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Ultrasound renal denervation (uRDN) was demonstrated to lower ambulatory systolic blood pressure (BP) versus a sham procedure at 2 months post-intervention in patients with mild to moderate hypertension (HTN)12 and resistant HTN3. While background medications were strictly controlled in these randomised studies, it is important to demonstrate the BP-lowering effect of uRDN in patients treated with antihypertensive medications (AHMs) prescribed by clinicians under unblinded conditions, reflecting a “real-world” setting.
The current analysis included pooled data from the 3 international, multicentre, randomised sham-controlled trials of the RADIANCE123 programme (ClinicalTrials.gov: NCT02649426 and NCT03614260), which compared changes in BP in patients with HTN who received either uRDN or a sham procedure. A list of the study investigators and lead coordinators can be found in Supplementary Appendix 1. All 3 studies required patients to be between 18 and 75 years of age, to have an estimated glomerular filtration rate (eGFR) of ≥40 mL/min/1.73 m2, and a suitable renal artery anatomy. The trials included patients with mild to moderate HTN on 0-2 AHMs12 or patients with resistant HTN despite ≥3 prescribed AHMs3. Patients were either taken off medications12 or were stabilised on a triple pill3 for 4 weeks prior to randomisation. Patients were randomised 1:112 or 2:12 if their daytime ambulatory BP (dABP) remained ≥135/85 mmHg.
Patients were to remain off additional AHMs throughout the first 2 months (primary endpoint ascertainment) of follow-up. After 6 months, AHMs were prescribed per the treating physician’s standard of care.
Patients were eligible to crossover to uRDN ≥6 months after randomisation to sham treatment or after failed uRDN if they had a requalifying (crossover baseline) daytime ambulatory systolic BP (dASBP) ≥135 mmHg and/or daytime ambulatory diastolic BP ≥85 mmHg despite the addition of AHMs. After the crossover procedure, AHMs could be adjusted at the physician’s discretion. Patients returned for follow-up visits, which included office BP measurement, ambulatory BP monitoring, review of medication use and assessment of safety events, at 2, 6, and 12 months after their uRDN crossover procedure. Adverse events were adjudicated according to definitions used in the RADIANCE-HTN trials, as previously reported123.
Linear mixed models for repeated measures were used to assess covariate-adjusted changes in number of AHMs and BP parameters up to 12 months after the crossover procedure. Fixed-effect terms included study and visit; crossover baseline BP and the number of AHMs were also included as fixed effects in the BP assessments. Also, changes in BP from crossover baseline up to 12 months are shown as unadjusted mean±standard deviation.
This analysis included 92/213 (43.2%) patients who received crossover uRDN: 91 patients were initially randomised to sham treatment, and 1 patient was initially randomised to uRDN but never received treatment. The average time from randomisation to crossover was 23.8±9.3 months. The average age was 53.7±9.2 years; 31.5% were female, and 76.1% were white. At crossover baseline, the mean dASBP of patients was 148.5±16.9 mmHg and the mean office systolic BP (OSBP) was 145.8±11.8 mmHg while being on 1.8±1.6 AHMs (median 2.0 [range 0.0-6.0]).
After crossover to uRDN, there were no significant changes in the number of AHMs: 0.0±0.6, 0.0±0.6, and 0.1±1.1 at 2, 6, and 12 months, respectively. The decrease in dASBP and office systolic BP over 12 months was −9.2 mmHg (95% confidence interval [CI]: −12.0 to −6.4; p<0.001) and −5.6 mmHg (95% CI: −8.5 to −2.7; p<0.001), respectively (Table 1). dABP was controlled (<135/85 mmHg) in 44.0% (37/84), 45.6% (31/68), and 39.1% (25/64) of patients at crossover 2-, 6-, and 12-month follow-ups, respectively. Office BP control (<140/90 mmHg) was achieved in 33.7% (28/83), 30.4% (21/69), and 23.0% (14/61) of patients at each respective follow-up visit.
There was 1 death at 21 days after crossover, which was adjudicated as not related to the device or procedure.
This analysis demonstrated consistent BP lowering with subsequent uRDN in patients with persistent uncontrolled HTN after being initially randomised to a sham procedure despite receiving a mean of 1.8 AHMs. These results build on those previously demonstrated with uRDN in the double-blind, sham-controlled trials, in which medications were held stable at 2 months123, and longer-term data, in which medications were added back in in a standardised fashion4. Pharmacological observational studies have shown that a reduction of 5 mmHg in OSBP is associated with a 10% reduction in major cardiovascular events, which suggest these reductions are clinically meaningful5.
Limitations to this analysis include that the results are observational and the reasons why eligible patients did not crossover were not captured. In addition, not all patients had reached their 12-month follow-up ascertainment after crossover uRDN. Background medication use was not standardised, and medication adherence was not systematically measured, reflective of real-world HTN management. It is possible that patients and/or physicians intentionally did not change their medications prior to crossover so they would be eligible for uRDN. While each of these limitations may add an element of uncertainty to the findings presented here, the findings increase the external validity of the results5.
In conclusion, patients who crossed over to open-label uRDN had statistically significant and clinically meaningful reductions in BP without an increase in medication burden.
Table 1. Change in daytime ambulatory and office blood pressure at crossover visits adjusting for study, visit, crossover baseline blood pressure, and number of antihypertensive medications.
| Difference: CO month 2 –CO baseline | Difference: CO month 6 –CO baseline | Difference: CO month 12 –CO baseline | Overall change from CO baseline without treatment arm by visit interaction | Overall change from CO baseline with treatment arm by visit interaction | |
|---|---|---|---|---|---|
| Daytime ambulatory systolic BP | −10.2±13.2 (84)*−9.9(−13.0 to −6.7; <0.001)¶ | −10.1±15.9 (68)*−9.0(−12.4 to −5.6; <0.001)¶ | −9.5±16.1 (64)*−8.3(−11.8 to −4.7; <0.001)¶ | −9.2(−12.0 to −6.4; <0.001)¶ | −9.0(−11.9 to −6.2; <0.001)¶ 0.623† |
| Daytime ambulatory diastolic BP | −6.5±8.6 (84)*−6.1(−8.1 to −4.1; <0.001)¶ | −6.9±10.4 (68)*−5.8(−7.9 to −3.6; <0.001)¶ | −6.4±10.4 (64)*−5.6(−7.8 to −3.3; <0.001)¶ | −5.9(−7.7 to −4.1; <0.001)¶ | −5.8(−7.6 to −4.0; <0.001)¶ 0.867† |
| Nighttime ambulatory systolic BP | −10.4±13.5 (84)* −9.9(−12.9 to −6.9; <0.001)¶ | −7.4±14.5 (68)*−6.4 (−9.6 to −3.2; <0.001)¶ |
−6.8±15.4 (63)*−6.1(−9.5 to −2.8; <0.001)¶ | −7.9 (−10.7 to −5.2; <0.001)¶ |
−7.5 (−10.2 to −4.7; <0.001)¶ 0.015† |
| Nighttime ambulatory diastolic BP | −6.9±9.7 (84)*−6.5(−8.4 to −4.6; <0.001)¶ | −5.4±10.1 (68)*−4.6(−6.7 to −2.6; <0.001)¶ | −4.0±10.7 (63)*−3.4(−5.6 to −1.3; 0.002)¶ | −5.2(−6.8 to −3.5; <0.001)¶ | −4.9(−6.6 to −3.2; <0.001)¶ 0.008† |
| 24-hour ambulatory systolic BP | −10.3±12.5 (84)*−9.8(−12.8 to −6.8; <0.001)¶ | −9.1±14.4 (68)*−8.0(−11.2 to −4.8; <0.001)¶ | −8.6±15.0 (64)*−7.5(−10.8 to −4.2; <0.001)¶ | −8.7(−11.4 to −6.0; <0.001)¶ | −8.5(−11.2 to −5.7; <0.001)¶ 0.235† |
| 24-hour ambulatory diastolic BP | −6.7±8.4 (84)* −6.2(−8.1 to −4.3; <0.001)¶ | −6.4±9.5 (68)*−5.4(−7.4 to −3.4; <0.001)¶ | −5.6±9.8 (64)*−4.8(−6.8 to −2.8; <0.001)¶ | −5.6(−7.3 to −3.9; <0.001)¶ | −5.5(−7.2 to −3.8; <0.001)¶ 0.287† |
| Office systolic BP | −7.3±16.9 (83)*−6.6(−10.0 to −3.2; <0.001)¶ | −4.8±18.9 (69)*−4.1(−7.8 to −0.4; 0.029)¶ | −7.0±18.0 (61)*−5.6(−9.5 to −1.7; 0.005)¶ | −5.6(−8.5 to −2.7; <0.001)¶ | −5.4(−8.3 to −2.5; <0.001)¶ 0.411† |
| Office diastolic BP | −5.1±10.8 (83)*−4.6(−6.8 to −2.4; <0.001)¶ | −3.6±11.9 (69)*−2.8(−5.1 to −0.4; 0.022)¶ | −4.0±10.5 (61)*−3.3(−5.8 to −0.8; 0.010)¶ | −3.7(−5.6 to −1.8; <0.001)¶ | −3.5 (−5.5 to −1.6; <0.001)¶ 0.262† |
| *Unadjusted mean±SD (n). ¶Least squares means (95% CI; p-value). Means from repeated measures model adjusted for study, crossover baseline value, visit, and number of antihypertensive medications at visit. †P-value for visit variable. BP: blood pressure; CI: confidence interval; CO: crossover; SD: standard deviation | |||||
Funding
RADIANCE-HTN SOLO, RADIANCE-HTN TRIO, and RADIANCE II were funded by Recor Medical, Palo Alto, CA, USA.
Conflict of interest statement
M.J. Bloch has received personal fees from Recor Medical and Medtronic. M. Azizi has received research grants from the European Horizon 2020 programme; has received grant support and non-financial support from Recor Medical, Novartis, and Idorsia; and has received personal fees from Alnylam Pharmaceutical, Novartis, Medtronic, and AstraZeneca. A.J. Kirtane reports institutional funding to Columbia University and/or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott, Amgen, CSI, Philips, Recor Medical, Neurotronics, Biotronik, Chiesi, Bolt Medical, Magenta Medical, Canon Medical Systems, SoniVie, and Merck & Co; in addition to research grants, institutional funding includes fees paid to Columbia University and/or Cardiovascular Research Foundation for consulting and/or speaking engagements in which he controlled the content; personal: consulting from IMDS; and travel expenses/meals from Medtronic, Boston Scientific, Abbott, CSI, Siemens, Philips, Recor Medical, Chiesi, OpSens, Zoll, and Regeneron. F. Mahfoud is supported by Deutsche Gesellschaft für Kardiologie (DGK), Deutsche Forschungsgemeinschaft (SFB TRR219, Project-ID 322900939), and Deutsche Herzstiftung; he has received scientific support from Ablative Solutions, Medtronic, and Recor Medical; and speaker honoraria/consulting fees from Ablative Solutions, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Inari Medical, Medtronic, Merck & Co, Recor Medical, Servier, and Terumo. A.S.P. Sharp has received personal fees from Recor Medical, Medtronic, Boston Scientific, Penumbra, and Philips. M. McGuire is an employee of Recor Medical. C.K. McClure is an employee of NAMSA; and a contractor for Recor Medical. M. Weber has received personal fees from Recor Medical, Medtronic, and Ablative Solutions.
Supplementary data
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