Renal sympathetic denervation: Ashes to ashes or rebirth from the ashes?

During the last 5 years, 2 furious debates have prevailed in the hypertension community. The first debate, regarding the initiation of antihypertensive treatment and the goal blood pressure with antihypertensive therapy, rendered the Atlantic Ocean an “unfriendly” sea of division1 and was generated by a positive study, the SPRINT trial.2 The second debate, regarding the efficacy of renal sympathetic denervation for the management of resistant hypertension, created a gap between clinical hypertension specialists and interventional cardiologists3 and was generated by a negative study, the Symplicity-3 trial.4 Regarding the latter debate (which is the topic of this editorial), the initial enthusiasm for the first studies (Symplicity-1 and -2), and numerous observational studies5-7 that were either not appropriately randomized or not appropriately controlled was dampened by the neutral findings of the Symplicity-3 trial4 and partially rekindled by the positive findings of the SPYRAL HTN-OFF MED study,8 resembling the movement of a pendulum and leaving the scientific community in a misty landscape. In this issue, Denegri and colleagues report a case series of 57 patients with resistant hypertension who were treated interventionally.9 Renal sympathetic denervation was performed with 3 different devices (Symplicity, EnligHTN, and Vessix). The primary safety endpoint was renal function, and the primary efficacy endpoint was systolic ambulatory blood pressure for a follow-up period of 24 months. Regarding safety, no deterioration of renal function was observed at 1 and 2 years following the performance of the procedure,9 overcoming concerns regarding renal function that were previously expressed.10 The procedure was not accompanied by any adverse event apart from a local complication (bleeding at the puncture site) that was easily managed. Regarding efficacy, renal sympathetic denervation resulted in pronounced blood pressure reduction. Office systolic blood pressure was reduced by 25 mm Hg and ambulatory systolic blood pressure was reduced by 14 mm Hg 2 years post procedure, whereas diastolic blood pressure was reduced by 7 mm Hg for both office and ambulatory measurements.9 There are 3 main strengths in the study by Denegri and colleagues.9 First, it provides real-life data, outside the “sterile” environment of clinical trials. Study participants were managed as usual patients reflecting everyday clinical practice and permitting the generalization of study findings in Caucasian patients with resistant hypertension. Second, and more important and clinically meaningful, renal sympathetic denervation was highly effective in this study, adding more fuel to the furious debate about the efficacy of this innovative interventional approach for the management of resistant hypertension.10-18 Of great importance, renal sympathetic denervation was performed by a single operator (Prof. Τ. Luscher in Zurich), who was very experienced and familiar with the procedure, and an extensive nerve destruction seems very likely because more than 15 ablations were performed on average in each patient. Third, the procedure was safe, without any significant short- and long-term complications, providing further support for the overall adequate safety of this intervention.7, 11 Some limitations can be recognized as well, as in every study. First, this is a retrospective analysis carrying the inherent limitations of this type of study. Second, a control group was not included in the study, casting doubts about the “true” antihypertensive effect of the intervention beyond a placebo effect, especially given the pronounced placebo effect in the Symplicity-3 trial.4 Third, the number of participants is relatively small and thus does not allow for definite conclusions, and the 2-year follow-up period does not ensure long-term safety and the durability of blood pressure reduction overtime. The efficacy of renal sympathetic denervation is a highly controversial aspect with passionate supporters and opponents. The impressive findings of the first clinical trials (Symplicity-1 and -2)5, 6 were replicated in numerous observational nonrandomized studies all over the world,7 generating great enthusiasm for the future of renal sympathetic denervation in the management of resistant hypertension and many other disease conditions characterized by sympathetic overactivity. In Symplicity-3, however, a total of 535 patients with resistant hypertension were randomized to denervation or a sham operation.4 Systolic blood pressure was significantly reduced by 14 mm Hg (office) and by 7 mm Hg (ambulatory) in the intervention group. However, similar blood pressure reductions were observed in the placebo group as well, without any significant differences between the 2 groups. Therefore, the results of the first large randomized study that was properly controlled (sham operation) tempered the enthusiasm, diminishing support for renal denervation. Although these results rendered the field inactive and several ongoing or ready-to-start studies (including large outcome studies) were put on hold, a few small studies were redesigned to further explore the efficacy of renal denervation. In the SPYRAL HTN-OFF MED study, a total of 80 patients with resistant hypertension who were off drugs (either naïve or discontinued therapy) were randomly assigned to renal denervation or sham control.8 At 3 months post procedure, systolic blood pressure was significantly reduced in the intervention group (office: 10/5 mm Hg; ambulatory: 6/5 mm Hg), whereas there was no blood pressure reduction in the sham-operated group, unveiling a significant difference between the 2 groups. Although the number of study participants was small and the design of the study (off antihypertensive drugs) limited the generalization of these findings, this study verified that renal denervation actually works and the concept remains viable. The Symplicity-3 trial is by far the largest randomized study in this field. However, it was heavily criticized for many reasons, including the baseline management of the patients that led to a marked placebo effect that was not observed in the SPYRAL HTN-OFF MED study. Most criticism focused on procedural aspects, in particular, the experience of interventionalists and the extent of renal denervation. Regarding the former, most sites performed 1-2 procedures, thus casting doubts about the familiarization of the operator with the technique. Although experienced interventional cardiologists were selected, they were not familiar with renal denervation, and it is known that a learning curve exists for each new approach, exerting a negative impact on the outcome of the first cases. Regarding the latter, a post-hoc analysis of the study revealed that the majority of patients received 4-6 ablations per artery, and of major importance only 19 participants received a circumferential ablation of both renal arteries.19 Of note, blood pressure response was associated with the number of ablations, and patients receiving more than 14 ablations experienced a sufficient systolic blood pressure reduction (office: 14 mm Hg; ambulatory: 7 mm Hg),19 thus underlining the importance of adequate renal denervation.20, 21 It is noteworthy that the study by Denegri and colleagues9 actually duplicates the findings of the post-hoc analysis of Symplicity-3, because for a similar number of ablations an identical blood pressure reduction is achieved. The experience of the performer and the number of ablations acquire larger dimensions and greater importance because renal denervation is actually a “blind” procedure. There is no accurate predictor identified to date to recognize the extent of renal denervation and answer whether the nerve destruction is sufficient or more ablations are needed.22 This is a major limitation of renal sympathetic denervation and requires an appropriate solution in order for the wide implementation of the technique. The efficacy of an approach in real life is the most important parameter from the clinical point of view, because randomized controlled trials (despite their unique unbeatable characteristics) “suffer” from strict inclusion/exclusion criteria that might limit the generalization of findings, and the close follow-up and the strict protocol procedures might not be feasible in everyday clinical practice, thus calling into question the efficacy and safety in real-world conditions. The study by Denegri and colleagues provides reassuring real-life evidence, which is in line with local registries23, 24 and the Global Symplicity Registry.25 Almost a decade later than the original proof-of-concept study, we are certainly wiser but we still remain dubious about the future of renal sympathetic denervation.26, 27 There is no doubt that interventional approaches aim to fill a real and not a perceived gap in the management of resistant hypertension, taking advantage of the limitations of antihypertensive drug therapy. Even though some studies suggest a similar efficacy of intensified medical treatment including mineralocorticoid receptor antagonists,28 such drugs are rarely administered in everyday clinical practice (approximately 6%)29 and are associated with poor compliance rates.30 Ongoing trials will clarify whether renal sympathetic denervation will turn to ashes or revive like the phoenix from its own ashes.