Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin, and Apixaban on Mortality
Background Mortality in coronavirus disease of 2019 (COVID-19) is associated with increases in prothrombotic parameters, particularly D-dimer levels. Anticoagulation has been proposed as therapy to decrease mortality, often adjusted for illness severity.
Objective We wanted to investigate whether anticoagulation improves survival in COVID-19 and if this improvement in survival is associated with disease severity.
Methods This is a cohort study simulating an intention-to-treat clinical trial, by analyzing the effect on mortality of anticoagulation therapy chosen in the first 48 hours of hospitalization. We analyzed 3,625 COVID-19+ inpatients, controlling for age, gender, glomerular filtration rate, oxygen saturation, ventilation requirement, intensive care unit admission, and time period, all determined during the first 48 hours.
Results Adjusted logistic regression analyses demonstrated a significant decrease in mortality with prophylactic use of apixaban (odds ratio [OR] 0.46, p = 0.001) and enoxaparin (OR = 0.49, p = 0.001). Therapeutic apixaban was also associated with decreased mortality (OR 0.57, p = 0.006) but was not more beneficial than prophylactic use when analyzed over the entire cohort or within D-dimer stratified categories. Higher D-dimer levels were associated with increased mortality (p < 0.0001). When adjusted for these same comorbidities within D-dimer strata, patients with D-dimer levels < 1 µg/mL did not appear to benefit from anticoagulation while patients with D-dimer levels > 10 µg/mL derived the most benefit. There was no increase in transfusion requirement with any of the anticoagulants used.
Conclusion We conclude that COVID-19+ patients with moderate or severe illness benefit from anticoagulation and that apixaban has similar efficacy to enoxaparin in decreasing mortality in this disease.
For original data, please contact the corresponding author.
H.H.B. originated the concept, helped in the analysis, and wrote the manuscript. M.R.G. helped originate the concept, helped in the analysis, and reviewed and edited the manuscript. J.S. helped in the statistical analysis and reviewed and edited the manuscript. K.I. helped in the analysis and reviewed and edited the manuscript. L.S. developed the cohorts, helped in the statistical analysis, and reviewed and edited the manuscript. Y.L. helped in the statistical analysis and reviewed and edited the manuscript. S.R. reviewed patient data and reviewed and edited the manuscript. J.D.G.L. reviewed patient data and reviewed and edited the manuscript. M.K. reviewed the data and edited the manuscript. M.B. reviewed patient data and reviewed and edited the manuscript. L.G. reviewed the data and edited the manuscript. E.B. developed the CLG program, developed the cohorts, performed the statistical analyses, and reviewed and edited the manuscript.
* Equal authorship.
Received: 25 August 2020
Accepted: 24 September 2020
13 November 2020 (online)
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- 1 Chen N, Zhou M, Dong X. et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395 (10223): 507-513
- 2 Middeldorp S, Coppens M, van Haaps TF. et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1995-2002
- 3 Lodigiani C, Iapichino G, Carenzo L. et al. Humanitas COVID-19 Task Force. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res 2020; 191: 9-14
- 4 Helms J, Tacquard C, Severac F. et al. CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; 46 (06) 1089-1098
- 5 Liu XL, Wang XZ, Liu XX. et al. Low-dose heparin as treatment for early disseminated intravascular coagulation during sepsis: a prospective clinical study. Exp Ther Med 2014; 7 (03) 604-608
- 6 Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020; 135 (23) 2033-2040
- 7 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; 18 (05) 1094-1099
- 8 Hanif A, Khan S, Mantri N. et al. Thrombotic complications and anticoagulation in COVID-19 pneumonia: a New York City hospital experience. Ann Hematol 2020; 99 (10) 2323-2328
- 9 Paranjpe I, Fuster V, Lala A. et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol 2020; 76 (01) 122-124
- 10 Bellin E, Fletcher DD, Geberer N, Islam S, Srivastava N. Democratizing information creation from health care data for quality improvement, research, and education-the Montefiore Medical Center Experience. Acad Med 2010; 85 (08) 1362-1368
- 11 Bellin E. Missing Management: Health-Care Analytic Discovery in a Learning Health System. South Carolina: Kindle Direct Publishing; 2019
- 12 Llitjos JF, Leclerc M, Chochois C. et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost 2020; 18 (07) 1743-1746
- 13 Thachil J. The versatile heparin in COVID-19. J Thromb Haemost 2020; 18 (05) 1020-1022
- 14 Cohoon KP, De Sanctis Y, Haskell L, McBane RD, Spiro TE. Rivaroxaban for thromboprophylaxis among patients recently hospitalized for acute infectious diseases: a subgroup analysis of the MAGELLAN study. J Thromb Haemost 2018; 16 (07) 1278-1287
- 15 Khorana AA, Soff GA, Kakkar AK. et al. CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med 2019; 380 (08) 720-728
- 16 Yoshida RdeA, Yoshida WB, Maffei FH, El Dib R, Nunes R, Rollo HA. Systematic review of randomized controlled trials of new anticoagulants for venous thromboembolism prophylaxis in major orthopedic surgeries, compared with enoxaparin. Ann Vasc Surg 2013; 27 (03) 355-369
- 17 Carrier M, Abou-Nassar K, Mallick R. et al. AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med 2019; 380 (08) 711-719
- 18 NIH ACTIV initiative launches adaptive clinical trials of blood-clotting treatments for COVID-19. Accessed October 12, 2020 at: https://www.nih.gov/news-events/news-releases/nih-activ-initiative-launches-adaptive-clinical-trials-blood-clotting-treatments-covid-19
- 19 Papadaki S, Tselepis AD. Nonhemostatic activities of factor Xa: are there pleiotropic effects of anti-FXa direct oral anticoagulants?. Angiology 2019; 70 (10) 896-907
- 20 Al-Harbi NO, Imam F, Alharbi MM. et al. Role of rivaroxaban in sunitinib-induced renal injuries via inhibition of oxidative stress-induced apoptosis and inflammation through the tissue necrosis factor-α induced nuclear factor-κappa B signaling pathway in rats. J Thromb Thrombolysis 2020; 50 (02) 361-370
- 21 Petrilli CM, Jones SA, Yang J. et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ 2020; 369: m1966
- 22 Wang M, Zhang J, Ye D. et al. Time-dependent changes in the clinical characteristics and prognosis of hospitalized COVID-19 patients in Wuhan, China: a retrospective study. Clin Chim Acta 2020; 510: 220-227
- 23 COVID-19 and VTE/Anticoagulation: Frequently Asked Questions. Accessed October 12, 2020 at: https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation
- 24 Thachil J, Juffermans NP, Ranucci M. et al. ISTH DIC subcommittee communication on anticoagulation in COVID-19. J Thromb Haemost 2020; 18 (09) 2138-2144