Impact of expected blood pressure reduction on patient preferences for pharmaceutical and renal denervation treatment.

BACKGROUND: Effective patient-centered care requires an adequate understanding of patient preferences for different therapeutic options. We modelled patient preference for blood pressure (BP) management by pharmaceutical or interventional treatments such as renal denervation in patients with different profiles of uncontrolled hypertension. METHODS: Modeling was based on the findings from a previously conducted quantitative discrete choice experiment (DCE). The likelihood of selecting either an interventional treatment option or additional antihypertensive medication option was calculated for three patient profiles that represent the range of patients with hypertension commonly encountered in clinical practice: treatment-naive, patients with uncontrolled BP while on one to three antihypertensive medications, and patients with drug-resistant hypertension. Variables in the preference model were treatment attributes from the DCE study: expected reduction in office SBP with each treatment, duration of treatment effect, risk of reversible drug side effects from drugs, and risk of temporary pain and/or bruising or vascular injury from interventions. Values of the variables were derived from published clinical studies or expert opinion. RESULTS: The model predicted that the likelihood of choosing renal denervation over initiating pharmacotherapy was 17.2% for previously untreated patients, 23.7% for patients with moderate hypertension currently on pharmacotherapy, and 41.8% for patients with drug-resistant hypertension. The dominant variable driving preference in these models was the expected BP reduction. Patient preferences for intervention are greater when drug nonadherence or increased SBP reduction at 3 vs. 1 year are included in the model. Baseline BP, drug side effects, or risks of the procedure had little influence on decisions. CONCLUSION: Modeling using patient preference weights predicts that a substantial minority of patients favor an interventional treatment such as renal denervation over initiation or escalation of medications. Awareness of a patient's interest in device-based versus pharmaceutical strategies should inform the shared decision-making process for hypertension treatment.

Patient Preferences for Pharmaceutical and Device-Based Treatments for Uncontrolled Hypertension: Discrete Choice Experiment.

BACKGROUND: Discrete choice experiment is a survey method used to understand how individuals make decisions and to quantify the relative importance of features. Using discrete choice experiment methods, we quantified patient benefit-risk preferences for hypertension treatments, including pharmaceutical and interventional treatments, like renal denervation. METHODS: Respondents from the United States with physician-confirmed uncontrolled hypertension selected between treatments involving a procedure or pills, using a structured survey. Treatment features included interventional, noninterventional, or no hypertension treatment; number of daily blood pressure (BP) pills; expected reduction in office systolic BP; duration of effect; and risks of drug side effects, access site pain, or vascular injury. The results of a random-parameters logit model were used to estimate the importance of each treatment attribute. RESULTS: Among 400 patients completing the survey between 2020 and 2021, demographics included: 52% women, mean age 59.2±13.0 years, systolic BP 155.1±12.3 mm Hg, and 1.8±0.9 prescribed antihypertensive medications. Reduction in office systolic BP was the most important treatment attribute. The remaining attributes, in decreasing order, were duration of effect, whether treatment was interventional, number of daily pills, risk of vascular injury, and risk of drug side effects. Risk of access site pain did not influence choice. In general, respondents preferred noninterventional over interventional treatments, yet only a 2.3 mm Hg reduction in office systolic BP was required to offset this preference. Small reductions in office systolic BP would offset risks of vascular injury or drug side effects. At least a 20% risk of vascular injury or drug side effects would be tolerated in exchange for improved BP. CONCLUSIONS: Reduction in systolic BP was identified as the most important driver of patient treatment preference, while treatment-related risks had less influence. The results indicate that respondents would accept interventional treatments in exchange for modest reductions in systolic BP compared with those observed in renal denervation trials.

Changes in Plasma Renin Activity After Renal Artery Sympathetic Denervation.

BACKGROUND: The renin-angiotensin-aldosterone system plays a key role in blood pressure (BP) regulation and is the target of several antihypertensive medications. Renal denervation (RDN) is thought to interrupt the sympathetic-mediated neurohormonal pathway as part of its mechanism of action to reduce BP. OBJECTIVES: The purpose of this study was to evaluate plasma renin activity (PRA) and aldosterone before and after RDN and to assess whether these baseline neuroendocrine markers predict response to RDN. METHODS: Analyses were conducted in patients with confirmed absence of antihypertensive medication. Aldosterone and PRA levels were compared at baseline and 3 months post-procedure for RDN and sham control groups. Patients in the SPYRAL HTN-OFF MED Pivotal trial were separated into 2 groups, those with baseline PRA ≥0.65 ng/ml/h (n = 110) versus <0.65 ng/ml/h (n = 116). Follow-up treatment differences between RDN and sham control groups were adjusted for baseline values using multivariable linear regression models. RESULTS: Baseline PRA was similar between RDN and control groups (1.0 ± 1.1 ng/ml/h vs. 1.1 ± 1.1 ng/ml/h; p = 0.37). Change in PRA at 3 months from baseline was significantly greater for RDN compared with control subjects (-0.2 ± 1.0 ng/ml/h; p = 0.019 vs. 0.1 ± 0.9 ng/ml/h; p = 0.14), p = 0.001 for RDN versus control subjects, and similar differences were seen for aldosterone: RDN compared with control subjects (-1.2 ± 6.4 ng/dl; p = 0.04 vs. 0.4 ± 5.4 ng/dl; p = 0.40), p = 0.011. Treatment differences at 3 months in 24-h and office systolic blood pressure (SBP) for RDN versus control patients were significantly greater for patients with baseline PRA ≥0.65 ng/ml/h versus <0.65 ng/ml/h, despite similar baseline BP. Differences in office SBP changes according to baseline PRA were also observed earlier at 2 weeks post-RDN. CONCLUSIONS: Plasma renin activity and aldosterone levels for RDN patients were significantly reduced at 3 months when compared with baseline as well as when compared with sham control. Higher baseline PRA levels were associated with a significantly greater reduction in office and 24-h SBP. (SPYRAL PIVOTAL - SPYRAL HTN-OFF MED Study; NCT02439749).

Imaging strategies for safety surveillance after renal artery denervation.

Renal denervation has emerged as a safe and effective therapy to lower blood pressure in hypertensive patients. In addition to the main renal arteries, branch vessels are also denervated in more contemporary studies. Accurate and reliable imaging in renal denervation patients is critical for long-term safety surveillance due to the small risk of renal artery stenosis that may occur after the procedure. This review summarizes three common non-invasive imaging modalities: Doppler ultrasound (DUS), computed tomography angiography (CTA), and magnetic resonance angiography (MRA). DUS is the most widely used owing to cost considerations, ease of use, and the fact that it is less invasive, avoids ionizing radiation exposure, and requires no contrast media use. Renal angiography is used to determine if renal artery stenosis is present when non-invasive imaging suggests renal artery stenosis. We compiled data from prior renal denervation studies as well as the more recent SPYRAL-HTN OFF MED Study and show that DUS demonstrates both high sensitivity and specificity for detecting renal stenosis de novo and in longitudinal assessment of renal artery patency after interventions. In the context of clinical trials DUS has been shown, together with the use of the baseline angiogram, to be effective in identifying stenosis in branch and accessory arteries and merits consideration as the main screening imaging modality to detect clinically significant renal artery stenosis after renal denervation and this is consistent with guidelines from the recent European Consensus Statement on Renal Denervation.

Effect of renal denervation in attenuating the stress of morning surge in blood pressure: post-hoc analysis from the SPYRAL HTN-ON MED trial.

BACKGROUND: Catheter-based renal denervation (RDN) reduces blood pressure (BP) throughout the 24-h period, as reported in several randomized sham-controlled trials. Reduction of BP in the early morning hours is especially important due to increased cardiovascular risks during that time. OBJECTIVE: In this report, we examine the impact of RDN on systolic BP (SBP) and diastolic BP (DBP) during the critical morning surge period in a post-hoc analysis of patients in the SPYRAL HTN-ON MED trial. METHODS AND RESULTS: Ambulatory BP measurements were collected at baseline and 6 months for treatment and control patient groups over 24-h periods. Average morning BP surge is the difference between average morning BP and average nighttime BP, and the morning surge slope reflects the rate of change of BP from nighttime to morning. Mean morning DBP surge slopes were significantly lower for RDN vs. control groups at 6 months (1.1 vs. 3.6 mmHg/h; p = 0.029). In the RDN group, morning DBP surge slopes were significantly lower at 6 months compared to baseline (1.1 vs. 4.1 mmHg/h; p = 0.006). Similar patterns were observed for mean morning SBP surge slope but did not reach statistical significance. CONCLUSIONS: This decrease in the morning DBP surge slope, an index of the sympathetically-mediated morning BP surge, thus indicates a drop in late morning BP relative to early morning/nocturnal BP in the RDN group. Thus, RDN appears effective in attenuating the slope of morning surge in DBP that might indicate possible benefits in a high-risk hypertensive population. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov (NCT02439775), registered May 12, 2015.

Prioritised endpoints for device-based hypertension trials: the win ratio methodology.

AIMS: Multiple endpoints with varying clinical relevance are available to establish the efficacy of device-based treatments. Given the variance among blood pressure measures and medication changes in hypertension trials, we performed a win ratio analysis of outcomes in a sham-controlled, randomised trial of renal denervation (RDN) in patients with uncontrolled hypertension despite commonly prescribed antihypertensive medications. We propose a novel prioritised endpoint framework for determining the treatment benefit of RDN compared with sham control. METHODS AND RESULTS: We analysed the SPYRAL HTN-ON MED pilot study data using a prioritised hierarchical endpoint comprised of 24-hour mean ambulatory systolic blood pressure (SBP), office SBP, and medication burden. A generalised pairwise comparisons methodology (win ratio) was extended to examine this endpoint. Clinically relevant thresholds of 5 and 10 mmHg were used for comparisons of ambulatory and office SBP, respectively, and therefore to define treatment "winners" and "losers". For a total number of 1,596 unmatched pairs, the RDN subject was the winner in 1,050 pairs, the RDN subject was the loser in 378 pairs, and 168 pairs were tied. The win ratio in favour of RDN was 2.78 (95% confidence interval [CI]: 1.58 to 5.48; p<0.001) and corresponding net benefit statistic was 0.42 (95% CI: 0.20 to 0.63). Sensitivity analyses performed with differing blood pressure thresholds and according to drug adherence testing demonstrated consistent results. CONCLUSIONS: The win ratio method addresses prior limitations by enabling inclusion of more patient-oriented results while prioritising those endpoints considered most clinically important. Applying these methods to the SPYRAL HTN-ON MED pilot study (ClinicalTrials.gov Identifier: NCT02439775), RDN was determined to be superior regarding a hierarchical endpoint and a "winner" compared with sham control patients.

Renal Denervation in High-Risk Patients With Hypertension.

BACKGROUND: Renal denervation (RDN) is under investigation for treatment of uncontrolled hypertension and might represent an attractive treatment for patients with high cardiovascular (CV) risk. It is important to determine whether baseline CV risk affects the efficacy of RDN. OBJECTIVES: The purpose of this study was to assess blood pressure (BP) reduction and event rates after RDN in patients with various comorbidities, testing the hypothesis that RDN is effective and durable in these high-risk populations. METHODS: BP reduction and adverse events over 3 years were evaluated for several high-risk subgroups in the GSR (Global proSpective registrY for syMPathetic renaL denervatIon in seleCted IndicatIons Through 3 Years Registry), an international registry of RDN in patients with uncontrolled hypertension (n = 2,652). Comparisons were made for patients age ≥65 years versus age <65 years, with versus without isolated systolic hypertension, with versus without atrial fibrillation, and with versus without diabetes mellitus. Baseline cardiovascular risk was estimated using the American Heart Association (AHA)/American College of Cardiology (ACC) atherosclerosis cardiovascular disease (ASCVD) risk score. RESULTS: Reduction in 24-h systolic BP at 3 years was -8.9 ± 20.1 mm Hg for the overall cohort, and for high-risk subgroups, BP reduction was -10.4 ± 21.0 mm Hg for resistant hypertension, -8.7 ± 17.4 mm Hg in patients age ≥65 years, -10.2 ± 17.9 mm Hg in patients with diabetes, -8.6 ± 18.7 mm Hg in isolated systolic hypertension, -10.1 ± 20.3 mm Hg in chronic kidney disease, and -10.0 ± 19.1 mm Hg in atrial fibrillation (p < 0.0001 compared with baseline for all). BP reduction in patients with measurements at 6, 12, 24, and 36 months showed similar reductions in office and 24-h BP for patients with varying baseline ASCVD risk scores, which was sustained to 3 years. Adverse event rates at 3 years were higher for patients with higher baseline CV risk. CONCLUSIONS: BP reduction after RDN was similar for patients with varying high-risk comorbidities and across the range of ASCVD risk scores. The impact of baseline risk on clinical event reduction by RDN-induced BP changes could be evaluated in further studies. (Global proSpective registrY for syMPathetic renaL denervatIon in seleCted IndicatIons Through 3 Years Registry; NCT01534299).

Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.

BACKGROUND: Catheter-based renal denervation has significantly reduced blood pressure in previous studies. Following a positive pilot trial, the SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medications. METHODS: In this international, prospective, single-blinded, sham-controlled trial, done at 44 study sites in Australia, Austria, Canada, Germany, Greece, Ireland, Japan, the UK, and the USA, hypertensive patients with office systolic blood pressure of 150 mm Hg to less than 180 mm Hg were randomly assigned 1:1 to either a renal denervation or sham procedure. The primary efficacy endpoint was baseline-adjusted change in 24-h systolic blood pressure and the secondary efficacy endpoint was baseline-adjusted change in office systolic blood pressure from baseline to 3 months after the procedure. We used a Bayesian design with an informative prior, so the primary analysis combines evidence from the pilot and Pivotal trials. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02439749. FINDINGS: From June 25, 2015, to Oct 15, 2019, 331 patients were randomly assigned to either renal denervation (n=166) or a sham procedure (n=165). The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0·999 for both. The treatment difference between the two groups for 24-h systolic blood pressure was -3·9 mm Hg (Bayesian 95% credible interval -6·2 to -1·6) and for office systolic blood pressure the difference was -6·5 mm Hg (-9·6 to -3·5). No major device-related or procedural-related safety events occurred up to 3 months. INTERPRETATION: SPYRAL Pivotal showed the superiority of catheter-based renal denervation compared with a sham procedure to safely lower blood pressure in the absence of antihypertensive medications. FUNDING: Medtronic.

Impact of Stroke Volume Index and Left Ventricular Ejection Fraction on Mortality After Aortic Valve Replacement.

OBJECTIVE: To assess the impact of stroke volume index (SVI) and left ventricular ejection fraction (LVEF) on prognosis in patients with severe aortic stenosis, comparing those undergoing transcatheter aortic valve replacement (TAVR) and those with surgical AVR (SAVR). PATIENTS AND METHODS: A total of 742 patients from the CoreValve US Pivotal High-Risk Trial randomized to TAVR (n=389) or SAVR (n=353) from February 2011 to September 2012 were stratified by an SVI of 35 mL/m2 and LVEF of 50% for comparing all-cause mortality at 1 year. RESULTS: The prevalence of an SVI of less than 35 mL/m2 in patients who underwent TAVR and SAVR was 35.8% (125 of 349) and 31.3% (96 of 307), respectively; LVEF of less than 50% was present in 18.1% (63 of 348) and 19.6% (60 of 306), respectively. Among patients with an SVI of less than 35 mL/m2, 1-year mortality was similar between patients with TAVR and SAVR (16.3% vs 22.2%; P=.25). However, in those with an SVI of 35 mL/m2 or greater, 1-year mortality was lower in those with TAVR than SAVR (10.3% vs 17.3%; P=.03). In patients with an LVEF of less than 50%, mortality was not affected by AVR approach (P>.05). In patients with an LVEF of 50% or higher, TAVR was associated with lower mortality than SAVR when SVI was preserved (9.8% vs 18.6%; P=.01). Mortality was not affected by SVI within the same AVR approach when LVEF was 50% or higher. CONCLUSION: In patients with severe aortic stenosis at high risk, there is a significant interaction between AVR approach and the status of SVI and LVEF. When LVEF or SVI was reduced, prognosis was similar regardless of AVR approach. In those with preserved LVEF or SVI, TAVR was associated with a better prognosis than SAVR. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01240902.

Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial.

BACKGROUND: Previous catheter-based renal denervation studies have reported variable efficacy results. We aimed to evaluate safety and blood pressure response after renal denervation or sham control in patients with uncontrolled hypertension on antihypertensive medications with drug adherence testing. METHODS: In this international, randomised, single-blind, sham-control, proof-of-concept trial, patients with uncontrolled hypertension (aged 20-80 years) were enrolled at 25 centres in the USA, Germany, Japan, UK, Australia, Austria, and Greece. Eligible patients had an office systolic blood pressure of between 150 mm Hg and 180 mm Hg and a diastolic blood pressure of 90 mm Hg or higher; a 24 h ambulatory systolic blood pressure of between 140 mm Hg and 170 mm Hg at second screening; and were on one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned to undergo renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were masked to randomisation assignments. The primary efficacy endpoint was blood pressure change from baseline (measured at screening visit two), based on ambulatory blood pressure measurements assessed at 6 months, as compared between treatment groups. Drug surveillance was used to assess medication adherence. The primary analysis was done in the intention-to-treat population. Safety events were assessed through 6 months as per major adverse events. This trial is registered with ClinicalTrials.gov, number NCT02439775, and follow-up is ongoing. FINDINGS: Between July 22, 2015, and June 14, 2017, 467 patients were screened and enrolled. This analysis presents results for the first 80 patients randomly assigned to renal denervation (n=38) and sham control (n=42). Office and 24 h ambulatory blood pressure decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24 h systolic blood pressure -7·0 mm Hg, 95% CI -12·0 to -2·1; p=0·0059, 24 h diastolic blood pressure -4·3 mm Hg, -7·8 to -0·8; p=0.0174, office systolic blood pressure -6·6 mm Hg, -12·4 to -0·9; p=0·0250, and office diastolic blood pressure -4·2 mm Hg, -7·7 to -0·7; p=0·0190). The change in blood pressure was significantly greater at 6 months in the renal denervation group than the sham-control group for office systolic blood pressure (difference -6·8 mm Hg, 95% CI -12·5 to -1·1; p=0·0205), 24 h systolic blood pressure (difference -7·4 mm Hg, -12·5 to -2·3; p=0·0051), office diastolic blood pressure (difference -3·5 mm Hg, -7·0 to -0·0; p=0·0478), and 24 h diastolic blood pressure (difference -4·1 mm Hg, -7·8 to -0·4; p=0·0292). Evaluation of hourly changes in 24 h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24 h for the renal denervation group. 3 month blood pressure reductions were not significantly different between groups. Medication adherence was about 60% and varied for individual patients throughout the study. No major adverse events were recorded in either group. INTERPRETATION: Renal denervation in the main renal arteries and branches significantly reduced blood pressure compared with sham control with no major safety events. Incomplete medication adherence was common. FUNDING: Medtronic.

Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial.

BACKGROUND: Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications. METHODS: SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749. FINDINGS: Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP -5·5 mm Hg (95% CI -9·1 to -2·0; p=0·0031), 24-h DBP -4·8 mm Hg (-7·0 to -2·6; p<0·0001), office SBP -10·0 mm Hg (-15·1 to -4·9; p=0·0004), and office DBP -5·3 mm Hg (-7·8 to -2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP -0·5 mm Hg (95% CI -3·9 to 2·9; p=0·7644), 24-h DBP -0·4 mm Hg (-2·2 to 1·4; p=0·6448), office SBP -2·3 mm Hg (-6·1 to 1·6; p=0·2381), and office DBP -0·3 mm Hg (-2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP -5·0 mm Hg (95% CI -9·9 to -0·2; p=0·0414), 24-h DBP -4·4 mm Hg (-7·2 to -1·6; p=0·0024), office SBP -7·7 mm Hg (-14·0 to -1·5; p=0·0155), and office DBP -4·9 mm Hg (-8·5 to -1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group. INTERPRETATION: Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation. FUNDING: Medtronic.

Sympathetic Response and Outcomes Following Renal Denervation in Patients With Chronic Heart Failure: 12-Month Outcomes From the Symplicity HF Feasibility Study.

BACKGROUND: Heart failure (HF) is associated with chronic sympathetic activation. Renal denervation (RDN) aims to reduce sympathetic activity by ablating the renal sympathetic nerves. We investigated the effect of RDN in patients with chronic HF and concurrent renal dysfunction in a prospective, multicenter, single-arm feasibility study. METHODS AND RESULTS: Thirty-nine patients with chronic systolic HF (left ventricular ejection fraction [LVEF] <40%, New York Heart Association class II-III,) and renal impairment (estimated glomerular filtration rate [eGFR; assessed with the use of the Modification of Diet in Renal Disease equation] < 75 mL • min-1 • 1.73 m-2) on stable medical therapy were enrolled. Mean age was 65 ± 11 years; 62% had ischemic HF. The average number of ablations per patient was 13 ± 3. No protocol-defined safety events were associated with the procedure. One subject experienced a renal artery occlusion that was possibly related to the denervation procedure. Statistically significant reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP; 1530 ± 1228 vs 1428 ± 1844 ng/mL; P = .006) and 120-minute glucose tolerance test (11.2 ± 5.1 vs 9.9 ± 3.6; P = .026) were seen at 12 months, but there was no significant change in LVEF (28 ± 9% vs 29 ± 11%; P= .536), 6-minute walk test (384 ± 96 vs 391 ± 97 m; P= .584), or eGFR (52.6 ± 15.3 vs 52.3 ± 18.5 mL • min-1 • 1.73 m-2; P= .700). CONCLUSIONS: RDN was associated with reductions in NT-proBNP and 120-minute glucose tolerance test in HF patients 12 months after RDN treatment. There was no deterioration in other indices of cardiac and renal function in this small feasibility study.

The SPYRAL HTN Global Clinical Trial Program: Rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications.

Renal sympathetic activation plays a key role in the pathogenesis of hypertension, as demonstrated by high renal norepinephrine spillover into plasma of patients with essential hypertension. Renal denervation has demonstrated a significant reduction in blood pressure in unblinded studies of hypertensive patients. The SYMPLICITY HTN-3 trial, the first prospective, masked, randomized study of renal denervation versus sham control, failed its primary efficacy end point and raised important questions around potentially confounding factors, such as drug changes and adherence, study population, and procedural methods. The SPYRAL HTN Global Clinical Trial Program is designed to address limitations associated with predicate studies and provide insight into the impact of pharmacotherapy on renal denervation efficacy. The 2 initial trials of the program focus on the effect of renal denervation using the Symplicity Spyral multielectrode renal denervation catheter in hypertensive patients in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. The SPYRAL HTN ON-MED study requires patients to be treated with a consistent triple therapy antihypertensive regimen, whereas the SPYRAL HTN OFF-MED study includes a 3- to 4-week drug washout period followed by a 3-month efficacy and safety end point in the absence of antihypertensive medications. The studies will randomize patients with combined systolic-diastolic hypertension to renal denervation or sham procedure. Both studies allow renal denervation treatments in renal artery branches and accessories. These studies will inform the design of the second pivotal phase of the program, which will more definitively analyze the antihypertensive effect of renal denervation.

Effect of Catheter-Based Renal Denervation on Morning and Nocturnal Blood Pressure: Insights From SYMPLICITY HTN-3 and SYMPLICITY HTN-Japan.

UNLABELLED: High nighttime and early morning blood pressure (BP) have been associated with greater risk for cardiovascular events than high clinic or daytime BP. BP is typically highest in the rising hours, when morning activities typically begin. We examined the effect of renal denervation on morning (6:00-8:59 AM), daytime (9:00 AM-8:59 PM), and nighttime (1:00-5:59 AM) ambulatory BP. Patient data from 2 prospective, randomized controlled trials of patients with treatment-resistant, uncontrolled hypertension, one conducted in a US population (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-3]) and the other in a Japanese population (SYMPLICITY HTN-Japan [HTN-Japan]), were analyzed. Patients in SYMPLICITY HTN-3 and HTN-Japan were prescribed a similar number of baseline antihypertensive medications (5.2±1.4 versus 4.9±1.6, P=0.28), but the classes prescribed and changes in prescription varied by study. Among patients treated with renal denervation, although the number of ablation treatments were similar in both studies (11.2±2.8 versus 11.5±1.9, P=0.55), patients in SYMPLICITY HTN-3 were less likely to receive at least 1 four-quadrant ablation treatment (25% versus 82%, P<0.001). In SYMPLICITY HTN-3, compared with controls (n=159), patients treated with renal denervation (n=325) experienced a significantly greater change in morning (-7.3±19.8 mm Hg, P<0.001) and nighttime (-6.1±18.2 versus -1.6±19.7 mm Hg, P=0.02) but not daytime systolic BP (-7.2±16.2 versus -6.4±18.6 mm Hg, P=0.67). This same trend was observed in the pooled analysis with HTN-Japan. Reduction of BP during these high-risk periods might provide cardiovascular protection in drug-resistant hypertensive patients, although this will need to be proved in future randomized trials. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov; Unique identifiers: NCT01418261 (SYMPLICITY HTN-3) and NCT01644604 (HTN-Japan).

12-month blood pressure results of catheter-based renal artery denervation for resistant hypertension: the SYMPLICITY HTN-3 trial.

BACKGROUND: Results of the SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial confirmed the safety but not the efficacy of renal denervation for treatment-resistant hypertension at 6 months post procedure. OBJECTIVES: This study sought to analyze the 12-month SYMPLICITY HTN-3 results for the original denervation group, the sham subjects who underwent denervation after the 6-month endpoint (crossover group), and the sham subjects who did not undergo denervation after 6 months (non-crossover group). METHODS: Eligible subjects were randomized 2:1 to denervation or sham procedure. Subjects were unblinded to their treatment group after the 6-month primary endpoint was ascertained; subjects in the sham group meeting eligibility requirements could undergo denervation. Change in blood pressure (BP) at 12 months post randomization (6 months for crossover subjects) was analyzed. RESULTS: The 12-month follow-up was available for 319 of 361 denervation subjects and 48 of 101 non-crossover subjects; 6-month denervation follow-up was available for 93 of 101 crossover subjects. In denervation subjects, the 12-month office systolic BP (SBP) change was greater than that observed at 6 months (-15.5 ± 24.1 mm Hg vs. -18.9 ± 25.4 mm Hg, respectively; p = 0.025), but the 24-h SBP change was not significantly different at 12 months (p = 0.229). The non-crossover group office SBP decreased by -32.9 ± 28.1 mm Hg at 6 months, but this response regressed to -21.4 ± 19.9 mm Hg (p = 0.01) at 12 months, increasing to 11.5 ± 29.8 mm Hg. CONCLUSIONS: These data support no further reduction in office or ambulatory BP after 1-year follow-up. Loss of BP reduction in the non-crossover group may reflect decreased medication adherence or other related factors. (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-3]; NCT01418261).

Impact of renal denervation on 24-hour ambulatory blood pressure: results from SYMPLICITY HTN-3.

BACKGROUND: Prior studies of catheter-based renal artery denervation have not systematically performed ambulatory blood pressure monitoring (ABPM) to assess the efficacy of the procedure. OBJECTIVES: SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) was a prospective, blinded, randomized, sham-controlled trial. The current analysis details the effect of renal denervation or a sham procedure on ABPM measurements 6 months post-randomization. METHODS: Patients with resistant hypertension were randomized 2:1 to renal denervation or sham control. Patients were on a stable antihypertensive regimen including maximally tolerated doses of at least 3 drugs including a diuretic before randomization. The powered secondary efficacy endpoint was a change in mean 24-h ambulatory systolic blood pressure (SBP). Nondipper to dipper (nighttime blood pressure [BP] 10% to 20% lower than daytime BP) conversion was calculated at 6 months. RESULTS: The 24-h ambulatory SBP changed -6.8 ± 15.1 mm Hg in the denervation group and -4.8 ± 17.3 mm Hg in the sham group: difference of -2.0 mm Hg (95% confidence interval [CI]: -5.0 to 1.1; p = 0.98 with a 2 mm Hg superiority margin). The daytime ambulatory SBP change difference between groups was -1.1 (95% CI: -4.3 to 2.2; p = 0.52). The nocturnal ambulatory SBP change difference between groups was -3.3 (95 CI: -6.7 to 0.1; p = 0.06). The percent of nondippers converted to dippers was 21.2% in the denervation group and 15.0% in the sham group (95% CI: -3.8% to 16.2%; p = 0.30). Change in 24-h heart rate was -1.4 ± 7.4 in the denervation group and -1.3 ± 7.3 in the sham group; (95% CI: -1.5 to 1.4; p = 0.94). CONCLUSIONS: This trial did not demonstrate a benefit of renal artery denervation on reduction in ambulatory BP in either the 24-h or day and night periods compared with sham (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-3]; NCT01418261).

A controlled trial of renal denervation for resistant hypertension.

BACKGROUND: Prior unblinded studies have suggested that catheter-based renal-artery denervation reduces blood pressure in patients with resistant hypertension. METHODS: We designed a prospective, single-blind, randomized, sham-controlled trial. Patients with severe resistant hypertension were randomly assigned in a 2:1 ratio to undergo renal denervation or a sham procedure. Before randomization, patients were receiving a stable antihypertensive regimen involving maximally tolerated doses of at least three drugs, including a diuretic. The primary efficacy end point was the change in office systolic blood pressure at 6 months; a secondary efficacy end point was the change in mean 24-hour ambulatory systolic blood pressure. The primary safety end point was a composite of death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis of more than 70% at 6 months. RESULTS: A total of 535 patients underwent randomization. The mean (±SD) change in systolic blood pressure at 6 months was -14.13±23.93 mm Hg in the denervation group as compared with -11.74±25.94 mm Hg in the sham-procedure group (P<0.001 for both comparisons of the change from baseline), for a difference of -2.39 mm Hg (95% confidence interval [CI], -6.89 to 2.12; P=0.26 for superiority with a margin of 5 mm Hg). The change in 24-hour ambulatory systolic blood pressure was -6.75±15.11 mm Hg in the denervation group and -4.79±17.25 mm Hg in the sham-procedure group, for a difference of -1.96 mm Hg (95% CI, -4.97 to 1.06; P=0.98 for superiority with a margin of 2 mm Hg). There were no significant differences in safety between the two groups. CONCLUSIONS: This blinded trial did not show a significant reduction of systolic blood pressure in patients with resistant hypertension 6 months after renal-artery denervation as compared with a sham control. (Funded by Medtronic; SYMPLICITY HTN-3 ClinicalTrials.gov number, NCT01418261.).

Five-year follow-up of the Sirolimus-Eluting Stents vs Vascular Brachytherapy for Bare Metal In-Stent Restenosis (SISR) trial.

OBJECTIVES: The aim of this study was to evaluate the 5-year clinical safety and efficacy outcomes of patients treated for in-stent restenosis of bare-metal stents (BMSs). BACKGROUND: The SISR trial is a prospective, randomized trial that compared the safety and efficacy of sirolimus-eluting stent (SES) vs vascular brachytherapy (VBT) for the treatment of BMS in-stent restenosis. METHODS: A total of 384 patients with BMS in-stent restenosis were randomized to treatment with SES (n = 259) or VBT (n = 125) and were followed for 5 years. RESULTS: At 5 years, the rates of target lesion revascularization (TLR) had narrowed and were nonsignificant between the SES and VBT groups, with TLR rates of 24.7% and 31.2% (95% CI -16.3% to 2.8%, P = .179) respectively. Target vessel failure was 33.6% vs 36.8% (95% CI -13.5% to 6.7% P = .568) for SES compared with VBT. The rate of major adverse cardiac event at 5 years was 34.0% vs 36.8% (95% CI -13.1% to7.1%, P = .648) for the SES compared with VBT. There were no differences between SES and VBT in terms of survival free from TLR (72.9% vs 66.4%, log-rank P = .08) or from target vessel failure (64.4% vs 61.3%, log-rank P = .349). There were no significant differences in the rates of definite/probable stent thrombosis (5.9% vs 2.5%, 95% CI -7.9% to 1.3%, P = .182) between the 2 groups. CONCLUSIONS: At a 5-year follow-up, no differences in safety or efficacy outcomes were observed for treatment of BMS restenosis with SES vs VBT. There were no significant differences in survival free from TLR, target vessel revascularization, or major adverse cardiac events between the 2 groups at 5 years. Sirolimus-eluting stent is a viable treatment option compared with VBT for BMS restenosis.

Frequency and impact of bleeding in elective coronary stent clinical trials--utility of three commonly used definitions.

BACKGROUND: Bleeding events are common after percutaneous coronary intervention (PCI) and have been shown to increase mortality in studies of acute coronary syndrome (ACS) and anti-thrombotic therapy. Despite this evidence, bleeding has not been included as a traditional major endpoint in clinical trials of low-risk populations enrolled in PCI clinical trials. Thus, the impact of specific bleeding definitions has not been evaluated fully among these patients. METHODS AND RESULTS: Using patient-level pooled data from sirolimus and zotarolimus drug-eluting stent clinical trials, we identified bleeding events using three common definitions of bleeding, ACUITY, TIMI, and GUSTO, and assessed the impact on mortality and MI at 12 months after PCI. The GUSTO, ACUITY, and TIMI classifications identified bleeding rates of 2.3%, 1.9%, and 2.1%, respectively. The GUSTO criteria classified all 118 suspected bleeding events. There were 22 (18.6%) and 8 (6.8%) suspected bleeding events that did not meet ACUITY and TIMI criteria, respectively. The combined endpoint of all-cause death or myocardial infarction (MI) at 12 months was significantly higher for patients with a bleeding event compared with those who did not bleed [hazard ratio 1.95 (95% CI 1.06-3.60)]. CONCLUSION: There is a substantial variability in the utility and inclusiveness of three widely used bleeding definitions in identifying clinically significant bleeding events in clinical trials of low risk patients undergoing PCI with DES. Patients with bleeding after elective PCI have an increased one-year risk of death or MI compared to those patients who do not bleed.