McBane, Robert D.

Background Cardiovascular surgical outcomes reports are few for vascular type IV of Ehlers- Danlos Syndrome (vEDS) compared to non-vascular types I-III (nEDS). Methods To define cardiovascular surgical outcomes among adult patients (≥18 years) with EDS types, a review of our institution's in-house STS Adult Cardiac Surgery Database-compliant software and electronic medical records from Mayo Clinic (1993–2019) was performed. Outcomes were compared for vEDS patients and nEDS patients. Demographics, baseline characteristics, operative, in-hospital complications and follow-up vital status were analyzed. Results Over the study time frame, 48 EDS patients underwent surgery (mean age 52.6 ± 14.6 years; 48% females). Of these, 17 patients had vEDS and 31 patients had nEDS. Six patients (12.5%) underwent prior sternotomy. Urgent or emergent surgery was performed in 10 patients (20.8%). Aortic (vEDS 76.5% vs. nEDS 16.1%) and mitral procedures (vEDS 11.8% vs. nEDS 48.4%) were the two most common cardiovascular surgeries performed (p < .01 and p = .007, respectively). Cardiopulmonary bypass time (CPB) (165 ± 18 vs. 90 ± 13 min; p = .015) and aortic cross clamp times (140 ± 14 vs. 62 ± 10 min; p < .001) were longer for vEDS patients. There was 1 (2.1%) early and 7 (14.6%) late deaths; 6 among vEDS and 2 among nEDS patients. Survival at 5 (80% vs. 93%), 10 (45% vs. 84%) and 15 years (45% vs. 84%) was lower in patients with vEDS (p = .015 for each comparison). Conclusion Cardiovascular surgeries are significantly more complex with longer bypass and cross clamp times for type IV vEDS compared to nEDS patients. Reduced overall survival underscores the complexity and fragility of vEDS patients.

Abstract Background: Reduced or low-dose direct oral anticoagulants (DOACs) have been studied in randomized control trials for the extended prevention of venous thromboembolism (VTE) after 6 months of treatment at the therapeutic doses. The real-world effectiveness as well as utilization of this approach in clinical practice compared to continuing at therapeutic doses is unknown. Aims: Evaluate the efficacy of reduced-dose DOACs compared to standard therapeutic anticoagulation in patients with extended anticoagulation. Methods: Consecutive patients with VTE were identified using the Mayo Clinic VTE Registry from March 1st , 2013 to December 31st, 2020. Patients were followed prospectively for outcomes of VTE recurrence, death, major bleeding and clinically relevant non major bleeding (CRNMB) either in person or by survey. Type of anticoagulation and dose changes were recorded, and progressing to a low dose was treated as an endpoint. In the models relating it to the outcome, it was treated as a time-dependent covariate in the cox models. After completing standard anticoagulation treatment for 3 months with any anticoagulant, patients continuing anticoagulation were divided into two groups: standard therapeutic anticoagulation (any drug) vs those who transitioned to rivaroxaban 10 mg daily or apixaban 2.5mg twice daily any time after 3 months. Patients with recurrent VTE, major or CRNMB during the first 3 months were excluded from further analysis. Results: 219 patients (153 on Apixaban and 66 on Rivaroxaban) were identified in the low dose DOAC and 2521 in the standard anticoagulation group. The mean age was 60.7 years, mean weight was 93.2 Kg and 55.9% were males (Table 1). Patients on low dose DOACs were about the same age and weight compared to standard anticoagulation group. Among all diagnosis categories, patients with active cancer were less likely to be prescribed low dose DOACs (HR 0.56; 95%CI 0.42-0.73; P&lt;0.001), while low dose DOACs prescription was more likely in patients with pulmonary embolism (HR 1.45; 95%CI 1.11-1.89; P=0.007). The median months to start a low dose DOAC after completing the 3 months was 3.1 months with standard deviation of 6.6 months and interquartile range 2.8 months. There was no statistically significant association in the likelihood of going to a low dose group in relation to VTE recurrence (HR 1.36; 95%CI 0.42-4.45; P=0.61) or major bleeding (HR 0.59; 95%CI 0.08-4.37; P=0.61). However, transitioning to low dose DOAC was associated with reduced mortality (HR 0.53; 95%CI 0.35-0.80; P=0.003). Also, patients on low dose DOACs were more likely to have a CRNMB (HR 2.76; 95%CI 1.15-6.62; P=0.02). Conclusion: In this study of patients continuing anticoagulation past 3 months for an initial acute venous thromboembolic event, transitioning to low dose DOACs was not associated with any statistically significant association with VTE recurrence or major bleeding. However, mortality was lower and CRNMB was higher in this unadjusted analysis. Our results show that physicians are not always waiting until 6 months to transition to low doses and low doses are being utilized in cancer patients. Further research is needed to better understand the higher risk for CRNMB identified in this group. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Patients with coronavirus disease 2019 (COVID-19) have an increased risk for venous thromboembolic events. Thrombotic events contribute to the morbidity and mortality associated with COVID-19 infection, and have prompted investigation into strategies for mitigating thrombosis risk in patients hospitalized with COVID-19 infection. Our team reviewed the charts of patients hospitalized with COVID-19 pneumonia at a tertiary hospital in metropolitan Phoenix Arizona between 2020-2021, to assess frequency and efficacy of utilizing a VTE prophylaxis algorithm designed to prevent thrombosis in patients infected with COVID-19. Methods: A total of 846 patients were retrospectively evaluated to determine if they were treated with guideline-appropriate anticoagulation while hospitalized with COVID-19, as well as if they developed venous or arterial thrombotic events, or major or minor bleeds. 317 patients were excluded for taking therapeutic anticoagulation prior to admission, or for having a COVID-19 diagnosis &gt;7 days after admission. Appropriate anticoagulation was determined by an institutionally designed COVID-19 thromboprophylaxis algorithm, based on platelet count, d-dimer, bleeding risk, and level of medical care required. Regimen options included: no anticoagulation, prophylactic enoxaparin (40 mg SQ daily) or heparin in the setting of kidney dysfunction, weight-based dosing of enoxaparin (40 mg SQ BID if BMI&gt;40), intermediate intensity enoxaparin without thrombus (30 mg BID if BMI&lt;40, or 40 mg BID if BMI&gt;40), and therapeutic anticoagulation (for example enoxaparin 1 mg/kg BID) with thrombus. Demographics: Demographic data and clinical characteristics were collected for 529 patients. Average age was 59 years old, and the majority were men (58.4%). Most patients were White (58.3%), followed by Hispanic (17.8%), or Native American (15.7%). Fewer patients had a normal BMI (21.3%; BMI 18.5 - 24.9) compared to those who were overweight (31.2%; BMI 25-29.9) or obese (43.1% BMI &gt; 30). Other comorbidities included Type 1 or Type 2 diabetes mellitus (N= 172, 32.5%), hypertension (N = 271, 51.2%), and hyperlipidemia (N = 176, 33.3%). Results: A total of 42 patients (8%), were diagnosed with a venous thrombosis during hospitalization. Patients admitted to the ICU were significantly more likely to have a thrombotic event of any type compared to non-ICU patients (21.6% to 5.7%; p &lt; 0.001). Specifically, critically ill patients had higher incidences of deep vein thrombosis (9.5% to 0.7%), pulmonary emboli (8.1% to 4.8%), and superficial thrombi (2.7% to 0.2%). Only 1.1% of patients (6/529) experienced any bleeding, of which 3 were classified as a major bleed. Discussion: Among patients hospitalized at our institution with COVID-19, the majority were anticoagulated appropriately according to the COVID-19 thromboprophylaxis algorithm. Overall incidence of thrombosis in the study population was 8%. A significantly higher percent of critically ill patients had thrombi, supporting reports of correlation between severity of illness and thrombosis risk. The two regimens of anticoagulation least adhered to were weight-based and intermediate-based dosing, likely reflecting a departure from the hospital's thromboprophylaxis regimens prior to COVID-19 pandemic. Further studies are needed to characterize whether identifiable risk factors correlate with the incidence of thrombosis, and whether treatment with lower than recommended doses of anticoagulation, based on the COVID-19 thromboprophylaxis algorithm, were associated with thrombosis. Disclosures No relevant conflicts of interest to declare.

Introduction: Triple oral antithrombotic therapy (TOAT) (aspirin, clopidogrel, and warfarin) is associated with an increased risk of bleeding. Despite this, the optimal management of patients with indications for warfarin following percutaneous coronary intervention (PCI) has not been established. We sought to compare long-term clinical outcomes between patients receiving TOAT with those receiving dual antiplatelet therapy (DAPT) (aspirin and clopidogrel) after PCI. Hypothesis: Patients with clinical indications for warfarin have higher baseline risk which is largely responsible for the observed differences in outcomes between patients receiving TOAT vs. DAPT. Methods: Retrospective analysis of prospectively collected data from 9,009 patients. The primary outcome was a composite of all-cause mortality, ischemic or embolic events (myocardial infarction or stroke), or bleeding. Secondary outcomes were death plus ischemic or embolic events, death plus bleeding, death, MI, stroke, and bleeding. A 2:1 propensity matched analysis was also performed. Results: In 9,009 patients, 812 received TOAT and 8,197 received DAPT. Median follow-up was 61 months. The primary end point occurred in 2,749 patients. At 1 year, 22% of patients treated with TOAT had the primary endpoint versus 11% of DAPT patients (p<0.001). At 1 year, secondary end points of death or ischemic or embolic events (19% vs. 10%, p<0.001), and death or bleeding events (15% vs. 5%, p<0.001) also occurred with a higher frequency with TOAT. After propensity matched analysis the above differences were no longer significant with 1 year primary endpoint rates of 19% vs. 17% respectively (HR 1.95%, CI 0.88, 1.47; p = 0.33). Following propensity matching the only significant difference between TOAT and DAPT groups was minor bleeding (5% vs. 2%; HR 2.65, 95% CI 1.39, 5.03; p=0.003). Conclusions: In a large single center registry with comprehensive follow up, patients treated with TOAT had higher rates of ischemic and bleeding events. However, when baseline risks are accounted for event rates are similar, other than minor bleeding, indicating patient risk characteristics are largely responsible for the observed differences in outcomes.

Background: Active malignancy accounts for 20% of venous thromboembolism (VTE) in the community and is the second leading cause of death among cancer patients. Rivaroxaban offers a convenient alternative to conventional anticoagulation for VTE in cancer patients but its efficacy and safety for this group of patients is not well documented. Patients and Methods: All patients with cancer-associated deep vein thrombosis (DVT) or pulmonary embolism (PE), enrolled into Mayo Rochester Thrombophilia Clinic Direct Oral Anticoagulants Registry between November 1, 2012 and April 30, 2015, were followed prospectively to provide an estimate of the efficacy and safety of this form of therapy. Follow up was obtained in person or by mailed or telephone survey. Results: Out of the 377 patients in the registry, 118 (31%) patients (51% female, mean age 66±10 years) had active malignancy related VTE (62% DVT, 24% PE, and 14% DVT/PE) treated with rivaroxaban. The most common malignancies in this group were: gastrointestinal (20%), lung (13%) and ovary/uterine (13%). Over the follow up period, the VTE recurrence rate was 3.3% (2 DVT and 2 PE; of these, 2 occurred during periprocedural interruptions of anticoagulation); and the major bleeding rate was 3%. There were 26 deaths (22%), none related to VTE or bleeding. The main reasons for choosing rivaroxaban were lower cost compared to LMWH, no need for injections, and the lack of food/drug interactions. Conclusions: These data support that rivaroxaban may provide a safe, effective, and convenient alternative treatment option to standard therapy for cancer related VTE treatment.

Introduction: Venous thromboembolism (VTE) is a cause of significant morbidity and mortality. The vascular endothelium may be involved in the pathogenesis of both VTE and arterial thrombosis, as endothelial injury and dysfunction may disrupt normal anticoagulation mechanisms. We aimed to test the hypothesis that coronary endothelial dysfunction (CED) is associated with development of VTE in prospective follow-up. Methods: Coronary vascular reactivity was evaluated in 502 patients with non-obstructive coronary artery disease by administration of intracoronary acetylcholine during diagnostic angiography. Microvascular CED was defined as ≤50% increase in coronary blood flow (CBF) from baseline in response to maximal dose of acetylcholine. After median follow-up of 6.3 years (IQR 3.5, 10.7), patients were assessed by standardized questionnaire, phone-call and review of medical records for development of VTE. Results: Median age of the population was 53 years (IQR 45, 62); 68% were females. Hypertension was prevalent in 40.8%, diabetes in 8.4%, and hyperlipidemia in 58.3% of patients. Of 502 patients, 279 had CED. There were no significant differences in baseline characteristics including cardiovascular and VTE risk factors between patients with and without CED (p>0.05). Eighty-nine percents of patients who developed VTE had CED. Patients who developed spontaneous or provoked VTE both had significantly lower % change in CBF than patients who did not develop VTE (p<0.05) (Figure 1). In univariate analysis, microvascular dysfunction was associated with increased risk of VTE (OR 6.55 (95% confidence interval (0.81, 52.79); p=0.04). Conclusion: We found a seven-fold increased risk of VTE with CED, suggesting a link between the two. Endothelial injury disrupting vascular homeostasis may predispose patients to VTE.

Background: Testicular vein thrombosis (TVT) is not currently well-described in the literature. A better understanding of the natural history of TVT will allow for development of optimal management strategies for this little known entity. Methods: The goal of this project was to compare TVT with ovarian vein thrombosis (OVT) and lower extremity deep vein thrombosis (DVT). Patients with TVT, OVT, or DVT between 1995 and 2015 were identified and a chart review was performed. Results: A total of 39 patients with TVT occurring between 1995 and 2015 were identified and compared with 35 patients with OVT and 114 randomly chosen DVT patients. Mean duration of follow-up was 2.9 years (range 0-16.1). Patient demographics can be seen in table 1. Cancer-related (p-value=<0.0001) and idiopathic thrombosis (p-value=0.01) rates were significantly different among the groups. Recurrence rates were similar between TVT and OVT (4.2 vs. 3 per 100 patient-years, p-value = 0.9) as well as TVT and DVT (4.2 vs 2.2 recurrences per 100 patient-years, p-value= 0.37). There were 25 deaths (22%) in DVT patients, 9 (26%) in OVT patients, and 12 (31%) in TVT patients (p-value= 0.541). There was one major bleeding event in both an OVT patient and a TVT patient. Conclusion: Etiology of TVT differs from that of OVT and DVT, specifically in cancer-related and idiopathic thrombosis rate. Our data supports a similar rate of recurrent venous thromboembolism and death in TVT as compared with DVT and OVT.

Abstract Background: Guidelines suggest the use of the Khorana score to select patients with solid cancer receiving chemotherapy for thromboprophylaxis to prevent venous thromboembolism (VTE), but its performance in different types of cancers remains uncertain. Methods: The present analysis includes individual patient data from seven randomized controlled trials that had compared prophylactic (ultra)-low-molecular-weight heparin (LMWH) with placebo or observation in patients with solid cancer. The analysis addresses the performance of the continuous and dichotomized Khorana score in predicting the 6-month risk of VTE in the trial control groups, overall and in types of cancer studies, as well as the efficacy and safety of LMWH among patients with a high-risk Khorana score. Random effects meta-analysis provided the basis for summary estimates. Findings: In the 3,403 patients from the control groups included in the analyses, the mean age was 61 years, 59% were male, and 58% had lung cancer. During 6-months of follow-up, 188 patients (5.5%) developed VTE. Overall, the 6-month VTE incidence was 9.8% among high-risk Khorana score patients and 6.4% among low-to-intermediate risk patients (OR 1.6; 95%-CI 1.1-2.2). The dichotomous Khorana score performed differently in lung cancer patients (OR 1.1; 95%-CI, 0.72-1.7) than in those with other types of cancer (OR 4.4; 95%-CI, 2.7-7.3; P interaction=0.002). Among high-risk patients, LMWH decreased the risk of VTE by 64% compared to placebo or observation (OR 0.36; 95%-CI, 0.22-0.58). In the group of patients with types of cancer other than lung cancer and a high-risk Khorana score (N=619), the 6-month VTE incidence was 3.3% (95% CI, 1.4 to 7.7) among LMWH recipients and 13% (95% CI, 6.8 to 24) among those not receiving LMWH (OR 0.23, 95% CI, 0.11 to 0.46; P &lt;0.001). There was no difference in major bleeding (OR 1.2, 95% CI, 0.56 to 2.5). Interpretation: The Khorana score performs poorly in differentiating between those at high and low risk of VTE in patients with lung cancer, but is associated with a 4-fold increased risk of VTE in those with other types of cancer. Thromboprophylaxis is effective and safe in patients with a high-risk Khorana score. Funding: Canadian Institutes of Health Research knowledge synthesis grant, KRS 126594 Registration: International Prospective Register for Systematic Reviews (PROSPERO), CRD42013003526. Disclosures Van Es: Pfizer: Employment, Other: Comment: Dr. van Es reports personal fees from Pfizer as a member of their advisory board. These fees are unrelated to this project.. Crowther: Alexion: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Leo Pharma: Research Funding; Pfizer: Honoraria; Portola: Consultancy; Shinogi: Consultancy. Macbeth: Cancer Research UK: Research Funding; Pfizer: Other: Provision of Dalteparin for FRAGMATIC trial. Griffiths: Pfizer: Consultancy, Other: Comment: I run an academic clinical trials unit, have received educational/investigator intiated research grants from companies that make these heparin agents. As consultant &gt; 3 years ago, advised Pfizer on clinical trial designs unrelated to this study., Research Funding. Streiff: Roche: Research Funding; Portola: Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Ageno: Daiichi Sankyo: Consultancy, Honoraria; Bayer AG: Consultancy, Honoraria, Research Funding; BMS-Pfizer: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria. Bozas: PharmaMar: Honoraria. Maraveyas: Bayer: Other: Personal fees and conference attendance; Bristol-Myers Squibb: Other: Grants and personal fees; Leo Pharma: Other: Grants, personal fees and conference attendance; Pfizer: Other: Personal fees. Loprinzi: Bristol Myers: Other: Grant - unrelated to this project; Janssen: Other: Grant - unrelated to this project. McBane: Bristol Myers Squibb: Other: Research grant for cancer associated VTE. Schünemann: Canadian Institutes of Health Research: Research Funding.