CURRENT STATUS OF COMBINATION THERAPY IN OTHER CARDIOVASCULAR-DISEASES

As in hypertension, the addition of a second active drug is believed to enhance treatment efficacy; however, the extent to which a combination of two low-dose drugs outperforms conventional monotherapy remains uncertain. Established treatments of angina comprises nitrates compounds, beta-blockers and calcium antagonists, which are often given in combination. Beta-blockers are major players in this field as they inhibit the tachycardia induced by nitrates and calcium antagonists; there is therefore a pathophysiological justification for their use in combination therapy, supported by repeated confirmation of positive clinical effect. The most widely chosen calcium antagonists are dihydropyridines; verapamil may impair conduction. However, it is not clear whether combination enhances the effects of the individual antianginal substances. Diuretics are for most clinicians the keystone treatment of heart failure; diuretics are often combined with other drugs, e.g. amiloride and spironolactone. The latter also have a beneficial effect on myocardial structure (myocardium/collagen ratio). ACE-inhibitors are of proven clinical efficacy, and, in addition, have a beneficial effect on survival. They combine well with diuretics: because the diuretic stimulates renin release, the ACE-inhibitor can be given at a lower dose (enhancement of effect). There are, however, certain drawbacks (hypotension, hyperkalemia with antialdosterones). The results of combining ACE-inhibitors with calcium antagonists and beta-blockers await investigation. The ISIS studies demonstrated the advantages of combining beta-blockers, thrombolysis and aspirin in acute infarction. ACE-inhibitors have recently been added to the regimen with a positive effect (extended survival), especially in the presence of a decreased ejection fraction (SAVE, AIRE, GISSI 3 and ISIS 4 studies). However, as in angina, an enhancement effect has not yet been conclusively demonstrated. To prove this last point, studies are mandatory, but they will be difficult, costly and require a large number of patients.