Girardo, Marlene

Abstract Context Peripheral artery disease (PAD) is highly prevalent in the general population, affecting up to 25% of patients 55 years of age or older. There is a known association with acute ischemic stroke, but limited large cohort studies exist pertaining to the relationship between PAD severity and incident ischemic stroke. Objectives To evaluate the risk of incident ischemic stroke and mortality along the spectrum of low and elevated ankle brachial index (ABI) measurement. Methods We performed a retrospective extraction of ABI data of all adult patients who underwent lower extremity physiology study for any indication from January 1, 1996 to June 30, 2018 in the Mayo Clinic health system. PAD was categorized into severe, moderate, mild, and borderline based on ABI measurements and poorly compressible arteries (PCA). These were compared with normal ABI measurements. Associations of PAD/PCA with new ischemic stroke events and all cause mortality were analyzed. Hazard ratios (HR) were calculated using multivariable Cox proportional regression with 95% confidence intervals. Results A total of 39,834 unique patients were included with a median follow up duration of 4.59 years. All abnormal ABI groups, except borderline PAD, were associated with increased risk of incident ischemic stroke after multivariate regression compared to normal ABI. A severity-dependent association was observed between PAD and ischemic stroke with moderate (HR, 1.22 [95% CI, 1.10–1.35]) and severe (HR, 1.19 [95% CI, 1.02–1.40]) categories conferring similar risk in comparison to normal ABI. Patients with PCA carried the greatest ischemic stroke risk (HR, 1.30 [95% CI, 1.15–1.46]). Similarly, abnormal ABI groups were associated with a significant risk for all cause mortality in a severity-dependent manner, with severe PAD conferring the greatest risk (HR, 3.07 [95% CI, 2.88–3.27]). Conclusions This study adds to the growing body of evidence that both PAD and PCA are independent risk factors for incident ischemic stroke and all cause mortality. The association of PAD severity and PCA with risk of ischemic stroke may help clinicians with risk stratification and determining treatment intensity.

Abstract Objective To assess the real‐world efficacy, tolerability, and safety of ubrogepant in a tertiary headache center. Background The efficacy and safety of ubrogepant for the acute treatment of migraine were established in phase 3 randomized controlled trials. However, there is no real‐world data of patient experience with ubrogepant in a population in which the majority of patients have chronic migraine, multiple prior unsuccessful treatments, complex medical comorbidities, and concurrent use of other migraine‐specific medications. Method This was a post‐market cohort study conducted at Mayo Clinic Arizona. All patients prescribed ubrogepant were tracked and contacted 1–3 months after the prescription to answer a list of standardized questions. Demographic information and additional headache history were obtained from chart review. Results We obtained eligible questionnaire responses from 106 patients. Chronic migraine accounted for 92/106 (86.8%) of the population. Complete headache freedom (from mild/moderate/severe to no pain) and headache relief (from moderate/severe to mild/no pain or mild to no pain) for ≥75% of all treated attacks at 2 hours after taking ubrogepant were achieved in 20/105 (19.0%) and 50/105 (47.6%) patients, respectively. A total of 33/106 (31.1%) patients reported being “very satisfied” with ubrogepant. Adverse events were reported in 42/106 (39.6%) patients, including fatigue in 29/106 (27.4%), dry mouth in 8/106 (7.5%), nausea/vomiting in 7/106 (6.6%), constipation in 5/106 (4.7%), dizziness in 3/106 (2.8%), and other adverse events in 7/106 (6.6%). Predictive factors for being a “good responder” to ubrogepant, defined as headache relief for ≥75% of all treated attacks at 2 hours after taking ubrogepant, included migraine with aura, episodic migraine, <5 prior unsuccessful preventive or acute treatment trials. Additionally, prior treatment responses to a CGRP monoclonal antibody and onabotulinumtoxinA injections are predictive of treatment responses and patient satisfaction to ubrogepant. For the 62/106 (58.5%) patients concurrently using a CGRP monoclonal antibody, there was no difference in the “good responder” rate or adverse event rate compared to those who were not on a CGRP monoclonal antibody, though the rate of moderate, as opposed to mild adverse events was higher, 11/62 (47.8%) versus 3/44 (17.6%), p = 0.048. Additionally, 16 patients had a history of significant cardiovascular or cerebrovascular diseases. No severe adverse events were reported in any patient. Conclusion Our study confirms and extends the efficacy profile and tolerability of ubrogepant in a real‐world tertiary headache clinic and identifies factors that may predict efficacy. Adverse event rates were higher than reported in clinical trials. Further studies are needed to confirm these findings and to evaluate the long‐term efficacy and safety of ubrogepant.

Abstract Introduction Antiplatelet therapy is the cornerstone of treatment for many atherosclerotic vascular pathologies including peripheral arterial disease (PAD). Patients with PAD often have comorbid conditions that require complex antithrombotic therapy, i.e. combined antiplatelet and anticoagulation. Methods All adult patients undergoing ankle brachial index (ABI) measurements were included in the study. ABI values between 1.00 and 1.40 were considered normal, and values below 1.00 or above 1.40 were considered PAD. Demographic, comorbidity and outcome data were obtained using diagnostic codes from the electronic health record. Three medication classes were analyzed: aspirin, non-aspirin oral antiplatelets (e.g. P2Y12 inhibitors) and oral anticoagulants (warfarin and the direct oral anticoagulants). Medication use was determined for patients who had been on a medication for at least one year. Cox proportional hazard analysis for the time to first bleeding event was analyzed. Bleeding was defined as any bleeding requiring medical evaluation (including clinically-relevant non-major bleeding and major bleeding). Results In all, 40,144 patients were included in the analysis (mean age 66±15, 43% female). Patients with PAD were more likely to be on double therapy (one antiplatelet with anticoagulation) (28% vs 19%) and triple therapy (dual antiplatelet with anticoagulation) (10% vs 4%). Unadjusted hazard ratios for bleeding risk showed increased risk of bleeding for patients with PAD (1.18, 95% confidence interval [CI]: 1.08–1.29), though the association is no longer present after adjustment for antithrombotic therapy. Adjusting for age, sex and PAD class, compared to no antithrombotic therapy, there was increased risk of bleeding for monotherapy (1.91, 95% CI: 1.61–2.26), double therapy (3.40, 95% CI: 2.89–4.00) and triple therapy (5.00, 95% CI: 4.21–5.96). Among medications, aspirin and anticoagulant use was independently associated with the greatest increase in risk of bleeding. Conclusion Patients in PAD are at increased risk of bleeding secondary to antithrombotic therapy. Complex antithrombotic therapy with double or triple therapy confer additional bleeding risk, particularly regimens containing aspirin and oral anticoagulants. Funding Acknowledgement Type of funding source: None

Abstract Introduction Given the potential side effects and the lack of data on its efficacy, the role of statins in the very elderly (age 75+) with peripheral arterial disease (PAD) is uncertain. Previous studies have shown significant mortality benefit in very elderly patients with coronary artery disease, but the effect in PAD has not been evaluated. Methods Very elderly patients aged 75 to 80 with at least five years of follow-up who underwent ankle-brachial index (ABI) measurement were included. PAD was defined as either low ABI &lt;0.90 or high ABI &gt;1.40. Demographic, medication use, comorbidity and mortality data was obtained using the electronic medical record. Univariate and multivariate Cox proportional hazard analyses were performed. Results In total, 4,560 very elderly subjects with PAD were included in the analysis. The median age was 77 (interquartile range 76–79) and 39% were female. 3,462 (76%) had low ABI while 1098 (24%) had high ABI. Univariate analysis showed that patients on statins were more likely to be male, have diabetes, have coronary artery disease, and have hyperlipidemia. Overall, 1,355 (30%) patients died in the five-year period. Unadjusted all-cause mortality hazard ratios for patients with low or high ABI with statin use was 0.66 (95% confidence interval [CI]: 0.57–0.75) and 0.80 (95% CI: 0.66–0.97), respectively. After adjusting for age, sex, coronary artery disease and diabetes, statin use in low and high ABI was still associated with significant reductions in risk of all-cause mortality of 0.59 (95% CI: 0.51–0.67) and 0.66 (95% CI: 0.54–0.80), respectively. The survival curve for very elderly patients with PAD by statin use is shown in Figure 1. Conclusion Statin use in the very elderly was associated with lower risk of all-cause mortality in the five-year period after diagnosis of PAD. There appears to be a mortality benefit with statin use in the very elderly with PAD, though careful consideration of benefits and side effects should be individualized in this age group. Figure 1 Funding Acknowledgement Type of funding source: None

Background Ankle‐brachial indexes ( ABI ) are a noninvasive diagnostic tool for peripheral arterial disease and a marker of increased cardiovascular risk. ABI is calculated using the highest systolic blood pressure of the 4 ankle arteries (bilateral dorsalis pedis and posterior tibial). Accordingly, patients may be assigned a normal ABI when the result would be abnormal if calculated using one of the other blood pressure readings. Cardiovascular outcomes for patients with discordant ABI s are undescribed. Methods and Results We performed a retrospective study of patients who underwent ABI measurement for any indication between January 1996 and June 2018. Those with normal ABI s (1.00–1.39) were included. We compared patients with all 4 normal ABI s (calculated using all 4 ankle arteries; n=15 577, median age 64.0 years, 54.4% men) to those with discordant ABI s (at least 1 abnormal ABI ≤0.99; n=2095, median age 66.0 years, 47.8% men). The outcomes assessed were ischemic stroke, myocardial infarction, and all‐cause mortality. Compared with patients with concordant normal ABI s, patients with discordant ABI s were older; women; smoked; and had chronic kidney disease, coronary artery disease, diabetes mellitus, chronic obstructive pulmonary disease, hypertension, or prior stroke. Patients with discordant ABI s had a greater risk of myocardial infarction (hazard ratio [HR], 1.31; 95% CI, 1.10–1.56), ischemic stroke ( HR, 1.53; 95% CI, 1.37–1.72), and all‐cause mortality ( HR, 1.27; 95% CI, 1.16–1.39), including after adjustment for baseline comorbidities. Conclusions Discordant ABI results were associated with an increased risk of myocardial infarction, stroke, and all‐cause mortality in the studied population. Clinicians should examine ABI calculations using all 4 ankle arteries to better characterize a patient's cardiovascular risk.

BACKGROUND: The proportion of women medical school graduates in the United States has grown substantially; however, representation of women in anesthesiology lags behind. We sought to investigate factors associated with women recommending against a career in anesthesiology due to obstacles related to motherhood. METHODS: We surveyed 9525 women anesthesiologist members of the American Society of Anesthesiologists (ASA) with a web-based survey distributed via e-mail. Associations between whether women would counsel against anesthesiology due to obstacles related to motherhood and 34 related categorical variables were estimated. Fisher exact test was used for categorical binary variables, and Wilcoxon-Mann-Whitney test was used for ranked variables. RESULTS: The response rate for the primary question was 19.2%. Among the 1827 respondents to the primary question, 11.6% would counsel a female medical student against a career in anesthesiology due to obstacles pertaining to motherhood. Counseling against an anesthesiology career was not associated with ever being pregnant ( P = .16), or whether a woman was pregnant during residency or fellowship training ( P = .41) or during practice ( P = .16). No association was found between counseling against anesthesiology and training factors: total number of weeks of maternity leave ( P = .18), the percentage of women faculty ( P = .96) or residents ( P = .34), or the number of pregnant coresidents ( P = .66). Counseling against a career in anesthesiology was significantly associated with whether respondents’ desired age of childbearing/motherhood and desired number of children were adversely affected by work demands (with Bonferroni adjustment for the 34 comparisons, both P < .0001). The risk ratio of respondents whose desired childbearing age and desired number of children were affected by work demands counseling against a career in anesthesiology was 5.1 compared to women whose desired childbearing age and desired number of children were not affected (99% confidence interval [CI], 3.3–7.9; P < .0001; odds ratio, 6.2). CONCLUSIONS: In this study of 1827 women anesthesiologists, approximately 1 in 10 would counsel a student against a career in anesthesiology due to obstacles pertaining to motherhood, and this was associated with altering one’s timing and number of children due to job demands. Further research is needed to understand how women’s perception of a career in anesthesiology is related to factors influencing personal choices. Understanding women’s perceptions of motherhood in anesthesiology may help leaders support career longevity and personal satisfaction in this growing cohort of anesthesiologists.

Introduction- Graft-versus-host disease (GVHD) is a major complicating factor in determining morbidity and mortality following allogeneic stem cell transplant. To prevent GVHD, our institution administers calcineurin inhibitors and low doses of methotrexate (MTX) (5-15 mg/m2) on days +1, +3, +6, +11 for GVHD prophylaxis. While MTX is an efficacious agent in preventing GVHD, one of the undesirable adverse effects, which can be a dose limiting toxicity, is mucositis. Proton pump inhibitors (PPIs) are used for the treatment of gastroesophageal reflux disease, pyrosis, and/or peptic ulcer disease. PPIs have been shown to inhibit the ATP-binding cassette drug transporter Breast Cancer Resistance Protein's (BCRP/ABCG2) ability to excrete methotrexate into the urine in a concentration-dependent manner. Delayed excretion of methotrexate can lead to adverse events such as renal impairment, increased severity of mucositis, and increased infection rates. High dose MTX, defined as 500mg/m2 or more, has been shown to have delayed excretion when administered concomitantly with PPIs. The purpose of this retrospective, single center study is to assess the clinical outcomes of patients receiving low dose MTX and PPIs compared to MTX and no PPI for GVHD prophylaxis. Patients and Methods- A single-site institutional review board exempt retrospective analysis of patients 18 years of age or older who underwent allogeneic stem cell transplantation from 2013 to 2018 at our institution. Only patients that received methotrexate for GVHD prophylaxis were included. Cases were identified from clinical databases at our institution and were divided into two cohorts, those on PPIs, and those not on PPIs (no-PPI). Chart review was performed for the clinical variables of interest. The primary endpoint was grade of mucositis in each cohort. Secondary endpoints were total parenteral nutrition (TPN) use, need for patient controlled analgesia (PCA), leucovorin use, time to engraftment of absolute neutrophil count (ANC) and hospital length of stay (LOS). Lab values for analysis were assessed at admission and days +1/+5/+15. Results- 284 cases were identified, 119 (42%) patients were on a PPI at the time of MTX administration. The median age of patients on PPI was younger than those not on PPI (60 vs 54 p <0.0001). There were no differences in sex, BSA, conditioning regimen intent (ie myeloablative vs reduced intensity), dose of MTX, degree of match, or stem cell source. Elevation in serum creatinine and liver function tests were similar in both cohorts prior to and during MTX administration. Patients on PPI had a higher incidence of grade 1-4 mucositis compared to no-PPI (Table 1) and a higher percentage of grade 3-4 mucositis (Figure 1). Patients on PPIs had a higher incidence of TPN use, need for PCA, but no increase in hospital LOS. Patients on PPI had higher use of leucovorin than those not on PPI (81.2% vs 58.2% p <0.0001). Use of PPI did not increase the time of ANC engraftment. Conclusions- The concurrent use of PPIs and MTX was associated with a higher incidence and severity of mucositis. PPIs were also shown to increase the need for PCA, and TPN. PPI use did not increase the average length of hospitalization. This study was limited by retrospective review. Grading of mucositis was based on clinician assessment and documentation. While the indications for PPI were not readily known, this study raises the question if PPIs should be discontinued or patients transitioned to a histamine blocker prior to MTX administration to improve severity of mucositis and reduce costs associated with TPN/PCA use. Additional studies are needed in order to further characterize the association of PPI with MTX and its impact on clinical outcomes. Disclosures No relevant conflicts of interest to declare.

Abstract Background Making the decision to stop antifungal therapy in patients with coccidioidomycosis can be challenging in patients with risk factors for relapsed infection. Spherulin-based coccidioidal skin testing was re-introduced to the market in 2014 and approved for the detection of delayed-type hypersensitivity in patients with a history of pulmonary coccidioidomycosis Methods We searched electronically for patients who had a spherulin skin test placed in our institution from January 1, 2015 through March 1, 2017, and then included patients age 18 years and older who met the definition for confirmed or probable pulmonary coccidioidomycosis. A retrospective chart review was conducted, and included details of clinical illness, antifungal treatment, serology, and chest imaging Results From January 1, 2015 to August 31, 2017, 172 patients with coccidioidomycosis had a spherulin skin test placed. We included for further study the 129 patients who had primary pulmonary coccidioidomycosis, followed for a median of 18 months (range 0–50 months); 56 (43.4/%) were male, 108 (85.7/%) Caucasian, median age was 55 years (range18–89).19/12914.7%)) were smokers, 14/129 (10.9%) were diabetic, 2 patients had HIV (1.6%) and 15/129 (11.6) we immunocompromised without HIV. 116/129(89.9%) % received antifungal treatment. Median time from illness to skin test was 13.5 months (range 0–78). Eighty-nine of 129 patients (69%) had a positive skin test, 40 (31%) had a negative test. Antifungal treatment was subsequently discontinued in 75/89 (84%), and one patient (1.2%) with a positive test, experienced relapsed infection. Among 30/40 with negative CST, antifungals were discontinued and none relapsed. Conclusion The presence of delayed-type hypersensitivity to coccidioidomycosis, manifested by a positive spherulin skin test, was associated with discontinuation of antifungal therapy, and a low percentage of relapsed infection. Disclosures All authors: No reported disclosures.