Combination therapy in hypertension: what are the best options according to clinical pharmacology principles and controlled clinical trial evidence?

Despite extensive debate about the first choice for treating essential hypertension, monotherapy effectively normalizes blood pressure (BP) values in only a limited number of hypertensive patients. Thus, the aim of combination therapy should always be to both improve BP control and to reduce cardiovascular events. Antihypertensive drugs can be effectively combined if they have different and complementary mechanisms of action. This is crucial to obtain additive BP-lowering effects without impacting on tolerability. One typical combination is the association of drugs blocking and stimulating the renin-angiotensin system (RAS) (angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker and calcium antagonist or diuretic, respectively). In contrast, some combinations (e.g., calcium antagonists plus diuretics or beta-blockers plus RAS blockers) have no additive BP-lowering effects, while other combinations (e.g., clonidine plus alpha-1 receptor blockers) can have a negative interaction. Regardless, BP reduction is not the only mechanism that reduces cardiovascular risk. Scientific evidence indicates that some drug classes are better than others in this respect, and therefore some drug combinations are also better than others. The results of the ASCOT-BPLA and ACCOMPLISH trials suggested that an ACE inhibitor/calcium antagonist combination had better cardioprotective effects than beta-blocker/diuretic or ACE inhibitor/diuretic combinations. It is worth noting that no controlled clinical trials have used hard endpoints when investigating the effects of an angiotensin receptor blocker/calcium antagonist combination. In conclusion, combination therapy is needed for optimal antihypertensive management, with the first choice being an ACE inhibitor plus a calcium antagonist. This approach should improve BP control and provide better cardiovascular protection.