Abstract
Background
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, in the last decade renal sympathetic ablation (renal denervation) has been proposed as a possible therapeutic alternative to treat this condition.
Objectives
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.
Search methods
For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to 3 November 2020: Cochrane Hypertension’s Specialised Register, CENTRAL (2020, Issue 11), Ovid MEDLINE, and Ovid Embase. The World Health Organization International Clinical Trials Registry Platform (via CENTRAL) and the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov were searched for ongoing trials. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions.
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.
Data collection and analysis
Two authors independently extracted data and assessed study risk 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). Certainty of evidence has been assessed using the GRADE approach.
Main results
We found 15 eligible studies (1416 participants). In four studies, renal denervation was compared to sham procedure; in the remaining studies, renal denervation was tested against standard or intensified antihypertensive therapy. Most studies had unclear or high risk of bias for allocation concealment and blinding.
When compared to control, there was low‐certainty evidence that renal denervation had little or no effect on the risk of myocardial infarction (4 studies, 742 participants; RR 1.31, 95% CI 0.45 to 3.84), ischaemic stroke (5 studies, 892 participants; RR 0.98, 95% CI 0.33 to 2.95), unstable angina (3 studies, 270 participants; RR 0.51, 95% CI 0.09 to 2.89) or hospitalisation (3 studies, 743 participants; RR 1.24, 95% CI 0.50 to 3.11). Based on moderate‐certainty evidence, renal denervation may reduce 24‐hour ambulatory blood pressure monitoring (ABPM) systolic BP (9 studies, 1045 participants; MD ‐5.29 mmHg, 95% CI ‐10.46 to ‐0.13), ABPM diastolic BP (8 studies, 1004 participants; MD ‐3.75 mmHg, 95% CI ‐7.10 to ‐0.39) and office diastolic BP (8 studies, 1049 participants; MD ‐4.61 mmHg, 95% CI ‐8.23 to ‐0.99). Conversely, this procedure had little or no effect on office systolic BP (10 studies, 1090 participants; MD ‐5.92 mmHg, 95% CI ‐12.94 to 1.10). Moderate‐certainty evidence suggested that renal denervation may not reduce serum creatinine (5 studies, 721 participants, MD 0.03 mg/dL, 95% CI ‐0.06 to 0.13) and may not increase the estimated glomerular filtration rate (eGFR) or creatinine clearance (6 studies, 822 participants; MD ‐2.56 mL/min, 95% CI ‐7.53 to 2.42).
Authors' conclusions
In patients with resistant hypertension, there is low‐certainty evidence that renal denervation does not improve major cardiovascular outomes and renal function. Conversely, moderate‐certainty evidence exists that it may improve 24h ABPM and diastolic office‐measured BP. Future trials measuring patient‐centred instead of surrogate outcomes, with longer follow‐up periods, larger sample size and more standardised procedural methods are necessary to clarify the utility of this procedure in this population.
Keywords: Humans, Antihypertensive Agents, Antihypertensive Agents/therapeutic use, Blood Pressure, Denervation, Hypertension, Hypertension/drug therapy, Kidney, Kidney/physiology, Kidney/surgery
Plain language summary
Renal denervation for improving outcomes in individuals with resistant hypertension
Key messages:
We don’t know if using renal denervation can improve risks to the heart, blood vessels and kidneys in people with resistant hypertension.
However, renal denervation might be effective in lowering blood pressure in people with resistant hypertension.
What is resistant hypertension?
Resistant hypertension is a condition in which high blood pressure levels continue even after several blood pressure‐lowering (antihypertensive) medicines have been given at high doses. It is estimated that 10% to 20% of people with hypertension have resistant hypertension.
What did we want to find out?
Renal denervation is a treatment that involves destroying renal nerves through a minimally invasive catheter‐based technique to treat high blood pressure. We wanted to know if renal denervation would safely reduce blood pressure and improve quality of life in people with resistant hypertension.
What did we do?
We searched for studies that compared renal denervation to other treatments or no treatment for who have resistant hypertension.
What did we find?
We found 15 studies that involved over 1400 people with resistant hypertension and lasted from 3 to 24 months.
Main results:
So far, we don’t know if using renal denervation can improve risks to the heart, blood vessels and kidneys in people with resistant hypertension. On the other hand, renal denervation might be effective in lowering blood pressure in people with resistant hypertension.
What are the main limitations of the evidence?
More studies that look at factors important to patients such as quality of life are needed. Studies that last longer and have more participants are needed to find out if denervation can lower blood pressure.
How up to date is the evidence?
The review updates our previous review. The evidence is up to date to November 2020
Summary of findings
Summary of findings 1. Summary of findings.
Renal denervation versus sham denervation or standard treatment | |||||
Patient or population: people with resistant hypertension Setting: outpatient Intervention: renal denervation Comparison: sham procedure 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) |
⊕⊕⊝⊝ low1,2 |
Ischaemic stroke | 14 per 1000 | 14 per 1000 (4 to 41) | RR 0.98 (0.33 to 2.95) | 892 (5 studies) |
⊕⊕⊝⊝ low1,2 |
Unstable angina | 22 per 1000 | 11 per 1000 (2 to 63) | RR 0.51 (0.09 to 2.89) | 270 (3 studies) |
⊕⊕⊝⊝ low1,2 |
Hospitalisation | 28 per 1000 | 35 per 1000 (14 to 87) | RR 1.24 (0.50 to 3.11) | 743 (3 studies) |
⊕⊕⊝⊝ low1,2 |
Systolic 24‐hour ABPM (mmHg) | The mean systolic 24‐hour ABPM ranged across control groups from 139 to 157.1 | The mean systolic 24‐hour ABPM in the intervention groups was on average 5.29 lower (95%CI ‐10.46 to ‐0.13) |
1045 (9 studies) | ⊕⊕⊕⊝ moderate1 | |
Diastolic 24‐hour ABPM (mmHg) | The mean diastolic 24‐hour ABPM ranged across control groups from 80 to 89.3 | The mean diastolic 24‐hour ABPM in the intervention groups was on average 3.75 lower (95%CI ‐7.10 to ‐0.39) | 1004 (8 studies) | ⊕⊕⊕⊝ moderate1 | |
Systolic office BP (mmHg) | The mean systolic office BP ranged across control groups from 140 to 165.7 | The mean systolic office BP in the intervention groups was on average 5.92 lower (95%CI ‐12.94 to 1.10) | 1090 (9 studies) | ⊕⊕⊕⊝ moderate1 | |
Diastolic office BP (mmHg) | The mean diastolic office BP ranged across control groups from 83.8 to 99.2 | The mean diastolic office BP in the intervention groups was on average 4.61 lower (95%CI ‐8.23 to 0.99) | 1049 (8 studies) | ⊕⊕⊕⊝ moderate1 | |
eGFR or creatinine clearance (mL/min/1.73m²) | The mean eGFR or creatinine clearance ranged across control groups from 70.59 to 92.4 | The mean eGFR or creatinine clearance in the intervention groups was on average 2.56 lower (95%CI ‐7.53 to 2.42) | 822 (6 studies) | ⊕⊕⊕⊝ moderate1 | |
Serum creatinine (mg/dL) | The mean serum creatinine ranged across control groups from 0.86 to 1.07 | The mean serum creatinine in the intervention groups was on average 0.03 higher (95%CI ‐0.06 to 0.13) | 721 (5 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 eGFR: estimated glomerular filtration rate MD: mean difference NA: information not available (data sparse or absent) RR: risk ratio.
1. Downgraded 1 level for serious imprecision: Wide confidence intervals
2. Downgraded 1 level because outcome reported by less than half of the studies
Background
Description of the condition
Resistant or refractory hypertension (RH) is characterised by blood pressure levels persistently above target, in spite of the concurrent use of three antihypertensive agents of different classes at best‐tolerated doses, including a diuretic (Calhoun 2008). Data from cross‐sectional and hypertension outcome studies suggest that this condition is not infrequent, with an estimated prevalence of 10% to 20% in the general hypertensive population (Myat 2012). Individuals with resistant hypertension are 50% more likely to experience poor outcomes and adverse cardiovascular events than those with controlled hypertension (Judd 2014). The lack of efficacy of multiple interventions in addition to pharmacological therapy, including dietary and lifestyle modifications, emphasises the importance of finding new effective and safe treatments for treating this condition.
Description of the intervention
Renal sympathetic denervation comprises the ablation of renal afferent and efferent nerves through a minimally invasive, catheter‐based percutaneous intervention performed via femoral access. This is achieved by a thermal increase generated by the application of low‐dose radiofrequency or focussed ultrasound energy that is effective in disrupting large portions of nervous fibres located within the adventitia of the renal artery. Alternative ways to ablate renal nerves, including the administration of neurotoxic agents, cryotherapy or brachytherapy are currently under investigation.
How the intervention might work
Sympathetic hyperactivity has long been acknowledged as a major player in the genesis of resistant hypertension (Huan 2013). In studies conducted in the eighties, surgical sympathectomy was effective in some individuals in lowering blood pressure and symptoms associated with severe hypertension. However, this procedure is no longer used because of considerable side effects (Leong 2014). As with sympathectomy, renal denervation might improve blood pressure control by reducing abnormal renal adrenergic nerve activity. Furthermore, since other conditions, such as congestive heart failure, atrial fibrillation, sleep breathing disorders, and diabetes mellitus are all associated with an overactive sympathetic drive, this procedure might result in pleiotropic benefits, including improvements in glycaemic levels, sleep apnoea, arrhythmias, and oxidative stress (Witkowski 2011). Of note, in spontaneously hypertensive rats, renal denervation was able to ameliorate metabolic control and to prevent hypertensive stroke and brain injury, in addition to controlling blood pressure (Nakagawa 2013a; Nakagawa 2013b).
Why it is important to do this review
As shown in a milestone meta‐analysis, renal denervation reduced mean blood pressure at six months in individuals with persistent hypertension; intra‐procedural complications, including renal artery dissection and femoral pseudoaneurysms, were rare (Davis 2013). Unfortunately, data were mostly derived from observational, uncontrolled studies with limited follow‐up, small sample sizes, and high heterogeneity in blood pressure measurement. Since then, randomised controlled trials (RCTs) (INSPIRED; Warchol 2014) evaluated the effectiveness of this procedure in treating RH with variable results. In more recent meta‐analyses including RCTs, renal denervation did not produce significant benefit on blood pressure control in individuals with persistent hypertension (Fadl Elmula 2017, Agasthi 2019). Whether BP control really benefits from renal denervation, and whether this procedure might impact hard outcomes, such as mortality and cardiovascular events, remains unknown at this time. Over the past year, new evidence, based on larger RCTs and long‐term data on the efficacy of renal denervation on surrogate and hard end points, is now accruing, showing promising results. Therefore, an updated assessment of the efficacy and safety profile of this procedure is mandatory to define whether the benefits of implementing renal denervation in the clinical management of individuals with resistant hypertension outweigh the harms.
Objectives
To evaluate the short‐ and long‐term effects of renal sympathetic denervation in individuals with resistant hypertension on:
patient‐centred end points, including cardiovascular morbidity and mortality, all‐cause mortality, hospital admissions, and quality of life;
blood pressure control;
cardiovascular and metabolic profile;
kidney function;
adverse events, including but not limited to bradycardia, hypotension episodes, femoral artery pseudoaneurysm, and renal artery dissection.
Methods
Criteria for considering studies for this review
Types of studies
All RCTs and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth, or other predictable methods) of individuals with resistant hypertension undergoing renal sympathetic denervation procedures, without duration or language restrictions.
Types of participants
Adults (older than 18 years), with refractory or resistant hypertension, defined by the presence of a clinic blood pressure above target (higher than 140/90 mmHg, or higher than 130/80 mmHg in individuals with type 2 diabetes mellitus), despite the concomitant use of three or more antihypertensive drugs of different classes, including a diuretic.
Types of interventions
Any transcatheter renal sympathetic denervation procedures performed using contemporary percutaneous catheters compared with standard medical therapy or sham intervention.
Types of outcome measures
We considered a set of primary and secondary outcomes, according to clinical importance:
Primary outcomes
Fatal and non‐fatal cardiovascular events, including but not limited to myocardial infarction, cerebrovascular accidents, and congestive heart failure
All‐cause mortality
Any hospitalisation and duration of hospital stay (if long‐term data are available)
Quality of life (assessed using validated scales or any other instrument as reported by authors, such as the Short‐Form Health Survey (SF‐36)
Secondary outcomes
Blood pressure control (change in ABPM and clinic systolic, diastolic, and mean blood pressure)
Left ventricular hypertrophy
Atrial fibrillation episodes
Obstructive sleep apnoea severity (apnoea‐hypopnoea index)
Kidney function (change in serum creatinine, glomerular filtration rate (GFR), proteinuria or albuminuria, need for renal replacement therapy)
Metabolic profile (change in lipid and blood glucose levels and insulin resistance indices)
Withdrawal due to adverse effects, including but not limited to bradycardia and hypotensive episodes, femoral artery pseudoaneurysm, renal artery dissection, transient dizziness, pitting oedema, flank pain, and anaemia
Search methods for identification of studies
Electronic searches
For this updated review, the Cochrane Hypertension Information Specialist conducted systematic searches in the following databases for randomised controlled trials without language, publication year or publication status restrictions:
the Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (to 3 November 2020);
the Cochrane Central Register of Controlled Trials (Issue 10, 2020) via Cochrane Register of Studies (to 3 November 2020);
Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions(R) (to 2 November 2020);
Ovid Embase (to 2 November 2020);
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov ClinicalTrials.gov (www.clinicaltrials.gov) (to 3 November 2020);
World Health Organization International Clinical Trials Registry Platform (via CENTRAL) (to 3 November 2020).
The Information Specialist modelled subject strategies for databases on the search strategy designed for MEDLINE. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Higgins 2011). Search strategies for major databases are provided in Appendix 1.
Searching other resources
The Cochrane Hypertension Information Specialist searched the Hypertension Specialised Register segment (which includes searches of MEDLINE and Epistemonikos for systematic reviews) to retrieve existing systematic reviews relevant to this systematic review, so that we could scan their reference lists for additional trials.
We checked the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials.
Where necessary, we contacted authors of key papers and abstracts to request additional information about their trials.
We did not perform a separate search for adverse effects of interventions used for the treatment of hypertension. We considered adverse effects described in included studies only.
We checked the reference lists of cardiology and nephrology textbooks for additional resources.
Data collection and analysis
Selection of studies
Two authors (AL and LFI) independently screened titles and abstracts, and retained studies and reviews that might include relevant data or information on trials for review in detail; studies that were not applicable were excluded. The same authors (AL and LFI) independently assessed retrieved abstracts and, if necessary, the full text of these studies to determine which studies satisfied the inclusion criteria.
Data extraction and management
Two authors (AL and LFI) independently carried out data extraction using a standard electronic data extraction form. We arranged for translations of studies reported in non‐English language journals before assessment. If more than one publication of a study existed, we grouped the reports together and used the publication with the most complete data in the analyses. If relevant outcomes were published only in earlier versions of the study, we used such data.
Assessment of risk of bias in included studies
Two authors (AL and LFI) independently assessed the following items using the risk of bias assessment tool (Higgins 2011), which contained the following domains:
Sequence generation (selection bias);
Allocation concealment (selection bias);
-
Blinding:
Participants and personnel (performance bias)
Outcome assessors (detection bias);
Completeness of outcome data (attrition bias);
Selective outcome reporting (reporting bias);
Other sources of bias: e.g. funding bias.
Measures of treatment effect
We expressed dichotomous outcome results as risk ratios (RRs) with 95% confidence intervals (CIs). Where continuous scales of measurement were used to assess the effects of treatment, we reported results as mean differences (MDs) or standardised mean differences (SMDs) if different scales were reported, with 95% CI.
Unit of analysis issues
We appraised unit of analysis issues according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). For studies with more than two arms, we included only arms that met the inclusion criteria of the review. There were no further unit of analysis issues as no‐cluster RCTs or crossover studies have been found.
Dealing with missing data
We requested additional information from the corresponding author(s) by email. We carefully evaluated important data, such as numbers of screened and randomised participants, as well as numbers of intention‐to‐treat, as‐treated, and per‐protocol populations. We explored attrition in the study, such as dropouts, losses to follow‐up, and withdrawals. We appraised issues of missing data and imputation methods (such as last‐observation‐carried‐forward) according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Assessment of heterogeneity
We tested heterogeneity with a Chi² test on n ‐ 1 degrees of freedom, using an alpha of 0.05 for statistical significance, and used the I² statistic (Higgins 2003). We considered I² values of 25%, 50%, and 75% to correspond to low, medium, and high levels of heterogeneity.
Assessment of reporting biases
Where possible, we had planned to construct funnel plots to assess for the potential existence of small study bias (Higgins 2011).
Data synthesis
We analysed data for each outcome using Review Manager Web (RevMan 2014) in an attempt to estimate the overall effect. Data were pooled using random‐effects meta‐analysis, but the fixed‐effect model was also analysed to ensure robustness of the model chosen and susceptibility to outliers.
Subgroup analysis and investigation of heterogeneity
We had planned subgroup analyses to explore possible sources of heterogeneity including:
participants (age, race)
type of intervention (type of catheter employed and technique used)
type of comparator (standard therapy, sham, other denervation procedure)
presence/absence of diabetes
presence/absence of CV disease
severity of renal function impairment
duration and severity of hypertension (number and dosage of antihypertensive drugs used)
We had also planned an exploration of the effect of short‐ and long‐term follow‐up as a source of significant heterogeneity between studies.
However, due to the few number of studies eventually included, the majority of these subgroup analyses was not feasible.
Sensitivity analysis
We had planned sensitivity analyses to explore the influence of the following factors on the effect size:
repeating the analysis excluding any large studies, to establish how much they impacted on the results;
repeating the analysis taking into account the risk of bias;
repeating the analysis excluding unpublished studies.
Summary of findings and assessment of the certainty of the evidence
We had planned to construct a summary table via the GRADEpro‐GDT(GRADEpro GDT 2015), reporting:
a summary of findings from all the primary outcomes and a summary of findings from some secondary outcomes, that have been pre‐selected according to their clinical importance. These included cardiovascular outcomes (myocardial infarction, ischaemic stroke, unstable angina), hospital admission, blood pressure outcomes (24 h‐ABPM and office blood pressure) and renal function (serum creatinine and eGFR).
the certainty of the body of evidence supporting each of these outcomes using the GRADE approach (GRADEpro GDT 2015).
Results
Description of studies
The literature search is current to 3 November 2020.
Results of the search
The search identified 2749 records; we also identified five more records from additional searches or handsearches. Full‐text assessment of 259 records for this updated review resulted in the inclusion of 15 eligible studies (88 articles), comprising a total of 1416 participants (DENER‐HTN 2015; DENERVHTA; Desch 2015; Franzen 2012; HTN‐JAPAN 2015; INSPIRED; Moiseeva 2020‐B; Oslo RDN 2014; Prague‐15; RELIEF 2012; ReSET 2015; SYMPATHY; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014; Warchol 2014), and 25 ongoing trials (27 articles; ALLEGRO‐HTN; DEPART; EnligHTN IV; ENSURE; KPS; NCT01848275; NCT01918111; NCT01968785; NCT02021019; NCT02346045; NCT02444442; NCT02608632; NCT02900729; NTR3444; PaCE; RADIANCE‐HTN; RAPID II; RDNP‐2012‐01; RENO; RENSYMPIS; ReSET‐2; RSD4CKD; RSDARH; RSDforAF; SYMPLICITY HTN‐4). We contacted the authors of some of the included studies for additional information about study methods and unreported data; five investigators responded to our queries (DENER‐HTN 2015; Moiseeva 2020‐B; Oslo RDN 2014; Prague‐15; SYMPLICITY HTN‐2 2010). Figure 1 depicts the flow of study selection.
1.
Study flow diagram
Included studies
All fifteen included studies were parallel‐group RCTs with adult participants (Characteristics of included studies). Study duration ranged from three to 24 months. All studies except ReSET 2015, SYMPATHY, and Warchol 2014 excluded patients with estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m². The renal sympathetic denervation procedure was performed with the electrode radiofrequency Symplicity catheter system in 11 studies (DENER‐HTN 2015; DENERVHTA; Desch 2015; HTN‐JAPAN 2015; Moiseeva 2020‐B; Oslo RDN 2014; Prague‐15; ReSET 2015; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014; Warchol 2014). Ablation was performed with an off‐the‐shelf saline‐irrigated radiofrequency catheter in RELIEF 2012. In INSPIRED and SYMPATHY, ablation was made with the EnligHTN™ multi‐electrode denervation system. In Franzen 2012, details of the denervation procedure were not provided. In seven studies, a series of four to six ablations per renal artery was performed (DENER‐HTN 2015; DENERVHTA; Desch 2015; HTN‐JAPAN 2015; Prague‐15; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014). Four ablations simultaneously were delivered at the mid/distal segment of the renal artery by INSPIRED and SYMPATHY. In Oslo RDN 2014, an average of eight (range 6 to 11) radiofrequency ablations were applied per renal artery. The number of ablations was not reported in five studies (Franzen 2012; Moiseeva 2020‐B; RELIEF 2012; ReSET 2015; Warchol 2014). In four studies, renal denervation was compared to sham procedure (Desch 2015; RELIEF 2012; ReSET 2015; SYMPLICITY HTN‐3 2014). Franzen 2012, HTN‐JAPAN 2015, INSPIRED, SYMPLICITY HTN‐2 2010, SYMPATHY, and Warchol 2014 compared renal denervation plus antihypertensive medications with antihypertensive medications alone. In five studies, the effects of renal denervation plus standard antihypertensive therapy were tested against an intensified pharmacological regimen (DENER‐HTN 2015; DENERVHTA; Moiseeva 2020‐B, Oslo RDN 2014; Prague‐15). One trial (Moiseeva 2020‐M; Moiseeva 2020‐B) randomly divided subjects into three equal groups according to the supplementation to the previously administered medication (M‐group, B‐group, D‐group). Outcomes available from studies were: incidence of myocardial infarction (DENER‐HTN 2015; Oslo RDN 2014; Prague‐15; SYMPLICITY HTN‐3 2014), ischaemic stroke (DENER‐HTN 2015; Prague‐15; ReSET 2015; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014), unstable angina (Prague‐15; ReSET 2015; SYMPLICITY HTN‐2 2010), all‐cause‐mortality and hospitalisations (Prague‐15; ReSET 2015; SYMPATHY; SYMPLICITY HTN‐3 2014), quality of life (self‐reported health status)( INSPIRED), 24‐hour ambulatory blood pressure monitoring (ABPM) (DENER‐HTN 2015; DENERVHTA; Desch 2015; HTN‐JAPAN 2015; INSPIRED; Moiseeva 2020‐B; Moiseeva 2020‐M; Oslo RDN 2014; Prague‐15; RELIEF 2012; ReSET 2015; SYMPATHY; SYMPLICITY HTN‐3 2014; Warchol 2014), daytime and/or night‐time ABPM (DENERVHTA; INSPIRED; Oslo RDN 2014; ReSET 2015; SYMPATHY; SYMPLICITY HTN‐3 2014; Warchol 2014), office BP (DENER‐HTN 2015; DENERVHTA; HTN‐JAPAN 2015; INSPIRED; Moiseeva 2020‐B; Moiseeva 2020‐M; Oslo RDN 2014; Prague‐15; RELIEF 2012; SYMPATHY; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014; Warchol 2014), home BP (DENER‐HTN 2015; HTN‐JAPAN 2015), left ventricular hypertrophy (DENERVHTA; Prague‐15; ReSET 2015; Warchol 2014) and kidney function (serum creatinine, eGFR) (DENER‐HTN 2015; DENERVHTA; HTN‐JAPAN 2015; INSPIRED; Oslo RDN 2014; Prague‐15; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014; Warchol 2014), glucose metabolism measures (Prague‐15; Warchol 2014). Only Warchol 2014 reported on obstructive sleep apnea (OSA) severity. In addition, DENER‐HTN 2015; DENERVHTA; Desch 2015; HTN‐JAPAN 2015; INSPIRED; Oslo RDN 2014; Prague‐15; ReSET 2015; SYMPATHY; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014; and Warchol 2014 looked systematically at the incidence of adverse effects associated to the procedure.
Excluded studies
We excluded 1056 records, 912 of which were excluded at title and abstract screening (Figure 1). One hundred and forty‐four records were excluded after full‐text evaluation. Reasons for exclusion were: inappropriate population, problem, or both (294 reports); inappropriate intervention, outcome, or both (463 reports); not an RCT (48 reports); editorial, comment, letter or review articles without reporting randomised trial data (251 reports). See Characteristics of excluded studies.
Risk of bias in included studies
We have shown summaries of the risks of bias in the included studies in Figure 2 and Figure 3.
2.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
The overall risk of selection bias was highly variable. Random sequence generation was detailed in seven studies with a low risk of bias (DENER‐HTN 2015; DENERVHTA; Desch 2015; INSPIRED; Oslo RDN 2014; ReSET 2015; SYMPATHY), while there were insufficient data to inform assessment in the remainder. Only two of the included studies adequately described the allocation concealment methodologies that were applied (Oslo RDN 2014; SYMPLICITY HTN‐2 2010); this information was not stated in the remainder.
Blinding
The risk of performance and detection bias was also variable. Eight studies were fully open‐label, thus allowing a high risk of both biases (DENERVHTA; HTN‐JAPAN 2015; INSPIRED; Oslo RDN 2014; Prague‐15; SYMPATHY; SYMPLICITY HTN‐2 2010; Warchol 2014). DENER‐HTN 2015 was an open‐label trial but outcome assessors were blinded to the procedure. ReSET 2015 was double‐blinded; participants and personnel were unaware of treatment arm, while blinding of outcome assessment was not stated. In Desch 2015 and SYMPLICITY HTN‐3 2014, participants and outcome assessors were blinded to the treatment. In RELIEF 2012, patients were blinded to renal denervation or sham procedure, while outcome assessor blinding was unclear. In Franzen 2012 and Moiseeva 2020‐B, no overall information on blinding was specified.
Incomplete outcome data
The overall dropout rate ranged from 3% to 37% with no differences among groups, with the exception of DENER‐HTN 2015, INSPIRED and SYMPLICITY HTN‐3 2014, in which dropouts were more prevalent in the treatment arm, and in Prague‐15, in which 31 participants (62%) dropped out from the control group. Three studies reported no dropouts (HTN‐JAPAN 2015; Oslo RDN 2014; ReSET 2015). The information provided on attrition bias was insufficient to permit assessment in three studies (Franzen 2012; Moiseeva 2020‐B; RELIEF 2012). Seven studies were analysed on an intention‐to‐treat basis (DENER‐HTN 2015; DENERVHTA; HTN‐JAPAN 2015; Oslo RDN 2014; ReSET 2015; SYMPATHY; SYMPLICITY HTN‐3 2014). In INSPIRED and SYMPLICITY HTN‐2 2010, analyses were performed on a per‐protocol basis. In Desch 2015 and Prague‐15, results were analysed on both a per‐protocol and intention‐to‐treat basis.
Selective reporting
All the predefined outcomes were reported in 11 studies (DENER‐HTN 2015; DENERVHTA; Desch 2015; HTN‐JAPAN 2015; INSPIRED; Moiseeva 2020‐B; Oslo RDN 2014; Prague‐15; SYMPATHY; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014). Some prespecified outcomes were not reported in RELIEF 2012 (office BP, serum creatinine) or in ReSET 2015 (daytime and night‐time BP, dipping status, diastolic and systolic ventricular function, left ventricular hypertrophy, renal sodium excretion, pulse wave velocity, a 25% or more decline in eGFR). Possible selective reporting was unclear in the remainder.
Other potential sources of bias
Seven studies declared funding from industry (DENER‐HTN 2015; DENERVHTA; HTN‐JAPAN 2015; Oslo RDN 2014; SYMPATHY; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014). In DENER‐HTN 2015 and DENERVHTA, the authors stated that the sponsor had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. In Oslo RDN 2014, the involvement of industry was unclear. In HTN‐JAPAN 2015, SYMPLICITY HTN‐2 2010, and SYMPLICITY HTN‐3 2014, the authors declared that data were monitored, collected, and managed by the sponsor. In SYMPATHY, an author received personal fees from Medtronic during the conduct of the study. No other sources of apparent bias were noticed in the other studies.
Effects of interventions
See: Table 1
The main effects of renal denervation on the primary outcomes and on the most important secondary outcomes are summarised in Table 1.
Primary outcomes
Non‐fatal cardiovascular events
In a meta‐analysis of four studies (742 participants), renal denervation may have little or no effect on the risk of myocardial infarction compared to sham or standard treatment (RR 1.31, 95% CI 0.45 to 3.84; Analysis 1.1); there was no heterogeneity (Chi² = 0.79; P = 0.85; I² = 0%; DENER‐HTN 2015; Oslo RDN 2014; Prague‐15; SYMPLICITY HTN‐3 2014). In data pooled from five studies (892 participants), renal denervation may have little or no effect on the risk of ischaemic stroke compared to no treatment (RR 0.98, 95% CI 0.33 to 2.95; Analysis 1.2); there was no heterogeneity (Chi² = 1.86; P = 0.76; I² = 0%; DENER‐HTN 2015; Prague‐15; ReSET 2015; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014). In a meta‐analysis of three studies (270 participants), renal denervation may have little or no effect on the risk of unstable angina compared to sham or standard therapy (RR 0.51, 95% CI 0.09 to 2.89; Analysis 1.3); there was no heterogeneity (Chi² = 0.0.44; P = 0.80; I² = 0%; Prague‐15; ReSET 2015; SYMPLICITY HTN‐2 2010).
1.1. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 1: Myocardial infarction
1.2. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 2: Ischaemic stroke
1.3. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 3: Unstable angina
All‐cause mortality
Data on all‐cause mortality were provided by two studies; in SYMPLICITY HTN‐3 2014, two patients in the renal denervation group and one in the sham group died. No deaths were recorded by Prague‐15 during the 24‐month follow‐up.
Hospitalisation
Data on hospitalisation were reported by three studies. In a meta‐analysis of three studies (743 participants), renal denervation may have little or no effect on the risk of hospitalisation compared to sham or standard treatment (RR 1.24, 95% CI 0.50 to 3.11; Analysis 1.4); there was no heterogeneity (Chi² = 1.00; P = 0.61; I² = 0%; ReSET 2015; SYMPATHY; SYMPLICITY HTN‐3 2014).
1.4. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 4: Hospital admission
SYMPLICITY HTN‐3 2014 recorded hospital admissions for atrial fibrillation episodes and for new‐onset of heart failure; otherwise, in ReSET 2015 and SYMPATHY, patients required hospitalisation to adjust antihypertensive medication.
Quality of life
Data on quality of life (self‐reported health status) were only available in INSPIRED. After six‐month follow‐up, the self‐reported health status was 53.8 ± 22.3 in the control group and 75.0 ± 14.1 (baseline‐adjusted between‐group difference: 13.6 ;95% CI ‐7.4 to 34.6; P = 0.28).
Secondary outcomes
24‐hour ambulatory blood pressure monitoring (ABPM)
Twenty‐four hour ABPM was measured in 13 studies (DENER‐HTN 2015; DENERVHTA; Desch 2015; HTN‐JAPAN 2015; INSPIRED; (Moiseeva 2020‐B; Moiseeva 2020‐M); Oslo RDN 2014; Prague‐15; RELIEF 2012; ReSET 2015; SYMPATHY; SYMPLICITY HTN‐3 2014; Warchol 2014). In a meta‐analysis of nine studies (10 subgroups) (1045 participants) (DENER‐HTN 2015; HTN‐JAPAN 2015; INSPIRED; Moiseeva 2020‐B; Moiseeva 2020‐M; Oslo RDN 2014; ReSET 2015; SYMPATHY; SYMPLICITY HTN‐3 2014; Warchol 2014), renal denervation may reduce systolic 24‐hour ABPM when compared with sham or standard therapy (MD ‐5.29 mmHg, 95% CI ‐10.46 to ‐0.13; Analysis 1.5). The high heterogeneity found in this analysis (Chi² = 39.14; P < 0.0001; I² = 77%) was fully dependent on the type of radiofrequency system, multi‐electrode instead of a single electrode catheter (I² = 6%). In data pooled from eight studies (9 subgroups) (1004 participants) (DENER‐HTN 2015; INSPIRED; Moiseeva 2020‐B; Moiseeva 2020‐M; Oslo RDN 2014; ReSET 2015; SYMPATHY; SYMPLICITY HTN‐3 2014; Warchol 2014), renal denervation may reduce diastolic 24‐hour ABPM as compared to sham or standard therapy (MD ‐3.75 mmHg, 95% CI ‐7.10 to ‐0.39; Analysis 1.6). There was high heterogeneity in this latter analysis (Chi² = 29.75, P = 0.0002; I² = 73%) that was reduced by selecting studies using different radiofrequency system (I² = 59%).
1.5. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 5: Systolic 24‐hour ABPM
1.6. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 6: Diastolic 24‐hour ABPM
In RELIEF 2012, the 24‐hour systolic/diastolic BP decreased by ‐17/‐12 mmHg (P = 0.006/P = 0.001) in the bilateral renal denervation group versus ‐5/‐5 mmHg (P = 0.22/P = 0.42) in the sham control group. In Prague‐15 , renal denervation (RD) and spironolactone addition (15 participants in both arms) showed a similar reduction in 24‐hour systolic/diastolic ABPM after 24‐month follow‐up (‐12.9/‐7.1 (RD) versus ‐13.9/‐7.0 mmHg (control). In DENERVHTA, spironolactone was superior to renal denervation (RDN) in reducing both 24‐hour SBP, ‐23.6 mmHg (‐31.9 to ‐15.3) versus ‐5.7 mmHg (‐14.8 to 3.4) and 24‐hour DBP, ‐10.2 (‐14.4 to ‐6.1) versus ‐3.7 (‐8.2 to 0.9), after six‐month follow‐up. HTN‐JAPAN 2015 recorded no difference between groups in 24‐hour diastolic BP (‐3.8 mmHg, 95% CI ‐8.3 to 0.6; P = 0.091). In Desch 2015, the mean change for the 24‐hour systolic BP was −7.0 mmHg (95% CI −10.8 to −3.2) for patients undergoing renal denervation and −3.5 mmHg (95% CI −6.7 to −0.2) in the sham group (P = 0.15), as analysed on an intention‐to‐treat basis. In the per‐protocol population, the change in 24‐hour systolic BP at six months was −8.3 mmHg (95% CI −11.7 to −5.0) for patients undergoing renal denervation and −3.5 mmHg (95% CI −6.8 to −0.2) in the sham group (P = 0.042). No changes in 24‐hour diastolic BP were recorded in either the intention‐to‐treat or per‐protocol analysis. All these single‐study data were directly retrieved from the correspondent papers.
Daytime ABPM
In separate meta‐analyses of five studies (234 participants), renal denervation may have no effect over standard treatment in reducing, respectively, systolic (MD 3.87 mmHg, 95% CI ‐5.02 to 12.76; I² = 70%; Analysis 1.7) and diastolic daytime ABMP (MD 2.93 mmHg, 95% CI ‐3.22 to 9.08; I² = 76%; Analysis 1.8) (DENERVHTA; INSPIRED; Oslo RDN 2014; SYMPATHY; Warchol 2014). Heterogeneity could not be further explored for the paucity of the studies included.
1.7. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 7: Systolic daytime ABPM
1.8. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 8: Diastolic daytime ABPM
In ReSET 2015, RD and sham groups had similar reductions at six months in daytime SBP and DBP compared, respectively, with baseline (SBP ‐6.1 ± 18.9 mmHg versus ‐4.3 ± 15.1 mmHg, P = 0.66; DBP ‐3.2 ± 10.8 versus ‐3.6 ± 8.3, P = 0.87).
Night‐time ABPM
In separate meta‐analyses of five studies (234 participants), renal denervation may have little or no effect on systolic (MD ‐1.65 mmHg, 95% CI ‐12.74 to 9.45; I² = 75%; Analysis 1.9) and diastolic night‐time ABPM (MD ‐1.08 mmHg, 95% CI ‐9.25 to 7.08; I² = 87%; Analysis 1.10) when compared with standard therapy (DENERVHTA; INSPIRED; SYMPATHY; Warchol 2014; Oslo RDN 2014). Heterogeneity could not be further explored for the paucity of the studies included.
1.9. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 9: Systolic night‐time ABPM
1.10. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 10: Diastolic night‐time ABPM
In ReSET 2015, after six‐month follow‐up, changes in night‐time SBP, (‐1.4 ± 18.2 mmHg (RD) versus ‐1.1 ± 14.4 mmHg (SHAM), P = 0.95) and DBP (‐0.6 ± 10.1 (RDN) versus ‐0.7 ± 8.8 (SHAM), P = 0.97) were very similar in both groups. In SYMPLICITY HTN‐3 2014, after six‐month follow‐up, the mean change in night‐time SBP was ‐6.1 ± 18.2 mmHg in the RDN group and ‐1.6 ± 19.7 mmHg in the sham group, P = 0.039 for RDN versus sham control during night‐time after Analysis of Covariance (ANCOVA) adjustment for baseline SBP.
Office BP
Office blood pressure (BP) was measured in 11 studies (DENER‐HTN 2015; DENERVHTA; HTN‐JAPAN 2015; INSPIRED; Moiseeva 2020‐B; Moiseeva 2020‐M; Oslo RDN 2014; Prague‐15; SYMPATHY; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014; Warchol 2014). In a meta‐analysis of nine studies (10 subgroups) (1090 participants) (DENER‐HTN 2015; HTN‐JAPAN 2015; INSPIRED; Moiseeva 2020‐B; Moiseeva 2020‐M; Oslo RDN 2014; SYMPATHY; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014; Warchol 2014), renal denervation had little or no effect on systolic office BP when compared with sham procedure or standard therapy (MD ‐5.92 mmHg, 95% CI ‐12.94 to 1.10; Analysis 1.11); there was high heterogeneity (Chi² = 64.48; P < 0.00001; I² = 86%). Performing subgroup analyses, benefits on systolic office BP became evident in studies using a multi‐electrode radiofrequency catheter (MD ‐5.10 mmHg, 95% CI ‐9.14 to ‐1.06) compared to in those using a single‐electrode catheter system, nullifying also the heterogeneity among studies (I² = 0%). In data pooled from eight studies (nine subgroups) (1049 participants) (DENER‐HTN 2015; INSPIRED; Moiseeva 2020‐B; Moiseeva 2020‐M; Oslo RDN 2014; SYMPATHY; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014; Warchol 2014), renal denervation may reduce diastolic office BP when compared with sham or standard therapy (MD ‐4.61 mmHg, 95% CI ‐8.23 to ‐0.99; Analysis 1.12); there was high heterogeneity (Chi² = 34.20; P < 0.0001; I² = 77%) that was completely nullified after excluding studies performing ablations with a single‐electrode catheter system (I² = 0%).
1.11. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 11: Systolic office BP
1.12. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 12: Diastolic office BP
In DENERVHTA, spironolactone addition was more effective than RD in reducing office SBP, ‐29.4 (‐40.7 to ‐18.1) versus ‐17.5 (‐29.7 to ‐5.1) and DBP, ‐12.7 (‐20.0 to ‐5.5) versus ‐7.5 (‐15.5 to 0.5), respectively. Similarly, Prague‐15 showed better efficacy of spironolactone addition than RD in office BP reduction. At 24‐month follow‐up, office systolic/diastolic BP decreased by ‐19.9/‐9.2 mmHg (P = 0.007/P = 0.04) in the RD group versus ‐17.8/‐15.8 mmHg (P = 0.005/P < 0.001) in the spironolactone group. HTN‐JAPAN 2015 recorded a greater average diastolic office BP reduction in the renal denervation group than in the control group, with a change difference of ‐6.9 mmHg (95% CI ‐13.2 to 0.5; P = 0.036). These data were obtained from the correspondent study articles.
Home BP
In HTN‐JAPAN 2015, no change difference in home systolic and diastolic BP was observed between the renal denervation and control groups (‐5.6 mmHg (95% CI ‐14.5 to 3.2; P = 0.205) and ‐4.8 mmHg (95% CI ‐9.8 to 0.3; P = 0.065), respectively). In DENER‐HTN 2015, the mean change in home systolic and diastolic BP was ‐15.4 mmHg (95% CI ‐20.4 to ‐10.4) and ‐8.7 mmHg (95% CI ‐12.1 to ‐5.4) in patients undergoing renal denervation and ‐11.8 mmHg (95% CI ‐16.5 to ‐7.1) and ‐6.7 mmHg (95% CI‐9.8 to ‐3.5) in the control group, with no differences between groups (P = 0.30 and P = 0.37) for systolic and diastolic BP, respectively.
Left ventricular hypertrophy (LVH)
Data on left ventricular mass (LVM) and LVM indexed (LVMI) were provided by four studies (DENERVHTA; Prague‐15; ReSET 2015; Warchol 2014). In data pooled from two studies, renal denervation had little or no effect over sham or standard treatment on LVMI (MD ‐2.34, 95% CI ‐12.93 to 8.25; Analysis 1.13); there was no heterogeneity (Chi² = 0.02; P = 0.89; I² = 0%; ReSET 2015; Warchol 2014).
1.13. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 13: Left ventricular mass index (LVMI)
DENERVHTA recorded no differences in LVMI between RD (mean difference 1.83 g/m2; 95% CI −16.6 to 20.2) and spironolactone addition groups (mean difference −5.41 g/m2; 95% CI −23.0 to 12.2). Prague‐15 provided 24‐month follow‐up data on LVM and LVMI, reporting a reduction from baseline in the RD group (LVM mean difference ‐50 g [95% CI ‐83 to ‐17, P = 0.007; LVMI ‐10.5 g/m2 95% CI ‐17.3 to ‐3.8, P = 0.007]). No changes in LVM and LVMI were recorded in the control group.
Obstructive sleep apnoea (OSA) severity
Data on obstructive sleep apnoea (OSA) were only available in Warchol 2014. Three months after the procedure, the RDN group showed a decrease in OSA severity as evaluated by apnea hypopnea index (AHI) (from 39.4 ± 25.5 to 31.2 ± 23.4 events/hour; P = 0.015), whereas no difference from baseline in the control group (AHI, 31.6 ± 19.1 versus 30.4 ± 22.3 events/hours) were observed.
Kidney function
In a meta‐analysis of five studies (721 participants), renal denervation may result in little or no difference over sham or standard treatment on serum creatinine levels (MD 0.03 mg/dL, 95% CI ‐0.06 to 0.13; Analysis 1.14), with a moderate level of heterogeneity (Chi² = 12.63; P = 0.01; I² = 68%), which could not be further explored, as only five studies were included (INSPIRED; Oslo RDN 2014; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014; Warchol 2014). Nevertheless, SYMPLICITY HTN‐3 2014 reported five cases in the renal denervation group and one case in the sham group, who had an increase in serum creatinine levels greater than 50% from baseline. One case of 50% increase in serum creatinine was also reported in the renal denervation group after six months of follow‐up in HTN‐JAPAN 2015.
1.14. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 14: Serum creatinine
In another meta‐analysis of six studies (822 participants), renal denervation had little or no effect on renal function, as estimated by eGFR or creatinine clearance, as compared to control (MD ‐2.56 mL/min, 95% CI ‐7.53 to 2.42; Analysis 1.15), with moderate heterogeneity (Chi² = 10.02, P = 0.07; I² = 50%), which could not be further explored (DENER‐HTN 2015; INSPIRED; Oslo RDN 2014; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014; Warchol 2014).
1.15. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 15: eGFR/creatinine clearance
In Prague‐15, no change from baseline in serum creatinine and creatinine clearance was observed between the RD (SCr: mean difference 0.9 µmol/L (95% CI ‐7.3, 9.2; P = 0.81); CrCl ‐0.5 mL/s/1.73m2 (95% CI ‐1.3, 0.3, P = 0.21) and control group (SCr 5.7 µmol/L (95% CI ‐0.4, 11.9; P = 0.06); CrCl ‐0.3 mL/s/1.73m2 (95% CI ‐0.5, 0.01; P = 0.06), respectively.
DENERVHTA observed a greater renal function decline in the spironolactone with respect to RDN group; eGFR: mean difference ‐13.7 mL/min/1.73m2 (95% CI ‐20.0 to ‐7.4) versus ‐3.0 (95% CI ‐9.8 to 3.9); SCr: 14.9 µmol/L (7.4 to 22.4) versus 5.9 (‐2.3 to 14.1). Otherwise, DENERVHTA recorded a decrease in UAE: −87.2 (95% CI −164.5 to −9.9) in the spironolactone compared with the RD group: −23.8 mg/g (95% CI −104.5 to 56.9), at six months.
Metabolic profile
Only Warchol 2014 reported information on glucose metabolism measures. After three months, there were no changes in fasting plasma glucose (RD, from 6.8 to 7.1 mmol/L; control group, from 6.7 to 6.7 mmol/L), insulin concentration (RD, from 13.4 to 12.8 mmol/L; control group, from 12.5 to 12.0 mmol/L) and glycosylated haemoglobin (RD, from 6.3 to 6.5%; control group, from 6.4 to 6.5%) in either group.
Adverse events
Major adverse events were systematically collected by 11 studies (DENER‐HTN 2015; DENERVHTA; HTN‐JAPAN 2015; INSPIRED; Oslo RDN 2014; Prague‐15; ReSET 2015; SYMPATHY; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014; Warchol 2014). SYMPATHY registered 36 serious adverse events (n = 24, 26% in the intervention group and n = 12, 27% in the usual care group) and 17 periprocedural complications, including vascular (n = 4), bleeding (n = 8) and five other mild complications (back pain, groin pain and hypotension in the RD group. ReSET 2015 recorded minor symptoms, such as headache, atypical chest pain, muscle convulsions and fatigue in five RD and six SHAM patients, respectively. DENERVHTA observed that mild groin haematoma and transient symptomatic hypotension developed in five patients in the RD group; one patient in the spironolactone group reported hyponatraemia, muscle cramps, and transient symptomatic hypotension. HTN‐JAPAN 2015 and INSPIRED reported no periprocedural complications in either the RD or control arms. No study provided information on the occurrence of transient dizziness or anaemia.
Bradycardia
In a meta‐analysis of three studies (220 participants), renal denervation may increase the risk of bradycardia occurrence than other treatments (RR 6.63, 95% CI 1.19 to 36.84; Analysis 1.16), with no heterogeneity (Chi² = 0.63; P = 0.73; I² = 0%; Oslo RDN 2014; Prague‐15; SYMPLICITY HTN‐2 2010). Warchol 2014 observed five episodes of bradycardia in the whole study population.
1.16. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 16: Bradycardia
Femoral artery pseudoaneurysm
Pooled data from two studies (201 participants) showed that renal denervation may have little or no effect on the risk for femoral artery pseudoaneurysm compared to standard therapy (RR 3.96, 95% CI 0.44 to 35.22; Analysis 1.17), with no heterogeneity (Chi² = 0.04; P = 0.84; I² = 0%; Prague‐15; SYMPLICITY HTN‐2 2010). SYMPATHY observed two cases of spurious aneurysm in the RD group.
1.17. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 17: Femoral artery pseudoaneurysm
Renal artery dissection
In Prague‐15, there was one case of renal artery dissection related to the procedure.
Renal artery vasospasm
Four cases of renal artery vasospasm in patients undergoing renal denervation were observed in Prague‐15. Warchol 2014 reported one case of transient renal artery spasm which occurred after radiofrequency application.
New renal‐artery stenosis
SYMPLICITY HTN‐3 2014 reported one case of re‐stenosis in the renal denervation group (documented as new renal artery stenosis of more than 70%) within the six‐month follow‐up.
Flank pain
In a meta‐analysis of two studies (199 participants), renal denervation may have little or no effect on the risk of flank pain compared to control (RR 4.30, 95% CI 0.48 to 38.28; Analysis 1.18), with no heterogeneity (Chi² = 0.08; P = 0.78; I² = 0%; DENER‐HTN 2015; SYMPLICITY HTN‐2 2010).
1.18. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 18: Flank pain
Pitting oedema
One case of oedema requiring hospital admission was recorded in SYMPLICITY HTN‐2 2010.
Hypotensive episodes
In a meta‐analysis of three studies (143 participants), the renal denervation procedure had little or no effect on the risk of hypotensive episodes compared to no treatment (RR 1.60, 95% CI 0.20 to 12.63; Analysis 1.19); the analysis had moderate heterogeneity (Chi² = 4.77; P = 0.09; I² = 58%; Oslo RDN 2014; SYMPLICITY HTN‐2 2010; DENERVHTA).
1.19. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 19: Hypotensive episodes
Hypertensive crisis
In data pooled from three studies (722 participants), renal denervation had little or no effect on the risk of hypertensive episodes as compared with controls (RR 0.71, 95% CI 0.35 to 1.45; Analysis 1.20), with no heterogeneity (Chi² = 1.83; P = 0.40; I² = 0%; DENER‐HTN 2015; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014).
1.20. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 20: Hypertensive crisis
Hyperkalaemia
In a meta‐analysis of three studies (224 participants), the denervation procedure had little or no effect on the risk of hyperkalaemia compared to standard therapy (RR 0.43, 95% CI 0.05 to 3.89; Analysis 1.21). There was low heterogeneity in this analysis (Chi² = 3.17; P = 0.21; I² = 37%), which could not be further explored, as only three studies were included (DENER‐HTN 2015; DENERVHTA; Prague‐15).
1.21. Analysis.
Comparison 1: Renal denervation vs. sham/standard therapy, Outcome 21: Hyperkalaemia
Syncope
In DENER‐HTN 2015, one patient in the control group experienced an episode of syncope. In DENERVHTA, no syncope occurred in either group.
Embolic events
In SYMPLICITY HTN‐3 2014, one case of embolic event resulting in end‐organ damage was reported in the renal denervation group.
Withdrawals
Twelve studies provided information on withdrawals (DENER‐HTN 2015; DENERVHTA; Desch 2015; HTN‐JAPAN 2015; INSPIRED; Oslo RDN 2014; Prague‐15; ReSET 2015; SYMPATHY; SYMPLICITY HTN‐2 2010; SYMPLICITY HTN‐3 2014; Warchol 2014). SYMPLICITY HTN‐3 2014 recorded 14 (3.8%) withdrawals from the renal denervation group and two (1.2%) from the control arm. In SYMPLICITY HTN‐2 2010, there were three withdrawals from both the intervention and control arms. DENER‐HTN 2015 reported five (10%) withdrawals from the renal denervation group. In Desch 2015, six participants (17%) withdrew from the renal denervation and two (5.55%) from the sham group. Prague‐15 recorded seven (13.7%) and 31 (62%) withdrawals from the renal denervation and control groups, respectively. Three studies reported no withdrawals (HTN‐JAPAN 2015; Oslo RDN 2014; ReSET 2015). SYMPATHY recorded eight withdrawals (5.8%) (five in the RDN and three in the usual care group).
Outcomes not stated
No RCT provided data on the following outcomes: fatal cardiovascular events, need for renal replacement therapy and proteinuria.
Sensitivity analyses, investigation of heterogeneity, and publication bias
Such investigations were not performed due to the small number of studies retrieved.
Discussion
Summary of main results
In patients with resistant hypertension, a renal denervation procedure may have little or no effect on the risk of major cardiovascular events, including myocardial infarction, ischaemic stroke, and unstable angina, as well as hospital admission, compared with controls. Nevertheless, this procedure may decrease 24‐hour ABPM and office diastolic blood pressure. Little or no effect was observed on renal function, while it likely increases the risk of bradycardia episodes. Renal denervation had little or no effect on the risk of other adverse effects, such as femoral artery pseudo‐aneurysm, flank pain, hypotensive or hypertensive episodes, and long‐term hyperkalaemia. Data on mortality and other adverse effects were limited to single studies.
Overall completeness and applicability of evidence
Our findings suggest that RD could be effective for blood pressure control and be safe, with a low complications and adverse events rate. Nevertheless, many clinically relevant outcomes, such as fatal cardiovascular events, quality of life, sleep apnoea severity, need for renal replacement therapy and metabolic profile, were absent or poorly explored in some included RCTs. Heterogeneity was high in the majority of analyses carried out, hampering the overall reliability of findings. Although exploration of heterogeneity was not feasible in the majority of analyses, due to the paucity of studies included, it can be speculated that differences among individual study designs (e.g. use of sham procedure or standard therapy as control, presence or absence of blinding in outcome assessment, use of multiple catheter systems) may represent one of the main causes underlying this phenomenon. In most trials, both study groups were simultaneously treated with optimal antihypertensive therapy to decrease blood pressure to an established target. Administration of these drugs was variable and non‐reproducible. Procedural methods were also heterogeneous among studies, particularly in terms of type of catheter employed, number of applications, energy delivered and target portion of the renal artery. Sakakura and colleagues recently observed that nervous fibres are mostly concentrated in the middle and proximal segments of the renal artery while their number decrease in the distal segment (Sakakura 2014). Previous data evidenced a maximum procedural efficacy after ablation in the whole circumference of the renal artery and a dose‐response dependency directly related to the amount of energy delivered (Kandzari 2015). The lack of standardised methods for renal denervation may hamper the reliability of comparisons among studies and, in some cases, even raise the question as to whether the procedure was truly successful (Esler 2015). Our results show a greater decrease in office and 24h ABPM among patients who underwent the multi‐electrode catheter denervation system, performing four ablations simultaneously delivered at the mid/distal segment of the renal artery, compared to the first generation procedures (radiofrequency ablation via single‐electrode catheter). Type of ablation therapy employed and target sites for ablation must be explored in future trials. The available evidence suggests that RD could be effective optimising the procedure by carefully selecting patients with truly resistant hypertension and applying new methods and technologies guided by a better understanding of renal nerve anatomy.
Quality of the evidence
The GRADE quality of the evidence (Guyatt 2008) was low for cardiovascular morbidity outcomes and adverse effects, moderate for blood pressure and renal function outcomes and low to very low for the remaining outcomes. The quality of evidence was mostly influenced by the imprecision of results (wide confidence intervals) or the low number of studies providing quantitative data on the same outcome, or both. Of note, although few studies were at high risk of bias for allocation concealment or blinding, in the majority of the included studies, the risk of bias remained unclear for most items, making it therefore difficult to evaluate the impact on the quality of evidence.
Potential biases in the review process
Points of strength of this review are represented by a peer‐reviewed protocol, a systematic search of electronic databases, and data extraction, analysis, and risk of bias assessment completed independently by two authors, according to current methodological standards. The main limitation is represented by the data obtainable from the included studies. Studies were mainly focussed on small populations and short treatment periods. As a result, most trials were not adequately powered to capture exhaustive information on hard, patient‐centred outcomes, such as fatal or non‐fatal cardiovascular events. Moreover, use of multiple catheter systems could potentially contribute to the heterogeneity observed in our analysis.
Agreements and disagreements with other studies or reviews
In a previous systematic review, renal denervation was apparently efficacious in reducing mean blood pressure at six months in individuals with resistant hypertension (RH) (Davis 2013). Unfortunately, this review was mostly based on data from observational, uncontrolled studies with limited follow‐up, small sample sizes and high heterogeneity in blood pressure measurement. Conversely, two of the most recent meta‐analyses (Fadl Elmula 2017 and Agasthi 2019) that included RCTs did not show any significant effect on blood pressure in patients with RH following renal denervation. The authors confirmed the lack of evidence supporting a widespread use of this procedure in clinical practice, advocating for future clinical trials with a longer observation time, sham control study design and novel renal denervation techniques. Over the past year, multiple randomised controlled trials evaluating the effect of RD on RH patients showed promising results (INSPIRED; Moiseeva 2020‐B; Moiseeva 2020‐M; Warchol 2014). Our meta‐analysis of high‐quality RCTs showed significant benefits of this procedure over sham/medical therapy in reducing 24‐hour ABPM and office diastolic blood pressure. Moreover, patients who underwent RD had no significant changes in renal function, supporting the safety profile of the procedure.
Authors' conclusions
Implications for practice.
The evidence accrued so far is insufficient to support the use of renal denervation as a clinically useful procedure for improving cardiovascular outcomes in patients with resistant hypertension. In contrast, a moderate‐quality body of evidence suggests that this procedure may result in a reduction in blood pressure levels, although it probably increases the risk of bradycardia episodes.
Implications for research.
Focussed trials, powered for patient‐centred instead of surrogate outcomes, with longer follow‐up periods, larger sample sizes, more standardised procedural methods and, possibly, examining particular subgroups of patients with resistant hypertension (e.g. subjects with different cardiovascular or renal risk profiles) are needed to clarify the optimal target population for this procedure. Study design providing a sham control procedure and blinded outcome assessors are indispensable for minimising bias and improving the reliability of findings. Results from ongoing trials testing alternative methods for performing renal nerve ablation, e.g. focussed ultrasounds, the administration of neurotoxic agents, cryotherapy or brachytherapy are also awaited.
What's new
Date | Event | Description |
---|---|---|
20 November 2021 | New citation required and conclusions have changed | 3 new studies incorporated. Conclusions changed. |
16 January 2021 | New search has been performed | Search findings were updated until 3 November 2020. The updated search identified three new trials. |
History
Protocol first published: Issue 1, 2015 Review first published: Issue 2, 2017
Acknowledgements
We thank Dr Murray Esler, Dr Michel Azizi, Dr Jan Rosa, Dr Sverre Erik Kjeldsen, Dr M. Fadl Elmula and Dr Anna Moiseeva for providing additional trial data. We would also like to thank the Cochrane Hypertension Group, particularly Mr Ciprian Jauca and Mr Douglas Salzwedel, for their valuable support, and the referees for their feedback and advice during the preparation of the review.
Appendices
Appendix 1. Search strategies
Database: Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions(R) <1946 to November 02, 2020> Search Date: 3 November 2020 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 denervation/ 2 *catheter ablation/ 3 radiofrequency ablation/ 4 ((kidney? or renal or transcatheter) adj6 (denervat$ or sympathectom$)).mp. 5 ((radiofrequency or radio frequency) adj2 (ablation? or catheter? or probe?)).tw,kf. 6 or/1‐5 7 hypertension/ 8 essential hypertension/ 9 (antihypertens$ or hypertens$).tw,kf. 10 ((elev$ or high$ or rais$) adj3 (arterial pressure or blood pressure or diastolic pressure or systolic pressure)).tw,kf. 11 ((elev$ or high$ or rais$) adj3 (bp or dbp or sbp)).tw,kf. 12 or/7‐11 13 randomized controlled trial.pt. 14 controlled clinical trial.pt. 15 randomized.ab. 16 placebo.ab. 17 dt.fs. 18 randomly.ab. 19 trial.ab. 20 groups.ab. 21 or/13‐20 22 animals/ not (humans/ and animals/) 23 21 not 22 24 6 and 12 and 23
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Database: Cochrane Hypertension Specialised Register via Cochrane Register of Studies
Search Date: 3 November 2020
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ #1 MESH DESCRIPTOR Denervation AND INSEGMENT #2 denerva* AND INSEGMENT #3 catheter ablation* AND INSEGMENT #4 radiofrequency ablation* AND INSEGMENT #5 sympathectom* AND INSEGMENT #6 (#1 OR #2 OR #3 OR #4 OR #5) AND INSEGMENT #7 MESH DESCRIPTOR Hypertension AND INSEGMENT #8 MESH DESCRIPTOR Essential Hypertension AND INSEGMENT #9 hypertens* AND INSEGMENT #10 ((elevated OR high* OR rais*) NEAR3 blood pressure) AND INSEGMENT #11 (#7 OR #8 OR #9 OR #10) AND INSEGMENT #12 (CCT OR RCT):DE AND INSEGMENT #13 Review:ODE AND INSEGMENT #14 (#12 OR #13) AND INSEGMENT #15 #6 AND #14 AND INSEGMENT
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Database: Cochrane Central Register of Controlled Trials (Issue 10, 2020) via Cochrane Register of Studies
Search Date: 3 November 2020 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ #1 MESH DESCRIPTOR Denervation AND CENTRAL:TARGET #2 denerva* AND CENTRAL:TARGET #3 catheter ablation* AND CENTRAL:TARGET #4 radiofrequency ablation* AND CENTRAL:TARGET #5 sympathectom* AND CENTRAL:TARGET #6 (#1 OR #2 OR #3 OR #4 OR #5) AND CENTRAL:TARGET #7 MESH DESCRIPTOR Hypertension AND CENTRAL:TARGET #8 MESH DESCRIPTOR Essential Hypertension AND CENTRAL:TARGET #9 hypertens* AND CENTRAL:TARGET #10 ((elevated OR high* OR rais*) NEAR3 blood pressure) AND CENTRAL:TARGET #11 (#7 OR #8 OR #9 OR #10) AND CENTRAL:TARGET #12 #6 AND #11 AND CENTRAL:TARGET
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Database: Embase <1974 to 2020 November 02> Search Date: 3 November 2020 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 renal denervation/ 2 *catheter ablation/ 3 *radiofrequency ablation/ 4 ((kidney? or renal or transcatheter) adj6 (denervat$ or sympathectom$)).tw. 5 ((radiofrequency or radio frequency) adj2 (ablation? or catheter? or probe?)).tw. 6 or/1‐5 7 exp hypertension/ 8 hypertens$.tw. 9 ((elev$ or high$ or rais$) adj3 (arterial pressure or blood pressure or diastolic pressure or systolic pressure)).tw. 10 ((elev$ or high$ or rais$) adj3 (bp or dbp or sbp)).tw. 11 or/7‐10 12 randomized controlled trial/ 13 controlled clinical trial/ 14 crossover procedure/ 15 double‐blind procedure/ 16 (randomi?ed or randomly).tw. 17 (crossover$ or cross‐over$).tw. 18 placebo.ab. 19 (doubl$ adj blind$).tw. 20 assign$.ab. 21 allocat$.ab. 22 or/12‐21 23 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) 24 22 not 23 25 6 and 11 and 24
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Database: ClinicalTrials.gov
Search Date: 3 November 2020
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Condition or disease: Hypertension Study type: Interventional Studies (Clinical Trials) Study Results: All Studies Intervention/treatment: denervation
Data and analyses
Comparison 1. Renal denervation vs. sham/standard therapy.
Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
---|---|---|---|---|
1.1 Myocardial infarction | 4 | 742 | Risk Ratio (M‐H, Random, 95% CI) | 1.31 [0.45, 3.84] |
1.2 Ischaemic stroke | 5 | 892 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.33, 2.95] |
1.3 Unstable angina | 3 | 270 | Risk Ratio (M‐H, Random, 95% CI) | 0.51 [0.09, 2.89] |
1.4 Hospital admission | 3 | 743 | Risk Ratio (M‐H, Random, 95% CI) | 1.24 [0.50, 3.11] |
1.5 Systolic 24‐hour ABPM | 10 | 1045 | Mean Difference (IV, Random, 95% CI) | ‐5.29 [‐10.46, ‐0.13] |
1.6 Diastolic 24‐hour ABPM | 9 | 1004 | Mean Difference (IV, Random, 95% CI) | ‐3.75 [‐7.10, ‐0.39] |
1.7 Systolic daytime ABPM | 5 | 234 | Mean Difference (IV, Random, 95% CI) | 3.87 [‐5.02, 12.76] |
1.8 Diastolic daytime ABPM | 5 | 234 | Mean Difference (IV, Random, 95% CI) | 2.93 [‐3.22, 9.08] |
1.9 Systolic night‐time ABPM | 5 | 234 | Mean Difference (IV, Random, 95% CI) | ‐1.65 [‐12.74, 9.45] |
1.10 Diastolic night‐time ABPM | 5 | 234 | Mean Difference (IV, Random, 95% CI) | ‐1.08 [‐9.25, 7.08] |
1.11 Systolic office BP | 10 | 1090 | Mean Difference (IV, Random, 95% CI) | ‐5.92 [‐12.94, 1.10] |
1.12 Diastolic office BP | 9 | 1049 | Mean Difference (IV, Random, 95% CI) | ‐4.61 [‐8.23, ‐0.99] |
1.13 Left ventricular mass index (LVMI) | 2 | 105 | Mean Difference (IV, Random, 95% CI) | ‐2.34 [‐12.93, 8.25] |
1.14 Serum creatinine | 5 | 721 | Mean Difference (IV, Random, 95% CI) | 0.03 [‐0.06, 0.13] |
1.15 eGFR/creatinine clearance | 6 | 822 | Mean Difference (IV, Random, 95% CI) | ‐2.56 [‐7.53, 2.42] |
1.16 Bradycardia | 3 | 220 | Risk Ratio (M‐H, Random, 95% CI) | 6.63 [1.19, 36.84] |
1.17 Femoral artery pseudoaneurysm | 2 | 201 | Risk Ratio (M‐H, Random, 95% CI) | 3.96 [0.44, 35.22] |
1.18 Flank pain | 2 | 199 | Risk Ratio (M‐H, Random, 95% CI) | 4.30 [0.48, 38.28] |
1.19 Hypotensive episodes | 3 | 143 | Risk Ratio (M‐H, Random, 95% CI) | 1.60 [0.20, 12.63] |
1.20 Hypertensive crisis | 3 | 722 | Risk Ratio (M‐H, Random, 95% CI) | 0.71 [0.35, 1.45] |
1.21 Hyperkalaemia | 3 | 224 | Risk Ratio (M‐H, Random, 95% CI) | 0.43 [0.05, 3.89] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
DENER‐HTN 2015.
Study characteristics | ||
Methods |
|
|
Participants |
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 |
|
|
Outcomes |
|
|
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%) dropouts 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 prespecified 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. |
DENERVHTA.
Study characteristics | ||
Methods |
|
|
Participants |
Exclusion criteria: pregnancy, secondary hypertension, eGFR < 45 mL/min/1.73 m², 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‐randomisation 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: n = 11, RDN plus usual medical treatment ⦁ Control group: n = 13, spironolactone (50 mg/day) plus usual medical treatment ⦁ Renal denervation procedure: radiofrequency Symplicity (Medtronic) 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 6 months | |
Outcomes |
|
|
Notes | Intention‐to‐treat analysis done by last‐observation‐carried‐forward method | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Quote: "Randomization sequence was generated by computer and stratified by centres using randomized 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 | High risk | Open‐label |
Incomplete outcome data (attrition bias) All outcomes | Low risk | 3/27 (11.1%) dropouts (2 in RDN and 1 in spironolactone group); intention‐to‐treat analysis |
Selective reporting (reporting bias) | Low risk | All the prespecified outcomes have been reported. |
Other bias | Low risk | The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. |
Desch 2015.
Study characteristics | ||
Methods |
|
|
Participants |
Exclusion criteria: mean daytime systolic BP on 24‐hour ABPM < 135 and > 149 mmHg or mean daytime 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 |
|
|
Outcomes |
|
|
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%) dropouts (6 in RD and 2 in sham procedure); intention‐to‐treat and per‐protocol analyses performed |
Selective reporting (reporting bias) | Low risk | All the prespecified outcomes have been reported. |
Other bias | Unclear risk | No apparent other sources of bias |
Franzen 2012.
Study characteristics | ||
Methods |
|
|
Participants |
|
|
Interventions |
|
|
Outcomes |
|
|
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.
Study characteristics | ||
Methods |
|
|
Participants |
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 nonadherence to medication within the previous year, type 1 diabetes mellitus and ≥ 1 episodes of orthostatic hypotension not related to medication changes, secondary hypertension |
|
Interventions |
|
|
Outcomes |
|
|
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 dropouts. Intention‐to‐treat analysis performed |
Selective reporting (reporting bias) | Low risk | All the prespecified outcomes have been reported. |
Other bias | High risk | Honoraria from Medtronic. Involvement of Medtronic in data collection and statistical analyses |
INSPIRED.
Study characteristics | ||
Methods |
|
|
Participants |
Antihypertensive treatment:
Exclusion criteria: pregnancy, secondary hypertension, eGFR < 45 mL/min/1.73 m², 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 |
|
|
Outcomes |
|
|
Notes | ||
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Quote: "Patients were randomized by means of a computerized random function with block size restriction". |
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 | 2/17 (11.7%) dropouts in RDN group; per‐protocol analysis |
Selective reporting (reporting bias) | Low risk | All the prespecified outcomes have been reported. |
Other bias | Low risk | No evidence of other bias |
Moiseeva 2020‐B.
Study characteristics | ||
Methods |
|
|
Participants |
|
|
Interventions |
|
|
Outcomes |
|
|
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 | 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) | Low risk | All the prespecified outcomes have been reported. |
Other bias | Unclear risk | Not specified |
Moiseeva 2020‐M.
Study characteristics | ||
Methods |
|
|
Participants |
|
|
Interventions |
|
|
Outcomes |
|
|
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 | 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) | Low risk | All the prespecified outcomes have been reported. |
Other bias | Unclear risk | Not specified |
Oslo RDN 2014.
Study characteristics | ||
Methods |
|
|
Participants |
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 |
|
|
Outcomes |
|
|
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 dropouts |
Selective reporting (reporting bias) | Low risk | All the prespecified outcomes were reported. |
Other bias | Unclear risk | Honoraria from Medtronic and Hemo Sapiens. Involvement of industry in data collection and analyses not specified |
Prague‐15.
Study characteristics | ||
Methods |
|
|
Participants |
Exclusion criteria: secondary hypertension, noncompliance 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 |
|
|
Outcomes |
|
|
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%) dropouts (7 in RD and 31 in PHAR group); intention‐to‐treat and per‐protocol analyses performed |
Selective reporting (reporting bias) | Low risk | All the prespecified outcomes have been reported. |
Other bias | Unclear risk | No apparent other sources of bias |
RELIEF 2012.
Study characteristics | ||
Methods |
|
|
Participants |
|
|
Interventions |
|
|
Outcomes |
|
|
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 prespecified outcomes were not reported. |
Other bias | Unclear risk | No apparent other sources of bias |
ReSET 2015.
Study characteristics | ||
Methods |
|
|
Participants |
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 |
|
|
Outcomes |
|
|
Notes | ||
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Patients were randomised using a computer. |
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 | Low risk | Quote: “No patients were lost to follow‐up, and no patients were unblinded prematurely.” |
Selective reporting (reporting bias) | High risk | Some prespecified outcomes were not reported. |
Other bias | High risk | Quote: “A.K. has received speaker honoraria from Medtronic". |
SYMPATHY.
Study characteristics | ||
Methods |
|
|
Participants |
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 |
|
|
Outcomes |
|
|
Notes | ||
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Quote:"Randomization in a 2:1 ratio using a web‐based computerized approach, with stratification by hospital and estimated glomerular filtration rate" |
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 | 8/139 (5.8%) dropout (5 in RDN and 3 in usual care group); modified intention‐to‐treat analysis |
Selective reporting (reporting bias) | Low risk | All the prespecified outcomes have been reported. |
Other bias | High risk | P.J. Blankestijn received grants from ZonMw, Dutch Kidney Foundation, Medtronic, and personal fees from Medtronic, during the conduct of the study. |
SYMPLICITY HTN‐2 2010.
Study characteristics | ||
Methods |
|
|
Participants |
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 |
|
|
Outcomes |
|
|
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%) dropouts (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 prespecified outcomes have been reported. |
Other bias | High risk | Data were monitored, collected, and managed by the sponsor (Ardian). |
SYMPLICITY HTN‐3 2014.
Study characteristics | ||
Methods |
|
|
Participants |
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 |
|
|
Outcomes |
|
|
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%) dropouts (14 in RD and 2 in sham procedure); ITT analysis performed |
Selective reporting (reporting bias) | Low risk | All the prespecified 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.
Study characteristics | ||
Methods |
|
|
Participants | ⦁ Number of patients randomised/analysed: 60/52
⦁ Age: mean 55.3 ± 9.3
⦁ Males (%): 80
⦁ Hypertension duration: 15
⦁ Smokers (%): 43
⦁ Diabetes mellitus type 2 (%): 38
⦁ Coronary heart disease (%): 30
⦁ Office BP (mmHg): 161/95
⦁ Office HR (bpm): 71
⦁ 24‐h ABPM (mmHg): 149/88
⦁ Mean daytime ABPM (mmHg): 151/90
⦁ Mean night‐time ABPM (mmHg): 140/81
⦁ Serum creatinine (μmol/L): 81
⦁ eGFR (mL/min/1.73 m²): 92.5
⦁ Cystatin C (mg/L): 0.9
⦁ Obstructive sleep apnoea (apnea/hypopnoea index, AHI): 35 events/hour
⦁ Number of drugs used: 5.0 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 = 30, RD plus antihypertensive medications
⦁ Control group: N = 30, antihypertensive medications alone ⦁ Renal denervation procedure: ablation done using a catheter‐based procedure (Symplicity). Discrete radio‐frequency ablations of ≤ 8 W were applied, lasting ≤ 2 minutes each, to obtain ≤ 6 ablations separated both longitudinally and rotationally within each renal artery. ⦁ Follow‐up: up to 6 months |
|
Outcomes | ⦁ Office BP ⦁ 24‐hour, daytime and night‐time ABPM ⦁ Change in OSA severity ⦁ Fasting plasma glucose and insulin concentration ⦁ Echocardiographic measures ⦁ Estimated GFR ⦁ Cardiovascular events and arrhythmias | |
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 | 8/60 (13.3%) dropouts (2 in RD and 6 in control group). Analysis performed not specified |
Selective reporting (reporting bias) | Low risk | All the prespecified outcomes have been reported. |
Other bias | Low risk | Quote: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript". |
ABPM: ambulatory blood pressure monitoring ACEI: angiotensin–converting enzyme inhibitors AHI: apnea hypopnea index ARB: angiotensin receptor blockers bpm: beats per minute BP: blood pressure BPV: blood pressure variability CCB: calcium channel blocker CPAP: continuous positive airway pressure therapy CVA: cerebrovascular accident CVD: cardiovascular disease DM: diabetes mellitus eGFR: estimated glomerular filtration rate EQ‐5D‐5L: euroQol five‐dimensional five‐levels HR: hearth rate INR: international normalized ratio ITT: intention to treat LAD: left anterior descending artery LV: left ventricle LVM: left ventricular mass LVMI: left ventricular mass index MRI: magnetic resonance imaing NYHA: New York Heart Association OSA: obstructive sleep apnea PHAR: pharmacological treatment PRD: percutaneous renal denervation PWV: pulse wave velocity RAS: renin‐angiotensin system RCT: randomized clinical trial RD: renal denervation RDN: renal denervation SBP: systolic blood pressure SSAHT: standardised stepped‐care antihypertensive treatment TIA: transient ischaemic attack TSH: thyroid stimulating hormone UAE: urinary albumine excretion W: wave
Characteristics of excluded studies [ordered by study ID]
Study | Reason for exclusion |
---|---|
Ahmed 2012b | Not RCT |
Ahmed 2013 | Wrong population |
Azizi 2018 | Wrong population |
Azizi 2019 | Wrong population |
Azizi M 2019 | Wrong population |
Baev 2017 | Wrong intervention |
Bohm 2018 | Wrong population |
Bohm 2019 | Wrong population |
Bohm 2020 | Wrong population |
Bohm 2020b | Wrong population |
Bohm 2020c | Wrong population |
Bosch 2020 | Not RCT |
Brandt 2012 | Not RCT |
Brandt 2012a | Not RCT |
Chen 2017 | Not RCT |
Chen 2019 | Wrong population |
Chen 2019b | Wrong population |
ChiCTR‐ONC‐12002901 | Not RCT |
ChiCTR‐ONC‐13003231 | Wrong intervention |
ChiCTR‐TNC‐12002900 | Not RCT |
Courand 2016 | Wrong outcome |
Courand 2017 | Wrong outcome |
de Jager, R. 2018 | Wrong outcome |
De Jager 2017 | Wrong outcome |
Dimitriadis 2017 | Wrong population |
DRKS00005865 | Wrong intervention |
DRKS00006405 | Wrong population |
DRKS00006420 | Not RCT |
DRKS00006493 | Wrong population |
Eikelis 2017 | Not RCT |
EnligHTN III | Not RCT |
Esler 2013 | Wrong population |
Ewen 2014 | Not RCT |
Fadl Elmula 2013 | Not RCT |
Fengler 2018 | Not RCT |
Forssell 2020 | Wrong intervention |
Grassi 2015 | Not RCT |
Hamdidouche 2019 | Wrong intervention |
Hering 2013 | Not RCT |
Kampmann 2016 | Not RCT |
Kandzari 2016 | Wrong population |
Kandzari 2018 | Wrong population |
Karbasi‐Afshar 2013 | Not RCT |
Kario 2018 | Wrong population |
Kario 2019 | Wrong intervention |
Kario 2020 | Wrong population |
Kario K 2018 | Wrong population |
Katholi 2014 | Wrong population |
Kjeldsen 2014 | Not RCT |
Krum 2014 | Not RCT |
Li 2019 | Wrong population |
Li 2019 | Wrong intervention |
Lobo 2015 | Not RCT |
Lurz 2020 | Not RCT |
Mahfoud 2011 | Wrong population |
Mahfoud 2011a | Wrong population |
Mahfoud 2012 | Not RCT |
Mahfoud 2013 | Not RCT |
Mahfoud 2014 | Not RCT |
Mahfoud 2019 | Wrong population |
Mahfoud 2020 | Not RCT |
Mahfoud 2020b | Not RCT |
Mahfoud 2020c | Wrong population |
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 |
NCT02667912 | Wrong intervention |
NCT03261375 | Wrong population |
NCT03465917 | Not RCT |
NCT03511313 | Wrong population |
NCT04248530 | Wrong population |
NCT04264403 | Wrong population |
NCT04307836 | Wrong population |
NCT04311086 | Not RCT |
NCT04535050 | Wrong population |
Palionis 2016 | Not RCT |
Pekarskiy 2016 | Wrong intervention |
Pekarskiy 2020 | Wrong intervention |
Persu 2018 | Not RCT |
Petrov 2019 | 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 SOLO | Wrong population |
RADIANCE II | Wrong population |
RAPID | Not RCT |
ReD | Not RCT |
REDUCE HTN:REINFORCE | Wrong population |
Ripp 2019 | Not RCT |
RNS‐NTR 4384 | Not RCT |
RSDAH | Wrong population |
Sanders 2016 | Wrong population |
Saxena 2017 | Wrong intervention |
Saxena 2018 | Wrong intervention |
Scalise 2020 | Not RCT |
Schmieder 2017 | Wrong intervention |
Schmieder 2018 | Wrong intervention |
Shipman 2014 | Not RCT |
Shugushev 2019 | Wrong intervention |
Shugushev 2019b | Wrong intervention |
Sievert 2014 | Not RCT |
Sitkova 2020 | Wrong intervention |
SPYRAL HTN‐OFF MED | Wrong population |
SPYRAL HTN‐ON MED | Wrong population |
Stoiber 2018 | Not RCT |
SYMPLICITY 2011 | Not RCT |
SYMPLICITY AF | Wrong population |
TARGET BP OFF‐MED | Wrong population |
Townsend 2017 | Wrong population |
Tsioufis 2016 | Wrong population |
UMIN000012020 | Not RCT |
Wage 2015 | Wrong outcome |
Waksman 2016 | Wrong outcome |
WAVE IV | Wrong intervention |
Wave VI | Wrong intervention |
Weber 2018 | Wrong population |
Weber 2020 | Wrong population |
Witkowski 2011 | Not RCT |
Xiang 2014 | Wrong intervention |
Yin 2013 | Wrong population |
Zhang 2014 | Not RCT |
RCT: randomized clinical trial
Characteristics of ongoing studies [ordered by study ID]
ALLEGRO‐HTN.
Study name | Renal denervation by Allegro System in patients with resistant hypertension |
Methods |
|
Participants |
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 |
|
Outcomes |
|
Starting date | May 2013 |
Contact information | Xiongjing Jiang: jxj103@hotmail.com |
Notes |
DEPART.
Study name | Study of catheter‐based renal denervation therapy in hypertension (DEPART) |
Methods |
|
Participants |
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 |
|
Outcomes |
|
Starting date | January 2012 |
Contact information | Contact: ARGACHA Jean Francois, MD Jean.Francois.Argacha@erasme.ulb.ac.be |
Notes |
EnligHTN IV.
Study name | Multi‐center, randomized, single‐blind, sham controlled clinical investigation of renal denervation for uncontrolled hypertension (EnligHTN IV) |
Methods |
|
Participants |
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 |
|
Outcomes |
|
Starting date | October 2013 |
Contact information | NA |
Notes |
ENSURE.
Study name | Effect of renal denervation on arterial stiffness and haemodynamics in patients with uncontrolled hypertension (ENSURE) |
Methods |
|
Participants |
Exclusion criteria: pregnancy, type 1 diabetes mellitus, chronic oxygen support or mechanical ventilation, primary pulmonary hypertension, ABPM 24‐hour average SBP < 135 mmHg |
Interventions |
|
Outcomes |
|
Starting date | September 2014 |
Contact information | Yawei Xu; yizshcn@gmail.com |
Notes |
KPS.
Study name | Renal protection using sympathetic denervation in patients with chronic kidney disease (KPS) |
Methods |
|
Participants |
Exclusion criteria: pregnancy, type 1 diabetes mellitus, significant valvular disease, renovascular abnormalities, secondary hypertension, white coat hypertension |
Interventions |
|
Outcomes |
|
Starting date | November 2013 |
Contact information | Jean Claude Lubanda, Ass.Prof. MD; Jean‐Claude.Lubanda@vfn.cz |
Notes |
NCT01848275.
Study name | Full length versus proximal renal arteries ablation |
Methods |
|
Participants |
Exclusion criteria: pregnancy, type 1 diabetes mellitus, significant valvular disease, ICD, renovascular abnormalities, secondary hypertension, white coat hypertension |
Interventions |
|
Outcomes |
|
Starting date | March 2011 |
Contact information | Yuehui Yin, MD; yinyh63@163.com |
Notes |
NCT01918111.
Study name | 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 |
|
Participants |
|
Interventions |
|
Outcomes |
|
Starting date | September 2013 |
Contact information | Yangsoo Jang, MD 82‐2‐2228‐8460, jangys1212@yuhs.ac |
Notes |
NCT01968785.
Study name | Renal denervation in patients with uncontrolled blood pressure |
Methods |
|
Participants |
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 |
|
Outcomes |
|
Starting date | August 2013 |
Contact information | Ron Waksman, MD |
Notes |
NCT02021019.
Study name | Renal denervation to improve outcomes in patients with end‐stage renal disease |
Methods |
|
Participants |
Exclusion criteria: myocardial infarction, unstable angina, cerebrovascular accident within 3 months of the screening visit |
Interventions |
|
Outcomes |
|
Starting date | January 2014 |
Contact information | Markus P Schlaich, MD Baker IDI Heart and Diabetes Institute |
Notes |
NCT02346045.
Study name | Effect of renal denervation in end staged renal disease with resistant hypertension |
Methods |
|
Participants |
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 |
|
Outcomes |
|
Starting date | September 2014 |
Contact information | Kiyuk Chang, MD, PhD; kiyuk@40catholic.ac.kr |
Notes |
NCT02444442.
Study name | The Australian SHAM controlled clinical trial of renal denervation in patients with resistant hypertension |
Methods |
|
Participants |
Exclusion criteria: renal artery anatomy ineligible for treatment, eGFR < 15 mL/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 |
|
Outcomes |
|
Starting date | June 2015 |
Contact information | Markus P Schlaich, Professor +61 3 85321502, Markus.Schlaich@bakeridi.edu.au Murray Esler, Professor +61 3 85321338, Murray.Esler@bakeridi.edu.au |
Notes |
NCT02608632.
Study name | High frequency guided renal artery denervation for improving outcome of renal ablation procedure |
Methods |
|
Participants |
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 |
|
Outcomes |
|
Starting date | February 2013 |
Contact information | NA |
Notes |
NCT02900729.
Study name | Efficacy and safety of renal denervation for Chinese patients with resistant hypertension using a microirrigated catheter: study design and protocol for a prospective multicentre randomised controlled trial |
Methods |
|
Participants |
Exclusion criteria: Acute or serious systemic infection. Renal artery interventional therapy. Lacks suitable renal artery anatomy. Myocardial infarction, unstable angina pectoris, syncope, or a cerebrovascular accident within 3 months of the screening period, or atherosclerosis, intravascular thrombosis. Aortic dissection aneurysm. Primary pulmonary hypertension. eGFR less than 40 mL/min/1.73 m2. Coronary heart disease requiring beta‐blockers. Class III‐IV heart failure or left ventricular ejection fraction < 45%. Atrial fibrillation. Significant bleeding tendency or blood system disease(s). Malignancy or end‐stage disease(s). Secondary hypertension. Type 1 diabetes mellitus |
Interventions |
|
Outcomes |
|
Starting date | October 2016 |
Contact information | Dr Junbo Ge; jbge@zs‐hospital.sh.cn |
Notes |
NTR3444.
Study name | Comparison of renal sympathetic denervation with spironolactone in patients with still a high blood pressure despite the use of 3 different antihypertensive agents |
Methods |
|
Participants |
Exclusion criteria: secondary hypertension, renal arteries inaccessible for endovascular denervation, suboptimal dosing of BP‐lowering medication, noncompliant 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 |
|
Outcomes |
|
Starting date | June 2012 |
Contact information | A Van den Meiracker, MD, PhD +31‐10‐4639222, a.vandenmeiracker@erasmusmc.nl |
Notes |
PaCE.
Study name | A study of renal denervation in patients with treatment resistant hypertension (PaCE) |
Methods |
|
Participants |
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 |
|
Outcomes |
|
Starting date | October 2013 |
Contact information | Harindra C. Wijeysundera, MD |
Notes |
RADIANCE‐HTN.
Study name | A study of the ReCor Medical Paradise System in clinical hypertension (RADIANCE‐HTN), Trio cohort |
Methods |
|
Participants |
TRIO Cohort:
Exclusion criteria: Renal artery anatomy on either side, ineligible for treatment. Single functioning kidney. Abnormal kidney tumours. Renal artery with aneurysm. Renal stent or history of renal artery angioplasty. Aortic stent or history of aortic aneurysm. Prior renal denervation procedure. Fibromuscular disease of the renal arteries. Presence of renal artery stenosis of any origin ≥ 30%. Secondary hypertension not including sleep apnoea. Type I diabetes mellitus or uncontrolled type II diabetes. History of chronic active inflammatory bowel disorders such as Crohn's disease or ulcerative colitis. eGFR < 40 mL/min/1.73 m2. Any history of cerebrovascular event within 3 months prior to consent. Any history of severe cardiovascular event within 3 months prior to consent. Atrial tachyarrhythmia. Active implantable medical device. Chronic oxygen support or mechanical ventilation other than nocturnal respiratory support for sleep apnoea. Primary pulmonary hypertension. Pregnant, nursing or planning to become pregnant |
Interventions |
|
Outcomes | Primary outcome:
Secondary outcome:
|
Starting date | March 2016 |
Contact information | Michel Azizi, MD, PhD Ajay J Kirtane, M.D |
Notes | Prior to randomisation, subjects will be hypertensive in the absence of hypertension medication (SOLO) or despite the presence of a stabilised, single pill, triple, fixed‐dose antihypertensive medication regimen (TRIO). |
RAPID II.
Study name | Rapid renal sympathetic denervation for resistant hypertension II (RAPID II) |
Methods |
|
Participants |
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 |
|
Outcomes |
|
Starting date | September 2013 |
Contact information | Dierk Scheinert, MD Guiseppe Mancia, MD Universita Milano‐Bicocca, Ospedale San Gerardo di Monza |
Notes |
RDNP‐2012‐01.
Study name | Renal denervation for resistant hypertension (RDNP‐2012‐01) |
Methods |
|
Participants |
Exclusion criteria: pregnancy, unsuitable anatomy of renal arteries (diameter < 4 mm and length < 20 mm) |
Interventions |
|
Outcomes |
|
Starting date | February 2012 |
Contact information | Markus Schlaich, MD Baker IDI Heart & Diabetes Institute |
Notes |
RENO.
Study name | Effect of renal denervation on no‐mediated sodium excretion and plasma levels of vasoactive hormones (RENO) |
Methods |
|
Participants |
Exclusion criteria: noncompliance, 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 |
|
Outcomes |
|
Starting date | March 2012 |
Contact information | Esper N Bech, MD, Ph.D; jnbech@dadlnet.dk |
Notes |
RENSYMPIS.
Study name | Renal sympathetic denervation and insulin sensitivity (RENSYMPIS study) |
Methods |
|
Participants |
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 (< 4 mm diameter, < 20 mm length) |
Interventions |
|
Outcomes |
|
Starting date | January 2013 |
Contact information | Tuomas Paana, M.D; tuomas.paana@satshp.fi |
Notes |
ReSET‐2.
Study name | Renal denervation in treatment resistant hypertension (ReSET‐2) |
Methods |
|
Participants |
Exclusion criteria: pregnancy, noncompliance, 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 |
|
Outcomes |
|
Starting date | January 2013 |
Contact information | Henrik Vase, MD, PhD henvas@rm.dk Ole Mathiassen, MD, PhD onm@farm.au.dk |
Notes |
RSD4CKD.
Study name | Renal sympathetic denervation in patients with chronic kidney disease and resistant hypertension (RSD4CKD) |
Methods |
|
Participants |
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 |
|
Outcomes |
|
Starting date | November 2012 |
Contact information | Shan Qi jun; qjshan@njmu.edu.cn |
Notes |
RSDARH.
Study name | Renal Sympathetic Denervation from the Adventitia on Resistant Hypertension (RSDARH) |
Methods |
|
Participants |
Exclusion criteria: secondary hypertension caused by any known cause; pregnant or planning to be pregnant; with renal artery diameter < 4 mm or length < 20 mm; patients with renal artery abnormalities. Acute myocardial infarction within six months, unstable angina or cerebrovascular disease; heart valve disease with significantly altered haemodynamics; other serious organic diseases |
Interventions |
|
Outcomes |
|
Starting date | October 2018 |
Contact information | Chuanyu Gao, Dr +86 13937165590 gaocy6802@163.com |
Notes |
RSDforAF.
Study name | Renal sympathetic denervation in patients with drug‐resistant hypertension and symptomatic atrial fibrillation (RSDforAF) |
Methods |
|
Participants |
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 |
|
Outcomes |
|
Starting date | July 2012 |
Contact information | Qijun Shan; qjshan@40njmu.edu.cn |
Notes |
SYMPLICITY HTN‐4.
Study name | Renal denervation in patients with uncontrolled hypertension (SYMPLICITY HTN‐4) |
Methods |
|
Participants |
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 |
|
Outcomes |
|
Starting date | October 2013 |
Contact information | David Kandzari, MD Piedmont Heart Institute |
Notes |
AAA: abdominal aortic aneurysm ABPM: ambulatory blood pressure monitoring AHI: apnea hypopnea index BMI: body mass index BP: blood pressure BUN: blood urea nitrogen CABG: Coronary artery bypass graft surgery CPAP: continuos positive airway pressure CT: calcitonin CTA: computed tomography angiography DBP: diastolic blood pressure eGFR: estimated glomerular filtration rate EQ‐5D: euroQOL five‐dimension ESRD: end‐stage renal disease HFS: high ‐frequency stimulation HOMA: Homeostasis model assessment ICD: implantable cardioverter defibrillator L‐NMMA: Nitric Oxide Synthase Inhibitor NG‐Monomethyl‐L‐Arginine MACR: microalbumin to creatinine ratio MAE: major adverse events MDRD: Modification of Diet in Renal Disease
MI: myocardial infarction MRA: magnetic resonance angiography MRCI: hypertensive medication complexity index NYHA: New York Heart Association PCI:percutaneous coronary intervention RCT: randomized clinical trial RD: renal denervation RF: radiofrequency RFA: radiofrequency ablation SBP: systolic blood pressure UACR: urinary albumin creatinine ratio W: wave
Differences between protocol and review
Authors order and contribution was updated after finalising the last revision of the review to best reflect individual contributions to this new version.
Contributions of authors
Drafting the protocol: GC, DB, AP, ER
Study selection: AL, LFI
Extracting data from studies: AL, LFI
Entering data into Review Manager: AP, LFI, DB
Carrying out the analysis: DB, AP
Interpreting the analysis: DB, AP, GC
Drafting the final review: DB, GC, AP, ER
Resolution of disagreements: AP, DB
Updating the review: DB, AP, GC, AL, LFI, ER
Sources of support
Internal sources
-
No sources of support, Other
N/A
External sources
-
No sources of support, Other
N/A
Declarations of interest
DB: in 2012, received an Honorary Fellowship from the Cochrane Renal Group as Fellow of the European Renal Best Practice (ERBP) group
AP: None known
GC: None known
AL: None known
LFI: None known
ER: None known
New search for studies and content updated (conclusions changed)
References
References to studies included in this review
DENER‐HTN 2015 {published data only}
- 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. [DOI] [PubMed] [Google Scholar]
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- Sapoval MR, Monge M, Pereira H, Azizi M. DENER-HTN trial: a prospective randomized control trial of the efficacy of renal artery denervation in resistant hypertension. Cardiovascular and Interventional Radiology 2014;1:S341. [Google Scholar]
DENERVHTA {published data only}
- De La Sierra A, Pareja J, Armario P, Barrera A, Sans L, Vazquez S, et al. Renal denervation versus spironolactone in resistant hypertension. effects on circadian patterns and blood pressure variability. Journal of Hypertension 2016;34(Suppl 2):e43. [DOI] [PubMed] [Google Scholar]
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- NCT02039492. Sympathetic renal denervation versus increment of pharmacological treatment in resistant arterial hypertension [Sympathetic renal denervation versus increment of pharmacological treatment in resistant arterial hypertension]. clinicaltrials.gov/show/NCT02039492 (first received 2012).
- Oliveras A, Armario P, Clara A, Sans-Atxer L, Vazquez S, Pascual J, et al. Spironolactone versus sympathetic renal denervation to treat true resistant hypertension: results from the DENERVHTA study: a randomized controlled trial. Journal of Hypertension 2016;34:1863–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Desch 2015 {published data only}
- Desch S, Okon T, Heinemann D, Kulle K, Rohnert K, Sonnabend M, et al. Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. Hypertension 2015;65:1202-8. [DOI] [PubMed] [Google Scholar]
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- NCT01656096. Renal sympathetic denervation in mild refractory hypertension [Renal sympathetic denervation in patients with mild refractory hypertension]. clinicaltrials.gov/show/NCT01656096 (first received 31 July 2012).
Franzen 2012 {published data only}
- Franzen KF, Mortensen K, Himmel F, Stritzke J, Koester J, Bock J, et al. Percutaneous renal denervation (PRD) improves central hemodynamics and arterial stiffness - a pilot study. European Heart Journal 2012;33:771. [DOI] [PMC free article] [PubMed] [Google Scholar]
HTN‐JAPAN 2015 {published data only}
- Kario K, Bakris G, Bhatt LD. Preferential reduction in morning/nocturnal hypertension by renal denervation for drug-resistant hypertension: a new ABPM analysis of SYMPLICITY HTN-3 and HTN-Japan. Journal of Hypertension 2015;33(Suppl 1):e52. [DOI: 10.1097/01.hjh.0000467484.20438.39] [DOI] [Google Scholar]
- Kario K, Bhatt DL, Brar S, Cohen SA, Fahy M, Bakris GL. Effect of catheter-based renal denervation on morning and nocturnal blood pressure: insights from SYMPLICITY HTN-3 and SYMPLICITY HTN-Japan. Hypertension 2015;66:1130-7. [EMBASE: 10.1161/HYPERTENSIONAHA.115.06260] [DOI] [PubMed] [Google Scholar]
- Kario K, Ogawa H, Okumura K, Okura T, Saito S, Ueno T, et al. SYMPLICITY HTN-Japan - First randomized controlled trial of catheter-based renal denervation in Asian patients. Circulation Journal 2015;79:1222-9. [DOI] [PubMed] [Google Scholar]
- NCT01644604. Renal denervation by MDT-2211 system in patients with uncontrolled hypertension [The clinical study of renal denervation by MDT-2211 system in patients with uncontrolled hypertension]. clinicaltrials.gov/show/NCT01644604 (first received 29 June 2012).
INSPIRED {published data only}
- Jacobs L, Persu A, Huang QF, Lengele JP, Thijs L, Hammer F, et al. Results of a randomized controlled pilot trial of intravascular renal denervation for management of treatment-resistant hypertension. Blood Pressure 2017;26(6):321-31. [DOI] [PubMed] [Google Scholar]
- Jin Y, Jacobs L, Baelen M, Thijs L, Renkin J, Hammer F, et al. Rationale and design of the investigator-steered project on intravascular renal denervation for management of drug-resistant hypertension (INSPiRED) trial. Blood Pressure 2014;23:138-46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- NCT01505010. Renal denervation for management of drug-resistant hypertension [Investigator-steered project on intravascular renal denervation for management of drug-resistant hypertension ]. clinicaltrials.gov/show/NCT01505010 (first received 2012). [DOI] [PMC free article] [PubMed]
Moiseeva 2020‐B {published data only}
- Moiseeva A, Caraus A, Moscalu V, Calenici O, Ciobanu N, Sapojnic N, et al. The influence of renal denervation treatment on blood pressure in patients with resistant hypertension. European Journal of Preventive Cardiology 2020;26:P711. [Google Scholar]
- Moiseeva A, Caraus A, Ciobanu N, Moscalu V, Surev A, Abras M, et al. The effects of renal artery denervation on blood pressure values and diastolic dysfunction in resistant hypertension. European Journal of Preventive Cardiology 2019;26(Suppl 1):S164-5. [Google Scholar]
Moiseeva 2020‐M {published data only}
- Moiseeva A, Caraus A, Moscalu V, Calenici O, Ciobanu N, Sapojnic N, et al. The influence of renal denervation treatment on blood pressure in patients with resistant hypertension. European Journal of Preventive Cardiology 2020;27(1 Suppl 1):P711. [Google Scholar]
- Moiseeva A, Caraus A, Ciobanu N Moscalu V, Surev A, Abras M, et al. The effects of renal artery denervation on blood pressure values and diastolic dysfunction in resistant hypertension. European Journal of Preventive Cardiology 2019;26(Suppl 1):S164-5. [Google Scholar]
Oslo RDN 2014 {published data only}
- Bergland OU , Søraas CL , Larstorp ACK, Halvorsen LV, Hjørnholm U, Hoffman P, et al. The randomised Oslo study of renal denervation vs. antihypertensive drug adjustments: efficacy and safety through 7 years of follow-up. Blood Pressure 2020;30:41-50. [DOI] [PubMed] [Google Scholar]
- Bergo KK, Larstorp AC, Hoffmann P, Hjørnholm U, Cataliotti A, Høieggen A, et al. Renal sympathetic denervation lowers systemic vascular resistance in true treatment-resistant hypertension. Blood pressure 2020;30:31-40. [DOI] [PubMed] [Google Scholar]
- Elmula MF, Hoffmann P, Larstorp AC, Brekke M, Fossum E, Stenehjem A, et al. Renal sympathetic denervation is inferior to adjusted drug treatment in patients with true treatment resistant hypertension, a randomized controlled trial. European Heart Journal 2014;35:718. [Google Scholar]
- Elmula MF, Hoffmann P, Larstorp AC, Fossum E, Brekke M, Kjeldsen SE, et al. Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension. Hypertension 2014;63:991-9. [DOI] [PubMed] [Google Scholar]
- Elmula MF, Hoffmann P, Larstorp AC, Hoieggen A, Kjeldsen S. Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment resistant hypertension, a randomized clinical trial. Journal of the American College of Cardiology 2014;1:A1306. [DOI] [PubMed] [Google Scholar]
- Elmula MF, Larstorp AC, Hoffmann P, Rostrup M, Hoieggen A, Kjeldsen S. One-year outcomes of a randomized study in renal denervation: Results for Oslo-RDN study. European Heart Journal 2016;37(Suppl 1):1056-7. [Google Scholar]
- Larstorp BK, Hoieggen ACK, Hjornholm A, Rostrup P, Elmula MF. Haemodynamic changes in patients with treatment-resistant hypertension after renal sympathetic denervation compared to individualized drug therapy. Journal of hypertension 2016;34(Suppl 2):e305. [Google Scholar]
- NCT01673516. Effect of renal sympathetic denervation on resistant hypertension and cardiovascular hemodynamic in comparison to intensive medical therapy utilizing impedance cardiography [Effect of renal sympathetic denervation on resistant hypertension and cardiovascular hemodynamic in comparison to intensive medical therapy utilizing impedance cardiography]. clinicaltrials.gov/show/NCT01673516 (first received 17 August 2012).
- Soeraas CL, Bergland O, Halvorsen LV, Larstorp AC, Hjornholm U, Kjaer VN, et al. Long-term outcome of the randomized Oslo-RDN study. Journal of hypertension 2018;36 Suppl 1:e238-9. [Google Scholar]
Prague‐15 {published data only}
- NCT01560312. Renal denervation in refractory hypertension [Renal denervation - hope for patients with refractory hypertension?]. clinicaltrials.gov/show/NCT01560312 (first received 16 May 2011).
- Rosa J, Widimsky P, Tousek P, Petrak O, Curila K, Waldauf P, et al. Randomized comparison of renal denervation versus intensified pharmacotherapy including spironolactone in true-resistant hypertension: six-month results from the Prague-15 study. Hypertension 2015;65:407-13. [DOI] [PubMed] [Google Scholar]
- Rosa J, Widimsky P, Waldauf P, Lambert L, Zelinka T, Taborsky M, et al. Role of adding spironolactone and renal denervation in true resistant hypertension: one-year outcomes of randomized PRAGUE-15 study. Hypertension 2016;67:397-403. [DOI] [PubMed] [Google Scholar]
- Rosa J, Widimsky P, Waldauf P, Lambert L, Zelinka T, Taborsky M, et al. The role of adding spironolactone and renal denervation in true resistant hypertension. One-year outcomes of randomized study. European Heart Journal 2016;37 Suppl 1:230. [DOI] [PubMed] [Google Scholar]
- Rosa J, Widimsky P, Waldauf P, Zelinka T, Petrak O, Taborsky M, et al. Renal denervation in comparison to intensified pharmacotherapy in true resistant hypertension. Two-year outcomes of randomised PRAGUE-15 study. European Heart Journal 2017;38 Suppl 1:157. [DOI] [PubMed] [Google Scholar]
- Rosa J, Widmsky P, Waldauf P, Zelinka T, Petak O, Taborsky M, et al. Renal denervation in comparison with intensified pharmacotherapy in true resistant hypertension: 2-year outcomes of randomized PRAGUE-15 study. Journal of Hypertension 2017;35:1093–9. [DOI] [PubMed] [Google Scholar]
- Rosa J, Zelinka T, Petrak O, Strauch B, Somloova Z, Indra T, et al. Importance of thorough investigation of resistant hypertension before renal denervation: should compliance to treatment be evaluated systematically? Journal of Human Hypertension 2014;28:684-8. [DOI] [PubMed] [Google Scholar]
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RELIEF 2012 {published data only}
- Ahmed H, Neuzil P, Schejbalova M, Bejr M, Kralovec S, Reddy VY. Renal sympathetic denervation for the management of chronic hypertension (RELIEF): 40 patient analysis. Circulation 2012;1(126):A17520. [Google Scholar]
- Ahmed H, Neuzil P, Schejbalova M, Bejr M, Kralovec S, Reddy VY. Renal sympathetic denervation for the management of chronic hypertension (RELIEF): an interim analysis. Heart Rhythm 2012;1:S469-70. [Google Scholar]
- NCT01628172. Renal sympathetic denervation for the management of chronic hypertension [Renal sympathetic denervation for the management of chronic hypertension]. clinicaltrials.gov/show/NCT01628172 (first received 2012).
ReSET 2015 {published data only}
- Engholm M, Bertelsen JB, Mathiassen ON, Botker HE, Vase H, Peters CD, et al . Effects of renal denervation on coronary flow reserve and forearm dilation capacity in patients with treatment-resistant hypertension. A randomized, double-blinded, sham-controlled clinical trial. International Journal of Cardiology 2018;250:29-34. [DOI] [PubMed] [Google Scholar]
- Mathiassen O, Bech JN, Buus NH, Christensen KL, Vase H, Bertelsen JB, et al. Renal sympathetic denervation in treatment resistant essential hypertension. A sham-controlled, double-blinded randomized trial (ReSET trial). Journal of the American College of Cardiology 2015;66:B41. [Google Scholar]
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- NCT01459900. Renal sympathectomy in treatment resistant essential hypertension: a sham controlled randomized trial [Renal sympathectomy in treatment resistant essential hypertension: a sham controlled randomized trial]. clinicaltrials.gov/show/NCT01459900 (first received 2011).
- Peters CD, Mathiassen ON, Vase H, Norgaard BJ, Christensen KL, Schroeder AP, et al. The effect of renal denervation on arterial stiffness, central blood pressure and heart rate variability in treatment resistant essential hypertension: a substudy of a randomized sham-controlled double-blinded trial (the ReSET trial). Blood Pressure 2017;26:366-80. [DOI] [PubMed] [Google Scholar]
SYMPATHY {published data only}
- Beus E, Jager RL, Beeftink MM, Sanders MF, Spiering W, Vonken EJ, et al. Salt intake and blood pressure response to percutaneous renal denervation in resistant hypertension. Journal of Clinical Hypertension 2017;19:1125-33. [DOI] [PMC free article] [PubMed] [Google Scholar]
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- NCT01850901. Renal sympathetic denervation as a new treatment for therapy resistant hypertension [Renal sympathetic denervation as a new treatment for therapy resistant hypertension - a multicenter randomized controlled trial]. clinicaltrials.gov/show/NCT01850901 (first received 2013).
- Vink EE, De Beus E, De Jager RL, Voskuil M, Spiering W, Vonken EJ, et al. The effect of renal denervation added to standard pharmacologic treatment versus standard pharmacologic treatment alone in patients with resistant hypertension: rationale and design of the SYMPATHY trial. American Heart Journal 2014;167:308-14.e3. [DOI] [PubMed] [Google Scholar]
SYMPLICITY HTN‐2 2010 {published data only}
- Boehm M, Schlaich MP, Krum H, Schmieder RE, Sobotka P, Esler MD. One-year pooled outcomes following renal sympathetic denervation in patients with resistant hypertension: from the SYMPLICITY HTN-2 trial. European Heart Journal 2012;33:770. [Google Scholar]
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- Symplicity HTN-2 Investigators, Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (the SYMPLICITY HTN-2 Trial): a randomised controlled trial. Lancet 2010;376(9756):1903-9. [DOI: 10.1016/S0140-6736(10)62039-9] [DOI] [PubMed] [Google Scholar]
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SYMPLICITY HTN‐3 2014 {published data only}
- Bakris GL, Townsend RR, Flack JM, Brar S, Cohen SA, D'Agostino, et al. 12-month blood pressure results of catheter-based renal artery denervation for resistant hypertension: the SYMPLICITY HTN-3 trial. Journal of the American College of Cardiology 2015;65:1314-21. [DOI] [PubMed] [Google Scholar]
- Bakris GL, Townsend RR, Liu M, Cohen SA, D'Agostino R, Flack JM, et al. Impact of renal denervation on 24-hour ambulatory blood pressure: results from SYMPLICITY HTN-3. Journal of the American College of Cardiology 2014;64:1071-8. [DOI] [PubMed] [Google Scholar]
- Bhatt DL, Bakris GL. Long-term (24-month) blood pressure results of catheter-based renal artery denervation: SYMPLICITY HTN-3 randomized controlled trial. Journal of the American College of Cardiology 2015;1:B38-9. [DOI] [PubMed] [Google Scholar]
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- Bhatt DL, Kandzari DE, O'Neill WW. A controlled trial of renal denervation for resistant hypertension. Journal of Vascular Surgery 2014;60:266. [DOI] [PubMed] [Google Scholar]
- Divison JA, Escobar CC, Segui DM. Controlled clinical trial on renal denervation in resistant hypertension. Semergen 2014;40:345-6. [DOI] [PubMed] [Google Scholar]
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- Flack JM, Bhatt DL, Kandzari DE, Brown D, Brar S, Choi J, et al. An analysis of the blood pressure and safety outcomes to renal denervation in African Americans and Non-African Americans in the SYMPLICITY HTN-3 trial. Journal of the American Society of Hypertension 2015;9:769-79. [DOI] [PubMed] [Google Scholar]
- Kandzari DE, Bhatt DL, Brar S, Devireddy CM, Esler M, Fahy M, et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. European Heart Journal 2015;36:219-27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kandzari DE, Bhatt DL, Sobotka PA, O'Neill WW, Esler M, Flack JM, et al. Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 trial. Clinical Cardiology 2012;35:528-35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kario K, Bakris G, Pocock S, Fahy M, Bhatt DL. Changes in nocturnal blood pressure post-renal denervation: comparison of treatment versus control groups in SYMPLICITY HTN-3. European Heart Journal 2019;40 Suppl 1:664. [Google Scholar]
- Kario K, Bakris GL, Bhatt D. Preferential reduction in morning/nocturnal hypertension by renal denervation for drug-resistant hypertension: a new ABPM analysis of SYMPLICITY HTN-3 and HTN-Japan. Journal of Hypertension 2015;33 Suppl 1:e52. [Google Scholar]
- Kario K, Bhatt DL, Brar S, Cohen SA, Fahy M, Bakris GL. Effect of catheter-based renal denervation on morning and nocturnal blood pressure: insights from SYMPLICITY HTN-3 and SYMPLICITY HTN-Japan. Hypertension 2015;66:1130-7. [DOI] [PubMed] [Google Scholar]
- Kario K, Bhatt DL, Townsend R, Flack J, Negoita M, Oparil S, et al. Potential reduction in office and nocturnal blood pressure after renal denervation in patients with obstructive sleep apnea: A subgroup analysis of SYMPLICITY HTN-3. European Heart Journal 2015;36:186. [Google Scholar]
- NCT01418261. SYMPLICITY HTN-3 renal denervation in patients with uncontrolled hypertension [Renal denervation in patients with uncontrolled hypertension (SYMPLICITY HTN-3)]. clinicaltrials.gov/show/NCT01418261 (first received 2011).
- Pekarskiy S, Baev A, Mordovin V, Sitkova E, Semke G, Ripp T, et al. Failure of renal denervation in SYMPLICITY HTN-3 is a predictable result of anatomically inadequate operative technique and not the true limitations of the technology. Journal of Hypertension 2015;33 Suppl 1:e108. [Google Scholar]
Warchol 2014 {published data only}
- NCT01366625. Renal denervation in patients with resistant hypertension and obstructive sleep apnea [Effects of renal denervation on blood pressure and clinical course of obstructive sleep apnea in patients with resistant hypertension]. clinicaltrials.gov/show/NCT01366625 (first received 2011).
- Warchol-Celinska E, Prejbisz A, Kadziela J, Florczak E, Januszewicz M, Michalowska I, et al. Renal Denervation in Resistant Hypertension and Obstructive Sleep Apnea: Randomized Proof-of-Concept Phase II Trial. Hypertension 2018;72:381-90. [DOI] [PubMed] [Google Scholar]
- Warchol-Celinska E, Prejbisz A, Kadziela J, Sliwinski P, Plywaczewski R, Florczak E, et al. Effect of renal denervation on blood pressure levels and clinical course of obstructive sleep apnea in patients with resistant hypertension-3 months outcomes of randomized trial. European Heart Journal 2016;37 Suppl 1:793. [Google Scholar]
- Warchol E, Prejbisz A, Kadziela J, Florczak E, Kabat M, Sliwinski P, et al. The impact of renal sympathetic denervation on office and ambulatory blood pressure levels in patients with true resistant hypertension and obstructive sleep apnea: the interim analysis. European Heart Journal 2014;35:231. [Google Scholar]
References to studies excluded from this review
Ahmed 2012b {published data only}
- 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. [DOI] [PubMed] [Google Scholar]
Ahmed 2013 {published data only}
- Ahmed H, Miller MA, Dukkipati SR, Cammack S, Koruth JS, Gangireddy S, et al. Adjunctive renal sympathetic denervation to modify hypertension as upstream therapy in the treatment of atrial fibrillation (H-FIB) study: clinical background and study design. Journal of Cardiovascular Electrophysiology 2013;24:503-9. [DOI] [PubMed] [Google Scholar]
Azizi 2018 {published data only}
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ChiCTR‐ONC‐12002901 {published data only}
- ChiCTR-ONC-12002901. Transcatheter renal denervation for patients with resistant hypertension [Transcatheter renal denervation for patients with resistant hypertension]. Http://www.chictr.org.cn/showproj.aspx? Proj=6653 2012.
ChiCTR‐ONC‐13003231 {published data only}
- ChiCTR-ONC-13003231. Noninvasive renal sympathetic denervation by high-intensity focused ultrasound (HIFU) in patients with refractory hypertension [Noninvasive renal sympathetic denervation by high-intensity focused ultrasound (HIFU) in patients with refractory hypertension]. http://www.chictr.org.cn/showproj.aspx?proj=6328 2013.
ChiCTR‐TNC‐12002900 {published data only}
- ChiCTR-TNC-12002900. A comprehensive assessment of the cardiovascular effects of transcatheter renal sympathetic nerve denervation [A comprehensive assessment of the cardiovascular effects of transcatheter renal sympathetic nerve denervation]. http://www.chictr.org.cn/showproj.aspx?proj=6654 2012.
Courand 2016 {published data only}
- Courand PY, Pereira H, Gosse P, Bobrie G, Delsart P, Mounier-Vehier C, et al. Presence of aortic abdominal calcifications in patients with resistant hypertension and bp response in the renal denervation for hypertension (DENERHTN) trial. Journal of Hypertension 2016;34 Suppl 2:e172. [Google Scholar]
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DRKS00005865 {published data only}
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DRKS00006405 {published data only}
- DRKS00006405. Safety and efficacy study investigating the effects of catheter-based renal denervation on different organ systems in patients with increased sympathetic activity. http://www.drks.de/DRKS00006405 2014.
DRKS00006420 {published data only}
DRKS00006493 {published data only}
- DRKS00006493. A randomized safety and efficacy study investigating the effects of catheter-based renal denervation in patients after renal transplantation. http://www.drks.de/DRKS00006493 2015.
Eikelis 2017 {published data only}
- Eikelis N, Hering D, Marusic P, Duval J, Hammond LJ, Walton AS, et al. The effect of renal denervation on plasma adipokine profile in patients with treatment resistant hypertension. Frontiers in Physiology 2017;8:369. [DOI] [PMC free article] [PubMed] [Google Scholar]
EnligHTN III {published data only}
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Esler 2013 {published data only}
- Esler M, Krum H, Schlaich M, Bohm M, Schmieder RE. Renal denervation via catheter-based delivery of radiofrequency energy significantly reduces blood pressure in subjects with severe treatment-resistant hypertension: long-term results from the SYMPLICITY-HTN clinical trials. Circulation 2013;128(S22):A14747. [Google Scholar]
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NCT01465724 {published data only}
- NCT01465724. Renal sympathetic denervation for treatment of metabolic syndrome associated hypertension (Metabolic Syndrome study). clinicaltrials.gov/show/NCT01465724 (first received 2013).
NCT01583881 {published data only}
- NCT01583881. Renal denervation in patients with heart failure with normal LV ejection fraction. clinicaltrials.gov/show/NCT01583881 (first received 2014).
NCT01631370 {published data only}
- NCT01631370. The effects of renal sympathetic denervation on insulin sensitivity in patients with resistant essential hypertension. clinicaltrials.gov/show/NCT01631370 (first received 2012).
NCT01635998 {published data only}
- NCT01635998. Adjunctive renal sympathetic denervation to modify hypertension as upstream therapy in the treatment of atrial fibrillation. clinicaltrials.gov/show/NCT01635998 (first received 2012). [DOI] [PubMed]
NCT01687725 {published data only}
- NCT01687725. Renal denervation in treatment resistant hypertension. clinicaltrials.gov/show/NCT01687725 (first received 2012).
NCT01733901 {published data only}
- NCT01733901. Renal sympathetic denervation as secondary prevention for patients after percutaneous coronary intervention. clinicaltrials.gov/show/NCT01733901 (first received 2012).
NCT01814111 {published data only}
- NCT01814111. Safety and effectiveness study of percutaneous catheter-based sympathetic denervation of the renal arteries in patients with hypertension and paroxysmal atrial fibrillation. clinicaltrials.gov/show/NCT01814111 (first received 2012).
NCT01848314 {published data only}
- NCT01848314. The effect of renal denervation on renal flow in humans. clinicaltrials.gov/show/NCT01848314 (first received 2013).
NCT01873352 {published data only}
- NCT01873352. Renal artery denervation in addition to catheter ablation to eliminate atrial fibrillation. clinicaltrials.gov/show/NCT01873352 (first received 2013).
NCT01888315 {published data only}
- NCT01888315. Influence of catheter-based renal denervation in diseases with increased sympathetic activity. clinicaltrials.gov/show/NCT01888315 (first received 2012).
NCT01897545 {published data only}
- NCT01897545. The role of renal denervation in improving outcomes of catheter ablation in patients with atrial fibrillation and arterial hypertension. clinicaltrials.gov/show/NCT01897545 (first received 2012).
NCT01901549 {published data only}
- NCT01901549. Renal denervation in patients after acute coronary syndrome. clinicaltrials.gov/show/NCT01901549 (first received 2013).
NCT01907828 {published data only}
- NCT01907828. A feasibility study to evaluate the effect of concomitant renal denervation and cardiac ablation on AF recurrence. clinicaltrials.gov/show/NCT01907828 (first received 2013).
NCT01932450 {published data only}
- NCT01932450. Radiofrequency ablation for ADPKD blood pressure and disease progression control. clinicaltrials.gov/show/NCT01932450 (first received 2013).
NCT02016573 {published data only}
- NCT02016573. Renal denervation for uncontrolled hypertension. clinicaltrials.gov/show/NCT02016573 (first received 2013).
NCT02057224 {published data only}
- NCT02057224. Metabolic and cardiovascular effects of renal denervation. clinicaltrials.gov/show/NCT02057224 (first received 2014).
NCT02115100 {published data only}
- NCT02115100. Treatment of atrial fibrillation in patients by pulmonary vein isolation, renal artery denervation or both. clinicaltrials.gov/show/NCT02115100 (first received 2014).
NCT02115230 {published data only}
- NCT02115230. Transcatheter renal denervation in heart failure with normal left ventricular ejection fraction - a safety and efficacy study of irrigated radiofrequency catheter. clinicaltrials.gov/show/NCT02115230 (first received 2014).
NCT02155790 {published data only}
- NCT02155790. The Peregrine study: a safety and performance study of renal denervation. clinicaltrials.gov/show/NCT02155790 (first received 2014).
NCT02164435 {published data only}
- NCT02164435. Effects of renal sympathetic denervation on the cardiac and renal functions in patients with drug-resistant hypertension through MRI evaluation (RDN). clinicaltrials.gov/show/NCT02164435 (first received 2014).
NCT02272920 {published data only}
- NCT02272920. PCI and renal denervation in hypertensive patients with acute coronary syndromes. clinicaltrials.gov/show/NCT02272920 (first received 2014).
NCT02559882 {published data only}
- NCT02559882. Testing effectiveness of renal denervation in patients with therapy-resistant hypertension. clinicaltrials.gov/show/NCT02559882 (first received 2015).
NCT02667912 {published data only}
- Baev, APekarskiy, SMordovin, VRipp, TFalkovskaya, ALichikaki, V et al. A distal mode of renal denervation in segmental branches of renal artery versus conventional main trunk therapy: a double blind randomized controlled study in patients with resistant hypertension. Journal of the american college of cardiology 2017;18 Suppl 1:B86. [Google Scholar]
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- NCT03261375. A clinical trial to evaluate safety and efficacy of a renal denervation system in treatment of hypertension. ClinicalTrials.gov/show/NCT03261375 2017.
NCT03465917 {published data only}
- NCT03465917. Physiological study of the efficacy and mechanistic effects of alcohol renal denervation. ClinicalTrials.gov/show/NCT03465917 2018.
NCT03511313 {published data only}
- NCT03511313. Renal denervation with sterile irrigated deflectable ablation catheter used in renal artery in primary hypertension. ClinicalTrials.gov/show/NCT03511313 2018.
NCT04248530 {published data only}
- DENEX renal denervation in patients With uncontrolled hypertension: safety study. clinicaltrials.gov/show/NCT04248530.
NCT04264403 {published data only}
- Renal denervation in chronic kidney disease - RDN-CKD study. https://clinicaltrials.gov/show/NCT04264403 (first received 11 February 2020).
NCT04307836 {published data only}
- DENEX renal denervation in patients with hypertension on no or 1-3 antihypertensive medications (DENEX HTN-KORAS). clinicaltrials.gov/show/NCT04307836 (first received 13 March 2020).
NCT04311086 {published data only}
- SPYRAL DYSTAL clinical study. clinicaltrials.gov/show/NCT04311086 (first received 17 March 2020).
NCT04535050 {published data only}
- DENEX renal denervation in patients with hypertension on no antihypertensive medications. clinicaltrials.gov/show/NCT04535050 (first received 1 September 2020).
Palionis 2016 {published data only}
- Palionis D, Berukstis A, Misonis N, Ryliskyte L, Celutkiene J, Zakarkaite D, et al . Could careful patient selection for renal denervation warrant a positive effect on arterial stiffness and left ventricular mass reduction? Acta cardiologica 2016;71:173-83. [DOI] [PubMed] [Google Scholar]
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RAPID {published data only}
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ReD {published data only}
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REDUCE HTN:REINFORCE {published data only}
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Ripp 2019 {published data only}
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RSDAH {published data only}
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Sanders 2016 {published data only}
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SPYRAL HTN‐ON MED {published data only}
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Stoiber 2018 {published data only}
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TARGET BP OFF‐MED {published data only}
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Townsend 2017 {published data only}
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Weber 2018 {published data only}
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References to ongoing studies
ALLEGRO‐HTN {published data only}
- NCT01874470. Renal denervation by Allegro system in patients with resistant hypertension. clinicaltrials.gov/show/NCT01874470 (first received 2013).
DEPART {published data only}
- NCT01522430. Denervation of renal sympathetic activity and hypertension study. clinicaltrials.gov/show/NCT01522430 (first received 2012).
EnligHTN IV {published data only}
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ENSURE {published data only}
- NCT02102126. Effect of renal denervation on arterial stiffness and haemodynamics in patients with uncontrolled hypertension (ENSURE). clinicaltrials.gov/show/NCT02102126 (first received 2014).
KPS {published data only}
- NCT02002585. Renal protection using sympathetic denervation in patients with chronic kidney disease (Kidney protection study - KPS Study). clinicaltrials.gov/show/NCT02002585 (first received 2013).
NCT01848275 {published data only}
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NCT01918111 {published data only}
- NCT01918111. 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). clinicaltrials.gov/show/NCT01918111 (first received 2013).
NCT01968785 {published data only}
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NCT02021019 {published data only}
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NCT02346045 {published data only}
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NCT02444442 {published data only}
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NCT02608632 {published data only}
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NCT02900729 {published data only}
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PaCE {published data only}
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RADIANCE‐HTN {published data only}
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RAPID II {published data only}
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RDNP‐2012‐01 {published data only}
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RENO {published data only}
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RENSYMPIS {published data only}
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ReSET‐2 {published data only}
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RSD4CKD {published data only}
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RSDARH {published data only}
- NCT03758196. Renal sympathetic denervation from the adventitia on resistant hypertension (RSDARH). clinicaltrials.gov/show/NCT03758196 (first received 29 November 2018 ).
RSDforAF {published data only}
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