Randomized, placebo-controlled, crossover, double-blind comparison of immediate- and sustained-release formulations of Gallopamil in elderly patients with stable effort angina

Abstract

Background The pharmacokinetics, efficacy, and safety of calcium channel blockers have rarely been investigated in the elderly. Gallopamil, a methoxy derivative of verapamil with calcium antagonistic properties, has been shown to be effective in the treatment of angina pectoris. Objective The aim of this study was to assess the anti-ischemic action of gallopamil, its effects on left ventricular and autonomic function, and its pharmacodynamics and safety in elderly patients. Methods We studied immediate-release (IR) and sustained-release (SR) formulations of gallopamil in 12 sedentary elderly patients with stable effort angina and angiographically documented coronary artery disease in a randomized, placebo-controlled, crossover, double-blind trial. Following a run-in period, patients received either IR gallopamil 50 mg TID or SR gallopamil 100 mg BID for 28 days, after which patients crossed over to the alternate regimen. A washout period of 4 days was incorporated between the 2 treatment phases. Antianginal efficacy was assessed by monitoring the number of angina episodes per week and the amount of sublingual nitroglycerin consumed per week as well as sequential cycloergometer exercise testing 2 and 6 hours postdose. Patients underwent clinical examination, electrocardiography (ECG), echocardiography, 24-hour Holter ECG monitoring, and blood testing at the beginning of the study and at the end of each phase. On the last day of the active treatment period, sequential blood samples were collected to determine plasma levels of gallopamil. Results Both IR and SR gallopamil reduced the number of angina episodes and the amount of nitroglycerin consumed per week. Gallopamil also reduced the number of ECG signs of ischemia at peak exercise testing, as well as symptomatic and asymptomatic ischemic episodes on 24-hour Holter ECG monitoring. IR and SR gallopamil did not affect left ventricular diameters, ejection fraction, and average heart rate, nor did they cause significant changes in heart rate variability. Peak plasma levels of gallopamil were reached rapidly after ingestion of the IR and SR formulations. The plasma concentrations of gallopamil and the norgallopamil metabolite were similar during the first 2 hours after administration of IR and SR gallopamil. Thereafter, patients who received the SR formulation showed significantly higher gallopamil ( P < 0.05) and norgallopamil ( P < 0.05) plasma concentrations than patients who received the IR formulation. The area under the concentration-time curve for SR gallopamil was significantly larger than for IR gallopamil; however, half-life, clearance, and peak plasma concentration were similar after IR and SR gallopamil treatment. Adverse effects, which were observed in 25% of patients, were minor and were not related to plasma levels of gallopamil; no patient suffered hemodynamic or major cardiac conduction abnormalities attributable to gallopamil. Conclusions Our data suggest that both IR and SR gallopamil were effective in reducing signs and symptoms of ischemia in elderly patients with stable effort angina, with few adverse effects.