Michel Azizi1, Kintur Sanghvi2, Manish Saxena3, Philippe Gosse4, John P Reilly5, Terry Levy6, Lars C Rump7, Alexandre Persu8, Jan Basile9, Michael J Bloch10, Joost Daemen11, Melvin D Lobo3, Felix Mahfoud12, Roland E Schmieder13, Andrew S P Sharp14, Michael A Weber15, Marc Sapoval16, Pete Fong17, Atul Pathak18, Pierre Lantelme19, David Hsi20, Sripal Bangalore21, Adam Witkowski22, Joachim Weil23, Benjamin Kably24, Neil C Barman25, Helen Reeve-Stoffer25, Leslie Coleman25, Candace K McClure26, Ajay J Kirtane27. 1. Université de Paris, Paris, France; Hypertension Department and DMU CARTE, AP-HP Hôpital Européen Georges-Pompidou, Paris, France; INSERM, CIC1418, Paris, France. Electronic address: michel.azizi@aphp.fr. 2. Deborah Heart and Lung Center, Browns Mills, NJ, USA. 3. Barts NIHR Biomedical Research Centre, William Harvey Research Institute, Queen Mary University of London, London, UK. 4. Hôpital Saint-André CHU, Bordeaux, France. 5. Ochsner Heart and Vascular Institute, New Orleans, LA, USA. 6. Royal Bournemouth Hospital, Bournemouth, UK. 7. University Clinic Dusseldorf, Dusseldorf, Germany. 8. Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium. 9. Seinsheimer Cardiovascular Health Program, Medical University of South Carolina, Ralph H Johnson VA Medical Center, Charleston, SC, USA. 10. Department of Medicine, University of Nevada School of Medicine, Vascular Care, Renown Institute of Heart and Vascular Health, Reno, NV, USA. 11. Erasmus MC, Department of Cardiology, University Medical Center Rotterdam, Rotterdam, Netherlands. 12. Klinik für Innere Medizin III, Saarland University Hospital, Homburg/Saar, Germany; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. 13. Nephrology and Hypertension, University Hospital Erlangen, Friedrich Alexander University, Erlangen, Germany. 14. Cardiology Department, University Hospital of Wales, Cardiff, UK; NIHR Clinical Research Facility, University of Exeter, Exeter, UK. 15. Division of Cardiovascular Medicine, State University of New York, Downstate Medical Center, New York, NY, USA. 16. Université de Paris, Paris, France; Hypertension Department and DMU CARTE, AP-HP Hôpital Européen Georges-Pompidou, Paris, France. 17. Vanderbilt University Medical Center, Nashville, TN, USA. 18. Department of Cardiovascular Medicine, Princess Grace Hospital, Monaco; UMR UT3 CNRS 5288, University of Toulouse, Toulouse, France. 19. Hôpital de la Croix Rousse, Lyon, France. 20. Stamford Hospital, Stamford, CT, USA. 21. NYU School of Medicine, New York, NY, USA. 22. Institute of Cardiology, Warsaw, Poland. 23. Sana Kliniken Lübeck, Lübeck, Germany. 24. Université de Paris, Paris, France; AP-HP Hôpital Européen Georges-Pompidou, Pharmacology Unit and DMU CARTE, Paris, France. 25. ReCor Medical, Palo Alto, CA, USA. 26. NAMSA, Minneapolis, MN, USA. 27. Columbia University Medical Center/New York-Presbyterian Hospital and the Cardiovascular Research Foundation, New York, NY, USA.
Abstract
BACKGROUND: Endovascular renal denervation reduces blood pressure in patients with mild-to-moderate hypertension, but its efficacy in patients with true resistant hypertension has not been shown. We aimed to assess the efficacy and safety of endovascular ultrasound renal denervation in patients with hypertension resistant to three or more antihypertensive medications. METHODS: In a randomised, international, multicentre, single-blind, sham-controlled trial done at 28 tertiary centres in the USA and 25 in Europe, we included patients aged 18-75 years with office blood pressure of at least 140/90 mm Hg despite three or more antihypertensive medications including a diuretic. Eligible patients were switched to a once daily, fixed-dose, single-pill combination of a calcium channel blocker, an angiotensin receptor blocker, and a thiazide diuretic. After 4 weeks of standardised therapy, patients with daytime ambulatory blood pressure of at least 135/85 mm Hg were randomly assigned (1:1) by computer (stratified by centres) to ultrasound renal denervation or a sham procedure. Patients and outcome assessors were masked to randomisation. Addition of antihypertensive medications was allowed if specified blood pressure thresholds were exceeded. The primary endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02649426. FINDINGS: Between March 11, 2016, and March 13, 2020, 989 participants were enrolled and 136 were randomly assigned to renal denervation (n=69) or a sham procedure (n=67). Full adherence to the combination medications at 2 months among patients with urine samples was similar in both groups (42 [82%] of 51 in the renal denervation group vs 47 [82%] of 57 in the sham procedure group; p=0·99). Renal denervation reduced daytime ambulatory systolic blood pressure more than the sham procedure (-8·0 mm Hg [IQR -16·4 to 0·0] vs -3·0 mm Hg [-10·3 to 1·8]; median between-group difference -4·5 mm Hg [95% CI -8·5 to -0·3]; adjusted p=0·022); the median between-group difference was -5·8 mm Hg (95% CI -9·7 to -1·6; adjusted p=0·0051) among patients with complete ambulatory blood pressure data. There were no differences in safety outcomes between the two groups. INTERPRETATION: Compared with a sham procedure, ultrasound renal denervation reduced blood pressure at 2 months in patients with hypertension resistant to a standardised triple combination pill. If the blood pressure lowering effect and safety of renal denervation are maintained in the long term, renal denervation might be an alternative to the addition of further antihypertensive medications in patients with resistant hypertension. FUNDING: ReCor Medical.
BACKGROUND: Endovascular renal denervation reduces blood pressure in patients with mild-to-moderate hypertension, but its efficacy in patients with true resistant hypertension has not been shown. We aimed to assess the efficacy and safety of endovascular ultrasound renal denervation in patients with hypertension resistant to three or more antihypertensive medications. METHODS: In a randomised, international, multicentre, single-blind, sham-controlled trial done at 28 tertiary centres in the USA and 25 in Europe, we included patients aged 18-75 years with office blood pressure of at least 140/90 mm Hg despite three or more antihypertensive medications including a diuretic. Eligible patients were switched to a once daily, fixed-dose, single-pill combination of a calcium channel blocker, an angiotensin receptor blocker, and a thiazide diuretic. After 4 weeks of standardised therapy, patients with daytime ambulatory blood pressure of at least 135/85 mm Hg were randomly assigned (1:1) by computer (stratified by centres) to ultrasound renal denervation or a sham procedure. Patients and outcome assessors were masked to randomisation. Addition of antihypertensive medications was allowed if specified blood pressure thresholds were exceeded. The primary endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02649426. FINDINGS: Between March 11, 2016, and March 13, 2020, 989 participants were enrolled and 136 were randomly assigned to renal denervation (n=69) or a sham procedure (n=67). Full adherence to the combination medications at 2 months among patients with urine samples was similar in both groups (42 [82%] of 51 in the renal denervation group vs 47 [82%] of 57 in the sham procedure group; p=0·99). Renal denervation reduced daytime ambulatory systolic blood pressure more than the sham procedure (-8·0 mm Hg [IQR -16·4 to 0·0] vs -3·0 mm Hg [-10·3 to 1·8]; median between-group difference -4·5 mm Hg [95% CI -8·5 to -0·3]; adjusted p=0·022); the median between-group difference was -5·8 mm Hg (95% CI -9·7 to -1·6; adjusted p=0·0051) among patients with complete ambulatory blood pressure data. There were no differences in safety outcomes between the two groups. INTERPRETATION: Compared with a sham procedure, ultrasound renal denervation reduced blood pressure at 2 months in patients with hypertension resistant to a standardised triple combination pill. If the blood pressure lowering effect and safety of renal denervation are maintained in the long term, renal denervation might be an alternative to the addition of further antihypertensive medications in patients with resistant hypertension. FUNDING: ReCor Medical.
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