Faculty Bibliography

BACKGROUND/UNASSIGNED:Clinical trials are increasingly using Bayesian methods for their design and analysis. Inference in Bayesian trials typically uses simulation-based approaches such as Markov Chain Monte Carlo methods. Markov Chain Monte Carlo has high computational cost and can be complex to implement. The Integrated Nested Laplace Approximations algorithm provides approximate Bayesian inference without the need for computationally complex simulations, making it more efficient than Markov Chain Monte Carlo. The practical properties of Integrated Nested Laplace Approximations compared to Markov Chain Monte Carlo have not been considered for clinical trials. Using data from a published clinical trial, we aim to investigate whether Integrated Nested Laplace Approximations is a feasible and accurate alternative to Markov Chain Monte Carlo and provide practical guidance for trialists interested in Bayesian trial design. METHODS/UNASSIGNED:Data from an international Bayesian multi-platform adaptive trial that compared therapeutic-dose anticoagulation with heparin to usual care in non-critically ill patients hospitalized for COVID-19 were used to fit Bayesian hierarchical generalized mixed models. Integrated Nested Laplace Approximations was compared to two Markov Chain Monte Carlo algorithms, implemented in the software JAGS and stan, using packages available in the statistical software R. Seven outcomes were analysed: organ-support free days (an ordinal outcome), five binary outcomes related to survival and length of hospital stay, and a time-to-event outcome. The posterior distributions for the treatment and sex effects and the variances for the hierarchical effects of age, site and time period were obtained. We summarized these posteriors by calculating the mean, standard deviations and the 95% equitailed credible intervals and presenting the results graphically. The computation time for each algorithm was recorded. RESULTS/UNASSIGNED:The average overlap of the 95% credible interval for the treatment and sex effects estimated using Integrated Nested Laplace Approximations was 96% and 97.6% compared with stan, respectively. The graphical posterior densities for these effects overlapped for all three algorithms. The posterior mean for the variance of the hierarchical effects of age, site and time estimated using Integrated Nested Laplace Approximations are within the 95% credible interval estimated using Markov Chain Monte Carlo but the average overlap of the credible interval is lower, 77%, 85.6% and 91.3%, respectively, for Integrated Nested Laplace Approximations compared to stan. Integrated Nested Laplace Approximations and stan were easily implemented in clear, well-established packages in R, while JAGS required the direct specification of the model. Integrated Nested Laplace Approximations was between 85 and 269 times faster than stan and 26 and 1852 times faster than JAGS. CONCLUSION/UNASSIGNED:Integrated Nested Laplace Approximations could reduce the computational complexity of Bayesian analysis in clinical trials as it is easy to implement in R, substantially faster than Markov Chain Monte Carlo methods implemented in JAGS and stan, and provides near identical approximations to the posterior distributions for the treatment effect. Integrated Nested Laplace Approximations was less accurate when estimating the posterior distribution for the variance of hierarchical effects, particularly for the proportional odds model, and future work should determine if the Integrated Nested Laplace Approximations algorithm can be adjusted to improve this estimation.

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.

Postoperative venous thromboembolism (VTE) is a common and costly complication following total joint arthroplasty (TJA). Development of a refined thrombophilic screening panel will better equip clinicians to identify patients at high-est risk for developing VTEs. In this pilot study, 62 high-risk TJA recipients who had developed pulmonary emboli (PE) within 90-days of surgery were eligible to participate. Of these patients, 14 were enrolled and subsequently adminis-tered a pre-determined panel of 18 hematologic tests with the aim of identifying markers that are consistently elevated or deficient in patients developing PE. A separate cohort of seven high-risk TJA recipients who did not report a symp-tomatic VTE within 90-days of surgery were then enrolled and Factor VIII and lipoprotein(a) levels were assessed. The most common aberrance was noted in 10 patients (71.4%) who had elevated levels of Factor VIII followed by five patients (35.7%) who had elevated levels of lipoprotein(a). Factor VIII was significantly prevalent (p < 0.001) while lipoprotein(a) failed to achieve statistical significance (p = 0.0708). Of the patients who were within normal limits of Factor VIII, three-fourths were "high-normal" with Fac-tor VIII levels within 5% of the upper limit of normal. This study demonstrates the potential utility of this hematologic panel as part of a perioperative screening protocol aimed at identifying patients at risk for developing VTEs. However, future larger scale studies assessing the capabilities and limitations of our findings are warranted.

BACKGROUND:Women with chronic coronary disease are generally older than men and have more comorbidities but less atherosclerosis. We explored sex differences in revascularization, guideline-directed medical therapy, and outcomes among patients with chronic coronary disease with ischemia on stress testing, with and without invasive management. METHODS AND RESULTS/RESULTS:=0.49), with no significant sex-by-treatment-group interactions. CONCLUSIONS:Women had less extensive coronary artery disease and, therefore, lower revascularization rates in the invasive group. Despite lower risk factor goal attainment, women with chronic coronary disease experienced similar risk-adjusted outcomes to men in the ISCHEMIA trial. REGISTRATION/BACKGROUND:URL: http://wwwclinicaltrials.gov. Unique identifier: NCT01471522.

BACKGROUND:Cardiometabolic risk factors diabetes, obesity, and hypertension are highly prevalent and contribute to increased cardiovascular disease (CVD). Endothelial dysfunction precedes CVD development. The current study aimed to investigate the EC transcriptome among individuals with varying degree of cardiometabolic risk. METHODS:Adult participants without CVD and various degrees of cardiometabolic risk factor burden (hypertension, diabetes, obesity) were included. Participants underwent brachial vein EC harvesting followed by RNA sequencing. To evaluate the association between cardiometabolic comorbidity burden and outcome transcripts we performed linear regression with multivariable models, adjusting for age, sex, and race/ethnicity. RESULTS:A total of 18 individuals were included in the present analysis (mean age 47 ± 14, 44% female, and 61% White adults). Endothelial cell RNA sequencing revealed 588 differentially expressed transcripts (p-adj <0.05) with excellent discrimination in unsupervised hierarchical clustering analysis. Gene ontology enrichment analysis revealed upregulated pathways associated with T-cell activation (NES = 2.22, p<0.001), leukocyte differentiation (NES= 2.16, p<0.001), leukocyte migration (NES= 2.12, p<0.001), regulation of cell-cell adhesion (NES= 1.91, p=0.006). Downregulated pathways of interest included endothelial cell proliferation (NES= -1.68, p=0.03) and response to interleukin-1 (NES= -1.61, p=0.04). Upregulated genes included VCAM1, CEACAM1, ADAM 17, and CD99L2, all with a log-2-fold change >3 and p-adj <0.05. These genes demonstrated a graded increase in mean normalized counts with increasing number of risk factors. CONCLUSIONS:We demonstrate a proinflammatory and pro-adhesive EC transcriptome associated with increased cardiometabolic risk factor burden offering insight into a potential mechanism linking these risk factors with the development of CVD.

BACKGROUND/UNASSIGNED:Identifying patients with the optimal risk:benefit for ticagrelor is challenging. The aim was to identify ticagrelor-responsive platelet transcripts as biomarkers of platelet function and cardiovascular risk. METHODS/UNASSIGNED:Healthy volunteers (n=58, discovery; n=49, validation) were exposed to 4 weeks of ticagrelor with platelet RNA data, platelet function, and self-reported bleeding measured pre-/post-ticagrelor. RNA sequencing was used to discover platelet genes affected by ticagrelor, and a subset of the most informative was summarized into a composite score and tested for validation. This score was further analyzed (1) in CD34+ megakaryocytes exposed to an P2Y12 inhibitor in vitro, (2) with baseline platelet function in healthy controls, (3) in peripheral artery disease patients (n=139) versus patient controls (n=30) without atherosclerosis, and (4) in patients with peripheral artery disease for correlation with atherosclerosis severity and risk of incident major adverse cardiovascular and limb events. RESULTS/UNASSIGNED:Ticagrelor exposure differentially expressed 3409 platelet transcripts. Of these, 111 were prioritized to calculate a Ticagrelor Exposure Signature score, which ticagrelor reproducibly increased in discovery and validation cohorts. Ticagrelor's effects on platelets transcripts positively correlated with effects of P2Y12 inhibition in primary megakaryocytes. In healthy controls, higher baseline scores correlated with lower baseline platelet function and with minor bleeding while receiving ticagrelor. In patients, lower scores independently associated with both the presence and extent of atherosclerosis and incident ischemic events. CONCLUSIONS/UNASSIGNED:Ticagrelor-responsive platelet transcripts are a biomarker for platelet function and cardiovascular risk and may have clinical utility for selecting patients with optimal risk:benefit for ticagrelor use.

BACKGROUND:Therapeutic-dose heparin decreased days requiring organ support in non-critically ill patients hospitalized for COVID-19 but its impact on persistent symptoms or quality of life (QoL) is unclear. RESEARCH QUESTION/OBJECTIVE:In the ACTIV-4a trial, was randomization of patients hospitalized for COVID-19 illness to therapeutic-dose vs. prophylactic heparin associated with less symptoms and better QoL at 90-days? STUDY DESIGN AND METHODS/METHODS:This was an open-label randomized controlled trial at 34 hospitals in the US and Spain. 727 non-critically ill patients hospitalized for COVID-19 from September 2020 to June 2021 were randomized to therapeutic-dose vs. prophylactic heparin. Only patients with 90-day data on symptoms and QoL were analyzed. We ascertained symptoms and QoL by EQ-5D-5L at 90-day follow-up in a pre-planned analysis for the ACTIV-4a trial. Individual domains assessed by the EQ-5D-5L were mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Univariate and multivariate analysis were performed. RESULTS:Among 571 patients, 288 (50.4%) reported at least one symptom. In 410 patients, 148 (36.1%) reported moderate to severe impairment in one or more domains of EQ-5D-5L. Presence of 90-day symptoms were associated with moderate-severe impairment in the EQ-5D-5L domains of mobility (adjusted odds ratio (aOR) 2.37, 95% CI 1.22-4.59), usual activity (aOR 3.66, 95% CI 1.75-7.65), pain (aOR 2.43, 95% CI 1.43-4.12), and anxiety (aOR 4.32, 95% CI 2.06-9.02), compared to patients reporting no symptoms There were no differences in symptoms or the overall EQ-5D-5L index score between treatment groups. Therapeutic-dose heparin was associated with less moderate-severe impairment in all physical functioning domains (mobility, self-care, usual activities) but was independently significant only in the self-care domain (aOR 0.32, CI 0.11-0.96). INTERPRETATION/CONCLUSIONS:In a randomized controlled trial of hospitalized non-critically ill patients with COVID-19, therapeutic-dose heparin was associated with less severe impairment in the self-care domain of EQ-5D-5L. However, this type of impairment was uncommon, affecting 23 individuals. CLINICAL TRIAL REGISTRATION/BACKGROUND:NCT04505774.

BACKGROUND/UNASSIGNED:Patients with COVID-19 have a higher risk of thrombosis and thromboembolism, but the underlying mechanism(s) remain to be fully elucidated. In patients with COVID-19, high lipoprotein(a) (Lp(a)) is positively associated with the risk of ischemic heart disease. Lp(a), composed of an apoB-containing particle and apolipoprotein(a) (apo(a)), inhibits the key fibrinolytic enzyme, tissue-type plasminogen activator (tPA). However, whether the higher Lp(a) associates with lower tPA activity, the longitudinal changes of these parameters in hospitalized patients with COVID-19, and their correlation with clinical outcomes are unknown. OBJECTIVES/UNASSIGNED:To assess if Lp(a) associates with lower tPA activity in COVID-19 patients, and how in COVID-19 populations Lp(a) and tPA change post infection. METHODS/UNASSIGNED:Endogenous tPA enzymatic activity, tPA or Lp(a) concentration were measured in plasma from hospitalized patients with and without COVID-19. The association between plasma tPA and adverse clinical outcomes was assessed. RESULTS/UNASSIGNED:In hospitalized patients with COVID-19, we found lower tPA enzymatic activity and higher plasma Lp(a) than that in non-COVID-19 controls. During hospitalization, Lp(a) increased and tPA activity decreased, which associates with mortality. Among those who survived, Lp(a) decreased and tPA enzymatic activity increased during recovery. In patients with COVID-19, tPA activity is inversely correlated with tPA concentrations, thus, in another larger COVID-19 cohort, we utilized plasma tPA concentration as a surrogate to inversely reflect tPA activity. The tPA concentration was positively associated with death, disease severity, plasma inflammatory, and prothrombotic markers, and with length of hospitalization among those who were discharged. CONCLUSION/UNASSIGNED:High Lp(a) concentration provides a possible explanation for low endogenous tPA enzymatic activity, and poor clinical outcomes in patients with COVID-19.