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To determine the effect of ranolazine, an anti-ischaemic agent with anti-arrhythmic properties, on the overall burden of atrial fibrillation (AF) in acute coronary syndromes (ACS) and determine whether ranolazine reduces the long-term incidence of clinical AF after ACS.MERLIN-TIMI 36 randomized patients with non-ST elevation ACS to ranolazine or placebo. Atrial fibrillation episodes detected on continuous electrocardiogram (cECG) monitoring were reviewed in 6351 patients (97% of trial). Atrial fibrillation burden was categorized according to the time in AF: clinically insignificant AF (<0.01% of time), paroxysmal AF (>0.01–98%), or predominantly persistent AF (>98%). Clinical AF events were identified through adverse event reporting for a median 1-year follow-up. Overall, patients assigned to ranolazine had a trend towards fewer episodes of AF [75 (2.4%) vs. 55 (1.7%) patients, P = 0.08] detected on cECG during the first 7 days after randomization. The pattern of new-onset AF differed between ranolazine vs. placebo: clinically insignificant AF (five patients in ranolazine vs. seven in placebo), paroxysmal AF (18 vs. 48 patients), and predominantly chronic AF (28 vs. 20 patients, three-way P < 0.01). Among patients with a paroxysmal AF pattern, the overall burden was lower with ranolazine than with placebo (median 4.4 vs.16.1%, P = 0.015). Over the median 1-year follow-up, fewer patients treated with ranolazine experienced an AF event compared with placebo (2.9 vs. 4.1%, RR 0.71, P = 0.01).Ranolazine, an anti-anginal agent with electrophysiological effects, may reduce the frequency of paroxysmal AF in patients with non-ST elevation ACS with a pattern of lower overall AF burden in this group. Ranolazine reduced the overall 1-year incidence of clinical AF events. These atrial-specific anti-arrhythmic properties of ranolazine may be of clinical interest and warrant additional investigation.NCT00099788.