The potential role of calcium antagonists in the management of congestive heart failure: Initial experience with lacidipine

First-generation calcium antagonists have been used in patients with congestive heart failure with rather disappointing results. Therefore, second-generation dihydropyridine calcium-channel blockers, such as felodipine and lacidipine, have been developed that may be beneficial in congestive heart failure owing to their high vasoselectivity and more favorable neurohumoral modulation. The effects of lacidipine in patients with congestive heart failure, who remain symptomatic despite receiving long-term therapy with angiotensin-converting enzyme inhibitors, digoxin, and diuretics, were investigated during a prospective, double-blind, randomized, placebo-controlled, parallel-group study. Twenty-five patients were randomized to receive either lacidipine (4 mg once daily; 12 patients) or placebo (once daily; 13 patients). After 8 weeks of treatment patients receiving lacidipine showed a significantly higher increase in cardiac output (p <0.01), and a significantly greater reduction in vascular resistance (p <0.02) than those patients in the placebo group. No significant changes were observed in filling pressures and heart rate. The arteriovenous oxygen content difference was significantly reduced in the lacidipine group (p <0.01) without significant changes in arterial oxygenation, suggesting an increase in flow that was not a result of pulmonary shunting. Further peak oxygen consumption during cardiopulmonary exercise testing increased significantly in the lacidipine patients (p <0.02). These beneficial effects were achieved without significant changes in neurohumoral parameters. Analysis of right and left ventricular ejection fractions revealed no cardiodepressant effects. Lacidipine was well tolerated during the course of the study, and adverse reactions were minor. These data suggest that lacidipine has a promising profile for the treatment of congestive heart failure patients, ana that further investigation with second-generation dihydropyridines in the field of congestive heart failure appears warranted

ORAL PHARMACOKINETICS OF FELODIPINE IN PATIENTS WITH CONGESTIVE HEART-FAILURE - VARIABLE PREDICTION USING INTRAVENOUS DATA

Peak and trough concentrations after 8 weeks oral therapy with felodipine, a vasodilating calciumantagonist of the dihydropyridine group, were predicted from intravenous pharmakocinetic data before therapy in 11 patients, randomly allocated to felodipine treatment 10 mg b.i.d., during a placebo controlled study in patients with congestive heart failure. Peak concentrations were well predictable, but trough levels varied between a good agreement in some patients to a large underestimation in others. Predictability was significantly correlated with half life, plasma clearance and distribution volume of the intravenous pharmacokinetic study. After 8 weeks chronic oral therapy no significant differences could be detected between the oral pharmacokinetics of predictable (n = 6) and unpredictable (n = 5) patients. This demonstrates that felodipine kinetics change during felodipine treatment. Differences in the distribution of blood flow before therapy combined with an interindividual variability in blood flow response during therapy is probably responsible for the observed impossibility to calculate trough levels, and thus oral dosage schedules, from intravenous pharmacokinetic data in patients with congestive heart failur