Publications

IMPORTANCE: Drug-coated balloons offer a potentially beneficial treatment strategy for the management of coronary in-stent restenosis. However, none have been previously evaluated or approved for use in coronary circulation in the United States.

OBJECTIVE: To evaluate whether a paclitaxel-coated balloon is superior to an uncoated balloon in patients with in-stent restenosis undergoing percutaneous coronary intervention.

DESIGN, SETTING, AND PARTICIPANTS: AGENT IDE, a multicenter randomized clinical trial, enrolled 600 patients with in-stent restenosis (lesion length <26 mm and reference vessel diameter >2.0 mm to ≤4.0 mm) at 40 centers across the United States between May 2021 and August 2022. One-year clinical follow-up was completed on October 2, 2023.

INTERVENTIONS: Participants were randomized in a 2:1 allocation to undergo treatment with a paclitaxel-coated (n = 406) or an uncoated (n = 194) balloon.

MAIN OUTCOMES AND MEASURES: The primary end point of 1-year target lesion failure-defined as the composite of ischemia-driven target lesion revascularization, target vessel-related myocardial infarction, or cardiac death-was tested for superiority.

RESULTS: Among 600 randomized patients (mean age, 68 years; 157 females [26.2%]; 42 Black [7%], 35 Hispanic [6%] individuals), 574 (95.7%) completed 1-year follow-up. The primary end point at 1 year occurred in 17.9% in the paclitaxel-coated balloon group vs 28.6% in the uncoated balloon group, meeting the criteria for superiority (hazard ratio [HR], 0.59 [95% CI, 0.42-0.84]; 2-sided P = .003). Target lesion revascularization (13.0% vs 24.7%; HR, 0.50 [95% CI, 0.34-0.74]; P = .001) and target vessel-related myocardial infarction (5.8% vs 11.1%; HR, 0.51 [95% CI, 0.28-0.92]; P = .02) occurred less frequently among patients treated with paclitaxel-coated balloon. The rate of cardiac death was 2.9% vs 1.6% (HR, 1.75 [95% CI, 0.49-6.28]; P = .38) in the coated vs uncoated balloon groups, respectively.

CONCLUSIONS AND RELEVANCE: Among patients undergoing coronary angioplasty for in-stent restenosis, a paclitaxel-coated balloon was superior to an uncoated balloon with respect to the composite end point of target lesion failure. Paclitaxel-coated balloons are an effective treatment option for patients with coronary in-stent restenosis.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04647253.

BACKGROUND: Vaccine hesitancy persists alongside concerns about the safety of coronavirus disease 2019 (COVID-19) vaccines. We aimed to examine the effect of COVID-19 vaccination on risk of death among US veterans.

METHODS: We conducted a target trial emulation to estimate and compare risk of death up to 60 days under two COVID-19 vaccination strategies: vaccination within 7 days of enrollment versus no vaccination through follow-up. The study cohort included individuals aged ≥18 years enrolled in the Veterans Health Administration system and eligible to receive a COVID-19 vaccination according to guideline recommendations from 1 March 2021 through 1 July 2021. The outcomes of interest included deaths from any cause and excluding a COVID-19 diagnosis. Observations were cloned to both treatment strategies, censored, and weighted to estimate per-protocol effects.

RESULTS: We included 3 158 507 veterans. Under the vaccination strategy, 364 993 received vaccine within 7 days. At 60 days, there were 156 deaths per 100 000 veterans under the vaccination strategy versus 185 deaths under the no vaccination strategy, corresponding to an absolute risk difference of -25.9 (95% confidence limit [CL], -59.5 to 2.7) and relative risk of 0.86 (95% CL, .7 to 1.0). When those with a COVID-19 infection in the first 60 days were censored, the absolute risk difference was -20.6 (95% CL, -53.4 to 16.0) with a relative risk of 0.88 (95% CL, .7 to 1.1).

CONCLUSIONS: Vaccination against COVID-19 was associated with a lower but not statistically significantly different risk of death in the first 60 days. These results agree with prior scientific knowledge suggesting vaccination is safe with the potential for substantial health benefits.

BACKGROUND: Implantable cardioverter-defibrillator (ICD) intervention is an established prophylactic measure. Identifying high-benefit patients poses challenges.

PURPOSE: To assess the prognostic value of cardiac magnetic resonance imaging (MRI) parameters including myocardial deformation for risk stratification of ICD intervention in non-ischemic cardiomyopathy (NICM) while accounting for competing mortality risk.

STUDY TYPE: Retrospective and prospective.

POPULATION: One hundred and fifty-nine NICM patients eligible for primary ICD (117 male, 54 ± 13 years) and 49 control subjects (38 male, 53 ± 5 years).

FIELD STRENGTH/SEQUENCE: Balanced steady state free precession (bSSFP) and three-dimensional phase-sensitive inversion-recovery late gadolinium enhancement (LGE) sequences at 1.5 T or 3 T.

ASSESSMENT: Patients underwent MRI before ICD implantation and were followed up. Functional parameters, left ventricular global radial, circumferential and longitudinal strain, right ventricular free wall longitudinal strain (RV FWLS) and left atrial strain were measured (Circle, cvi42). LGE presence was assessed visually. The primary endpoint was appropriate ICD intervention. Models were developed to determine outcome, with and without accounting for competing risk (non-sudden cardiac death), and compared to a baseline model including LGE and clinical features.

STATISTICAL TESTS: Wilcoxon non-parametric test, Cox's proportional hazards regression, Fine-Gray competing risk model, and cumulative incidence functions. Harrell's c statistic was used for model selection. A P value <0.05 was considered statistically significant.

RESULTS: Follow-up duration was 1176 ± 960 days (median: 896). Twenty-six patients (16%) met the primary endpoint. RV FWLS demonstrated a significant difference between patients with and without events (-12.5% ± 5 vs. -16.4% ± 5.5). Univariable analyses showed LGE and RV FWLS were significantly associated with outcome (LGE: hazard ratio [HR] = 3.69, 95% CI = 1.28-10.62; RV FWLS: HR = 2.04, 95% CI = 1.30-3.22). RV FWLS significantly improved the prognostic value of baseline model and remained significant in multivariable analysis, accounting for competing risk (HR = 1.73, 95% CI = 1.12-2.66).

DATA CONCLUSIONS: In NICM, RV FWLS may provide additional predictive value for predicting appropriate ICD intervention.

LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 5.

BACKGROUND: Frailty is associated with adverse cardiovascular outcomes independent of age and comorbidities, yet the independent influence of frailty progression remains uncertain.

METHODS: Medicare Fee-for-service beneficiaries ≥ 65 years at cohort inception with continuous enrollment from 2003-2015 were included. Frailty trajectory was measured by annualized change in a validated claims-based frailty index (CFI) over a 5-year period. Linear mixed effects models, adjusting for baseline frailty, were used to estimate CFI change over a 5-year period. Survival analysis was used to evaluate associations of frailty progression and future health outcomes (major adverse cardiovascular and cerebrovascular events [MACCE], all-cause death, heart failure, myocardial infarction, ischemic stroke, and days alive at home [DAH] within the following calendar year).

RESULTS: 26.4 million unique beneficiaries were included (mean age 75.4 ± 7.0 years, 57% female, 13% non-White). In total, 20% had frailty progression, 66% had no change in frailty, and 14% frailty regression over median follow-up of 2.4 years. Compared to those without a change in CFI, when adjusting for baseline frailty, those with frailty progression had significantly greater risk of incident MACCE (hazard ratio [HR] 2.30, 95% confidence interval [CI] 2.30-2.31), all-cause mortality (HR 1.59, 95% CI 1.58-1.59), acute myocardial infarction (HR 1.78, 95% CI 1.77-1.79), heart failure (HR 2.78, 95% CI 2.77-2.79), and stroke (HR 1.78, 95% CI 1.77-1.79). There was also a graded increase in risk of each outcome with more rapid progression and significantly fewer DAH with the most rapid vs. the slowest progression group (270.4 ± 112.3 vs. 308.6 ± 93.0 days, rate ratio 0.88, 95% CI 0.87-0.88, p < 0.001).

CONCLUSIONS: In this large, nationwide sample of Medicare beneficiaries, frailty progression, independent of baseline frailty, was associated with fewer DAH and a graded risk of MACCE, all-cause mortality, myocardial infarction, heart failure, and stroke compared to those without progression.

A goal of evidence synthesis for trials of complex interventions is to inform the design or implementation of novel versions of complex interventions by predicting expected outcomes with each intervention version. Conventional aggregate data meta-analyses of studies comparing complex interventions have limited ability to provide such information. We argue that evidence synthesis for trials of complex interventions should forgo aspirations of estimating causal effects and instead model the response surface of study results to 1) summarize the available evidence and 2) predict the average outcomes of future studies or in new settings. We illustrate this modeling approach using data from a systematic review of diabetes quality improvement (QI) interventions involving at least 1 of 12 QI strategy components. We specify a series of meta-regression models to assess the association of specific components with the posttreatment outcome mean and compare the results to conventional meta-analysis approaches. Compared with conventional approaches, modeling the response surface of study results can better reflect the associations between intervention components and study characteristics with the posttreatment outcome mean. Modeling study results using a response surface approach offers a useful and feasible goal for evidence synthesis of complex interventions that rely on aggregate data.

IMPORTANCE: The National Lung Screening Trial (NLST) found that screening for lung cancer with low-dose computed tomography (CT) reduced lung cancer-specific and all-cause mortality compared with chest radiography. It is uncertain whether these results apply to a nationally representative target population.

OBJECTIVE: To extend inferences about the effects of lung cancer screening strategies from the NLST to a nationally representative target population of NLST-eligible US adults.

DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness study included NLST data from US adults at 33 participating centers enrolled between August 2002 and April 2004 with follow-up through 2009 along with National Health Interview Survey (NHIS) cross-sectional household interview survey data from 2010. Eligible participants were adults aged 55 to 74 years, and were current or former smokers with at least 30 pack-years of smoking (former smokers were required to have quit within the last 15 years). Transportability analyses combined baseline covariate, treatment, and outcome data from the NLST with covariate data from the NHIS and reweighted the trial data to the target population. Data were analyzed from March 2020 to May 2023.

INTERVENTIONS: Low-dose CT or chest radiography screening with a screening assessment at baseline, then yearly for 2 more years.

MAIN OUTCOMES AND MEASURES: For the outcomes of lung-cancer specific and all-cause death, mortality rates, rate differences, and ratios were calculated at a median (25th percentile and 75th percentile) follow-up of 5.5 (5.2-5.9) years for lung cancer-specific mortality and 6.5 (6.1-6.9) years for all-cause mortality.

RESULTS: The transportability analysis included 51 274 NLST participants and 685 NHIS participants representing the target population (of approximately 5 700 000 individuals after survey-weighting). Compared with the target population, NLST participants were younger (median [25th percentile and 75th percentile] age, 60 [57 to 65] years vs 63 [58 to 67] years), had fewer comorbidities (eg, heart disease, 6551 of 51 274 [12.8%] vs 1 025 951 of 5 739 532 [17.9%]), and were more educated (bachelor's degree or higher, 16 349 of 51 274 [31.9%] vs 859 812 of 5 739 532 [15.0%]). In the target population, for lung cancer-specific mortality, the estimated relative rate reduction was 18% (95% CI, 1% to 33%) and the estimated absolute rate reduction with low-dose CT vs chest radiography was 71 deaths per 100 000 person-years (95% CI, 4 to 138 deaths per 100 000 person-years); for all-cause mortality the estimated relative rate reduction was 6% (95% CI, -2% to 12%). In the NLST, for lung cancer-specific mortality, the estimated relative rate reduction was 21% (95% CI, 9% to 32%) and the estimated absolute rate reduction was 67 deaths per 100 000 person-years (95% CI, 27 to 106 deaths per 100 000 person-years); for all-cause mortality, the estimated relative rate reduction was 7% (95% CI, 0% to 12%).

CONCLUSIONS AND RELEVANCE: Estimates of the comparative effectiveness of low-dose CT screening compared with chest radiography in a nationally representative target population were similar to those from unweighted NLST analyses, particularly on the relative scale. Increased uncertainty around effect estimates for the target population reflects large differences in the observed characteristics of trial participants and the target population.

When planning a cluster randomized trial, evaluators often have access to an enumerated cohort representing the target population of clusters. Practicalities of conducting the trial, such as the need to oversample clusters with certain characteristics in order to improve trial economy or support inferences about subgroups of clusters, may preclude simple random sampling from the cohort into the trial, and thus interfere with the goal of producing generalizable inferences about the target population. We describe a nested trial design where the randomized clusters are embedded within a cohort of trial-eligible clusters from the target population and where clusters are selected for inclusion in the trial with known sampling probabilities that may depend on cluster characteristics (e.g., allowing clusters to be chosen to facilitate trial conduct or to examine hypotheses related to their characteristics). We develop and evaluate methods for analyzing data from this design to generalize causal inferences to the target population underlying the cohort. We present identification and estimation results for the expectation of the average potential outcome and for the average treatment effect, in the entire target population of clusters and in its non-randomized subset. In simulation studies, we show that all the estimators have low bias but markedly different precision. Cluster randomized trials where clusters are selected for inclusion with known sampling probabilities that depend on cluster characteristics, combined with efficient estimation methods, can precisely quantify treatment effects in the target population, while addressing objectives of trial conduct that require oversampling clusters on the basis of their characteristics.

Epidemiologists are attempting to address research questions of increasing complexity by developing novel methods for combining information from diverse sources. Cole et al. (Am J Epidemiol. 2022;XXX(XX):XXXX-XXXX) provide two examples of combining information to draw inferences about a population proportion. In this commentary, we consider combining information to learn about a target population as an epidemiological activity and distinguish it from more conventional meta-analyses. We examine possible rationales for combining information and discuss broad methodological considerations, with an emphasis on aspects of study design, including the selection among candidate data sources and the sampling of observations from these sources.