More is Less? Optimal Combination Therapy for Adequate Blood Pressure Lowering in Hypertension

Fixed dose formulations of rational antihypertensive drug combinations are being used increasingly early in the management of hypertension [1]. Fixed combinations for hypertension management were long viewed with suspicion, although the scientific and medical community widely accepted combination treatments in many other fields of medicine, e.g Parkinson's disease (L‐dopa plus an extracerebral dopa‐decarboxylase inhibitor) or infectious diseases (trimethoprim and sulfamethoxazole as co‐trimoxazole). Today, however, there is a strong interest in the use of fixed low‐dose combination therapy as well as an increasing recognition that the combination approach may offer significant benefits for the hypertensive patient population, not only for the sake of simplicity, but also in terms of efficacy and tolerability [2].

The Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial was the first study to compare the cardiovascular outcomes of initial fixed‐dose combination angiotensin‐converting enzyme inhibitor (ACEI)/calcium channel blocker (CCB) and ACEI/diuretic therapy in patients with hypertension at high risk for cardiovascular events [3–6]. Results indicate that initial combination therapy is effective in this population, with ACEI/CCB therapy providing the greater benefit with the largerreduction in risk for cardiovascular events [7]. The potential to extend the findings of ACCOMPLISH to other renin‐angiotensin‐aldosterone system (RAAS) inhibitor/CCB combinations, such as angiotensin II type 1 receptor blocker (ARB)/CCB combinations, has yet to be investigated.

In the absence of direct comparisons of ACEI/CCB and ARB/CCB combinations, it appears reasonable to explore the possibility that the beneficial results of ACCOMPLISH extend to other RAAS inhibitor/CCB combinations. Data from multiple clinical studies in a range of patient populations indicate that ACEI and ARB provide similar cardiovascular benefits. Comparable morbidity and mortality outcomes have been reported for patients with vascular disease or high‐risk diabetes [8], acute myocardial infarction [9], [10] and heart failure [11–14]. Furthermore, in patients with heart failure, the ARB candesartan was as effective as enalapril in preventing left ventricular remodelling [15]. In general, tolerability was comparable or greater in the ARB (vs. ACEI) treatment groups in these studies. In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)‐Alternative trial [13], the ARB candesartan was used successfully in patients who were intolerant to ACEI therapy.

Furthermore, results of a systematic review of data from 61 comparative studies indicate that ACEIs and ARBs have no clinically meaningful differences in terms of benefits for individuals with hypertension [16]. Both classes of drugs provide similar BP control and comparable effects on death, cardiovascular events, major adverse events, quality of life, and cardiovascular risk factors including lipid levels, diabetes mellitus, and left ventricular mass and function. The only clinically significant difference between ACEIs and ARBs found in this analysis was the incidence of cough, which was higher with ACEIs (mean rate, 10% for ACEI vs. 3% for ARB). In addition, ARBs were also associated with higher rates of persistence during initial therapy.

Despite the availability of a wide variety of treatment options, the full benefits of early fixed combination therapy remain to be established. Current guidelines recommend that, for most patients, such therapy may be implemented only after failure of first‐line mono‐therapy. Results of the ACCOMPLISH trial challenge this approach by providing strong evidence that initial combination therapy is beneficial and well tolerated in a high risk hypertensive population. ACCOMPLISH also demonstrated that appropriately dosed ACEI/CCB therapy provided the greater benefit in terms of reduced cardiovascular morbidity and mortality relative to initial ACEI/diuretic combination therapy with the diuretic dosed at usual levels (12.5–25 mg HCTZ). With respect to the documented beneficial therapeutic profiles of the ACEIs and ARBs as cited above [16], it is reasonable to assume that ARB/CCB combinations will provide similar benefits as an ACEI/CCB combination. Although this remains to be definitely shown in clinical trials, there are strong reasons to believe that optimal fixed dose combination therapy with an ARB as compared to an ACE inhibitor will demonstrate comparable BP lowering effects and cardiovascular benefits, as well as an improved tolerability. Therefore, a judicious approach to hypertension management would be a wider use of a low‐dose ARB/CCB combination treatments early in the treatment plan.