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Background: Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension., Methods: PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174., Findings: The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was -15·3 (SE 0·9) mm Hg for aprocitentan 12·5 mg, -15·2 (0·9) mm Hg for aprocitentan 25 mg, and -11·5 (0·9) mm Hg for placebo, for a difference versus placebo of -3·8 (1·3) mm Hg (97·5% CI -6·8 to -0·8, p=0·0042) and -3·7 (1·3) mm Hg (-6·7 to -0·8; p=0·0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was -4·2 mm Hg (95% CI -6·2 to -2·1) and -5·9 mm Hg (-7·9 to -3·8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 to 7·9, p<0·0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, during the 4-week double-blind part, respectively. This event led to discontinuation in seven patients treated with aprocitentan. During the trial, a total of 11 treatment-emergent deaths occurred, none of which were regarded by the investigators to be related to study treatment., Interpretation: In patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40., Funding: Idorsia Pharmaceuticals and Janssen Biotech., Competing Interests: Declaration of interests MPS has received institutional grants or contracts and personal consulting fees from Medtronic, Abbott Laboratories, and ReCor Medical; personal payment or honoraria from Medtronic, Abbott Laboratories, Merck, and Servier Laboratories; personal support for attending meetings, travel, or both from Medtronic and Abbott Laboratories; serves as the President of the High Blood Pressure Research Council of Australia; and is on the International Society of Hypertension scientific committee. MB is an employee of Idorsia Pharmaceuticals. MAW is has received consulting fees or performed research services for Janssen, Bristol Myers Squibb, CinCor, Medtronic, ReCor, and Ablative Solutions. PD and RFD are employees of Idorsia Pharmaceuticals and hold stock or stock options in Idorsia Pharmaceuticals. GLB has received consulting fees from Bayer, KBP BioSciences, Ionis Pharmaceuticals, Alnylam Pharmaceuticals, AstraZeneca, Quantum Genomics, Novo Nordisk, Janssen, Dia Medica Therapeutics, and InREGEN. JMF has received consulting fees from Ardelyx, Janssen, Amgen, FibroGen, Teva Pharmaceuticals, and ReCor Medical; and payment for a lecture at a continuing medical education event from Janssen. MS-S is an employee of Idorsia Pharmaceuticals. LPH is an employee of Janssen and holds stock in Janssen. KN has received personal honoraria from Bausch Health, Berlin-Chemie (Menarini Group), Egis, Gedeon Richter, Krka, Medtronic, Merck, Novo Nordisk, Polpharma, Recordati, and Servier Laboratories; and has participated in an advisory board for Idorsia Pharmaceuticals. J-GW declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of interests MA has received research grants from the French Ministry of Health, Quantum Genomics, and the European Horizon 2020 programme; has received grant support and non-financial support from ReCor Medical and Idorsia; and has received personal fees from CVRx, AstraZeneca, Alnylam Pharmaceutical, and Poxel Pharma. KS has received grant support and personal fees from ReCor Medical and Medtronic, and has received grant support from Cardiovascular Systems. MSax has received grant support and personal fees from ReCor Medical. PG has received grant support from the University Hospital of Bordeaux. LCR has received personal fees from ReCor Medical. APe has received personal fees from Quantum Genomics and grant support from Ablative Solutions, Quantum Genomics, and ReCor Medical. JB has received grant support from ReCor Medical and Ablative Solutions. MJB has received personal fees from ReCor Medical and Medtronic. JD has received grant support from ReCor Medical, Medtronic, Boston Scientific, Abbott Vascular, Acist Medical, AstraZeneca, Pie Medical, and Pulse Cath, and personal fees from ReCor Medical, Medtronic, Acist Medical, Boston Scientific, Pie Medical, and Pulse Cath. MDL has received personal fees from ReCor Medical, Medtronic, CVRx, Ablative Solutions, Vascular Dynamics, ROX Medical, and Tarilan Laser Technologies, and grants from Medtronic. FM is supported by Deutsche Gesellschaft für Kardiologie and Deutsche Forschungsgemeinschaft (SFB TRR 219); and has received grant support and personal fees from ReCor Medical, Medtronic, Berlin Chemie, Bayer, and Boehringer Ingelheim. RES has received grant support and personal fees from ReCor Medical, Medtronic, and Ablative Solutions. ASPS has received personal fees from ReCor Medical, Medtronic, Boston Scientific, and Philips. MAW has received personal fees from ReCor Medical, Medtronic, Boston Scientific, and Ablative Solutions. APa has received grant support and personal fees from ReCor Medical, Medtronic, and Ablative Solutions. DH reports institutional funding to Stamford Hospital from ReCor Medical. SB has received grant support from Abbott Vascular, the National Heart, Lung, and Blood Institute, and REATA; and personal fees from Abbott Vascular, Biotronik, REATA, Amgen, Pfizer, Boehringer Ingelheim, and Meril. JW has received personal fees from ReCor Medical and Medtronic. NCB is an employee of ReCor Medical and is the author on multiple patents in the field of renal denervation. HR-S is an employee of ReCor Medical. LC is an employee of ReCor Medical. CKM is an employee of North American Science Associates and a contractor for ReCor Medical. AJK reports institutional funding (in addition to research grants, institutional funding includes fees paid for speaking engagements or consulting) to Columbia University or the Cardiovascular Research Foundation (New York, NY, USA) from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, Cardiovascular Systems, CathWorks, Siemens, Philips, and ReCor Medical. AJK also reports travel expenses or meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, Cardiovascular Systems, CathWorks, Siemens, Philips, Chiesi, OpSens, Zoll, Regeneron, and ReCor Medical. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Early studies suggest that radiofrequency-based renal denervation reduces blood pressure in patients with moderate hypertension. We investigated whether an alternative technology using endovascular ultrasound renal denervation reduces ambulatory blood pressure in patients with hypertension in the absence of antihypertensive medications., Methods: RADIANCE-HTN SOLO was a multicentre, international, single-blind, randomised, sham-controlled trial done at 21 centres in the USA and 18 in Europe. Patients with combined systolic-diastolic hypertension aged 18-75 years were eligible if they had ambulatory blood pressure greater than or equal to 135/85 mm Hg and less than 170/105 mm Hg after a 4-week discontinuation of up to two antihypertensive medications and had suitable renal artery anatomy. Patients were randomised (1:1) to undergo renal denervation with the Paradise system (ReCor Medical, Palo Alto, CA, USA) or a sham procedure consisting of renal angiography only. The randomisation sequence was computer generated and stratified by centres with randomised blocks of four or six and permutation of treatments within each block. Patients and outcome assessors were blinded to randomisation. The primary effectiveness endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Patients were to remain off antihypertensive medications throughout the 2 months of follow-up unless specified blood pressure criteria were exceeded. Major adverse events included all-cause mortality, renal failure, an embolic event with end-organ damage, renal artery or other major vascular complications requiring intervention, or admission to hospital for hypertensive crisis within 30 days and new renal artery stenosis within 6 months. This study is registered with ClinicalTrials.gov, number NCT02649426., Findings: Between March 28, 2016, and Dec 28, 2017, 803 patients were screened for eligibility and 146 were randomised to undergo renal denervation (n=74) or a sham procedure (n=72). The reduction in daytime ambulatory systolic blood pressure was greater with renal denervation (-8·5 mm Hg, SD 9·3) than with the sham procedure (-2·2 mm Hg, SD 10·0; baseline-adjusted difference between groups: -6·3 mm Hg, 95% CI -9·4 to -3·1, p=0·0001). No major adverse events were reported in either group., Interpretation: Compared with a sham procedure, endovascular ultrasound renal denervation reduced ambulatory blood pressure at 2 months in patients with combined systolic-diastolic hypertension in the absence of medications., Funding: ReCor Medical., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Conflicting blood pressure-lowering effects of catheter-based renal artery denervation have been reported in patients with resistant hypertension. We compared the ambulatory blood pressure-lowering efficacy and safety of radiofrequency-based renal denervation added to a standardised stepped-care antihypertensive treatment (SSAHT) with the same SSAHT alone in patients with resistant hypertension., Methods: The Renal Denervation for Hypertension (DENERHTN) trial was a prospective, open-label randomised controlled trial with blinded endpoint evaluation in patients with resistant hypertension, done in 15 French tertiary care centres specialised in hypertension management. Eligible patients aged 18-75 years received indapamide 1·5 mg, ramipril 10 mg (or irbesartan 300 mg), and amlodipine 10 mg daily for 4 weeks to confirm treatment resistance by ambulatory blood pressure monitoring before randomisation. Patients were then randomly assigned (1:1) to receive either renal denervation plus an SSAHT regimen (renal denervation group) or the same SSAHT alone (control group). The randomisation sequence was generated by computer, and stratified by centres. For SSAHT, after randomisation, spironolactone 25 mg per day, bisoprolol 10 mg per day, prazosin 5 mg per day, and rilmenidine 1 mg per day were sequentially added from months two to five in both groups if home blood pressure was more than or equal to 135/85 mm Hg. The primary endpoint was the mean change in daytime systolic blood pressure from baseline to 6 months as assessed by ambulatory blood pressure monitoring. The primary endpoint was analysed blindly. The safety outcomes were the incidence of acute adverse events of the renal denervation procedure and the change in estimated glomerular filtration rate from baseline to 6 months. This trial is registered with ClinicalTrials.gov, number NCT01570777., Findings: Between May 22, 2012, and Oct 14, 2013, 1416 patients were screened for eligibility, 106 of those were randomly assigned to treatment (53 patients in each group, intention-to-treat population) and 101 analysed because of patients with missing endpoints (48 in the renal denervation group, 53 in the control group, modified intention-to-treat population). The mean change in daytime ambulatory systolic blood pressure at 6 months was -15·8 mm Hg (95% CI -19·7 to -11·9) in the renal denervation group and -9·9 mm Hg (-13·6 to -6·2) in the group receiving SSAHT alone, a baseline-adjusted difference of -5·9 mm Hg (-11·3 to -0·5; p=0·0329). The number of antihypertensive drugs and drug-adherence at 6 months were similar between the two groups. Three minor renal denervation-related adverse events were noted (lumbar pain in two patients and mild groin haematoma in one patient). A mild and similar decrease in estimated glomerular filtration rate from baseline to 6 months was observed in both groups., Interpretation: In patients with well defined resistant hypertension, renal denervation plus an SSAHT decreases ambulatory blood pressure more than the same SSAHT alone at 6 months. This additional blood pressure lowering effect may contribute to a reduction in cardiovascular morbidity if maintained in the long term after renal denervation., Funding: French Ministry of Health., (Copyright © 2015 Elsevier Ltd. All rights reserved.)