Faculty Bibliography

PURPOSE/OBJECTIVE:The purpose of this study was to describe the rationale and design of the Zoster Eye Disease Study (ZEDS). METHODS:ZEDS is a National Eye Institute-supported randomized clinical trial designed to determine whether 1 year of suppressive valacyclovir in patients with herpes zoster ophthalmicus (HZO) reduces complications because there is currently no high-quality evidence to support its use. Eligible patients are 18 years and older, immunocompetent, have a history of a typical rash at disease onset, and have had a record of active epithelial or stromal keratitis or iritis within 1 year before enrollment. Exclusion criteria include estimated glomerular filtration rate less than 45 or pregnancy. The primary endpoint is the time to first occurrence of new or worsening dendriform epithelial keratitis, stromal keratitis without or with ulceration, endothelial keratitis, or iritis due to HZO during 12 months of study treatment requiring prespecified treatment changes. The study has 80% power to detect a 30% difference between treatment groups, with a 30% rate of endpoints by 1 year assumed among controls. Secondary and exploratory questions include whether there is a persistent treatment benefit during the 6 months after treatment, whether development of postherpetic neuralgia varies by treatment group, and whether vaccinations against herpes zoster affect study outcomes and coronavirus disease 19 status. RESULTS:Over approximately 4 years, over 400 study participants have been enrolled. CONCLUSIONS:ZEDS aims to provide scientific evidence on whether suppressive valacyclovir treatment improves outcomes in HZO and should become the standard of care.

Gender-specific differences in thrombosis have been reported in hospitalized patients with COVID-19. We sought to investigate the influence of age on the relation between gender and incident thrombosis or death in COVID-19. We identified consecutive adults aged ≥18 years hospitalized with COVID-19 from March 1, 2020, to April 17, 2020, at a large New York health system. In-hospital thrombosis and all-cause mortality were evaluated by gender and stratified by age group. Logistic regression models were generated to estimate the odds of thrombosis or death after multivariable adjustment. In 3,334 patients hospitalized with COVID-19, 61% were men. Death or thrombosis occurred in 34% of hospitalizations and was more common in men (36% vs 29% in women, p <0.001; adjusted odds ratio [aOR] 1.61, 95% confidence interval [CI] 1.36 to 1.91). When stratified by age, men had a higher incidence of death or thrombosis in younger patients (aged 18 to 54 years: 21% vs 9%, aOR 3.17, 95% CI 2.06 to 5.01; aged 55 to 74 years: 39% vs 28%, aOR 1.63, 95% CI 1.28 to 2.10), but not older patients (aged ≥75 years: 55% vs 48%; aOR 1.20, 95% CI 0.90 to 1.59) (interaction p value: 0.01). For the individual end points, men were at higher risk of thrombosis (19% vs 12%; aOR 1.65, 95% CI 1.33 to 2.05) and mortality (26% vs 23%; aOR 1.41, 95% CI 1.17 to 1.69) than women, and gender-specific differences were attenuated with older age. Associations between thrombosis and mortality were most striking in younger patients (aged 18 to 54 years, aOR 8.25; aged 55 to 74 years, aOR 2.38; aged >75 years, aOR 1.88; p for interaction <0.001) but did not differ by gender. In conclusion, the risk of thrombosis or death in COVID-19 is higher in men compared with women and is most apparent in younger age groups.

BACKGROUND:ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) compared an initial invasive treatment strategy (INV) with an initial conservative strategy in 5179 participants with chronic coronary disease and moderate or severe ischemia. The ISCHEMIA research program included a comprehensive quality-of-life (QOL) substudy. METHODS:In 1819 participants (907 INV, 912 conservative strategy), we collected a battery of disease-specific and generic QOL instruments by structured interviews at baseline; at 3, 12, 24, and 36 months postrandomization; and at study closeout. Assessments included angina-related QOL (19-item Seattle Angina Questionnaire), generic health status (EQ-5D), depressive symptoms (Patient Health Questionnaire-8), and, for North American patients, cardiac functional status (Duke Activity Status Index). RESULTS:Median age was 67 years, 19.2% were female, and 15.9% were non-White. The estimated mean difference for the 19-item Seattle Angina Questionnaire Summary score favored INV (1.4 points [95% CI, 0.2-2.5] over all follow-up). No differences were observed in patients with rare/absent baseline angina (SAQ Angina Frequency score >80). Among patients with more frequent angina at baseline (SAQ Angina Frequency score <80, 744 patients, 41%), those randomly assigned to INV had a mean 3.7-point higher 19-item Seattle Angina Questionnaire Summary score than conservative strategy (95% CI, 1.6-5.8) with consistent effects across SAQ subscales: Physical Limitations 3.2 points (95% CI, 0.2-6.1), Angina Frequency 3.2 points (95% CI, 1.2-5.1), Quality of Life/Health Perceptions 5.3 points (95% CI, 2.8-7.8). For the Duke Activity Status Index, no difference was estimated overall by treatment, but in patients with baseline SAQ Angina Frequency scores <80, Duke Activity Status Index scores were higher for INV (3.2 points [95% CI, 0.6-5.7]), whereas patients with rare/absent baseline angina showed no treatment-related differences. Moderate to severe depression was infrequent at randomization (11.5%-12.8%) and was unaffected by treatment assignment. CONCLUSIONS:In the ISCHEMIA comprehensive QOL substudy, patients with more frequent baseline angina reported greater improvements in the symptom, physical functioning, and psychological well-being dimensions of QOL when treated with an invasive strategy, whereas patients who had rare/absent angina at baseline reported no consistent treatment-related QOL differences. REGISTRATION/BACKGROUND:URL: https://www. CLINICALTRIALS/RESULTS:gov; Unique identifier: NCT01471522.

As the nation seeks to recruit and retain physician-scientists, gaps remain in understanding and addressing mitigatable challenges to the success of faculty from underrepresented minority (URM) backgrounds. The Doris Duke Charitable Foundation Fund to Retain Clinical Scientists program, implemented in 2015 at 10 academic medical centers in the United States, seeks to retain physician-scientists at risk of leaving science because of periods of extraordinary family caregiving needs, hardships that URM faculty-especially those who identify as female-are more likely to experience. At the annual Fund to Retain Clinical Scientists program directors conference in 2018, program directors-21% of whom identify as URM individuals and 13% as male-addressed issues that affect URM physician-scientists in particular. Key issues that threaten the retention of URM physician-scientists were identified through focused literature reviews; institutional environmental scans; and structured small- and large-group discussions with program directors, staff, and participants. These issues include bias and discrimination, personal wealth differential, the minority tax (i.e., service burdens placed on URM faculty who represent URM perspectives on committees and at conferences), lack of mentorship training, intersectionality and isolation, concerns about confirming stereotypes, and institutional-level factors. The authors present recommendations for how to create an environment in which URM physician-scientists can expect equitable opportunities to thrive, as institutions demonstrate proactive allyship and remove structural barriers to success. Recommendations include providing universal training to reduce interpersonal bias and discrimination, addressing the consequences of the personal wealth gap through financial counseling and benefits, measuring the service faculty members provide to the institution as advocates for URM faculty issues and compensating them appropriately, supporting URM faculty who wish to engage in national leadership programs, and sustaining institutional policies that address structural and interpersonal barriers to inclusive excellence.

Randomized controlled trials (RCTs) remain the gold standard to evaluate clinical interventions, producing the highest level of evidence while minimizing potential bias. Inadequate recruitment is a commonly encountered problem that undermines the completion and generalizability of RCTs-and is even more challenging when enrolling amidst a pandemic. Here, we reflect on our experiences with virtual recruitment of non-hospitalized patients in the United States for ColCorona, an international, multicenter, randomized, placebo-controlled coronavirus disease 2019 (COVID-19) drug trial. Recruitment challenges during a pandemic include constraints created by shelter-in-place policies and targeting enrollment according to national and local fluctuations in infection rate. Presenting a study to potential participants who are sick with COVID-19 and may be frightened, overwhelmed, or mistrusting of clinical research remains a challenge. Strategies previously reported to improve recruitment include transparency, patient and site education, financial incentives, and person-to-person outreach. Active measures taken during ColCorona to optimize United States recruitment involved rapid expansion of sites, adjustment of recruitment scripts, assessing telephone calls versus text messages for initial contact with participants, institutional review board-approved financial compensation, creating an infrastructure to systematically identify potentially eligible patients, partnering with testing sites, appealing to both self-interest and altruism, and large-scale media efforts with varying degrees of success.

BACKGROUND:Patients with significant (≥50%) left main disease (LMD) have a high risk of cardiovascular events, and guidelines recommend revascularization to improve survival. However, the impact of intermediate LMD (stenosis, 25%-49%) on outcomes is unclear. METHODS:Randomized ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) participants who underwent coronary computed tomography angiography at baseline were categorized into those with (25%-49%) and without (<25%) intermediate LMD. The primary outcome was a composite of cardiovascular mortality, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. The primary quality of life outcome was the Seattle Angina Questionnaire summary score. RESULTS: CONCLUSIONS:In the ISCHEMIA trial, there was no meaningful heterogeneity of treatment benefit from an invasive strategy regardless of intermediate LMD status except for a greater absolute risk reduction in nonprocedural MI with invasive management in those with intermediate LMD. An invasive strategy increased procedural MI, reduced nonprocedural MI, and improved angina-related quality of life. REGISTRATION/BACKGROUND:URL: https://www. CLINICALTRIALS/RESULTS:gov; Unique identifier: NCT01471522.

Background In participants with concomitant chronic coronary disease and advanced chronic kidney disease (CKD), the effect of treatment strategies on the timing of dialysis initiation is not well characterized. Methods and Results In ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease), 777 participants with advanced CKD and moderate or severe ischemia were randomized to either an initial invasive or conservative management strategy. Herein, we compare the proportion of randomized participants with non-dialysis-requiring CKD at baseline (n=362) who initiated dialysis and compare the time to dialysis initiation between invasive versus conservative management arms. Using multivariable Cox regression analysis, we also sought to identify the effect of invasive versus conservative chronic coronary disease management strategies on dialysis initiation. At a median follow-up of 23 months (25th-75th interquartile range, 14-32 months), dialysis was initiated in 18.9% of participants (36/190) in the invasive strategy and 16.9% of participants (29/172) in the conservative strategy (P=0.22). The median time to dialysis initiation was 6.0 months (interquartile range, 3.0-16.0 months) in the invasive group and 18.2 months (interquartile range, 12.2-25.0 months) in the conservative group (P=0.004), with no difference in procedural acute kidney injury rates between the groups (7.8% versus 5.4%; P=0.26). Baseline clinical factors associated with earlier dialysis initiation were lower baseline estimated glomerular filtration rate (hazard ratio [HR] associated with 5-unit decrease, 2.08 [95% CI, 1.72-2.56]; P<0.001), diabetes (HR, 2.30 [95% CI, 1.28-4.13]; P=0.005), hypertension (HR, 7.97 [95% CI, 1.09-58.21]; P=0.041), and Hispanic ethnicity (HR, 2.34 [95% CI, 1.22-4.47]; P=0.010). Conclusions In participants with non-dialysis-requiring CKD in ISCHEMIA-CKD, randomization to an invasive chronic coronary disease management strategy (relative to a conservative chronic coronary disease management strategy) is associated with an accelerated time to initiation of maintenance dialysis for kidney failure. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01985360.

Data monitoring committees (DMCs) play a critical role in protecting the safety of participants and integrity of clinical studies. While there are well-established DMC guidelines for traditional, randomized controlled trials, the clinical trial community is still in the search for best practices in data and safety monitoring in pragmatic clinical trials. ADAPTABLE was a large, open label, pragmatic, randomized controlled trial, harnessing real world data from multiple sources and studying the comparative effectiveness of the two most common dosages of aspirin in patients with atherosclerotic cardiovascular disease. Specific issues arose in ADAPTABLE such as data quality, information latency, and protocol adherence, and these issues were both expected and unexpected features of the pragmatic study design. These issues imposed great challenges to the DMC members who were tasked to make critical decisions during the study. This article summarizes the unique experience of the ADAPTABLE DMC, including the internal debates and concerns, the concerted efforts to accomplish its mission, and the special contribution of the patient representatives. We also offer recommendations on data and safety monitoring for future pragmatic trials.