Advertisement

Catheter-based Renal Artery Denervation for Resistant Hypertension: Promise Unfulfilled or Unsettled?

  • Matthew G. Denker
  • Debbie L. Cohen
  • Raymond R. TownsendEmail author
Clinical Trials and Their Interpretations (J Kizer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Clinical Trials and Their Interpretations

Abstract

Resistant hypertension affects approximately 10–15 % of the hypertensive population and is associated with an increased occurrence of adverse cardiovascular outcomes. Recently, renal denervation (RDN) has emerged as a novel, non-pharmacologic therapy for resistant hypertension that is designed to ablate the sympathetic nerves distributed around the renal arteries, thus diminishing sympathetic nervous system activity and its influence on hypertension. RDN appeared to have a powerful BP-lowering effect in early clinical trials. However, a pivotal follow-up trial, SYMPLICITY HTN-3, showed no additional benefit of the therapy when compared with a sham procedure. Various aspects of the trial have been examined to explain this inconsistency, including a potent placebo effect and uncertainty about whether RDN actually occurred. Further research is needed to clarify the role of RDN in the management of resistant hypertension.

Keywords

Renal denervation Sympathetic nervous system Resistant hypertension Blood pressure 

Notes

Compliance with Ethics Guidelines

Conflict of Interest

Matthew G. Denker declares that he has no conflict of interest.

Debbie L. Cohen has received a grant and travel support from Medtronic.

Raymond R. Townsend has received consulting fees/honorarium from Medtronic and funding from the NIH.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spectrum: current outcomes and control in the community. JAMA. 2005;294:466–72.CrossRefPubMedGoogle Scholar
  2. 2.
    Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension. 2011;57:1076–80.CrossRefPubMedGoogle Scholar
  3. 3.
    Smith SM, Gong Y, Handberg E, et al. Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension. J Hypertens. 2014;32:635–43.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Acelajado MC, Pisoni R, Dudenbostel T, et al. Refractory hypertension: definition, prevalence, and patient characteristics. J Clin Hypertens (Greenwich). 2012;14:7–12.CrossRefGoogle Scholar
  5. 5.
    Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001;23:1296–310.CrossRefPubMedGoogle Scholar
  6. 6.
    Kjeldsen SE, Schork NJ, Leren P, Eide IK. Arterial plasma norepinephrine correlates to blood pressure in middle-aged men with sustained essential hypertension. Am Heart J. 1989;118:775–81.CrossRefPubMedGoogle Scholar
  7. 7.
    Smith PA, Graham LN, Mackintosh AF, Stoker JB, Mary DA. Relationship between central sympathetic activity and stages of human hypertension. Am J Hypertens. 2004;17:217–22.CrossRefPubMedGoogle Scholar
  8. 8.
    Huggett RJ, Scott EM, Gilbey SG, Stoker JB, Mackintosh AF, Mary DA. Impact of type 2 diabetes mellitus on sympathetic neural mechanisms in hypertension. Circulation. 2003;108:3097–101.CrossRefPubMedGoogle Scholar
  9. 9.
    Ishii M, Ikeda T, Takagi M, et al. Elevated plasma catecholamines in hypertensives with primary glomerular diseases. Hypertension. 1983;5:545–51.CrossRefPubMedGoogle Scholar
  10. 10.
    Grassi G, Seravalle G, Cattaneo BM, et al. Sympathetic activation in obese normotensive subjects. Hypertension. 1995;25:560–3.CrossRefPubMedGoogle Scholar
  11. 11.
    Narkiewicz K, van de Borne PJ, Cooley RL, Dyken ME, Somers VK. Sympathetic activity in obese subjects with and without obstructive sleep apnea. Circulation. 1998;98:772–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Mancia G. Baroreflex control of sympathetic nerve activity in essential and secondary hypertension. Hypertension. 1998;31:68–72.CrossRefPubMedGoogle Scholar
  13. 13.
    Grassi G, Seravalle G, Quarti-Trevano F, et al. Adrenergic, metabolic, and reflex abnormalities in reverse and extreme dipper hypertensives. Hypertension. 2008;52:925–31.CrossRefPubMedGoogle Scholar
  14. 14.
    Greenwood JP, Scott EM, Stoker JB, Mary DA. Hypertensive left ventricular hypertrophy: relation to peripheral sympathetic drive. J Am Coll Cardiol. 2001;38:1711–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation. 2003;108:560–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Katholi RE. Renal nerves in the pathogenesis of hypertension in experimental animals and humans. Am J Physiol. 1983;245:F1–14.PubMedGoogle Scholar
  17. 17.
    Harris SH. Renal sympathectomy: its scope and limitations: (section of urology). Proc R Soc Med. 1935;28:1497–510.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Grimson KS, Orgain ES, et al. Results of treatment of patients with hypertension by total thoracic and partial to total lumbar sympathectomy, splanchnicectomy and celiac ganglionectomy. Ann Surg. 1949;129:850–71.PubMedCentralCrossRefGoogle Scholar
  19. 19.
    Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med. 2009;361:932–4.CrossRefPubMedGoogle Scholar
  20. 20.
    Hering D, Lambert EA, Marusic P, et al. Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant hypertension. Hypertension. 2013;61:457–64.CrossRefPubMedGoogle Scholar
  21. 21.
    Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–81.CrossRefPubMedGoogle Scholar
  22. 22.•
    Krum H, Schlaich MP, Sobotka PA, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet. 2014;383:622–9. A report on long-term follow-up of patients who underwent RDN. Significant BP reduction was sustained after 3 years. CrossRefPubMedGoogle Scholar
  23. 23.
    Symplicity HTNI, Esler MD, Krum H, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903–9.CrossRefGoogle Scholar
  24. 24.
    Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation. 2012;126:2976–82.CrossRefPubMedGoogle Scholar
  25. 25.
    Demaria AN. Reflections on renal denervation. J Am Coll Cardiol. 2014;63:1452–3.CrossRefPubMedGoogle Scholar
  26. 26.
    Ormiston JA, Watson T, van Pelt N, et al. Renal denervation for resistant hypertension using an irrigated radiofrequency balloon: 12-month results from the Renal Hypertension Ablation System (RHAS) trial. EuroIntervention. 2013;9:70–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Worthley SG, Tsioufis CP, Worthley MI, et al. Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur Heart J. 2013;34:2132–40.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.••
    Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393–401. Major trial that was the largest, first to include a US cohort, and the first to perform a sham procedure in the control group. Contrary to prior studies, there was no difference in BP reduction between groups. CrossRefPubMedGoogle Scholar
  29. 29.•
    Kandzari DE, Bhatt DL, Brar S, et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J. 2015;36:219–27. These analyses delved deeper into the results from SYMPLICITY HTN-3 to identify possible explanations for the latter study’s findings and to identify predictors of BP response to RDN. CrossRefPubMedGoogle Scholar
  30. 30.•
    Azizi M, Sapoval M, Gosse P, et al. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet. 2015. First RCT to examine the role of RDN in patients with less severe hypertension than those enrolled in previous trials.Google Scholar
  31. 31.
    Desch S, Okon T, Heinemann D, et al.: randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. Hypertension. 2015.Google Scholar
  32. 32.
    O’Brien E, Parati G, Stergiou G, et al. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hyperten. 2013;31:1731–68.Google Scholar
  33. 33.
    Warren RE, Marshall T, Padfield PL, Chrubasik S. Variability of office, 24-hour ambulatory, and self-monitored blood pressure measurements. Br J Gen Pract. 2010;60:675–80.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Mancia G, Zanchetti A, Agabiti-Rosei E, et al. Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. SAMPLE Study Group. Study on ambulatory monitoring of blood pressure and lisinopril evaluation. Circulation. 1997;95:1464–70.CrossRefPubMedGoogle Scholar
  35. 35.
    Sakakura K, Ladich E, Cheng Q, et al. Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol. 2014;64:635–43.CrossRefPubMedGoogle Scholar
  36. 36.
    Mahfoud F, Edelman ER, Bohm M. Catheter-based renal denervation is no simple matter: lessons to be learned from our anatomy? J Am Coll Cardiol. 2014;64:644–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Bohm M, Mahfoud F, Ukena C, et al. First report of the global SYMPLICITY registry on the effect of renal artery denervation in patients with uncontrolled hypertension. Hypertension. 2015;65:766–74.CrossRefPubMedGoogle Scholar
  38. 38.
    Bacaksiz A, Uyarel H, Jafarov P, Kucukbuzcu S. Iatrogenic renal artery stenosis after renal sympathetic denervation. Int J Cardiol. 2014;172:e389–90.CrossRefPubMedGoogle Scholar
  39. 39.
    Jaen Aguila F, Mediavilla Garcia JD, Molina Navarro E, Vargas Hitos JA, Fernandez-Torres C. Bilateral renal artery stenosis after renal denervation. Hypertension. 2014;63:e126–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Kaltenbach B, Id D, Franke JC, et al. Renal artery stenosis after renal sympathetic denervation. J Am Coll Cardiol. 2012;60:2694–5.CrossRefPubMedGoogle Scholar
  41. 41.
    Versaci F, Trivisonno A, Olivieri C, Caranci F, Brunese L, Prati F. Late renal artery stenosis after renal denervation: is it the tip of the iceberg? Int J Cardiol. 2014;172:e507–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Vonend O, Antoch G, Rump LC, Blondin D. Secondary rise in blood pressure after renal denervation. Lancet. 2012;380:778.CrossRefPubMedGoogle Scholar
  43. 43.
    Geisler BP, Egan BM, Cohen JT, et al. Cost-effectiveness and clinical effectiveness of catheter-based renal denervation for resistant hypertension. J Am Coll Cardiol. 2012;60:1271–7.CrossRefPubMedGoogle Scholar
  44. 44.
    Brandt MC, Reda S, Mahfoud F, Lenski M, Bohm M, Hoppe UC. Effects of renal sympathetic denervation on arterial stiffness and central hemodynamics in patients with resistant hypertension. J Am Coll Cardiol. 2012;60:1956–65.CrossRefPubMedGoogle Scholar
  45. 45.
    Hering D, Mahfoud F, Walton AS, et al. Renal denervation in moderate to severe CKD. JASN. 2012;23:1250–7.PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Schlaich MP, Bart B, Hering D, et al. Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease. Int J Cardiol. 2013;168:2214–20.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Matthew G. Denker
    • 1
  • Debbie L. Cohen
    • 1
  • Raymond R. Townsend
    • 1
    • 2
    Email author
  1. 1.Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Renal, Electrolyte and Hypertension DivisionUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations