Faculty Bibliography

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:Public health emergencies require rapid generation, synthesis, and translation of clinical evidence into practice guidelines; yet, systematic synthesis of the challenges and lessons from these processes remains limited. OBJECTIVES/OBJECTIVE:The purpose of this study was to examine how evidence on anticoagulation in COVID-19 was generated and translated into clinical guidance, using randomized controlled trials (RCTs) as a case study, and to contextualize these processes with an individual participant data meta-analysis (IPDMA). METHODS:Systematic searches identified RCTs comparing therapeutic- vs nontherapeutic-dose anticoagulation in noncritically ill patients hospitalized for COVID-19. Trial characteristics, evidence accumulation, and associated guideline recommendations were summarized over time. An IPDMA was performed to estimate summary treatment effects using mixed-effects logistic regression. RESULTS:Evidence evolved from an early coordinated platform RCT (preprint May 2021) to subsequent RCTs published between June 2021 and July 2023. In exploratory counterfactual sequential IPDMA, the pooled treatment effect on organ support or death became statistically significant in May 2021, approximately 13 months after first patient enrollment (adjusted OR: 0.73; 95% CI: 0.58-0.91; 6 RCTs, n = 3,944). Guideline recommendations shifted from uniform endorsement of prophylactic-dose anticoagulation in 2020 to recommendations supporting therapeutic-dose anticoagulation in 2022, with variation in certainty across guidelines. Individual participant data were obtained after completion of data transfer in April 2024 and included 7 RCTs comprising 6,362 patients. Therapeutic-dose anticoagulation reduced the odds of organ support or death (12.9% vs 16.2%; adjusted OR: 0.81; 95% CI: 0.67-0.97). Major bleeding was rare (0.8% vs 0.5%). CONCLUSIONS:The COVID-19 anticoagulation experience highlights how delays in coordination, data sharing, and synthesis can slow the translation of evidence into practice. Therapeutic-dose anticoagulation was associated with reduced odds of organ support or death and, in this context, serves as a case study of how evidence emerges and is acted upon under conditions of uncertainty. Strengthening coordinated research networks, platform trial infrastructures, prioritized funding, and near-real-time cross-trial synthesis may improve the timeliness, reliability, and responsiveness of evidence systems during future health emergencies.

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.

Chronic coronary disease (CCD) remains a leading cause of morbidity and mortality worldwide. However, current clinical assessments, including tests of inducible ischemia or coronary artery disease severity poorly discriminate risk for future cardiovascular (CV) disease events among this population with established CCD. To address this gap, our study leverages high-dimensional molecular data from the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) Trials biorepository to molecularly characterize patients with CCD. By integrating transcriptomic (N = 646) and methylomic (N = 732) data with core-lab confirmed clinical phenotyping, we describe molecular signatures associated with disease severity and identify distinct whole-blood molecular subtypes of CCD. These subtypes demonstrate differential risks of CV events, independent of traditional clinical risk scores, and have distinct molecular and immune profiles. Validation of the transcriptomic and methylomic subtypes in two independent external cohorts confirms the clinical relevance and generalizability of our findings. These findings underscore the potential of blood-based multi-omic approaches to refine risk stratification, improve personalized treatment strategies and advance secondary prevention in CCD. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT01471522; https://clinicaltrials.gov/ct2/show/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.

BACKGROUND:In the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial, women had worse angina than men despite less severe coronary artery disease (CAD) and ischemia. We examined which patient and treatment factors might explain sex-based differences in angina. METHODS:ISCHEMIA randomized patients with moderate or severe ischemia to an initial invasive strategy of cardiac catheterization with complete revascularization plus guideline-directed medical therapy (GDMT), or an initial conservative strategy of GDMT alone with invasive management reserved for GDMT failure. Coronary CT angiography was performed in most participants. Angina-related health status was collected at baseline and 1-year using the Seattle Angina Questionnaire (SAQ). RESULTS:Of 4,617 ISCHEMIA participants with complete SAQ data, women averaged 6.5 points (95% CI 5.2-7.8) lower (worse) baseline SAQ summary scores (SS) than men. This difference was not reduced by adjustment for demographics and clinical characteristics. Women had lower unadjusted 1-year SAQ-SS than men (Invasive -3.8 points, Conservative -5.7 points). These sex-based differences were attenuated but not eliminated by adjustment for baseline SAQ-SS. Adjustment for post-randomization treatment (GDMT intensity, risk factor goal achievement and, in the invasive strategy, complete revascularization) did not narrow the sex difference. CONCLUSIONS:Women with chronic CAD in ISCHEMIA had worse angina-related health status than men at baseline and 1-year. Differences were not explained by demographic or clinical characteristics, intensity of GDMT, or completeness of revascularization. It is thus important to consider other factors that may mediate these results, including differences in nociception, coronary microvascular dysfunction and/or vasospasm.

BACKGROUND:Myocardial infarction with non-obstructive coronary arteries (MINOCA) has several underlying causes, including mimicking conditions in some cases. Imaging is recommended to identify MINOCA etiologies, but it remains unclear which patients are most likely to have abnormal findings. We characterized MINOCA mechanisms, analyzed predictors of imaging abnormalities and explored sex differences. METHODS:We enrolled patients with clinical diagnosis of MI in an international, prospective, diagnostic study at 28 sites in US, Canada and UK. After a women-only phase, we included both sexes. Individuals with ≥50% diameter stenosis or coronary dissection on angiography, or alternate causes for the clinical presentation, were excluded. Participants had multi-vessel coronary optical coherence tomography (OCT) during index coronary angiography and cardiac magnetic resonance imaging (CMR) within one week. Independent core laboratories interpreted imaging, blinded to other results. RESULTS:Among 754 patients enrolled, 389 had MINOCA and 336 with MINOCA underwent OCT (270 women and 66 men); CMR was completed in 284 (85%). An OCT-defined culprit lesion was identified in 45% (116/270 women [43% ] and 35/66 men [53%], p=0.18). CMR demonstrated an ischemic pattern in 114/284 (40%), similar by sex (96/225 women [43%] vs. 18/59 men [31%], p=0.12). A non-ischemic pattern was observed in 23% (23% of women, 25% of men, p=0.78). We identified a cause of the clinical presentation in 79% of patients with both tests completed: 59% had an ischemic cause of MINOCA and 20% had a non-ischemic mimicking condition. OCT alone found a MINOCA etiology in 151/336 (45%) and CMR alone in 180/284 (63%). Predictors of an OCT culprit lesion included age, abnormal angiogram, and number of vessels imaged, but 27% of normal angiograms harbored a culprit lesion. Predictors of abnormal CMR were peak troponin, shorter time to CMR, and non-Asian race, but CMR was abnormal in 40% when troponin was <4-fold above the upper reference limit. CONCLUSIONS:The combination of multi-vessel coronary OCT and CMR in patients with a clinical diagnosis of MINOCA confirmed MI in 59% and identified an alternate cause (MINOCA mimic) in 20%. Clinical factors had limited utility to predict imaging abnormalities. No sex differences in imaging results were detected.

BACKGROUND/UNASSIGNED:In team science, invitation to writing groups can be subjective and secretive. Confronted with this challenge in the ISCHEMIA trial, with 320 participating sites, 4 coordinating centers, 6 core laboratories, and numerous committees, we adapted an existing model to develop a transparent, objective, and equitable method for determining authorship eligibility. METHODS/UNASSIGNED:We developed a scoring system based on site performance of tasks critical to trial success that meet the ICJME criteria for authorship. Sites were ranked according to points earned, and points required for potential authorship were communicated to all sites. Site investigators were surveyed for their manuscript topic preferences for writing groups. Beyond the point-based system, authorship positions were also reserved for trial contributors who were not site investigators. RESULTS/UNASSIGNED:To date, 50 original, peer-reviewed ISCHEMIA trial manuscripts have been published. In total, 208 authors from 33 countries participated in at least one publication. Of the 87 sites that randomized at least 15 participants over a mean of 5 years, 72% had authorship positions across published manuscripts. Surveys were sent to 334 site investigators and 27% responded. Among respondents, 61% indicated that ISCHEMIA was the first trial they had worked on with performance-based criteria for authorship invitation. Respondents agreed the system was transparent (81%), objective (83%), and equitable for early career researchers (70%) and underrepresented minorities in research (57%). CONCLUSIONS/UNASSIGNED:ISCHEMIA employed a point-based authorship eligibility system that most authors found objective, merit-based, transparent, and equitable. Implementation of such a system should be considered for team science publications.

PURPOSE/OBJECTIVE:To report on the presentation, treatment, and visual outcome of stromal keratitis (SK) in the Zoster Eye Disease Study (ZEDS). DESIGN/METHODS:Secondary analysis of SK endpoint of randomized clinical trial. SUBJECTS/METHODS:Herpes Zoster Ophthalmicus (HZO) patients were randomized in a double-masked clinical trial of oral valacyclovir 1g daily or placebo for 1 year. They were followed prospectively every 3 months for 18 months for endpoints of SK, iritis (IR), endothelial keratitis (EK), or dendritiform epithelial keratitis (DEK). METHODS:Presentation of recurrent, new, or worsening SK was evaluated retrospectively by treatment assignment, randomization strata, and use of topical steroids. Investigators had been allowed discretionary treatment of endpoints including open label valacyclovir and topical steroids. Visual outcome and treatment with open label oral valacyclovir and topical steroids were evaluated. MAIN OUTCOME MEASURES/METHODS:Use of open label valacyclovir and topical steroid treatment of recurrent, new, or worsening SK, and visual acuity at 12 months. RESULTS:Recurrent, new, or worsening SK occurred in 105/527(20%) participants. Randomization group was not associated with this complication. Mean best corrected visual acuity at enrollment was logMAR 0.10±0.14 with no difference at 1 year, logMAR 0.13±0.2, and no difference between valacyclovir and placebo groups at enrollment or at 1 year. Among the 105 instances of SK, 79(75%) were recognized at scheduled study visits rather than at episodic visits. In only 11/105(10%) of recurrent, new, or worsening SK, did masked investigators opt to treat with open label oral antiviral. At the time of SK complication, 52/105(50%) were on topical steroid, but 47/52(90%) on topical steroids were using 1x daily or less, 21/47(45%) high potency and 26/47(55%) low potency (p=0.47). Of 48/105(47%) on no topical steroids at recurrent, new, or worsening SK, 18/48(38%) had discontinued steroids in the prior 3 months. 38/48(75%) on no topical steroids at complication SK were subsequently treated with high potency steroids 2x daily or more. Of 26/52(50%) on low potency steroids at complication SK, 23/26(88%) were treated with increase in frequency only. CONCLUSIONS:Individuals with ocular complications of HZO who develop SK generally maintain very good vision without use of oral antiviral therapy when monitored closely and SK is recognized and treated. Low potency topical steroids should be considered for treatment and ongoing suppression of SK in HZO.