Study design and setting
This study is a post hoc analysis of the AFTER-ICU study, a prospective observational study that included 423 patients with new-onset AF in 32 Japan intensive care units (ICUs) [10,27]. Patients admitted to the ICU between April 1, 2017, and March 31, 2018, were enrolled. We followed up all study patients until hospital discharge. This study is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology statement [28].
Participants
We enrolled patients who developed new-onset AF during their ICU stay. The exclusion criteria were as follows: age <18 years; history of AF; discharged from the ICU within 24 hours after ICU admission; admitted to the ICU after cardiac surgery or cardiac arrest; with a pacemaker at AF onset; withheld or withdrew medical therapy at AF onset; declined enrollment in this study. AF was defined as an arrhythmia with irregular R-R intervals without apparent P waves or with F waves that persisted longer than 5 minutes or with recurrent episodes within 5 minutes, as confirmed by 12-lead electrocardiograms or continuous 3-lead electrocardiograms [3,6,14,16,22,29]. Physicians (intensivists or cardiologists) in the participating hospitals made the diagnoses of new-onset AF.
Variables and measurement
To assess the impact of rhythm-control therapy on SR restoration, we compared patients with rhythm-control therapy to those without. We obtained the following information from the AFTER-ICU study: patient demographics, physiological data, and drugs used at AF onset. We also obtained the following information within 7 days after initial AF onset or during ICU stay, whichever was shorter: timing of direct-current cardioversion, drugs used for new-onset AF, adverse events (bleeding events or cardiac arrhythmia other than AF), and timing of cardiac rhythm transition. The rhythm-control drugs for new-onset AF were magnesium sulfate, amiodarone, pilsicainide, aprindine, cibenzoline, adenosine triphosphate, disopyramide, flecainide, bepridil, and lidocaine. The rate control drugs were beta-blocking agents (landiolol, bisoprolol, propranolol, and carvedilol), calcium-channel blockers (diltiazem and verapamil), and digoxin. We also defined the use of rhythm-control drugs and/or undergoing direct-cardioversion as rhythm-control therapy.
Outcomes
Our primary outcome was the last SR restoration within 7 days after the initial AF onset or during the ICU stay, whichever was shorter. SR restoration was defined as sustained SR for longer than 24 hours after the conversion from AF to SR. If the patients were discharged from ICU with SR within 24 hours after the conversion of cardiac rhythm from AF to SR, they were also defined as those with SR restoration. The secondary outcomes were the patients’ cardiac rhythm at ICU discharge, AF duration, ICU length of stay, hospital length of stay, adverse events, ICU mortality, hospital mortality, and in-hospital stroke. In-hospital stroke was defined as symptomatic cerebral infarction diagnosed by a neurologist or a neurosurgeon or determined via new computed tomography or magnetic resonance imaging findings [14]. The definition of the other collected variables is detailed in Additional table 1.
Statistical analysis
The study results are presented as median and interquartile range or as absolute numbers with percentage, as appropriate. In all analyses, the number of missing data was reported, and cases with missing data were excluded from each analysis. Comparisons between the two groups were conducted using chi-square test or Fisher’s exact test for categorical variables and Mann-Whitney U test for continuous variables. P<0.05 was considered statistically significant.
To assess the association between rhythm-control therapy and SR restoration, we modeled the time from AF onset to SR restoration using Cox proportional hazards regression. Patients who were later initiated on rhythm-control therapy might have longer time until SR restoration. To address time-related bias, we used the rhythm-control therapy as a time-varying covariate in this model. The following variables were included in this model according to their clinical relevance and importance in previous studies [3–5,8,9,11,18,30,31]: age, previous history of congestive heart failure, patient category (nonscheduled surgical, scheduled surgical, and medical), Acute Physiology and Chronic Health Evaluation (APACHE) II scores [32] at ICU admission, infection at AF onset, renal replacement therapy at AF onset, mechanical ventilation at AF onset, administration of drugs (any vasopressors, inotropes, and dexmedetomidine) at AF onset, heart rate at AF onset, and the laboratory data (potassium and white blood cells) before AF onset. To account for the nonlinear effects of age, heart rate at AF onset, potassium, and white blood cells on outcomes, the penalized smoothing spline function was incorporated into the Cox proportional hazards model. Patients who were discharged from the ICU or died with remaining AF within 7 days after AF onset were censored because we could not measure their duration until SR restoration. The Cox proportional hazards regression analyses were performed using R version 3.5.1 (The R Foundation for Statistical Computing, Vienna, Austria). All other analyses were performed using Stata version 16 (StataCorp, College Station, TX, USA).
Sensitivity analyses
Although direct-current cardioversion is a rhythm-control therapy, undergoing DC direct-current cardioversion does not have the effect of sustained SR, which is different from the pharmacologic interventions. Therefore, we performed sensitivity analysis using Cox proportional hazards regression for the rhythm-control therapy without direct-current cardioversion.