Renal Denervation after Symplicity HTN-3: An Update

Abstract

After three years of excessive confidence, overoptimistic expectations and performance of 15 to 20,000 renal denervation procedures in Europe, the failure of a single well-designed US trial—Symplicity HTN-3—to meet its primary efficacy endpoint has cast doubt on renal denervation as a whole. The use of a sound methodology, including randomisation and blinded endpoint assessment was enough to see the typical 25–30 mmHg systolic blood pressure decrease observed after renal denervation melt down to less than 3 mmHg, the rest being likely explained by Hawthorne and placebo effects, attenuation of white coat effect, regression to the mean and other physician and patient-related biases. The modest blood pressure benefit directly assignable to renal denervation should be balanced with unresolved safety issues, such as potentially increased risk of renal artery stenosis after the procedure (more than ten cases reported up to now, most of them in 2014), unclear long-term impact on renal function and lack of morbidity–mortality data. Accordingly, there is no doubt that renal denervation is not ready for clinical use. Still, renal denervation is supported by a strong rationale and is occasionally followed by major blood pressure responses in at-risk patients who may otherwise have remained uncontrolled. Upcoming research programmes should focus on identification of those few patients with truly resistant hypertension who may derive a substantial benefit from the technique, within the context of well-designed randomised trials and independent registries. While electrical stimulation of baroreceptors and other interventional treatments of hypertension are already “knocking at the door”, the premature and uncontrolled dissemination of renal denervation should remain an example of what should not be done, and trigger radical changes in evaluation processes of new devices by national and European health authorities.

Blood pressure reductions following catheter-based renal denervation are not related to improvements in adherence to antihypertensive drugs measured by urine/plasma toxicological analysis

“…Following the publication of the blinded, sham-controlled Symplicity HTN-3 study [13], which met its primary safety endpoint, but did not reach its efficacy endpoint, several possibilities were discussed regarding why the results were disparate compared with prior clinical trials and registries [25,27]. It has been argued that the absence of a positive finding in Symplicity HTN-3 was mainly related to adding a control group (receiving sham procedure) and blinding of patients as well as follow-up assessors [15]. In previously published studies [7][8][9][10][11][12][13][14], drug adherence was not thoroughly monitored, either before RDN or during follow-up.…”

“…It has been postulated that behavioral changes may cause or contribute to observed effects following RDN. Specifically, changes of medication adherence and the Hawthorne effect could be of major importance in patients included in a clinical trial [15]. In the conduct of earlier trials in RDN therapy, it has been questioned whether the population was truly resistant to medical therapy or merely non-adherent to antihypertensive drugs, with the caveat that adherence has neither been investigated systematically before nor following RDN.…”

Unilateral renal sympathetic denervation may reduce blood pressure in patients with refractory hypertension

“…To our knowledge, up to now at least 13 cases of significant renal artery stenosis have been documented after renal denervation using different renal ablation systems; therefore, that complication is a matter of concern. 18 We believe that the patients need a prolonged and adequate follow-up in expert centers. In our case, the current 12 months follow-up clearly shows no complications on renal arteries and renal function.…”

Design of renal denervation studies not confounded by antihypertensive drugs

“…Even though RDN with the Symplicity catheter appears to have a low rate of periprocedural and 6-month adverse events, this may not be true for other RDN catheters, or other invasive methods including baroreceptor stimulation 17 and central arteriovenous anastomosis with a metallic coupler. 18 In the long term, the risk of RDN-induced renal artery stenosis, whose incidence is increasing, 19,20 but not well-documented, should also be carefully evaluated, especially if RDN is applied more distally in the renal artery as suggested by the expert panel on the basis of new anatomical studies. Indeed, very distal RDN-induced renal artery stenosis will be more challenging to re-vascularize by angioplasty and stenting or surgery.…”