Faculty Bibliography

AIMS/OBJECTIVE:Treatment discontinuation is a common intercurrent event in randomized clinical trials (RCTs) that can bias treatment effect estimates, yet it remains under recognized and inconsistently addressed. Antithrombotic trials provide a relevant case, as bleeding-related discontinuation is common and more often occur in patients at increased risk also for ischaemic events. METHODS AND RESULTS/RESULTS:We reviewed large antithrombotic RCTs published in The New England Journal of Medicine (2020-2025) to assess reporting and analytic handling of treatment discontinuation. We also conducted simulations to examine how discontinuation patterns influence efficacy estimates under three scenarios: discontinuation only in the treatment arm, in both arms with similar patterns, and in both arms but outcome-associated only in the treatment arm. Treatment policy (intention-to-treat) and while-on-treatment strategies were compared within the ICH E9(R1) framework. Among fourteen reviewed antithrombotic RCTs, about one-third of patients discontinued treatment in trials with more than 6 months follow-up, with higher imbalance in open-label studies. Over half of discontinuations were safety-related, yet timing and temporary interruptions were rarely reported. Most reported both ITT and per-protocol (PP) analyses, with PP assuming non-informative censoring and yielding larger efficacy estimates. In simulations, treatment policy and while-on-treatment strategies were biased when discontinuation was outcome-associated, while Simon-Makuch curves helped identify prognostic discontinuation differing by treatment arm. CONCLUSION/CONCLUSIONS:Discontinuation is common, prognostically meaningful, and often oversimplified in analysis, threatening the validity of RCT findings. Explicitly addressing discontinuation as an intercurrent event within the estimand framework, along with stratified outcome curves, can improve interpretation and support more robust trial conclusions.

BACKGROUND:Poor sleep after acute cardiovascular events is associated with increased mortality. Women are more likely than men to report sleep disturbances after cardiovascular events, but other sleep metrics linked to cardiometabolic health remain underexplored. OBJECTIVES/OBJECTIVE:We characterize multiple dimensions of sleep and examine factors associated with poor sleep among women with prior myocardial infarction (MI). METHODS:Participants completed 7 nights of wrist actigraphy, which measured sleep duration, sleep efficiency, and wake after sleep onset (WASO), and sleep diary, which measured self-reported sleep quality using a Likert scale. Multivariable regression modeled associations between sociodemographic, clinical, and psychosocial characteristics and sleep measures. RESULTS:Among 94 post-MI women (median days since MI 93; IQR: 69-709), mean age was 60 years, and 67.0% identified as non-Hispanic White. The mean sleep duration was 405.1 minutes (approximately 6.8 hours), sleep efficiency 86.3%, WASO 61.6 minutes, and self-reported sleep quality 3.3, indicating fair-to-good sleep quality. Overall, 64.9% of women had short (<7 hours) or long (>9 hours) sleep duration, 33% low sleep efficiency (<85%), and 88.3% long WASO (>30 minutes). In exploratory analyses, associations with poor sleep included identifying as other than non-Hispanic White (shorter sleep duration, lower efficiency, and longer WASO), being nonpartnered (shorter sleep duration), hypertension (lower sleep efficiency), and higher depressive symptoms (lower sleep quality). CONCLUSIONS:Many women with prior MI had suboptimal sleep (short or long sleep duration, low sleep efficiency, and/or long WASO). Our results highlight the importance of discussing multiple dimensions of sleep with women post-MI to optimize cardiovascular health.

BACKGROUND/UNASSIGNED:Myocardial infarction with nonobstructive coronary arteries (MINOCA) accounts for 6% to 15% of acute coronary syndromes and disproportionately affects women. Although coronary culprit lesions are present in 45% of patients with MINOCA, multivessel optical coherence tomography (OCT) is infrequently performed. We evaluated whether interventional cardiologists can identify coronary arteries with culprit lesions using invasive coronary angiography in women with MINOCA. METHODS/UNASSIGNED:Women with MINOCA who had a coronary culprit lesion identified by multivessel OCT were included. A core laboratory confirmed and localized OCT-defined culprit lesions using angiographic coregistration. Two interventional cardiologists blinded to OCT findings independently reviewed invasive coronary angiography, before and after review of ECG and transthoracic echocardiography, to identify the culprit artery. RESULTS/UNASSIGNED:=0.97). Culprit arteries were identified by at least 1 cardiologist in 87.5% of plaque rupture cases. Only 11% of circumflex lesions were identified. CONCLUSIONS/UNASSIGNED:Interventional cardiologists could not reliably identify culprit arteries using coronary angiography in women with MINOCA, even after ECG and transthoracic echocardiography review. Our findings suggest that invasive angiography alone should not guide vessel selection for intracoronary imaging and support multivessel imaging when evaluating MINOCA. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02905357.

BACKGROUND:The ISCHEMIA trial randomized participants with chronic coronary disease and moderate or severe ischemia by site assessment to an initial invasive strategy plus guideline-directed medical therapy (GDMT) or to an initial conservative strategy of GDMT alone. This secondary analysis examines the association of pre-randomization ischemia severity, from stress testing assessed by a core laboratory, and anatomic severity of coronary artery disease (CAD), assessed by coronary computed tomography angiography (CCTA), with 1-year health status outcomes. METHODS:The associations of ischemia and CAD severity with 1-year health status were assessed using proportional odds models, adjusted for age, sex, and baseline health status and stratified by baseline angina; Seattle Angina Questionnaire (SAQ) Angina Frequency [AF] score < 100 (and angina) vs. 100 (no angina). RESULTS:Among 4,558 participants with baseline and 1-year SAQ assessments, 2936 (64.4%) had baseline angina. Among these, ischemia was categorized as no/mild (363), moderate (986) and severe (1587). Among participants reporting angina at baseline, those with severe baseline ischemia had more frequent angina compared with those having less ischemia (SAQ AF, 70.6 vs 73.0, p=0.029). However, the adjusted odds ratio for better 1-year overall health status, assessed by the SAQ Summary Score, was 1.29 (95% CI, CI 1.05-1.59, p=0.007) for participants with severe vs. those with less baseline ischemia. No differences in 1-year health status were observed by CAD severity or in asymptomatic patients categorized by ischemia or CAD severity. CONCLUSIONS:Among participants with baseline angina in the ISCHEMIA trial, severe ischemia was independently associated with more frequent angina at baseline and at 1 year, but also with better 1-year overall health status compared with less ischemia. Anatomic CAD severity was not associated with angina severity.

BACKGROUND/UNASSIGNED:Myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA) accounts for 6-8% of all MIs and is more common in women than men. After an episode of MINOCA, patients may experience a substantial symptom burden and reduced health-related quality of life (HRQoL). The aim of this post-hoc analysis was to describe clinical characteristics, residual symptoms and HRQoL, including sex differences in patients with a working diagnosis of MINOCA and preserved left ventricular ejection fraction (LV-EF). METHODS/UNASSIGNED:reatment in MINOCA patients (MINOCA-BAT) was an international clinical trial. Patients with a working diagnosis of MINOCA and LV-EF ≥ 40% were randomized to beta-blocker versus no beta-blocker and ACEI/ARB versus no ACEI/ARB. The trial was prematurely terminated after 192 enrolled participants (median age 59; 63% women). Clinical events, symptoms and HRQoL (EQ-5D-3L) were assessed at 7 weeks and 12 months after the index event. RESULTS/UNASSIGNED:The cohort represented a low-risk population. At one year, one patient had died, one had a re-infarction, 14% reported chest pain and 9% dyspnea. Median EQ-5D index scores did not change significantly between 7 weeks and 12 months (0.86 vs. 0.78) and were comparable to age-matched general population norms. Women reported slightly lower HRQoL than men. CONCLUSIONS/UNASSIGNED:Patients with a working diagnosis of MINOCA and preserved LV-EF constitute a low-risk population and demonstrate a favorable prognosis with symptom resolution within one year. Their HRQoL appears broadly similar to that observed in the general population, with only modest differences between the sexes.

BACKGROUND/UNASSIGNED:Patient-centered prognostic assessment in chronic coronary disease is vital for treatment optimization. Although the Seattle Angina Questionnaire Summary Score (SAQ-SS) correlates with clinical outcomes, clinicians lack guidance on how to weigh prior, current, or changes in scores, and whether prognostic significance varies by revascularization strategy. METHODS/UNASSIGNED:The ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches; 2012-2019) was a global, multicenter, randomized controlled trial. This secondary analysis evaluated the prognostic value of serial SAQ-SS assessments. The SAQ-SS ranges from 0 to 100, with higher scores indicating better health status. To simulate routine clinical care, the follow-up in ISCHEMIA was equated to outpatient clinic visits-we defined the 3-month SAQ-SS as the prior score and the 6-month assessment as the current score in the clinic. Analyses were stratified by treatment strategy: conservative management and invasive management with revascularization. Cox proportional hazards models assessed the association of the prior score, the current score, and the change in scores with ISCHEMIA's primary composite end point (cardiovascular death, myocardial infarction, hospitalization for unstable angina, heart failure, and resuscitated cardiac arrest), adjusting for 17 clinical covariates. RESULTS/UNASSIGNED:This analysis included 3405 participants (1965 in conservative management: 77.4% male, mean age 64.3 years±9.5; 1440 in invasive management: 77.6% male, mean age 64.0 years±9.4). Over a median follow-up of 3.2 years, 215 (11.0%) and 96 (6.7%) participants in the conservative and invasive cohorts, respectively, experienced the primary composite end point. Higher prior, current, and change SAQ-SS were each independently associated with a lower risk of cardiovascular events. In the conservative cohort, each 5-point increase in the current SAQ-SS was associated with a 7% lower risk of the primary end point (hazard ratio, 0.93 [95% CI, 0.90-0.96]); in the invasive cohort, the association was 9% (hazard ratio, 0.91 [95% CI, 0.86-0.96]). CONCLUSIONS/UNASSIGNED:In patients with chronic coronary disease, the most recent SAQ-SS is the strongest health status predictor of future cardiovascular events. Serial SAQ-SS assessments provide a practical, dynamic, and patient-centered approach for updating prognosis in chronic coronary disease management. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

BACKGROUND:Coronary microvascular dysfunction (CMD) is a mechanism of ischemia with nonobstructive coronary arteries (INOCA) diagnosed by invasive coronary function testing (CFT). It is unknown whether CMD reflects a systemic microcirculatory disorder. Sidestream darkfield (SDF) microscopy permits noninvasive imaging of red blood cells (RBCs) in the sublingual microcirculation. OBJECTIVES/OBJECTIVE:We sought to evaluate whether SDF microscopy identifies sublingual microvascular abnormalities in patients with INOCA due to CMD. METHODS:Adults with INOCA underwent CFT for CMD, defined by abnormal coronary flow reserve <2.5 or index of microcirculatory resistance ≥25. Sublingual SDF microscopy was performed to determine the endothelial glycocalyx perfused boundary region (PBR), RBC filling percentage (%RBC), and perfused microvascular density (PMVD). RESULTS:A total of 135 participants with INOCA (mean age 59.3 ± 12.1 years, 80% female) underwent CFT and sublingual SDF microscopy. CMD was present in 63 participants (46.7%). The median PBR was 1.96 (IQR: 0.4), median %RBC was 72.6 (IQR: 8.0), and median PMVD was 406 (IQR: 141). No differences in sublingual PBR, %RBC, and PMVD were observed by CMD status. No correlations between sublingual parameters and continuous measures of coronary flow reserve or index of microcirculatory resistance were observed. CONCLUSIONS:Noninvasive SDF microscopy did not identify sublingual microvascular abnormalities in INOCA patients with CMD.

BACKGROUND:Myocardial Infarction with No Obstructive Coronary Arteries (MINOCA) or Nonischemic Myocardial Injury affects approximately 1 in 9 patients presenting with acute coronary syndrome, yet evidence-based therapies are lacking. Coronary microvascular dysfunction is implicated in the pathogenesis of suspected MINOCA, but its prevalence, prognostic implications and treatment are uncertain. The objectives are, first, to assess the prevalence of coronary microvascular dysfunction in patients with suspected MINOCA and, second, to implement endotype-informed stratified medicine involving patients with coronary microvascular dysfunction to treatment with eplerenone, a cardio- and vasculo-protective mineralocorticoid receptor antagonist. METHODS:This is a prospective, registry-based, multicenter, diagnostic study and nested, randomized, controlled, open-label, blinded-endpoint (PROBE) basket trial. Up to 400 patients with clinically suspected MINOCA and one or more cardiovascular risk factors will be enrolled into a registry-based diagnostic study. Coronary microvascular function will be assessed during invasive angiography using thermodilution. Patients with an index of coronary microvascular resistance (IMR) ≥25 will be randomized 1:1 to eplerenone (25-50 mg daily for 6 months) or standard care without eplerenone (control group) (n=150 randomized). Final endotypes will be centrally adjudicated by a panel of blinded cardiologists. The primary outcome of the diagnostic study is the proportion of patients with IMR ≥25 during index coronary angiography. Secondary outcomes include coronary flow reserve, cardiovascular MRI parameters, patient-reported outcome measures, biomarkers of myocardial fibrosis and vascular inflammation, health outcomes and health economic assessments. The primary outcome of the randomized trial is the within-individual change in NT-proBNP at baseline, 1 month, and 6 months, based on intention-to-treat. Secondary outcomes include mechanistic blood biomarkers and patient-reported outcome measures. VALUE/METHODS:This registry-based randomized trial will provide novel evidence on endotype-informed secondary prevention therapy with eplerenone for suspected MINOCA.

BACKGROUND/UNASSIGNED:Cardiac stress testing is a cornerstone of risk stratification and management in patients with chronic coronary disease, yet the consistency and accuracy of its interpretation remain poorly defined. This analysis evaluated variation in the interpretation of myocardial ischemia between enrollment sites and core laboratories in the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches). METHODS/UNASSIGNED:ISCHEMIA was a global (37 countries, 2012-2018) randomized trial of an initial invasive versus conservative strategy in patients with chronic coronary disease and moderate or severe ischemia. This analysis included participants with site-interpreted qualifying stress tests-nuclear, echocardiography (echo), cardiac magnetic resonance, or exercise tolerance test-and independent core laboratory adjudication. Core laboratories, serving as the reference standard, reinterpreted tests blinded to site results. A trinary outcome variable (site underestimation, concordance, or overestimation) was defined by comparing site-determined ischemia levels to standardized core lab assessments. Adjusted mixed-effects logistic regression models with random site intercepts assessed variability. RESULTS/UNASSIGNED:Among 6971 participants (mean age, 62.8 years; 73% men), site interpretations showed 0% no/mild (by design), 43% moderate, and 57% severe ischemia. Core labs reclassified these as 8% none, 11% mild, 30% moderate, and 51% severe ischemia. For the imaging modalities, median site-core lab agreement rates were ≈55%; nearly 25% of site-classified moderate/severe cases were downgraded to no or mild ischemia by core labs. Adjusted median odds ratios for site overestimation were 2.36 (95% CI, 2.02-2.82; nuclear), 1.98 (95% CI, 1.62-2.60; echo), 1.89 (95% CI, 1.0-5.41; cardiac magnetic resonance), and 2.15 (95% CI, 1.76-2.79; exercise tolerance test). Adjusted median odds ratios for underestimation ranged from 1.25 to 1.77. CONCLUSIONS/UNASSIGNED:In ISCHEMIA, enrollment sites frequently overestimated or underestimated the severity of myocardial ischemia compared with core laboratory assessments, highlighting the need for strategies to improve the consistency and accuracy of stress testing interpretation in patients with chronic coronary disease. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

BACKGROUND:The frequency of residual angina and its impact on health status and death following anatomic complete revascularization in symptomatic patients with chronic coronary disease are unknown. METHODS:Data were analyzed from ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial participants randomized to invasive management with baseline angina (Seattle Angina Questionnaire Angina Frequency score <100), no prior coronary artery bypass graft surgery, and anatomic complete revascularization within 90 days of randomization. The primary outcome was frequency of residual angina after revascularization, defined as a Seattle Angina Questionnaire Angina Frequency score <100 within 6 months of randomization. Secondary outcomes included 6-month health status and medication use and 5-year all-cause and cardiovascular death. RESULTS:=0.006). Five-year all-cause and cardiovascular death did not differ significantly between groups. CONCLUSIONS:Residual angina is common (>40%) following anatomic complete revascularization for chronic coronary disease and is associated with reduced quality of life and greater antianginal medication use but no increase in death. REGISTRATION/BACKGROUND:Unique Identifier: NCT01471522.