Key result
Fourth-line aldosterone-targeted therapies like lorundrostat drive the largest SBP reductions of ~12 mmHg versus placebo.
Why the study?
While fourth-line intensification is recommended for resistant hypertension, comparative evidence regarding the efficacy and safety of fourth-line antihypertensives remains scattered.
Does fourth-line antihypertensive therapy reduce clinic systolic blood pressure in adults with resistant hypertension?
Meta-Analysis (n=3,931)
Does fourth-line antihypertensive therapy reduce clinic systolic blood pressure in adults with resistant hypertension?
Aldosterone-targeted therapies, including aldosterone synthase inhibitors and spironolactone, provide the most significant SBP reductions as fourth-line agents in resistant hypertension without increasing serious adverse event risk.
Supports aldosterone-targeted therapies as preferred fourth-line agents in resistant hypertension; extends meta-analytic evidence for targeted blockade.
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. Resistant hypertension means blood pressure stays high even after taking three blood pressure medicines, including a water pill.People with resistant hypertension have a higher risk of heart disease, stroke, and kidney problems.We reviewed randomized trials published from 2015 to 2026 that tested a fourth blood pressure medicine in adults with resistant hypertension.We compared how well these medicines lowered the top blood pressure number measured in the clinic over 4 to 12 weeks.
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Alam et al. (2026) conducted a meta-analysis in Resistant hypertension (rHTN) (n=3,931). Fourth-line antihypertensive therapy (e.g., lorundrostat, baxdrostat, spironolactone) vs. Placebo was evaluated on Clinic systolic blood pressure (SBP) (MD -11.70, 95% CI -16.07, -7.33). Fourth-line aldosterone-targeted therapies, including lorundrostat (MD -11.70 mmHg; 95% CI -16.07 to -7.33), provided the largest clinically significant systolic blood pressure reductions versus placebo.
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