https://orcid.org/0000-0003-1434-9556
In both the absence (SPYRAL HTN-OFF MED)4 and the presence (SPYRAL HTN-ON MED)5 of antihypertensive medication, radiofrequency-based RDN using the Symplicity Spyral multielectrode RDN catheter (Medtronic; Galway, Ireland) lowered office and ambulatory BP.
Similarly, in the sham-controlled RADIANCE-HTN SOLO trial, RDN using the ultrasound-based Paradise catheter system (Recor; Palo Alto, CA, USA) significantly reduced daytime ambulatory systolic BP between baseline and 2 months in patients without concomitant antihypertensive medications.6
A third catheter system, the Peregrine catheter-system (Ablative Solutions; San Jose, CA, USA) which uses microneedles to inject pure alcohol into the perivascular space, has achieved similar BP reductions in a multicentre, open-label trial.7
Two sham-controlled trials investigating alcohol-mediated RDN in patients with (TARGET BP I, NCT02910414) and without (TARGET BP OFF-MED; NCT03503773) antihypertensive medications are currently enrolling.
What is new in 2020?
The sham-controlled SPYRAL HTN-OFF4 and HTN-ON MED5 studies were designed to overcome limitations of previous trials, but, in contrast to the RADIANCE-HTN trial,6 were not powered for efficacy outcomes. In spring 2020, the results of the SPYRAL HTN-OFF MED Pivotal trial, which was powered to show the superiority of RDN over a sham procedure in reducing 24-h ambulatory BP in the absence of antihypertensive medications, were published.8,9 In this trial, a Bayesian approach was used, which allowed to include data from the pilot study to limit the exposure of patients to sham treatment.9 Compared with the sham treatment, RDN significantly reduced both 24-h (primary outcome) and office BP (powered secondary endpoint).9 Importantly, the BP reduction observed at 3 months was consistent with the reduction of other recent sham-controlled trials investigating ultrasound- and radiofrequency-based RDN (Figure 1).
Change in office and 24-h ambulatory systolic blood pressure following renal denervation in the second generation of sham-controlled trials. *Statistically powered trials to assess the BP-lowering efficacy of renal denervation. Data are presented as mean and 95% confidence intervals. Mean between-group differences were adjusted for baseline blood pressure.
Long-term efficacy and safety data can be derived mainly from registries. The single-arm, open-label Global SYMPLICITY (proSpective registrY for syMPathetic renaL denervatIon in seleCted Indications Through 3 Years) Registry, which, to date, included nearly 3000 patients with uncontrolled hypertension that underwent radiofrequency-based RDN at almost 200 sites, demonstrated significant and sustained office and ambulatory BP reductions up to 3 years.10 At 3 years, 24-h systolic BP was significantly reduced in patients with severe uncontrolled hypertension, elderly patients (defined as ≥65 years), patients with an increased atherosclerosis cardiovascular disease risk score and patients with comorbidities associated with an increased sympathetic activity, such as diabetes, chronic kidney disease, and atrial fibrillation.11 While previous trials suggested a less pronounced BP reduction following RDN in patients with isolated systolic compared with combined systolic–diastolic hypertension,12–14 the data from the Global SYMPLICITY Registry, which was adjusted for baseline BP, showed no difference between both hypertension phenotypes. However, further randomized controlled trials are needed to evaluate the role of RDN in patients with isolated systolic hypertension.
Especially when treating patients with mild-to-moderate hypertension and low cardiovascular risk, long-term safety is an inevitable prerequisite. Both the first and the second generation of sham-controlled trials for RDN reported only very few procedural and vascular adverse events.2,4–6,9 A recent meta-analysis of 50 published trials of radiofrequency-based RDN, including 5769 patients and 10 249 patients years of follow-up, provided reassurance for the procedure’s safety.15 In total, 26 patients with renal artery stenosis or dissection were identified, of whom 24 required renal artery stenting.15 Most events occurred within the first year post-procedure. 15
Moreover, no deterioration of renal function has been noticed so far. Data from the Global SYMPLICITY Registry suggests that the estimated glomerular filtration rate (eGFR) declined by 7.1 ± 16.7 mL/min/1.73 m2 in patients with preserved kidney function at baseline (eGFR >60 mL/min/1.73 m2) and by 3.7 ± 16.2 mL/min/1.73 m2 in patients with initially impaired eGFR (eGFR <60 mL/min/1.73 m2) between baseline and 3 years.10 The reduction in eGFR was in line with the expected decrease in patients with severe hypertension and with increasing age.10
Open key questions
Ten years after the introduction of RDN for the treatment of arterial hypertension, the adequately powered and sham-controlled trials have finally provided substantial evidence for its BP-lowering efficacy and reaffirmed the procedural and vascular safety. However, several questions remain to be answered.
What role will renal denervation play in the treatment of arterial hypertension?
In the near future, RDN might constitute one pillar of antihypertensive treatment, in addition to conventional lifestyle changes and antihypertensive medication. The interventional approach offers two substantial benefits over pharmacotherapy. First, time-trend analyses using ambulatory BP monitoring showed that the BP reductions persisted consistently throughout the entire day and, in contrast to pharmacotherapy, are independent of serum drug concentrations.4–6,9 This ‘always-on-effect’ is particularly important, given that higher night-time and early morning BP are significantly associated with cardiovascular risk.16,17 Second, the BP effect of RDN does not require adherence to antihypertensive treatment.
Non-adherence to prescribed drug treatment frequently occurs in chronic conditions, such as hypertension, for various reasons.18 A cross-sectional survey of 1000 US residents has shown that 8% if adults would trade-off 2 years of their life to avoid taking an additional preventive pill daily.19 A second survey performed in patients with hypertension in Germany found that 38.2% of the therapy-naïve patients would prefer RDN over pharmacotherapy for the treatment of hypertension.20 Of those already on drug therapy, 28.2% would have chosen RDN.20 Therefore, RDN could be considered as a complementary approach in patients with difficult-to-control hypertension (with office systolic BP of 140–170 mmHg or diastolic BP of 90–109 mmHg) with antihypertensive medications to achieve BP control to target values and lower the pill-burden to reduce drug–drug interactions and the risk of non-adherence.21
In patients strictly not willing or unable to take antihypertensive drugs because of drug intolerance/side effects, or unaffordable costs, RDN might offer an alternative treatment approach to antihypertensive medications.22
The US Patient Preference Study, a trial investigating patient preference in relation to RDN as an adjunct to the current standard of care, is currently under development as part of the SPYRAL HTN Global Clinical Trial Program. However, patients need to be provided with balanced information concerning the variability of the BP response and that most patients require additional antihypertensive medication post-RDN. In the RADIANCE-HTN SOLO trial, for example, only 20–25% of the patients achieved controlled BPs in the absence of medication after 2 months.6
Moreover, RDN should further be investigated in patients with comorbidities at high cardiovascular risk such as coronary artery disease, diabetes, and chronic kidney disease.22 Lowering BP with antihypertensive medications was shown to reduce the risk of cardiovascular disease and death.23 Although, a meta-analysis of 17 observational studies indicated that RDN might ameliorate hypertensive-mediated organ damage24 no appropriately conducted prospective trial investigated the effect of RDN on hard clinical outcomes.
Who will most likely benefit from renal denervation?
Even in the meticulously designed sham-controlled trials, there was a considerable variability of the BP response following RDN. Therefore, identifying patients with the highest likelihood of response should be given a high priority. The only consistent predictor of BP response to RDN was high baseline BP, which is a non-specific and commonly observed phenomenon (Wilder’s principle).25 It remains unclear to what extent this phenomenon has to be attributed to regression to the mean or higher sympathetic activity in individuals with the highest baseline BP.26
Various other potential predictors of response have been derived from retrospective analyses but were not consistently associated with BP reduction.27 It seems probable that patients with signs of increased sympathetic nerve activity (young age,2 abdominal obesity,6 combined systolic–diastolic hypertension after the exclusion of secondary causes,12 and high baseline heart rate28) may be responsive to RDN.
Perspectives
Currently, several trials investigating RDN are ongoing. The single-arm SYPRAL DYSTAL study (NCT04311086) evaluates if a simplified approach focusing on treating the distal main renal artery and primary branches with fewer radiofrequency ablations lower BP to a similar extent as the procedural approach of the SPYRAL HTN-OFF MED trial. Possible advantages of the treatment strategy are decreased exposure to radiation, reduced use of contrast dye, shorter procedures, and increased patient comfort. The rationale for focusing on distal artery segments is provided by anatomical studies, which have shown that renal nerves congregate closer to the artery in distal artery segments29 and preclinical studies showing less variability of response and significantly greater reduction of both norepinephrine after the combined treatment of distal segments of the main renal artery and branches compared with the treatment of the main renal artery only.30
Moreover, the procedure is investigated in other diseases associated with increased sympathetic nerve activity, such as chronic kidney disease (RDN-CKD, NCT04264403), heart failure with reduced ejection fraction (RE-ADAPT-HF, NCT02085668), and arrhythmias, in particular in atrial fibrillation in combination with pulmonary vein isolation (SYMPLICITY AF, NCT02064764, and ASAF, NCT02115100) (Figure 2).
Potential indications for catheter-based renal denervation.
Lucas Lauder1, MD, Michael Böhm1, MD, and Felix Mahfoud1,2, MD
1Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Saarland University, Homburg/Saar, Germany; and 2Institute for Medical Engineering and Science, MIT, Cambridge, MA and Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA
Conflict of interest: L.L. declared no conflicts of interest. M.B. has received support from Abbott, Amgen, Astra-Zeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Deutsche Forschungsgemeinschaft (DFG, SFB TRR219, S-01, M-03, M-05), Medtronic, Novartis, ReCor Medical, Servier, and Vifor. F.M. is supported by Deutsche Gesellschaft für Kardiologie (DGK), and Deutsche Forschungsgemeinschaft (SFB TRR219) and has received scientific support and speaker honoraria from Bayer, Boehringer Ingelheim, Medtronic, and ReCor Medical.
References
References are available as supplementary material at European Heart Journal online. 
