Research Spotlight

Carey, S.A., Afzal, A., Jamil, A., Williams, S. and Gottlieb, R.L. (2020). “Outpatient COVID-19 surveillance testing in orthotopic heart transplant recipients.” Clin Transplant Sep 25;e14105. [Epub ahead of print.]. e14105.

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COVID-19 case fatality rate in the United States is currently reported at 4.8% based on the confirmed cases of COVID-19. However, there are conflicting reports of estimated deaths in the post-cardiac transplantation patient population associated with COVID-19. METHODS: Observational, retrospective analysis of a large cohort of post Orthotopic Heart Transplantation (OHT) patients in a high volume heart transplantation program in Dallas, Texas underwent outpatient COVID-19 screening and testing for both SARS-CoV-2 nasopharyngeal RT-PCR and anti-SARS-CoV2 IgG serology as a result of a clinic protocol to facilitate re-opening of face-to-face outpatient clinical visits. RESULTS: The full outpatient cohort tested at time of their clinic visit tested negative for COVID-19 by nasopharyngeal RT-PCR. Only 2 patients tested seropositive for anti-SARS-COV2 IgG. Five positive inpatient cases were also identified and all, but one recovered. CONCLUSION: A COVID-19 surveillance protocol can be easily instituted in this high-risk population and facilitate safe transplant clinic operation. As the cases and prevalence increase across the United States, further strategies will need to be developed to determine the best course of action to help manage this select population while minimizing their exposure to the ongoing pandemic.

Spinner, C.D., Gottlieb, R.L., Criner, G.J., Arribas López, J.R., Cattelan, A.M., Soriano Viladomiu, A., Ogbuagu, O., Malhotra, P., Mullane, K.M., Castagna, A., Chai, L.Y.A., Roestenberg, M., Tsang, O.T.Y., Bernasconi, E., Le Turnier, P., Chang, S.C., SenGupta, D., Hyland, R.H., Osinusi, A.O., Cao, H., Blair, C., Wang, H., Gaggar, A., Brainard, D.M., McPhail, M.J., Bhagani, S., Ahn, M.Y., Sanyal, A.J., Huhn, G. and Marty, F.M. (2020). “Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial.” Jama 324(11): 1048-1057.

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IMPORTANCE: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown. OBJECTIVE: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020. INTERVENTIONS: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d. MAIN OUTCOMES AND MEASURES: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group. RESULTS: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care. CONCLUSIONS AND RELEVANCE: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04292730.

Gong, T. and Hall, S. (2020). “Considerations and experience driving expansion of combined heart-liver transplantation.” Curr Opin Organ Transplant 25(5): 496-500

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PURPOSE OF REVIEW: Heart transplantation concomitant with a liver transplant may be warranted when end-stage heart failure results in irreversible liver failure. Previously reported outcomes have been excellent yet the specific immunoprotective role of the liver allograft is not known. We review the current literature about the immunologic benefit for combined heart and liver transplantation (CHLT). RECENT FINDINGS: The total number of combined heart and liver transplants continues to increase and accounts for approximately 25 cases per year. Familial amyloid polyneuropathy with cardiac cirrhosis is the most common indication for CHLT while adult congenital heart disease (CHD) with associated cirrhosis is increasing in frequency. The majority of recent registry data suggest a statistically equivalent to modestly improved survival advantage for CHLT compared with isolated heart transplantation. Direct mechanisms accounting for this survival advantage are not proven, but combined heart and liver transplants experience lower rates of acute cardiac rejection and cardiac allograft vasculopathy (CAV). SUMMARY: Combined heart and liver transplants remain a small percentage of the total heart transplants worldwide, but the majority of recent literature confirms the safety and viability of this option for patients with end-stage heart and liver disease. Equivalent to modestly improved survival outcomes, lower rates of acute cardiac rejection and CAV warrant further investigation into the liver allograft’s immunoprotective effect on the transplanted heart. The key mechanisms of tolerogenicity have important implications for surgical technique and immunosuppression requirements. Future directions include development of criteria for heart-liver transplant candidacy and identification of equitable allocation protocols.

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.