Calcium antagonist use in heart failure: A re-evalutaion of treatment options

The pharmacological management of heart failure has evolved during the last decade from therapies focused on improving haemodynamics to others that modulate neurohormonal systems which are activated in the setting of left ventricular dysfunction. Despite optimal inhibition of these systems with drugs such as ACE inhibitors, β-blockers, digoxin and, most recently, spironolactone, the mortality rate remains unacceptably high. Calcium antagonists have long been investigated for use in a variety of cardiovascular diseases, including ischaemic heart disease, hypertension, and heart failure. However, concern has arisen with regard to the use of calcium antagonists in the treatment of left ventricular dysfunction - particularly those agents with negative inotropic activity. In addition, first generation dihydropyridines have also generated concern because of their profound vasodilatory effects and the fact that they have been shown to increase noradrenaline (norepinephrine) levels and neurohormonal activity. The third generation dihydropyridine calcium antagonists appear to be more promising therapies for heart failure, given their pharmacological properties of higher vascular selectivity and their minimal effects on neurohormonal activation. Several trials have been conducted with third generation dihydropyridines and additional trials are ongoing. A new class of calcium antagonists, which blocks the T-type calcium channel, was introduced in 1998. The prototype drug, mibefradil, was rigorously tested for use in heart failure in the Mortality Assessment in Congestive Heart Failure (MACH-1) trial. It was expected that calcium antagonists blocking the T-type calcium channel would be of benefit, because of their lack of negative inotropic effects and their ability to induce regression of hypertrophy. The results of the MACH-1 trial were disappointing, and the trial was prematurely discontinued as a result of excess mortality in the mibefradil arm. The purpose of this review is to examine the evidence-based pharmacotherapeutic strategies in the management of heart failure, and to discuss current and potential roles for calcium antagonists in the therapeutic regimen.

Duke Scholars

Author Christopher Michael O'Connor Medicine, Clinical Pharmacology