Response to ‘Why the lack of enthusiasm for renal denervation?’

We read with interest the editorial by Messerli et al. (2024) titled ‘Why the lack of enthusiasm for renal denervation?’ [1]. This editorial was in response to our published systematic review and meta-analysis on the efficacy of renal denervation (RDN) for uncontrolled hypertension by Sharp et al. (2024) [2]. We thank Prof Messerli and colleagues for their interest in our study and wish to respond to some of the comments made. The authors commented that the mean difference between patients receiving RDN versus control was modest, with a 3.6 mmHg reduction in 24-h ambulatory SBP. The effect size of RDN described in our meta-analysis reports control-subtracted randomized controlled trial (RCT) effect sizes in patients with mostly mild-moderate hypertension; however, in real-world registries, patients with more severe hypertension are being treated. Starting blood pressure is the only variable to be consistently associated with the magnitude of blood pressure reduction following renal denervation, demonstrated in over 40 published studies to date [3], and as a result, the blood pressure reductions demonstrated in real-world clinical use are greater. For example, a quartile analysis by Sharp et al. [4] reported mean reductions in daytime ambulatory SBP following RDN in 253 patients treated in the UK were 0.4, 6.5, 14.5 and 22.1 mmHg where mean starting ambulatory SBP was 143, 162, 176 and 199 mmHg, respectively (P < 0.001 for trend). Additionally, in a recent pooled analysis of over 3900 patients treated with radiofrequency RDN, Schmieder et al. [5] reported that patients with higher office SBP at baseline had a greater absolute reduction in blood pressure at 6 months. Baseline office SBPs of 160, 170 and 180 mmHg were associated with 6 months office SBP reductions of 9.2, 15.1 and 21.0 mmHg, respectively [5]. The sham-controlled trials included within our meta-analysis required a relatively low mean starting blood pressure to protect patients in the sham group from potential harm incurred by being left with uncontrolled BP during follow-up and so would be expected to have a smaller magnitude of response. The control-subtracted office BP reduction after RDN in the meta-analysis was still 8.5 mmHg, similar to the effect size of a single antihypertensive drug. Reference is made to other antihypertensive drugs that have also been shown to reduce ambulatory SBP. The importance of RDN is that it is free from adherence issues, unlike currently approved drugs or some of the new drugs that are pending approval (e.g. aldosterone synthase inhibitors or endothelin receptor antagonists) and can provide an “always-on” background effect of lowering BP. The “always on” effect refers not only to blood pressure reduction through the 24-h period, but the perhaps clinically more important aspect, which is a BP response lasting for years. The blood pressure lowering effect of RDN has been reported as persisting out to 3 years in thousands of patients treated [6] and in hundreds of patients out to beyond 8 years [7–10], with preclinical work suggesting that durability is likely [11]. We agree with the authors that drugs which are independent of adherence, such as zilebesiran, are an exciting development. Renal denervation has been used to treat over 25 000 patients globally, with excellent safety and tolerability data published in over 5000 patients [12]. Once there is a similar volume of experience beyond 12 weeks for small interfering (siRNA) drug therapy, we expect these agents will become another important tool for tackling uncontrolled blood pressure, at which point patient preference becomes an even more important part of decision-making when treating patients with uncontrolled hypertension [13]. The editorial also suggested that there could be a reluctance from patients and/or non-interventional colleagues to undergo or refer suitable patients for RDN. Whilst device therapy may seem invasive to some doctors, a patient preference study in German patients for therapies of hypertension demonstrated that 38.2% of those not already on medication would opt for RDN and 28.2% of those already on medication would opt for RDN [14]. A recent discrete choice experiment from the United States also explored patient preferences for interventional and/or oral antihypertensive treatments, reporting that patients were willing to accept the risks of an intervention in exchange for reductions in office SBP as low as 2.3 mmHg [15]. Now that RDN is recommended for clinical use by the European Society of Hypertension guidelines and the US Food and Drug Administration [16,17], it seems likely that the recent positive European trend in therapy acceptance and number of physicians offering RDN will continue to increase in accordance with guideline recommendations. ACKNOWLEDGEMENTS Previous presentations of the whole or part of the work: This commentary piece is related to a previously published systematic review and meta-analysis: Sharp ASP, Sanderson A, Hansell N, Reddish K, Miller P, Moss J, Schmieder RE, McCool R. Renal denervation for uncontrolled hypertension: a systematic review and meta-analysis examining multiple subgroups. J Hypertens. 2024 Jul 1;42(7):1133-1144. This commentary piece is in response to a published editorial relating to the Sharp et al. systematic review and meta-analysis: Messerli FH, Schoenenberger-Berzins R and Messerli AW. Why the lack of enthusiasm for renal denervation? Journal of Hypertension. 2024;42(7):1145-6. A.L.S., N.H., K.R., P.M., J.M. and R.M. are all employees of YHEC. YHEC was commissioned by Medtronic to conduct the systematic review and meta-analysis. Conflicts of interest Prof Sharp is a consultant and speaker for Medtronic and Recor Medical Prof Schmieder is a consultant and speaker for Medtronic, Recor and Ablative Solutions and his Institution received grants from Medtronic, Recor and Ablative Solutions.