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, beta-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.