Faculty Bibliography

BACKGROUND:ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) reported an initial invasive treatment strategy did not reduce the risk of death or nonfatal myocardial infarction (MI) compared with a conservative treatment strategy in patients with advanced chronic kidney disease, stable coronary disease, and moderate or severe myocardial ischemia. The cumulative frequency of different MI type after randomization and subsequent prognosis have not been reported. METHODS:MI classification was based on the Third Universal Definition for MI. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary MI definition used cTn (cardiac troponin); both definitions included elevated biomarker-only events with higher thresholds than nonprocedural MIs. The cumulative frequency of MI type according to treatment strategy was determined. The association of MI with subsequent all-cause death and new dialysis initiation was assessed by treating MI as a time-dependent covariate. RESULTS:The 3-year incidence of type 1 or 2 MI with the primary MI definition was 11.2% in invasive treatment strategy and 13.6% in conservative treatment strategy (hazard ratio [HR], 0.66 [95% CI, 0.42-1.02]). Procedural MIs were more frequent in invasive treatment strategy and accounted for 9.8% and 28.3% of all MIs with the primary and secondary MI definitions, respectively. Patients had an increased risk of all-cause death after type 1 MI (adjusted HR, 4.35 [95% CI, 2.73-6.93]) and after procedural MI with the primary (adjusted HR, 2.75 [95% CI, 0.99-7.60]) and secondary MI definitions (adjusted HR, 2.91 [95% CI, 1.73-4.88]). Dialysis initiation was increased after a type 1 MI (HR, 6.45 [95% CI, 2.59-16.08]) compared with patients without an MI. CONCLUSIONS:In ISCHEMIA-CKD, the invasive treatment strategy had higher rates of procedural MIs, particularly with the secondary MI definition, and lower rates of type 1 and 2 MIs. Procedural MIs, type 1 MIs, and type 2 MIs were associated with increased risk of subsequent death. Type 1 MI increased the risk of dialysis initiation. REGISTRATION/BACKGROUND:URL: https://www. CLINICALTRIALS/RESULTS:gov; Unique identifier: NCT01985360.

Importance/UNASSIGNED:Prior trials of invasive vs conservative management of chronic coronary disease (CCD) have not enrolled patients with severe chronic kidney disease (CKD). As such, outcomes across kidney function are not well characterized. Objectives/UNASSIGNED:To evaluate clinical and quality-of-life (QoL) outcomes across the spectrum of CKD following conservative and invasive treatment strategies. Design, Setting, and Participants/UNASSIGNED:Participants from the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) and ISCHEMIA-Chronic Kidney Disease (CKD) trials were categorized by CKD stage: stage 1 (estimated glomerular filtration rate [eGFR] 90 mL/min/1.73m2 or greater), stage 2 (eGFR 60-89 mL/min/1.73m2), stage 3 (eGFR 30-59 mL/min/1.73m2), stage 4 (eGFR 15-29 mL/min/1.73m2), or stage 5 (eGFR less than 15 mL/min/1.73m2 or receiving dialysis). Enrollment took place from July 26, 2012, through January 31, 2018, with a median follow-up of 3.1 years. Data were analyzed from January 2020 to May 2021. Interventions/UNASSIGNED:Initial invasive management of coronary angiography and revascularization with guideline-directed medical therapy (GDMT) vs initial conservative management of GDMT alone. Main Outcomes and Measures/UNASSIGNED:The primary clinical outcome was a composite of death or nonfatal myocardial infarction (MI). The primary QoL outcome was the Seattle Angina Questionnaire (SAQ) summary score. Results/UNASSIGNED:Among the 5956 participants included in this analysis (mean [SD] age, 64 [10] years; 1410 [24%] female and 4546 [76%] male), 1889 (32%), 2551 (43%), 738 (12%), 311 (5%), and 467 (8%) were in CKD stages 1, 2, 3, 4, and 5, respectively. By self-report, 18 participants (<1%) were American Indian or Alaska Native; 1676 (29%), Asian; 267 (5%), Black; 861 (16%), Hispanic or Latino; 18 (<1%), Native Hawaiian or Other Pacific Islander; 3884 (66%), White; and 13 (<1%), multiple races or ethnicities. There was a monotonic increase in risk of the primary composite end point (3-year rates, 9.52%, 10.72%, 18.42%, 34.21%, and 38.01% respectively), death, cardiovascular death, MI, and stroke in individuals with higher CKD stages. Invasive management was associated with an increase in stroke (3-year event rate difference, 1%; 95% CI, 0.3 to 1.7) and procedural MI (1.6%; 95% CI, 0.9 to 2.3) and a decrease in spontaneous MI (-2.5%; 95% CI, -3.9 to -1.1) with no difference in other outcomes; the effect was similar across CKD stages. There was heterogeneity of treatment effect for QoL outcomes such that invasive management was associated with an improvement in angina-related QoL in individuals with CKD stages 1 to 3 and not in those with CKD stages 4 to 5. Conclusions and Relevance/UNASSIGNED:Among participants with CCD, event rates were inversely proportional to kidney function. Invasive management was associated with an increase in stroke and procedural MI and a reduced risk in spontaneous MI, and the effect was similar across CKD stages with no difference in other outcomes, including death. The benefit for QoL with invasive management was not observed in individuals with poorer kidney function.

OBJECTIVES/OBJECTIVE:We designed this study to test whether clazakizumab, a direct interleukin-6 inhibitor, benefits patients hospitalized with severe or critical COVID-19 disease accompanied by hyperinflammation. DESIGN/METHODS:Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial. SETTING/METHODS:Five U.S. medical centers. PATIENTS/METHODS:Adults inpatients with severe COVID-19 disease and hyperinflammation. INTERVENTIONS/METHODS:Eighty-one patients enrolled in phase II, randomized 1:1:1 to low-dose (12.5 mg) or high-dose (25 mg) clazakizumab or placebo. Ninety-seven patients enrolled in phase III, randomized 1:1 to high-dose clazakizumab or placebo. MEASUREMENTS AND MAIN RESULTS/RESULTS:The primary outcome was 28-day ventilator-free survival. Secondary outcomes included overall survival ,frequency and duration of intubation, and frequency and duration of ICU admission. Per Data Safety and Monitoring Board recommendations, additional secondary outcomes describing clinical status and status changes, as measured by an ordinal scale, were added. Bayesian cumulative proportional odds, logistic, and Poisson regression models were used. The low-dose arm was dropped when the phase II study suggested superiority of the high-dose arm. We report on 152 patients, 74 randomized to placebo and 78 to high-dose clazakizumab. Patients receiving clazakizumab had greater odds of 28-day ventilator-free survival (odds ratio [OR] = 3.84; p [OR > 1] 99.9%), as well as overall survival at 28 and 60 days (OR = 1.75; p [OR > 1] 86.5% and OR = 2.53; p [OR > 1] 97.7%). Clazakizumab was associated with lower odds of intubation (OR = 0.2; p [OR] < 1; 99.9%) and ICU admission (OR = 0.26; p [OR < 1] 99.6%); shorter durations of ventilation and ICU stay (risk ratio [RR] < 0.75; p [RR < 1] > 99% for both); and greater odds of improved clinical status at 14, 28, and 60 days (OR = 2.32, p [OR > 1] 98.1%; OR = 3.36, p [OR > 1] 99.6%; and OR = 3.52, p [OR > 1] 99.8%, respectively). CONCLUSIONS:Clazakizumab significantly improved 28-day ventilator-free survival, 28- and 60-day overall survival, as well as clinical outcomes in hospitalized patients with COVID-19 and hyperinflammation.

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.

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.

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.

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.

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.