitzAbstract:Abstract Background Dabigatran and idarucizumab, its reversal agent, are renally cleared. Objectives The purpose of this study was to determine the extent of reversal and outcomes according to baseline renal function in Dabigatran-treated nondialysis patients receiving idarucizumab. Methods In 503 patients in RE-VERSE AD (Reversal of Effects of Idarucizumab in Patients on Active Dabigatran), the extent of Dabigatran reversal and clinical outcomes were compared according to baseline renal function (creatinine clearance: normal ≥80, mild 50 to Results Compared with patients with normal renal function, those with impaired renal function were older, were more often women, and had lower body mass indexes, more comorbidities, higher CHADS2 scores, and higher Dabigatran plasma levels despite more frequent use of lower-dose Dabigatran regimens. Regardless of renal function, median reversal measured by dilute thrombin time was 100% within 4 h of idarucizumab administration, and over 98% of patients achieved this with corresponding undetectable levels of unbound Dabigatran. By 12 or 24 h, 56% of patients with severe, 29.1% with moderate, and 9.2% with mild renal impairment had Dabigatran levels >20 ng/ml compared with 8.3% of patients with normal renal function at baseline. Time to cessation of bleeding and the proportion with normal hemostasis with procedures were similar regardless of renal function, but patients with severe renal impairment had higher 30- and 90-day mortality rates. Conclusions Idarucizumab completely reverses Dabigatran in >98% of patients regardless of renal function. Although re-elevation of Dabigatran levels within 12 to 24 h is more common with renal impairment, the time to bleeding cessation and the extent of hemostasis during procedures are similar. (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab; NCT02104947 )
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Letter to the Editor: Managing Dabigatran-Related Bleeding
Journal of intensive care medicine, 2015Co-Authors: Jerrold H. Levy, Jeffrey I. Weitz, Paul A Reilly, John W Eikelboom, Richard A. Bernstein, Elaine M. Hylek, Menno V. Huisman, Thorsten Steiner, Pieter W. Kamphuisen, Chak Wah KamAbstract:Kumar et al report their experience (n 1⁄4 7) and present a thoughtful set of recommendations for managing lifethreatening, Dabigatran-associated hemorrhage. Randomized trials have shown the overall frequency of bleeding complications with Dabigatran and warfarin to be similar, although intracranial bleeding events are lower with Dabigatran. Furthermore, all anticoagulants have the potential to cause bleeding, and the benefit-to-risk profile of each agent needs to be considered when making treatment decisions. The authors state that ‘‘there is no quick method to assess plasma Dabigatran activity or a specific antidote for its reversal.’’ As members of the study leadership for the Reversal of Active Dabigatran (RE-VERSE AD) study, we would like to make several comments. First, the thrombin clotting time (TCT) and activated partial thromboplastin time (aPTT) provide qualitative measures of the anticoagulant activity of Dabigatran, whereas the dilute thrombin time and chromogenic ecarin assay with Dabigatran calibrators can be used for quantitative assessment of Dabigatran concentrations in plasma. These tests, together with information about the timing of the last dose and current renal function, can be helpful to determine the expected duration of anticoagulation in Dabigatran-treated patients who require urgent surgery or interventions. Completely normal aPTT or TCT provides reassurance that very little anticoagulant activity attributable to Dabigatran is in effect. Likewise, in Dabigatran-treated patients who present with serious bleeding, the potential contribution of Dabigatran to the bleeding can be assessed by considering coagulation assay values, renal status, and time since last dose. Second, the authors point out that there is no specific antidote for Dabigatran. However, idarucizumab, a monoclonal antibody fragment against Dabigatran, has been developed and shown to completely reverse Dabigatran effects in healthy volunteers, and a study evaluating its utility for reversal of the anticoagulant effects of Dabigatran in patients with serious bleeding or in those requiring urgent surgery is currently underway (clinicaltrials.gov NCT02104947). Idarucizumab almost instantaneously shortens the clotting times in animals and healthy human volunteers treated with Dabigatran. We believe that the availability of an effective antidote will enhance the safety profile of Dabigatran, as its use expands into new indications besides stroke prevention in nonvalvular atrial fibrillation, such as treatment of venous thromboembolism. Third, until idarucizumab is available for clinical use, it is important to point out that repletion strategies, such as recombinant factor VIIa and prothrombin complex concentrate (PCC), which are suggested by Kumar and colleagues, as well as fresh frozen plasma, have not been definitively shown to be of benefit in managing Dabigatran-associated bleeding. Nonetheless, because PCC reduces Dabigatran-induced bleeding in various animal models, it can be considered in patients with life-threatening hemorrhage. Finally, we wish to point out that despite logistical challenges, hemodialysis is an effective method for reducing plasma concentrations of Dabigatran. Until the results of the RE-VERSE AD study are known, our best guidance for the evaluation and management of
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Dabigatran etexilate and reduction in serum apolipoprotein B
Heart (British Cardiac Society), 2015Co-Authors: Philip Joseph, John W Eikelboom, Lars Wallentin, Michael D Ezekowitz, Salim Yusuf, Stuart J Connolly, Jia Wang, Guillaume Paré, Agneta Siegbahn, Paul A ReillyAbstract:Objective Carboxylesterases, which convert Dabigatran etexilate to its active form, Dabigatran, have also been shown to influence lipoprotein metabolism, although any pleotropic effects of the drug based on this possible mechanism has not been evaluated. We examined the effects of Dabigatran etexilate on serum lipoprotein markers in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study. Methods 2513 participants from the RE-LY randomised control trial with baseline and 3-month apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) measurements were included. We prospectively compared the effects of Dabigatran 110 mg twice daily, Dabigatran 150 mg twice daily and warfarin on changes in ApoB and ApoA1 concentrations using a mixed model analysis. Results From baseline to 3 months, a significant reduction in ApoB concentration was observed with low-dose Dabigatran (−0.057 (95% CI −0.069 to −0.044) g/L, p Conclusions Dabigatran is associated with a significant (∼7%) reduction in ApoB concentration, suggesting a novel effect of this drug on lipoprotein metabolism. Further studies are needed to determine the mechanism of this observed effect, and its impact on clinical outcomes.
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periprocedural bleeding and thromboembolic events with Dabigatran compared with warfarin results from the randomized evaluation of long term anticoagulation therapy re ly randomized trial
Circulation, 2012Co-Authors: Jeff S Healey, John W Eikelboom, James D Douketis, Lars Wallentin, Jonas Oldgren, Sean Yang, Ellison Themeles, Hein Heidbuchel, Alvaro Avezum, Paul A ReillyAbstract:BACKGROUND: Dabigatran reduces ischemic stroke in comparison with warfarin; however, given the lack of antidote, there is concern that it might increase bleeding when surgery or invasive procedures are required. METHODS AND RESULTS: The current analysis was undertaken to compare the periprocedural bleeding risk of patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial treated with Dabigatran and warfarin. Bleeding rates were evaluated from 7 days before until 30 days after invasive procedures, considering only the first procedure for each patient. A total of 4591 patients underwent at least 1 invasive procedure: 24.7% of patients received Dabigatran 110 mg, 25.4% received Dabigatran 150 mg, and 25.9% received warfarin, P=0.34. Procedures included: pacemaker/defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy (8.6%), and joint replacement (6.2%). Among patients assigned to either Dabigatran dose, the last dose of study drug was given 49 (35-85) hours before the procedure on comparison with 114 (87-144) hours in patients receiving warfarin, P<0.001. There was no significant difference in the rates of periprocedural major bleeding between patients receiving Dabigatran 110 mg (3.8%) or Dabigatran 150 mg (5.1%) or warfarin (4.6%); Dabigatran 110 mg versus warfarin: relative risk, 0.83; 95% CI, 0.59 to 1.17; P=0.28; Dabigatran 150 mg versus warfarin: relative risk, 1.09; 95% CI, 0.80 to 1.49; P=0.58. Among patients having urgent surgery, major bleeding occurred in 17.8% with Dabigatran 110 mg, 17.7% with Dabigatran 150 mg, and 21.6% with warfarin: Dabigatran 110 mg; relative risk, 0.82; 95% CI, 0.48 to 1.41; P=0.47; Dabigatran 150 mg: relative risk, 0.82; 95% CI, 0.50 to 1.35; P=0.44. CONCLUSIONS: Dabigatran and warfarin were associated with similar rates of periprocedural bleeding, including patients having urgent surgery. Dabigatran facilitated a shorter interruption of oral anticoagulation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.
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myocardial ischemic events in patients with atrial fibrillation treated with Dabigatran or warfarin in the re ly randomized evaluation of long term anticoagulation therapy trial
Circulation, 2012Co-Authors: Stefan H Hohnloser, Paul A Reilly, John W Eikelboom, Lars Wallentin, Jonas Oldgren, Sean Yang, Michael D Ezekowitz, Martina Brueckmann, Salim Yusuf, Stuart J ConnollyAbstract:Background—There is a modest risk of myocardial infarction (MI) and myocardial ischemic events in patients with atrial fibrillation. Methods and Results—Data from the RE-LY study (Randomized Evaluation of Long-Term Anticoagulation Therapy) were used to report rates of MI, unstable angina, cardiac arrest, and cardiac death and the prespecified net clinical benefit and treatment effects of Dabigatran versus warfarin. MI occurred at annual rates of 0.82% and 0.81% with Dabigatran 110 or 150 mg BID compared with 0.64% with warfarin (hazard ratio [HR] 1.29, 95% confidence interval [CI] 0.96–1.75, P=0.09 for Dabigatran 110 mg; HR 1.27, 95% CI 0.94–1.71, P=0.12 for Dabigatran 150 mg). Annual rates of a composite of MI, unstable angina, cardiac arrest, and cardiac death were 3.16% per year with Dabigatran 110 mg, 3.33% per year with Dabigatran 150 mg, and 3.41% per year with warfarin (HR versus warfarin 0.93, 95% CI 0.80–1.06, P=0.28 for Dabigatran 110 mg and HR 0.98, 95% CI 0.85–1.12, P=0.77 for Dabigatran 150 m...
Gregory Y H Lip - One of the best experts on this subject based on the ideXlab platform.
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bleeding events among new starters and switchers to Dabigatran compared with warfarin in atrial fibrillation
The American Journal of Medicine, 2014Co-Authors: Torben Larsen, Lars Hvilsted Rasmussen, Flemming Skjoth, Mary Rosenzweig, Gregory Y H Lip, Anders GorstrasmussenAbstract:Abstract Background The bleeding risk among patients with atrial fibrillation is higher early after initiating therapy with vitamin K antagonists (VKAs). Evidence is limited on how prior VKA experience affects bleeding risk when initiating novel oral anticoagulant therapy. We investigated this among patients with atrial fibrillation initiating Dabigatran therapy. Methods By using nationwide Danish prescription and patient registries, we identified 11,315 first-time Dabigatran users with atrial fibrillation. Warfarin controls were matched in a 2:1 ratio according to VKA experience status. The average follow-up time was 13 months. Across the 6 combinations of treatment (Dabigatran 110 mg, Dabigatran 150 mg, and warfarin) and VKA experience status (naive or experienced), VKA-naive warfarin initiators had the highest rate of any bleeding event. Cox regressions adjusted for baseline characteristics showed reductions relative to this group ranging from 19% for VKA-experienced Dabigatran 110 mg users (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.66-1.00) to 41% for VKA-experienced Dabigatran 150 mg users (HR, 0.59; 95% CI, 0.46-0.75). Among switchers to Dabigatran from warfarin, when comparing with warfarin-persisting users, the rate of any bleeding was nonsignificantly decreased for switchers to Dabigatran 150 mg (HR, 0.80; 95% CI, 0.62-1.03) but not for switchers to Dabigatran 110 mg (HR, 1.12; 95% CI, 0.90-1.41). Results for major bleeding were similar. Crude rates of fatal, intracranial, and gastrointestinal bleeding were low. Conclusions VKA-naive warfarin initiators had the highest overall bleeding rate. We found no evidence of marked excess of overall bleeding events when comparing Dabigatran with warfarin users, irrespective of prior VKA experience.
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efficacy and safety of Dabigatran etexilate and warfarin in real world patients with atrial fibrillation a prospective nationwide cohort study
Journal of the American College of Cardiology, 2013Co-Authors: Torben Larsen, Lars Hvilsted Rasmussen, Flemming Skjoth, Karen Margrete Due, Torbjorn Callreus, Mary Rosenzweig, Gregory Y H LipAbstract:Objectives The aim of this study was to assess the efficacy and safety in an “everyday clinical practice” population of anticoagulant-naive patients with atrial fibrillation (AF) treated with Dabigatran etexilate after its post-approval availability in Denmark, compared with warfarin. Background Concerns have been raised about an excess of bleeding events or myocardial infarction (MI) among patients treated with the new oral direct thrombin inhibitor, Dabigatran etexilate. Methods From the Danish Registry of Medicinal Product Statistics, we identified a Dabigatran-treated group and a 1:2 propensity-matched warfarin-treated group of 4,978 and 8,936, respectively. Comparisons on efficacy and safety outcomes were made on the basis of Cox-proportional hazards models stratified on propensity-matched groups. Results Stroke and systemic embolism were not significantly different between warfarin- and Dabigatran-treated patients. Adjusted mortality was significantly lower with both Dabigatran doses (110 mg b.i.d., propensity-match group stratified hazard ratio [aHR]: 0.79, 95% confidence interval [CI]: 0.65 to 0.95; 150 mg b.i.d., aHR: 0.57, 95% CI: 0.40 to 0.80), when compared with warfarin. Pulmonary embolism was lower compared with warfarin for both doses of Dabigatran. Less intracranial bleeding was seen with both Dabigatran doses (110 mg b.i.d., aHR: 0.24, 95% CI: 0.08 to 0.56; 150 mg b.i.d., aHR: 0.08, 95% CI: 0.01 to 0.40). The incidence of MI was lower with both Dabigatran doses (110 mg b.i.d., aHR: 0.30, 95% CI: 0.18 to 0.49; 150 mg b.i.d., aHR: 0.40, 95% CI: 0.21 to 0.70). Gastrointestinal bleeding was lower with Dabigatran 110 mg b.i.d. (aHR: 0.60, 95% CI: 0.37 to 0.93) compared with warfarin but not Dabigatran 150 mg b.i.d. The main findings were broadly consistent in a subgroup analysis of Dabigatran users with ≥1-year follow-up (median follow-up 13.9 months [interquartile range: 12.6 to 15.3 months]). Conclusions In this “everyday clinical practice” post-approval nationwide clinical cohort, there were similar stroke/systemic embolism and major bleeding rates with Dabigatran (both doses) compared with warfarin. Mortality, intracranial bleeding, pulmonary embolism, and MI were lower with Dabigatran, compared with warfarin. We found no evidence of an excess of bleeding events or MI among Dabigatran-treated patients in this propensity-matched comparison against warfarin, even in the subgroup with ≥1-year follow-up.
Michael D Ezekowitz - One of the best experts on this subject based on the ideXlab platform.
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Dabigatran etexilate and reduction in serum apolipoprotein B
Heart (British Cardiac Society), 2015Co-Authors: Philip Joseph, John W Eikelboom, Lars Wallentin, Michael D Ezekowitz, Salim Yusuf, Stuart J Connolly, Jia Wang, Guillaume Paré, Agneta Siegbahn, Paul A ReillyAbstract:Objective Carboxylesterases, which convert Dabigatran etexilate to its active form, Dabigatran, have also been shown to influence lipoprotein metabolism, although any pleotropic effects of the drug based on this possible mechanism has not been evaluated. We examined the effects of Dabigatran etexilate on serum lipoprotein markers in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study. Methods 2513 participants from the RE-LY randomised control trial with baseline and 3-month apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) measurements were included. We prospectively compared the effects of Dabigatran 110 mg twice daily, Dabigatran 150 mg twice daily and warfarin on changes in ApoB and ApoA1 concentrations using a mixed model analysis. Results From baseline to 3 months, a significant reduction in ApoB concentration was observed with low-dose Dabigatran (−0.057 (95% CI −0.069 to −0.044) g/L, p Conclusions Dabigatran is associated with a significant (∼7%) reduction in ApoB concentration, suggesting a novel effect of this drug on lipoprotein metabolism. Further studies are needed to determine the mechanism of this observed effect, and its impact on clinical outcomes.
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intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or Dabigatran the re ly trial
Stroke, 2012Co-Authors: Robert G Hart, Paul A Reilly, Lars Wallentin, Sean Yang, Michael D Ezekowitz, Stuart J Connolly, Hanschristoph Diener, Salim YusufAbstract:Background and Purpose—Intracranial hemorrhage is the most devastating complication of anticoagulation. Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus Dabigatran have not been defined. Methods—Analysis of 18 113 participants with atrial fibrillation in the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial assigned to adjusted-dose warfarin (target international normalized ratio, 2–3) or Dabigatran (150 mg or 110 mg, both twice daily). Results—During a mean of 2.0 years of follow-up, 154 intracranial hemorrhages occurred in 153 participants: 46% intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The rates of intracranial hemorrhage were 0.76%, 0.31%, and 0.23% per year among those assigned to warfarin, Dabigatran 150 mg, and Dabigatran 110 mg, respectively (P<0.001 for either Dabigatran dose versus warfarin). Fewer fatal intracranial hemorrhages occurred among those assigned Dabigatran 150 ...
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myocardial ischemic events in patients with atrial fibrillation treated with Dabigatran or warfarin in the re ly randomized evaluation of long term anticoagulation therapy trial
Circulation, 2012Co-Authors: Stefan H Hohnloser, Paul A Reilly, John W Eikelboom, Lars Wallentin, Jonas Oldgren, Sean Yang, Michael D Ezekowitz, Martina Brueckmann, Salim Yusuf, Stuart J ConnollyAbstract:Background—There is a modest risk of myocardial infarction (MI) and myocardial ischemic events in patients with atrial fibrillation. Methods and Results—Data from the RE-LY study (Randomized Evaluation of Long-Term Anticoagulation Therapy) were used to report rates of MI, unstable angina, cardiac arrest, and cardiac death and the prespecified net clinical benefit and treatment effects of Dabigatran versus warfarin. MI occurred at annual rates of 0.82% and 0.81% with Dabigatran 110 or 150 mg BID compared with 0.64% with warfarin (hazard ratio [HR] 1.29, 95% confidence interval [CI] 0.96–1.75, P=0.09 for Dabigatran 110 mg; HR 1.27, 95% CI 0.94–1.71, P=0.12 for Dabigatran 150 mg). Annual rates of a composite of MI, unstable angina, cardiac arrest, and cardiac death were 3.16% per year with Dabigatran 110 mg, 3.33% per year with Dabigatran 150 mg, and 3.41% per year with warfarin (HR versus warfarin 0.93, 95% CI 0.80–1.06, P=0.28 for Dabigatran 110 mg and HR 0.98, 95% CI 0.85–1.12, P=0.77 for Dabigatran 150 m...
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Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke a subgroup analysis of the re ly trial
Lancet Neurology, 2010Co-Authors: Hanschristoph Diener, Paul A Reilly, Lars Wallentin, Sean Yang, Michael D Ezekowitz, Stuart J Connolly, Denis Xavier, Giuseppe Di Pasquale, Salim YusufAbstract:Summary Background In the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, Dabigatran reduced occurrence of both stroke and haemorrhage compared with warfarin in patients who had atrial fibrillation and were at increased risk of stroke. We aimed to assess the effects of Dabigatran compared with warfarin in the subgroup of patients with previous stroke or transient ischaemic attack. Methods In the RE-LY trial, 18 113 patients from 967 centres in 44 countries were randomly assigned to 110 mg or 150 mg Dabigatran twice daily or to warfarin dose adjusted to international normalised ratio 2·0 to 3·0. Median follow-up was 2·0 years (IQR 1·14–2·86), and the primary outcome was stroke or systemic embolism. The primary safety outcome was major haemorrhage. Patients and investigators were aware of whether patients received warfarin or Dabigatran, but not of Dabigatran dose, and event adjudicators were masked to treatment. In a predefined analysis, we investigated the outcomes of the RE-LY trial in subgroups of patients with or without previous stroke or transient ischaemic attack. RE-LY is registered with ClinicalTrials.gov, NCT00262600. Findings Within the subgroup of patients with previous stroke or transient ischaemic attack, 1195 patients were from the 110 mg Dabigatran group, 1233 from the 150 mg Dabigatran group, and 1195 from the warfarin group. Stroke or systemic embolism occurred in 65 patients (2·78% per year) on warfarin compared with 55 (2·32% per year) on 110 mg Dabigatran (relative risk 0·84, 95% CI 0·58–1·20) and 51 (2·07% per year) on 150 mg Dabigatran (0·75, 0·52–1·08). The rate of major bleeding was significantly lower in patients on 110 mg Dabigatran (RR 0·66, 95% CI 0·48–0·90) and similar in those on 150 mg Dabigatran (RR 1·01; 95% CI 0·77–1·34) compared with those on warfarin. The effects of both doses of Dabigatran compared with warfarin were not significantly different between patients with previous stroke or transient ischaemic attack and those without for any of the outcomes from RE-LY apart from vascular death (110 mg group compared with warfarin group, interaction p=0·038). Interpretation The effects of 110 mg Dabigatran and 150 mg Dabigatran twice daily in patients with previous stroke or transient ischaemic attack are consistent with those of other patients in RE-LY, for whom, compared with warfarin, 150 mg Dabigatran reduced stroke or systemic embolism and 110 mg Dabigatran was non-inferior. Funding Boehringer Ingelheim.
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Dabigatran versus warfarin in patients with atrial fibrillation
The New England Journal of Medicine, 2009Co-Authors: Stuart J Connolly, Paul A Reilly, John W Eikelboom, Jonas Oldgren, Ellison Themeles, Michael D Ezekowitz, Amit Parekh, Janice Pogue, Jeanne Varrone, Susan WangAbstract:Background Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. Methods In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of Dabigatran — 110 mg or 150 mg twice daily — or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. Results Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of Dabigatran (relative risk with Dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of Dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of Dabigatran (P = 0.003) and 3.11% per year in the group receiving 150 mg of Dabigatran (P = 0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of Dabigatran (P<0.001) and 0.10% per year with 150 mg of Dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of Dabigatran (P = 0.13) and 3.64% per year with 150 mg of Dabigatran (P = 0.051). Conclusions In patients with atrial fibrillation, Dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)
