Journal of the American College of Cardiology最新文献

Background: Cardiovascular disease (CVD) is increasing among young adults. The American Heart Association's PREVENT (Predicting Risk of Cardiovascular Disease Events) equations estimate risk of CVD, atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF) for primary prevention. Augmented equations additionally include zip code-based social deprivation index (SDI) to address adverse social exposures.

Objectives: We assessed performance and algorithmic fairness of base and SDI-augmented PREVENT equations in young adults aged 30 to 39 years, defining fairness as similar performance across racial and ethnic groups. An exploratory analysis was conducted among young adults aged 20 to 29 years.

Methods: We included Kaiser Permanente Southern California members aged 20 to 39 years without prior CVD between 2008 and 2009, followed through 2019. We compared 10-year predicted and observed CVD, ASCVD, and HF events for base and SDI-augmented PREVENT models. Performance (Harell's C, calibration slopes, mean calibration) and fairness (concordance imparity, fair calibration) were estimated by race and ethnicity and age group (30-39 years [primary analysis], 20-29 years [exploratory analysis]).

Results: Among 161,202 young adults aged 30 to 39 years (60.0% women; 51.7% Hispanic, 26.9% non-Hispanic White, 12.5% Asian/Pacific Islander, 8.9% non-Hispanic Black), 10-year CVD incidence was 0.7%. Race-specific Harrell's C-statistics for the base PREVENT CVD model ranged from 0.68 to 0.72, yielding low concordance imparity (0.04; 95% CI: 0.02-0.22) which implies fair discrimination. Mean calibration showed underprediction in non-Hispanic Black participants (0.54; 95% CI: 0.48-0.65) vs other groups (range: 0.96-1.07). In fair calibration testing, prediction errors differed across racial and ethnic groups. Results were similar for ASCVD and HF. Adding SDI did not improve performance or fairness despite disparities across groups. In exploratory analyses among 80,978 individuals aged 20 to 29 years, performance and fairness results were similar.

Conclusions: This large, diverse cohort of young adults demonstrates how the PREVENT equations may perform when applied in real-world clinical settings, reflecting the true operational environment faced by large health systems. Applications of PREVENT in clinical patient care, eg, early initiation of preventive strategies, should consider variations in model performance across age, race, and ethnicity.

Background: For patients with asymptomatic severe aortic stenosis (AS), the EARLY TAVR trial demonstrated that early transcatheter aortic valve replacement (TAVR) was superior to clinical surveillance (CS).

Objectives: In this study, the authors sought to evaluate whether baseline left ventricular (LV) health altered the treatment effect of early intervention and to examine longitudinal LV health under different treatment strategies.

Methods: At 75 centers in the United States and Canada, 901 patients underwent randomization to TAVR (n = 455) or CS (n = 446). Echocardiographic measurements were made in a core laboratory. The protocol defined integrated LV health as the composite of absolute LV global longitudinal strain (GLS) ≥15%, LV mass index (LVMi) <115 g/m² (men) or <95 g/m² (women), and left atrial volume index (LAVi) ≤34 mL/m². Integrated LV health was a prespecified secondary endpoint and the protocol outlined longitudinal measurements to be made in the intention-to-treat (ITT) and valve implant populations. As a stratification variable for effect-modification testing, LV health was not prespecified, so those analyses are exploratory. The trial's primary endpoint and 2 secondary composites were examined.

Results: At randomization, in the ITT population, 27% had normal integrated LV health (64% normal LVMi, 42% normal LAVi, 88% normal GLS). Abnormal integrated LV health and each component were generally associated with higher event rates across several composite endpoints. Benefit of early TAVR, compared with CS, was consistently observed regardless of whether LV health (evaluated as an integrated measure and as individual components) was normal or not. In the ITT population, the CS group exhibited normal LV health less frequently at 2 years than those treated early according to the integrated LV health measure (35.9% vs 48.1%; P < 0.001) and component measures. Among CS patients undergoing delayed AVR, LV health tended to decline from randomization to preprocedure (P < 0.10 for all measures except GLS), but baseline LV health did not predict timing of conversion to AVR nor severity of presentation.

Conclusions: For patients with asymptomatic severe AS, the benefit of early TAVR, compared with CS, is consistent regardless of baseline LV health according to integrated or individual measures. These exploratory findings suggest limited value for measures of LV health to guide the timing of TAVR in asymptomatic patients. Whether the worsening of LV health associated with CS and delayed aortic valve replacement underlies increased clinical events in that treatment arm requires further study. (Evaluation of TAVR Compared to Surveillance for Patients With Asymptomatic Severe Aortic Stenosis [EARLY TAVR]; NCT03042104).

Background: Following the primary publication of a clinical trial, questions of longer-term efficacy and safety remain unanswered. Investigators often have sequel publications based on extended follow-up; yet, no guidelines exist for such extension reports.

Objectives: The purpose of this analysis was to assess the characteristics of extension reports of cardiovascular trials published in 7 high-impact medical journals METHODS: We searched MEDLINE to identify cardiovascular trial extension papers published between January 2019 and October 2023 in 7 high-impact medical journals. Extension reports were defined as those presenting additional follow-up data after publication of the primary results. Papers were screened by 2 reviewers before extracting data using a standard proforma.

Results: After screening 1,388 papers, 69 extension reports across 64 trials were identified. A variety of cardiovascular topics were covered, coronary heart disease (n = 20) being the most common. Interventions were medical devices, drugs, surgery, or treatment strategies. Duration of follow-up varied considerably, most common being an original 1-year report (n = 20) with extension at 2, 3, 5, or 10 years. Nearly all extension reports had a superiority hypothesis (n = 68). Most extensions (n = 53) examined the same primary outcome as the original publication. There were also 7 nonrandomized open-label extensions, which suffered from the lack of a concurrent control arm. In 18 reports, treatment crossovers were permitted during the extension, and in 16 cases, alternatives to analysis by intention to treat were utilized. One-half of the extension studies were prespecified (n = 38), and only 10 had dedicated protocols or statistical analysis plans. No study used multiplicity corrections to control type I error across the totality of evidence. Landmark analyses were common (n = 39) which, while descriptively useful, were not based on the original randomized groups. Considerable loss to follow-up (>10%) occurred in 10 of 50 extension reports with clear reporting of this issue. For some trials, the conclusions regarding treatment effects were altered by the extended follow-up. In a previous survey of cardiovascular trials published in the New England Journal of Medicine, Lancet, and Journal of the American Medical Association in 2019, we identified a total of 23 of 84 trials involving extensions in some form.

Conclusions: This first systematic investigation into the reporting of extension studies found a great diversity in practice, noting several issues that need more adequate consideration. Considerations are provided on what trialists should consider when planning, conducting, and reporting extension studies.

Circulating and urinary laboratory biomarkers are central to cardiovascular, kidney, and metabolic drug development, and they support diagnosis, risk stratification, dose finding, safety monitoring, and, in selected settings, endpoint definition. Yet only a few materially shape trial design or regulatory decisions, and still fewer meet stringent criteria for surrogate endpoints. This review proposes a context-of-use framework in which circulating biomarkers are assessed along 2 converging "evidence lanes": analytical readiness and clinical or statistical validation. The review outlines fit-for-purpose requirements for enrichment tools, pharmacodynamic and dose-ranging markers, safety biomarkers, and candidate surrogates, by emphasizing preanalytical, analytical, and postanalytical sources of variability. Particular attention is given to surrogate validation, highlighting frequent discordance between biological plausibility or prognostic strength and treatment-induced changes that reliably predict clinical benefit (eg, albuminuria, natriuretic peptides, and glycemic, inflammatory, and lipid markers). The review describes how biomarkers can be embedded prospectively in phase 1 through phase 4 trials to guide dose selection, enrich populations, trigger adaptive design decisions, and support postmarketing surveillance while generally retaining hard outcomes as the basis for efficacy claims. A dedicated section summarizes perspectives from major regulatory agencies, and another applies the framework to concrete cardiovascular examples, illustrating both successful and unsuccessful uses. Finally, the review discusses practical barriers-analytical variability, operational burden, and limited commercial incentives-and proposes shared solutions, including standardized assays, harmonized data standards, open access platforms, and cross-trial biobanks.

Background: Single-pill low-dose combination (LDC) antihypertensive therapy is an emerging strategy for improving blood pressure (BP) control. Although previous phase II and pragmatic studies suggested promise, these are the first phase III, double-blind, active-controlled trials comparing a single-pill ultra-low-dose triple combination with standard-dose monotherapy.

Objectives: In these studies, we sought to compare a single-pill combination of 1.67 mg amlodipine, 16.67 mg losartan potassium, and 4.17 mg chlorthalidone (LDC-ALC) with standard-dose monotherapy-5 mg amlodipine or 50 mg losartan potassium-in patients with mild-to-moderate hypertension.

Methods: HM-APOLLO-301 (Study 301, May 2022-June 2023) and HM-APOLLO-302 (Study 302, March-December 2024) were multicenter, randomized, double-blind, active-controlled, phase III studies in South Korea. Study 301 compared LDC-ALC and amlodipine; Study 302 compared LDC-ALC and losartan. Adults (≥19 years of age) with systolic blood pressure (SBP) 140 to <180 mm Hg and diastolic blood pressure (DBP) <110 mm Hg after 4-week placebo run-in were randomized to 8 weeks of treatment. The primary endpoint was SBP reduction at week 8, assessed first for noninferiority, then for superiority.

Results: In Study 301, LDC-ALC exhibited noninferiority to amlodipine in reducing SBP at week 8 (upper bound of 1-sided 97.5% CI: 2.8 mm Hg [<3 mm Hg noninferiority margin]), and similar efficacy (least-squares mean change: -19.1 vs -19.9 mm Hg; 95% CI: -1.5 to 3.1; P = 0.495), with similar DBP reduction and blood pressure control rate. In Study 302, LDC-ALC was both noninferior (upper bound of one-sided 97.5% CI: -0.6 mm Hg) and superior to losartan (least-squares mean change: -19.9 vs -16.4 mm Hg; 95% CI: -6.6 to -0.2; P = 0.037) in SBP reduction at week 8, with greater DBP reduction and a higher blood pressure control rate than losartan. Adverse events were similar between groups (LDC-ALC vs amlodipine: 11.7% vs 13.9%; LDC-ALC vs losartan: 6.4% vs 3.3%), with ≤1% treatment withdrawals and no serious drug-related events.

Conclusions: Single-pill LDC-ALC achieved BP reductions similar to those with amlodipine and greater than those with losartan monotherapy over 8 weeks, with similar short-term tolerability. These findings support LDC-ALC as an effective and well tolerated alternative initial therapy for mild-to-moderate hypertension, expanding the set of validated strategies alongside established monotherapies. (A Study to Evaluate Efficacy and Safety of HCP1803 in Patients With Essential Hypertension [HM-APOLLO-301; NCT05362110]; A Study to Evaluate Efficacy and Safety of HCP1803 Compared to RLD2001-1 in Patients with Essential Hypertension [HM-APOLLO-302, NCT06438172]).