Objective:

To assess the efficacy and tolerability of dual combination of blood pressure (BP)-lowering drugs as initial treatment for hypertension.

Methods:

MEDLINE, Embase, CENTRAL were searched until August 2017 for randomized, double-blind trials of dual combination therapy vs. monotherapy in adults with hypertension who were either treatment naïve or untreated for at least 4 weeks. Regimens were classified with reference to usual daily ‘standard-dose’; for example,< 1+< 1 for a combination of two drugs both at less than one standard-dose. Random-effects models were used for meta-analysis.

Results:

Thirty-three trials (13 095 participants) with mean baseline mean BP 155/100 mmHg were included. Compared with standard-dose monotherapy, dual combinations of< 1+< 1, 1+< 1 and 1+ 1 (ie low-to-standard dose), showed a dose–response relationship in reducing SBP [mean differences (95% confidence interval) of 2.8 (1.6–4.0), 4.6 (3.4–5.7) and 7.5 (5.4–9.5) mmHg, respectively], and in improving BP control [risk ratio (RR)(95% confidence interval) 1.11 (0.92–1.34), 1.25 (1.16–1.35) and 1.42 (1.27–1.58), respectively]. Withdrawals due to adverse events were uncommon with low-to-standard dose dual combinations, with no significant difference compared with standard-dose monotherapy [2.9 vs. 2.2%; RR 1.28 (0.85 to 1.92)]. There were fewer data for higher dose dual combinations, which did not appear to produce substantial additional efficacy and could potentially be less tolerable.

Conclusion:

Compared with standard-dose monotherapy, initiating treatment with low-to-standard dose dual combination therapy is more efficacious without increasing withdrawals due to adverse events.

PROSPERO registration:

CRD42016032822.

INTRODUCTION

Recent hypertension guidelines have placed increased emphasis on initial use of combination therapy for most individuals [1, 2], in contrast to previous ones that traditionally recommended stepped-care strategy with initial monotherapy [3, 4]. This change in emphasis reflects several factors. Although most hypertensive patients need treatment with two or more drugs to achieve goal blood pressure (BP)[3, 4] many do not receive such therapy mainly due to treatment inertia [5, 6]. Concerns have also been expressed about the risks associated with prolonged times to control BP and whether the need for multiple clinic visits might adversely affect long-term adherence. These factors have intensified clinical interest in the use of combination therapy as initial treatment. However, concerns also remain about the evidence base to support such a strategy, in particular, in relation to risk of adverse events. Although previous reviews have demonstrated the increased efficacy of dual therapy compared with monotherapy [7], limited data were reported on tolerability and the reviews of initial combination therapy were limited to the combinations of amlodipine/benazepril [8], perindopril/indapamide [9]. There are no systematic reviews that examined the role of drug doses within different initial therapies of dual combinations. Given the critical impact of regimen tolerability, and the likely importance of doses on both efficacy and tolerability, this systematic review and meta-analysis sought to address these uncertainties.

METHODS

Literature search and selection of trials

The current review was registered with PROSPERO (CRD42016032822) before screening for eligible studies. MEDLINE, Cochrane Central Registry of Controlled Trials and Embase were systematically searched until August 2017 to identify relevant trials. The search strategy included Cochrane's highly sensitive search strategy for randomized controlled trials …