Lenient rate control versus strict rate control for atrial fibrillation: a statistical analysis plan for the Danish Atrial Fibrillation (DanAF) randomized clinical trial.

BACKGROUND: A key decision in the treatment of atrial fibrillation is choosing between a rhythm control strategy or a rate control strategy as the main strategy. When choosing rate control, the optimal heart rate target is uncertain. The Danish Atrial Fibrillation trial is a randomized, multicenter, two-group, superiority trial comparing strict rate control versus lenient rate control in patients with either persistent or permanent atrial fibrillation at inclusion. To prevent bias arising from selective reporting and data-driven analyses, we developed a predefined description of the statistical analysis. METHODS: The primary outcome of this trial is the physical component score of the SF-36 questionnaire. A total of 350 participants will be enrolled based on a minimal important difference of 3 points on the physical component score of the SF-36 questionnaire, a standard deviation of 10 points, a statistical power of 80% (beta of 20%), and an acceptable risk of type I error of 5%. All secondary, exploratory, and echocardiographic outcomes will be hypothesis-generating. The analyses of all outcomes will be based on the intention-to-treat principle. We will analyze continuous outcomes using linear regression adjusting for "site," type of atrial fibrillation at inclusion (persistent/ permanent), left ventricular ejection fraction (≥ 40% or < 40%), and the baseline value of the outcome (all as fixed effects). We define our threshold for statistical significance as a p-value of 0.05 and assessments of clinical significance will be based on the anticipated intervention effects defined in the sample size and power estimations. Thresholds for both statistical and clinical significance will be assessed according to the 5-step procedure proposed by Jakobsen and colleagues. DISCUSSION: This statistical analysis plan will be published prior to enrolment completion and before any data are available and is sought to increase the validity of the DANish Atrial Fibrillation trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT04542785. Registered on Sept 09, 2020.

Subclinical atherosclerosis is associated with incident atrial fibrillation: a systematic review and meta-analysis.

AIMS: Coronary artery disease is an established risk factor for incident atrial fibrillation (AF), but it is unclear whether subclinical atherosclerosis also increases the risk of incident AF. Therefore, the aim was to assess the association between subclinical atherosclerosis, defined by increased carotid intima-media thickness (cIMT) or coronary artery calcium score (CACS), and incident AF. METHODS AND RESULTS: A systematic review of MEDLINE, EMBASE, and Cochrane was done to find all cohort studies investigating the association between subclinical atherosclerosis, defined by increased cIMT or CACS, and incident AF. Eligible articles had to be available in an English full-text version; include adults over the age of 18 years; include ≥100 participants; and have a follow-up period ≥12 months. Data on cIMT were pooled using a fixed-effects model, while data on CACS (I2 >25) were pooled using a random-effects model. Five studies on cIMT including 36 333 patients and two studies on CACS including 34 603 patients were identified. All studies investigating the association between increased cIMT and incident AF showed a significant association, with an overall hazard ratio (HR) of 1.43 [95% confidence interval (CI) 1.27-1.59]. The two studies investigating the association between increased CACS and AF also showed a significant association with an overall HR of 1.07 (95% CI 1.02-1.12). CONCLUSION: Data from seven observational studies suggest that subclinical atherosclerosis defined by increased cIMT or CACS is associated with an increased risk of incident AF. These findings emphasize the need for further research investigating whether treatment of subclinical atherosclerosis should be a part of the initiatives to prevent AF.