Faculty Bibliography

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 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.

BACKGROUND:Patients with significant (≥50%) left main disease (LMD) have a high risk of cardiovascular events, and guidelines recommend revascularization to improve survival. However, the impact of intermediate LMD (stenosis, 25%-49%) on outcomes is unclear. METHODS:Randomized ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) participants who underwent coronary computed tomography angiography at baseline were categorized into those with (25%-49%) and without (<25%) intermediate LMD. The primary outcome was a composite of cardiovascular mortality, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. The primary quality of life outcome was the Seattle Angina Questionnaire summary score. RESULTS: CONCLUSIONS:In the ISCHEMIA trial, there was no meaningful heterogeneity of treatment benefit from an invasive strategy regardless of intermediate LMD status except for a greater absolute risk reduction in nonprocedural MI with invasive management in those with intermediate LMD. An invasive strategy increased procedural MI, reduced nonprocedural MI, and improved angina-related quality of life. REGISTRATION/BACKGROUND:URL: https://www. CLINICALTRIALS/RESULTS:gov; Unique identifier: NCT01471522.

BACKGROUND:Clinical characteristics of patients with acute myocardial infarction after gastrointestinal bleeding are poorly characterized. We sought to evaluate the incidence, management and outcomes of myocardial infarction following hospitalization for gastrointestinal bleeding. METHODS:Patients admitted with a diagnosis of gastrointestinal bleeding with and without subsequent hospital readmissions for acute myocardial infarction within 90 days were identified in the 2014 United States Nationwide Readmission Database. Patients with myocardial infarction with and without a recent prior gastrointestinal bleed were compared to determine differences in management and in-hospital outcomes. Logistic regression models were used to estimate odds of invasive management and all-cause in-hospital mortality after covariate adjustment. RESULTS:A total of 644,622 patients with gastrointestinal bleeding were identified, of which 7,523 (1.2%) were readmitted for myocardial infarction within 90 days. Compared to myocardial infarction patients without recent gastrointestinal bleeding, patients with myocardial infarction within 90 days after gastrointestinal bleeding were older, more likely to be women, have kidney disease, present with non-ST segment elevation MI, and were less likely to undergo invasive management of AMI (28% vs 63%, P<0.01). Prior gastrointestinal bleeding was associated with higher all-cause in-hospital myocardial infarction mortality (22% vs 9%, P<0.01). CONCLUSION/CONCLUSIONS:In the first 3 months after hospitalization for gastrointestinal bleeding, 1 of every 83 patients was readmitted with acute myocardial infarction. Patients with myocardial infarction after gastrointestinal bleeding were less likely to undergo invasive management and coronary revascularization and had higher mortality than those without recent bleeding.

Myocardial injury after non-cardiac surgery (MINS) is common. We investigated the incidence and outcomes of MINS, and mechanistic underpinnings using pre-operative whole blood gene expression profiling in a prospective cohort study of individuals undergoing lower extremity revascularization (LER) for peripheral artery disease (PAD). Major adverse cardiovascular and limb events (MACLE) were defined as a composite of death, myocardial infarction, stroke, major lower extremity amputation or reoperation. Among 226 participants undergoing LER, MINS occurred in 53 (23.5%). Patients with MINS had a greater incidence of major adverse cardiovascular events (49.1% vs. 22.0%, adjusted HR 1.87, 95% CI 1.07-3.26) and MACLE (67.9% vs. 44.5%; adjusted HR 1.66, 95% CI 1.08-2.55) at median 20-month follow-up. Pre-operative whole blood transcriptome profiling of a nested matched MINS case-control cohort (n = 41) identified upregulation of pathways related to platelet alpha granules and coagulation in patients who subsequently developed MINS. Thrombospondin 1 (THBS1) mRNA expression was 60% higher at baseline in patients who later developed MINS, and was independently associated with long-term cardiovascular events in the Duke Catheterization Genetics biorepository cohort. In conclusion, pre-operative THBS1 mRNA expression is higher in patients who subsequently develop MINS and is associated with incident cardiovascular events. Pathways related to platelet activity and coagulation associated with MINS provide novel insights into mechanisms of myocardial injury.

Gender-specific differences in thrombosis have been reported in hospitalized patients with COVID-19. We sought to investigate the influence of age on the relation between gender and incident thrombosis or death in COVID-19. We identified consecutive adults aged ≥18 years hospitalized with COVID-19 from March 1, 2020, to April 17, 2020, at a large New York health system. In-hospital thrombosis and all-cause mortality were evaluated by gender and stratified by age group. Logistic regression models were generated to estimate the odds of thrombosis or death after multivariable adjustment. In 3,334 patients hospitalized with COVID-19, 61% were men. Death or thrombosis occurred in 34% of hospitalizations and was more common in men (36% vs 29% in women, p <0.001; adjusted odds ratio [aOR] 1.61, 95% confidence interval [CI] 1.36 to 1.91). When stratified by age, men had a higher incidence of death or thrombosis in younger patients (aged 18 to 54 years: 21% vs 9%, aOR 3.17, 95% CI 2.06 to 5.01; aged 55 to 74 years: 39% vs 28%, aOR 1.63, 95% CI 1.28 to 2.10), but not older patients (aged ≥75 years: 55% vs 48%; aOR 1.20, 95% CI 0.90 to 1.59) (interaction p value: 0.01). For the individual end points, men were at higher risk of thrombosis (19% vs 12%; aOR 1.65, 95% CI 1.33 to 2.05) and mortality (26% vs 23%; aOR 1.41, 95% CI 1.17 to 1.69) than women, and gender-specific differences were attenuated with older age. Associations between thrombosis and mortality were most striking in younger patients (aged 18 to 54 years, aOR 8.25; aged 55 to 74 years, aOR 2.38; aged >75 years, aOR 1.88; p for interaction <0.001) but did not differ by gender. In conclusion, the risk of thrombosis or death in COVID-19 is higher in men compared with women and is most apparent in younger age groups.

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.

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.

OBJECTIVE:Amputation remains a frequent and feared outcome in patients with peripheral artery disease (PAD). Although typically characterized as major or minor on the extent of tissue loss, the etiologies and outcomes after amputation by extent are not well-understood. In addition, emerging data suggest that the drivers and outcomes of amputation in patients with PAD may differ in those with and without diabetes mellitus (DM). METHODS:The EUCLID trial randomized 13,885 patients with symptomatic PAD, including 5345 with concomitant diabetes, to ticagrelor or clopidogrel and followed them for long-term outcomes. Amputations were prospectively reported by trial investigators. Their primary and contributing drivers were adjudicated using safety data, including infection, ischemia, or multifactorial etiologies. Outcomes following major and minor amputations were analyzed, including recurrent amputation, major adverse limb events, adverse cardiovascular events, and mortality. Multivariable logistic regression models were used to identify independent predictors of minor amputations. Analyses were performed overall and stratified by the presence or absence of DM at baseline. RESULTS:Of the patients randomized, 398 (2.9%) underwent at least one lower extremity nontraumatic amputation, for a total of 511 amputations (255 major and 256 minor) over a median of 30 months. A history of minor amputation was the strongest independent predictor for a subsequent minor amputation (odds ratio, 7.29; 95% confidence interval, 5.17-10.30; P < .001) followed by comorbid DM (odds ratio, 4.60; 95% confidence interval, 3.16-6.69; P < .001). Compared with patients who had a major amputation, those with a minor amputation had similar rates of subsequent major amputation (12.2% vs 13.6%), major adverse limb events (15.1% vs 14.9%), and major adverse cardiovascular events (17.6% vs 16.3%). Ischemia alone was the primary driver of amputation (51%), followed by infection alone (27%), and multifactorial etiologies (22%); however, infection was the most frequent driver in those with DM (58%) but not in those without DM (15%). CONCLUSIONS:Outcomes after amputation remain poor regardless of whether they are categorized as major or minor. The pattern of amputation drivers in PAD differs by history of DM, with infection being the dominant etiology in those with DM and ischemia in those without DM. Greater focus is needed on the prognostic importance of minor amputation and of the multifactorial etiologies of amputation in PAD. Nomenclature with anatomical description of amputations and eliminating terms "major" or "minor" would seem appropriate.

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.