Faculty Bibliography

INTRODUCTION/BACKGROUND:The healthcare resource utilization (HRU) and costs of oral anticoagulant-naïve patients with non-valvular atrial fibrillation (NVAF) and diabetes initiated on rivaroxaban or warfarin in the United States (US) has not been previously evaluated. METHODS:Data Mart Database (1 January, 2012 to 30 September, 2021) to evaluate the HRU and costs of adult patients with NVAF and diabetes newly initiated on rivaroxaban or warfarin (on or after January 2013). Inverse probability of treatment weighting (IPTW) was used to adjust for confounding between cohorts. HRU and costs (USD 2021) were assessed per patient-year (PPY) post-treatment initiation. Weighted cohorts were compared using rate ratios (RR) from Poisson regression models, odds ratios (OR) from logistic regression models, and cost differences; 95% confidence intervals (CI) and p values were generated using non-parametric bootstrap procedures. RESULTS:After IPTW, 17,881 and 19,274 patients initiated on rivaroxaban and warfarin were included, respectively (mean age: 73 years; 40% female). During 12 months of follow-up, the rivaroxaban cohort had lower all-cause HRU PPY across all components, including lower rates of inpatient stays (RR: 0.84, 95% CI 0.81, 0.88), outpatient visits (RR: 0.67, 95% CI 0.66, 0.68), and 30 day hospital readmission (OR: 0.75, 95% CI 0.66, 0.83; all p < 0.001) compared to the warfarin cohort. Moreover, rivaroxaban was associated with medical cost savings PPY (mean cost difference: - $9306, 95% CI - $11,769, - $6607), which compensated for higher pharmacy costs relative to warfarin (mean cost difference: $5518, 95% CI $5193, $5839), resulting in significantly lower all-cause total healthcare costs for rivaroxaban versus warfarin (mean cost difference: - $3788, 95% CI - $6258, - $1035; all p < 0.001). CONCLUSION/CONCLUSIONS:Among NVAF patients with diabetes in a real-world US setting, rivaroxaban was associated with lower healthcare costs compared to warfarin.

BACKGROUND:Perioperative bleeding is a common and potentially life-threatening complication after surgery. We sought to identify the frequency, patient characteristics, causes, and outcomes of perioperative bleeding in patients undergoing noncardiac surgery. METHODS:In a retrospective cohort study of a large administrative database, adults aged ≥45 years hospitalized for noncardiac surgery in 2018 were identified. Perioperative bleeding was defined using ICD-10 diagnosis and procedure codes. Clinical characteristics, in-hospital outcomes, and first hospital readmission within 6 months were assessed by perioperative bleeding status. RESULTS:We identified 2,298,757 individuals undergoing noncardiac surgery, among which 35,429 (1.54%) had perioperative bleeding. Patients with bleeding were older, less likely to be female, and more likely to have renal and cardiovascular disease. All-cause, in-hospital mortality was higher in patients with vs without perioperative bleeding (6.0% vs 1.3%; adjusted OR [aOR] 2.38, 95% CI 2.26-2.50). Patients with vs without bleeding had a prolonged inpatient length of stay (6 [IQR 3-13] vs 3 [IQR 2-6] days, P < .001). Among those who were discharged alive, hospital readmission was more common within 6 months among patients with bleeding (36.0% vs 23.6%; adjusted HR 1.21, 95% CI 1.18-1.24). The risk of in-hospital death or readmission was greater in patients with vs without bleeding (39.8% vs 24.5%; aOR 1.33, 95% CI 1.29-1.38). When stratified by revised cardiac risk index , there was a stepwise increase in surgical bleeding risk with increasing perioperative cardiovascular risks. CONCLUSIONS:Perioperative bleeding is reported in 1 out of every 65 noncardiac surgeries, with a higher incidence in patients at elevated cardiovascular risk. Among postsurgical inpatients with perioperative bleeding, approximately 1 of every 3 patients died during hospitalization or were readmitted within 6-months. Strategies to reduce perioperative bleeding are warranted to improve outcomes following non-cardiac surgery.

AIM/OBJECTIVE:The Diabetes risk index (DRI) is a composite of NMR-measured lipoproteins and branched chain amino acids predictive of diabetes mellitus development. Bariatric surgery is indicated in patients with severe obesity, many of whom are at high-risk for developing diabetes. Substantial weight loss occurs following bariatric surgery and sustained weight loss likely contributes to reductions in the development of diabetes and cardiovascular disease. However, some evidence suggests that bariatric surgical procedures themselves may contribute to reducing risk of these conditions independent of weight loss. We aimed to investigate DRI and its association with reductions in body weight and adiposity over one year following bariatric surgery. METHODS:; n = 15). RESULTS:, but DRI decreased so that it no longer differed from that of normal BMI controls (1.9 [1, 17] vs control 12 [1, 20]; p = 0.35). Subjects continued to lose weight, whereas DRI remained similar, throughout follow-up with DRI 1.0 [1, 7] at 12 months. Changes in DRI did not correlate with changes in BMI, body weight or waist circumference at any time during follow-up. There was no difference in change in DRI between surgical procedures or pre-operative metabolic syndrome status. CONCLUSIONS:Our analysis of DRI scores supports the capacity of bariatric surgery to reduce risk of developing diabetes in severely obese individuals. Our findings suggest that bariatric surgical techniques may have inherent effects that improve cardiometabolic risk independent of reductions in body weight or adiposity.

BACKGROUND: Monocyte-platelet aggregates (MPAs) represent the crossroads between thrombosis and inflammation, and targeting this axis may suppress thromboinflammation. While antiplatelet therapy (APT) reduces platelet-platelet aggregation and thrombosis, its effects on MPA and platelet effector properties on monocytes are uncertain. OBJECTIVES/OBJECTIVE: To analyze the effect of platelets on monocyte activation and APT on MPA and platelet-induced monocyte activation. METHODS:, GP IIb/IIIa, and COX-1 inhibitors and assessed for platelet and monocyte activity via flow cytometry. RNA-Seq of monocytes incubated with platelets was used to identify platelet-induced monocyte transcripts and was validated by RT-qPCR in monocyte-PR co-incubation ± APT. RESULTS:inhibition attenuates platelet-induced monocyte activation.

Platelets, key facilitators of primary hemostasis and thrombosis, have emerged as crucial cellular mediators of innate immunity and inflammation. Exemplified by their ability to alter the phenotype and function of monocytes, activated platelets bind to circulating monocytes to form monocyte-platelet aggregates (MPA). The platelet-monocyte axis has emerged as a key mechanism connecting thrombosis and inflammation. MPA are elevated across the spectrum of inflammatory and autoimmune disorders, including cardiovascular disease, systemic lupus erythematosus (SLE), and COVID-19, and are positively associated with disease severity. These clinical disorders are all characterized by an increased risk of thromboembolic complications. Intriguingly, monocytes in contact with platelets become proinflammatory and procoagulant, highlighting that this interaction is a central element of thromboinflammation.

INTRODUCTION:Thromboinflammatory complications are well described sequalae of Coronavirus Disease 2019 (COVID-19), and there is evidence of both hyperreactive platelet and inflammatory neutrophil biology that contributes to the thromoinflammatory milieu. It has been demonstrated in other thromboinflammatory diseases that the circulating environment may affect cellular behavior, but what role this environment exerts on platelets and neutrophils in COVID-19 remains unknown. We tested the hypotheses that 1) plasma from COVID-19 patients can induce a prothrombotic platelet functional phenotype, and 2) contents released from platelets (platelet releasate) from COVID-19 patients can induce a proinflammatory neutrophil phenotype. METHODS:We treated platelets with COVID-19 patient and disease control plasma, and measured their aggregation response to collagen and adhesion in a microfluidic parallel plate flow chamber coated with collagen and thromboplastin. We exposed healthy neutrophils to platelet releasate from COVID-19 patients and disease controls and measured neutrophil extracellular trap formation and performed RNA sequencing. RESULTS:. Neither disease condition increased the number of platelets adhered to a collagen and thromboplastin coated parallel plate flow chamber, but both markedly reduced platelet size. COVID-19 patient platelet releasate increased myeloperoxidasedeoxyribonucleic acid complexes and induced changes to neutrophil gene expression. DISCUSSION:Together these results suggest aspects of the soluble environment circulating platelets, and that the contents released from those neutrophil behavior independent of direct cellular contact.

BACKGROUND:Early life stress (ELS) is associated with increased morbidity and mortality across the lifecourse. Studies observing a relationship between ELS and stress physiology (cortisol), may help explain the connection to poor health outcomes, but have been limited by cortisol measures used. PURPOSE/OBJECTIVE:We examined the association between ELS measured by a Risky Family (RF) environment questionnaire, and adult diurnal cortisol profile inclusive of multiple cortisol measures. METHODS:RF and cortisol were collected from Coronary Artery Risk Development in Young Adults Study participants at follow-up (Year 15). Complete case (n = 672) data were included in multi-variable regression analyses with log transformed cortisol measures (outcomes) including wake-up cortisol, cortisol awakening response [CAR], AUC and five other cortisol diurnal curve measures. RESULTS:Participants were age 39.9 + /- 3.7 years and 51.6% Black. For every 1 unit increase in RF, there was a 1.4% greater wake-up cortisol and flatter CAR after adjustment for age, sex, income, and smoking (B=0.014, p = 0.023; B=-0.014, p = 0.028, respectively). Each unit increase in caregiver warmth/affection was associated with a 6.9% higher (steeper) CAR (B=0.069, p = 0.03). Results remained significant after adjusting for other covariates except social support in adulthood. An interaction between child abuse and caregiver warmth was nearly significant (p = 0.068), such that for those with exposure to the greatest caregiver warmth and lowest child abuse, CAR was steepest CONCLUSIONS: We demonstrate that ELS is associated with altered cortisol regulation in adulthood. However, further research is needed to assess how healthy relationships throughout the life course may modulate cortisol regulation in adulthood.

OBJECTIVE:To compare rates of clopidogrel response among patients receiving medication produced by 2 different manufacturers after acute coronary syndrome (ACS) and/or percutaneous coronary intervention. METHODS:This quality-improvement project included 515 adult patients receiving clopidogrel for ACS or ischemic heart disease and referred for coronary angiography/ percutaneous coronary intervention. The project was divided into 2 phases: (1) retrospective collection of baseline data (April 2019-October 2020); and (2) two 12-week, prospective phases in which all clopidogrel in the hospital was restricted to a single manufacturer at a time (November 2020-May 2021). The primary outcome was clopidogrel response measured by platelet function testing, defined as adenosine diphosphate (ADP) response <40% on light transmission aggregometry. RESULTS:Of 515 total patients included in both phases (mean age, 64.5 ± 11.4 years; 351 men [68.2%]; 450 with ACS [87.4%]), 52% were found to be clopidogrel responders based on results of platelet function testing. Among 135 patients in the prospective phase, there was a significantly lower proportion of patients who were clopidogrel responders in the Manufacturer 1 group compared with the Manufacturer 2 group (34.8% vs 55.1%, respectively; P=.03). After adjustment for age, sex, body mass index, aspirin response, therapeutic hypothermia, left heart catheterization indication, clopidogrel loading dose, time between loading dose and lab measurement, and manufacturer, aspirin response (odds ratio 0.96; 95% confidence interval, 0.95-0.97; P<.001) and manufacturer (odds ratio, 2.45; 95% confidence interval, 1.18-5.22; P=.02) were associated with clopidogrel response. CONCLUSIONS:In a large public hospital, we observed that pharmacodynamic response to clopidogrel varied by drug manufacturer. Further investigation and/or regulation is needed to minimize inter-manufacturer variability.

BACKGROUND:Posttraumatic venous thromboembolism (VTE) remains prevalent in severely injured patients despite chemoprophylaxis. Importantly, although platelets are central to thrombosis, they are not routinely targeted in prevention of posttraumatic VTE. Furthermore, platelets from injured patients show ex vivo evidence of increased activation yet impaired aggregation, consistent with functional exhaustion. However, the relationship of this platelet functional phenotype with development of posttraumatic VTE is unknown. We hypothesized that, following injury, impaired ex vivo platelet aggregation (PA) is associated with the development of posttraumatic VTE. METHODS:We performed a secondary analysis of 133 severely injured patients from a prospective observational study investigating coagulation and inflammation (2011-2019). Platelet aggregation in response to stimulation with adenosine diphosphate (ADP), collagen, and thrombin was measured at presentation (preresuscitation) and 24 hours (postresuscitation). Viscoelastic clot strength and lysis were measured in parallel by thromboelastography. Multivariable regression examined relationships between PA at presentation, 24 hours, and the change (δ) in PA between presentation and 24 hours with development of VTE. RESULTS:The 133 patients were severely injured (median Injury Severity Score, 25), and 14% developed VTE (all >48 hours after admission). At presentation, platelet count and PA were not significantly different between those with and without incident VTE. However, at 24 hours, those who subsequently developed VTE had significantly lower platelet counts (126 × 10 9 /L vs. 164 × 10 9 /L, p = 0.01) and lower PA in response to ADP ( p < 0.05), collagen ( p < 0.05), and thrombin ( p = 0.06). Importantly, the magnitude of decrease in PA (δ) from presentation to 24 hours was independently associated with development of VTE (adjusted odds ratios per 10 aggregation unit decrease: δ-ADP, 1.31 [ p = 0.03]; δ-collagen, 1.36 [ p = 0.01]; δ-thrombin, 1.41 [ p < 0.01]). CONCLUSION:Severely injured patients with decreasing ex vivo measures of PA despite resuscitation have an increased risk of developing VTE. This may have implications for predicting development of VTE and for studying platelet targeted chemoprophylaxis regimens. LEVEL OF EVIDENCE:Prognostic/Epidemiological; Level III.