Background:Patient-reported outcomes (PROs) are increasingly used as endpoints in clinical trials. However, the magnitude of observed changes in control arms attributable to placebo effects, as compared with other benefits of trial participation, has not been described.This study seeks to estimate the magnitude of the placebo effect by calculating changes in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) scores, which quantify the impact of heart failure on patients' symptoms, function, and quality of life, after participants were unblinded to treatment. Methods:REDUCE LAP-HF II randomized participants to atrial shunt or sham procedure, with unblinding after 2 years. The KCCQ was collected at baseline, 2, and 3 years after randomization. KCCQ-OS change from baseline to 2 years (placebo effect plus other benefits from trial participation) and the change from 2 to 3 years (placebo effect loss after unblinding) were calculated in sham-treated patients using mean±SD, as were changes from 2 to 3 years in shunt-treated patients (placebo effect benefit). Results:The analytic cohort included 421 participants (median age 72 years, 65.6% female). Among sham-treated participants (N=182), the mean±SD KCCQ-OS 2-year improvement from baseline was +9.3±22.4 points, with a decrement after unblinding of -1.7±18.2 points from 2 to 3 years. Among shunt-treated patients (N=239), mean±SD KCCQ-OS 2-year improvement was +12.7±22.8 points, with an improvement after unblinding of +1.9±18.2 points. In a hypothetical unblinded trial where placebo effect benefit would be expected in the active intervention arm, and none in the untreated arm, the combined effects would be 3.6 points. Conclusions:In a sham-controlled device trial that collected PRO data during blinded allocation to treatment or sham and after unblinding, the estimated mean placebo effect benefit and loss on the KCCQ-OS were small (≤2 points). Finding a modest placebo effect on PROs may increase confidence in their use as clinical trial outcomes.

BACKGROUND:Drug-eluting stents (DESs) are recommended treatment for coronary in-stent restenosis (ISR) but are not used in >20% of cases. OBJECTIVES:The aim of the SELUTION4ISR (SELUTION SLR 014 In-stent Restenosis) trial was to assess the safety and effectiveness of a novel sirolimus drug-eluting balloon (DEB). METHODS:After successful lesion predilation, patients with ISR were randomly assigned to the SELUTION Sustained Limus Release (MedAlliance) DEB or a control strategy of usual care, including any approved DES or balloon angioplasty (BA) on the basis of operator selection prerandomization. Randomization to selected BA control treatment was limited to 20% of patients. The primary outcome was target lesion failure (TLF) (cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization) assessed at 1 year in the per protocol group (all treated eligible patients with complete primary endpoint follow-up). Noninferiority was established if the upper limit of the 2-sided 95% credible interval was smaller than 10%. A sequential secondary hypothesis test was performed comparing DEB with DES in patients with single-layer ISR. RESULTS:From July 2020 to July 2024, 418 patients were randomly assigned to the DEB group (n = 210) or the control group (n = 208), with 390 patients per protocol (DEB, 197; control, 193 [154 DES; 39 BA]). TLF occurred in 32 (16.2%) of 197 patients in the DEB group and in 28 (14.5%) of 193 patients in the control group (difference: 1.7%; 95% credible interval: -5.5% to 8.9%; posterior probability of noninferiority: 98.80%). In the secondary hypothesis test, TLF occurred in 22 (14.2%) of 155 patients in the DEB group and in 9 (6.5%) of 138 patients in the DES control group (difference: 7.7%; 95% credible interval: 0.6%-14.6%, posterior probability for noninferiority: 76.07%). TLF according to operator selected control was higher for DEB compared with DES (15.3% vs 7.1%; difference: 8.1%; 95% credible interval: 1.4%-15.0%) and lower for DEB compared with BA (23.6% vs 43.6%; difference: 23.7%; 95% credible interval: -41.4% to -1.5%; Pforinteraction = 0.0026). CONCLUSIONS:The sirolimus DEB was noninferior to a usual care control strategy including 80% repeat DES but not noninferior to DES for single-layer ISR for TLF at 12 months. There was significant interaction on the basis of operator selection of DES vs BA. (SELUTION SLR 014 In-stent Restenosis [SELUTION4ISR]; NCT04280029).

BACKGROUND:Pathophysiologic features associated with increased risk in heart failure with preserved ejection fraction (HFpEF) may reflect distinct phenotypes or disease stages related to heart failure (HF) duration. OBJECTIVES:This study aims to determine how duration of HF diagnosis influences cardiac structure and function, hemodynamics, risk for worsening HF, and treatment response. METHODS:Baseline cardiac structure and function, hemodynamics, and outcomes following randomization were evaluated among individuals participating in the REDUCE LAP-HF II trial (N = 626): patients with HF, left ventricular ejection fraction ≥40%, and exercise pulmonary capillary wedge pressure ≥25 mm Hg, categorized by HF duration: <1 year, 1-3 years, and >3 years. RESULTS:Longer HF duration was associated with greater cardiac remodeling and dysfunction, including lower left ventricular global longitudinal strain (16.4% [Q1-Q3: 14.3%-18.6%] vs 17.7% [Q1-Q3: 15.4%-20.0%] vs 18.4% [Q1-Q3: 16.3%-20.5%]; P < 0.0001) and right ventricular free wall strain (20.8% [Q1-Q3: 16.7%-24.6%] vs 22.2% [Q1-Q3: 17.6%-26.1%] vs 24.4% [Q1-Q3: 19.2%-27.2%]; P < 0.0001), and more biatrial myopathy (48.8% vs 40.8% vs 28.2%; P < 0.0001). Resting pulmonary capillary wedge pressure elevation was more common with longer duration (75.8% vs 70.7% vs 64.9%; P = 0.024). These findings were confirmed in an independent sample of patients with HFpEF undergoing evaluation at Mayo Clinic. HF event risk increased with longer duration (HR: 1.70 [95% CI: 1.17-2.48]; P = 0.006 for >3 years vs <1 year). No significant heterogeneity in atrial shunt response was observed across duration groups. CONCLUSIONS:Longer duration of HFpEF diagnosis is associated with more advanced cardiac remodeling and dysfunction and higher risk of worsening HF, underlining the priority for earlier diagnosis to improve outcomes. (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure [REDUCE LAP-HF TRIAL II]; NCT03088033).

Innovation in the treatment of ascending aorta and arch pathology with novel catheter-based and hybrid procedures has driven the need for a strategy to guide their safe application. The ARCH-ARC (Aortic Arch Academic Research Consortium) was established to pragmatically develop consistent clinical end points and to standardize definitions for use in studies of these new technologies. The ARCH-ARC team, consisting of independent international specialists in cardiac surgery, vascular surgery, vascular medicine, cardiology, neurology, radiology, and clinical trials, along with US Food and Drug Administration, industry, and contract research organization representatives, held virtual meetings from 2021 to 2025. Consensus was used to identify appropriate clinical end points and to standardize definitions of end points for endovascular, hybrid, and open surgical procedures in clinical trials in the ascending aorta and arch. Drawing on previous ARC work in cardiac, neurological, renal, and bleeding end points, the ARCH-ARC focused on definitions and end points related to aortic arch-specific anatomy, pathology, and procedures and clinical, device, and imaging. The adoption of the ARCH-ARC consensus definitions and end points will provide a template for consistent adjudication and event reporting and facilitate comparisons of clinical research studies involving devices for ascending aorta and arch pathology.

BACKGROUND AND AIMS:Type 2 diabetes mellitus (T2DM) and obesity are the archetypal components of cardiometabolic syndromes associated with heart failure (HF) with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). The specific contribution of T2DM, independent of obesity, to myocardial adaptations and outcomes remains uncertain. We aimed to explore the obesity-independent contribution of T2DM to cardiac structure, function, central haemodynamics, and outcomes. METHODS:We leveraged the sham-control arm of the REDUCE LAP-HF II trial (n = 312), a prospectively phenotyped cohort of patients with HFpEF/HFmrEF undergoing invasive haemodynamic assessment. Multivariable models were used to adjust for body mass index (BMI) and clinical covariates. Outcomes included cardiovascular (CV) death and total HF events. RESULTS:T2DM was present in 37% of patients and was associated with higher BMI, chronic kidney disease, and prior HF hospitalization. Obesity was present in 62% of patients and was more prevalent in those with T2DM (70% vs 57%, P = .032). After adjustment for BMI, T2DM remained independently associated with greater left ventricular mass, lower EF, impaired left ventricular global longitudinal strain, reduced right ventricular free-wall strain, and higher resting filling pressures. Over a median of 4.0-year (2.5-5.0) follow-up, T2DM was independently associated with increased risk of HF events or CV death (adjusted hazard ratio: 1.96, 95% confidence interval: 1.28-3.00), driven by HF events, whereas BMI was not independently prognostic. CONCLUSIONS:HFpEF/HFmrEF patients with T2DM experience adverse myocardial remodelling, impaired biventricular function, adverse central haemodynamics, and worse clinical outcomes independent of obesity. These findings indicate that T2DM confers additional metabolic burden to the myocardium, beyond that attributable to obesity alone.

Rationale & Objective: Although renal artery stenosis (RAS) and heart failure (HF) have been linked, the incidence and predictors of HF among patients with RAS are not well described. Study Design: Post hoc analysis of the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) multicenter, open-label, randomized controlled trial (RCT). Settings and Participants: Patients with atherosclerotic RAS and elevated blood pressure, chronic kidney disease, or both, and without a history of HF at enrollment. Intervention: Medical therapy alone versus medical therapy plus renal artery stenting. Outcomes: Incident HF events. Results: This analysis included 808 participants enrolled in the CORAL trial without evidence of baseline HF. During a median follow-up of 4.8 years, 54 participants (6.7%) developed incident HF. HF incidence rates did not differ by randomized intervention (HR, 0.84; 95% confidence interval [CI], 0.49-1.43 for stent arm with medical arm as reference). Baseline diabetes (subdistribution hazard ratio (sHR), 2.07; 95% CI, 1.20-3.58), albuminuria (sHR, 1.12 per doubling of urinary albumin-creatinine ratio, 95% CI, 1.02-1.24), lower eGFR (sHR, 0.78 per 10 mL/min/1.73 m2 estimated glomerular fi ltration rate calculated with cystatin C and creatinine, 95% CI, 0.69-0.88), and peripheral vascular disease (PVD) (sHR, 2.18, 95% CI, 1.213.91) were independent predictors of incident HF. Participants who experienced incident HF had greater kidney function decline before HF events. Limitations: This is a post hoc analysis of a RCT. The number of HF events is small. Conclusions: In patients with RAS, rates of incident HF did not differ between participants randomized to optimal medical therapy alone versus optimal medical therapy plus renal artery stenting. The presence of diabetes, PVD, and worse kidney health at baseline were associated with future HF events.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a challenging and heterogeneous condition with limited effective treatments. Elevated left atrial pressure is a key driver of HF symptoms and complications, making it a compelling therapeutic target. Interatrial shunts have been proposed as a novel strategy to reduce left atrial pressure and improve outcomes in patients with HF. Two major randomized controlled trials, REDUCE LAP-HF II (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) and RELIEVE-HF (Reducing Lung Congestion Symptoms in Advanced Heart Failure), investigated the efficacy of atrial shunts and yielded seemingly contradictory results. REDUCE LAP-HF II, which focused on patients with HF and ejection fraction (EF) >40%, identified a responder subgroup-patients without latent pulmonary vascular disease or cardiac rhythm management devices-who experienced significant clinical benefits and favorable cardiac remodeling. Nonresponders, however, demonstrated worse outcomes. RELIEVE-HF, which included patients across a broad range of EFs, reported worse outcomes in patients with HF and EF >40% treated with shunts. Notably, these patients shared key characteristics with REDUCE LAP-HF II nonresponders, including more advanced echocardiographic abnormalities, elevated resting pulmonary vascular resistance, and increased markers of HF severity. Here, we compare the design and outcomes of both trials to explore the possibility of underlying concordance in their findings. By highlighting the importance of detailed phenotyping, including invasive exercise hemodynamics, we demonstrate the potential benefit of interatrial shunts for carefully selected patients with HFpEF and provide supportive evidence for ongoing trials like RESPONDER-HF using refined patient selection to optimize outcomes for atrial shunts in HFpEF and HF with mildly reduced EF.

BACKGROUND:Repeat drug-eluting stenting is superior to balloon angioplasty for prevention of recurrent in-stent restenosis (ISR), but carries a potential disadvantage of multiple layers of stent. The safety and effectiveness of a sirolimus drug-eluting balloon as an alternative has not been assessed. STUDY DESIGN AND METHODS:The SELUTION4ISR trial is a prospective, multicenter, single-blinded, randomized, controlled trial. A total of 418 subjects with bare metal or drug-eluting stent (DES) ISR with up to 2 previous stent procedures at the target lesion, lesion length <26 mm and reference diameter ≥2.0 mm - ≤4.5 mm will be randomized 1:1 to treatment with either the SELUTION SLR™ DEB (SLR DEB) or standard of care (SOC), which includes either repeat DES or balloon angioplasty without drug coating. A subset of subjects will undergo planned angiographic and optical coherence tomography follow-up. The primary endpoint will be target lesion failure, defined as cardiac death, target vessel myocardial infarction, or clinically-driven target lesion revascularization at 12 months follow-up. The study will sequentially assess noninferiority of the SLR DEB to SOC in the overall cohort, followed by noninferiority then superiority of the SLR DEB to DES in the cohort with only 1 previous stent at the target lesion. TRIAL REGISTRATION:The trial is registered at Clinicaltrials.gov (NCT04280029). CURRENT STATUS:The trial completed enrollment in July 2024. CONCLUSION:The SELUTION4ISR study will evaluate the safety and effectiveness of SLR DEB in a prospective, randomized, international, multicenter trial for treatment of coronary ISR.

BACKGROUND:Worsening heart failure (WHF) events, whether or not leading to hospitalization, may reflect therapeutic benefits of an intervention. OBJECTIVES:The study aimed to assess the associations between an expanded definition of WHF and treatment effect, mortality and change in Kansas City Cardiomyopathy Questionnaire-Overall Summary Score. METHODS:In the randomized REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial of atrial shunt vs sham control procedure, WHF was classified as level 1 (hospitalization requiring intravenous diuretics), level 2 (urgent outpatient encounters with diuretic intensification), or level 3 (nonurgent encounters with augmentation of oral diuretics). Patients were classified as responders/nonresponders based on peak exercise pulmonary vascular resistance or presence of a pacemaker device, as previously published. RESULTS:By 24 months, 161 (25.9%) of 621 patients had at least 1 WHF event, including 108 (17.4%) with any level 1 WHF event, 22 (3.5%) with a level 2 WHF event, and 31 (5.0%) with only level 3 WHF events. In the overall population, there were no differences for shunt vs control device by any definition. In a recurrent events analysis in the responder group, a numerical difference in favor of the atrial shunt was present for level 1 WHF alone but increased and became statistically significant with inclusion of level 2 and level 3 events. Level 1 WHF, but not level 2 or 3, was associated with higher mortality (HR: 3.54 [95% CI: 1.83-6.87]; P = 0.0002). Inclusion of level 2 and 3 events strengthened the association of WHF with less favorable changes in Kansas City Cardiomyopathy Questionnaire-Overall Summary Score. CONCLUSIONS:An expanded definition of WHF more clearly identified the treatment effect of an atrial shunt in a responder group and the negative association of WHF with change in quality of life. (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure [REDUCE LAP-HF TRIAL II]; NCT03088033).

External validity of clinical research can be optimized by an adequate representation of all patient groups within a disease spectrum. This emphasizes the need of enrolling patient groups who have been historically underrepresented on the basis of sex, age, demographic groups, or geographical background. Especially in countries with pronounced disparities, raising awareness regarding the existing gaps in future clinical studies continues to be a priority. Census-defined demographic minority groups have been reported to have less access to high-quality healthcare, are less studied in clinical trials, and have less group-specific high-quality data on outcomes after treatment. Additionally, efforts should continue towards enrolling a balanced or at least representative distribution of women and men in clinical trials; and, enrolling age ranges that are consistent with patients suffering from the index disease. Aiming for heterogeneity in study populations will undoubtedly contribute to advancements in medicine, the development of improved therapies, and better outcomes. Analyses on demographic groups have revealed significant disparities within some regions of the world, underlining the need to further investigate whether access to advanced therapies is consistently offered to all members of a nation. To foster international collaboration in cutting-edge clinical research with adequate patient representation, this document presents insights and consensus on fundamental issues, including available classifications of demographic groups in Europe and North America, and presents a standardized approach for collecting geographical background data.

BACKGROUND Worsening heart failure (WHF) events, whether or not leading to hospitalization, may reflect therapeutic benefits of an intervention. OBJECTIVES The study aimed to assess the associations between an expanded definition of WHF and treatment effect, mortality and change in Kansas City Cardiomyopathy Questionnaire-Overall Summary Score. METHODS In the randomized REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial of atrial shunt vs sham control procedure, WHF was classified as level 1 (hospitalization requiring intravenous diuretics), level 2 (urgent outpatient encounters with diuretic intensification), or level 3 (nonurgent encounters with augmentation of oral diuretics). Patients were classified as responders/nonresponders based on peak exercise pulmonary vascular resistance or presence of a pacemaker device, as previously published. RESULTS By 24 months, 161 (25.9%) of 621 patients had at least 1 WHF event, including 108 (17.4%) with any level 1 WHF event, 22 (3.5%) with a level 2 WHF event, and 31 (5.0%) with only level 3 WHF events. In the overall population, there were no differences for shunt vs control device by any definition. In a recurrent events analysis in the responder group, a numerical difference in favor of the atrial shunt was present for level 1 WHF alone but increased and became statistically significant with inclusion of level 2 and level 3 events. Level 1 WHF, but not level 2 or 3, was associated with higher mortality (HR: 3.54 [95% CI: 1.83-6.87]; P = 0.0002). Inclusion of level 2 and 3 events strengthened the association of WHF with less favorable changes in Kansas City Cardiomyopathy Questionnaire-Overall Summary Score. CONCLUSIONS An expanded definition of WHF more clearly identified the treatment effect of an atrial shunt in a responder group and the negative association of WHF with change in quality of life. (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure [REDUCE LAP-HF TRIAL II]; NCT03088033) (JACC Heart Fail. 2025;13:102571) (c) 2025 by the American College of Cardiology Foundation.

The Drug Coated Balloon Academic Research Consortium project originated from the lack of standardization and comparability between studies using drug-coated balloons in the treatment of obstructive coronary artery disease. This document is a collaborative effort between academic research organizations and percutaneous coronary intervention societies in Europe, the USA, and Asia. This consensus sought to standardize study designs and endpoints for clinical trials involving drug-coated balloons, including defining angiographic, intravascular, and non-invasive imaging methods for lesion assessment, alongside considerations for post-revascularization pharmaco-therapy. The concept of 'blended therapy', which advocates for combining device strategies, is also discussed. This paper delineates study types, endpoint definitions, follow-up protocols, and analytical approaches, aiming to provide consistency and guidance for interventional cardiologists and trialists.

BACKGROUND:Epicardial adipose tissue (EAT) may play a role in the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). OBJECTIVES:This study examined associations between increased EAT, functional status, and invasive exercise hemodynamics in a large cohort of HFpEF patients. METHODS:All patients underwent echocardiography, 6-minute walk distance (MWD) test, Kansas City Cardiomyopathy Questionnaire, and invasive hemodynamic assessment at rest and during ergometry. EAT thickness was measured alongside the right ventricle on echocardiography, expressed in mm and patients were divided according to EAT tertiles. RESULTS:In total, 566 patients were examined with mean age 72 ± 8 years, 62% women, mean EAT thickness was 6.0 ± 2.4 mm and 11.5% had EAT ≥9 mm. With increasing EAT thickness tertiles, 6-MWD and Kansas City Cardiomyopathy Questionnaire overall summary score were significantly lower (320 [247-385] vs 315 [244-383] vs 287 [210-364] meters, P = 0.001; 51 [32-67] vs 45 [32-63] vs 41, [26-56], P = 0.003; respectively), whereas the latter was independent of body mass index (P = 0.004). At rest, invasive hemodynamics were not different across EAT tertiles. At peak exercise, patients in the highest EAT thickness tertile had higher pulmonary capillary wedge pressure and pulmonary capillary wedge pressure to right atrial pressure gradient, compared to patients in the first and second EAT thickness tertiles (36 ± 8 vs 34 ± 8 mm Hg, P = 0.009; 18 ± 7 vs 16 ± 7 mm Hg, P = 0.002, respectively). CONCLUSIONS:EAT thickness was associated with impaired quality of life, lower 6-MWD, and higher left-sided filling pressures at peak exercise. Excess EAT may therefore play an important role in functional status and exercise hemodynamics in patients with HFpEF.