Amit Parekh

Dabigatran versus Warfarin in Patients with Atrial Fibrillation

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.)

Dabigatran Versus Warfarin in Patients With Atrial Fibrillation An Analysis of Patients Undergoing Cardioversion

Background— The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial compared dabigatran 110 mg BID (D110) and 150 mg BID (D150) with warfarin for stroke prevention in 18 113 patients with nonvalvular atrial fibrillation. Methods and Results— Cardioversion on randomized treatment was permitted. Precardioversion transesophageal echocardiography was encouraged, particularly in dabigatran-assigned patients. Data from before, during, and 30 days after cardioversion were analyzed. A total of 1983 cardioversions were performed in 1270 patients: 647, 672, and 664 in the D110, D150, and warfarin groups, respectively. For D110, D150, and warfarin, transesophageal echocardiography was performed before 25.5%, 24.1%, and 13.3% of cardioversions, of which 1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous treatment with study drug for ≥3 weeks before cardioversion was lower in D110 (76.4%) and D150 (79.2%) compared with warfarin (85.5%; P<0.01 for both). Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6% (D110 versus warfarin, P=0.71; D150 versus warfarin, P=0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin, P=0.06; D150 versus warfarin, P=0.99). Conclusions— This study is the largest cardioversion experience to date and the first to evaluate a novel anticoagulant in this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00262600.Background– The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial compared dabigatran 110 mg BID (D110) and 150 mg BID (D150) with warfarin for stroke prevention in 18 113 patients with nonvalvular atrial fibrillation. Methods and Results– Cardioversion on randomized treatment was permitted. Precardioversion transesophageal echocardiography was encouraged, particularly in dabigatran-assigned patients. Data from before, during, and 30 days after cardioversion were analyzed. A total of 1983 cardioversions were performed in 1270 patients: 647, 672, and 664 in the D110, D150, and warfarin groups, respectively. For D110, D150, and warfarin, transesophageal echocardiography was performed before 25.5%, 24.1%, and 13.3% of cardioversions, of which 1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous treatment with study drug for ≥3 weeks before cardioversion was lower in D110 (76.4%) and D150 (79.2%) compared with warfarin (85.5%; P <0.01 for both). Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6% (D110 versus warfarin, P =0.71; D150 versus warfarin, P =0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin, P =0.06; D150 versus warfarin, P =0.99). Conclusions– This study is the largest cardioversion experience to date and the first to evaluate a novel anticoagulant in this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion. Clinical Trial Registration– URL: . Unique identifier: [NCT00262600][1]. # Clinical Perspective {#article-title-31} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00262600&atom=%2Fcirculationaha%2F123%2F2%2F131.atom

Rationale and design of RE-LY: Randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran

Vitamin K antagonists (VKAs) are effective for stroke prevention in patients with atrial fibrillation (AF) but are difficult to use. Dabigatran etexilate is a prodrug that is rapidly converted to the active direct thrombin inhibitor dabigatran. It is administered in a fixed dose without laboratory monitoring and is being compared with warfarin (international normalized ratio 2-3) in the RE-LY trial. Two doses of dabigatran (110 and 150 mg BID) are being evaluated. RE-LY is a phase 3, prospective, randomized, open-label multinational (44 countries) trial of patients with nonvalvular AF and at least 1 risk factor for stroke. Recruitment concluded with a total of 18,113 patients. Patients who were VKA-naive and experienced are included in balanced proportions. The primary outcome is stroke (including hemorrhagic) or systemic embolism. Safety outcomes are bleeding, liver function abnormalities, and other adverse events. Adjudication of end points is blinded to drug assignment. The trial is expected to accrue a minimum of 450 events with a minimum 1-year of follow-up. RE-LY is the largest AF stroke prevention trial yet undertaken. It is unique because it includes equal numbers of VKA-experienced and naive patients and evaluates 2 different dosages of dabigatran, which may allow tailoring of dosing to individual patient needs. The worldwide site distribution and broad range of stroke risk further increase the general applicability of the trial. Results are expected in 2009.

Dabigatran and Warfarin in Vitamin K Antagonist–Naive and –Experienced Cohorts With Atrial Fibrillation

Background— The comparison of anticoagulants dabigatran and warfarin might be most equitable in vitamin K antagonist (VKA)–naive patients. Methods and Results— Warfarin and 2 doses of dabigatran—110 mg BID (D110) and 150 mg BID (D150)—were compared in a balanced population of VKA-naive (≤62 days of lifetime VKA exposure, with 33% never prescribed a VKA) and VKA-experienced patients with atrial fibrillation (n=18 113). For VKA-naive and -experienced patients assigned warfarin, the time in therapeutic range (international normalized ratio 2.0 to 3.0) was 62% and 67%, respectively, and 61% and 66% for those never and ever prescribed a VKA. In VKA-naive patients, stroke and systemic embolism rates were 1.57%, 1.07%, and 1.69% per year for D110, D150, and warfarin, respectively. D110 was similar to warfarin (P=0.65); D150 was superior (P=0.005). Major bleeding rates were 3.11%, 3.34%, and 3.57% per year, respectively. D110 and D150 were similar to warfarin (P=0.19 and P=0.55). Intracranial bleeding rates were 0.19%, 0.33%, and 0.73% per year, respectively. D110 and D150 were lower than warfarin (P<0.001 and P=0.005). In VKA-experienced patients, stroke and systemic embolism rates were 1.51%, 1.15%, and 1.74% per year for D110, D150, and warfarin, respectively. D110 was similar to warfarin (P=0.32); D150 was superior (P=0.007). Major bleeding rates were 2.66%, 3.30%, and 3.57% per year, respectively. D110 was lower than warfarin (P=0.003); D150 was similar (P=0.41). Intracranial bleeding rates were 0.26%, 0.32%, and 0.79% per year, respectively. D110 and D150 were lower than warfarin (P<0.001 for both). Results were similar for patients never on a VKA. Conclusions— Previous VKA exposure does not influence the benefits of dabigatran at either dose compared with warfarin. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

Dabigatran Versus Warfarin in Patients With Atrial FibrillationClinical Perspective: An Analysis of Patients Undergoing Cardioversion

Background— The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial compared dabigatran 110 mg BID (D110) and 150 mg BID (D150) with warfarin for stroke prevention in 18 113 patients with nonvalvular atrial fibrillation. Methods and Results— Cardioversion on randomized treatment was permitted. Precardioversion transesophageal echocardiography was encouraged, particularly in dabigatran-assigned patients. Data from before, during, and 30 days after cardioversion were analyzed. A total of 1983 cardioversions were performed in 1270 patients: 647, 672, and 664 in the D110, D150, and warfarin groups, respectively. For D110, D150, and warfarin, transesophageal echocardiography was performed before 25.5%, 24.1%, and 13.3% of cardioversions, of which 1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous treatment with study drug for ≥3 weeks before cardioversion was lower in D110 (76.4%) and D150 (79.2%) compared with warfarin (85.5%; P<0.01 for both). Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6% (D110 versus warfarin, P=0.71; D150 versus warfarin, P=0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin, P=0.06; D150 versus warfarin, P=0.99). Conclusions— This study is the largest cardioversion experience to date and the first to evaluate a novel anticoagulant in this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00262600.Background– The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial compared dabigatran 110 mg BID (D110) and 150 mg BID (D150) with warfarin for stroke prevention in 18 113 patients with nonvalvular atrial fibrillation. Methods and Results– Cardioversion on randomized treatment was permitted. Precardioversion transesophageal echocardiography was encouraged, particularly in dabigatran-assigned patients. Data from before, during, and 30 days after cardioversion were analyzed. A total of 1983 cardioversions were performed in 1270 patients: 647, 672, and 664 in the D110, D150, and warfarin groups, respectively. For D110, D150, and warfarin, transesophageal echocardiography was performed before 25.5%, 24.1%, and 13.3% of cardioversions, of which 1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous treatment with study drug for ≥3 weeks before cardioversion was lower in D110 (76.4%) and D150 (79.2%) compared with warfarin (85.5%; P <0.01 for both). Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6% (D110 versus warfarin, P =0.71; D150 versus warfarin, P =0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin, P =0.06; D150 versus warfarin, P =0.99). Conclusions– This study is the largest cardioversion experience to date and the first to evaluate a novel anticoagulant in this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion. Clinical Trial Registration– URL: . Unique identifier: [NCT00262600][1]. # Clinical Perspective {#article-title-31} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00262600&atom=%2Fcirculationaha%2F123%2F2%2F131.atom

Dabigatran Versus Warfarin in Patients With Atrial FibrillationClinical Perspective

Background— The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial compared dabigatran 110 mg BID (D110) and 150 mg BID (D150) with warfarin for stroke prevention in 18 113 patients with nonvalvular atrial fibrillation. Methods and Results— Cardioversion on randomized treatment was permitted. Precardioversion transesophageal echocardiography was encouraged, particularly in dabigatran-assigned patients. Data from before, during, and 30 days after cardioversion were analyzed. A total of 1983 cardioversions were performed in 1270 patients: 647, 672, and 664 in the D110, D150, and warfarin groups, respectively. For D110, D150, and warfarin, transesophageal echocardiography was performed before 25.5%, 24.1%, and 13.3% of cardioversions, of which 1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous treatment with study drug for ≥3 weeks before cardioversion was lower in D110 (76.4%) and D150 (79.2%) compared with warfarin (85.5%; P<0.01 for both). Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6% (D110 versus warfarin, P=0.71; D150 versus warfarin, P=0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin, P=0.06; D150 versus warfarin, P=0.99). Conclusions— This study is the largest cardioversion experience to date and the first to evaluate a novel anticoagulant in this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00262600.Background– The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial compared dabigatran 110 mg BID (D110) and 150 mg BID (D150) with warfarin for stroke prevention in 18 113 patients with nonvalvular atrial fibrillation. Methods and Results– Cardioversion on randomized treatment was permitted. Precardioversion transesophageal echocardiography was encouraged, particularly in dabigatran-assigned patients. Data from before, during, and 30 days after cardioversion were analyzed. A total of 1983 cardioversions were performed in 1270 patients: 647, 672, and 664 in the D110, D150, and warfarin groups, respectively. For D110, D150, and warfarin, transesophageal echocardiography was performed before 25.5%, 24.1%, and 13.3% of cardioversions, of which 1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous treatment with study drug for ≥3 weeks before cardioversion was lower in D110 (76.4%) and D150 (79.2%) compared with warfarin (85.5%; P <0.01 for both). Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6% (D110 versus warfarin, P =0.71; D150 versus warfarin, P =0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin, P =0.06; D150 versus warfarin, P =0.99). Conclusions– This study is the largest cardioversion experience to date and the first to evaluate a novel anticoagulant in this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion. Clinical Trial Registration– URL: . Unique identifier: [NCT00262600][1]. # Clinical Perspective {#article-title-31} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00262600&atom=%2Fcirculationaha%2F123%2F2%2F131.atom

The Case of a Disappearing Left Atrial Appendage Thrombus

53-year-old female with atrial fibrillation underwent transesophageal echocardiography for a suspected cardiac source of a thromboembolic episode. A thrombus was identified in the left atrial appendage. During the transesophageal echocardiography, the thrombus disappeared, under direct visualization, from the left atrial appendage. Four hours later, the patient developed a stroke. We believe that this is the first case describing direct visualization of left atrial thrombus migration in the English-language literature. Sequential frames are shown in the Figure. The development of neurological symptoms 4 hours (rather than immediately) after visualized thrombus migration is of interest. The luminal diameter of the internal carotid artery is highly variable, but it is unlikely that a 21-cm thrombus entered the carotid artery system. We hypothesize that the observed clot migration was not the culprit event but that there were subsequent emboli, despite a therapeutic activated partial thromboplastin time level of intravenous unfractionated heparin, resulting in the stroke. Data from carotid artery stenting studies1,2 suggest that this time interval is somewhere in the range of a few minutes to a few hours, which is consistent with the time line of events seen in our patient.A 53-year-old female with atrial fibrillation underwent transesophageal echocardiography for a suspected cardiac source of a thromboembolic episode. A thrombus was identified in the left atrial appendage. During the transesophageal echocardiography, the thrombus disappeared, under direct visualization, from the left atrial appendage. Four hours later, the patient developed a stroke. We believe that this is the …