More than ever before, arterial hypertension represents one of the greatest health threats and challenges for both patients and treating physicians. With the new adjustment and narrowing of blood pressures targets for antihypertensive treatment, the number of patients with uncontrolled hypertension is increasing. Importantly, despite advances in drug therapy, reality proves that adherence to medication is very limited, worsens with increasing number of drugs and is difficult to predict. Consequently, non-pharmaceutical, interventional treatment options bear the hope of adding a “one-stop-always-on” therapy to the vast but still not efficient armoury against hypertension. In this commentary, Philipp Lurz reviews the latest evidence for renal denervation and whether it is starting to live up to its initial promise.
Renal denervation is one of several innovative device-based interventional therapies, that is aiming for better blood pressure control. It is safe, minimally invasive, and does not leave any implants behind. The effectiveness of this procedure, however, is still subject to fierce debate and controversy.
The available evidence
Recently, the SYMPLICITY ON/OFF MED (Medtronic) and RADIANCE SOLO (ReCor Medical) trials indicated a significant reduction in ambulatory blood pressure with renal denervation (with the Sypral and Paradise systems respectively) vs. a sham procedure. These trial programmes were influenced by the painful experience of the neutral SIMPLICITY HTN-3 trial, which failed to show an efficacy benefit with the first-generation Symplicity system, and show substantial similarities in study design and patient selection.
Most importantly, both programmes implemented a very thorough protocol—including a roll-in period, witnessed pill intake, serial ambulatory blood pressure monitoring (ABPM) measurements, screening for drug adherence, and inclusion of drug-naive patients. These protocol specifications were implemented to reduce major confounding effects of changes in antihypertensive medication and to minimise effects such as regression to the mean or Hawthorne. Consequently, in these recent trials, very little blood pressure reduction was observed in the sham procedure group and the reduction that did occur was significantly less than that seen in the renal denervation groups, supporting the overall concept of the procedure.
These positive results were achieved in both drug-naive patients and patients on one to three antihypertensive drugs. A truly therapy resistant population is being investigated within the RADIANCE TRIO trial (standardised medication using a three-combination polypill) and the results of this study are eagerly awaited (due 2019). Until then, the question of who represents the ideal target for renal denervation remains unanswered. A previous analysis suggested that renal denervation is less effective in isolated systolic hypertension than in combined systolic and diastolic hypertension, leading to exclusion of patients with isolated hypertension in the latest trials. However, there is evidence that subgroups of such patients can benefit from renal denervation equally. A randomised controlled trial focusing on patients with isolated systolic hypertension is needed to clarify the role of renal denervation in these patients.
In summary, there is sound evidence about the effectiveness of renal denervation in drug-naive patients with probable mild and early stage hypertension—a group of patients with projected low cardiovascular risk—but there are still some uncertainties in patients with truly resistant hypertension (RADIANCE TRIO cohort). In the meantime, patients with uncontrolled hypertension despite the intake of some antihypertensive drugs (Symplicity ON MED cohort) and an intermediate cardiovascular risk should represent the most appropriate target for renal denervation.
The technology and technique used for renal denervation needs consideration when interpreting study results. Currently, denervation is either performed using radiofrequency energy (Symplicity, Medtronic) or ultrasound energy (Paradise, ReCor Medica). The latter is believed to achieve a penetration depth of 6mm, which is the expected location of sympathetic nerves in the adventitia of the main renal artery. In contrast, the procedural specifics applied in the SPYRAL HTN-OFF MED and ON-MED trails included the use of a spiral catheter with ablations delivered in the main and branch renal arteries, based on the finding that sympathetic nerves run closer to the lumen within the branch renal arteries and therefore more amenable to renal denervation.
Results of recent trials suggest that both strategies are effective and safe, however, comparisons of different techniques and technologies are scarce. At the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA), I presented the results of the RADIOSOUND trial. This study compared radiofrequency main renal artery ablation vs. radiofrequency main and branch renal artery ablation vs. ultrasound ablation in the main renal artery only. With all three approaches, a significant reduction in blood pressure was achieved. Endovascular ultrasound based renal denervation was found to be superior to radiofrequency ablation of the main renal arteries only, whereas a combined approach of radiofrequency ablation of the main arteries, accessories and side branches was not. Numbers in this trial are small (40 patients in each treatment arm) and no definite recommendations about the preferred technology and technique for renal denervation could be given. Overall, the positive results of the second-generation trials helped renal denervation to resurrect as a hopeful therapy for hypertension. Important tasks for the future include refinements in patient selection and technique as well as establishing a measure of procedural success for renal denervation, which at present is still an interventional unknown.
Philipp Lurz is at Department of Cardiology, Heart Center Leipzig, University of Leipzig, Leipzig, Germany