Major adverse cardiac events with haloperidol: A meta-analysis

BACKGROUND: Haloperidol is a commonly used antipsychotic drug and a frequent source of medication safety alerts because of its listing as a "known risk" QT interval-prolonging medication (QTPmed). We aimed to summarize the high-quality literature on the frequency and nature of proarrhythmic major adverse cardiac events (MACE) associated with haloperidol. METHODS: We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central for randomized controlled trials (RCTs) involving patients 18 years or older comparing haloperidol to placebo. The FDA-adapted MACE composite included death, non-fatal cardiac arrest, ventricular tachyarrhythmia including torsades de pointes, and seizure or syncope. Random-effects meta-analyses were performed with a treatment-arm continuity correction for single and double zero event studies. RESULTS: 84 RCTs (n = 12180, 46% female), 23.8% of trials reported mean or median ages of their participants to be older than 65 years with 37 (44.0%) involving participants with psychiatric diagnoses, and 50 (59.5%) including electrocardiograms. Median follow-up duration was 28.0 days (interquartile range IQR=51.0). There were 1144 events, of which 97.8% were deaths, with 22 ventricular arrhythmias and 3 seizures or syncope. There was no difference in MACE with exposure to haloperidol compared to placebo (risk ratio RR 0.93, 95% CI: 0.80-1.08; I2 = 0%). IV haloperidol was not associated with increased risk of mortality (n = 5873, RR: 0.88, 95%CI:0.72-1.08). CONCLUSIONS: We did not find that haloperidol was arrhythmogenic or increased mortality in these largely short-duration trials. Further research to clarify actual clinical outcomes related to QTPmeds is important to inform safe prescribing practices.