Effects of propafenone on ventricular arrhythmias: Double-blind, parallel, randomized, placebo-controlled dose-ranging study

Bramah N. Singh*, Elieser Kaplinsky, Edward Kirsten, Juan Guerrero

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Propafenone is a new class Ic antiarrhythmic compound with a broad pharmacologic profile. In this study, its dose-response relationship was examined in a double-blind, randomized, placebo-controlled five treatment parallel design protocol. Patients enrolled had heart disease with Lown grade 2 premature ventricular contractions (PVCs) (≥30/hr) documented on 24-hour Holter recordings. Propafenone was compared in four doses (337.5, 450, 675, and 900 mg/day) to placebo. The double-blind phase lasted 2 weeks. Two hundred twenty-six patients were enrolled, of whom 171 were men and 55 were women; their mean age was 59.8 years and 85% were Caucasian and 4% were black. The arrhythmias were symptomatic in 173. Twenty (8.8%) withdrew from the study before completion: 15 had adverse reactions, two had intercurrent illnesses, and three withdrew for administrative reasons. In one patient, the density of arrhythmia appeared to increase with propafenone. Side effects were of central nervous system or gastrointestinal origin; less than 5% of patients developed first-degree atrioventricular block or intraventricular conduction defect. There were no deaths in the study. The occurrence of side effects was not related to dose. Propafenone had no effect on heart rate. It increased the PR interval at all doses (9% to 22% compared to placebo at baseline; p < 0.01) at 450 to 900 mg/day after 2 weeks of therapy. The drug increased the QRS duration at all doses, highly significantly at 675 mg/day (8.5 msec; p < 0.01) and at 900 mg/day (15.7 msec; p < 0.01) after 2 weeks of therapy. Only at the highest dose was the QTc slightly but significantly (14.3 msec; p < 0.01) increased. Propafenone exerted a dose-dependent effect on PVCs recorded on serial 24-hour Holter recordings: compared to placebo, at 2 weeks 337.5 mg/day reduced PVCs by 70.8% (p < 0.05), 450 mg/day reduced PVCs by 82.0% (p < 0.01), 675 mg/day reduced PVCs by 90.2% (p < 0.01) and 900 mg/day reduced PVCs by 95.3% (p < 0.01). The effects of the two highest doses of propafenone were significantly greater than those of 337.5 mg/day. In 68% of the patients receiving 900 mg/day, 80% or greater reduction in total PVCs was found. In addition, there was a greater than 90% decrease in ventricular couplets, and 96% decrease in ventricular tachycardia (VT) beats. Propafenone eliminated PVCs in 8% of all patients, ventricular couplets in 58%, and VT beats in 91%. The median percentage of hours in which propafenone reduced PVCs by over 80% increased as a function of drug dose. A dose-response effect of propafenone on PVC suppression was evident during the first 24 hours. The data indicate that propafenone is a potent suppressant of ventricular arrhythmias with a more striking effect on ventricular couplets and VT beats than on total PVCs at a given dose. A significant dose relationship was evident with respect to all parameters of arrhythmia suppression with a low arrhythmogenic potential, excellent tolerability by patients, and a low incidence of drug-induced ECG abnormalities.

Original languageEnglish
Pages (from-to)1542-1551
Number of pages10
JournalAmerican Heart Journal
Volume116
Issue number6 PART 1
DOIs
StatePublished - Dec 1988

Funding

FundersFunder number
Medical Veterans Administration

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