Faculty Bibliography

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.

Aspirin's clinical efficacy may be influenced by body weight and mass. Although inadequate platelet inhibition by aspirin is suggested as responsible, evidence for this in non-diabetic patients is sparse. We investigated the influence of body weight and mass on aspirin's inhibition of platelet aggregation in healthy adults without diabetes. Cohort one (NYU, n = 84) had light transmission aggregometry (LTA) of platelet-rich plasma to submaximal adenosine diphosphate (ADP) and arachidonic acid (AA) before and following 1 week of daily 81 mg non-enteric coated aspirin. Subjects in the validation cohort (Duke, n = 66) were randomized to 81 mg or 325 mg non-enteric coated aspirin for 4 weeks, immediately followed by 4 weeks of the other dose, with LTA to submaximal collagen, ADP, and AA before and after each dosage period. Body mass index (BMI) range was 18.0-57.5 kg/m² and 25% were obese. Inhibition of platelet aggregation was similar irrespective of BMI, body weight and aspirin dose. There was no correlation between platelet aggregation before or after aspirin with BMI or body weight. Our data demonstrate that aspirin produces potent inhibition of direct and indirect COX1-mediated platelet aggregation in healthy adults without diabetes regardless of body weight or mass - suggesting that other mechanisms explain lower preventive efficacy of low-dose aspirin with increasing body weight/mass.

Background Peripheral artery disease (PAD) is associated with heightened risk for major adverse cardiovascular and limb events, but data on the burden of risk for total (first and potentially subsequent) events, and the association with polyvascular disease, are limited. This post hoc analysis of the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial evaluated total cardiovascular and limb events among patients with symptomatic PAD, overall and by number of symptomatic vascular territories. Methods and Results In the EUCLID trial, patients with symptomatic PAD (lower extremity revascularization >30 days before randomization or ankle-brachial index ≤0.80) were randomized to treatment with ticagrelor or clopidogrel. Relative effects on total events (cardiovascular death; nonfatal myocardial infarction and ischemic stroke; acute limb ischemia, unstable angina, and transient ischemic attack requiring hospitalization; coronary, carotid, and peripheral revascularization procedures; and amputation for symptomatic PAD) were summarized by hazard ratios (HRs), whereas absolute risks were estimated by incidence rates and mean cumulative functions. Among 13 885 randomized patients, 7600 total cardiovascular and limb events occurred during a median 2.7 years of follow-up, translating to 60.0 and 62.5 events per 100 patients through 3 years for the ticagrelor and clopidogrel groups, respectively (HR, 0.96; 95% CI, 0.89-1.03; P=0.27). Among 1393 patients with disease in 3 vascular territories, event accrual rates through 3 years for the ticagrelor and clopidogrel groups were 87.3 and 97.7 events per 100 patients, respectively. Absolute risk reductions for ticagrelor relative to clopidogrel at 3 years were -0.2, 6.7, and 10.3 events per 100 patients for 1, 2, and 3 affected vascular territories, respectively (P

BACKGROUND:Type 2 myocardial infarction (MI) occurs due to a mismatch in myocardial oxygen supply and demand without unstable coronary artery disease. We sought to identify patterns, predictors and outcomes of invasive management of type 2 MI in the USA. METHODS:Adults aged ≥18 years hospitalized with type 2 MI were identified in a cross-sectional study from the 2018 National Inpatient Sample. Invasive management was defined as invasive coronary angiography or revascularization. Patient, hospital and geographic characteristics associated with invasive management were identified by multivariable logistic regression. Propensity-matched cohorts were generated to evaluate associations between invasive vs. conservative management and mortality. RESULTS:We identified 268 850 admissions with type 2 MI in 2018. Type 2 MI patients had a high burden of comorbidities and were commonly admitted with diagnoses of circulatory (39.7%), infectious (23.1%) or respiratory (10.8%) illness. Only 11.2% of type 2 MI were managed invasively, of which 17.9% underwent coronary revascularization. Odds of invasive management were higher with commercial insurance [adjusted OR (aOR) 1.39; 95% confidence interval (CI), 1.27-1.52] and lower with Medicaid (aOR 0.86; 95% CI, 0.76-0.96) vs. Medicare. Significant heterogeneity in invasive management of type 2 MI was observed by geographic region (range 7.2-13.8%), independent of patient and hospital factors. Invasive management was associated with lower in-hospital mortality than conservative management overall (3.9 vs. 9.1%; P < 0.001) and in propensity-matched analyses (OR, 0.70; 95% CI, 0.59-0.84). CONCLUSION/CONCLUSIONS:Invasive management of type 2 MI varies by insurance status and geography, highlighting uncertainty regarding optimal management and potential disparities in clinical care.

OBJECTIVES/OBJECTIVE:Clopidogrel is effective at decreasing cardiovascular events in patients with peripheral artery disease (PAD); however, its effect on limb outcomes are less known. This study investigated the variability in response to clopidogrel and its relationship with clinical limb outcomes. METHODS: RESULTS: CONCLUSIONS:Among patients undergoing lower extremity revascularization on clopidogrel, higher baseline percent aggregation is associated with increased risk for major adverse limb events.

INTRODUCTION/BACKGROUND:The impact of diabetes mellitus (DM) on outcomes of lower extremity revascularization (LER) for peripheral artery disease (PAD) is uncertain. We characterized associations between DM and post-procedural outcomes in PAD patients undergoing LER. METHODS:Adults undergoing surgical or endovascular LER were identified from the 2014 Nationwide Readmissions Database. DM was defined by ICD-9 diagnosis codes and sub-classified based on the presence or absence of complications (poor glycemic control or end-organ damage). Major adverse cardiovascular and limb events (MACLE) were defined as the composite of death, myocardial infarction, ischaemic stroke, or major limb amputation during the index hospitalization for LER. For survivors, all-cause 6-month hospital readmission was determined. RESULTS:Among 39,441 patients with PAD hospitalized for LER, 50.8% had DM. The composite of MACLE after LER was not different in patients with and without DM after covariate adjustment, but patients with DM were more likely to require major limb amputation (5.5% vs. 3.2%, p < 0.001; adjusted odds ratio [aOR] 1.22, 95% CI 1.03-1.44) and hospital readmission (59.2% vs. 41.3%, p < 0.001; aOR 1.44, 95% CI 1.34-1.55). Of 20,039 patients with DM hospitalized for LER, 55.7% had DM with complications. These patients were more likely to have MACLE after LER (11.1% vs. 5.2%, p < 0.001; aOR 1.56 95% CI 1.28-1.89) and require hospital readmission (61.1% vs. 47.2%, p < 0.001; aOR 1.41 95% CI 1.27-1.57) than patients with uncomplicated DM. CONCLUSIONS:DM is present in ≈50% of patients undergoing LER for PAD and is an independent risk factor for major limb amputation and 6-month hospital readmission.

Background Vascular function is compromised in Alzheimer disease (AD) years before amyloid and tau pathology are detected and a substantial body of work shows abnormal platelet activation states in patients with AD. The aim of our study was to investigate whether platelet function in middle age is independently associated with future risk of AD. Methods and Results We examined associations of baseline platelet function with incident dementia risk in the community-based FHS (Framingham Heart Study) longitudinal cohorts. The association between platelet function and risk of dementia was evaluated using the cumulative incidence function and inverse probability weighted Cox proportional cause-specific hazards regression models, with adjustment for demographic and clinical covariates. Platelet aggregation response was measured by light transmission aggregometry. The final study sample included 1847 FHS participants (average age, 53.0 years; 57.5% women). During follow-up (median, 20.5 years), we observed 154 cases of incident dementia, of which 121 were AD cases. Results from weighted models indicated that platelet aggregation response to adenosine diphosphate 1.0 µmol/L was independently and positively associated with dementia risk, and it was preceded in importance only by age and hypertension. Sensitivity analyses showed associations with the same directionality for participants defined as adenosine diphosphate hyper-responders, as well as the platelet response to 0.1 µmol/L epinephrine. Conclusions Our study shows individuals free of antiplatelet therapy with a higher platelet response are at higher risk of dementia in late life during a 20-year follow-up, reinforcing the role of platelet function in AD risk. This suggests that platelet phenotypes may be associated with the rate of dementia and potentially have prognostic value.

Patients with ischemic heart disease frequently undergo noncardiac surgery. We examined perioperative surgical outcomes in patients with and without previous coronary revascularization by coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). Adults ≥45 years old who underwent noncardiac surgery between 2010 and 2014 were identified from the National Inpatient Sample. Previous CABG and PCI were identified using International Classification of Diseases, Ninth Revision codes. Major adverse cardiovascular and cerebrovascular events (MACCE) were defined as the composite of in-hospital mortality, acute myocardial infarction, and acute ischemic stroke. Multivariable logistic regression models were used to estimate associations between previous coronary revascularization and surgical outcomes after adjustment for clinical covariates. We identified 25,091,140 hospitalizations for noncardiac surgery, of which 8.4% had a history of coronary revascularization (47% previous CABG without PCI, 45% previous PCI without CABG, and 8% previous CABG and PCI). Hospitalized patients with versus without previous coronary revascularization had a higher crude incidence (4.0% vs 2.6%, p <0.001) but lower odds of MACCE (adjusted odds ratio 0.96, 95% CI 0.94 to 0.98) driven by a lower risk of death and ischemic stroke. When analyzed by revascularization strategy, lower odds of MACCE were restricted to patients with previous CABG, driven by excess perioperative acute myocardial infarction risks after PCI. In patients with established cardiovascular disease, previous coronary revascularization was associated with lower odds of MACCE (adjusted odds ratio 0.76, 95% CI 0.75 to 0.78), regardless of revascularization strategy. In conclusion, previous coronary revascularization is associated with lower odds of MACCE after noncardiac surgery, but perioperative risks vary by mode of coronary revascularization.