Faculty Bibliography

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.

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.

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.

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:Perioperative myocardial infarction is frequently attributed to type 2 myocardial infarction, a mismatch in myocardial oxygen supply-demand without unstable coronary artery disease. Our aim was to identify characteristics, management, and outcomes of perioperative type 1 versus type 2 myocardial infarction among surgical inpatients. METHODS:Adults age ≥45 years hospitalized for noncardiac surgery were identified in the United States. Perioperative myocardial infarction were identified using International Classification of Diseases, 10th revision (ICD-10) codes. Clinical characteristics, invasive myocardial infarction management, mortality, and readmissions were assessed by myocardial infarction subtype. RESULTS:Among 4,755,382 surgical hospitalizations, we identified 38,975 perioperative myocardial infarctions (0.82%), with type 2 infarction in 42%. Patients with type 2 myocardial infarction were older, more likely to be women, and less likely to have cardiovascular comorbidities compared with type 1 myocardial infarction. Fewer patients with type 2 myocardial infarction underwent invasive management than type 1 myocardial infarction (6.7% vs 28.8%, P < .001). Type 2 myocardial infarction mortality was lower than type 1 myocardial infarction mortality (12.1% vs 17.4%, P < .001; adjusted odds ratio [aOR] 0.51, 95% confidence interval [CI] 0.45-0.59). Invasive management of perioperative myocardial infarction was associated with lower mortality in type 1 (aOR 0.56, 95% CI 0.49-0.74) but not type 2 (aOR 1.19, 95% CI 0.77-1.85) myocardial infarction. Among survivors, there was no difference in 90-day hospital readmission between type 2 and type 1 perioperative myocardial infarction (36.5% vs 36.1%, P = .72). CONCLUSIONS:Type 2 myocardial infarctions account for approximately 40% of perioperative myocardial infarctions. Patients with type 2 perioperative myocardial infarction are less likely to undergo invasive management and have lower mortality compared with those with type 1 perioperative myocardial infarction.

Importance:Platelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19. Objective:To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19. Design, Setting, and Participants:An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021. Interventions:Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n = 293) or a therapeutic dose of heparin only (usual care) (n = 269) in a 1:1 ratio for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. Main Outcomes and Measures:The composite primary outcome was organ support-free days evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and, for those who survived to hospital discharge, the number of days free of respiratory or cardiovascular organ support up to day 21 of the index hospitalization (range, -1 to 21 days; higher scores indicate less organ support and better outcomes). The primary safety outcome was major bleeding by 28 days as defined by the International Society on Thrombosis and Hemostasis. Results:Enrollment of non-critically ill patients was discontinued when the prespecified criterion for futility was met. All 562 patients who were randomized (mean age, 52.7 [SD, 13.5] years; 41.5% women) completed the trial and 87% received a therapeutic dose of heparin by the end of study day 1. In the P2Y12 inhibitor group, ticagrelor was used in 63% of patients and clopidogrel in 37%. The median number of organ support-free days was 21 days (IQR, 20-21 days) among patients in the P2Y12 inhibitor group and was 21 days (IQR, 21-21 days) in the usual care group (adjusted odds ratio, 0.83 [95% credible interval, 0.55-1.25]; posterior probability of futility [defined as an odds ratio <1.2], 96%). Major bleeding occurred in 6 patients (2.0%) in the P2Y12 inhibitor group and in 2 patients (0.7%) in the usual care group (adjusted odds ratio, 3.31 [95% CI, 0.64-17.2]; P = .15). Conclusions and Relevance:Among non-critically ill patients hospitalized for COVID-19, the use of a P2Y12 inhibitor in addition to a therapeutic dose of heparin, compared with a therapeutic dose of heparin only, did not result in an increased odds of improvement in organ support-free days within 21 days during hospitalization. Trial Registration:ClinicalTrials.gov Identifier: NCT04505774.

The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) found that there was no statistical difference in cardiovascular events with an initial invasive strategy as compared with an initial conservative strategy of guideline-directed medical therapy for patients with moderate to severe ischemia on noninvasive testing. In this study, we describe the reasons that potentially eligible patients who were screened for participation in the ISCHEMIA trial did not advance to enrollment, the step prior to randomization. Of those who preliminarily met clinical inclusion criteria on screening logs submitted during the enrollment period, over half did not participate due to physician or patient refusal, a potentially modifiable barrier. This analysis highlights the importance of physician equipoise when advising patients about participation in randomized controlled trials.