Effect of Fourth-Line Antihypertensive Therapy on Clinic Systolic Blood Pressure in Resistant Hypertension: A Systematic Review and Meta-Analysis

INTRODUCTION/BACKGROUND: Resistant hypertension (rHTN) is defined as uncontrolled blood pressure despite ≥3 antihypertensives, including a diuretic. While fourth-line intensification is recommended, comparative evidence remains scattered. RESEARCH QUESTIONS/HYPOTHESIS: This meta-analysis evaluates the efficacy and safety of fourth-line antihypertensives in reducing clinic systolic blood pressure (SBP) in rHTN. METHODS/APPROACH: A literature search across PubMed, Embase, Scopus, and Web of Science (2015-2026) identified eligible randomized controlled trials (RCTs) of ≥4 weeks duration. Risk of bias was assessed using Cochrane RoB 2. An initially planned network meta-analysis was deemed unreliable due to statistical inconsistencies and transitivity violations across the evidence base. Consequently, data were analyzed via pairwise meta-analysis using R software (version 4.5.1) to calculate mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CI). RESULTS/DATA: Eleven RCTs involving 3,931 adults with rHTN were included. Pairwise comparisons against placebo showed that aldosterone targeted therapies produced the largest reductions in SBP, with lorundrostat (MD -11.70 mmHg [95% CI -16.07, -7.33]) and baxdrostat 2 mg (MD -10.10 [-12.63, -7.58]) showing comparable effects, while baxdrostat 1 mg (MD -8.56 [-11.08 to -6.04]) demonstrated reductions similar in magnitude to spironolactone (MD -7.95 [-10.10, -5.80]). β-blockers, including bisoprolol (MD = -6.71 mm Hg), also demonstrated modest SBP reductions, while aprocitentan 12.5 mg reduced SBP by -3.80 mmHg [-6.65, -0.95]. No intervention significantly increased serious adverse events versus placebo. Significant increases in any adverse events were observed with aprocitentan 25 mg (RR 1.89 [1.39, 2.57]) and doxazosin (RR 1.55 [1.09, 2.20]). CONCLUSIONS: Fourth-line agents targeting the aldosterone pathway, including aldosterone synthase inhibitors and spironolactone, provide clinically significant SBP reductions in rHTN without increasing serious adverse event risk. Due to transitivity violations across trials, indirect comparative rankings remain invalid. Future trials are required to establish efficacy and assess outcomes.