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Renal denervation for resistant hypertension

closing in on potential confounders

Schlaich, Markus P.; Schultz, Carl; Shetty, Sharad

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doi: 10.1097/HJH.0000000000001016
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The initial description of catheter-based renal sympathetic denervation as a potential alternative treatment for resistant hypertension in 2009 [1] sparked a great deal of interest among scientists and clinicians alike. The prospects of an interventional approach, if proven safe and effective, in a clinical field traditionally dominated by lifestyle-related and pharmacologic therapies was an excitement for many colleagues regularly exposed to a rather heterogeneous group of hypertensive patients in whom blood pressure (BP) control was not achievable despite appropriate combination of available therapies. Moreover, the rationale of targeting renal sympathetic nerves therapeutically has a strong pathophysiologic foundation with both experimental studies in a range of animal models [2] and application of radiotracer dilution methodologies in humans to measure noradrenaline spillover from renal sympathetic nerves to plasma [3] providing unequivocal evidence for an important neurogenic contribution to BP elevation.

A series of randomized controlled and uncontrolled studies in patients with resistant hypertension and other conditions commonly characterized by heightened sympathetic nerve activity demonstrated the safety and feasibility of renal sympathetic denervation and provided a clear signal for efficacy with clinically relevant BP reductions. As with any therapy, not all patients that were treated showed a BP response and in those who did substantial variability was observed. The relevance of appropriate patient selection, various procedural aspects, more rigorous assessment of medication adherence, and BP changes among several others became apparent [4] and the demand for a sham-controlled trial to properly assess the BP-lowering efficacy of renal denervation was conveyed both by the scientific community and regulatory bodies. As a consequence, Symplicity HTN-3 was designed as the largest and the first randomized controlled trial to include a sham control arm [5]. The failure of Symplicity HTN-3 to demonstrate a BP-lowering effect beyond that of a sham control caught most by surprise and seemed to confirm the sceptical view of some. Further analyses of the trial data were interpreted to suggest that among others, population characteristics, medication changes that occurred in the postprocedural period prior to primary endpoint assessment, operator inexperience, and inadequate efficiency of denervation with the single-electrode catheter may have contributed to the unexpected findings [6].

In the current issue of the Journal, Mathiassen and colleagues [7] present data from their ReSET trial, a small but well designed, single-center double-blind randomized sham-controlled trial assessing the BP-lowering efficacy of renal denervation using a single-electrode catheter. Their main finding is that the BP reduction at 3 and 6 months follow-up did not differ between the active treatment and the sham control group. Although the authors conclude that their study confirms the results from the Symplicity HTN-3 trial, they emphasize the need for further sham-controlled studies using multielectrode catheters to ultimately determine the potential role of renal denervation (RDN) in the treatment of (resistant) hypertension.

This study is a solid body of work and the authors are to be commended to have performed a sham-controlled study taking into account several, albeit not all of the previous criticisms raised in regard to Symplicity HTN-3. Specifically, they used the mean change in daytime ambulatory SBP from baseline to 3 months as the primary efficacy endpoint thereby avoiding the more pronounced variability typically introduced by office BP readings. Of note, the ambulatory recordings appeared to be of sufficient quality with an overall average of successful readings for each ambulatory BP monitoring (ABPM) of 86%. Unfortunately, observed pill intake prior to ambulatory BP monitoring was not performed, which would have strengthened their data further, as would have testing for drug metabolites to assess medication adherence.

Follow-up examination and further medical treatment of study patients were performed in an outpatient setting by physicians who were unaware of the patients’ randomization, making physician bias unlikely. None of the 69 patients were lost to follow-up, and premature unblinding did not occur in any patient. However, almost half of the patients had changes in antihypertensive medication at 3 and 6 months follow-up. Although according to the authors, most changes in medications were minor and differences between groups in antihypertensive treatment regimes remained insignificant, there was a tendency toward a reduction in the defined daily dose of antihypertensives in the RDN group and an increment in the SHAM group (P = 0.08). In this context, the observation of a borderline significant difference in daytime systolic ABPM of −6.0 mmHg in favor of RDN (P = 0.08), and a significant difference in daytime DBP of −4.4 mmHg (P = 0.02) at 1-month follow-up, when medical changes were few, may be of relevance, particularly when considering the size of the cohort.

Operator inexperience has been identified as a potentially important confounder in Symplicity HTN-3 [5,6]. It is widely accepted that achieving a circumferential ablation pattern with a single-electrode device is by no means a trivial task. Indeed, post hoc analysis from Symplicity HTN-3 revealed that a bilateral circumferential ablation pattern was achieved in less than 10% of the patients who were treated. Unsurprisingly, adequate energy delivery in a four-quadrant pattern and a higher number of ablations was identified as a determinant of greater office and ambulatory SBP reduction [6]. The fact that in the current study, all renal denervation procedures were carried out in the same interventional cardiovascular center and performed by a single experienced operator who had been proctored and had substantial experience with the procedure prior to treating study participants is another strength of the study. However, the authors did not provide direct evidence to support the claim that a circumferential ablation pattern has actually been achieved. Furthermore, while the mean number of successful ablations in each renal artery (5.4 ± 1.0 on the left and 5.5 ± 0.9 on the right) compares favorably to Symplicity HTN-3 [5,6], the number of ablations is likely too low to achieve sufficient denervation. A recent study in a canine model demonstrated that five treatments with a quadruple-electrode catheter (n = 20 ablations per artery) were required to demonstrate complete absence of a BP response to renal nerve stimulation after denervation [8]. Two other recent observations are highly relevant in this context. One relates to the impact of lesion placement on the efficacy of catheter-based radiofrequency ablation in a pig model with a more consistent and more marked reduction in renal noradrenaline content when branches of the renal artery are treated in addition to the main artery [9]. Data from patients with resistant hypertension in whom accessory renal arteries were left untreated support these experimental findings and suggest that more complete denervation is associated with a more pronounced BP reduction [10].

The authors make a very valid point when they conclude that we will have to await results from ongoing sham-controlled clinical trials with multielectrode catheters targeting both the main renal artery and its branches to ultimately define the utility of catheter-based renal denervation as a therapeutic approach for hypertension.

ACKNOWLEDGEMENTS

M.P.S. is supported by an NHMRC Research Fellowship and has received consulting fees, and/or travel and research support from Medtronic, Abbott, Novartis, Servier, Pfizer and Boehringer-Ingelheim. C.S. and S.S have received consulting fees and/or honoraria from Medtronic and St Jude.

Conflicts of interest

There are no conflicts of interest.

REFERENCES

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