A Systematic Review of Add-on Pharmacologic Therapy in the Treatment of Resistant Hypertension.

INTRODUCTION: The objective of this systematic review was to evaluate the efficacy and safety of add-on pharmacologic therapies in the treatment of resistant hypertension (RH), defined as blood pressure (BP) above target despite three antihypertensive agents.

METHODS: A systematic search was performed in MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov, and Google Scholar (inception to June 2016) to identify randomized controlled trials (RCTs) that compared any antihypertensive agent with control in patients with RH. Outcomes of interest included differences in BP, cardiovascular events, and serious adverse events. The Cochrane Collaboration's tool for assessing risk of bias in RCTs was used to evaluate the quality of the included trials.

RESULTS: Six RCTs were identified, including 749 participants. Four RCTs compared spironolactone with placebo and two used an active comparator. Four of the six studies did not report sufficient information regarding methods. A quantitative meta-analysis was not performed because of clinical heterogeneity among the RCTs. Compared with placebo, spironolactone reduced mean office BP by ~10 to 20 mmHg/~3 to 9 mmHg and home BP by ~10/4 mmHg. Compared with doxazosin or bisoprolol, spironolactone reduced clinic and home systolic BP, but not diastolic BP. Hyperkalemia occurred in ~3% of patients receiving spironolactone. Cardiovascular events were not consistently reported. All trials were limited by low enrollment, short follow-up, and inconsistent reporting of clinically meaningful outcomes and/or serious adverse events.

CONCLUSIONS: Spironolactone has the best evidence as add-on pharmacologic therapy in patients with RH, but data are limited.