Renal denervation for resistant hypertension

Giuseppe Coppolino; Anna Pisano; Laura Rivoli; Davide Bolignano

doi:10.1002/14651858.CD011499.pub2

Denervación renal para la hipertensión resistente

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References

References to studies included in this review

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excluded studies
ongoing studies
additional references

Azizi M, Sapoval M, Gosse P, Monge M, Bobrie G, Delsart P, et al. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENER‐HTN): a multicentre, open‐label, randomised controlled trial. Lancet 2015;385(9981):1957‐65.

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References to studies excluded from this review

Jump to:

included studies
ongoing studies
additional references

Ahmed H, Neuzil P, Skoda J, Petru J, Sediva L, Schejbalova M, et al. Renal sympathetic denervation using an irrigated radiofrequency ablation catheter for the management of drug‐resistant hypertension. JACC. Cardiovascular Interventions 2012;5:758‐65.

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Yin Y, Chen W, Ling Z, Xu Y, Liu Z, Su L, et al. Preliminary effects of renal sympathetic denervation with saline irrigated catheter on systolic function in patients with heart failure ‐ a feasibility report from the swan‐HF pilot study. Circulation 2013;128(S22):A17684.

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References to ongoing studies

Jump to:

included studies
excluded studies
additional references

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Jin Y, Jocobs L, Hammer F, Renkin J, Persu A, Staessen JA. Rationale and design of the investigator‐steered project on intravascular renal denervation for management of drug‐resistant hypertension (INSPiRED) trial. Journal of the American Society of Hypertension 2014;8(S4):e71.

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NCT02667912. Distal renal denervation. clinicaltrials.gov/ct2/show/NCT02667912(first received 2016).

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ongoing studies

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Katayama T, Sueta D, Kataoka K, Hasegawa Y, Koibuchi N, Toyama K, et al. Long‐term renal denervation normalizes disrupted blood pressure circadian rhythm and ameliorates cardiovascular injury in a rat model of metabolic syndrome. Journal of the American Heart Association 2013;2(4):e000197.

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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excluded studies
ongoing studies

DENER‐HTN 2015

Methods	Study type: parallel, RCT Country: France Setting: University
Participants	Number of patients randomised/analysed: 106/101 Age: range 18 to 75 years, mean 55.2 Males (%): ˜62.2 Office Blood Pressure (BP; mmHg): ˜158/93 Diabetes mellitus (%): ˜21.7 Hyperlipidaemia (%): ˜46.2 Prior cardiovascular event (%): ˜25.5 Prior stroke (%): ˜10.4 Obstructive sleep apnoea (%): ˜27.4 eGFR (mL/min/1.73 m²): ˜89 Antihypertensive treatment Diuretics (%): 100 ACEIs (%): 84 ARBs (%): 16 CCBs (%): 94.3 Exclusion criteria: secondary hypertension, eGFR < 40 mL/min/1.73 m², history of severe cardiovascular disease or stroke in the previous three months, history of contraindication or intolerance to the study drugs, type 1 diabetes mellitus, brachial circumference > 42 cm, atrial fibrillation, unsuitable renal artery anatomy (accessory renal arteries > 3 mm in diameter, main renal artery < 4 mm in diameter or < 20 mm in length, renal artery stenosis > 30%, prior renal artery intervention or kidney length < 90 mm) ruled out by computed tomography angiogram, magnetic resonance angiogram or renal angiogram
Interventions	Treatment group: N = 48, renal denervation plus standardised stepped‐care antihypertensive treatment (SSAHT) Control group: N = 53, standardised stepped‐care antihypertensive treatment (SSAHT) alone Renal denervation procedure: Ablation done with the single electrode radiofrequency Symplicity catheter. A series of four to six ablations per renal artery were performed. SSAHT: Initial standardised triple therapy (indapamide 1.5 mg, ramipril 10 mg or irbesartan 300 mg, and amlodipine 10 mg daily) + spironolactone 25 mg per day, bisoprolol 10 mg per day, prazosin 5 mg per day, and rilmenidine 1 mg per day Follow‐up: up to 6 months
Outcomes	Day‐time ambulatory blood pressure monitoring (ABPM) 24‐hour ABPM Office and home ABPM Proportion of patients with controlled blood pressure estimated Glomerular Filtration Rate (eGFR) Adverse events
Notes	Modified intention‐to‐treat and per‐protocol analyses performed
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	quote: "The randomisation sequence was generated by computer and stratified by centres using randomised blocks of small size and permutation of treatments within each block"
Allocation concealment (selection bias)	Unclear risk	not specified
Blinding of participants and personnel (performance bias) All outcomes	High risk	open label
Blinding of outcome assessment (detection bias) All outcomes	Low risk	blinded outcome assessors
Incomplete outcome data (attrition bias) All outcomes	Low risk	5/48 (10%) drop‐outs in treatment group (three lost to follow‐up and two with missing ABPM). A modified intention‐to‐treat analysis was performed
Selective reporting (reporting bias)	Low risk	all the pre‐specified outcomes have been reported
Other bias	Low risk	The funder of the study (French Ministry of Health) had no role in study design, data collection, data analysis, data interpretation, or writing of the report

Desch 2015

Methods	Study type: parallel, RCT Country: Germany Setting: University
Participants	Number of patients randomised/analysed (intention‐to‐treat, per‐protocol): 71/(67,63) Age: ˜60 years Males (%): ˜73 Day‐time ABPM (mmHg): ˜144/82 Smokers (%): 14 History of stroke/transient ischaemic attack (%): 7 Coronary artery disease (%): ˜53 Peripheral arterial disease (%): ˜9 Diabetes mellitus (%): ˜45 eGFR (mL/min/1.73 m²): ˜82 Antihypertensive drugs (n): ˜4.4 ≥ 5 antihypertensive drugs (%): ˜40 Antihypertensive treatment Diuretics (%): ˜96 ACEIs (%): ˜54 ARBs (%): ˜47 CCBs (%): ˜67 Direct renin inhibitors (%): ˜6 β‐blockers (%): ˜93 α‐blockers (%): ˜18 Aldosterone antagonists (%): ˜5 Exclusion criteria: mean day‐time systolic BP on 24‐hour ABPM < 135 and > 149 mmHg or mean day‐time diastolic BP < 90 and > 94 mmHg, unsuitable anatomy for renal denervation, severe renal artery stenosis, eGFR < 45 mL/min/1.73 m², change in BP medication in the 4 weeks preceding randomisation, unwillingness to adhere to unchanging BP medication during the study period of 6 months, unstable angina pectoris, myocardial infarction within 6 months prior to randomisation, planned surgery or cardiovascular intervention within 6 months after randomisation, severe heart valve disease, pregnancy, and severe comorbidities with limited life expectancy
Interventions	Treatment group: N = 35, renal denervation Control group: N = 36, sham procedure Renal denervation procedure: Ablation done with the Symplicity Flex catheter. Four to 6 ablation runs of 2 minutes for each renal artery were delivered circumferentially to the renal artery wall from distal to proximal Sham procedure: Angiography of the renal arteries and a simulated renal denervation procedure with 4 to 6 sham runs for each renal artery guided by 2‐minute acoustic signals similar to those of the Symplicity generator Follow‐up: up to 6 months
Outcomes	24‐hour BP in the intention‐to‐treat population 24‐hour BP in the per‐protocol population Adverse events All‐cause death
Notes	Intention‐to‐treat and per‐protocol analyses performed
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	quote: "Patients were assigned to the treatment groups by simple randomisation, in a 1:1 ratio, via an internet‐based system using a computer‐generated list of random numbers"
Allocation concealment (selection bias)	Unclear risk	not specified
Blinding of participants and personnel (performance bias) All outcomes	Low risk	single blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	all investigators (including personnel responsible for BP assessment) were blinded to treatment assignment
Incomplete outcome data (attrition bias) All outcomes	Low risk	8/71 (11%) drop‐outs (6 in RD and 2 in sham procedure); intention‐to‐treat and per‐protocol analyses performed
Selective reporting (reporting bias)	Low risk	all the pre‐specified outcomes have been reported
Other bias	Unclear risk	no apparent other sources of bias

Franzen 2012

Methods	Study type: parallel, RCT Country: Germany Setting: Hospital
Participants	Number of patients randomised/analysed: 27/27 Age: range 18 to 82 years, mean 63 Systolic BP (mmHg): > 150 Antihypertensive drugs (n): ˜4.7
Interventions	Treatment group: N = 21 Control group: N = 6 Follow‐up: up to 6 months
Outcomes	Peripheral systolic BP Central systolic BP Pulse wave velocity (PWV) Aortic stiffness parameters
Notes	study in abstract version only. Unclear if patients were truly randomised (quote: "21 patients were randomised to PRD. 6 patients served as controls")
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	not specified
Allocation concealment (selection bias)	Unclear risk	not specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	not specified
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	not specified
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	not specified
Selective reporting (reporting bias)	Unclear risk	not specified
Other bias	Unclear risk	not specified

HTN‐JAPAN 2015

Methods	Study type: parallel, RCT Country: Japan Setting: University and Hospital
Participants	Number of patients randomised/analysed: 41/41 Age: range 20 to 80 years, mean: ˜58 Males (%): ˜76 Office systolic BP (mmHg): ˜180 24‐h mean systolic ABPM (mmHg): ˜164 type 2 diabetes mellitus (%): ˜50 Hypercholesterolemia (%): ˜32 Prior stroke (%): ˜17 Obstructive sleep apnoea (%): ˜10 eGFR (mL/min/1.73 m²): ≥45 Antihypertensive drugs (n): ˜4.9 Antihypertensive treatment Diuretics (%): 100 ACEIs (%): ˜12 ARBs (%): ˜98 CCBs (%): ˜95 Direct renin inhibitors (%): 0 β‐blockers (%): ˜75 α‐blockers (%): ˜33 Aldosterone antagonist (%): ˜41 Exclusion criteria: Main renal arteries < 4 mm in diameter or < 20 mm treatable length, multiple renal arteries, renal artery stenosis > 50% or renal artery aneurysm in either renal artery, history of prior renal artery intervention including balloon angioplasty or stenting and unilateral (functional or morphological) kidney, > 1 inpatient hospitalisation for hypertensive crisis not related to non‐adherence to medication within the previous year, type 1 diabetes mellitus and ≥ 1 episodes of orthostatic hypotension not related to medication changes, secondary hypertension
Interventions	Treatment group: N = 22, Renal denervation plus antihypertensive medications Control group: N = 19, antihypertensive medications alone Renal denervation procedure: Ablation done with the Symplicity™ RDN system (Medtronic, Santa Rosa, CA, USA). Four to 6 ablation runs of 120 sec for each renal artery were delivered circumferentially to the renal artery wall from distal to proximal Follow‐up: up to 6 months
Outcomes	Change in office BP Change in 24‐hour ABPM and home BP Incidence of major adverse events (composite of 1‐month all‐cause mortality, end stage renal disease, significant embolic event resulting in end‐organ damage, renal artery dissection or perforation requiring intervention, vascular complications, hospitalisation for hypertensive crisis or new renal artery stenosis > 70% confirmed on angiography within 6 months after randomisation)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	not specified
Allocation concealment (selection bias)	Unclear risk	not specified
Blinding of participants and personnel (performance bias) All outcomes	High risk	open label
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	not specified
Incomplete outcome data (attrition bias) All outcomes	Low risk	No drop‐outs. Intention‐to‐treat analysis performed
Selective reporting (reporting bias)	Low risk	all the pre‐specified outcomes have been reported
Other bias	High risk	Honoraria from Medtronic. Involvement of Medtronic in data collection and statistical analyses

Oslo RDN 2014

Methods	Study type: parallel, RCT Country: Norway Setting: University
Participants	Number of patients randomised/analysed: 19/19 Age: range 37 to 70 years, mean ˜60 Males (%): ˜89 Office BP (mmHg): ˜158/90 Diabetes mellitus (%): ˜26 Coronary artery disease (%): ˜35 Left ventricular hypertrophy (%): ˜58 Peripheral arteriosclerosis (%): ˜5 Previous stroke (%): ˜10 Hypercholesterolaemia (%): ˜31 Microalbuminuria (%): ˜37 Cystatin C (mg/L): ˜1.0 Antihypertensive drugs (n): ˜5.1 Antihypertensive treatment Diuretics (%): 100 ACEIs/ARBs (%): 100 CCBs (%): ˜80 Direct renin inhibitors (%): ˜10 β‐blockers (%): ˜73 α‐blockers (%): ˜37 Aldosterone antagonist (%): ˜47 Exclusion criteria: secondary and spurious hypertension, known primary hyperaldosteronism not adequately treated, eGFR < 45 mL/min/1.73 m², urine albumin/creatinine ratio > 50 mg/mmol, type 1 diabetes mellitus, stenotic valvular heart disease, myocardial infarction, unstable angina, or CVA in the prior 6 months, haemodynamically or anatomically significant renal artery abnormalities or stenosis > 50% or prior renal artery intervention, known primary pulmonary hypertension, known pheochromocytoma, Cushing's disease, coarctation of the aorta, hyperthyroidism or hyperparathyroidism
Interventions	Treatment group: N = 9, renal denervation plus baseline antihypertensive treatment Control group: N = 10, drug‐adjusted treatment Renal denervation procedure: renal denervation performed using a 6 French guide Symplicity catheter system. On average 8 (range 6 to 11) radiofrequency ablations were applied per renal artery Follow‐up: up to 6 months
Outcomes	24‐hour ABPM Office BP Day‐time ABPM Normalization of haemodynamics: cardiac index, heart rate, stroke systemic vascular resistance index, pulse wave velocity (PWV), and central blood pressure Adverse events
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	quote: "randomisation performed using a permuted block randomisation list"
Allocation concealment (selection bias)	Low risk	quote: "A hospital employee opened a sealed envelope arranged in a fixed order"
Blinding of participants and personnel (performance bias) All outcomes	High risk	open label
Blinding of outcome assessment (detection bias) All outcomes	High risk	open label
Incomplete outcome data (attrition bias) All outcomes	Low risk	no drop‐outs
Selective reporting (reporting bias)	High risk	some pre‐specified outcomes were not reported
Other bias	Unclear risk	Honoraria from Medtronic and Hemo Sapiens. Involvement of industry in data collection and analyses not specified

Prague‐15 2016

Methods	Study type: parallel, RCT Country: Czech Republic Setting: University
Participants	Number of patients randomised/analysed: 101/101 Age: ˜58 years Males (%): ˜70 Office BP (mmHg): ˜157/91 24‐hour ABPM (mmHg): ˜148/85 Duration of hypertension (yrs): ˜17 Diabetes mellitus (%): ˜20 Coronary heart disease (%): ˜6 Smokers (%): 15 Statin users (%): ˜53 Creatinine (µmol/L): ˜86 Creatinine clearance (mL/s/1.73 m²): ˜1.6 Antihypertensive drugs (n): ˜5.3 Antihypertensive treatment Diuretics (%): 100 ACEIs/ARBs (%): 100 CCBs (%): 89 β‐blockers (%): ˜67 α‐blockers (%): ˜50 Exclusion criteria: secondary hypertension, non‐compliance with medical treatment, presence of any chronic renal disease (serum creatinine > 200 µmol/L), pregnancy, history of myocardial infarction or stroke in the previous 6 months, presence of severe valvular stenotic disease, anatomical abnormality or a variant structure of either renal artery, including aneurysm, stenosis, a reference diameter < 4 mm and a length < 20 mm, an increased bleeding risk (thrombocytopenia < 50.000 platelets/µL and an INR > 1.5)
Interventions	Treatment group: N = 51, renal denervation plus baseline medical therapy Control group: N = 50, intensified pharmacological treatment including spironolactone (PHAR) Renal denervation procedure: ablation involved ≥ 4 to 6 applications of low‐power (8 W) radiofrequency energy to each renal artery using the Symplicity renal denervation system Follow‐up: up to 12 months
Outcomes	24‐hour ABPM Office BP Average number of antihypertensive drugs used after 6 months Renal function (serum creatinine, creatinine clearance)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not specified
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open label
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open label
Incomplete outcome data (attrition bias) All outcomes	Low risk	38/101 (37%) drop‐outs (7 in RD and 31 in PHAR group); intention‐to‐treat and per‐protocol analyses performed
Selective reporting (reporting bias)	Low risk	All the pre‐specified outcomes have been reported
Other bias	Unclear risk	No apparent other sources of bias

RELIEF 2012

Methods	Study type: parallel, RCT Country: Czech Republic Setting: Hospital
Participants	Number of patients randomised/analysed: 23/23 Age: range 18 to 85 years Office BP (mmHg): ≥ 140 Exclusion criteria: secondary hypertension, eGFR < 45 mL/min/1.73 m², type 1 diabetes mellitus, renovascular abnormalities (renal artery stenosis, previous renal artery stenting or angioplasty), life expectancy < 1 year for any medical condition
Interventions	Treatment group: N = 11, bilateral RD with a saline‐irrigated catheter Control group: N = 12, sham procedure Renal denervation procedure: ablation performed with an off‐the‐shelf saline‐irrigated radiofrequency ablation catheter Sham procedure: angiography of the renal arteries (manipulation of catheter within the renal arteries without the delivery of any energy) Follow‐up: up to 3 months
Outcomes	24‐hour ABPM Office BP Serum creatinine
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not specified
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Single‐blind
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not specified
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not specified
Selective reporting (reporting bias)	High risk	Some pre‐specified outcomes were not reported
Other bias	Unclear risk	No apparent other sources of bias

ReSET 2015

Methods	Study type: parallel, RCT Country: Denmark Setting: University and Hospital
Participants	Number of patients randomised/analysed: 69/69 Age: range 30 to 70 years, mean: 56 ± 9 24‐h systolic ABPM (mmHg): ˜159 eGFR (mL/min/1.73 m²): ≥ 30 Exclusion criteria: pregnancy, no compliance, heart failure (NYHA 3 to 4), left ventricular ejection fraction < 50%. Unstable coronary heart disease, coronary intervention within 6 months, myocardial infarction within 6 months. Claudication. Orthostatic syncope within 6 months, secondary hypertension, permanent atrial fibrillation. significant heart valve disease. Clinically significant abnormal electrolytes, haemoglobin, liver enzymes and TSH. Second and third degree heart block, macroscopic haematuria, proximal significant coronary stenosis, renal artery anatomy not suitable for renal artery ablation (stenosis, diameter < 4 mm, length < 20 mm, multiple renal arteries, severe calcifications)
Interventions	Treatment group: N = 36, renal denervation Control group: N = 33, sham procedure Renal denervation procedure: catheter‐based renal denervation by applying low power radiofrequency to the renal artery using the Ardian Medtronic Simplicity catheter. Follow‐up: up to 6 months
Outcomes	24‐hour systolic ABPM after 3‐month follow‐up Daytime and night time BP, dipping status, morning BP surge and BP variation Coronary flow reserve (LAD), diastolic and systolic ventricular function. Left ventricular hypertrophy. Biomarkers of renal sodium excretion Pulse wave velocity, augmentation index, central BP estimates Decline in eGFR ≥ 25% Forearm minimum vascular resistance
Notes	study in abstract version only
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	not specified
Allocation concealment (selection bias)	Unclear risk	not specified
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	not specified
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	not specified
Selective reporting (reporting bias)	High risk	Some pre‐specified outcomes were not reported
Other bias	Unclear risk	not specified

SYMPLICITY HTN‐2 2010

Methods	Study type: parallel, RCT Country: Multicentre Setting: Hospital, University
Participants	Number of patients randomised/analysed: 106/100 Age: 58 years Males (%): ˜57 BP (mmHg): ˜178/98 Race (white) (%): ˜97 Diabetes mellitus (%): ˜97 Coronary artery disease (%): ˜13 Hypercholesterolaemia (%): ˜52 eGFR (mL/min/1.73 m²): ˜82 Serum creatinine (μmol/L): ˜85 Urine albumin‐to‐creatinine ratio (mg/g): ˜118 Cystatin C (mg/L): ˜0.9 Antihypertensive drugs (n): ˜5.3 Antihypertensive treatment Diuretics (%): ˜90 ACEIs/ARBs (%): ˜95 CCBs (%): ˜81 Direct renin inhibitors (%): ˜17 β‐blockers (%): ˜76 α‐blockers (%): ˜26 Aldosterone antagonists (%): ˜17 Vasodilators (%): ˜16 Exclusion criteria: eGFR < 45 mL/min/1.73 m², type 1 diabetes mellitus, contraindications to MRI, substantial stenotic valvular heart disease, pregnancy or planned pregnancy during the study, history of myocardial infarction, unstable angina or cerebrovascular accident in the previous 6 months, haemodynamically significant renal artery stenosis, previous renal artery intervention or renal artery anatomy ineligible for treatment (< 4 mm diameter, < 20 mm length or more than one main renal arteries)
Interventions	Treatment group: N = 52, bilateral renal denervation plus baseline antihypertensive medications Control group: N = 54, baseline antihypertensive medications Renal denervation procedure: renal denervation with Symplicity catheter system. Four to six discrete, low‐power radio frequency treatments were applied along the length of both main renal arteries Follow‐up: up to 6 months
Outcomes	Office BP Short and long‐term safety profile: reduction of eGFR > 25% or new stenosis > 60%, composite cardiovascular end point (myocardial infarction, sudden cardiac death, new onset heart failure, death from progressive heart failure, stroke, aortic or lower limb revascularization procedure, lower limb amputation, death from aortic or peripheral arterial disease, dialysis, death because of renal failure, hospital admission for hypertensive emergency unrelated to non‐adherence or non‐persistence with drugs and hospital admission for atrial fibrillation)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not specified
Allocation concealment (selection bias)	Low risk	quote: "Randomisation was done with sealed envelopes"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open label
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Data analysers were not masked to treatment assignment
Incomplete outcome data (attrition bias) All outcomes	Low risk	6/100 (6%) drop‐outs (3 in RD and 3 in control group); quote: "all analyses were done with data for all patients at randomisation minus those lost to follow‐up"
Selective reporting (reporting bias)	Low risk	All the pre‐specified outcomes have been reported
Other bias	High risk	Data were monitored, collected, and managed by the sponsor (Ardian)

SYMPLICITY HTN‐3 2014

Methods	Study type: parallel, RCT Country: US Setting: Hospital, University
Participants	Number of patients randomised/analysed: 535/535 Age: ˜57 years Males (%): ˜62 Race Black (%): ˜27 White (%): ˜70 Asian (%): ˜0.3 Other (%): ˜1.5 24‐hour ABPM (mmHg): ˜160/90 eGFR < 60 mL/min/1.73 m² (%): ˜9.5 Renal artery stenosis (%): ˜1.8 Obstructive sleep apnoea (%): ˜29 Stroke (%): ˜10 Transient ischaemic attack (%): ˜4 Peripheral artery disease (%): ˜4 Coronary artery disease (%): ˜26 Myocardial infarction (%): ˜8 Diabetes mellitus (%): ˜44 Hyperlipidemia (%): ˜67 Smokers (%): ˜11 Hospitalisation for hypertensive crisis (%): ˜23 Hospitalisation for hypotension (%): ˜2 Antihypertensive drugs (n): ˜5.2 Antihypertensive treatment Diuretics (%): ˜100 ACEIs (%): ˜45 ARBs (%): ˜52 CCBs (%): ˜72 Direct renin inhibitors (%): ˜7 β‐blockers (%): ˜86 α‐blockers (%): ˜12 Aldosterone antagonists (%): ˜25 Exclusion criteria: secondary causes of hypertension or more than one hospitalisation for hypertensive emergency in the previous year, primary pulmonary hypertension, 24‐h ABPM average SBP < 135 mmHg, eGFR < 45 mL/min/1.73 m², type 1 diabetes mellitus, chronic oxygen support or mechanical ventilation other than nocturnal respiratory support for sleep apnoea, renal artery stenosis > 50%, renal artery aneurysm, prior renal artery intervention, multiple renal arteries, renal artery diameter < 4 mm or treatable segment < 20 mm in length, myocardial infarction, unstable angina pectoris, syncope or a cerebrovascular accident within 6 months of the screening period, history of pheochromocytoma, Cushing’s disease, coarctation of the aorta, hyperthyroidism or hyperparathyroidism, pregnancy, nursing or planning to be pregnant
Interventions	Treatment group: N = 364, bilateral renal denervation plus baseline antihypertensive medications Control group: N = 171, sham procedure plus baseline antihypertensive medications Renal denervation procedure: Four to six ablations of up to 120 seconds delivered to the renal artery wall beginning at the distal end of the artery Sham procedure: angiography of the renal arteries Follow‐up: up to 6 months
Outcomes	24‐hour ABPM Office systolic BP Day‐time and night‐time BP Incidence of major adverse events (composite of: all‐cause mortality, end‐stage renal disease, significant embolic event resulting in end‐organ damage, renal artery perforation or dissection requiring intervention, vascular complications, hospitalisation for hypertensive crisis not related to non‐adherence with medications or new renal artery stenosis > 70%)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	quote: "Randomization (2:1 ratio) is performed using an interactive voice response system"
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Single‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	quote: "Outcome's assessors were blinded to the treatment. Blood pressure assessments were done by blinded, trained personnel".
Incomplete outcome data (attrition bias) All outcomes	Low risk	16/535 (3%) drop‐outs (14 in RD and 2 in sham procedure); ITT analysis performed
Selective reporting (reporting bias)	Low risk	All the pre‐specified outcomes have been reported
Other bias	High risk	quote: "Data were collected and analysed by the sponsor (Medtronic, Minneapolis, Minnesota) and independently validated by Harvard Clinical Research Institute (Boston, Massachusetts)"

Warchol 2014

Methods	Study type: parallel, RCT Country: Poland Setting: Institute of Cardiology
Participants	Number of patients randomised/analysed: 35/35 Age: range 32 to 69 years, mean 55.4 ± 7.9 Males (%): 77 Office BP (mmHg): ≥140/90 Obstructive sleep apnoea (apnea/hypopnoea index, AHI): ≥ 15 events/hour Exclusion criteria: renal artery abnormalities, eGFR < 60mL/min, previous TIA, stroke, heart failure, type 1 diabetes mellitus, implantable cardioverter defibrillator or pacemaker
Interventions	Treatment group: N = 19, renal denervation plus antihypertensive medications Control group: N = 16, antihypertensive medications alone Renal denervation procedure: ablation done using a catheterbased procedure (Symplicity) Follow‐up: 3 months
Outcomes	Office BP 24‐hour, day‐time and night‐time ABPM Responses to renal denervation (sleep apnoea course, metabolic assessment, cardiac changes)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not specified
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open label
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open label
Incomplete outcome data (attrition bias) All outcomes	Low risk	No drop‐outs
Selective reporting (reporting bias)	Unclear risk	Not specified
Other bias	Unclear risk	No apparent other sources of bias

Xiang 2014

Methods	Study type: parallel, RCT Country: China Setting: University
Participants	Number of patients randomised/analysed: 16/16 Age: range 18 to 85 years, mean 67.5 Males (%): 100 BP (mmHg): ˜186/98 Diabetes mellitus (%): 31.2 Coronary artery disease (%): 12.5 Hypercholesterolaemia (%): 12.5 Atrial fibrillation (%): 6.25 Heart failure (%): 12.5 eGFR (mL/min/1.73 m²): ˜76 Antihypertensive treatment Diuretics (%): 100 ACEIs/ARBs (%): 100 CCBs (%): 100 Direct renin inhibitors (%): 6.25 β‐blockers (%): 100 α‐blockers (%): 6.25 Exclusion criteria: eGFR < 45 mL/min/1.73 m², type 1 diabetes mellitus, stenotic valvular heart disease and pregnancy. Renal artery anatomy ineligible for treatment (main renal arteries < 4 mm in diameter or < 20 mm in length, abnormality or stenosis in either renal artery, prior renal artery angioplasty or stenting or multiple main renal arteries)
Interventions	Treatment group: N = 8, proximal ablation Control group: N = 8, whole ablation Renal denervation procedure: ablation made through a radiofrequency catheter (5 French, IBI‐Therapy, St. Jude Medical). Six ablations were performed for the whole ablation group, whereas three ablations at the proximal segment for the proximal ablation group. Follow‐up: up to 6 months
Outcomes	Office BP Adverse events
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	quote: "All the patients were randomly divided using a computer algorithm into two groups"
Allocation concealment (selection bias)	Unclear risk	not specified
Blinding of participants and personnel (performance bias) All outcomes	High risk	open label
Blinding of outcome assessment (detection bias) All outcomes	High risk	open label
Incomplete outcome data (attrition bias) All outcomes	Low risk	no drop‐outs
Selective reporting (reporting bias)	Low risk	all the pre‐specified outcomes have been reported
Other bias	Unclear risk	no apparent other sources of bias

Legend
ABPM: ambulatory blood pressure monitoring; ACEi: Angiotensin‐converting enzyme inhibitors; ARBs: Angiotensin receptor blockers; BP: blood pressure; CCBs: calcium channel blockers; CVA: cardiovascular; eGFR: estimated glomerular filtration rate; ITT: intention‐to‐treat; RCT: randomized controlled trial; RD: renal denervation; SBP: systolic blood pressure.

Characteristics of excluded studies [ordered by study ID]

Jump to:

included studies
ongoing studies

Study	Reason for exclusion
Ahmed 2012b	not RCT
Ahmed 2013	wrong population
Brandt 2012	not RCT
Brandt 2012a	not RCT
ChiCTR‐ONC‐12002901	not RCT
ChiCTR‐ONC‐13003231	wrong intervention
ChiCTR‐TNC‐12002900	not RCT
EnligHTN III	not RCT
Esler 2013	wrong population
Ewen 2014	not RCT
Fadl Elmula 2013	not RCT
Grassi 2015	not RCT
Hering 2013	not RCT
Kandzari 2016	wrong population
Karbasi‐Afshar 2013	not RCT
Katholi 2014	wrong population
Kjeldsen 2014	not RCT
Krum 2014	not RCT
Mahfoud 2011	wrong population
Mahfoud 2011a	wrong population
Mahfoud 2012	not RCT
Mahfoud 2014	not RCT
NCT01117025	wrong intervention
NCT01465724	not RCT
NCT01583881	wrong population
NCT01631370	not RCT
NCT01635998	wrong population
NCT01687725	not RCT
NCT01733901	wrong population
NCT01814111	wrong population
NCT01848314	not RCT
NCT01873352	wrong population
NCT01888315	not RCT
NCT01897545	wrong intervention
NCT01901549	wrong population
NCT01907828	wrong population
NCT01932450	wrong population
NCT02016573	wrong population
NCT02057224	not RCT
NCT02115100	wrong population
NCT02115230	wrong population
NCT02155790	not RCT
NCT02164435	not RCT
NCT02272920	wrong population
NCT02559882	wrong intervention
Pokushalov 2012	wrong intervention
Pokushalov 2012a	wrong intervention
Pokushalov 2012b	wrong intervention
Pokushalov 2014	wrong intervention
Pokushalov 2014a	not RCT
Pokushalov 2014b	wrong intervention
RADIANCE‐HTN	wrong population
RAPID	not RCT
ReD	not RCT
REDUCE HTN:REINFORCE	wrong population
RNS‐NTR 4384	not RCT
RSDAH	wrong population
Shipman 2014	not RCT
SPYRAL HTN‐OFF MED	wrong population
SPYRAL HTN‐ON MED	wrong population
SYMPLICITY 2011	not RCT
SYMPLICITY AF	wrong population
UMIN000012020	not RCT
Wage 2015	wrong outcome
WAVE IV	wrong intervention
Wave VI	wrong intervention
Witkowski 2011	not RCT
Yin 2013	wrong population
Zhang 2014	not RCT

Characteristics of ongoing studies [ordered by study ID]

Jump to:

included studies
excluded studies

ALLEGRO‐HTN

Trial name or title	Renal denervation by Allegro System in patients with resistant hypertension
Methods	Study type: parallel, RCT Country: China Setting: Hospital
Participants	Estimated number of patients: 160 Age: range 18 to 65 years Office BP (mmHg): ≥ 160/100 (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) ABPM (mmHg): ≥ 140/90 eGFR (mL/min/1.73 m²): ≥ 45 Exclusion criteria: pregnancy, type 1 diabetes mellitus, secondary hypertension. ICD or pacemaker, myocardial infarction, unstable angina, syncope, cerebrovascular accident in the previous 6 months. Intravascular thrombosis or unstable atherosclerotic plaques, significant valvular heart disease. Renal artery stenosis (≥ 50%) or renal artery aneurysm in either renal artery, history of prior renal artery intervention including balloon angioplasty or stenting. Multiple renal arteries where the main renal artery is estimated to supply < 75% of the kidney. Main renal arteries with < 4 mm diameter or with < 20 mm treatable length (by visual estimation), renal artery abnormalities
Interventions	Treatment group: renal angiography followed by renal sympathetic denervation Control group: renal angiography alone Renal denervation procedure: Allegro Renal Denervation System (AngioCare) Follow‐up: up to 48 months
Outcomes	Change in office SBP from baseline to 6 months Change in average 24‐hour SBP by ABPM from baseline to 6 months Incidence of major adverse events (MAE) at 1 month post‐randomisation Office SBP and DBP at 1, 3, 6 months post‐randomisation Patient‐recorded home systolic blood pressure at 1, 3, 6 months post‐randomisation MAE at 6‐month post‐randomisation, including new renal artery stenosis > 60%
Starting date	May 2013
Contact information	Xiongjing Jiang: [email protected]
Notes

DENERVHTA

Trial name or title	Sympathetic renal denervation versus increment of pharmacological treatment in resistant arterial hypertension
Methods	Study type: parallel, RCT Country: Spain Setting: Hospital
Participants	Estimated number of patients: 50 Age: range 18 to 80 years Office BP (mmHg): ≥ 140/90 (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) eGFR (mL/min/1.73 m²): ≥ 45 Exclusion criteria: pregnancy, secondary hypertension, unsuitable anatomy of renal arteries (diameter < 4 mm and length < 20 mm) including significant (≥ 50%) renal arterial stenosis, renal artery stent, single functional kidney, previous nephrectomy, contrast agent allergy, hyperthyroidia, Treatment with an aldosterone receptor blocker (spironolactone, eplerenone), pre‐randomization serum potassium (K⁺) level ≥ 5.5 mmol/L, significant renal vascular anomalies, significant valvular heart disease, major vascular event (myocardial infarction, unstable angina or cerebrovascular disease) < 6 months prior to study enrolment
Interventions	Treatment group: sympathetic renal denervation Control group: treatment with aldactone Renal denervation procedure: radiofrequency catheter‐based therapy for renal denervation. Four‐to‐six low‐power radio frequency treatments along the length of both main renal arteries. Follow‐up: up to 36 months
Outcomes	24‐hour SBP
Starting date	September 2012
Contact information	Anna OLiveras, PhD 0034932483162 87052 @parcdesalutmar.cat
Notes

DEPART

Trial name or title	Study of catheter‐based renal denervation therapy in hypertension (DEPART)
Methods	Study type: parallel, RCT Country: Belgium Setting: Hospital
Participants	Estimated number of patients: 240 Age: range 18 to 85 years Office BP (mmHg): ≥ 135/85 eGFR (mL/min/1.73 m²): ≥ 30 Exclusion criteria: unsuitable anatomy of renal arteries (diameter < 4 mm and length < 20 mm) including significant (≥ 50%) renal arterial stenosis, renal artery stent or single functional kidney. Secondary hypertension, previous nephrectomy, contrast agent allergy, Hyperthyroidia
Interventions	Treatment group: renal angiography followed by renal sympathetic denervation Control group: renal angiography alone Renal denervation procedure: radiofrequency catheter‐based therapy for renal denervation. Four‐to‐six low‐power radio frequency treatments along the length of both main renal arteries. Follow‐up: up to 48 months
Outcomes	24‐hour SBP Change in GFR and 24h urine sample measure Baroreflex sensitivity Biological markers of acute kidney injury
Starting date	January 2012
Contact information	Contact: ARGACHA Jean Francois, MD [email protected]
Notes

EnligHTN IV

Trial name or title	Multi‐center, randomized, single‐blind, sham controlled clinical investigation of renal denervation for uncontrolled hypertension (EnligHTN IV)
Methods	Study type: parallel, RCT Country: US Setting: University and Hospital
Participants	Estimated number of patients: 590 Age: range 18 to 80 years Office BP (mmHg): ≥ 160 Systolic ABPM ≥ 140 mmHg (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) eGFR (mL/min/1.73 m²): ≥ 45 Exclusion criteria: pregnancy, type 1 diabetes mellitus, chronic oxygen support or mechanical ventilation, primary pulmonary hypertension. Previous renal denervation, secondary hypertension, significant renovascular abnormalities. Myocardial infarction, unstable angina pectoris, or cerebrovascular accident < 180 days prior to enrolment. Blood clotting abnormalities, life expectancy < 12 months. Renal arteries < 4 mm in diameter or < 20 mm in length or multiple renal arteries where the main renal arteries supply < 75% of the kidney, abdominal aortic aneurysm (AAA), pheochromocytoma, Cushing's disease, coarctation of the aorta, hyperthyroidism and hyperparathyroidism
Interventions	Treatment group: renal denervation Control group: sham procedure Renal denervation procedure: renal artery ablation with the EnligHTN™ Renal Denervation System Follow‐up: up to 36 months
Outcomes	Proportion of subjects who experience any major adverse event (MAE) Reduction of office systolic BP at 6 months Procedure‐related adverse events Incidence of achieving ≥ 10 mmHg, ≥ 15 mmHg, and ≥ 20 mmHg reductions in office BP Reduction in ABPM
Starting date	October 2013
Contact information	NA
Notes

ENSURE

Trial name or title	Effect of renal denervation on arterial stiffness and haemodynamics in patients with uncontrolled hypertension (ENSURE)
Methods	Study type: parallel, RCT Country: China Setting: Hospital
Participants	Estimated number of patients: 400 Age: range 18 to 80 years Office BP (mmHg): ≥ 160/100 (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) ABPM (mmHg): ≥ 140/90 eGFR (mL/min/1.73 m²): ≥ 45 Exclusion criteria: pregnancy, type 1 diabetes mellitus, chronic oxygen support or mechanical ventilation, primary pulmonary hypertension, ABPM 24 hour average SBP < 135 mmHg
Interventions	Treatment group: Renal denervation Control group: Baseline anti‐hypertensive medications Renal denervation procedure: MDT‐2211 Renal Denervation System Follow‐up: up to 36 months
Outcomes	Change in 24‐hour ambulatory aortic and brachial blood pressure and blood pressure variability Incidence of major adverse events through 1 month post‐randomisation Change in asymptomatic organ damages (including electrocardiographically or echocardiographically diagnosed left ventricular hypertrophy, carotid intima‐media thickness or plaque, microalbuminuria, pulse wave velocity).
Starting date	September 2014
Contact information	Yawei Xu; [email protected]
Notes

INSPIRED

Trial name or title	Investigatorsteered project on intravascular renal denervation for management of drugresistant hypertension (INSPiRED)
Methods	Study type: parallel, RCT Country: Belgium Setting: University
Participants	Estimated number of patients: 240 Age: range 20 to 69 years Office BP (mmHg): ≥ 140/90 eGFR (mL/min/1.73 m²): ≥ 60 Exclusion criteria: pregnancy, secondary hypertension, unsuitable anatomy of renal arteries (diameter < 4 mm and length < 20 mm) including significant (≥ 50%) renal arterial stenosis, renal artery stent or single functional kidney, isolated systolic or isolated diastolic hypertension, body mass index ≥ 40 kg/m², unstable diabetes mellitus, major cardiovascular events within 6 months prior to enrolment, any serious medical condition, alcohol or substance abuse or psychiatric illnesses, patients on the waiting list of elective surgery
Interventions	Treatment group: renal denervation plus usual medical treatment Control group: usual medical treatment alone Renal denervation procedure: ablation done using the EnligHTN™ multi‐electrode denervation system performing four ablations simultaneously delivered at the mid/distal segment of the renal artery Follow‐up: up to 36 months
Outcomes	24‐hour SBP Change in eGFR proportion of patients reaching and maintaining blood pressure control acute and chronic procedural safety new renal artery stenosis of over 60% decline in eGFR ≥ 25% cardiovascular outcomes
Starting date	April 2014
Contact information	Jan A. Staessen, MD, PhD; [email protected]
Notes

KPS

Trial name or title	Renal protection using sympathetic denervation in patients with chronic kidney disease (KPS)
Methods	Study type: parallel, RCT Country: Czech Republic Setting: University/Hospital
Participants	Estimated number of patients: 40 Age: range 18 to 80 years Office SBP (mmHg): ≥ 140 mmHg (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) eGFR (mL/min/1.73 m²): ≤ 45 Exclusion criteria: pregnancy, type 1 diabetes mellitus, significant valvular disease, renovascular abnormalities, secondary hypertension, white coat hypertension
Interventions	Treatment group: renal denervation and optimal medical therapy Control group: optimal medical therapy alone Follow‐up: up to 60 months
Outcomes	Changes of eGFR Changes in proteinuria (microalbuminuria) Changes in Cystatin C values Time to the development of end‐stage renal disease (ESRD)/Hemodialysis Combined renal end point All‐cause mortality Cardiovascular mortality Changes of systolic and diastolic blood pressure at 6 months Changes in concentration of blood urea nitrogen (BUN), creatinine in 6 months Changes in cardiac structure and function Changes in renal resistive index
Starting date	November 2013
Contact information	Jean Claude Lubanda, Ass.Prof. MD; Jean‐[email protected]
Notes

NCT01848275

Trial name or title	Full length versus proximal renal arteries ablation
Methods	Study type: parallel, RCT Country: China Setting: University
Participants	Estimated number of patients: 40 Age: > 18 Office SBP (mmHg): ≥ 160 eGFR (mL/min/1.73 m²): ≥ 45 Exclusion criteria: pregnancy, type 1 diabetes mellitus, significant valvular disease, ICD, renovascular abnormalities, secondary hypertension, white coat hypertension
Interventions	Treatment group: full length renal denervation by the Thermocool®R catheter Control group: proximity renal denervation by the Thermocool®R catheter Follow‐up: up to 36 months
Outcomes	Office BP ABPM Ablation‐related complications
Starting date	March 2011
Contact information	Yuehui Yin, MD; [email protected]
Notes

NCT01918111

Trial name or title	Effects of renal denervation for resistant hypertension on exercise diastolic function and regression of atherosclerosis and the evaluation of new methods predicting a successful renal sympathetic denervation (RENEWAL‐EXERCISE, ‐REGRESS, and ‐PREDICT Trial From RENEWAL RDN Registry)
Methods	Study type: cross‐over, RCT Country: Republic of Korea Setting: University
Participants	Estimated number of patients: 52 Age: range 20 to 85 years BP ≥ 140/90 mmHg or ≥ 130/80 mmHg for patients with diabetes (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) Exclusion criteria: Hemodynamically or anatomically significant renal artery abnormalities, main renal arteries < 4 mm in diameter or < 20 mm in length or prior renal artery intervention, eGFR < 30 mL/min/1.73m², using the MDRD formula. Valvular heart disease, history of congestive heart failure with left ventricular ejection fraction < 35%, ST‐segment elevation MI within 48 hours, scheduled or planned surgery or cardiovascular intervention in the 6 months after procedure. Chronic diseases with life expectancy < 1 year, hormone replace treatment and/or oral contraceptives, pregnant, nursing or planning to be pregnant, chronic liver cirrhosis
Interventions	Treatment group: renal denervation Control group: adenosine infusion treatment Renal denervation procedure: catheter‐based renal denervation performed via common femoral artery with standard endovascular technique and Simplicity catheter Follow‐up: up to 24 months
Outcomes	Change in BP at 6 and 12 months post procedure
Starting date	September 2013
Contact information	Yangsoo Jang, MD 82‐2‐2228‐8460, [email protected]
Notes

NCT01968785

Trial name or title	Renal denervation in patients with uncontrolled blood pressure
Methods	Study type: parallel, RCT Country: US Setting: University
Participants	Estimated number of patients: 20 Age: range 18 to 85 years Office SBP (mmHg): ≥ 160 (≥ 150 mmHg for type 2 diabetics) (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) eGFR (mL/min/1.73 m²): ≥ 45 Exclusion criteria: pregnancy, type 1 diabetes mellitus, chronic oxygen support or mechanical ventilation, primary pulmonary hypertension, previous renal denervation. Secondary hypertension, significant renovascular abnormalities, myocardial infarction, unstable angina pectoris, or cerebrovascular accident < 180 days prior to enrolment. Blood clotting abnormalities, life expectancy < 12 months, renal arteries < 4 mm in diameter or < 20 mm in length or multiple renal arteries where the main renal arteries supply < 75% of the kidney, abdominal aortic aneurysm (AAA). Pheochromocytoma, Cushing's disease, coarctation of the aorta, hyperthyroidism, hyperparathyroidism
Interventions	Treatment group: beta radiation dosage of 50 Gy during renal denervation procedure Control group: beta radiation dosage of 25 Gy during renal denervation procedure Follow‐up: up to 24 months
Outcomes	Safety (need for intervention to treat renal artery injury induced by the procedure within 6 months) Decrease in SBP and DBP ≥ 10 mmHg at six months following the procedure Effects on Blood Pressure Acute procedural safety; renal artery dissection or perforation requiring intervention and serious groin complications specifically eGFR drop > 25% or new renal artery stenosis > 60% confirmed by angiogram at six months following renal artery brachytherapy procedure Medication changes Serious Adverse Events
Starting date	August 2013
Contact information	Ron Waksman, MD
Notes

NCT02021019

Trial name or title	Renal denervation to improve outcomes in patients with end‐stage renal disease
Methods	Study type: parallel, RCT Country: Australia Setting: University
Participants	Estimated number of patients: 100 Age: range 18 to 85 years Office SBP (mmHg): ≥ 140/90 End stage renal disease Exclusion criteria: myocardial infarction, unstable angina, cerebrovascular accident within 3 months of the screening visit
Interventions	Treatment group: renal denervation Control group: usual care Renal denervation procedure: ablation done using catheter‐based (Symplicity) radiofrequency approach Follow‐up: up to 24 months
Outcomes	Office SBP change 6 months after the procedure
Starting date	January 2014
Contact information	Markus P Schlaich, MD Baker IDI Heart and Diabetes Institute
Notes

NCT02346045

Trial name or title	Effect of renal denervation in end staged renal disease with resistant hypertension
Methods	Study type: parallel, RCT Country: South Korea Setting: Hospital
Participants	Estimated number of patients: 40 Age: range 18 to 90 years Office BP (mmHg): ≥ 160 (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) Haemodialysis patients Exclusion criteria: pregnancy, type 1 diabetes mellitus, secondary hypertension. ICD or pacemaker, myocardial infarction, unstable angina pectoris, syncope, cerebrovascular accident in the previous 6 months. Intravascular thrombosis or unstable atherosclerotic plaques, significant valvular heart disease, renal artery stenosis (≥ 50%) or renal artery aneurysm in either renal artery, history of prior renal artery intervention including balloon angioplasty or stenting, multiple renal arteries where the main renal artery is estimated to supply < 75% of the kidney. Main renal arteries with < 4 mm diameter or with < 20 mm treatable length (by visual estimation). Renal artery abnormalities.
Interventions	Treatment group: renal sympathetic denervation + medical therapy Control group: sham procedure + medical therapy Renal denervation procedure: renal denervation from distal to proximal portion by a Symplicity radiofrequency ablation catheter. Four to five ablations per each renal artery Follow‐up: up to 24 months
Outcomes	Change in office SBP Change in office DBP Change in ABPM Change in plasma norepinephrine Change in pulse wave velocity
Starting date	September 2014
Contact information	Kiyuk Chang, MD, PhD; [email protected]
Notes

NCT02444442

Trial name or title	The Australian SHAM controlled clinical trial of renal denervation in patients with resistant hypertension
Methods	Study type: parallel, RCT Country: Australia Setting: Hospital
Participants	Estimated number of patients: 105 Age: range 18 to 85 years Systolic BP ≥ 140 mmHg and ambulatory day time average ≥ 130mmHg despite concurrent treatment with ≥ 3 anti‐hypertensive drugs Exclusion criteria: renal artery anatomy ineligible for treatment, eGFR < 15mL/min/1.73m² (using MDRD calculation), myocardial infarction, unstable angina or cerebrovascular accident within 3 months of screening visit, life expectancy < 12 months, pregnancy
Interventions	Treatment group: renal denervation Control group: sham procedure Renal denervation procedure: radiofrequency catheter‐based therapy for renal denervation Follow‐up: up to 36 months
Outcomes	Change in ambulatory SBP from baseline to 6 months Change in mean 24‐hour SBP from baseline to 6 months Change in mean office SBP from baseline to 6 months Change in left ventricular function 6 months post procedure Change in serum biochemistry (Plasma Renin Activity, aldosterone levels, estimated Glomerular Filtration Rate (eGFR), inflammatory markers, fasting glucose, fasting insulin, C‐peptide, Homeostasis Model Assessment (HOMA) index, Lipid profile) 6 months post procedure Change in urine biochemistry (Urinary albumin creatinine ratio (UACR), 24 hour urinary creatinine clearance, sodium) 6 months post procedure Change in quality of life
Starting date	June 2015
Contact information	Markus P Schlaich, Professor +61 3 85321502, [email protected] Murray Esler, Professor +61 3 85321338, [email protected]
Notes

NCT02608632

Trial name or title	High frequency guided renal artery denervation for improving outcome of renal ablation procedure
Methods	Study type: parallel, RCT Country: Russia Setting: Research Institute/Hospital
Participants	Estimated number of patients: 170 Age: range 18 to 80 years Office BP (mmHg): ≥ 140/90 mm Hg and < 160/100 mm Hg (moderate resistant hypertension) or ≥160/100 mm Hg (severe resistant hypertension), despite treatment with 3 antihypertensive drugs (including a diuretic) eGFR (mL/min/1⋅73 m²): ≥ 45 (MDRD formula) Exclusion criteria: secondary hypertension, severe renal artery stenosis or dual renal arteries, congestive heart failure, left ventricular ejection fraction < 35%, previous renal artery stenting or angioplasty, type 1 diabetes mellitus
Interventions	Treatment group: renal denervation guided by HFS Control group: renal denervation as standard procedure Renal denervation guided by HFS: high‐frequency stimulation (HFS) used before the initial and after each radiofrequency (RF) delivery within the renal artery. Ablations of 8 to 12 watts applied from the first distal main renal artery bifurcation all the way back to the ostium and performed both longitudinally and rotationally within each renal artery. Renal denervation as standard procedure: ablations of 8 to 12 watts applied from the first distal main renal artery bifurcation all the way back to the ostium and performed both longitudinally and rotationally within each renal artery Follow‐up: 12 months
Outcomes	Number of responders to RD procedure up to 12 months Incidence of adverse events through 12 months after procedure
Starting date	February 2013
Contact information	NA
Notes

NCT02667912

Trial name or title	Distal renal denervation
Methods	Study type: parallel, RCT Country: Russia Setting: Research Institute
Participants	Estimated number of patients: 45 Age: range 18 to 80 years Office BP (mmHg): ≥ 160/100 mmHg, with full doses of at least 3 antihypertensive drugs including a diuretic Exclusion criteria: secondary hypertension, 24‐h mean systolic BP < 135 mmHg, eGFR < 30 mL/min/1.73 m², disease of renal artery, any clinically important disorders/comorbidities significantly increasing risk of endovascular intervention
Interventions	Treatment group: distal renal denervation Control group: conventional renal denervation Distal renal denervation procedure: catheter‐based renal denervation applied to inner surface of segmental branches renal artery in a number of points equally distributed along the length and circumference of the vessels Conventional renal denervation procedure: catheter‐based renal denervation applied to inner surface of the main trunk of renal artery in a number of points equally distributed along its length and circumference Follow‐up: up to 12 months
Outcomes	Between‐group difference in change of 24‐hour mean systolic and diastolic BP assessed by ambulatory blood pressure monitoring (ABPM) at 6 and 12 months of follow‐up Between‐group difference in change of office systolic and diastolic BP at 6 and 12 months of follow‐up Between‐group difference in change of daytime/nighttime systolic and diastolic BP at 6 and 12 months of follow‐up Between‐group difference in renal function (serum creatine and eGFR) at 6 and 12 months of follow‐up Between‐group difference in the incidence of adverse events
Starting date	January 2013
Contact information	Stanislav Pekarskiy, MD, PhD
Notes

NTR3444

Trial name or title	Comparison of renal sympathetic denervation with spironolactone in patients with still a high blood pressure despite the use of 3 different antihypertensive agents
Methods	Study type: parallel, RCT Country: The Netherlands Setting: Hospital
Participants	Estimated number of patients: not provided Age: range 18 to 75 years Treatment‐resistent hypertension Exclusion criteria: secondary hypertension, renal arteries inaccessible for endovascular denervation, suboptimal dosing of BP lowering medication, non compliant to treatment, white coat hypertension, pregnancy, eGFR < 45 mL/min/1.73 m², use of vitamin K antagonist that can not be discontinued for a short period, spironolactone intolerance, myocardial infarction or cerebrovascular accident 3 months prior to randomisation, life expectancy < 2 years
Interventions	Treatment group: renal denervation Control group: antihypertensive treatment + spironolactone Renal denervation procedure: catheter‐based renal denervation Follow‐up: up to 6 months
Outcomes	Between groups difference in 24‐hour ambulatory BP after 6 months of follow‐up Between groups difference in quality of life score
Starting date	June 2012
Contact information	A van den Meiracker, MD, PhD +31‐10‐4639222, [email protected]
Notes

PaCE

Trial name or title	A study of renal denervation in patients with treatment resistant hypertension (PaCE)
Methods	Study type: parallel, RCT Country: Canada Setting: Hospital
Participants	Estimated number of patients: 100 Age: range 18 to 85 years eGFR (mL/min/1.73m²): ≥ 45 Office SBP ≥ 160 mmHg (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) Baseline average systolic ABPM ≥ 135 mmHg Exclusion criteria: pregnancy, type 1 diabetes mellitus, chronic oxygen support or mechanical ventilation, primary pulmonary hypertension, previous renal denervation, secondary hypertension, significant renovascular abnormalities. Myocardial infarction, unstable angina pectoris or cerebrovascular accident < 180 days prior to enrolment. Blood clotting abnormalities, life expectancy < 12 months, renal arteries < 4 mm in diameter or < 20 mm in length or multiple renal arteries where the main renal arteries supply < 75% of the kidney. Pheochromocytoma, Cushing's disease, coarctation of the aorta
Interventions	Treatment group: early renal denervation Control group: delayed renal denervation (6 months after patient's randomisation) Renal denervation procedure: catheter‐based renal denervation by applying low power radiofrequency to the renal artery using the Ardian Medtronic Simplicity catheter Follow‐up: up to 24 months
Outcomes	Average systolic ABPM Proportion of patients achieving target SBP Average daytime and night‐time systolic ambulatory BP Variability of 24‐hour ambulatory systolic BP Average office BP using an approved, automated office BP device Hypertensive medication complexity index (MRCI) Number of hypertensive medications Periprocedural mean cost per patient in Canadian dollars Generic quality of life (EQ‐5D) Body mass index (BMI) 24‐hour urine sodium Acute periprocedural renal injury Creatinine clearance measured on 24‐hour urine Vascular complications Evidence of renal artery stenosis compared to pre‐procedure (determined by renal imaging, CT or MRA) for early intervention group Composite cardiovascular end points Microalbumin to creatinine ratio (MACR) from random urine sample
Starting date	October 2013
Contact information	Harindra C. Wijeysundera, MD
Notes

RAPID II

Trial name or title	Rapid renal sympathetic denervation for resistant hypertension II (RAPID II)
Methods	Study type: parallel, RCT Country: Italy Setting: Hospital/University
Participants	Estimated number of patients: not provided Age: range 18 to 75 years SBP (mmHg): ≥ 160 (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) Exclusion criteria: pregnancy,type 1 diabetes mellitus, renal anatomy unsuitable for treatment, significant valvular heart disease, scheduled or planned surgery within 6 months of study entry
Interventions	Treatment group: bilateral renal ablation plus antihypertensive medications Control group: optimal medical therapy Renal denervation procedure: catheter‐based renal denervation by applying low power radiofrequency to the renal artery using the OneShot system Follow‐up: up to 60 months
Outcomes	Major adverse event (MAE) rate through 30 days post randomisation Change in office SBP from baseline to 6 months Acute procedural safety Chronic procedural safety Reduction in SBP > 10 mmHg at 6 months Changes in office SBP and DBP from baseline to follow‐up visits
Starting date	September 2013
Contact information	Dierk Scheinert, MD Guiseppe Mancia, MD Universita Milano‐Bicocca, Ospedale San Gerardo di Monza
Notes

RDNP‐2012‐01

Trial name or title	Renal denervation for resistant hypertension (RDNP‐2012‐01)
Methods	Study type: parallel, RCT Country: Australia Setting: Hospital
Participants	Estimated number of patients: 100 Age: range 18 to 85 years SBP ≥ 140 mmHg or ≥ 130 mmHg for patients with diabetes (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) eGFR (mL/min/1.73 m²): ≥ 15 Exclusion criteria: pregnancy, unsuitable anatomy of renal arteries (diameter < 4 mm and length < 20 mm)
Interventions	Treatment group: renal denervation Control group: usual care Renal denervation procedure: catheter‐based renal denervation by applying low power radiofrequency to the renal artery using the Ardian Medtronic Symplicity catheter Follow‐up: up to 24 months
Outcomes	Percentage of patients achieving BP target (BP < 140/90 mmHg, or < 130/80 mmHg in diabetic patients) at 6 months post procedure Time to achieve BP target Change in markers of sympathetic nerve activity Change in left ventricular structure and function Change in quality of life Serum and urine biochemistry Change in markers of arterial stiffness
Starting date	February 2012
Contact information	Markus Schlaich, MD Baker IDI Heart & Diabetes Institute
Notes

RENO

Trial name or title	Effect of renal denervation on no‐mediated sodium excretion and plasma levels of vasoactive hormones (RENO)
Methods	Study type: parallel, RCT Country: Denmark Setting: Hospital
Participants	Estimated number of patients: 30 Age: range 30 to 70 years Office BP (mmHg): ≥ 145/75 eGFR (mL/min/1.73 m²): ≥ 45 Exclusion criteria: non‐compliance, pregnancy, radiocontrast allergy, malignancy, congestive heart failure, unstable angina pectoris, previous myocardial infarction or PCI (< 6 mdr), secondary hypertension, renal artery stenosis or multiple renal arteries on CT, claudication
Interventions	Treatment group: renal denervation plus L‐NMMA treatment Control group: sham procedure plus L‐NMMA treatment Renal denervation procedure: catheter‐based renal denervation by applying low power radiofrequency to the renal artery using the Ardian Medtronic Simplicity catheter Follow‐up: up to 24 months
Outcomes	Fractional excretion of sodium after acute L‐NMMA treatment Glomerular filtration rate (GFR) before and after L‐NMMA treatment
Starting date	March 2012
Contact information	Esper N Bech, MD, Ph.D; [email protected]
Notes

RENSYMPIS

Trial name or title	Renal sympathetic denervation and insulin sensitivity (RENSYMPIS Study)
Methods	Study type: parallel, RCT Country: Finland Setting: University
Participants	Estimated number of patients: 60 Age: range 30 to 69 years Office systolic BP (mmHg): ≥ 160 eGFR (mL/min/1.73 m²): ≥ 45 Exclusion criteria: secondary hypertension, pseudohypertension, pregnancy, significant stenotic valvular disease, oral anticoagulation, CCS III‐IV symptoms or CABG/PCI in the previous 6 months, prior stroke, contrast agent allergy, inappropriate renal artery anatomy (< 4mm diameter, < 20mm length)
Interventions	Treatment group: renal artery denervation Control group: optimisation of medical therapy Renal denervation procedure: catheter‐based renal denervation by applying low power radiofrequency to the renal artery using the Ardian Medtronic Simplicity catheter Follow‐up: up to 36 months
Outcomes	Office BP Ambulatory BP Insulin resistance Endothelial function
Starting date	January 2013
Contact information	Tuomas Paana, M.D; [email protected]
Notes

ReSET‐2

Trial name or title	Renal denervation in treatment resistant hypertension (ReSET‐2)
Methods	Study type: parallel, RCT Country: Denmark Setting: University
Participants	Estimated number of patients: 70 Age: range 30 to 70 years Systolic daytime (24‐hour ambulatory blood pressure measurement) > 135 mmHg and < 145 mmHg eGFR (mL/min/1.73 m²): > 30 Exclusion criteria: pregnancy, non compliance, heart failure (NYHA 3‐4), Left ventricular ejection fraction < 50%, unstable coronary heart disease, coronary intervention within 6 months, myocardial infarction within 6 months, claudication, orthostatic syncope within 6 months, secondary hypertension, permanent atrial fibrillation, significant heart valve disease. Clinically significant abnormal electrolytes, haemoglobin, liver enzymes and TSH. Second and third degree heart block, macroscopic haematuria, proximal significant coronary stenosis, renal artery anatomy not suitable for renal ablation (stenosis, diameter < 4 mm, length < 20 mm, multiple renal arteries, severe calcifications). Moderate/severe obstructive sleep apnoea (AHI > 15) if on CPAP treatment
Interventions	Treatment group: renal denervation Control group: sham procedure Renal denervation procedure: catheter‐based renal denervation by applying low power radiofrequency to the renal artery using the EnligHTN catheter Follow‐up: up to 36 months
Outcomes	Change from baseline in daytime SBP Change from baseline in ABPM Change from baseline in central BP, augmentation index and pulse wave velocity Change from baseline in cold pressor response Change from baseline in intensity of medical antihypertensive therapy BP (clinic measurement) Renal function (eGFR and electrolytes)
Starting date	January 2013
Contact information	Henrik Vase, MD, PhD [email protected] Ole Mathiassen, MD, PhD [email protected]
Notes

RSD4CKD

Trial name or title	Renal sympathetic denervation in patients with chronic kidney disease and resistant hypertension (RSD4CKD)
Methods	Study type: parallel, RCT Country: Japan Setting: University
Participants	Estimated number of patients: 100 Age: range 18 to 75 years eGFR (mL/min/1.73 m²): > 20 and < 70 Serum creatinine (mg/dL): 1.5‐5.0 Persistent proteinuria Resistant hypertension Nondiabetic renal disease Exclusion criteria: treatment with corticosteroids, nonsteroidal antiinflammatory or immunosuppressive drugs, connective‐tissue disease, obstructive uropathy, congestive heart failure (NYHA class III or IV), significant renovascular abnormalities (history of prior renal artery intervention, including balloon angioplasty or stenting; double renal artery on one side, distortion, and extension), measured by abdominal ultrasound or renal angiograms. History of myocardial infarction, unstable angina, cerebrovascular accident or alimentary tract haemorrhage in the previous 3 months, sick sinus syndrome, history of allergy to contrast media, psychiatric disorders, drug or alcohol abuse and pregnancy
Interventions	Treatment group: renal denervation + standard therapy Control group: standard therapy Renal denervation procedure: six to nine ablations at 10 W for 1 min each in both renal arteries Follow‐up: up to 36 months
Outcomes	All‐cause mortality Doubling of serum creatinine or end‐stage renal disease Urinary protein excretion and renal function Blood pressure Blood glucose Cardiac function and structure Arrhythmia Pulse wave velocity Quality of life Rehospitalisation rate Dialysis proportion
Starting date	November 2012
Contact information	Shan Qi jun; [email protected]
Notes

RSDforAF

Trial name or title	Renal sympathetic denervation in patients with drug‐resistant hypertension and symptomatic atrial fibrillation (RSDforAF)
Methods	Study type: parallel, RCT Country: China Setting: Hospital
Participants	Estimated number of patients: 200 Age: range 18 to 75 years Office SPB ≥ 160 mmHg (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) Baseline average systolic AMBP ≥ 135 mmHg eGFR (mL/min/1.73 m²): ≥ 45 Paroxysmal and persistent AF Exclusion Criteria: pregnancy, type 1 diabetes mellitus, chronic oxygen support or mechanical ventilation, primary pulmonary hypertension, white‐coat hypertension, previous renal denervation, secondary hypertension, significant renovascular abnormalities, myocardial infarction, unstable angina pectoris or cerebrovascular accident < 180 days prior to enrolment. Blood clotting abnormalities, life expectancy < 12 months, renal arteries < 4 mm in diameter or < 20 mm in length or multiple renal arteries where the main renal arteries supply < 75% of the kidney. Pheochromocytoma, Cushing's disease, coarctation of the aorta, severely enlarged left atria ≥ 55 mm, sick sinus syndrome, reversible causes of AF
Interventions	Treatment group: renal denervation + drugs + cardioversion Control group: drugs Renal denervation procedure: four to eight ablations at 10 W for 60 seconds each in both renal arteries. In patients with persistent AF, direct‐current cardioversion performed immediately after renal sympathetic denervation Follow‐up: up to 36 months
Outcomes	Change in atrial fibrillation burden Rate controlling in persistent AF patients Office SBP Changes in cardiac structure and function Fasting blood glucose Glycated haemoglobin Blood lipids Apnea‐hypopnea index Pulse wave velocity Quality of life
Starting date	July 2012
Contact information	Qijun Shan; [email protected]
Notes

SYMPATHY

Trial name or title	Renal sympathetic denervation as a new treatment for therapy resistant hypertension (SYMPATHY)
Methods	Study type: parallel, RCT Country: The Netherlands Setting: Hospital
Participants	Estimated number of patients: 300 Age: ≥ 18 years Average systolic ABPM ≥ 135 mmHg (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) Exclusion Criteria: Pregnancy, type 1 diabetes mellitus, eGFR (mL/min/1.73 m²) < 20, chronic oxygen support or mechanical ventilation, primary pulmonary hypertension, white‐coat hypertension, previous renal denervation, secondary hypertension, significant renovascular abnormalities. Myocardial infarction, unstable angina pectoris or cerebrovascular accident < 180 days prior to enrolment. Blood clotting abnormalities, life expectancy < 12 months, renal arteries < 4 mm in diameter or < 20 mm in length or multiple renal arteries where the main renal arteries supply < 75% of the kidney. Pheochromocytoma, Cushing's disease, coarctation of the aorta
Interventions	Treatment group: renal denervation plus usual medical treatment Control group: usual medical treatment alone Renal denervation procedure: ablation done using the EnligHTN™ multi‐electrode denervation system performing four ablations simultaneously. One 60‐s ablation delivered at the mid/distal segment of the renal artery Follow‐up: up to 12 months
Outcomes	Change in ABPM Change in the amount of antihypertensive medication Change in BP in eGFR strata Change in office BP Impact on quality of life Cost‐effectiveness
Starting date	May 2013
Contact information	Peter J Blankestijn, MD, PhD; [email protected]
Notes

SYMPLICITY HTN‐4

Trial name or title	Renal denervation in patients with uncontrolled hypertension (SYMPLICITY HTN‐4)
Methods	Study type: parallel, RCT Country: USA Setting: University
Participants	Estimated number of patients: 44 Age: range 18 to 80 years eGFR (mL/min/1.73 m²): > 30 Office SBP > 140 mmHg and < 160 mmHg (despite stable medication regimen including 3 or more antihypertensive medications of different classes, including a diuretic) ABPM average SBP > 135 mmHg Exclusion Criteria: pregnancy, inappropriate renal artery anatomy, type 1 diabetes mellitus, one or more episodes of orthostatic hypotension, chronic oxygen other than nocturnal respiratory support for sleep apnoea, primary pulmonary hypertension, previous organ transplant
Interventions	Treatment group: renal denervation Control group: sham procedure Renal denervation procedure: ablations done with the SYMPLICITY system Follow‐up: up to 24 months
Outcomes	Reaching BP goal Incidence of major adverse events through 1 month post‐procedure Renal artery stenosis measured at 6 months
Starting date	October 2013
Contact information	David Kandzari, MD Piedmont Heart Institute
Notes

Data and analyses

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Comparison 1. Renal denervation vs. sham/standard therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Myocardial infarction Show forest plot	4	742	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.45, 3.84]
Open in figure viewer Analysis 1.1 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 1 Myocardial infarction.
2 ischaemic stroke Show forest plot	4	823	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.36, 3.72]
Open in figure viewer Analysis 1.2 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 2 ischaemic stroke.
3 unstable angina Show forest plot	2	201	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.08, 5.06]
Open in figure viewer Analysis 1.3 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 3 unstable angina.
4 systolic 24‐hour ABPM Show forest plot	5	797	Mean Difference (IV, Random, 95% CI)	0.28 [‐3.74, 4.29]
Open in figure viewer Analysis 1.4 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 4 systolic 24‐hour ABPM.
5 diastolic 24‐hour ABPM Show forest plot	4	756	Mean Difference (IV, Random, 95% CI)	0.93 [‐4.50, 6.36]
Open in figure viewer Analysis 1.5 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 5 diastolic 24‐hour ABPM.
6 systolic office BP Show forest plot	6	886	Mean Difference (IV, Random, 95% CI)	‐4.08 [‐15.26, 7.11]
Open in figure viewer Analysis 1.6 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 6 systolic office BP.
7 diastolic office BP Show forest plot	5	845	Mean Difference (IV, Random, 95% CI)	‐1.30 [‐7.30, 4.69]
Open in figure viewer Analysis 1.7 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 7 diastolic office BP.
8 serum creatinine Show forest plot	3	736	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.12, 0.14]
Open in figure viewer Analysis 1.8 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 8 serum creatinine.
9 eGFR/creatinine clearance Show forest plot	4	837	Mean Difference (IV, Random, 95% CI)	‐2.09 [‐8.12, 3.95]
Open in figure viewer Analysis 1.9 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 9 eGFR/creatinine clearance.
10 bradycardia Show forest plot	3	220	Risk Ratio (M‐H, Random, 95% CI)	6.63 [1.19, 36.84]
Open in figure viewer Analysis 1.10 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 10 bradycardia.
11 femoral artery pseudoaneurysm Show forest plot	2	201	Risk Ratio (M‐H, Random, 95% CI)	3.96 [0.44, 35.22]
Open in figure viewer Analysis 1.11 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 11 femoral artery pseudoaneurysm.
12 flank pain Show forest plot	2	199	Risk Ratio (M‐H, Random, 95% CI)	4.30 [0.48, 38.28]
Open in figure viewer Analysis 1.12 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 12 flank pain.
13 hypotensive episodes Show forest plot	2	119	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.07, 6.64]
Open in figure viewer Analysis 1.13 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 13 hypotensive episodes.
14 hypertensive crisis Show forest plot	3	722	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.35, 1.45]
Open in figure viewer Analysis 1.14 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 14 hypertensive crisis.
15 hyperkalemia Show forest plot	2	200	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.01, 21.33]
Open in figure viewer Analysis 1.15 Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 15 hyperkalemia.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 1 Myocardial infarction.

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Analysis 1.2

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 2 ischaemic stroke.

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Analysis 1.3

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 3 unstable angina.

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Analysis 1.4

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 4 systolic 24‐hour ABPM.

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Analysis 1.5

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 5 diastolic 24‐hour ABPM.

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Analysis 1.6

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 6 systolic office BP.

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Analysis 1.7

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 7 diastolic office BP.

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Analysis 1.8

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 8 serum creatinine.

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Analysis 1.9

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 9 eGFR/creatinine clearance.

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Analysis 1.10

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 10 bradycardia.

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Analysis 1.11

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 11 femoral artery pseudoaneurysm.

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Analysis 1.12

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 12 flank pain.

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Analysis 1.13

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 13 hypotensive episodes.

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Analysis 1.14

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 14 hypertensive crisis.

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Analysis 1.15

Comparison 1 Renal denervation vs. sham/standard therapy, Outcome 15 hyperkalemia.

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Renal denervation versus sham denervation or standard treatment
Patient or population: people with resistant hypertension Setting: Outpatient Intervention: renal denervation Comparison: sham denervation or standard treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Effect estimate (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Sham denervation/ Standard treatment	Renal denervation
myocardial infarction	14 per 1000	18 per 1000 (6 to 54)	RR 1.31 (0.45 to 3.84)	742 (4 studies)	⊕⊕⊝⊝ low^1,2
ischaemic stroke	12 per 1000	14 per 1000 (4 to 45)	RR 1.15 (0.36 to 3.72)	823 (4 studies)	⊕⊕⊝⊝ low^1,2
unstable angina	20 per 1000	12 per 1000 (2 to 101)	RR 0.63 (0.08 to 5.06)	201 (2 studies)	⊕⊕⊝⊝ low^1,2
systolic 24‐hour ABPM (mmHg)	‐	‐	MD 0.28 (‐3.74 to 4.29)	797 (5 studies)	⊕⊕⊕⊝ moderate¹
diastolic 24‐hour ABPM (mmHg)	‐	‐	MD 0.93 (‐4.50 to 6.36)	756 (4 studies)	⊕⊕⊕⊝ moderate¹
systolic office BP (mmHg)	‐	‐	MD ‐4.08 (‐15.26 to 7.11)	886 (6 studies)	⊕⊕⊕⊝ moderate¹
diastolic office BP (mmHg)	‐	‐	MD ‐1.30 (‐7.30 to 4.69)	845 (5 studies)	⊕⊕⊕⊝ moderate¹
eGFR or creatinine clearance (mL/min/1.73m²)	‐	‐	MD ‐2.09 (‐8.12 to 3.95)	837 (4 studies)	⊕⊕⊕⊝ moderate¹
The assumed risk* is the observed risk in the reference (control) group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. Legend ABPM: ambulatory blood pressure monitoring; BP: blood pressure; CI: Confidence interval; CV: cardiovascular; NA: information not available (data sparse or absent); eGFR: estimated glomerular filtration rate; MD: mean difference; RR: Risk Ratio. 1. Wide confidence intervals. 2. Only reported by less than half of the studies.

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Comparison 1. Renal denervation vs. sham/standard therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Myocardial infarction Show forest plot	4	742	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.45, 3.84]

2 ischaemic stroke Show forest plot	4	823	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.36, 3.72]

3 unstable angina Show forest plot	2	201	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.08, 5.06]

4 systolic 24‐hour ABPM Show forest plot	5	797	Mean Difference (IV, Random, 95% CI)	0.28 [‐3.74, 4.29]

5 diastolic 24‐hour ABPM Show forest plot	4	756	Mean Difference (IV, Random, 95% CI)	0.93 [‐4.50, 6.36]

6 systolic office BP Show forest plot	6	886	Mean Difference (IV, Random, 95% CI)	‐4.08 [‐15.26, 7.11]

7 diastolic office BP Show forest plot	5	845	Mean Difference (IV, Random, 95% CI)	‐1.30 [‐7.30, 4.69]

8 serum creatinine Show forest plot	3	736	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.12, 0.14]

9 eGFR/creatinine clearance Show forest plot	4	837	Mean Difference (IV, Random, 95% CI)	‐2.09 [‐8.12, 3.95]

10 bradycardia Show forest plot	3	220	Risk Ratio (M‐H, Random, 95% CI)	6.63 [1.19, 36.84]

11 femoral artery pseudoaneurysm Show forest plot	2	201	Risk Ratio (M‐H, Random, 95% CI)	3.96 [0.44, 35.22]

12 flank pain Show forest plot	2	199	Risk Ratio (M‐H, Random, 95% CI)	4.30 [0.48, 38.28]

13 hypotensive episodes Show forest plot	2	119	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.07, 6.64]

14 hypertensive crisis Show forest plot	3	722	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.35, 1.45]

15 hyperkalemia Show forest plot	2	200	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.01, 21.33]

Comparison 1. Renal denervation vs. sham/standard therapy

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References

References to studies included in this review

DENER‐HTN 2015 {published data only}

Desch 2015 {published data only}

Franzen 2012 {published data only}

HTN‐JAPAN 2015 {published data only}

Oslo RDN 2014 {published data only}

Prague‐15 2016 {published data only}

RELIEF 2012 {published data only}

ReSET 2015 {published data only}

SYMPLICITY HTN‐2 2010 {published data only}

SYMPLICITY HTN‐3 2014 {published data only}

Warchol 2014 {published data only}

Xiang 2014 {published data only}

References to studies excluded from this review

Ahmed 2012b {published data only}

Ahmed 2013 {published data only}

Brandt 2012 {published data only}

Brandt 2012a {published data only}

ChiCTR‐ONC‐12002901 {published data only}

ChiCTR‐ONC‐13003231 {published data only}

ChiCTR‐TNC‐12002900 {published data only}

EnligHTN III {published data only}

Esler 2013 {published data only}

Ewen 2014 {published data only}

Fadl Elmula 2013 {published data only}

Grassi 2015 {published data only}

Hering 2013 {published data only}

Kandzari 2016 {published data only}

Karbasi‐Afshar 2013 {published data only}

Katholi 2014 {published data only}

Kjeldsen 2014 {published data only}

Krum 2014 {published data only}

Mahfoud 2011 {published data only}

Mahfoud 2011a {published data only}

Mahfoud 2012 {published data only}

Mahfoud 2014 {published data only}

NCT01117025 {published data only}

NCT01465724 {published data only}

NCT01583881 {published data only}

NCT01631370 {published data only}

NCT01635998 {published data only}

NCT01687725 {published data only}

NCT01733901 {published data only}

NCT01814111 {published data only}

NCT01848314 {published data only}

NCT01873352 {published data only}

NCT01888315 {published data only}

NCT01897545 {published data only}

NCT01901549 {published data only}

NCT01907828 {published data only}

NCT01932450 {published data only}

NCT02016573 {published data only}

NCT02057224 {published data only}

NCT02115100 {published data only}

NCT02115230 {published data only}

NCT02155790 {published data only}

NCT02164435 {published data only}

NCT02272920 {published data only}

NCT02559882 {published data only}

Pokushalov 2012 {published data only}

Pokushalov 2012a {published data only}

Pokushalov 2012b {published data only}

Pokushalov 2014 {published data only}

Pokushalov 2014a {published data only}

Pokushalov 2014b {published data only}

RADIANCE‐HTN {published data only}

RAPID {published data only}

ReD {published data only}

REDUCE HTN:REINFORCE {published data only}

RNS‐NTR 4384 {published data only}

RSDAH {published data only}

Shipman 2014 {published data only}

SPYRAL HTN‐OFF MED {published data only}

SPYRAL HTN‐ON MED {published data only}

SYMPLICITY 2011 {published data only}

SYMPLICITY AF {published data only}

UMIN000012020 {published data only}