John S. Garrett M.D.

Garrett, J., Vanston, A., Ogola, G., da Graca, B., Cassity, C., Kouznetsova, M.A., Hall, L.R. and Qiu, T. (2021). “Predicting opioid-induced oversedation in hospitalised patients: a multicentre observational study.” BMJ Open 11(11): e051663.

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OBJECTIVES: Opioid-induced respiratory depression (OIRD) and oversedation are rare but potentially devastating adverse events in hospitalised patients. We investigated which features predict an individual patient’s risk of OIRD or oversedation; and developed a risk stratification tool that can be used to aid point-of-care clinical decision-making. DESIGN: Retrospective observational study. SETTING: Twelve acute care hospitals in a large not-for-profit integrated delivery system. PARTICIPANTS: All inpatients ≥18 years admitted between 1 July 2016 and 30 June 2018 who received an opioid during their stay (163 190 unique hospitalisations). MAIN OUTCOME MEASURES: The primary outcome was occurrence of sedation or respiratory depression severe enough that emergent reversal with naloxone was required, as determined from medical record review; if naloxone reversal was unsuccessful or if there was no evidence of hypoxic encephalopathy or death due to oversedation, it was not considered an oversedation event. RESULTS: Age, sex, body mass index, chronic obstructive pulmonary disease, concurrent sedating medication, renal insufficiency, liver insufficiency, opioid naïvety, sleep apnoea and surgery were significantly associated with risk of oversedation. The strongest predictor was concurrent administration of another sedating medication (adjusted HR, 95% CI=3.88, 2.48 to 6.06); the most common such medications were benzodiazepines (29%), antidepressants (22%) and gamma-aminobutyric acid analogue (14.7%). The c-statistic for the final model was 0.755. The 24-point Oversedation Risk Criteria (ORC) score developed from the model stratifies patients as high (>20%, ≥21 points), moderate (11%-20%, 10-20 points) and low risk (≤10%, <10 points). CONCLUSIONS: The ORC risk score identifies patients at high risk for OIRD or oversedation from routinely collected data, enabling targeted monitoring for early detection and intervention. It can also be applied to preventive strategies-for example, clinical decision support offered when concurrent prescriptions for opioids and other sedating medications are entered that shows how the chosen combination impacts the patient's risk.

Kline, J.A., Adler, D.H., Alanis, N., Bledsoe, J.R., Courtney, D.M., d’Etienne, J.P., Diercks, D.B., Garrett, J.S., Jones, A.E., Mackenzie, D.C., Madsen, T., Matuskowitz, A.J., Mumma, B.E., Nordenholz, K.E., Pagenhardt, J., Runyon, M.S., Stubblefield, W.B. and Willoughby, C.B. (2021). “Monotherapy Anticoagulation to Expedite Home Treatment of Patients Diagnosed With Venous Thromboembolism in the Emergency Department: A Pragmatic Effectiveness Trial.” Circ Cardiovasc Qual Outcomes Jun 21;CIRCOUTCOMES120007600. [Epub ahead of print]. Circoutcomes120007600.

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BACKGROUND: The objective was to test if low-risk emergency department patients with vitamin K antagonist (venous thromboembolism [VTE]; including venous thrombosis and pulmonary embolism [PE]) can be safely and effectively treated at home with direct acting oral (monotherapy) anticoagulation in a large-scale, real-world pragmatic effectiveness trial. METHODS: This was a single-arm trial, conducted from 2016 to 2019 in accordance with the Standards for Reporting Implementation Studies guideline in 33 emergency departments in the United States. Participants had newly diagnosed VTE with low risk of death based upon either the modified Hestia criteria, or physician judgment plus the simplified PE severity index score of zero, together with nonhigh bleeding risk were eligible. Patients had to be discharged within 24 hours of triage and treated with either apixaban or rivaroxaban. Effectiveness was defined by the primary efficacy and safety outcomes, image-proven recurrent VTE and bleeding requiring hospitalization >24 hours, respectively, with an upper limit of the 95% CI for the 30-day frequency of VTE recurrence below 2.0% for both outcomes. RESULTS: We enrolled 1421 patients with complete outcomes data, including 903 with venous thrombosis and 518 with PE. The recurrent VTE requiring hospitalization occurred in 14/1421 (1.0% [95% CI, 0.5%-1.7%]), and bleeding requiring hospitalization occurred in 12/1421 (0.8% [0.4%-1.5%). The rate of severe bleeding using International Society for Thrombosis and Haemostasis criteria was 2/1421 (0.1% [0%-0.5%]). No patient died, and serious adverse events occurred in 2.5% of venous thrombosis patients and 2.3% of patients with PE. Medication nonadherence was reported by patients in 8.0% (6.6%-9.5%) and was associated with a risk ratio of 6.0 (2.3-15.2) for VTE recurrence. Among all patients diagnosed with VTE in the emergency department during the period of study, 18% of venous thrombosis patients and 10% of patients with PE were enrolled. CONCLUSIONS: Monotherapy treatment of low-risk patients with venous thrombosis or PE in the emergency department setting produced a low rate of bleeding and VTE recurrence, but may be underused. Patients with venous thrombosis and PE should undergo risk-stratification before home treatment. Improved patient adherence may reduce rate of recurrent VTE. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03404635.

Shao, Q., Rascati, K.L., Lawson, K.A., Wilson, J.P., Shah, S. and Garrett, J.S. (2021). “Impact of emergency department opioid use on future health resource utilization among patients with migraine.” Headache 61(2): 287-299.

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OBJECTIVE: The purpose of this study was to evaluate the subsequent health resource utilization (HRU) between patients with migraine who received opioid medications at their emergency department (ED) visits (“opioid recipients”) versus patients with migraine who did not receive opioid medications at their ED visits (“non-recipients”). BACKGROUND: Previous studies have found that opioid use is common among patients with migraine at emergency settings. Medication overuse, especially the use of opioids, is associated with migraine progression, which can ultimately lead to substantial health resource use and costs. There is limited evidence on opioid use specifically in emergency settings and its impact on future HRU among people with migraine. METHOD: This retrospective cohort study used electronic health record data from the Baylor Scott & White Health between December 2013 and April 2017. Adult patients who had at least 6 months of continuous enrollment before (baseline or pre-index) and after (follow-up) the first date they had an ED visit with a diagnosis of migraine (defined as index date) were enrolled in the study. Opioid use and HRU during follow-up period between opioid recipients and non-recipients were summarized and compared. RESULTS: A total of 788 patients met the eligibility criteria and were included in this study. During the 6-month follow-up period, compared to patients with migraine who were non-recipients at their index ED visits, opioid recipients had significantly more all-cause (3.6 [SD = 6.3] vs. 1.9 [SD = 4.8], p < 0.0001) and migraine-related (1.6 [SD = 4.2] vs. 0.6 [SD = 2.1], p < 0.0001) opioid prescriptions (RXs), and more all-cause (2.6 [SD = 4.3] vs. 1.6 [SD = 2.6], p = 0.002) and migraine-related (0.6 [SD = 1.4] vs. 0.3 [SD = 0.8], p = 0.001) ED visits. In addition, opioid recipients had higher risk of future migraine-related ED visits controlling for covariates (HR = 1.49, 95% CI = 1.09-2.03, p = 0.013). Factors that were significantly (p < 0.05) related to future migraine-related ED visits include previous opioid use (HR = 2.12, 95% CI = 1.24-3.65, p = 0.007), previous ED visits (HR = 2.38, 95% CI = 1.23-4.58, p = 0.010), hypertension (HR = 1.46, 95% CI = 1.07-2.00, p = 0.017), age between 45 and 64 years (HR = 0.68, 95% CI = 0.48-0.97, p = 0.033), female sex (HR = 1.82, 95% CI = 1.12-2.86, p = 0.015), and tobacco use disorder (HR = 1.45, 95% CI = 1.07-1.97, p = 0.017). Sub-analyses were restricted to the group of patients who were opioid naïve at baseline (n = 274, defined as having ≤1 opioid RXs during the 6-month pre-index period). Patients who were baseline opioid naïve but received opioids during their index ED visits were more likely to have future migraine-related ED visits compared to patients who were baseline opioid naïve and did not receive any opioids during their index ED visits, controlling for covariates (HR = 2.90, 95% CI = 1.54-5.46, p = 0.001). CONCLUSION: Opioid use among patients with migraine presenting to the ED is associated with increased future HRU, which highlights the need for optimizing migraine management in emergency settings.

Rowell, S.E., Meier, E.N., McKnight, B., Kannas, D., May, S., Sheehan, K., Bulger, E.M., Idris, A.H., Christenson, J., Morrison, L.J., Frascone, R.J., Bosarge, P.L., Colella, M.R., Johannigman, J., Cotton, B.A., Callum, J., McMullan, J., Dries, D.J., Tibbs, B., Richmond, N.J., Weisfeldt, M.L., Tallon, J.M., Garrett, J.S., Zielinski, M.D., Aufderheide, T.P., Gandhi, R.R., Schlamp, R., Robinson, B.R.H., Jui, J., Klein, L., Rizoli, S., Gamber, M., Fleming, M., Hwang, J., Vincent, L.E., Williams, C., Hendrickson, A., Simonson, R., Klotz, P., Sopko, G., Witham, W., Ferrara, M. and Schreiber, M.A. (2020). “Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury.” Jama 324(10): 961-974.

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IMPORTANCE: Traumatic brain injury (TBI) is the leading cause of death and disability due to trauma. Early administration of tranexamic acid may benefit patients with TBI. OBJECTIVE: To determine whether tranexamic acid treatment initiated in the out-of-hospital setting within 2 hours of injury improves neurologic outcome in patients with moderate or severe TBI. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, double-blinded, randomized clinical trial at 20 trauma centers and 39 emergency medical services agencies in the US and Canada from May 2015 to November 2017. Eligible participants (N = 1280) included out-of-hospital patients with TBI aged 15 years or older with Glasgow Coma Scale score of 12 or less and systolic blood pressure of 90 mm Hg or higher. INTERVENTIONS: Three interventions were evaluated, with treatment initiated within 2 hours of TBI: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (bolus maintenance group; n = 312), out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (bolus only group; n = 345), and out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion (placebo group; n = 309). MAIN OUTCOMES AND MEASURES: The primary outcome was favorable neurologic function at 6 months (Glasgow Outcome Scale-Extended score >4 [moderate disability or good recovery]) in the combined tranexamic acid group vs the placebo group. Asymmetric significance thresholds were set at 0.1 for benefit and 0.025 for harm. There were 18 secondary end points, of which 5 are reported in this article: 28-day mortality, 6-month Disability Rating Scale score (range, 0 [no disability] to 30 [death]), progression of intracranial hemorrhage, incidence of seizures, and incidence of thromboembolic events. RESULTS: Among 1063 participants, a study drug was not administered to 96 randomized participants and 1 participant was excluded, resulting in 966 participants in the analysis population (mean age, 42 years; 255 [74%] male participants; mean Glasgow Coma Scale score, 8). Of these participants, 819 (84.8%) were available for primary outcome analysis at 6-month follow-up. The primary outcome occurred in 65% of patients in the tranexamic acid groups vs 62% in the placebo group (difference, 3.5%; [90% 1-sided confidence limit for benefit, -0.9%]; P = .16; [97.5% 1-sided confidence limit for harm, 10.2%]; P = .84). There was no statistically significant difference in 28-day mortality between the tranexamic acid groups vs the placebo group (14% vs 17%; difference, -2.9% [95% CI, -7.9% to 2.1%]; P = .26), 6-month Disability Rating Scale score (6.8 vs 7.6; difference, -0.9 [95% CI, -2.5 to 0.7]; P = .29), or progression of intracranial hemorrhage (16% vs 20%; difference, -5.4% [95% CI, -12.8% to 2.1%]; P = .16). CONCLUSIONS AND RELEVANCE: Among patients with moderate to severe TBI, out-of-hospital tranexamic acid administration within 2 hours of injury compared with placebo did not significantly improve 6-month neurologic outcome as measured by the Glasgow Outcome Scale-Extended. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01990768.

Kline, J., Adler, D., Alanis, N., Bledsoe, J., Courtney, D., D’Etienne, J., D, B.D., Garrett, J., Jones, A.E., MacKenzie, D., Madsen, T., Matuskowitz, A., Mumma, B., Nordenholz, K., Pagenhardt, J., Runyon, M., Stubblefield, W. and Willoughby, C. (2020). “Study protocol for a multicentre implementation trial of monotherapy anticoagulation to expedite home treatment of patients diagnosed with venous thromboembolism in the emergency department.” BMJ Open 10(10): e038078.

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INTRODUCTION: In the USA, many emergency departments (EDs) have established protocols to treat patients with newly diagnosed deep vein thrombosis (DVT) as outpatients. Similar treatment of patients with pulmonary embolism (PE) has been proposed, but no large-scale study has been published to evaluate a comprehensive, integrated protocol that employs monotherapy anticoagulation to treat patients diagnosed with DVT and PE in the ED. METHODS AND ANALYSIS: This protocol describes the implementation of the Monotherapy Anticoagulation To expedite Home treatment of Venous ThromboEmbolism (MATH-VTE) study at 33 hospitals in the USA. The study was designed and executed to meet the requirements for the Standards for Reporting Implementation Studies guideline. The study was funded by investigator-initiated awards from industry, with Indiana University as the sponsor. The study principal investigator and study associates travelled to each site to provide on-site training. The protocol identically screens patients with both DVT or PE to determine low risk of death using either the modified Hestia criteria or physician judgement plus a negative result from the simplified PE severity index. Patients must be discharged from the ED within 24 hours of triage and treated with either apixaban or rivaroxaban. Overall effectiveness is based upon the primary efficacy and safety outcomes of recurrent VTE and bleeding requiring hospitalisation respectively. Target enrolment of 1300 patients was estimated with efficacy success defined as the upper limit of the 95% CI for the 30-day frequency of VTE recurrence below 2.0%. Thirty-three hospitals in 17 states were initiated in 2016-2017. ETHICS AND DISSEMINATION: All sites had Institutional Review Board approval. We anticipate completion of enrolment in June 2020; study data will be available after peer-reviewed publication. MATH-VTE will provide information from a large multicentre sample of US patients about the efficacy and safety of home treatment of VTE with monotherapy anticoagulation.