title: Arrhythmias Seen in Baseline 24-Hour Holter ECG Recordings in Healthy Normal Volunteers During Phase 1 Clinical Trials.
abstract: Regulatory agencies encourage sponsors to submit 24-hour ambulatory ECG data for assessing cardiac safety of new drugs, and some arrhythmias, hitherto considered rare, have been observed in some early-phase studies. Interpretation of these observations is difficult given the dearth of published data on the prevalence of cardiac arrhythmias seen during 24-hour continuous ECG monitoring in healthy volunteers (HV) from clinical trials. We analyzed drug-free ambulatory ECG recordings from 1273 HV (1000 males, 273 females; age 18-65 years) from 22 phase 1 studies that were analyzed in a core ECG laboratory; all subjects had normal screening ECGs. Supraventricular arrhythmias such as supraventricular premature complexes were observed in 60.8% of healthy volunteers, supraventricular tachycardia in 2.2%, and atrial fibrillation in 0.1%. Ventricular arrhythmias included premature ventricular complexes (PVCs) in 43.4%, >200 PVCs per 24 hours in 3.3%, multifocal PVCs in 5.3%, nonsustained ventricular tachycardia in 0.7%, and accelerated idioventricular rhythm in 0.3%. Bradyarrhythmias included sinus pause >3 seconds in 0.3%, and second-degree AV block in 2.4%. Complete heart block and torsades de pointes were not seen in any subject. Based on the observed incidence, we estimated the maximum number of healthy subjects in whom these arrhythmias may be seen as a matter of chance in studies with smaller sample sizes if the study drug has no arrhythmogenic effect. Our results and these estimates could help interpret whether cardiac arrhythmias observed in early-phase studies are due to chance or possibly are a drug effect.
authors.affiliation: Quintiles Cardiac Safety Services, Mumbai, India.
authors.forename: Pooja
authors.initials: P
authors.lastname: Hingorani
authors.affiliation: Quintiles Cardiac Safety Services, Mumbai, India.
authors.forename: Dilip R
authors.initials: DR
authors.lastname: Karnad
authors.affiliation: Quintiles Cardiac Safety Services, Mumbai, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Rohekar
authors.affiliation: Quintiles Cardiac Safety Services, Mumbai, India.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Kerkar
authors.affiliation: Quintiles Cardiac Safety Services, Mumbai, India.
authors.forename: Yash Y
authors.initials: YY
authors.lastname: Lokhandwala
authors.affiliation: Quintiles Cardiac Safety Services, Mumbai, India.
authors.forename: Snehal
authors.initials: S
authors.lastname: Kothari
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000175:diagnosis* / Q000503:physiopathology*; D015716:Electrocardiography, Ambulatory / Q000379:methods* / Q000639:trends*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors; D055815:Young Adult
keywords: ambulatory ECG; cardiac arrhythmias; cardiac safety; clinical trials; drug development; electrocardiography; sample size