Faculty Bibliography

IMPORTANCE:Platelet activation is a potential therapeutic target in patients with COVID-19. OBJECTIVE:To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS:This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients. INTERVENTION:Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. MAIN OUTCOMES AND MEASURES:The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis. RESULTS:At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support-free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77). CONCLUSIONS AND RELEVANCE:In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT04505774.

Background Psychological well-being is important among individuals with myocardial infarction (MI) given the clear links between stress, depression, and adverse cardiovascular outcomes. Stress and depressive disorders are more prevalent in women than men after MI. Resilience may protect against stress and depressive disorders after a traumatic event. Longitudinal data are lacking in populations post MI. We examined the role of resilience in the psychological recovery of women post MI, over time. Methods and Results We analyzed a sample from a longitudinal observational multicenter study (United States, Canada) of women post MI, between 2016 and 2020. Perceived stress (Perceived Stress Scale-4 [PSS-4]) and depressive symptoms (Patient Health Questionnaire-2 [PHQ-2]) were assessed at baseline (time of MI) and 2 months post MI. Demographics, clinical characteristics, and resilience (Brief Resilience Scale [BRS]) were collected at baseline. Low and normal/high resilience groups were established as per published cutoffs (BRS scores <3 or ≥3). Mixed-effects modeling was used to examine associations between resilience and psychological recovery over 2 months. The sample included 449 women, mean (SD) age, 62.2 (13.2) years, of whom 61.1% identified as non-Hispanic White, 18.5% as non-Hispanic Black, and 15.4% as Hispanic/Latina. Twenty-three percent had low resilience. The low resilience group had significantly higher PSS-4 and PHQ-2 scores than the normal/high resilience group at all time points. In adjusted models, both groups showed a decrease in PSS-4 scores over time. Conclusions In a diverse cohort of women post MI, higher resilience is associated with better psychological recovery over time. Future work should focus on developing strategies to strengthen resilience and improve psychological well-being for women with MI. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02905357; Unique identifier: NCT02905357.

BACKGROUND:Mineralocorticoid receptor antagonists (MRA) are under-prescribed for patients with heart failure with reduced ejection fraction (HFrEF). OBJECTIVE:To compare effectiveness of two automated, electronic health record (EHR)-embedded tools vs. usual care on MRA prescribing in eligible patients with HFrEF. METHODS:BETTER CARE-HF (Building Electronic Tools To Enhance and Reinforce CArdiovascular REcommendations for Heart Failure) was a three-arm, pragmatic, cluster-randomized trial comparing the effectiveness of an alert during individual patient encounters vs. a message about multiple patients between encounters vs. usual care on MRA prescribing. We included adult patients with HFrEF, no active MRA prescription, no contraindication to MRA, and an outpatient cardiologist in a large health system. Patients were cluster-randomized by cardiologist (60 per arm). RESULTS:The study included 2,211 patients (alert: 755, message: 812, usual care [control]: 644), with average age 72.2 years, average EF 33%, who were predominantly male (71.4%) and White (68.9%). New MRA prescribing occurred in 29.6% of patients in the alert arm, 15.6% in the message arm, and 11.7% in the control arm. The alert more than doubled MRA prescribing compared to control (RR: 2.53, 95% CI: 1.77-3.62, p<0.0001), and improved MRA prescribing compared to the message (RR: 1.67, 95% CI: 1.21-2.29, p=0.002). The number of patients with alert needed to result in an additional MRA prescription was 5.6. CONCLUSIONS:An automated, patient-specific, EHR-embedded alert increased MRA prescribing compared to both a message and usual care. Our findings highlight the potential for EHR-embedded tools to substantially increase prescription of life-saving therapies for HFrEF. (NCT05275920).

BACKGROUND/UNASSIGNED:Coronary artery spasm is an established mechanism of myocardial infarction with non-obstructive coronary arteries (MINOCA). Various mechanisms have been proposed, ranging from vascular smooth muscle hyperreactivity to endothelial dysfunction, to autonomic nervous system dysregulation. CASE SUMMARY/UNASSIGNED:We report a case of a 37-year-old woman who presented with recurrent non-ST elevation myocardial infarction (NSTEMI), coinciding with her menstrual periods. Intracoronary acetylcholine provocation testing resulted in coronary spasm in the left anterior descending artery (LAD) that was relieved with nitroglycerine. Initiating calcium channel blockade and suppressing cyclical variation in sex hormones resulted in improvement of her symptoms and cessation of monthly NSTEMI events due to coronary spasm. DISCUSSION/UNASSIGNED:Initiating calcium channel blockade and suppressing cyclical variation in sex hormones resulted in improvement of her symptoms and cessation of monthly NSTEMI events due to coronary spasm. Catamenial coronary artery spasm is a rare, but clinically important, presentation of myocardial infarction with non-obstructive coronary arteries (MINOCA).

Myocardial infarction with nonobstructive coronary arteries (MINOCA) is an important subtype of myocardial infarction (MI) that occurs in approximately 6-8% of patients with spontaneous MI who are referred for coronary angiography. MINOCA disproportionately affects women, but men are also affected. Pathogenesis is more variable than in MI with obstructive coronary artery disease (MI-CAD). Dominant mechanisms include atherosclerosis, thrombosis, and coronary artery spasm. Management of MINOCA varies based on the underlying mechanism of infarction. Therefore, systematic approaches to diagnosis are recommended. The combination of invasive coronary angiography, multivessel intracoronary imaging, provocative testing for coronary spasm, and cardiac magnetic resonance imaging provides the greatest diagnostic yield. Current clinical practice guidelines for the secondary prevention of MI are based largely on data from patients with MI-CAD. Thus, optimal medications after MINOCA are uncertain. Clinical trials focused on the treatment of patients with MINOCA are urgently needed to define optimal care. Expected final online publication date for the Annual Review of Medicine, Volume 74 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

BACKGROUND:In ISCHEMIA-CKD, 777 patients with advanced chronic kidney disease and chronic coronary disease had similar all-cause mortality with either an initial invasive or conservative strategy (27.2% vs 27.8%, respectively). OBJECTIVES/OBJECTIVE:This prespecified secondary analysis from ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) was conducted to determine whether an initial invasive strategy compared with a conservative strategy decreased the incidence of cardiovascular (CV) vs non-CV causes of death. METHODS:Three-year cumulative incidences were calculated for the adjudicated cause of death. Overall and cause-specific death by treatment strategy were analyzed using Cox models adjusted for baseline covariates. The association between cause of death, risk factors, and treatment strategy were identified. RESULTS:A total of 192 of the 777 participants died during follow-up, including 94 (12.1%) of a CV cause, 59 (7.6%) of a non-CV cause, and 39 (5.0%) of an undetermined cause. The 3-year cumulative rates of CV death were similar between the invasive and conservative strategies (14.6% vs 12.6%, respectively; HR: 1.13, 95% CI: 0.75-1.70). Non-CV death rates were also similar between the invasive and conservative arms (8.4% and 8.2%, respectively; HR: 1.25; 95% CI: 0.75-2.09). Sudden cardiac death (46.8% of CV deaths) and infection (54.2% of non-CV deaths) were the most common cause-specific deaths and did not vary by treatment strategy. CONCLUSIONS:In ISCHEMIA-CKD, CV death was more common than non-CV or undetermined death during the 3-year follow-up. The randomized treatment assignment did not affect the cause-specific incidences of death in participants with advanced CKD and moderate or severe myocardial ischemia. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease [ISCHEMIA-CKD]; NCT01985360).

BACKGROUND:Beart failure with reduced ejection fraction (HFrEF) is a leading cause of morbidity and mortality. However, shortfalls in prescribing of proven therapies, particularly mineralocorticoid receptor antagonist (MRA) therapy, account for several thousand preventable deaths per year nationwide. Electronic clinical decision support (CDS) is a potential low-cost and scalable solution to improve prescribing of therapies. However, the optimal timing and format of CDS tools is unknown. METHODS AND RESULTS/RESULTS:We developed two targeted CDS tools to inform cardiologists of gaps in MRA therapy for patients with HFrEF and without contraindication to MRA therapy: (1) an alert that notifies cardiologists at the time of patient visit, and (2) an automated electronic message that allows for review between visits. We designed these tools using an established CDS framework and findings from semistructured interviews with cardiologists. We then pilot tested both CDS tools (n = 596 patients) and further enhanced them based on additional semistructured interviews (n = 11 cardiologists). The message was modified to reduce the number of patients listed, include future visits, and list date of next visit. The alert was modified to improve noticeability, reduce extraneous information on guidelines, and include key information on contraindications. CONCLUSIONS:The BETTER CARE-HF (Building Electronic Tools to Enhance and Reinforce CArdiovascular REcommendations for Heart Failure) trial aims to compare the effectiveness of the alert vs. the automated message vs. usual care on the primary outcome of MRA prescribing. To our knowledge, no study has directly compared the efficacy of these two different types of electronic CDS interventions. If effective, our findings can be rapidly disseminated to improve morbidity and mortality for patients with HFrEF, and can also inform the development of future CDS interventions for other disease states. (Trial registration: Clinicaltrials.gov NCT05275920).

BACKGROUND:Ischemia with nonobstructive coronary arteries (INOCA) is common clinically, particularly among women, but its prevalence among patients with at least moderate ischemia and the relationship between ischemia severity and non-obstructive atherosclerosis severity are unknown. OBJECTIVES/OBJECTIVE:The authors investigated predictors of INOCA in enrolled, nonrandomized participants in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), sex differences, and the relationship between ischemia and atherosclerosis in patients with INOCA. METHODS:Core laboratories independently reviewed screening noninvasive stress test results (nuclear imaging, echocardiography, magnetic resonance imaging or nonimaging exercise tolerance testing), and coronary computed tomography angiography (CCTA), blinded to results of the screening test. INOCA was defined as all stenoses <50% on CCTA in a patient with moderate or severe ischemia on stress testing. INOCA patients, who were excluded from randomization, were compared with randomized participants with ≥50% stenosis in ≥1 vessel and moderate or severe ischemia. RESULTS:Among 3,612 participants with core laboratory-confirmed moderate or severe ischemia and interpretable CCTA, 476 (13%) had INOCA. Patients with INOCA were younger, were predominantly female, and had fewer atherosclerosis risk factors. For each stress testing modality, the extent of ischemia tended to be less among patients with INOCA, particularly with nuclear imaging. There was no significant relationship between severity of ischemia and extent or severity of nonobstructive atherosclerosis on CCTA. On multivariable analysis, women female sex was independently associated with INOCA (odds ratio: 4.2 [95% CI: 3.4-5.2]). CONCLUSIONS:Among participants enrolled in ISCHEMIA with core laboratory-confirmed moderate or severe ischemia, the prevalence of INOCA was 13%. Severity of ischemia was not associated with severity of nonobstructive atherosclerosis. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

BACKGROUND:Male sex, elevated troponin levels, and elevated D-dimer levels are associated with more complicated COVID-19 illness and greater mortality; however, while there are known sex differences in the prognostic value of troponin and D-dimer in other disease states, it is unknown whether they exist in the setting of COVID-19. OBJECTIVE:We assessed whether sex modified the relationship between troponin, D-dimer, and severe COVID-19 illness (defined as mechanical ventilation, ICU admission or transfer, discharge to hospice, or death). METHODS:We conducted a retrospective cohort study of patients hospitalized with COVID-19 at a large, academic health system. We used multivariable regression to assess associations between sex, troponin, D-dimer, and severe COVID-19 illness, adjusting for demographic, clinical, and laboratory covariates. To test whether sex modified the relationship between severe COVID-19 illness and troponin or D-dimer, models with interaction terms were utilized. RESULTS:Among 4,574 patients hospitalized with COVID-19, male sex was associated with higher levels of troponin and greater odds of severe COVID-19 illness, but lower levels of initial D-dimer when compared with female sex. While sex did not modify the relationship between troponin level and severe COVID-19 illness, peak D-dimer level was more strongly associated with severe COVID-19 illness in male patients compared to female patients (males: OR=2.91, 95%CI=2.63-2.34, p<0.001; females: OR=2.31, 95%CI=2.04-2.63, p<0.001; p-interaction=0.005). CONCLUSION/CONCLUSIONS:Sex did not modify the association between troponin level and severe COVID-19 illness, but did modify the association between peak D-dimer and severe COVID-19 illness, suggesting greater prognostic value for D-dimer in males with COVID-19.