Renal denervation (RDN) with percutaneous, catheter-based radiofrequency ablation was shown to reduce blood pressure (BP) in patients with true treatment-resistant hypertension in the initial registry of RDN [Schlaich MP et al. Hypertension. 2009] and in the Symplicity HTN trials [Symplicity HTN-1 Investigators. Hypertension. 2011; Symplicity HTN-2 Investigators. Lancet. 2010].

However, the promising results found in these trials of reductions in systolic blood pressure (SBP), such as −33 mm Hg at 3 years in the nonrandomized Symplicity HTN-1 trial (P < .01 vs baseline) and −32 mm Hg at 6 months in seated office SBP versus sham (P < .0001) in the randomized Symplicity HTN-2 trial, were not supported by the results of the Symplicity HTN-3 trial [Bhatt DL et al. N Engl J Med. 2014]. No significant difference was found for the primary efficacy end point of change in office SBP at 6 months between the denervation and sham groups (−2.39 mm Hg; 95% CI, −6.89 to 2.12; P = .26).

A number of potential explanations have emerged for the negative results in Symplicity HTN-3 and were reviewed by Oscar A. Mendiz, MD, Favaloro University, Buenos Aires, Argentina. These include technical issues such as catheter design and level of operator experience, trial conduct, Hawthorne effect, placebo effect, patient demographics, and medication changes or adherence.

In regard to catheter design, with the monopolar single-point catheter, there is energy loss into tissue and blood and nonhomogeneous injury distribution. Animal data have shown that the number of ablations is correlated with the concentration of norepinephrine and that approximately 6 to 10 ablations are required to achieve sufficient RDN [Mazor M. J Am Coll Cardiol. 2012]. Subanalyses of the Symplicity HTN-3 data revealed a significant reduction in SBP at 6 months in nonblack patients, which raises the question of whether this is because of racial differences or adherence to medication, said Prof Mendiz. RDN was also effective in patients taking an aldosterone antagonist at study entry.

Whether adequate maximal sympathetic blockade was achieved before RDN in Symplicity HTN-3 is questioned, because approximately 40% of the patients in the RDN and sham groups had changes in their medication between baseline and 6 months. Patients were taking about 5 drugs each, > 50% had ≥ 1 drug change, 69% of all medication changes were “escape” changes, and about 50% were taking central-acting sympatholytics.

A subanalysis of Symplicity HTN-3 showed that the use of aldosterone antagonists at baseline, the total number of ablation attempts, and baseline office SBP ≥ 180 mm Hg were predictors of a change in SBP at 6 months in the RDN group [Kandzari D et al. EuroPCR. 2014]. A matched cohort analysis by these authors also showed an association between the number of ablations and change in office and ambulatory SBP, with ≥ 10 ablations associated with a significant reduction.

The ALSTER BP real-world registry of the Symplicity RDN system showed that there are 3 types of responders: early, late, and non [Kaiser L et al. EuroIntervention. 2014]. In 5 of 8 nonresponders who had a second RDN procedure, SBP was reduced at 6 months. The company-sponsored Global SYMPLICITY Registry [NCT01534299] showed that there were reductions in the mean 24-hour ambulatory SBP and in office SBP (by 11.9 to 20.2 mm Hg) in its first 1581 patients.

Prof Mendiz stated that patients with true treatment-resistant hypertension would be considered candidates for RDN after careful patient selection using a team approach with well-defined criteria in a well-trained catheterization laboratory, which should perform ≥ 14 ablations per patient. New RDN devices are showing promising preliminary outcomes, and new applications for different clinical settings (eg, for kidney failure, heart failure, obesity, diabetes, and sleep apnea) are being investigated.