Giuseppe Coppolino, Anna Pisano, Laura Rivoli, Davide Bolignano

Resistant hypertension is highly prevalent among the general hypertensive population and the clinical management of this condition remains problematic. Different approaches, including a more intensified antihypertensive therapy, lifestyle modifications, or both, have largely failed to improve patients' outcomes and to reduce cardiovascular and renal risk. As renal sympathetic hyperactivity is a major driver of resistant hypertension, renal sympathetic ablation (renal denervation) has been recently proposed as a possible therapeutic alternative to treat this condition. We sought to evaluate the short- and long-term effects of renal denervation in individuals with resistant hypertension on clinical end points, including fatal and non-fatal cardiovascular events, all-cause mortality, hospital admissions, quality of life, blood pressure control, left ventricular hypertrophy, cardiovascular and metabolic profile, and kidney function, as well as the potential adverse events related to the procedure. We searched the following databases to 17 February 2016 using relevant search terms: the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ClinicalTrials.gov SELECTION CRITERIA: We considered randomised controlled trials (RCTs) that compared renal denervation to standard therapy or sham procedure to treat resistant hypertension, without language restriction. Two authors independently extracted data and assessed study risks of bias. We summarised treatment effects on available clinical outcomes and adverse events using random-effects meta-analyses. We assessed heterogeneity in estimated treatment effects using Chi² and I² statistics. We calculated summary treatment estimates as a mean difference (MD) or standardised mean difference (SMD) for continuous outcomes, and a risk ratio (RR) for dichotomous outcomes, together with their 95% confidence intervals (CI). We found 12 eligible studies (1149 participants). In four studies, renal denervation was compared to sham procedure; one study compared a proximal ablation to a complete renal artery denervation; in the remaining, renal denervation was tested against standard or intensified antihypertensive therapy.None of the included trials was designed to look at hard clinical end points as primary outcomes.When compared to control, there was low quality evidence that renal denervation did not reduce the risk of myocardial infarction (4 studies, 742 participants; RR 1.31, 95% CI 0.45 to 3.84), ischaemic stroke (4 studies, 823 participants; RR 1.15, 95% CI 0.36 to 3.72), or unstable angina (2 studies, 201 participants; RR 0.63, 95% CI 0.08 to 5.06), and moderate quality evidence that it had no effect on 24-hour ambulatory blood pressure monitoring (ABPM) systolic BP (5 studies, 797 participants; MD 0.28 mmHg, 95% CI -3.74 to 4.29), diastolic BP (4 studies, 756 participants; MD 0.93 mmHg, 95% CI -4.50 to 6.36), office measured systolic BP (6 studies, 886 participants; MD -4.08 mmHg, 95% CI -15.26 to 7.11), or diastolic BP (5 studies, 845 participants; MD -1.30 mmHg, 95% CI -7.30 to 4.69). Furthermore, low quality evidence suggested that this procedure produced no effect on either serum creatinine (3 studies, 736 participants, MD 0.01 mg/dL; 95% CI -0.12 to 0.14), estimated glomerular filtration rate (eGFR), or creatinine clearance (4 studies, 837 participants; MD -2.09 mL/min, 95% CI -8.12 to 3.95). Based on low-quality evidence, renal denervation significantly increased bradycardia episodes compared to control (3 studies, 220 participants; RR 6.63, 95% CI 1.19 to 36.84), while the risk of other adverse events was comparable or not assessable.Data were sparse or absent for all cause mortality, hospitalisation, fatal cardiovascular events, quality of life, atrial fibrillation episodes, left ventricular hypertrophy, sleep apnoea severity, need for renal replacement therapy, and metabolic profile.The quality of the evidence was low for cardiovascular outcomes and adverse events and moderate for lack of effect on blood pressure and renal function. In patients with resistant hypertension, there is low quality evidence that renal denervation does not change major cardiovascular events, and renal function. There was moderate quality evidence that it does not change blood pressure and and low quality evidence that it caused an increaseof bradycardia episodes. Future trials measuring patient-centred instead of surrogate outcomes, with longer follow-up periods, larger sample size and more standardized procedural methods are necessary to clarify the utility of this procedure in this population.