BACKGROUND: Dabigatran, an oral thrombin inhibitor, and rivaroxaban and apixaban, oral factor Xa inhibitors, have been found to be safe and effective in reducing stroke risk in patients with atrial fibrillation. We sought to compare the efficacy and safety of the 3 new agents based on data from their published warfarin-controlled randomized trials, using the method of adjusted indirect comparisons. METHODS AND RESULTS: We included findings from 44 535 patients enrolled in 3 trials of the efficacy of dabigatran (Randomized Evaluation of Long-Term Anticoagulation Therapy [RELY]), apixaban (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]), and rivaroxaban (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF]), each compared with warfarin. The primary efficacy end point was stroke or systemic embolism; the safety end point we studied was major hemorrhage. To address a lack of comparability between trial populations caused by the restriction of ROCKET-AF to high-risk patients, we conducted a subgroup analysis in patients with a CHADS(2) score >/=3. We found no statistically significant efficacy differences among the 3 drugs, although apixaban and dabigatran were numerically superior to rivaroxaban. Apixaban produced significantly fewer major hemorrhages than dabigatran and rivaroxaban. CONCLUSIONS: An indirect comparison of new anticoagulants based on existing trial data indicates that in patients with a CHADS(2) score >/=3 dabigatran 150 mg, apixaban 5 mg, and rivaroxaban 20 mg resulted in statistically similar rates of stroke and systemic embolism, but apixaban had a lower risk of major hemorrhage compared with dabigatran and rivaroxaban. Until head-to-head trials or large-scale observational studies that reflect routine use of these agents are available, such adjusted indirect comparisons based on trial data are one tool to guide initial therapeutic choices.

Aims Previous studies have suggested that upstream medical therapy to modulate the renin-angiotensin axis may facilitate left atrial remodelling and thereby prevent new-onset atrial fibrillation (AF). The purpose of this study was to evaluate the association between angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARB) on new-onset AF in a large cohort of patients with coronary artery disease (CAD).Methods and results This was a population-based study of 28 620 patients, from community-dwelling Medicare beneficiaries who had been hospitalized for acute myocardial infarction or coronary revascularization (1995–2004). All patients, 65 years and older, had a mean follow-up period of upto 3.8 ± 3.0 years. Patients with a history of AF before and during hospitalization were excluded.  We compared the incidence of new-onset AF between patients who were (N= 10 918) and were not (N= 17 702) prescribed ACEI and/or ARB within 1 month of hospital discharge following cardiac event. New-onset AF within 5 and 10 years was 39.1 and 61.1%, respectively, in patients who received ACEI/ARB, compared  34.9 and 53.6% in patients who did not receive them [unadjusted hazard ratio (HR): 1.16; 95% confidence interval (CI): 1.11, 1.21]. Multivariable analysis adjusting for patient- and hospital-related characteristics indicated that ACEI/ARB use independently had no impact on the risk of developing new-onset AF compared with non-users (adjusted HR: 0.99; 95% CI: 0.94, 1.04). Adjustment for propensity-score and health-seeking behaviours yielded nearly identical results.Conclusion Angiotensin converting enzyme inhibitor/ARB therapy initiated within 1 month after hospital discharge is not associated with a reduction in the risk of new-onset AF after myocardial infarction or coronary revascularization.

BACKGROUND: In the treatment of patients with refractory atrial fibrillation (AF), the safety and efficacy of atrioventricular nodal ablation (AVNA) versus pharmacotherapy alone remains unclear. Additionally, the impact of AVNA in patients with reduced systolic function is of growing interest. METHODS AND RESULTS: A total of 5 randomized or prospective trials were included for efficacy review (314 patients), 11 studies for effectiveness review (810 patients), and 47 studies for safety review (5632 patients). All-cause mortality was similar between AVNA and medical therapy (3.1% versus 3.3%; relative risk ratio, 1.05; 95% confidence interval [CI], 0.29-3.85). There was no significant difference in exercise duration or ejection fraction (EF) with AVNA relative to pharmacotherapy. In subgroup analysis, patients with baseline systolic dysfunction (116 patients; mean EF, 44%) showed significant relative improvement in EF after AVNA (+4% greater; 95% CI, 3.11-4.89). In pooled observational analysis, AVNA was also associated with significant improvement in EF only in patients with systolic dysfunction (+7.44%; 95% CI, 5.4-9.5). The incidence of procedure-related mortality (0.27%) and malignant arrhythmia (0.57%) was low. At mean follow-up of 26.5 months, the incidence of sudden cardiac death after AVNA was 2.1%. There was significant heterogeneity in quality-of-life scales used; compared with pharmacotherapy, AVNA was associated with significant improvement in several symptoms (palpitations, dyspnea). CONCLUSIONS: In the management of refractory AF, AVNA is associated with improvement in symptoms and quality of life, with a low incidence of procedure morbidity. In patients with reduced systolic function, AVNA demonstrates small but significantly improved echocardiographic outcomes relative to medical therapy alone.

SummaryBackground and objectives Although generally recommended in atrial fibrillation (AF) patients, the effectiveness and safety of oral anticoagulation in dialysis patients with AF is unknown.Design, setting, participants, & measurements We assembled a cohort of older hemodialysis patients who initiated dialysis without prior record of AF and who had prescription drug benefits through three state-administered programs. The index event was a first hospitalization with diagnosed AF; patients with any recorded prior warfarin use were excluded. Eligible patients survived >/=30 days from discharge, and new warfarin use was recorded from prescription records during that 30-day window. Propensity-matched warfarin users and nonusers were compared using Cox regression. Outcomes included ischemic stroke, hemorrhagic stroke, and mortality.Results Among 2313 patients with new AF who survived 30 days from discharge, 249 (10.8%) filled a prescription for warfarin. Comparing 237 warfarin users and 948 propensity-matched nonusers over 2287 person-years of follow-up, the occurrence of ischemic stroke was similar (HR = 0.92; 95% CI, 0.61 to 1.37), whereas warfarin users experienced twice the risk of hemorrhagic stroke (HR = 2.38; 95% CI, 1.15 to 4.96). The risks of stroke, gastrointestinal hemorrhage, and mortality did not differ between groups. As-treated analyses yielded similar findings, as did analyses restricted to patients with CHADS(2) scores >/=2.Conclusions Although we confirmed association between warfarin use and hemorrhagic stroke in dialysis patients with AF, we found no association between warfarin use and ischemic stroke. Adequately powered randomized trials are required to conclusively determine the risks and benefits of the studied warfarin indication in hemodialysis patients.

PURPOSE: The study investigated the determinants of warfarin use in patients with atrial fibrillation (AF). METHODS: We assembled a retrospective cohort of community-dwelling elderly patients (aged > or = 66 years) with AF using linked administrative databases. We identified the physicians responsible for the ambulatory care of these patients using physician service claims and compared patients who did and did not have an identifiable provider. For those patients with an identifiable provider, we assessed the association between patient, physician, and hospital factors and warfarin use. RESULTS: Our cohort consisted of 140,185 patients, of whom 116,200 (83%) had an identifiable cardiac provider. Patients without a provider were significantly more likely to have comorbid conditions that increase their risk of warfarin-associated bleeding. After adjustment for clinical factors, patients without a provider were significantly less likely to receive warfarin (odds ratio 0.37, 95% confidence interval: 0.36-0.38). Of patients with providers, 50,551 patients (43.5%) received warfarin within 180 days after hospital discharge. Warfarin use was positively associated with AF-associated stroke risk factors (eg, prior stroke, congestive heart failure) and negatively associated with warfarin-associated bleeding risk factors (eg, history of intracerebral hemorrhage). After controlling for patient and hospital factors, patients cared for by noncardiologist physicians with cardiology consultation were more likely to receive warfarin then patients treated in noncollaborative environments. CONCLUSIONS: Warfarin continues to be substantially underprescribed to patients who are at high risk for AF-associated cardioembolic stroke. Our findings highlight the need for targeted quality improvement interventions and suggest preferred models of AF care involving routine collaboration between cardiologists and other physicians.

OBJECTIVES: To quantify the influence of physicians' experiences of adverse events in patients with atrial fibrillation who were taking warfarin. DESIGN: Population based, matched pair before and after analysis. SETTING: Database study in Ontario, Canada. PARTICIPANTS: The physicians of patients with atrial fibrillation admitted to hospital for adverse events (major haemorrhage while taking warfarin and thromboembolic strokes while not taking warfarin). Pairs of other patients with atrial fibrillation treated by the same physicians were selected. MAIN OUTCOME MEASURES: Odds of receiving warfarin by matched pairs of a given physician's patients (one treated after and one treated before the event) were compared, with adjustment for stroke and bleeding risk factors that might also influence warfarin use. The odds of prescriptions for angiotensin converting enzyme (ACE) inhibitor before and after the event was assessed as a neutral control. RESULTS: For the 530 physicians who had a patient with an adverse bleeding event (exposure) and who treated other patients with atrial fibrillation during the 90 days before and the 90 days after the exposure, the odds of prescribing warfarin was 21% lower for patients after the exposure (adjusted odds ratio 0.79, 95% confidence interval 0.62 to 1.00). Greater reductions in warfarin prescribing were found in analyses with patients for whom more time had elapsed between the physician's exposure and the patient's treatment. There were no significant changes in warfarin prescribing after a physician had a patient who had a stroke while not on warfarin or in the prescribing of ACE inhibitors by physicians who had patients with either bleeding events or strokes. CONCLUSIONS: A physician's experience with bleeding events associated with warfarin can influence prescribing warfarin. Adverse events that are possibly associated with underuse of warfarin may not affect subsequent prescribing.

BACKGROUND: The AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) trial demonstrated that rate control and rhythm control strategies result in similar survival and quality of life for patients with atrial fibrillation (AF). Because of superior safety and lower cost, rate control is now the recommended strategy for the management of most elderly, high-risk AF patients. OBJECTIVE: To determine the extent to which the AFFIRM trial results have been adopted into actual practice. METHODS: We conducted a time-series analysis of 3 population-based cohorts of patients with AF who were 66 years of age or older in Pennsylvania and Ontario. We stratified patients in Ontario by socioeconomic status (SES) and examined changes in quarterly prescription rates for rate control and rhythm controlling medications as well as cardioversion procedures before and after publication of the AFFIRM trial. RESULTS: The publication of the AFFIRM trial resulted in statistically significant reductions in the use of rhythm controlling medications in all 3 cohorts (p < 0.01). The magnitude of these changes in the non-low SES Canadian cohort was approximately 1% per quarter and was greater than the magnitude observed in the other cohorts (p < 0.001). The use of cardioversion procedures also decreased in all study regions (p < 0.01). In contrast, AFFIRM publication was also associated with a small increase in the use of rate controlling medications in Canada (p < 0.01) but not in the US (p = 0.23). CONCLUSIONS: Publication of the AFFIRM trial resulted in small but statistically significant changes in the care of patients with AF.

OBJECTIVES: This study is a meta-analysis of prospective cohort studies comparing the impact of cardiac resynchronization therapy (CRT) for patients in atrial fibrillation (AF) and sinus rhythm (SR). BACKGROUND: Although close to one-third of advanced heart failure patients exhibit AF, the impact of CRT in this group remains unclear. METHODS: Prospective cohort studies comparing patients in normal SR and chronic AF treated with CRT were included. All studies reported death, New York Heart Association functional class, ejection fraction, 6-min walk test, and the Minnesota score or its equivalent as outcomes. Data sources included Ovid MEDLINE In-Process & Other Non-Indexed Citations, the Cochrane Central Register of Controlled Trials, the Database of Abstracts of Reviews of Effects, and the American College of Physicians Journal Club. RESULTS: Of 2,487 reports identified, 5 studies following a total of 1,164 patients were included. Both AF and SR patients benefited significantly from CRT. Mortality was not significantly different at 1 year (relative risk ratio: 1.57, 95% confidence interval [CI]: 0.87 to 2.81). The New York Heart Association functional class improved similarly for both groups (-0.90 for SR patients, -0.84 for AF patients). SR patients showed greater relative improvement in the 6-min walk test (11.6 m greater, 95% CI: 10.4 to 12.8 m) and the Minnesota score (3.9 points less, 95% CI: 3.4 to 4.5 points) than AF patients. AF patients, however, achieved a small but statistically significant greater change in ejection fraction (0.39% greater change in ejection fraction, 95% CI: 0.22% to 0.55%). CONCLUSIONS: Patients in AF show significant improvement after CRT, with similar or improved ejection fraction as SR patients, but smaller benefits in regard to functional outcomes.

BACKGROUND: CYP2C9 and VKORC1 genotyping has been advocated as a means of improving the accuracy of warfarin dosing. However, the effectiveness of genotyping in improving anticoagulation control and reducing major bleeding has not yet been compellingly demonstrated. Genotyping currently costs $400 to $550. METHODS AND RESULTS: We constructed a Markov model to evaluate whether and under what circumstances genetically-guided warfarin dosing could be cost-effective for newly diagnosed atrial fibrillation patients. Estimates of clinical event rates, treatment and adverse event costs, and utilities for health states were derived from the published literature. The cost-effectiveness of genetically-guided dosing was highly dependent on the assumed effectiveness of genotyping in increasing the amount of time patients spend appropriately anticoagulated. If genotyping increases the time spent in the target international normalized ratio range by <5 percentage points, its incremental cost-effectiveness ratio would be greater than $100,000 per quality-adjusted life year. The incremental cost-effectiveness ratio falls below $50,000 per quality-adjusted life year if genotyping increases the time spent in range by 9 percentage points. The results were also sensitive to assumptions about the rate of major bleeding events during treatment initiation and the cost of the test. CONCLUSIONS: Our results suggest that genotyping before warfarin initiation will be cost-effective for patients with atrial fibrillation only if it reduces out-of-range international normalized ratio values by more than 5 to 9 percentage points compared with usual care. Given the current uncertainty surrounding genotyping efficacy, caution should be taken in advocating the widespread adoption of this strategy.

Mounting evidence suggests that statins possess antiarrhythmic properties and inhibit atrial fibrillation (AF). The goal of this study was to evaluate the relation between statin use and new-onset AF in a large cohort of patients with coronary artery disease. We identified all Medicare beneficiaries > or =65 years old who had been hospitalized for acute myocardial infarction or coronary revascularization from 1995 to 2004 and participated in 1 of 2 government-sponsored medication benefit programs. Patients with a history of AF before and during hospitalization were excluded. This yielded a cohort of 29,088. The incidence of new AF was compared between patients who were (n = 8,450) and were not (n = 20,638) prescribed statins within 1 month of hospital discharge after their cardiac event. New-onset AFs within 5 and 10 years were 32.6% and 51.2%, respectively, in patients who received statins compared to 38.3% and 58.0% in patients who did not receive statins (unadjusted hazard ratio 0.82, 95% confidence interval 0.78 to 0.86). Multivariable analysis controlling for demographic and clinical confounders indicated that statin use independently decreased the risk of developing new-onset AF compared to nonusers (adjusted hazard ratio 0.90, 95% confidence interval 0.85 to 0.94). Adjustment for propensity-score and health-seeking behaviors yielded nearly identical results. In conclusion, statin therapy initiated within 1 month after hospital discharge is independently associated with a decrease in the risk of new-onset AF after myocardial infarction or coronary revascularization. These findings lend support to the antiarrhythmic effects of statins and suggest another benefit for their use in patients with coronary artery disease.

BACKGROUND:: Pulmonary vein isolation (PVI) is recognized as a potentially curative treatment for atrial fibrillation (AF). Ablation of complex fractionated atrial electrograms (CFAEs) in addition to PVI has been advocated as a means to improve procedural outcomes, but the benefit remains unclear. OBJECTIVE:: To synthesize the available data testing the incremental benefit of adding CFAE ablation to PVI. METHODS:: We performed a meta-analysis of controlled studies comparing the effect of PVI with CFAE ablation versus PVI alone in patients with paroxysmal and nonparoxysmal AF. RESULTS:: Of the 481 reports identified, 8 studies met our inclusion criteria. There was a statistically significant increase in freedom from atrial tachyarrhythmia (AT) with the addition of CFAE ablation (RR 1.15, p=0.03). In the 5 reports of nonparoxsymal AF (3 randomized controlled trials, one controlled clinical trial, and one trial using matched historical controls), addition of CFAE ablation resulted in a statistically significant increase in freedom from AT (n=112/181 [62%] for PVI+CFAE versus n=84/179 [47%] for PVI alone; RR 1.32, p=0.02). In trials of paroxysmal AF (3 randomized controlled trials and one trial using matched historical controls), addition of CFAE ablation did not result in a statistically significant increase in freedom from AT (n=131/166 [79%] for PVI+CFAE versus n=122/164 [74%] for PVI alone; RR 1.04, p=0.52). CONCLUSIONS:: In these studies of patients with nonparoxysmal AF, addition of CFAE ablation to PVI results in greater improvement in freedom from AF. No additional benefit of this combined approach was observed in patients with paroxysmal AF.