Effect of fourth-line antihypertensive therapy on clinic systolic blood pressure in resistant hypertension: a...

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.

To evaluate the efficacy and safety of fourth-line antihypertensives in reducing clinic systolic blood pressure (SBP) in rHTN.

PubMed, Embase, Scopus, and Web of Science were searched (2015-2026) for randomized controlled trials (RCTs) with ≥4 weeks follow-up. Risk of bias was assessed using Cochrane RoB 2. A planned network meta-analysis was not performed because statistical inconsistency and transitivity violations rendered indirect comparisons unreliable. Therefore, pairwise meta-analyses were conducted using random-effects models, with results reported as mean differences (MD) or risk ratios (RR) with 95% confidence intervals (CIs).

Eleven RCTs involving 3,931 adults with rHTN were included. Compared with placebo, the largest SBP reductions were observed with lorundrostat (MD -11.70 mmHg [95% CI -16.07, -7.33]) and baxdrostat 2 mg (MD -10.10 [-12.63, -7.58]). Baxdrostat 1 mg (MD -8.56 [-11.08, -6.04]) produced reductions similar to spironolactone (MD -7.95 [-10.10, -5.80]). Bisoprolol achieved a modest SBP reduction (MD -6.71 mmHg), whereas aprocitentan 12.5 mg reduced SBP by -3.80 mmHg [-6.65, -0.95]. No intervention significantly increased serious adverse events. Higher rates of 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]).

Aldosterone-targeted therapies, including aldosterone-synthase inhibitors and spironolactone, provide clinically meaningful SBP reductions in rHTN without increasing serious adverse event risk. Future trials should clarify comparative efficacy and long-term outcomes.