Comparative Efficacy of Treatments for Resistant or Uncontrolled Hypertension: A Network Meta-Analysis of Randomized Trials

Background: Many patients with hypertension fail to achieve recommended blood pressure targets despite treatment with 2 or more antihypertensive drugs. Objectives: We aimed to compare the efficacy of add-on treatments for the management of resistant or uncontrolled hypertension. Methods: We searched Embase and MEDLINE through November 2025. We included randomized trials comparing add-on treatments for resistant or uncontrolled hypertension. The certainty of evidence was assessed using the Confidence In Network Meta-Analysis (CINeMA) framework. The primary outcome was the change in office systolic blood pressure from baseline. Summary mean differences were estimated using random-effects network meta-analysis within a Bayesian framework in patients with resistant hypertension and in the broader population with uncontrolled hypertension. Results: We included 35 trials (8,648 patients and 12 individual treatments) in the systematic review and 30 trials (8,187 patients and 10 individual treatments) in the network meta-analysis. In patients with resistant hypertension, spironolactone (mean difference: -12.43 mm Hg; 95% credible interval: -17.68 to -7.18; CINeMA moderate) and radiofrequency renal denervation (mean difference: -8.74 mm Hg; 95% credible interval: -12.96 to -4.52; CINeMA moderate) were more effective than baseline treatment in reducing office systolic blood pressure. Similar findings were observed in patients with uncontrolled hypertension. No intervention demonstrated clear superiority over another because most head-to-head comparisons included the possibility of no effect. Conclusions: In head-to-head comparisons, no significant differences were observed between add-on treatments in reducing blood pressure among patients with resistant or uncontrolled hypertension. Treatment selection should prioritize treatments with demonstrated superiority over baseline treatment, including spironolactone, baxdrostat, and radiofrequency renal denervation.