Which is the optimal antihypertensive combination in different diseases, a renin- angiotensin-aldosterone system inhibitor with a diuretic or with a calcium channel blocker?

Successful treatment of hypertension often requires the association of drugs from different classes. Combination therapy takes advantage of complementary mechanisms of action, in order to reach target blood pressure (BP) earlier and to minimize the side effects of medications. In the last decade, several randomized trials have demonstrated the efficacy of combining a renin-angiotensin-aldosterone system (RAAS) inhibitor with a calcium channel blocker (CCB) or with a diuretic in different populations. The ACCOMPLISH trial was the only large clinical trial that directly compared the two combination strategies. In hypertensive individuals at high cardiovascular risk, benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing the primary composite endpoint of cardiovascular events plus death from cardiovascular causes. Small randomized trials have evaluated the two combination therapies in surrogate endpoints, such as microalbuminuria, with contrasting results. Current European and American guidelines recommend combination therapy as first-line when BP is at least 20/10 mmHg above treatment goals. However, the choice of the best combination therapy is still debated: the National Institute for Health and Clinical Excellence guidelines recommend a RAAS inhibitor plus a CCB, while the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines underline the pivotal role of thiazide diuretics. The combination of a RAAS inhibitor with a CCB demonstrated the best efficacy in reducing cardiovascular endpoint. However, the combination of a RAAS inhibitor with a diuretic has shown beneficial results in particular subgroup of patients, such as patients with heart failure or with African American origin. This review will focus on the rationale and current evidences about combination therapy in the management of arterial hypertension.