Renal denervation in hypertension: is it the end or the beginning of a SPYRAL?

The first observation that blood pressure (BP) could be controlled by catheter-based radiofrequency denervation of the renal arteries in patients with resistant hypertension and the subsequent results of SYMPLICITY HTN-2, a randomized controlled study without sham intervention, have generated a fantastic upward spiral of enthusiasm for this new approach of treating resistant hypertension [1,2]. In SYMPLICITY HTN-2, impressive decreases in office BP were reported, reaching −32/12 mmHg at 6 months in the denervation group versus 1/0 mmHg in the medically-treated control group. Thereafter, a multitude of studies, often poorly controlled, with small numbers of participants, and based essentially on office BP, have been published, confirming these initial results. Consequently, thousands of patients with apparent resistant hypertension have undergone renal artery denervation around the world with more or less success. Beyond reducing BP, renal denervation has been found to have multiple beneficial properties, including improving insulin sensitivity, reducing sleep apnea, stabilizing renal function, and improving endothelial function.

Yet, in subsequent years, doubts started to appear questioning the efficacy of the procedure [3]. Good candidates for renal denervation could not be easily identified. Hence, clinical results were very heterogeneous, with some patients experiencing a marked BP response and others no reduction in BP at all, without a clear explanation for the difference. At this stage, investigators began to realize that resistant hypertension is not only a question of persistent BP elevation in the face of 3 or more BP drugs prescribed, and that many aspects of hypertension management should be taken into account in this patient population, including the quality of BP measurement (ambulatory vs. office BP), adherence to therapy and possible underestimation of the frequency of hyperaldosteronism in patients with resistant hypertension. Positive byproducts of the renal denervation programs include renewed interest in ambulatory BP monitoring and the sudden discovery by interventionists that non-adherence to pharmacologic therapy is a very frequent cause of apparent resistance to antihypertensive treatment [4]. The consequences of these observations are a greater use of ambulatory BP monitoring and the development of new rigorous techniques to diagnose non-adherence, such as the determination of antihypertensive drug levels in plasma or urine [5].

Publication of the SYMPLICITY HTN-3 trial, a prospective, randomized single-blind trial, in which patients with resistant hypertension were randomly allocated to undergo either renal denervation or a sham procedure, was the beginning of a downward spiral for renal denervation [6]. The trial did not confirm the initial results of the SYMPLICITY program. No significant difference was found between the changes in systolic BP obtained with renal denervation vs. the sham procedure, but the procedure was considered safe. These surprising results generated extensive discussion, and the supporters of renal denervation raised several issues: firstly, a large decrease in BP was observed in the control group, which likely means that drug adherence improved in the sham-operated group; secondly, the extent of the renal denervation could not be ascertained; thirdly, many of the investigators had limited experience with renal denervation, thus reducing the chances of successful denervation. In contrast, the DENERHTN study, which compared the ambulatory BP-lowering efficacy and safety of renal denervation added to a standardized stepped-care antihypertensive treatment to the same medical treatment alone in patients with resistant hypertension, had a positive outcome. Renal denervation in DENERHTN had an additive effect on BP reduction, lowering 24-hour systolic and diastolic BP by an additional −5.9/−3.1 mmHg.

The major direct consequence of the SYMPLICITY HTN-3 trial was the interruption of many renal denervation programs in the absence of proven benefits on BP and cardiovascular outcomes. More basic work on selection of patients, the quality of the catheter and the procedure itself had to be done. A group of European experts published a consensus document defining the missing information on renal denervation and what experimental and clinical studies should be conducted before launching a new program on renal denervation [7]. These investigators positioned themselves as leaders in the design of future clinical trials. One of the proposals was to perform a study in hypertensive patients not on drug treatment, thereby avoiding the confounding effect of changes in drug therapies after renal denervation. This was the basis of the SPYRAL HTN-OFF MED study.

Results of the SPYRAL HTN-OFF MED study were presented at the recent meeting of the European Society of Cardiology in Barcelona in August 2017. In this study, 80 patients were randomly assigned to renal denervation (n = 38) or sham control (n = 42) and followed up for 3 months [8]. The primary endpoint was the change in 24-hour ambulatory BP at 3 months. Participants were not on antihypertensive medication (85% of patients had negative urine drug testing for antihypertensive drugs at 3 months), the number of renal denervation sites was almost 10 times higher than in previous studies, with an average of 43.8 sites of denervation and denervation at more distal sites in renal arteries. In addition, all investigators were experienced in performing renal denervation, and a different catheter was used i.e. the Symplicity Spyral multielectrode catheter (Medtronic, Galway, Ireland) to perform the renal ablations. The results showed a significant difference in favor of renal denervation with a placebo-corrected decrease in ambulatory BP at 3 months of −5·0 mmHg for systolic and −4·4 mmHg for diastolic BP. The difference between the 2 groups in office BP was −7.1/−5.0 mmHg. Of note, the heterogeneity of the BP response to the procedure was still relatively high in both groups, although slightly less than in previous trials.

The results of the SPYRAL HTN-OFF MED study provoked mixed reactions. For some specialists, the study clearly demonstrated the efficacy of renal denervation in reducing BP, leading them to advocate for the design and conduct of future trials. For others, the magnitude of BP reduction was considered small, with only about a third of patients experiencing a reduction in 24-hour ambulatory systolic BP of >10 mmHg at 3 months. Since the mean in-office systolic BP of study participants was 162 mmHg at baseline, it is clear that few untreated patients would actually reach the recommended target office BP of <140 mmHg systolic with the renal denervation only. Thus, it is unlikely that renal denervation alone will be adequate to manage most hypertensive patients without adding antihypertensive drugs. This will need to be tested in a head to head study comparing renal denervation with a monotherapy in never treated hypertensive patients. Further, increasing the number of ablation sites and including the distal branches of the renal arteries does not appear to increase BP reduction, as results were similar to those obtained in DENERHTN. Thus, the optimal procedure for renal denervation remains to be defined.

In conclusion, results of the SPYRAL HTN-OFF MED study show that renal denervation can lower BP in hypertension patients not on antihypertensive medications. At this stage one should be cautious with the interpretation of this study, as it was a preliminary study with a limited objective and a small number of participants. Therefore, it remains difficult to predict whether the SPYRAL of renal denervation will rise again or continue to descend.

Disclosure statement

MB, KN, and SEK are editors of Blood Pressure and report no relevant conflicts of interest to disclose related to this commentary. SO is also an editor of Blood Pressure and declares the following COI: ROX Medical, Inc. (Rox Control HTN 2 Study – US IDE Steering Committee Member); (multicenter study/ROX coupler-HTN); Vascular Dynamics, Inc. (site investigator, multicenter pivotal study/PMA for resistant HTN).