The 2023 ESH Hypertension Guidelines revisit the role of renal denervation

The recommendations for RDN in the 2018 ESC/ESH guidelines were based on the first generation of sham-controlled renal denervation trials,² most prominently, the Symplicity HTN-3 trial.³ This led to the recommendation that device-based therapies are “not recommended for the routine treatment of hypertension, unless in the context of clinical studies and randomized controlled trials, until further evidence regarding their safety and efficacy becomes available.”² Ever since then the evidence supporting the use of renal denervation in hypertension has significantly changed and the guidelines were already outdated by the day they were published.⁴ Several second-generation RDN trials confirmed the blood pressure lowering efficacy and safety of radiofrequency and ultrasound catheter systems in a broad range of hypertension, including drug-naïve patients (in proof-of-principle trials) and those with “true” resistant hypertension on a triple fix combination.⁴

Moreover, the decrease in BP was sustained for up to 36 months after RDN in sham-controlled trials,^5,6 and up to 10 years in open-label studies.⁷ Several consensus documents and position papers of national and international societies, including a joint clinical consensus statement of the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI),⁴ were published reviewing the evidence and providing consensus statements for patient selection, procedural aspects, and future study design. The 2023 ESH guidelines, however, are the first guidelines to consider the second sham-controlled RDN trials for their recommendations on RDN.¹

The ESH guidelines recommend that:

1. RDN can be considered as a treatment option in patients with an estimated glomerular filtration rate (eGFR) >40 ml/min/1.73 m² who have uncontrolled blood pressure despite the use of antihypertensive drug combination therapy, or if drug treatment elicits serious side effects and poor quality of life (class of recommendation [CoR] II, level of evidence [LoE] B).¹
2. RDN can be considered as an additional treatment option in patients with resistant hypertension if eGFR is >40 ml/min/1.73 m² (CoR II, LoE B).¹

Of note, the 2023 ESH guidelines applied new criteria for grading the level of evidence. The level of evidence “A” was only considered if cardiovascular outcome data were available.¹ Since these data are currently unavailable for RDN, the level of evidence was graded as “B”. One has to keep in mind, though, that this also applies to most second-line antihypertensive drugs, including spironolactone, since trials have proven the BP-lowering efficacy, which strongly associates with cardiovascular protection, but no reduction in cardiovascular events.⁸ For RDN, it is unlikely that an adequately powered outcome trial will be conducted, given the required approximate randomized sample size of 20,000 patients.⁴

The minimum eGFR threshold of 40 ml/min/1.73 m² reflects the inclusion criteria of the RADIANCE-HTN trials.^9,10 Registries¹¹ and single-center studies indicate that RDN might also be safe and effective in patients with more advanced chronic kidney disease.¹² Moreover, the guidelines recommend involving patients in a shared decision-making process (CoR A, LoE C) and performing RDN in experienced specialized centers with an established multidisciplinary team evaluating, selecting, and treating the patients (CoR A, LoE C).

Overall, the recommendations of the ESH guidelines¹ and the ESC/EAPCI consensus statement⁴ for RDN strengthen the position of RDN as an additional treatment option in the management of hypertension. They both emphasize the importance of managing patients through multidisciplinary teams at specialized centers. These guideline recommendations should inform clinical decision-making, and barriers to implementation need to be overcome - now more than ever.

References

1. Mancia G, Kreutz R, Brunstrom M, Burnier M, Grassi G, Januszewicz A, Muiesan ML, Tsioufis K, Agabiti-Rosei E, Algharably EAE, et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension Endorsed by the European Renal Association (ERA) and the International Society of Hypertension (ISH). J Hypertens. 2023. doi: 10.1097/HJH.0000000000003480
2. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, Clement DL, Coca A, de Simone G, Dominiczak A, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39:3021-3104. doi: 10.1093/eurheartj/ehy339
3. Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393-1401. doi: 10.1056/NEJMoa1402670
4. Barbato E, Azizi M, Schmieder RE, Lauder L, Böhm M, Brouwers S, Bruno RM, Dudek D, Kahan T, Kandzari DE, et al. Renal denervation in the management of hypertension in adults. A clinical consensus statement of the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI). EuroIntervention. 2023;18:1227-1243. doi: 10.4244/EIJ-D-22-00723
5. Rader F, Kirtane AJ, Wang Y, Daemen J, Lurz P, Sayer J, Saxena M, Levy T, Scicli AP, Thackeray L, et al. Durability of blood pressure reduction after ultrasound renal denervation: three-year follow-up of the treatment arm of the randomised RADIANCE-HTN SOLO trial. EuroIntervention. 2022;18:e677-e685. doi: 10.4244/EIJ-D-22-00305
6. Mahfoud F, Kandzari DE, Kario K, Townsend RR, Weber MA, Schmieder RE, Tsioufis K, Pocock S, Dimitriadis K, Choi JW, et al. Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial. Lancet. 2022;399:1401-1410. doi: 10.1016/S0140-6736(22)00455-X
7. Al Ghorani H, Kulenthiran S, Recktenwald MJM, Lauder L, Kunz M, Gotzinger F, Ewen S, Ukena C, Bohm M, Mahfoud F. 10-Year Outcomes of Catheter-Based Renal Denervation in Patients With Resistant Hypertension. J Am Coll Cardiol. 2023;81:517-519. doi: 10.1016/j.jacc.2022.11.038
8. Blood Pressure Lowering Treatment Trialists’ Collaboration. Age-stratified and blood-pressure-stratified effects of blood-pressure-lowering pharmacotherapy for the prevention of cardiovascular disease and death: an individual participant-level data meta-analysis. Lancet. 2021;398:1053-1064. doi: 10.1016/S0140-6736(21)01921-8
9. Azizi M, Schmieder RE, Mahfoud F, Weber MA, Daemen J, Davies J, Basile J, Kirtane AJ, Wang Y, Lobo MD, et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. The Lancet. 2018;391:2335-2345. doi: 10.1016/s0140-6736(18)31082-1
10. Azizi M, Sanghvi K, Saxena M, Gosse P, Reilly JP, Levy T, Rump LC, Persu A, Basile J, Bloch MJ, et al. Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial. The Lancet. 2021;397:2476-2486. doi: 10.1016/s0140-6736(21)00788-1
11. Ott C, Mahfoud F, Mancia G, Narkiewicz K, Ruilope LM, Fahy M, Schlaich MP, Bohm M, Schmieder RE. Renal denervation in patients with versus without chronic kidney disease: results from the Global SYMPLICITY Registry with follow-up data of 3 years. Nephrol Dial Transplant. 2022;37:304-310. doi: 10.1093/ndt/gfab154
12. Marin F, Fezzi S, Gambaro A, Ederle F, Castaldi G, Widmann M, Gangemi C, Ferrero V, Pesarini G, Pighi M, et al. Insights on safety and efficacy of renal artery denervation for uncontrolled-resistant hypertension in a high risk population with chronic kidney disease: first Italian real-world experience. J Nephrol. 2021;34:1445-1455. doi: 10.1007/s40620-021-00966-7