Faculty Bibliography

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: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: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:Coronary microvascular dysfunction (CMD) is present in approximately 40% of patients with ischemia with no obstructive coronary arteries (INOCA) and has been associated with inflammation. We investigated associations between measures of inflammation of the coronary perivascular adipose tissue assessed by coronary computed tomography angiography (CCTA) and results of invasive coronary function testing (CFT) to diagnose CMD. METHODS:Adults referred for clinically indicated invasive coronary angiography who had less than 50% stenosis in all epicardial arteries were prospectively enrolled. CMD was defined as a coronary flow reserve (CFR) less than 2.5 or index of microvascular resistance (IMR) greater than or equal to 25 using bolus thermodilution in the left anterior descending (LAD) coronary artery. Coronary perivascular fat attenuation index was assessed by CCTA in the right coronary artery (RCA) and LAD. T tests were used to evaluate differences in perivascular FAI by CMD status. RESULTS:A total of 31 participants underwent CFT and CCTA. The mean age was 58 ± 11.7 years, 77% were female, and 61% were white. CMD was present in 15 participants (48%). No differences in perivascular FAI were observed in patients with and without CMD, either in the RCA [-74.2 ± 9.8 vs. -69.9 ± 10.3 Hounsfield units (HU), P = 0.24] or LAD (-76.4 ± 10.2 vs. -74.8 ± 12.7 HU, P = 0.69). Perivascular FAI was not correlated with CFR or IMR measurements in the RCA or LAD. CONCLUSION/CONCLUSIONS:There were no associations between CMD diagnosed by invasive CFT and perivascular FAI by CCTA in patients with INOCA. Further research is needed to understand the relationship between vascular inflammation and CMD in INOCA.

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.

AIMS/OBJECTIVE:To assess whether baseline functional performance assessed by exercise treadmill stress testing (EST) has additive value to coronary computed tomography angiography (CCTA) for risk stratification among patients with chronic coronary disease (CCD) and moderate or severe ischemia. METHODS AND RESULTS/RESULTS:We performed a subgroup analysis of the ISCHEMIA trial including participants who underwent EST and CCTA. EST data and severity of coronary artery disease (CAD) on CCTA were evaluated by core laboratories, blinded to clinical data and results of the other test. The primary outcome for this analysis was all-cause death. Secondary outcomes were cardiovascular death, cardiovascular death or myocardial infarction (MI), MI and a composite of cardiovascular death, MI, or hospitalization for heart failure, unstable angina, or resuscitated cardiac arrest. EST and number of vessels diseased on CCTA were both interpretable in 1864 patients (median age 62 years, IQR 55-68, 83% males). During a median follow-up of 3.1 years, 69 patients died. Higher peak metabolic equivalents (METs) achieved on the qualifying stress test was associated with lower all-cause death (HR 0.86, CI 0.76-0.98; p=0.025). The addition of peak METs to CAD severity improved the predictive ability of the all-cause death and CV death models by 10-20% and 8-13% respectively, depending on the metrics used for CCTA. Adding peak METs to CCTA anatomical models resulted in better prediction of MI by 11-17%, cardiovascular death or MI by 10-14%, and 5-component composite outcome by 12-16%. CONCLUSION/CONCLUSIONS:Peak METs on EST, a marker of functional performance, added prognostic value to models including CCTA anatomical findings in patients with CCD and moderate or severe ischemia.

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.