Faculty Bibliography

BACKGROUND:Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been proposed as a potential treatment for adults hospitalised with COVID-19, due to their potential anti-inflammatory and endothelial protective effects. Published evidence from randomised control trials (RCTs) does not provide evidence of benefit. We aimed to estimate the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo in adults hospitalised with COVID-19. METHODS:Eligible RCTs that estimated the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo on 28-day all-cause mortality (primary outcome) were included in this prospective meta-analysis. The primary safety outcome was ketoacidosis by 28 days. Trials were identified through systematic searches of ClinicalTrials.gov, EudraCT, and the WHO ISRCTN registry between Nov 1, 2022 and Jan 31, 2023. The search terms were "random*" AND "COVID" AND each SGLT2i, not restricted by trial status or language. Individual searches were then combined. Prespecified summary outcome data, overall and within subgroups of interest, were provided by each trial. The primary analyses were inverse variance weighted meta-analysis of odds ratios (ORs). Risk of bias was assessed using the Cochrane Risk of Bias tool. This study was registered with PROSPERO, CRD42023406442. FINDINGS/RESULTS:for inconsistency across trials 0%). The risk of bias was assessed as being low. Ketoacidosis was observed in seven participants in the SGLT2 inhibitor group and two patients in the usual care or placebo group. INTERPRETATION/CONCLUSIONS:Although administration of SGLT2 inhibitor was safe, we found no clear evidence that adding SGLT2 inhibitor therapy improved outcomes in patients hospitalised with COVID-19 compared with usual care or placebo. These data do not support the use of SGLT2 inhibitors as standard treatment in adults hospitalised for COVID-19. FUNDING/BACKGROUND:None.

BACKGROUND:Patients hospitalised for COVID-19 are at risk for multiorgan failure and death. Sodium-glucose co-transporter-2 (SGLT2) inhibitors provide cardiovascular and kidney protection in patients with cardiometabolic conditions and could provide organ protection during COVID-19. We aimed to investigate whether SGLT2 inhibitors can reduce the need for organ support in patients hospitalised for COVID-19. METHODS:This pragmatic, multicentre, open-label, randomised, controlled, platform trial was conducted across 63 sites in the USA, Spain, Brazil, Italy, and Mexico. Patients aged at least 18 years hospitalised for COVID-19 (moderate or severe illness) were randomly assigned (1:1), via an interactive voice system or web-response system, to receive locally available SGLT2 inhibitor (administered orally, once daily) plus standard-of-care or standard-of-care for 30 days. The primary outcome was organ support-free days evaluated through 21 days, assessed using intention-to-treat approach. This trial is registered on ClinicalTrials.gov, NCT04505774. FINDINGS/RESULTS:The first patient was randomly assigned to the SGLT2 inhibitor domain on Dec 3, 2021. On March 31, 2023, at the recommendation of the data and safety monitoring board, enrolment in the SGLT2 inhibitor domain for both moderately and severely ill hospitalised patients was stopped prematurely for futility due to a low likelihood of finding a treatment benefit. The final randomised population consisted of 575 patients (mean age 72 years [SD 13], 242 (42%) female and 154 (27%) Hispanic; 504 in the moderate illness group and 71 in the severe illness group). 573 patients had a known 21-day outcome; 215 (75%) of 285 patients in the SGLT2 inhibitor plus standard-of-care group did not require respiratory or cardiovascular organ support versus 231 (80%) of 288 patients in the standard-of-care group. The adjusted odds ratio (OR) for an SGLT2 inhibitor effect on organ support-free days was 0·74 (95% Credible Interval [CrI] 0·48-1·13; where OR higher than 1 indicated treatment benefit, yielding a posterior probability of futility P(OR <1·2) of 99% and a posterior probability of inferiority P(OR<1·0) of 91%). There were 37 deaths (13%) in the SGLT2 inhibitor plus standard-of-care group and 42 deaths (15%) in the standard-of-care group at 90 days (hazard ratio 0·91 [95% CrI 0·58-1·43], probability of hazard ratio <1 of 66%). No safety concerns were observed with SGLT2 inhibitors, including no cases of ketoacidosis. INTERPRETATION/CONCLUSIONS:SGLT2 inhibitors did not significantly increase days free of organ support or reduce mortality in patients hospitalised with COVID-19. SGLT2 inhibitors were well tolerated with no observed safety concerns. Overall, these findings do not support the use of SGLT2 inhibitors as standard care in patients hospitalised with COVID-19. FUNDING/BACKGROUND:National Institutes of Health.

BACKGROUND/UNASSIGNED:Pursuing initial invasive or conservative management of chronic coronary disease (CCD) is a preference-sensitive decision that should include shared decision-making. Communicating the benefits of either approach is challenging, as individual patients rarely achieve the population-averaged outcomes reported in clinical trials. Our objective was to develop a patient decision aid (PDA) with patient-specific estimates of outcomes for initial invasive versus conservative management of CCD, based on the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches). METHODS/UNASSIGNED:This was a multiphase mixed-methods study using focus groups of outpatients with CCD, caregivers, clinicians, and researchers. Focus groups were held in Kansas City, MO and New York City, NY between September 2021 and June 2022. Patients with CCD were included if they had a positive stress test within 1 year. Phase 1 focused on patient priorities for outcomes to guide treatment decisions. Phase 2 involved PDA development and refinement. Phase 3 involved further refinement and member checking. Key themes involving shared decision-making and treatment preferences were elicited from focus groups using a deductive approach to develop a PDA representing the outcomes most important to patients. RESULTS/UNASSIGNED:Of 46 patient and caregiver participants, the mean age was 63.5 years, 53% were female, 61% were White, 24% were Black, and 9% were Hispanic. When deciding between treatments, participants valued shared decision-making but generally deferred decisions to clinicians. The outcomes most important to participants were survival and quality of life, followed by physical functioning and symptoms. To represent these outcomes, participants favored simple visualizations, such as a speedometer or health meter. When deciding between treatment options, participants preferred to use the PDA collaboratively with a clinician instead of as a stand-alone tool. CONCLUSIONS/UNASSIGNED:Our novel, patient-centered approach to developing a PDA for CCD with patient-specific outcomes has the potential to rapidly translate clinical trial results to individual patients and support shared decision-making.

BACKGROUND/UNASSIGNED:The ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) demonstrated greater health status benefits with an initial invasive strategy, as compared with a conservative one, for patients with chronic coronary disease and moderate or severe ischemia. Whether these benefits vary globally is important to understand to support global adoption of the results. METHODS/UNASSIGNED:We analyzed participants' disease-specific health status using the validated 7-item Seattle Angina Questionnaire (SAQ: >5-point differences are clinically important) at baseline and over 1-year follow-up across 37 countries in 6 international regions. The average effect of initial invasive versus conservative strategies on 1-year SAQ scores was estimated using Bayesian proportional odds regression and compared across regions. RESULTS/UNASSIGNED:Considerable regional variation in baseline health status was observed among 4617 participants (mean age=64.4±9.5 years, 24% women), with the mean SAQ summary scores of 67.4±19.5 in Eastern Europe participants (17% of the total), 71.4±15.4 in Asia-Pacific (18%), 74.9±16.7 in Central and South America (10%), 75.5±19.5 in Western Europe (26%), and 78.6±19.2 in North America (28%). One-year improvements in SAQ scores were greater in regions with lower baseline scores with initial invasive management (17.7±20.9 in Eastern Europe and 11.4±19.3 in North America), but similar in the conservative arm. Adjusting for baseline SAQ scores, similar health status benefits of an initial invasive strategy on 1-year SAQ scores were observed (ranging from 2.38 points [95% CI, 0.04-4.50] in North America to 4.66 points [95% CI, 2.46-6.94] in Eastern Europe), with an 88.3% probability that the difference in benefit across regions was <5 points. CONCLUSIONS/UNASSIGNED:In patients with chronic coronary disease and moderate or severe ischemia, initial invasive management was associated with a consistent health status benefit across regions, with modest regional variability, supporting the international generalizability of health status benefits from invasive management of chronic coronary disease. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

BACKGROUND AND AIMS/OBJECTIVE:The aim of this study was to determine the prognostic value of coronary computed tomography angiography (CCTA)-derived atherosclerotic plaque analysis in ISCHEMIA. METHODS:Atherosclerosis imaging quantitative computed tomography (AI-QCT) was performed on all available baseline CCTAs to quantify plaque volume, composition, and distribution. Multivariable Cox regression was used to examine the association between baseline risk factors (age, sex, smoking, diabetes, hypertension, ejection fraction, prior coronary disease, estimated glomerular filtration rate, and statin use), number of diseased vessels, atherosclerotic plaque characteristics determined by AI-QCT, and a composite primary outcome of cardiovascular death or myocardial infarction over a median follow-up of 3.3 (interquartile range 2.2-4.4) years. The predictive value of plaque quantification over risk factors was compared in an area under the curve (AUC) analysis. RESULTS:Analysable CCTA data were available from 3711 participants (mean age 64 years, 21% female, 79% multivessel coronary artery disease). Amongst the AI-QCT variables, total plaque volume was most strongly associated with the primary outcome (adjusted hazard ratio 1.56, 95% confidence interval 1.25-1.97 per interquartile range increase [559 mm3]; P = .001). The addition of AI-QCT plaque quantification and characterization to baseline risk factors improved the model's predictive value for the primary outcome at 6 months (AUC 0.688 vs. 0.637; P = .006), at 2 years (AUC 0.660 vs. 0.617; P = .003), and at 4 years of follow-up (AUC 0.654 vs. 0.608; P = .002). The findings were similar for the other reported outcomes. CONCLUSIONS:In ISCHEMIA, total plaque volume was associated with cardiovascular death or myocardial infarction. In this highly diseased, high-risk population, enhanced assessment of atherosclerotic burden using AI-QCT-derived measures of plaque volume and composition modestly improved event prediction.

Platelets are key mediators of atherothrombosis, yet, limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study, we investigate the association of platelet hyperreactivity and cardiovascular events, and introduce a tool, the Platelet Reactivity ExpreSsion Score (PRESS), which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD), those with a hyperreactive platelet response (>60% aggregation) to 0.4 µM epinephrine had a higher incidence of the 30 day primary cardiovascular endpoint (37.2% vs. 15.3% in those without hyperreactivity, adjusted HR 2.76, 95% CI 1.5-5.1, p = 0.002). PRESS performs well in identifying a hyperreactive phenotype in patients with PAD (AUC [cross-validation] 0.81, 95% CI 0.68 -0.94, n = 84) and in an independent cohort of healthy participants (AUC [validation] 0.77, 95% CI 0.75 -0.79, n = 35). Following multivariable adjustment, PAD individuals with a PRESS score above the median are at higher risk for a future cardiovascular event (adjusted HR 1.90, CI 1.07-3.36; p = 0.027, n = 129, NCT02106429). This study derives and validates the ability of PRESS to discriminate platelet hyperreactivity and identify those at increased cardiovascular risk. Future studies in a larger independent cohort are warranted for further validation. The development of a platelet reactivity expression score opens the possibility for a personalized approach to antithrombotic therapy for cardiovascular risk reduction.

Cardiometabolic comorbidities, diabetes (DM), hypertension (HTN), and obesity, contribute to cardiovascular disease (CVD). Circulating biomarkers facilitate prognostication for patients with CVD. We explored the relationship between cardiometabolic comorbidity burden in patients with chronic coronary disease (CCD) and biomarkers of myocardial stretch, injury, inflammation, and platelet activity. We analyzed participants from the ISCHEMIA Trials biorepository with plasma biomarkers (NT-proBNP, hs-cTnT, hs-CRP, IL-6, sCD40L, and GDF-15) and clinical risk factors [hemoglobin A1c (HbA1c), systolic blood pressure (SBP), and body mass index (BMI)] at baseline. We defined cardiometabolic comorbidities as DM, HTN, and obesity at baseline. Comorbidity burden characterized by number and severity of comorbidities. Controlled comorbidities were defined as HbA1c <7% for those with DM, SBP <130 mmHg for those with HTN and BMI <30 kg/m². Severely uncontrolled was defined as HbA1c ≥8%, SBP ≥160 mmHg, and BMI ≥35 kg/m². We performed linear regression analyses to examine the association between comorbidity burden and log-transformed biomarker levels adjusting for age, sex, eGFR controlled for hemodialysis, and left ventricular ejection fraction. A total of 752 individuals (mean age 66, 19% female, 84% white) were included in this analysis. Self-reported Black race, current smokers, history of MI and HF had greater cardiometabolic comorbidity burden. The presence of ≥ 1 severely uncontrolled comorbidity was associated with significantly higher baseline levels of hs-cTnT, hs-CRP, IL-6, and GDF-15 compared to participants with no comorbidities. In conclusion, increasing cardiometabolic comorbidity burden in patients with CCD is associated with higher levels of circulating biomarkers of myocardial injury and inflammation.

BACKGROUND:Myocardial infarction and heart failure are major cardiovascular diseases that affect millions of people in the US with the morbidity and mortality being highest among patients who develop cardiogenic shock. Early recognition of cardiogenic shock allows prompt implementation of treatment measures. Our objective is to develop a new dynamic risk score, called CShock, to improve early detection of cardiogenic shock in cardiac intensive care unit (ICU). METHODS:We developed and externally validated a deep learning-based risk stratification tool, called CShock, for patients admitted into the cardiac ICU with acute decompensated heart failure and/or myocardial infarction to predict onset of cardiogenic shock. We prepared a cardiac ICU dataset using MIMIC-III database by annotating with physician adjudicated outcomes. This dataset that consisted of 1500 patients with 204 having cardiogenic/mixed shock was then used to train CShock. The features used to train the model for CShock included patient demographics, cardiac ICU admission diagnoses, routinely measured laboratory values and vital signs, and relevant features manually extracted from echocardiogram and left heart catheterization reports. We externally validated the risk model on the New York University (NYU) Langone Health cardiac ICU database that was also annotated with physician adjudicated outcomes. The external validation cohort consisted of 131 patients with 25 patients experiencing cardiogenic/mixed shock. RESULTS:CShock achieved an area under the receiver operator characteristic curve (AUROC) of 0.821 (95% CI 0.792-0.850). CShock was externally validated in the more contemporary NYU cohort and achieved an AUROC of 0.800 (95% CI 0.717-0.884), demonstrating its generalizability in other cardiac ICUs. Having an elevated heart rate is most predictive of cardiogenic shock development based on Shapley values. The other top ten predictors are having an admission diagnosis of myocardial infarction with ST-segment elevation, having an admission diagnosis of acute decompensated heart failure, Braden Scale, Glasgow Coma Scale, Blood urea nitrogen, Systolic blood pressure, Serum chloride, Serum sodium, and Arterial blood pH. CONCLUSIONS:The novel CShock score has the potential to provide automated detection and early warning for cardiogenic shock and improve the outcomes for the millions of patients who suffer from myocardial infarction and heart failure.