Safety and Efficacy of Therapeutic Anticoagulation on Clinical Outcomes in Hospitalized Patients With COVID-19

Summary

The coronavirus disease 2019 (COVID-19) global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused considerable morbidity and mortality in over 170 countries. Increasing age and burden of cardiovascular comorbidities are associated with a worse prognosis among patients with COVID-19. In addition, serologic markers of more severe disease including coagulation abnormalities and thrombocytopenia, are not uncommon among patients hospitalized with severe COVID-19 infection and are more common in patients who died in-hospital. As the COVID-19 pandemic continues to grow, there is a pressing need to identify safe, effective, and widely available therapies that can be scaled and rapidly incorporated into clinical practice. Understanding the putative mechanism of increased mortality risk associated with abnormal coagulation function and cardiac injury is critical to guide studies of promising therapeutic interventions. Published and anecdotal reports indicate that endothelial dysfunction and thrombosis are common in critically ill patients with COVID-19, including reports of diffuse microvascular thrombosis in the lungs, heart, liver, and kidneys. Patients with cardiovascular disease (CVD) and CVD risk factors are known to have endothelial dysfunction and a heightened risk of thrombosis. A recent study of COVID-19 inpatients from Wuhan, China observed that an elevated D-dimer level greater than 1 ug/mL was associated with an 18 times higher risk of in-hospital death, underscoring the importance of increased coagulation activity as a potential modifiable risk marker that may drive end-organ injury. Given the established link between endothelial dysfunction and thrombosis in patients with cardiovascular disease, and the association between coagulopathy and adverse outcomes in patients with sepsis, the association between increased coagulation activity, end-organ injury, and mortality risk may represent a modifiable risk factor among COVID-19 patients with critical illness. Therefore, we propose to conduct a randomized, open-label trial of therapeutic anticoagulation in COVID-19 patients with an elevated D-dimer to evaluate the efficacy and safety.

Timeline

Start

2020-05-15

Primary completion

2022-06-01

Completion

2022-06-01

Publications

• Background Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020 May;20(5):533-534. doi: 10.1016/S1473-3099(20)30120-1. Epub 2020 Feb 19. No abstract available.
• Background The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19) - China, 2020. China CDC Wkly. 2020 Feb 21;2(8):113-122. No abstract available.
• Background Schindler TH, Dilsizian V. Coronary Microvascular Dysfunction: Clinical Considerations and Noninvasive Diagnosis. JACC Cardiovasc Imaging. 2020 Jan;13(1 Pt 1):140-155. doi: 10.1016/j.jcmg.2018.11.036. Epub 2019 Apr 12.
• Background Dellinger RP. Inflammation and coagulation: implications for the septic patient. Clin Infect Dis. 2003 May 15;36(10):1259-65. doi: 10.1086/374835. Epub 2003 May 8.
• Background Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res. 2008;122(6):743-52. doi: 10.1016/j.thromres.2006.10.026. Epub 2007 Aug 28.
• Results Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, Lee M. Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State. JAMA. 2020 Apr 28;323(16):1612-1614. doi: 10.1001/jama.2020.4326.
• Results Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24.
• Results Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585.
• Results Frencken JF, Donker DW, Spitoni C, Koster-Brouwer ME, Soliman IW, Ong DSY, Horn J, van der Poll T, van Klei WA, Bonten MJM, Cremer OL. Myocardial Injury in Patients With Sepsis and Its Association With Long-Term Outcome. Circ Cardiovasc Qual Outcomes. 2018 Feb;11(2):e004040. doi: 10.1161/CIRCOUTCOMES.117.004040.
• Results Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, Huang H, Yang B, Huang C. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol. 2020 Jul 1;5(7):802-810. doi: 10.1001/jamacardio.2020.0950.
• Results C. P. COVID-19: Abnormal Clotting Common in More Severe Disease. 2020.
• Results Chan MY, Andreotti F, Becker RC. Hypercoagulable states in cardiovascular disease. Circulation. 2008 Nov 25;118(22):2286-97. doi: 10.1161/CIRCULATIONAHA.108.778837. No abstract available.
• Results Zarychanski R, Doucette S, Fergusson D, Roberts D, Houston DS, Sharma S, Gulati H, Kumar A. Early intravenous unfractionated heparin and mortality in septic shock. Crit Care Med. 2008 Nov;36(11):2973-9. doi: 10.1097/CCM.0b013e31818b8c6b.
• Results Jaimes F, De La Rosa G, Morales C, Fortich F, Arango C, Aguirre D, Munoz A. Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study). Crit Care Med. 2009 Apr;37(4):1185-96. doi: 10.1097/CCM.0b013e31819c06bc.
• Results Safety of Heparin in Patients with Septic Shock.
• Results Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 May;18(5):1094-1099. doi: 10.1111/jth.14817. Epub 2020 Apr 27.
• Results Iba T, Levy JH, Warkentin TE, Thachil J, van der Poll T, Levi M; Scientific and Standardization Committee on DIC, and the Scientific and Standardization Committee on Perioperative and Critical Care of the International Society on Thrombosis and Haemostasis. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost. 2019 Nov;17(11):1989-1994. doi: 10.1111/jth.14578. Epub 2019 Aug 13. No abstract available.
• Results Zarychanski R, Abou-Setta AM, Kanji S, Turgeon AF, Kumar A, Houston DS, Rimmer E, Houston BL, McIntyre L, Fox-Robichaud AE, Hebert P, Cook DJ, Fergusson DA; Canadian Critical Care Trials Group. The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis. Crit Care Med. 2015 Mar;43(3):511-8. doi: 10.1097/CCM.0000000000000763.
• Results Zidane M, Schram MT, Planken EW, Molendijk WH, Rosendaal FR, van der Meer FJ, Huisman MV. Frequency of major hemorrhage in patients treated with unfractionated intravenous heparin for deep venous thrombosis or pulmonary embolism: a study in routine clinical practice. Arch Intern Med. 2000 Aug 14-28;160(15):2369-73. doi: 10.1001/archinte.160.15.2369.
• Results Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.
• Results Morris TA, Castrejon S, Devendra G, Gamst AC. No difference in risk for thrombocytopenia during treatment of pulmonary embolism and deep venous thrombosis with either low-molecular-weight heparin or unfractionated heparin: a metaanalysis. Chest. 2007 Oct;132(4):1131-9. doi: 10.1378/chest.06-2518. Epub 2007 Jul 23.
• Results Stein PD, Hull RD, Matta F, Yaekoub AY, Liang J. Incidence of thrombocytopenia in hospitalized patients with venous thromboembolism. Am J Med. 2009 Oct;122(10):919-30. doi: 10.1016/j.amjmed.2009.03.026. Epub 2009 Aug 13.

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Indications