Rangadham Nagarakanti

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

Common atrial fibrillation risk alleles at 4q25 predict recurrence after catheter-based atrial fibrillation ablation

BACKGROUND Common single nucleotide polymorphisms at chromosome 4q25 (rs2200733, rs10033464) are associated with both lone and typical atrial fibrillation (AF). Risk alleles at 4q25 have recently been shown to predict recurrence of AF after ablation in a population of predominately lone AF, but lone AF represents only 5%-30% of AF cases. OBJECTIVE To test the hypothesis that 4q25 AF risk alleles can predict response to AF ablation in the majority of AF cases. METHODS Patients enrolled in the Vanderbilt AF Registry underwent 378 catheter-based AF ablations (median age 60 years; 71% men; 89% typical AF) between 2004 and 2011. The primary end point was time to recurrence of any nonsinus atrial tachyarrhythmia (atrial tachycardia, atrial flutter, or AF). RESULTS Two-hundred atrial tachycardia, atrial flutter, or AF recurrences (53%) were observed. In multivariable analysis, the rs2200733 risk allele predicted a 24% shorter recurrence-free time (survival time ratio 0.76; 95% confidence interval [CI] 0.6-0.95; P = .016) compared with wild type. The heterozygous haplotype demonstrated a 21% shorter recurrence-free time (survival time ratio 0.79; 95% CI 0.62-0.99) and the homozygous risk allele carriers a 39% shorter recurrence-free time (survival time ratio 0.61; 95% CI 0.37-1.0; P = .037). CONCLUSIONS Risk alleles at the 4q25 loci predict impaired clinical response to AF ablation in a population of patients with predominately typical AF. Our findings suggest that the rs2200733 polymorphism may hold promise as an objectively measured patient characteristic that can be used as a clinical tool for selecting patients for AF ablation.

Comparison of Dabigatran and Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy).

Background: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. Methods: This is a post hoc analysis of the RE-LY trial. Results: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16–1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88–1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56–0.95 with VHD; HR, 0.84; 95% CI, 0.71–0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64–1.06) or without VHD (HR, 0.98; 95% CI, 0.83–1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37–0.93) and those without VHD (HR, 0.67; 95% CI, 0.52–0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65–1.45; and HR, 0.88; 95% CI, 0.70–1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. Conclusions: The presence of any VHD did not influence the comparison of dabigatran with warfarin. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.Background: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. Methods: This is a post hoc analysis of the RE-LY trial. Results: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16–1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88–1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56–0.95 with VHD; HR, 0.84; 95% CI, 0.71–0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64–1.06) or without VHD (HR, 0.98; 95% CI, 0.83–1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37–0.93) and those without VHD (HR, 0.67; 95% CI, 0.52–0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65–1.45; and HR, 0.88; 95% CI, 0.70–1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. Conclusions: The presence of any VHD did not influence the comparison of dabigatran with warfarin. Clinical Trial Registration: URL: . Unique identifier: [NCT00262600][1]. # Clinical Perspective {#article-title-14} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00262600&atom=%2Fcirculationaha%2F134%2F8%2F589.atom

Relation of morbid obesity and female gender to risk of procedural complications in patients undergoing atrial fibrillation ablation.

Obese patients with atrial fibrillation (AF) are frequently treated with AF ablation. We sought to examine whether a body mass index (BMI) threshold exists beyond which the odds of experiencing a complication from AF ablation increases. All patients enrolled in the Vanderbilt AF Registry who underwent catheter-based AF ablation from May 1999 to February 2012 were included. Major complications were recorded. Morbid obesity was defined as a BMI >40 kg/m(2) and examined in multivariable analysis. A total of 35 complications (6.8%) occurred in 512 ablations. Morbidly obese patients experienced a greater rate of complications (6 of 42, 14.3%) than the nonmorbidly obese (29 of 470, 6.2%; p = 0.046). Using a discrete BMI cutoff, the odds of complications increased 3.1-fold in those with morbid obesity (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.1 to 8.4, p = 0.03) and 2.1-fold for female gender (OR 2.1, 95% CI 1.04 to 4.38, p = 0.04). With BMI as a continuous variable, the odds of complications increased by 5% per 1 unit increase in BMI (OR 1.05, 95% CI 1.0 to 1.11, p = 0.05), and the increase for female gender was 2.2-fold (OR 2.2, 95% CI 1.1 to 4.6, p = 0.03). In conclusion, morbid obesity represents a BMI threshold above which the odds of complications with AF ablation increase significantly. The increase in complications appears to be driven primarily by events in women, suggesting that morbidly obese women are a special population when considering AF ablation.

COMPARISON OF DABIGATRAN VERSUS WARFARIN IN PATIENTS WITH ATRIAL FIBRILLATION AND VALVULAR HEART DISEASE: THE RE-LY® TRIAL

Patients with valvular heart disease (VHD) were allowed into the RE-LY® trial if their VHD was considered unlikely to result in an intervention before study completion or if prosthetic heart valves or hemodynamically-significant mitral stenosis was present. The aim of this analysis was to compare

Dabigatran in Clinical Practice

BACKGROUND Stroke and systemic thromboembolism remain critical causes of mortality and morbidity in patients with paroxysmal or persistent atrial fibrillation. Dabigatran etexilate is a novel oral direct thrombin inhibitor, which provides stroke risk reduction for patients with nonvalvular atrial fibrillation. Randomized clinical data demonstrate dabigatran to be an alternative oral anticoagulant with an improved efficacy profile compared with oral warfarin dose adjusted to an INR (international normalized ratio) target of 2.0 to 3.0. OBJECTIVES Our aim was to review the pharmacology, mechanism of action, drug metabolism, and clinical trial data supporting dabigatran use. METHODS We reviewed all the major published clinical studies of dabigatran and analyzed data regarding practical applications in selected clinical scenarios. RESULTS This review provides recommendations for clinicians regarding dosing during invasive surgical procedures, transitioning off alternative anticoagulants, and a discussion of storage and handling of the drug. CONCLUSIONS Our effort should facilitate the safe and effective use of dabigatran in atrial fibrillation.

The future of implantable defibrillator and cardiac resynchronization therapy trials

Implantable cardioverter defibrillator (ICD) trials were initially limited to survivors of sudden death. The focus of defibrillator trials in the last decade has been in prophylactic implantation of the device in high risk populations for the prevention of sudden cardiac death. It is the contention in this review that the new focus for implantable defibrillator trials in 2008 and beyond will be on more selective and focused use of this therapy. This could be achieved by selecting ICD patients based on their pathophysiologic and genetic risk. Increasing effort will also be placed on using the device for prevention of spontaneous malignant ventricular tachyarrhythmias and the index clinical sudden death event. Finally, implantable defibrillators will be used in combination in a “hybrid” therapy approach. ICDs will be increasingly combined either with ventricular tachycardia ablation or ventricular fibrillation ablation using catheter techniques. With the addition of cardiac resynchronization therapy in these devices, new clinical trials that use cardiac resynchronization therapy as an early intervention in specific high risk heart failure populations and refinement of the CRT technique to improved optimal results are in progress. Finally, combining ICD devices and regenerative medicine approaches to myocardial replacement therapy are being explored.

Comparison of Dabigatran and Warfarin in Patients With Atrial Fibrillation and Valvular Heart DiseaseClinical Perspective

Background: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. Methods: This is a post hoc analysis of the RE-LY trial. Results: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16–1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88–1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56–0.95 with VHD; HR, 0.84; 95% CI, 0.71–0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64–1.06) or without VHD (HR, 0.98; 95% CI, 0.83–1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37–0.93) and those without VHD (HR, 0.67; 95% CI, 0.52–0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65–1.45; and HR, 0.88; 95% CI, 0.70–1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. Conclusions: The presence of any VHD did not influence the comparison of dabigatran with warfarin. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.Background: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. Methods: This is a post hoc analysis of the RE-LY trial. Results: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16–1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88–1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56–0.95 with VHD; HR, 0.84; 95% CI, 0.71–0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64–1.06) or without VHD (HR, 0.98; 95% CI, 0.83–1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37–0.93) and those without VHD (HR, 0.67; 95% CI, 0.52–0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65–1.45; and HR, 0.88; 95% CI, 0.70–1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. Conclusions: The presence of any VHD did not influence the comparison of dabigatran with warfarin. Clinical Trial Registration: URL: . Unique identifier: [NCT00262600][1]. # Clinical Perspective {#article-title-14} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00262600&atom=%2Fcirculationaha%2F134%2F8%2F589.atom

Comparison of Dabigatran and Warfarin in Patients With Atrial Fibrillation and Valvular Heart DiseaseClinical Perspective: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy)

Background: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. Methods: This is a post hoc analysis of the RE-LY trial. Results: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16–1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88–1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56–0.95 with VHD; HR, 0.84; 95% CI, 0.71–0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64–1.06) or without VHD (HR, 0.98; 95% CI, 0.83–1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37–0.93) and those without VHD (HR, 0.67; 95% CI, 0.52–0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65–1.45; and HR, 0.88; 95% CI, 0.70–1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. Conclusions: The presence of any VHD did not influence the comparison of dabigatran with warfarin. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.Background: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. Methods: This is a post hoc analysis of the RE-LY trial. Results: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16–1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88–1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56–0.95 with VHD; HR, 0.84; 95% CI, 0.71–0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64–1.06) or without VHD (HR, 0.98; 95% CI, 0.83–1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37–0.93) and those without VHD (HR, 0.67; 95% CI, 0.52–0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65–1.45; and HR, 0.88; 95% CI, 0.70–1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. Conclusions: The presence of any VHD did not influence the comparison of dabigatran with warfarin. Clinical Trial Registration: URL: . Unique identifier: [NCT00262600][1]. # Clinical Perspective {#article-title-14} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00262600&atom=%2Fcirculationaha%2F134%2F8%2F589.atom

ATRIAL FIBRILLATION “BURDEN” RATHER THAN A SINGLE ARRHYTHMIA RECURRENCE IDENTIFIES RISK OF ADVERSE CARDIOVASCULAR EVENTS ON ANTIARRHYTHMIC DRUGS: FURTHER INSIGHTS FROM THE AFFIRM TRIAL

The relationship between atrial fibrillation (AF) recurrences & major cardiovascular events is unclear. We quantitated electrocardiographic burden (“burden”) of recurrent AF in the rhythm control arm of the AFFIRM trial. We examined cardiovascular hospitalizations(CVH) & death (D), based on