Dataset Information

Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design.

ABSTRACT:

Background

The SPYRAL HTN clinical trial program was initiated with two 80-patient pilot studies, SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED, which provided biological proof of principle that renal denervation has a blood pressure-lowering effect versus sham controls for subjects with uncontrolled hypertension in the absence or presence of antihypertensive medications, respectively.

Trial design

Two multicenter, prospective, randomized, sham-controlled trials have been designed to evaluate the safety and efficacy of catheter-based renal denervation for the reduction of blood pressure in subjects with hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) or presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications. The primary efficacy endpoint is baseline-adjusted change from baseline in 24-h ambulatory systolic blood pressure. The primary safety endpoint is incidence of major adverse events at 1 month after randomization (or 6 months in cases of new renal artery stenosis). Both trials utilize a Bayesian design to allow for prespecified interim analyses to take place, and thus, the final sample sizes are dependent on whether enrollment is stopped at the first or second interim analysis. SPYRAL HTN-OFF MED Pivotal will enroll up to 300 subjects and SPYRAL HTN-ON MED Expansion will enroll up to 221 subjects. A novel Bayesian power prior approach will leverage historical information from the pilot studies, with a degree of discounting determined by the level of agreement with data from the prospectively powered studies.

Conclusions

The Bayesian paradigm represents a novel and promising approach in device-based hypertension trials.

Clinical trial registration

URL: https://www.clinicaltrials.gov. Unique identifier: NCT02439749 (SPYRAL HTN-OFF MED Pivotal) and NCT02439775 (SPYRAL HTN-ON MED Expansion).

SUBMITTER: Bohm M

PROVIDER: S-EPMC7042193 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design.

Böhm Michael M Townsend Raymond R RR Kario Kazuomi K Kandzari David D Mahfoud Felix F Weber Michael A MA Schmieder Roland E RE Tsioufis Konstantinos K Hickey Graeme L GL Fahy Martin M DeBruin Vanessa V Brar Sandeep S Pocock Stuart S

Clinical research in cardiology : official journal of the German Cardiac Society 20200207 3

<h4>Background</h4>The SPYRAL HTN clinical trial program was initiated with two 80-patient pilot studies, SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED, which provided biological proof of principle that renal denervation has a blood pressure-lowering effect versus sham controls for subjects with uncontrolled hypertension in the absence or presence of antihypertensive medications, respectively.<h4>Trial design</h4>Two multicenter, prospective, randomized, sham-controlled trials have been designed to e ...[more]

PMID: 32034481

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Project description:ImportanceUltrasound renal denervation (uRDN) was shown to lower blood pressure (BP) in patients with uncontrolled hypertension (HTN). Establishing the magnitude and consistency of the uRDN effect across the HTN spectrum is clinically important.ObjectiveTo characterize the effectiveness and safety of uRDN vs a sham procedure from individual patient-level pooled data across uRDN trials including either patients with mild to moderate HTN on a background of no medications or with HTN resistant to standardized triple-combination therapy.Data sourcesA Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN SOLO and TRIO) and A Study of the ReCor Medical Paradise System in Stage II Hypertension (RADIANCE II) trials.Study selectionTrials with similar designs, standardized operational implementation (medication standardization and blinding of both patients and physicians to treatment assignment), and follow-up.Data extraction and synthesisPooled analysis using individual patient-level data using linear regression models to compare uRDN with sham across the trials.Main outcomes and measuresThe primary outcome was baseline-adjusted change in 2-month daytime ambulatory systolic BP (dASBP) between groups.ResultsA total of 506 patients were randomized in the 3 studies (uRDN, 293; sham, 213; mean [SD] age, 54.1 [9.3]; 354 male [70.0%]). After a 1-month medication stabilization period, dASBP was similar between the groups (mean [SD], uRDN, 150.3 [9.2] mm Hg; sham, 150.8 [10.5] mm Hg). At 2 months, dASBP decreased by 8.5 mm Hg to mean (SD) 141.8 (13.8) mm Hg among patients treated with uRDN and by 2.9 mm Hg to 147.9 (14.6) mm Hg among patients treated with a sham procedure (mean difference, -5.9; 95% CI, -8.1 to -3.8 mm Hg; P < .001 in favor of uRDN). BP decreases from baseline with uRDN vs sham were consistent across trials and across BP parameters (office SBP: -10.4 mm Hg vs -3.4 mm Hg; mean difference, -6.4 mm Hg; 95% CI, -9.1 to -3.6 mm Hg; home SBP: -8.4 mm Hg vs -1.4 mm Hg; mean difference, -6.8 mm Hg; 95% CI, -8.7 to -4.9 mm Hg, respectively). The BP reductions with uRDN vs sham were consistent across prespecified subgroups. Independent predictors of a larger BP response to uRDN were higher baseline BP and heart rate and the presence of orthostatic hypertension. No differences in early safety end points were observed between groups.Conclusions and relevanceResults of this patient-level pooled analysis suggest that BP reductions with uRDN were consistent across HTN severity in sham-controlled trials designed with a 2-month primary end point to standardize medications across randomized groups.Trial registrationClinicalTrials.gov Identifier: NCT02649426 and NCT03614260.

Project description:BackgroundRenal denervation (RDN) lowers blood pressure (BP), but BP response is variable in individual patients. We investigated whether measures of pulsatile hemodynamics, obtained during 24-hour ambulatory BP monitoring, predict BP drop following RDN.MethodsFrom the randomized, sham-controlled SPYRAL HTN-OFF MED Pivotal trial, we performed a post hoc analysis of BP waveforms from 111 RDN patients and 111 sham controls, obtained with a brachial cuff-based sphygmomanometer. Waveforms were acquired during ambulatory BP monitoring at diastolic BP level and processed with validated ARCSolver algorithms to derive hemodynamic parameters (augmentation index; augmentation pressure; backward and forward wave amplitude; estimated aortic pulse wave velocity). We investigated the relationship between averaged 24-hour values at baseline and the change in 24-hour BP at 3 months in RDN patients, corrected for observed trends in the sham group.ResultsThere was a consistent inverse relationship between baseline augmentation index/augmentation pressure/backward wave amplitude/forward wave amplitude/estimated aortic pulse wave velocity and BP response to RDN: the decrease in 24-hour systolic BP/diastolic BP was 7.8/5.9 (augmentation index), 8.0/6.3 (augmentation pressure), 6.7/5.4 (backward wave amplitude), 5.7/4.7 (forward wave amplitude), and 7.8/5.2 (estimated aortic pulse wave velocity) mm Hg greater for patients below versus above the respective median value (P<0.001 for all comparisons, respectively). Taking augmentation index/augmentation pressure/backward wave amplitude/forward wave amplitude/estimated aortic pulse wave velocity into account, a favorable BP response following RDN, defined as a drop in 24-hour systolic blood pressure of ≥5 mm Hg, could be predicted with an area under the curve of 0.70/0.74/0.70/0.65/0.62 (P<0.001 for all, respectively).ConclusionsThese results suggest that pulsatile hemodynamics, obtained during 24-hour ambulatory BP monitoring, may predict BP response to RDN.

Project description:AbstractMedication nonadherence represents a modifiable risk factor for patients with hypertension. Identification of nonadherent patients could have significant clinical and economic implications in the management of uncontrolled hypertension.We analysed the results of 174 urinary adherence screens from patients referred to Addenbrooke's Hospital, Cambridge, for uncontrolled hypertension. Cases were identified for evaluation by results of liquid chromatography-tandem mass spectrometry of urine samples (males: 91; females: 83; age range: 17-87). We performed a binary logistic regression analysis for nonadherence using age, sex, and number of medications prescribed (both antihypertensives and non-antihypertensives separately) as independent predictors. Rates of nonadherence for individual antihypertensive drugs were calculated if prescribed to ≥10 patients.The overall rate of nonadherence to one or more prescribed antihypertensive medications was 40.3%. 14.4% of all patients were nonadherent to all prescribed antihypertensive medications (complete nonadherence), whereas 25.9% of all patients were nonadherent to at least 1, (but not all) prescribed antihypertensive medications (partial nonadherence). 72% of patients were prescribed ≥3 antihypertensives And for every increase in the number of antihypertensive medications prescribed, nonadherence increased with adjusted odds ratios of 2.9 (P < .001). Logistic regression showed that women were 3.3 times more likely to be nonadherent (P = .004). Polypharmacy (≥6 medications prescribed for hypertension and/or concomitant comorbidities) was prevalent in 52%. Bendroflumethiazide and chlortalidone demonstrated the highest and lowest nonadherences respectively (45.5% and 11.8%).Rate of nonadherence in patients with hypertension was significantly impacted by sex and number of antihypertensive medications prescribed. Understanding these factors is crucial in identifying and managing nonadherence.

Project description:BackgroundThe Global SYMPLICITY Registry DEFINE (Denervation Findings in Real World) investigates radiofrequency renal denervation (RDN) in a broad range of patients with hypertension. We evaluated whether the number or type of antihypertensive medications were associated with increased long-term blood pressure (BP) reductions and cardiovascular outcomes following radiofrequency RDN.MethodsPatients underwent radiofrequency RDN and were categorized by baseline number (0-3 and ≥4) and different combinations of medication classes. BP changes were compared between groups through 36 months. Individual and composite major adverse cardiovascular events were analyzed.ResultsOf 2746 evaluable patients, 18% were prescribed 0 to 3 and 82% prescribed ≥4 classes. At 36 months, office systolic BP significantly decreased (P<0.0001) by -19.0±28.3 and -16.2±28.6 mm Hg in the 0 to 3 and ≥4 class groups, respectively. Twenty-four-hour mean systolic BP significantly decreased (P<0.0001) by -10.7±19.7 and -8.9±20.5 mm Hg, respectively. BP reduction was similar between the medication subgroups. Antihypertensive medication classes decreased from 4.6±1.4 to 4.3±1.5 (P<0.0001). Most decreased (31%) or had no changes (47%) to the number of medications, while 22% increased. The number of baseline antihypertensive medication classes was inversely related to the change in prescribed classes at 36 months (P<0.001). Cardiovascular event rates were generally low. More patients in the ≥4 compared with 0 to 3 medication classes had myocardial infarction at 36 months (2.8% versus 0.3%; P=0.009).ConclusionsRadiofrequency RDN reduced BP safely through 36 months, independent of the number and type of baseline antihypertensive medication classes. More patients decreased than increased their number of medications. Radiofrequency RDN is a safe and effective adjunctive therapy regardless of antihypertensive medication regimen.RegistrationURL: https://www.Clinicaltrialsgov; Unique identifier: NCT01534299.

Dataset Information

Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design.

Background

Trial design

Conclusions

Clinical trial registration

Publications

Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design.

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