Blood pressure lowering with alcohol-mediated renal denervation using the Peregrine infusion Catheter is independent of injection site location

Objectives The current analysis utilized core laboratory angiographic data from a prospective, single-arm, open-label, multi-center feasibility study to ascertain whether the location of alcohol infusion within main renal arteries during renal denervation (RDN) had an impact on the BP-lowering effect at 6 months. Background The influence of the location of alcohol infusion during RDN, within the main renal artery (proximal, middle, or distal), on the magnitude of the blood pressure (BP) lowering is unstudied. Methods The Peregrine Catheter was used to perform alcohol-mediated RDN with an infusion of 0.6 mL of alcohol per artery as the neurolytic agent in 90 main arteries and four accessory arteries of 45 patients with hypertension. Results No relationship between the site of alcohol infusion and change from baseline in both office systolic and 24-hour systolic ambulatory BP (ABP) at 6 months was observed. When analyzed at the artery level, the least squares (LS) mean changes ± SEM from baseline to 6 months post-procedure in 24-hour systolic ABP when analyzed by renal arterial location were −11.9 ± 2.4 mmHg (distal), −10 ± 1.6 mmHg (middle), and −10.6 ± 1.3 mmHg (proximal) (all p < 0.0001 for change from baseline within groups). The results were similar for office systolic BP. There was no difference between treated locations (proximal is reference). Conclusion In this post-hoc analysis, the location of alcohol infusion within the main renal artery using the Peregrine system, with alcohol as the neurolytic agent for chemical RDN, did not affect the magnitude of BP changes at 6 months

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: 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)

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 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)

Comprehensive Meta-Analysis of Safety and Efficacy of Bivalirudin Versus Heparin With or Without Routine Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndrome

AbstractObjectivesThe aim of this meta-analysis was to compare the 30-day safety and efficacy of bivalirudin with those of heparin with or without routine administration of a glycoprotein IIb/IIIa inhibitor (GPI) in patients with acute coronary syndrome (ACS).BackgroundBivalirudin has been a mainstay of anticoagulation in patients with ACS compared with heparin. The extent to which trial results have been affected by the coadministration of heparin with a GPI, however, remains unclear.MethodsA total of 13 randomized, controlled trials involving 24,605 patients were included.ResultsThere was no significant difference in 30-day mortality or myocardial infarction rate with bivalirudin compared with heparin with or without routine GPI administration. A reduction of 30-day major bleeding was observed with bivalirudin compared with heparin that was significant when GPI was routinely administered (odds ratio [OR]: 0.52, 95% confidence interval [CI]: 0.45 to 0.60), p < 0.001) but not with provisionally administered GPI (OR: 0.66, 95% CI: 0.33 to 1.32; p = 0.24). The occurrence of stent thrombosis (ST) at 30 days was significantly increased with bivalirudin compared with heparin plus routinely administered GPI (OR: 1.67, 95% CI: 1.13 to 2.45, p = 0.02), but not compared with heparin plus provisionally administered GPI (OR: 2.08, 95% CI: 0.35 to 12.32, p = 0.42). The rate of acute ST (≤24 h), however, was almost 4.5-fold higher with bivalirudin compared with heparin with or without GPI, whereas the rate of subacute ST (24 h to 30 days) did not differ significantly.ConclusionsOverall, bivalirudin in ACS patients is associated with a significant reduction of major bleeding compared with heparin plus routinely administered GPI, but with a marked increase in ST rates compared with heparin with or without GPI

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: 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)

A re-examination of the SPYRAL HTN-OFF MED Pivotal trial with respect to the underlying model assumptions

Background: The SPYRAL HTN-OFF MED Pivotal trial demonstrated that RDN was efficacious compared to a sham control. The underlying model was an extension of the analysis of covariance (ANCOVA) model, adjusted for baseline blood pressure (BP), and allowed borrowing of information from the previously reported feasibility study using a novel Bayesian method. Fundamental to the estimation of a treatment effect for efficacy are a multitude of statistical modelling assumptions, including the role of outliers, linearity of the association between baseline BP and outcome, and parallelism of the treatment effect difference over the baseline BP range. In this report, we examine the validity of these assumptions to verify the robustness of the treatment effect measured. Methods: We examined the requisite modelling assumptions of the ANCOVA model fitted to the SPYRAL HTN-OFF MED Pivotal trial using Bayesian methods. To address outliers, we fit a robust regression model (with heavy tailed errors) to the data with diffuse weakly informative prior distributions on the parameters. To address linearity, we replaced the linear baseline term by a natural spline term with 4 degrees of freedom. To address parallelism, we refit the ANCOVA model with an interaction term for treatment arm and baseline BP. Results: ANCOVA models were fitted to the trial data (pooled across the feasibility and pivotal cohorts) using Bayesian methodology with diffuse (non-informative) prior distributions. The modelling assumptions inherent to the ANCOVA models were shown to be broadly satisfied. A robust ANCOVA model yielded a posterior treatment effect of -4.1 mmHg (95% credible interval: -6.3 to -1.9) indicating the influence of outlier values was small. There was moderate evidence of an interaction term effect between baseline BP and treatment, but no evidence of gross violation of linearity in baseline BP. Conclusion: The posterior treatment effect estimate is shown to be robust to underlying model assumptions, thus further supporting the evidence of RDN to be an efficacious treatment for resistant hypertension

Use of the Limited Antegrade Subintimal Tracking Technique in Chronic Total Occlusion Percutaneous Coronary Intervention

BACKGROUND There are limited data on the limited antegrade subintimal tracking (LAST) technique for chronic total occlusion (CTO) percutaneous coronary intervention (PCI).OBJECTIVES The aim of this study was to analyze the frequency of use and outcomes of the LAST technique for CTO PCI.METHODS We analyzed 2,177 CTO PCIs performed using antegrade dissection and re-entry (ADR) in the PROGRESS-CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention) registry between 2012 and January 2022 at 39 centers. ADR was attempted in 1,465 cases (67.3%).RESULTS Among antegrade re-entry cases, LAST was used in 163 (11.1%) (primary LAST in 127 [8.7%] and secondary LAST [LAST after other ADR approaches failed] in 36 [2.5%]), the Stingray system (Boston Scientific) in 980 (66.9%), subintimal tracking and re-entry in 387 (26.4%), and contrast-guided subintimal tracking and re-entry in 29 (2.0%). The mean patient age was 65.2 similar to 10 years, and 85.8% were men. There was no significant difference in technical (71.8% vs 77.8%; P 1/4 0.080) and procedural (69.9% vs 75.3%; P 1/4 0.127) success and major cardiac adverse events (1.84% vs 3.53%; P 1/4 0.254) between LAST and non-LAST cases. However, on multivariable analysis, the use of LAST was associated with lower procedural success (OR: 0.61; 95% CI: 0.41-0.91). Primary LAST was associated with higher technical (76.4% vs 55.6%; P 1/4 0.014) and procedural (75.6% vs 50.0%; P 1/4 0.003) success and similar major adverse cardiac event (1.57% vs 2.78%; P 1/4 0.636) rates compared with secondary LAST.CONCLUSIONS LAST was used in 11.1% of antegrade re-entry CTO PCI cases and was associated with lower procedural success on multivariable analysis, suggesting a limited role of LAST in contemporary CTO PCI. (J Am Coll Cardiol Intv 2022;15:2284-2293) (c) 2022 by the American College of Cardiology Foundation

Cardiac mortality in patients randomised to elective coronary revascularisation plus medical therapy or medical therapy alone: A systematic review and meta-analysis

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/)Aims:The value of elective coronary revascularisation plus medical therapy over medical therapy alone in managing stable patients with coronary artery disease is debated. We reviewed all trials comparing the two strategies in this population. Methods and results:From inception through November 2020, Medline, Embase, Google Scholar and other databases were searched for randomised trials comparing revascularisation to medical therapy alone in clinically stable coronary artery disease patients. Treatment effects were measured by rate ratios (RR) with 95% confidence intervals using random-effects models. Cardiac mortality was the prespecified primary endpoint. Spontaneous myocardial infarction (MI) and its association with cardiac mortality were secondary endpoints. Further endpoints included all-cause mortality, any MI and stroke. Longest follow-up data were abstracted. The study is registered with PROSPERO (CRD42021225598). Twenty-five trials involving 19,806 patients (10,023 randomised to revascularisation plus medical therapy and 9,783 to medical therapy alone) were included. Compared to medical therapy alone, revascularisation was associated with a lower risk of cardiac death (RR 0.79 [0.67-0.93], p<0.01) and spontaneous MI (RR 0.74 [0.64-0.86], p<0.01). By meta-regression, the cardiac death risk reduction after revascularisation, compared to medical therapy alone, was linearly associated with follow-up duration (RR per 4-year follow-up: 0.81 [0.69-0.96], p=0.008) and spontaneous MI absolute difference (p=0.01). Trial sequential and sensitivity analyses confirmed the reliability of the cardiac mortality findings. All cause mortality (0.94 [0.87-1.01], p=0.11), any MI (p=0.14) and stroke risk (p=0.30) did not differ significantly between strategies. Conclusion:In stable coronary artery disease patients, randomisation to elective coronary revascularisation plus medical therapy led to reduced cardiac mortality compared to medical management alone. The cardiac survival benefit after revascularisation improved with longer follow-uptimes and was associated with fewer spontaneous MIs.Peer reviewedFinal Published versio