Renal denervation for hypertension: what is needed, and what is next.

Renal denervation therapy for hypertension has travelled a storied path over the past decade, from unbridled enthusiasm to abrupt disillusionment, and now renewed but still cautious interest. Against the early background of one randomized trial and observational studies suggesting clinically significant reductions in blood pressure among patients with severe treatment-resistant hypertension, renal denervation was poised as a breakthrough therapy with global public health impact. Following the lack of demonstrable efficacy compared with antihypertensive therapy alone in the SYMPLICITY HTN 3 trial, however, the prospect of renal denervation’s role in clinical practice vanished and seemingly validated earlier criticisms of trial conduct and more broadly device-based therapies for hypertension. Amidst this disappointment, however, additional exploratory clinical and preclinical studies continued, and a signal of efficacy with renal denervation persisted, motivating the pursuit of further study. As a consequence of this perseverance, three sham-controlled, randomized feasibility studies have demonstrated clinically meaningful reductions in blood pressure with renal denervation in both the absence and presence of co-existing antihypertensive therapies; together, these studies not only reaffirm the biological proof of principle for this novel treatment but also offer insight into its complementary benefit in uncontrolled hypertension despite prescribed medications. What else then is needed before accepting renal denervation as a safe and effective therapy for the world’s leading cause of death and disability? Although recent trials have revitalized the potential of renal denervation therapy, past experience mandates a more graduated approach to generation of evidence and, understandably, scepticism remains. Early enthusiasm for clinical adoption outpaced the available science, followed only by a single randomized trial that swiftly ended its use in clinical practice and for a time in clinical trials. Results of the SYMPLICITY HTN 3 trial readily discounted the benefits observed in previous studies. Yet with more thoughtful study considerate of the patient population, trial methods, and procedural technique, these now promising results raise questions as to when sham-controlled trials may no longer be needed, what purpose nonrandomized studies have in this space, and what additional study is needed to overcome disbelief. To address many of these outstanding uncertainties, the Global SYMPLICITY Registry was developed to characterize safety and efficacy outcomes with renal denervation among a broader, less selected hypertensive patient population compared with the more restrictive enrolment criteria of randomized trials. Representing the largest survey of renal denervation and specific to radiofrequency ablation, the programme began prior to the SYMPLICITY HTN 3 trial and has since endeavoured to enrol consecutive patients treated for hypertension. Although previous reports from the multinational registry have described early and intermediate outcomes following renal denervation, the present analysis in this issue of the European Heart Journal represents the most comprehensive follow-up to date of efficacy and safety outcomes through 3 years. Among 1742 treated patients [average 24-h systolic ambulatory blood pressure measurement (ABPM) 154 ± 18 mmHg), the reduction in systolic office (–16.5 ± 28.6 mmHg) and ambulatory blood pressure (–8.0 ± 20 mmHg) was maintained through 3 years, representing not only a statistically significant decrease but also one deemed clinically important by societal consensus. In addition, the investigators describe an annualized decline in the estimated glomerular filtration rate (eGFR) and a very low incidence of renal artery stenosis (0.1%) that are overall consistent with predicted estimates. Aside from the unblinded, single-arm trial design, the study is limited to patients treated with a predicate device and with nascent procedural technique compared with contemporary studies showing benefit in both onand off-medication cohorts that involve approximately four times the number of ablations with extension into the renal branch vasculature. Further, as a study representative of realworld practice, sophisticated monitoring of drug adherence as well as