Optimizing platelet inhibition in peripheral artery disease: A comparison of mono-antiplatelet therapy and dual-antiplatelet therapy using thromboelastography.

BACKGROUND: Antiplatelet therapy is used to prevent thrombosis in patients with peripheral artery disease (PAD) following revascularization. However, the current standard of care for these patients remains at the physician's discretion, varying from mono-antiplatelet therapy (MAPT) to dual-antiplatelet therapy (DAPT). Viscoelastic assays such as Thromboelastography with Platelet Mapping (TEG-PM) provide insight into individual coagulation profiles and measure real-time platelet function. This prospective, observational study looks at the differences in platelet function for patients on MAPT versus DAPT using TEG-PM. METHODS: Patients with PAD undergoing revascularization were prospectively evaluated between December 2020 and June 2023. TEG-PM analysis compared platelet function for patients prescribed MAPT (aspirin or clopidogrel) at the initial encounter and DAPT (aspirin and clopidogrel) at the next visit. Platelet function measured in percent inhibition was evaluated at these visits, and within-group t-tests were performed. RESULTS: Of the 195 patients enrolled, 486 samples were analyzed by TEG-PM. Sixty-four patients met the study criteria. At the initial visit, 52 patients had been prescribed aspirin, and 12 patients had been prescribed clopidogrel. For patients initially prescribed aspirin MAPT, an increase of 96.8%in the mean ADP platelet inhibition was exhibited when transitioning to DAPT [22.0% vs. 43.3%, p < .01], as well as an increase of 34.6%in the mean AA platelet inhibition when transitioning to DAPT [60.9% vs. 82.0%, p < .01]. For patients prescribed initial clopidogrel MAPT, an increase of 100% in AA platelet inhibition was exhibited on DAPT compared to the MAPT state [42.3% vs. 84.6%, p < .01]. CONCLUSIONS: Patients on DAPT showed a significant increase in platelet inhibition when compared to initial aspirin MAPT. A significant difference in AA %platelet inhibition was shown for patients on DAPT when compared to initial clopidogrel MAPT. The results show that patients may benefit from DAPT post-revascularization. Personalizing antiplatelet therapy with objective viscoelastic testing to confirm adequate treatment may be the next step in optimizing patient outcomes to reduce thrombosis in PAD patients.

Local Anesthesia for Endovascular Repair of Abdominal Aortic Aneurysm Allows for Accurate Graft Deployment with Durable Results.

BACKGROUND: Local anesthesia (LA) is sparsely used in endovascular aneurysm repair (EVAR) despite short-term benefit, likely secondary to concerns over patient movement preventing accurate endograft deployment. The objective of this study is to examine the association between anesthesia type and endoleak, sac regression, reintervention, and mortality. METHODS: The Vascular Quality Initiative database was queried for all EVAR cases from 2014 to 2022. Patients were included if they underwent percutaneous elective EVAR with anatomical criteria within instructions for use of commercially approved endografts. Multivariable logistic regression with propensity score weighting was used to determine the association between anesthesia type on the risk of any endoleak noted by intraoperative completion angiogram and sac regression. Multivariable survival analysis with propensity score weighting was used to determine the association between anesthesia type and endoleak at 1 year, long-term reintervention, and mortality. RESULTS: Thirteen thousand nine hundred thirty two EVARs met inclusion criteria: 1,075 (8%) LA and 12,857 (92%) general anesthesia (GA). On completion angiogram, LA was associated with fewer rates of any endoleaks overall (16% vs. 24%, P < 0.001). On multivariable analysis with propensity score weighting, LA was associated with similar adjusted odds of any endoleak on intraoperative completion angiogram (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.47-0.68) as well as combined type 1a and type 1b endoleaks (OR 0.72, 95% CI 0.47-1.09). Follow-up computed tomography imaging at 1 year was available for 4,892 patients, 377 (8%) LA and 4,515 (92%) GA. At 1 year, LA was associated with similar rate of freedom from any endoleaks compared to GA (0.66 [95% CI 0.63-0.69] vs. 0.71 [95% CI 0.70-0.72], P = 0.663) and increased rates of sac regression (50% vs. 45%, P = 0.040). On multivariable analysis with propensity score weighting, LA and GA were associated with similar adjusted odds of sac regression (OR 1.22, 95% CI 0.97-1.55). LA and GA had similar rates of endoleak at 1 year (hazard ratio [HR] 0.14, 95% CI 0.63-1.07); however, LA was associated with decreased hazards of combined type 1a and 1b endoleaks at 1 year (HR 0.87, 95% CI 0.80-0.96). LA and GA had similar adjusted long-term reintervention rate (HR 0.77, 95% CI 0.44-1.38) and long-term mortality (HR 1.100, 95% CI 079-1.25). CONCLUSIONS: LA is not associated with increased adjusted rates of any endoleak on completion angiogram or at 1-year follow-up compared to GA. LA is associated with decreased adjusted rates of type 1a and type 1b endoleak at 1 year, but similar rates of sac regression, long-term reintervention, and mortality. Concerns for accurate graft deployment should not preclude use of LA and LA should be increasingly considered when deciding on anesthetic type for standard elective EVAR.

Popliteal artery aneurysm ultrasound criteria for reporting characteristics.

INTRODUCTION: Duplex ultrasound (DUS) is the modality of choice for surveillance of popliteal artery aneurysms (PAAs). However, noninvasive vascular laboratories have no standard guidelines for reporting results. This study assessed reports of PAA DUS for inclusion of information pertinent to operative decision-making and timing of surveillance. METHODS: This study was a retrospective review of a multi-institutional repository that was queried for all patients with a PAA from 2008 to 2022 and confirmed via manual chart review. DUS reports were abstracted and images were individually annotated for features of interest including dimensions, flow abnormalities, and percent thrombus burden. RESULTS: A total of 166 PAAs in 130 patients had at least one DUS available for viewing. Postoperative surveillance of PAAs was performed at several intervals: the first at 30 months (IQR 3.7-113, n = 44), the second at 64 months (IQR 20-172, n = 31), and the third at 152 months (IQR 46-217, n = 16) after the operation. The largest diameter of operative PAAs (median 27.5 mm, IQR 21.8-38.0) was significantly greater than nonoperative PAAs (median 20.9 mm, IQR 16.7-27.3); p < 0.01. Fewer than 33 (21%) reports commented on patency of distal runoff. We calculated an average percent thrombus of 60% (IQR 19-81) in nonoperative PAAs, which is significantly smaller than 75% (IQR 58-89) in operative PAAs; p < 0.01. CONCLUSION: In this multi-institutional retrospective study, PAAs are often not followed at intervals recommended by the Society for Vascular Surgery guidelines and do not include all measurements necessary for clinical decision-making in the multi-institutional repository studied. There should be standardization of PAA DUS protocols performed by all noninvasive vascular laboratories to ensure completeness of PAA DUS images and inclusion of characteristics pertinent to clinical decision-making in radiology reports.

Impact of Factor Xa Inhibition on Coagulation, Platelet Reactivity, and Thrombosis in Patients with Peripheral Artery Disease.

BACKGROUND: The role of thrombin in vascular pathology is a focus of investigation. The incorporation of direct Factor Xa inhibition into practice patterns is based on its theoretical dual-pathway attenuation of both thrombin generation and platelet aggregation. However, quantification of the effect of direct anti-Xa medications on platelet function is not established. Thromboelastography with platelet mapping (TEG-PM) leverages dual-pathway metrics to provide comprehensive coagulation profiles. We evaluated the effects of direct oral anticoagulants (DOACs) on coagulation and platelet function profiles and correlate these data with postoperative major adverse limb events (MALEs) in patients with PAD. METHODS: We conducted a prospective study of patients undergoing lower extremity revascularization with serial perioperative TEG-PM analysis. Patients on DOACs were compared to those not on DOACs, and stratified by concurrent mono-antiplatelet or dual-antiplatelet regimens (MAPT/DAPT). Postoperative MALE was recorded and difference in antithrombotic regimens and TEG-PM analysis compared between groups. RESULTS: Four hundred seventy-one samples from 141 patients were analyzed. Twenty-nine point five percent were reflective of circulating DOAC therapy. Compared to MAPT alone, patients on DOAC + MAPT exhibited longer time to clot formation (R-time) [7.4 (±2.4) vs. 6.7 (±2.7); P < 0.02], but less platelet inhibition. Patients on DAPT exhibited greater platelet inhibition compared to either group [23.7 (±26.9) vs. 31.0 (±28.3) vs. 42.2 (±31.2); P < 0.01]. Patients who experienced MALE were more likely to be on DOAC therapy [43.8% vs. 22.0% P = 0.02]. Thromboelastography with platelet mapping analysis from patients who experienced MALE also demonstrated longer R-time [8.6 (±3.9 vs. 7.3 (±3.0); P = 0.05] and increased maximum clot amplitude (MA) [66.7 (±4.2) vs. 61.8 (±8.2); P = 0.001]. CONCLUSIONS: Direct oral anticoagulant therapy resulted in a prolonged R-time but had no impact on platelet inhibition. Patients who experienced MALE were more often on DOACs and demonstrated an increased R-time, but also showed greater platelet reactivity evident by increased MA, suggesting DOACs may not be effective at protecting against MALE. Further research comparing DOAC therapy to a DAPT approach may add clarity to emerging multimodal antithrombotic recommendations.

Increased anti-thrombotic therapy is associated with decreased major adverse limb events in patients with low wound and foot infection scores.

INTRODUCTION: The optimal anti-thrombotic management of patients after lower extremity bypass has yet to be fully elucidated, in part due to significant heterogeneity in patient presentation and practice patterns. The Wound, Ischemia, and foot Infection (WIfI) score is a validated scoring system to assist in the management of patients with chronic limb threatening ischemia (CLTI). We hypothesized that performing a restriction analysis based on WIFI scores would assist in the postoperative anti-thrombotic management of patients undergoing infrainguinal bypass. METHODS: A retrospective cohort of infrainguinal bypass procedures completed at a single hospital system between January 2018 and January 2021 was selected, and preoperative WIfI scores were extracted for each patient. Patients with either Wound scores of 2 and 3, or Ischemia Scores of 0 and 1, or Foot Infection Scores of 3 were excluded. Based on the type of anti-thrombotic regimen on discharge, demographics, comorbidities, type of bypass, 30-day rates of graft occlusion, major amputation, mortality, and major adverse limb events (MALE) were analyzed. Statistical analysis included t-tests, chi square tests, and time-to-event survival analysis. RESULTS: 230 procedures were included in the study. 69 (30.0%) patients were discharged on single antiplatelet therapy (SAPT), compared to 161 (70.0%) who were discharged on either dual antiplatelet therapy or anticoagulation (DAPT/AC). There was a higher prevalence of bypasses using prosthetic conduit in the DAPT/AC group (45.9 vs 31.8%, p = .047); no other demographic or procedural variable analyzed had any significant differences. At 30-days postoperatively, there was no significant difference in postoperative reintervention rates, however, the DAPT/AC group had significantly lower rates of mortality (1.2 vs 7.2%, p = .01), major amputation (1.2% vs 5.8%, p = .04), and MALE (3.7 vs 13.0%, p < .01). There were no significant differences in bleeding complications. Survival analysis demonstrated that MALE-free survival was higher in the DAPT/AC group compared to the SAPT group (p < .01). On Cox regression analysis, DAPT/AC was associated with significantly decreased rates of MALE + mortality (Hazard Ratio (HR) 0.20 [0.06 - 0.66]). CONCLUSION: Lower extremity bypasses patients with low Wound and low foot Infection scores who are discharged on DAPT/AC postoperatively have a significantly higher 30-day MALE-free survival rate compared to patients discharged on SAPT; consideration could be made to preferentially discharge such post-bypass patients on DAPT/AC.

Outcomes of symptomatic penetrating aortic ulcer and intramural hematoma in the endovascular era.

BACKGROUND: Although endovascular technology has resulted in a paradigm shift in treatment, medical management remains the standard of care for penetrating aortic ulcer (PAU) and intramural hematoma (IMH). This study aimed to detail the short- and long-term outcomes of symptomatic PAU/IMH. METHODS: Institutional data on symptomatic PAU/IMH were gathered (2005-2020). The primary outcome was the composite of recurrent symptoms, radiographic progression, intervention, rupture, and death from related or unknown cause. Factors associated with the primary outcome were determined using a Fine-Gray model with death from an unrelated cause as a competing risk. RESULTS: A total of 83 symptomatic patients treated with medical management aside from ruptures and type A dissections: 21 isolated PAU, 30 isolated IMH, and 32 IMH and PAU. Adverse outcomes included symptom recurrence in 14 (16.9%), radiographic progression to dissection or saccular aneurysm in 17 (20.5%), surgery in 20 (24.1%) (17 thoracic endovascular aortic repair, 1 endovascular aortic repair, 1 frozen elephant trunk, and 1 open repair), and rupture in 4 (4.8%). Twenty-seven patients (32.5%) died during follow-up: 6 from IMH treatment complications, 8 from an unknown cause, and 13 from other causes. The 30-day, 1-year, and 5-year cumulative incidences of the primary outcome was 26.5% (95% confidence interval [CI], 16.9%-37.0%), 44.9% (95% CI, 32.8%-56.2%), and 57.5% (95% CI, 42.4%-69.9%), respectively. IMH with PAU was associated with a significantly higher risk of the primary outcome compared with isolated IMH (subdistribution hazard ratio, 2.21; 95% CI, 1.09-4.50; P = .027) and isolated PAU (subdistribution hazard ratio, 3.58; 95% CI, 1.44-8.88; P = .006). CONCLUSIONS: Complications from symptomatic PAU and IMH are frequent, with intervention, recurrent symptoms, radiographic progression, rupture, or death affecting 25% of patients at 30 days after diagnosis and almost one-half of patients 1 year after diagnosis. Given the high rate of adverse events in this population, investigation into a more aggressive interventional strategy may warranted, especially in patients with a combined IMH and PAU.

Implementation of a Consensus-Driven Quality Improvement Protocol to Decrease Length of Stay after Elective Carotid Endarterectomy.

BACKGROUND: National guidelines stipulate that postoperative length-of-stay (LOS) after elective carotid endarterectomy (CEA) should not exceed 1 day on average, yet perioperative care coordination gaps may limit the ability for institutions to achieve this goal. Internal review determined that increased LOS after CEA at our institution was frequently attributable to urinary retention or postoperative hypertension. We designed and implemented a quality improvement (QI) protocol aiming to better our institutional performance in postoperative LOS after CEA, consisting of 2 Plan-Do-Study-Act (PDSA) cycles. METHODS: In the first PDSA cycle, a division-wide standardized protocol was developed by which antihypertensive medications were managed preoperatively and through postoperative day (POD) 1. This protocol included dedicated patient outreach with instructions for at-home antihypertensive management through the morning of POD 0. Second, alpha-1-blockade was administered to all male patients preoperatively. All patients receiving an elective CEA performed at our institution by vascular surgeons were included in the protocol. The primary outcome measure was defined percent failure of the LOS >1 day metric, with raw LOS as a secondary outcome measure. Process measures included adherence to the antihypertensive medication protocol and adherence to preoperative alpha-1 blockade. Balance measures included documented intraoperative hypotension and 30-day readmission. Fisher's exact test was used to evaluate relationships between preintervention and postintervention cohorts and the outcome measure. Wilcoxon rank-sum tests were used to evaluate relationships between cohorts and total LOS. RESULTS: Baseline performance on the LOS >1 day metric after elective CEA was 58.3% in the 8 months prior to intervention, across 48 patients. Both PDSA interventions were implemented simultaneously. In the 12 months after intervention, 64 patients met protocol inclusion criteria, including 19 symptomatic patients (29.7%). Process measure success for preoperative antihypertensive regimen adherence was 89.8%. For males not chronically prescribed alpha-1 blockade preoperatively, process measure success for adherence to preoperative alpha-1 blockade was 78.8%. The intraoperative hypotension balance measure occurred in 1 patient (1.6%). Performance on the LOS >1 day outcome measure was improved to 32.8% (P = 0.01). Performance on the raw LOS outcome measure was similar between the preintervention cohort (median 2 days, interquartile range [IQR] 1-2) and postintervention cohort (median 1 day, IQR 1-2, P = 0.07). Performance on the 30-day readmission balance measure was similar between preintervention (6.3%) and postintervention cohorts (9.4%, P = 0.73). CONCLUSIONS: The consensus-driven development and implementation of a QI protocol to reduce postoperative LOS after CEA showed promising results in our institution, with approximately 40% improvement in the primary outcome measure. Wider efforts to improve LOS after CEA should include a focus on minimization of postoperative hypertension and urinary retention.

Atorvastatin Effect on Clopidogrel Efficacy in Patients with Peripheral Artery Disease.

BACKGROUND: Both clopidogrel and atorvastatin metabolism are rooted in hepatic cytochrome p450 activation. There are published reports of atorvastatin interfering with clopidogrel metabolism by inhibiting the activation of clopidogrel. This in turn would decrease the therapeutic effect of clopidogrel potentially resulting in an increase in thrombotic events in patients who are taking both medications. The emergence of viscoelastic assays, such as Thromboelastography with platelet mapping (TEG-PM), has been utilized to identify prothrombotic states and may provide insight into a patient's microvascular coagulation profile. The aim of this prospective, observational study was to delineate the differences in platelet function between patients on clopidogrel alone versus those on clopidogrel and atorvastatin in patients that are undergoing peripheral revascularization. METHODS: All patients undergoing revascularization between December 2020 and August 2022 were prospectively evaluated. Patients on clopidogrel and atorvastatin were compared to those on clopidogrel alone. Serial perioperative TEG-PM analysis was performed up to 6 months postoperatively and the platelet function in terms of percent inhibition was evaluated in both groups. Statistical analysis was performed using unpaired t-test to identify differences in platelet function. RESULTS: Over the study period, a total of 182 patients were enrolled. Of this cohort 72 patients met study criteria. 87 samples from the 72 patients were analyzed. 31 (43.05%) patients were on clopidogrel alone and 41 (56.94%) were on clopidogrel and atorvastatin. Patients on clopidogrel alone showed significantly greater platelet inhibition compared to those on clopidogrel and atorvastatin [49.01% vs. 34.54%, P = 0.03]. There was no statistical difference in platelet inhibition between groups in terms of aspirin use alone versus aspirin and atorvastatin. CONCLUSIONS: Patients on clopidogrel and atorvastatin showed significantly less platelet inhibition compared to those on clopidogrel alone, supporting the concept that atorvastatin may interfere with the therapeutic effect of clopidogrel. Patients taking atorvastatin may require an alternative antiplatelet therapy regimen that does not include clopidogrel to achieve adequate thromboprophylaxis.

Wall shear rate and energy loss coefficient measures using conventional Doppler ultrasound do not predict carotid plaque progression.

Background: The rate of carotid plaque progression is believed to be related to blood flow hemodynamics and shear stress. Our objective was to determine if wall shear rate (WSR) and the energy loss coefficient (ELC) measured by Doppler ultrasound could predict atherosclerotic carotid disease progression. Patients and methods: Patients at a large tertiary center with an initial ultrasound between 2016 and 2018 with a significant carotid plaque were included if they had at least one 6 months follow-up comparative study. Stenosis progression was assessed according to the NASCET (The North American Symptomatic Carotid Endarterectomy Trial) percentage criterion. Results: The average annual progression rate for the 74 plaques included was 5.7% NASCET per year. We identified 18 plaques with ≥10% NASCET progression and 56 plaques without significant progression <10% NASCET. Among the plaques with progression, only four plaques had progression greater than 20% NASCET. Median WSR was 6266 s-1 [5813-8974] in plaques with progression and 6564 s-1 [5285-8766] in stable plaques (p=0.643). Median ELC was 3.86 m2 [2.78-5.53] in plaque with progression and 4.32 m2 [3.42-6.81] in stable plaques (p=0.296). Conclusions: Although it is a widely accepted hypothesis that shear stress and hemodynamics of the carotid bifurcation contribute to plaque progression, we found that WSR and ELC estimated by Doppler ultrasound do not reliably predict atherosclerotic plaque progression in the carotid artery. Other ultrasound modalities, such as 3D imaging, may be used to assess the influence of plaque geometry and hemodynamics in plaque progression.

Infectious Aortitis of Thoracic Aortic Aneurysm From Clostridium Septicum.

A 71-year-old male presented with 1-day history of back pain. Imaging displayed an enlarging thoracic aortic aneurysm with gas in the aortic wall. Blood cultures grew Clostridium septicum. He underwent resection, debridement, and in situ aortic replacement with a rifampin-soaked graft under deep hypothermic circulatory arrest. His recovery was uncomplicated. (Level of Difficulty: Beginner.).

Routine Completion Angiography for Infrainguinal Bypasses Using Prosthetic Conduit: No Effect on Postoperative Patency.

BACKGROUND: Recent studies have demonstrated increased postoperative patency with the use of routine completion angiography for bypass using venous conduit. Compared to vein conduits, however, prosthetic conduits are less plagued by technical issues such as unlysed valves or arteriovenous fistulae. The effect of routine completion angiography on bypass patency in prosthetic bypasses has yet to be compared to the more traditional selective use of completion imaging. METHODS: A retrospective review of all infrainguinal bypass procedures using prosthetic conduit completed at a single hospital system from 2001 to 2018 was performed. Demographics, comorbidities, intraoperative reintervention rates, and 30-day rates of graft thrombosis were analyzed. Statistical analysis included t-tests, chi-square tests, and cox regression. RESULTS: Four hundred and ninety-eight bypasses that were performed in 426 patients met inclusion criteria. Fifty-six (11.2%) bypasses were classified into the routine completion angiogram group compared to 442 (88.8%) into the no completion angiogram group. Patients who underwent routine completion angiograms had a rate of intraoperative reintervention of 21.4%. When comparing bypasses that underwent routine completion angiography versus no completion angiography, there were no significant differences in rates of reintervention (3.5% vs. 4.5%, P = 0.74) or graft occlusion (3.5% vs. 4.7%, P = 0.69) at 30-days postoperatively. CONCLUSIONS: Almost one-quarter of lower extremity bypasses using prosthetic conduit that undergo routine completion angiography undergo postangiogram bypass revision; however, this is not associated with an increased graft patency at 30 days postoperatively.

Use of Thromboelastography with Platelet Mapping to Identify Prothrombotic Coagulation Profiles in Patients with History of Cardiac Intervention Undergoing Lower Extremity Revascularization.

BACKGROUND: Patients with concomitant coronary and peripheral artery disease (CAD and PAD) are at significant risk for major adverse limb events (MALEs). Prevention of thrombosis in this population is of paramount importance. Identifying prothrombotic coagulation profiles in this cohort may facilitate targeted thromboprophylaxis. We compared coagulation profiles of those with CAD and PAD to those with PAD alone during the perioperative period of lower extremity revascularization. STUDY DESIGN: Patients undergoing lower extremity revascularization underwent thromboelastography-platelet mapping (TEG-PM) analysis preoperatively and at serial intervals for up to 6 months. Coagulation profiles of patients with significant CAD (defined as history of coronary artery bypass graft or percutaneous coronary intervention) and PAD were compared with those with PAD alone. MALE in the postoperative period was recorded. RESULTS: Four hundred seventy-seven TEG-PM samples from 114 patients were analyzed; 28.1% had a history of significant CAD. The incidence of atrial fibrillation was higher in this group. The significant CAD group had lower ADP-platelet inhibition, higher ADP-platelet aggregation, and greater maximum clot strength compared with patients with PAD alone. Patients with significant CAD were more frequently on full-dose anticoagulation, but less frequently on dual antiplatelet therapy; 28.1% of patients with significant CAD developed postoperative MALE compared with 22.9% of patients with PAD alone (p = 0.40). For both groups, patients who developed postoperative MALE demonstrated greater ADP-platelet aggregation and lower ADP-platelet inhibition. CONCLUSIONS: Patients with a history of significant CAD undergoing lower extremity revascularization demonstrated prothrombotic TEG-PM profiles, less frequent use of dual antiplatelet therapy, and greater rates of full-dose anticoagulation. Decreased platelet inhibition was also associated with postoperative MALE. This study underscores the potential utility of viscoelastic assays for coagulation profiling in complex cardiovascular patients.

Analysis of Female Participant Representation in Registered Oncology Clinical Trials in the United States from 2008 to 2020.

BACKGROUND: Female underrepresentation in oncology clinical trials can result in outcome disparities. We evaluated female participant representation in US oncology trials by intervention type, cancer site, and funding. MATERIALS AND METHODS: Data were extracted from the publicly available Aggregate Analysis of ClinicalTrials.gov database. Initially, 270,172 studies were identified. Following the exclusion of trials using Medical Subject Heading terms, manual review, those with incomplete status, non-US location, sex-specific organ cancers, or lacking participant sex data, 1650 trials consisting of 240,776 participants remained. The primary outcome was participation to prevalence ratio (PPR): percent females among trial participants divided by percent females in the disease population per US Surveillance, Epidemiology, and End Results Program data. PPRs of 0.8-1.2 reflect proportional female representation. RESULTS: Females represented 46.9% of participants (95% CI, 45.4-48.4); mean PPR for all trials was 0.912. Females were underrepresented in surgical (PPR 0.74) and other invasive (PPR 0.69) oncology trials. Among cancer sites, females were underrepresented in bladder (odds ratio [OR] 0.48, 95% CI 0.26-0.91, P = .02), head/neck (OR 0.44, 95% CI 0.29-0.68, P < .01), stomach (OR 0.40, 95% CI 0.23-0.70, P < .01), and esophageal (OR 0.40 95% CI 0.22-0.74, P < .01) trials. Hematologic (OR 1.78, 95% CI 1.09-1.82, P < .01) and pancreatic (OR 2.18, 95% CI 1.46-3.26, P < .01) trials had higher odds of proportional female representation. Industry-funded trials had greater odds of proportional female representation (OR 1.41, 95% CI 1.09-1.82, P = .01) than US government and academic-funded trials. CONCLUSIONS: Stakeholders should look to hematologic, pancreatic, and industry-funded cancer trials as exemplars of female participant representation and consider female representation when interpreting trial results.

Predicting Arterial Thrombotic Events Following Peripheral Revascularization Using Objective Viscoelastic Data.

Background Peripheral artery disease is endemic in our globally aging population, with >200 million affected worldwide. Graft/stent thrombosis after revascularization is common and frequently results in amputation, major adverse cardiovascular events, and cardiovascular mortality. Optimizing medications to decrease thrombosis is of paramount importance; however, limited guidance exists on how to use and monitor antithrombotic therapy in this heterogeneous population. Thromboelastography with platelet mapping (TEG-PM) provides comprehensive coagulation metrics and may be integral to the next stage of patient-centered thrombophrophylaxis. This prospective study aimed to determine if TEG-PM could predict subacute graft/stent thrombosis following lower extremity revascularization, and if objective cut point values could be established to identify those high-risk patients. Methods and Results We conducted a single-center prospective observational study of patients undergoing lower extremity revascularization. Patients were followed up for the composite end point postoperative graft/stent thrombosis at 1 year. TEG-PM analysis of the time point before thrombosis in the event group was compared with the last postoperative visit in the nonevent group. Cox proportional hazards analysis examined the association of TEG-PM metrics to thrombosis. Cut point analysis explored the predictive capacity of TEG-PM metrics for those at high risk. A total of 162 patients were analyzed, of whom 30 (18.5%) experienced graft/stent thrombosis. Patients with thrombosis had significantly greater platelet aggregation (79.7±15.7 versus 58.5±26.4) and lower platelet inhibition (20.7±15.6% versus 41.1±26.6%) (all P<0.01). Cox proportional hazards analysis revealed that for every 1% increase in platelet aggregation, the hazard of experiencing an event during the study period increased by 5% (hazard ratio, 1.05 [95% CI, 1.02-1.07]; P<0.01). An optimal cut point of >70.8% platelet aggregation and/or <29.2% platelet inhibition identifies those at high risk of thrombosis with 87% sensitivity and 70% to 71% specificity. Conclusions Among patients undergoing lower extremity revascularization, increased platelet reactivity was predictive of subacute postoperative graft/stent thrombosis. On the basis of the cut points of >70.8% platelet aggregation and <29.2% platelet inhibition, consideration of an alternative or augmented antithrombotic regimen for high-risk patients may decrease the risk of postoperative thrombotic events.

Feasibility of Encord Artificial Intelligence Annotation of Arterial Duplex Ultrasound Images.

DUS measurements for popliteal artery aneurysms (PAAs) specifically can be time-consuming, error-prone, and operator-dependent. To eliminate this subjectivity and provide efficient segmentation, we applied artificial intelligence (AI) to accurately delineate inner and outer lumen on DUS. DUS images were selected from a cohort of patients with PAAs from a multi-institutional platform. Encord is an easy-to-use, readily available online AI platform that was used to segment both the inner lumen and outer lumen of the PAA on DUS images. A model trained on 20 images and tested on 80 images had a mean Average Precision of 0.85 for the outer polygon and 0.23 for the inner polygon. The outer polygon had a higher recall score than precision score at 0.90 and 0.85, respectively. The inner polygon had a score of 0.25 for both precision and recall. The outer polygon false-negative rate was the lowest in images with the least amount of blur. This study demonstrates the feasibility of using the widely available Encord AI platform to identify standard features of PAAs that are critical for operative decision making.

Metabolite patterns associated with individual response to supervised exercise therapy in patients with intermittent claudication.

Objective: Supervised exercise therapy (SET) is the first line treatment for intermittent claudication owing to peripheral arterial disease. Despite multiple randomized controlled trials proving the efficacy of SET, there are large differences in individual patient's responses. We used plasma metabolomics to identify potential metabolic influences on the individual response to SET. Methods: Primary metabolites, complex lipids, and lipid mediators were measured on plasma samples taken at before and after Gardner graded treadmill walking tests that were administered before and after 12 weeks of SET. We used an ensemble modeling approach to identify metabolites or changes in metabolites at specific time points that associated with interindividual variability in the functional response to SET. Specific time points analyzed included baseline metabolite levels before SET, dynamic metabolomics changes before SET, the difference in pre- and post-SET baseline metabolomics, and the difference (pre- and post-SET) of the dynamic (pre- and post-treadmill). Results: High levels of baseline anandamide levels pre- and post-SET were associated with a worse response to SET. Increased arachidonic acid (AA) and decreased levels of the AA precursor dihomo-γ-linolenic acid across SET were associated with a worse response to SET. Participants who were able to tolerate large increases in AA during acute exercise had longer, or better, walking times both before and after SET. Conclusions: We identified two pathways of relevance to individual response to SET that warrant further study: anandamide synthesis may activate endocannabinoid receptors, resulting in worse treadmill test performance. SET may train patients to withstand higher levels of AA, and inflammatory signaling, resulting in longer walking times. Clinical Relevance: This manuscript describes the use of metabolomic techniques to measure the interindividual effects of SET in patients with peripheral artery disease (PAD). We identified high levels of AEA are linked to CB1 signaling and activation of inflammatory pathways. This alters energy expenditure in myoblasts by decreasing glucose uptake and may induce an acquired skeletal muscle myopathy. SET may also help participants tolerate increased levels of AA and inflammation produced during exercise, resulting in longer walking times. This data will enhance understanding of the pathophysiology of PAD and the mechanism by which SET improves walking intolerance.

Understanding motivations behind medical student involvement in COVID-19 pandemic relief efforts.

BACKGROUND: Although students were removed from patient-facing settings at the beginning of the COVID-19 pandemic due to concerns of burdening teaching physicians and depleting personal protective equipment, some leaders suggest students can be effectively utilized when personnel resources may be scarce. There have been narrative discussions surrounding medical student involvement, but no studies exploring the attitudes of these students. The authors aim to quantify the degree to which factors influenced a medical student's decision to or to not volunteer during the pandemic and to characterize medical students' attitudes towards medical professionals' duty to serve in a pandemic. METHODS: The authors developed and tested a secure web-based survey before distribution to students at 23 different US allopathic medical schools that did not graduate medical students early to aid in pandemic efforts between April and June 2020. Of the 599 students who completed the survey, 65.5% self-identified as female and were on average 25.94 years old (SD = 2.5). Multiple comparisons were made based on volunteer status. Ordinal scale questions were compared with the Mann Whitney U test, and the Chi-Squared test was used for categorical variables using R version 3.62. RESULTS: 67.6% of students volunteered in pandemic relief activities and a majority of those students volunteered in non-patient-facing roles. Community service, new skills, and time commitment were top 3 influencing factors for students who volunteered, while risk to other, time commitment, and risk to self were top 3 influencing factors for students who chose not to volunteer. Compared to other specialties, students interested in primary care specialties agreed to a greater degree that physicians have a duty to serve in pandemic relief efforts. CONCLUSIONS: Medical students who volunteered cited self-serving factors and altruistic values as significant motivators. Students who did not volunteer were significantly more concerned with risks of COVID-19 exposure. However, medical students in general agreed that students should be allowed to volunteer in COVID-19 related relief efforts. As large areas of the United States continue to experience increases in COVID-19 cases, institutions should involve medical students in balancing the level of acceptable risk with the educational benefits.

Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure.

Heart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution of common genetic variation to heart failure risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We report a multi-ancestry genome-wide association study meta-analysis of all-cause heart failure including up to 115,150 cases and 1,550,331 controls of diverse genetic ancestry, identifying 47 risk loci. We also perform multivariate genome-wide association studies that integrate heart failure with related cardiac magnetic resonance imaging endophenotypes, identifying 61 risk loci. Gene-prioritization analyses including colocalization and transcriptome-wide association studies identify known and previously unreported candidate cardiomyopathy genes and cellular processes, which we validate in gene-expression profiling of failing and healthy human hearts. Colocalization, gene expression profiling, and Mendelian randomization provide convergent evidence for the roles of BCKDHA and circulating branch-chain amino acids in heart failure and cardiac structure. Finally, proteome-wide Mendelian randomization identifies 9 circulating proteins associated with heart failure or quantitative imaging traits. These analyses highlight similarities and differences among heart failure and associated cardiovascular imaging endophenotypes, implicate common genetic variation in the pathogenesis of heart failure, and identify circulating proteins that may represent cardiomyopathy treatment targets.