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Atrial fibrillation with rapid ventricular response (RVR) is common during critical illness. In this study, we explore the comparative effectiveness of three commonly used drugs (metoprolol, diltiazem, and amiodarone) in the management of atrial fibrillation with RVR in the intensive care unit (ICU).Data pertaining to the first ICU admission were extracted from the Medical Information Mart for Intensive Care III database. Patients who received one of the above pharmacologic agents while their heart rate was > 110 bpm and had atrial fibrillation documented in the clinical chart were included. Propensity score weighting using a generalized boosted model was used to compare medication failure rates (second agent prior to termination of RVR). Secondary outcomes included time to control, control within 4 h, and mortality.One thousand six hundred forty-six patients were included: 736 received metoprolol, 292 received diltiazem, and 618 received amiodarone. Compared with those who received metoprolol, failure rates were higher amongst those who received amiodarone (OR 1.39, 95% CI 1.03–1.87, P = 0.03) and there was a trend towards increased failure rates in patients who received diltiazem (OR 1.35, CI 0.89–2.07, P = 0.16). Amongst patients who received a single agent, patients who received diltiazem were less likely to be controlled at 4-h than those who received metoprolol (OR 0.64, CI 0.43–097, P = 0.03). Initial agent was not associated with in-hospital mortality.In this study, metoprolol was the most commonly used agent for atrial fibrillation with RVR. Metoprolol had a lower failure rate than amiodarone and was superior to diltiazem in achieving rate control at 4 h.