Hypertension is the most prevalent modifiable cardiovascular risk factor, affecting more than 1 billion people worldwide and causing the death of more than 9 million people each year.1 Observational studies have revealed a progressive association between elevated blood pressure (BP) and the development of cardiovascular disease,2 with an increase of 20mmHg in systolic BP and of 10mmHg in diastolic BP, doubling the risk of cardiovascular death.3

Despite efforts to control the condition, data from 2010 show that one-third of individuals with hypertension in developed countries were unaware of having the disease, slightly more than half received drug therapy, and less than a third had adequate pressure control.4 Due to the limited ability of drug therapy to normalize BP in a significant number of patients, various nonpharmacological options have emerged in recent years for the management of hypertension. One such approach is percutaneous renal denervation (pRDN), a treatment based on modulation of the sympathetic nervous system. The renal sympathetic nervous system is involved in the development and progression of hypertension and in the organ damage caused by the condition. Afferent sympathetic nerve fibers projecting to the central nervous system are activated in the kidney and in response to different local stimuli; this activation increases the sympathetic tone and thereby elevates BP by increasing cardiac contractility, promoting vasoconstriction, and stimulating the renin-angiotensin-aldosterone axis and renal sodium retention, all mediated by efferent sympathetic pathways.5

pRDN is a minimally invasive procedure involving the introduction of a catheter into the renal artery that, by releasing energy (typically, radiofrequency energy), produces a lesion in the afferent and efferent nerves of the sympathetic nervous system surrounding the renal arteries.6 Interruption of afferent renal sympathetic pathways decreases BP by reducing vascular tone and cardiac contractility while increasing natriuresis, whereas interruption of efferent renal sympathetic pathways decreases the activation of the renin-angiotensin-aldosterone system and sodium retention.5

Despite the initial expectations generated by the first published studies, which showed improved BP values after radiofrequency-based pRDN in patients with resistant hypertension,7,8 pRDN failed to improve BP vs a sham procedure in the SYMPLICITY HTN-3 study.9 This unexpected result did not correspond to those of previous studies7,8 or the data derived from real-world registries,10 but still led to an almost complete abandonment of the technique. However, several recent studies conducted in a small number of patients with moderate hypertension have shown that pRDN effectively improves both office BP and, more importantly, 24-hour ambulatory BP monitoring (ABPM) levels in both patients without drug therapy and patients with incomplete treatment.11–13

In Spain, pRDN was introduced at the same time as in other European countries and Australia for the treatment of resistant hypertension, although its penetration was significantly lower. In 2014, a working group on renal denervation was established with the aim of sharing experiences with this new technique for the treatment of hypertension. We present data from a retrospective multicenter registry of patients with resistant hypertension who underwent pRDN with a unipolar (SYMPLICITY FLEX, Medtronic Inc) or tetrapolar (SYMPLICITY SPYRAL, Medtronic Inc) radiofrequency catheter between 2009 and 2018.

This multicenter registry with retrospective data collection included consecutive patients with resistant hypertension who underwent pRDN with SYMPLICITY FLEX (2009-2015) or SPYRAL (2015-2018) catheter in 7 Spanish centers.

Analysis of the data from this multicenter registry of patients with resistant hypertension treated with pRDN in a real-life setting has shown that the treatment effectively decreases office BP and, more importantly, ABPM values, with a reduction in the number of antihypertensive drugs taken by the patients. The procedure was safe, with a very low rate of intervention-related complications. The success of the intervention was independent of the type of radiofrequency catheter used, although variability in the response rate per center was observed.

The fall in BP values shown in our registry is in agreement with that obtained in previous studies with real-world data.10,16–19 In addition, the BP improvement was also seen in the 24-hour ABPM. This result is particularly important because a recent study showed that it is a better predictor of cardiovascular mortality than office BP.20 In addition, this improvement correlated with a decrease in the number of drugs taken, in contrast to previous registries that showed no significant decrease in drug therapy.10,16–19 The only drugs whose prescription increased were aldosterone antagonists. These drugs were established with a I B level of recommendation as a fourth-line treatment for patients with resistant hypertension in the latest 2018 European guidelines for the treatment of hypertension.14 Thus, it is notable that only 51% of the denervation candidates were being treated with these drugs. However, this recommendation was more controversial in the previous guidelines from 2013, which awarded it a IIa B level recommendation,21 and our series includes patients from 2009. In addition, the pRDN response was significantly worse in patients not taking aldosterone antagonists. Nowadays, candidates for pRDN should be under treatment with aldosterone antagonists.

Despite the promising results of the initial studies of pRDN, the first study to compare pRDN with a sham pRDN procedure in patients with refractory hypertension, the SYMPLICITY HTN-3 trial, showed no benefit of treatment on office or ambulatory BP.9 The results of that study have been questioned since its publication22 and, in a post hoc analysis, Kandzari et al.23 determined a lower than expected response in the group treated with pRDN and a much higher than expected response in the control group vs previous experiences. This analysis revealed potential confounding factors that could explain, at least partly, the unexpected results, such as operator inexperience, the inclusion of patients with isolated systolic hypertension, poor adherence to drug therapy before selection and during the study, inclusion of a high percentage of African-American patients, and procedural deficiencies in terms of ablation number and location.23 Regarding the procedure, reasonable doubts arose about whether the pRDN was performed in the same way as in the first studies, given that the GLOBAL SYMPLICITY Registry, with experienced operators and in a similar population, calculated a mean systolic BP fall of 19.3±22.4mmHg at 6 months with a greater number of ablations per patient (13.5±4.1).10 A lack of ablations in the 4 quadrants and the number of radiofrequency ablations were correlated with the reduction in BP.23 Our registry has no procedural information but does highlight the heterogeneity in the pRDN response rate among centers. This finding, consistent with that observed in the SYMPLICITY HTN-3 study, most likely indicates the importance of good patient selection and of performing as meticulous a procedure as possible. In this regard, the indication for pRDN should always be based on the ABPM results to exclude pseudoresistance or white-coat hypertension, after all secondary causes of resistant hypertension have been ruled out, with a medication adjustment in line with the guidelines and stable medication for at least 4 weeks before the denervation. Regarding the intervention, the SYMPLICITY HTN-3 trial was criticized because more than 50% of the patients included were treated by operators who were performing their first or second procedure, suggesting that the learning curve might have influenced the intervention outcomes.23 In our registry, the procedures were performed by the same operators (1 or 2 per center), with a volume equal to or higher than that in the SYMPLICITY HTN-1 or SYMPLICITY HTN-2 studies and much higher than in the SYMPLICITY HTN-3 trial. Currently, with what has been learned after the analysis of previous studies and taking into account the anatomy of the sympathetic plexus at the kidney level,24 the intervention objectives should be to treat the 4 quadrants of the renal artery, with the maximum number of radiofrequency ablations possible (leaving a safe 5-mm distance between applications), as well as the main renal artery and its branches (with a diameter> 3mm).6 Unexpectedly, there was no difference in the efficacy of the intervention between the SYMPLICITY FLEX and SYMPLICITY SPYRAL catheters, even though the latter was designed to improve the efficacy of the procedure.6

The results of this registry reinforce the role of pRDN in the management of hypertension and, even though the indication for pRDN was drastically reduced after the publication of the SYMPLICITY HTN-3 trials, the recently published SPYRAL HTN ON-MED, SPYRAL HTN OFF-MED, and RADIANCE SOLO studies have provided the first consistent evidence on the potential clinical usefulness of pRDN in the treatment of patients who cannot or do not want to take antihypertensive drugs. These studies included patients with moderate hypertension, with nonoptimized drug therapy or without treatment, and a control group with pRDN sham and identified significant decreases in office BP and ABPM values in the treated patients, although the number of patients included was small and the follow-up short.11–13 In addition, a recent meta-analysis of pRDN included 977 patients from 6 clinical trials, including the SYMPLICITY HTN-3 study: compared with a sham control group, pRDN improved BP control in treated patients.25 These results should be confirmed in studies that are already underway and are likely to change the approach to the treatment of hypertension in the coming years.26 In this regard, one of the most novel findings of our registry vs previous ones is that pRDN can not only improve BP control, but also simultaneously reduce pharmacological treatment.

In real-world patients with resistant hypertension treated with radiofrequency-based pRDN, there is a fall in office BP and, more importantly, 24-hour ABPM values in up to 80% of patients, with a significant decrease in drug therapy. The procedure is safe, with a very low rate of intervention-related complications. The pRDN response is independent of the type of radiofrequency catheter used, although there is significant variability in the response rate per center.

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