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Recent randomized sham-controlled trials have demonstrated significant blood pressure reductions following renal denervation (RDN) in patients with hypertension, both in the presence and absence of antihypertensive therapy. These new data encouraged us to revisit previously published insights into potential clinical trial confounding factors that informed the design and conduct of forthcoming trials. Initially identified confounders related to procedural technique, medication variability, and selected patient subgroups have been addressed in contemporary trial design. Regarding procedural method and technology, blood pressure reductions may be improved by ensuring circumferential lesion creation in the distal renal arteries and branch vessels. Safety of the RDN procedure has been demonstrated in multiple independent meta-analyses including thousands of treated patients with low reported rates of renal vessel complications and maintenance of renal function. However, a newer generation of RDN trials has also introduced insights related to medication adherence, patient selection, and the definition of treatment response. Evolving evidence indicates that RDN therapy may be considered in higher risk populations of uncontrolled hypertension regardless of ethnicity and in patients expressing a strong preference for a nondrug therapy option. Despite advances in procedural technique and clinical trial conduct, inconsistent antihypertensive-drug adherence behavior remains perhaps the most critical clinical trial design issue for device-based hypertension therapies. As the balance in clinical equipoise increasingly favors RDN, justification of sham-controlled trial designs will be revisited, and novel study designs may be required to evaluate the safety and efficacy of novel devices and procedures intended to address the escalating prevalence of poorly controlled hypertension. © 2020 International Anesthesia Research Society.

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Aims: Resting heart rate (RHR) has been shown to be associated with cardiovascular outcomes in various conditions. It is unknown whether different levels of RHR and different associations with cardiovascular outcomes occur in patients with or without diabetes, because the impact of autonomic neuropathy on vascular vulnerability might be stronger in diabetes. Methods and results: We examined 30937 patients aged 55years or older with a history of or at high risk for cardiovascular disease and after myocardial infarction, stroke, or with proven peripheral vascular disease from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination followed for a median of 56months. We analysed the association of mean achieved RHR on-treatment with the primary composite outcome of cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, the components of the composite primary outcome, and all-cause death as continuous and categorical variables. Data were analysed by Cox regression analysis, ANOVA, and chi2 test. These trials were registered with ClinicalTrials.gov.number NCT00153101. Patients were recruited from 733 centres in 40 countries between 1 December 2001 and 31 July 2008 (ONTARGET) and 1 November 2001 until 30 May 2004 (TRANSCEND). In total, 19450 patients without diabetes and 11487 patients with diabetes were stratified by mean RHR. Patients with diabetes compared to no diabetes had higher RHRs (71.8 ± 9.0 vs. 67.9 ± 8.8, P

Background: Previous catheter-based renal denervation studies have reported variable efficacy results. We aimed to evaluate safety and blood pressure response after renal denervation or sham control in patients with uncontrolled hypertension on antihypertensive medications with drug adherence testing. Methods: In this international, randomised, single-blind, sham-control, proof-of-concept trial, patients with uncontrolled hypertension (aged 20–80 years) were enrolled at 25 centres in the USA, Germany, Japan, UK, Australia, Austria, and Greece. Eligible patients had an office systolic blood pressure of between 150 mm Hg and 180 mm Hg and a diastolic blood pressure of 90 mm Hg or higher; a 24 h ambulatory systolic blood pressure of between 140 mm Hg and 170 mm Hg at second screening; and were on one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned to undergo renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were masked to randomisation assignments. The primary efficacy endpoint was blood pressure change from baseline (measured at screening visit two), based on ambulatory blood pressure measurements assessed at 6 months, as compared between treatment groups. Drug surveillance was used to assess medication adherence. The primary analysis was done in the intention-to-treat population. Safety events were assessed through 6 months as per major adverse events. This trial is registered with ClinicalTrials.gov, number NCT02439775, and follow-up is ongoing. Findings: Between July 22, 2015, and June 14, 2017, 467 patients were screened and enrolled. This analysis presents results for the first 80 patients randomly assigned to renal denervation (n=38) and sham control (n=42). Office and 24 h ambulatory blood pressure decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24 h systolic blood pressure −7·0 mm Hg, 95% CI −12·0 to −2·1; p=0·0059, 24 h diastolic blood pressure −4·3 mm Hg, −7·8 to −0·8; p=0.0174, office systolic blood pressure −6·6 mm Hg, −12·4 to −0·9; p=0·0250, and office diastolic blood pressure −4·2 mm Hg, −7·7 to −0·7; p=0·0190). The change in blood pressure was significantly greater at 6 months in the renal denervation group than the sham-control group for office systolic blood pressure (difference −6·8 mm Hg, 95% CI −12·5 to −1·1; p=0·0205), 24 h systolic blood pressure (difference −7·4 mm Hg, −12·5 to −2·3; p=0·0051), office diastolic blood pressure (difference −3·5 mm Hg, −7·0 to −0·0; p=0·0478), and 24 h diastolic blood pressure (difference −4·1 mm Hg, −7·8 to −0·4; p=0·0292). Evaluation of hourly changes in 24 h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24 h for the renal denervation group. 3 month blood pressure reductions were not significantly different between groups. Medication adherence was about 60% and varied for individual patients throughout the study. No major adverse events were recorded in either group. Interpretation: Renal denervation in the main renal arteries and branches significantly reduced blood pressure compared with sham control with no major safety events. Incomplete medication adherence was common. Funding: Medtronic. © 2018 Elsevier Ltd

Initial studies of catheter-based renal denervation (RDN) for uncontrolled HTN using radiofrequency ablation in the main renal arteries showed that RDN was effective in lowering office blood pressure (BP). However, the first randomized sham-controlled trial, SYMPLICITY-HTN-3, did not show significantly lower office or 24-h ambulatory systolic BP compared with sham treatment. Subsequent studies in both animals and humans demonstrated the potential importance of more distal and branch renal artery radiofrequency ablation, and a second-generation multielectrode system became available. Two recent randomized sham-controlled trials in patients not taking antihypertensive drugs (SPYRAL HTN-OFF MED) or continuing to take drugs (SPYRAL HTN-ON MED) performed RDN with the second-generation radiofrequency ablation system using an ablation protocol that included treatment of the distal renal artery as well as the branch renal arteries. These studies showed that RDN significantly reduced office and 24-h ambulatory BP compared with sham treatment. Another recent randomized sham-controlled trial in patients not receiving medications showed that RDN with catheter-based ultrasound (RADIANCE-HTN SOLO) applied in just the main renal arteries significantly lowered daytime ambulatory and office BP compared with sham treatment. These trials have renewed clinical and scientific interest in defining the appropriate role of RDN in hypertension treatment. In addition, other important issues will need to be addressed in the future such as the development of tests to determine the extent of RDN at the time of the procedure and the potential of renal nerve fibers to regain their patency at some later stage following the ablation procedure. © 2019 American College of Cardiology Foundation

Previous catheter-based renal denervation studies have reported variable efficacy results. We aimed to evaluate safety and blood pressure response after renal denervation or sham control in patients with uncontrolled hypertension on antihypertensive medications with drug adherence testing. : In this international, randomised, single-blind, sham-control, proof-of-concept trial, patients with uncontrolled hypertension (aged 20-80 years) were enrolled at 25 centres in the USA, Germany, Japan, UK, Australia, Austria, and Greece. Eligible patients had an office systolic blood pressure of between 150 mm Hg and 180 mm Hg and a diastolic blood pressure of 90 mm Hg or higher; a 24 h ambulatory systolic blood pressure of between 140 mm Hg and 170 mm Hg at second screening; and were on one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned to undergo renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were masked to randomisation assignments. The primary efficacy endpoint was blood pressure change from baseline (measured at screening visit two), based on ambulatory blood pressure measurements assessed at 6 months, as compared between treatment groups. Drug surveillance was used to assess medication adherence. The primary analysis was done in the intention-to-treat population. Safety events were assessed through 6 months as per major adverse events. This trial is registered with ClinicalTrials.gov, number NCT02439775, and follow-up is ongoing. : Between July 22, 2015, and June 14, 2017, 467 patients were screened and enrolled. This analysis presents results for the first 80 patients randomly assigned to renal denervation (n=38) and sham control (n=42). Office and 24 h ambulatory blood pressure decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24 h systolic blood pressure -7·0 mm Hg, 95% CI -12·0 to -2·1; p=0·0059, 24 h diastolic blood pressure -4·3 mm Hg, -7·8 to -0·8; p=0.0174, office systolic blood pressure -6·6 mm Hg, -12·4 to -0·9; p=0·0250, and office diastolic blood pressure -4·2 mm Hg, -7·7 to -0·7; p=0·0190). The change in blood pressure was significantly greater at 6 months in the renal denervation group than the sham-control group for office systolic blood pressure (difference -6·8 mm Hg, 95% CI -12·5 to -1·1; p=0·0205), 24 h systolic blood pressure (difference -7·4 mm Hg, -12·5 to -2·3; p=0·0051), office diastolic blood pressure (difference -3·5 mm Hg, -7·0 to -0·0; p=0·0478), and 24 h diastolic blood pressure (difference -4·1 mm Hg, -7·8 to -0·4; p=0·0292). Evaluation of hourly changes in 24 h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24 h for the renal denervation group. 3 month blood pressure reductions were not significantly different between groups. Medication adherence was about 60% and varied for individual patients throughout the study. No major adverse events were recorded in either group. : Renal denervation in the main renal arteries and branches significantly reduced blood pressure compared with sham control with no major safety events. Incomplete medication adherence was common. : Medtronic.

Introduction: Although the first results from studies suggested important benefits regarding blood pressure (BP) control in resistant hypertension by the use of diverse systems of renal denervation (RDN) in the setting of resistant hypertension, the Symplicity HTN-3, randomized sham-controlled trial reduced the enthusiasm and led to a more critical approach towards this neuromodulation innovative therapy. Nowadays there is an ongoing research attempt to justify the pathophysiological background of RDN since overdrive of the sympathetic nervous system is one of the key mechanisms leading to the development and progression of the hypertensive and cardiovascular diseases. Conclusion: Future RDN trials based on the clinical findings and gaps from previous works will try to identify those parameters to help identify better BP response, target the most suitable population and conclude whether this interventional approach can contribute to the clinical problem of uncontrolled hypertension. © 2018 Bentham Science Publishers.

This ESH update was deemed necessary with the publication of new results of sham-controlled randomized blinded prospective trials with renal denervation (RDN). Proof of concept studies and first randomized trials (some were sham-controlled) displayed discrepant results about the efficacy of RDN. Three sham-controlled randomized trials of the 2.0 generation yielded now similarity in the average blood pressure decrease following RDN. Reduction of ambulatory blood pressure was approximately 5 to 7 mmHg and of office blood pressure 10 mmHg. Such a decrease in blood pressure by pharmacologic therapy has been found to be associated with lower incidence of cardiovascular events in particular with respect to heart failure and stroke by roughly 25%. Nevertheless, some questions about renal denervation are unanswered. The heterogeneity of the blood pressure-lowering response point to the clinical need to identify predictors for efficacy, and questions on long-term safety could not have been answered due to the short duration of the sham-controlled randomized clinical trials. © 2018 Wolters Kluwer Health, Inc.

These practice guidelines on the management of arterial hypertension are a concise summary of the more extensive ones prepared by the Task Force jointly appointed by the European Society of Hypertension and the European Society of Cardiology. These guidelines have been prepared on the basis of the best available evidence on all issues deserving recommendations; their role must be educational and not prescriptive or coercive for the management of individual subjects who may differ widely in their personal, medical and cultural characteristics. The members of the Task Force have participated independently in the preparation of these guidelines, drawing on their academic and clinical experience and by objective examination and interpretation of all available literature. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.