Renal Denervation Versus Sham Control for Resistant and Difficult-to-Control Hypertension

Background: Catheter-based renal denervation (RDN) has regained interest as an adjunctive therapy for difficult-to-control hypertension following newer sham-controlled trials using improved devices and more rigorous trial designs. However, the magnitude and consistency of its blood pressure-lowering effect in resistant and treatment-resistant populations remain uncertain. Methods: We followed the PRISMA guidelines and searched the databases - PubMed, Embase, and Cochrane CENTRAL - up to May 2026. We also manually checked the references from eligible trials and recent systematic reviews to supplement our search. The primary analysis included sham-controlled catheter-based RDN trials enrolling resistant, treatment-resistant, or difficult-to-control treated hypertension populations. Strict resistant-hypertension trials and broader uncontrolled-hypertension trials were evaluated separately in sensitivity analyses. Ambulatory systolic blood pressure (SBP) was pooled using random-effects generic inverse-variance models, reporting mean differences (MDs) and 95% confidence intervals (CIs). Risk of bias was assessed using the Cochrane RoB 2 framework. Results: Among 51 screened records, 7 randomized sham-controlled trials involving 1,555 participants met criteria for the primary analysis. Included trials evaluated radiofrequency, ultrasound, and alcohol-mediated RDN platforms. Compared with sham control, RDN significantly reduced ambulatory SBP in resistant/difficult-to-control treated hypertension (MD –3.54 mmHg; 95% CI –5.99 to –1.09; I 2 =60.1%). The results showed a moderate level of heterogeneity, which likely reflected the differences in the devices used, the medication protocols, and the enrolled hypertension phenotype. In a strict resistant-hypertension sensitivity analysis excluding Iberis-HTN and TARGET BP I, the effect remained significant but smaller (MD –2.30 mmHg; 95% CI –4.22 to –0.38; I 2 =0%). In a broader sensitivity analysis of 14 catheter-based sham-controlled trials across resistant and uncontrolled hypertension populations (n=2,872), RDN reduced ambulatory SBP by MD –3.68 mmHg (95% CI –5.24 to –2.11; I 2 =64.6%). Major adverse events, renal artery stenosis, and clinically significant renal function decline were uncommon, with no consistent excess signal observed with RDN versus sham. Conclusions: In randomized sham-controlled trials, catheter-based RDN produced a clinically modest but statistically significant reduction in ambulatory SBP among patients with resistant or difficult-to-control treated hypertension. These findings support RDN as an adjunctive blood pressure-lowering strategy in carefully selected patients, while emphasizing the importance of patient selection, medication protocol, and device platform when interpreting treatment effects.