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Abstract

Coagulopathy is one of the complications of COVID-19 and is associated with a higher risk of mortality. However, evidence regarding the effectiveness and safety of anticoagulant therapy in various doses among COVID-19 patients is limited. This systematic review and meta-analysis aims to review and explore the effect of using heparinoids as a systemic anticoagulant at prophylactic doses on mortality in COVID-19 patients. Systematic searches were conducted of various databases (Pubmed, ScienceDirect, SpringerLink, Scopus, and ProQuest) covering the period 2019-2021. We assessed the quality of the articles using the STROBE checklist. Studies with a high risk of bias were excluded before pooled effect size was synthesized with 95% confidence intervals (CI) using random-effects models. From the 12 identified studies (N=8,968), six observational studies (N=7,176) were involved in the meta-analysis. The studies reviewed in the paper used a retrospective cohort design in various settings. The pooled effect size of mortality comparing prophylactic anticoagulant and no anticoagulant in three studies showed that there was an association between using prophylactic anticoagulant and a lower risk of in-hospital mortality (pooled OR= 0.47; 95% CI 0.19-0.76). A prophylactic dose of heparinoid anticoagulant was also associated with lower mortality (pooled OR= 0.51; 95% CI 0.21-0.82) and with lower bleeding events compared to intermediate-to-therapeutic dose anticoagulants. Administration of heparinoid anticoagulants at prophylactic doses was associated with reduced mortality risk in hospitalized COVID-19 patients. Due to the increased risk of bleeding with therapeutic doses, the use of prophylaxis anticoagulant is suggested in COVID-19 patients who are not critically ill.

References

Abou-Ismail, M. Y., Diamond, A., Kapoor, S., Arafah, Y., & Nayak, L. (2020). The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management. Thrombosis Research, 194(May), 101–115. https://doi.org/10.1016/j.thromres.2020.06.029

Albani, F., Sepe, L., Fusina, F., Prezioso, C., Baronio, M., Caminiti, F., … Natalini, G. (2020). Thromboprophylaxis with enoxaparin is associated with a lower death rate in patients hospitalized with SARS-CoV-2 infection. A cohort study. EClinicalMedicine, 27(April), 0–5. https://doi.org/10.1016/j.eclinm.2020.100562

Bikdeli, B., Madhavan, M. V., Jimenez, D., Chuich, T., Dreyfus, I., Driggin, E., … Lip, G. Y. H. (2020). COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. Journal of the American College of Cardiology, 75(23), 2950–2973. https://doi.org/10.1016/j.jacc.2020.04.031

Billett, H., Reyes Gil, M., Szymanski, J., Ikemura, K., Stahl, L., Lo, Y., … Bellin, E. (2020). Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin and Apixaban on Mortality. SSRN Electronic Journal. https://doi.org/10.2139/ssrn.3679919

Buijsers, B., Yanginlar, C., Maciej-Hulme, M. L., de Mast, Q., & van der Vlag, J. (2020). Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients. EBioMedicine, 59. https://doi.org/10.1016/j.ebiom.2020.102969

Canoglu, K., & Saylan, B. (2020). Therapeutic dosing of low-molecular-weight heparin may decrease mortality in patients with severe COVID-19 infection. Annals of Saudi Medicine, 40(6), 462–468. https://doi.org/10.5144/0256-4947.2020.462

Cuker, A., Tseng, E. K., Nieuwlaat, R., Angchaisuksiri, P., Blair, C., Dane, K., … Schünemann, H. J. (2021). American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Advances, 5(3), 872–888. https://doi.org/10.1182/bloodadvances.2020003763

Farrar, J. E., Trujillo, T. C., Mueller, S. W., Beltran, L., Nguyen, C., Hassell, K., & Kiser, T. H. (2021). Evaluation of a patient-specific, targeted-intensity pharmacologic thromboprophylaxis protocol in hospitalized patients with COVID-19. Journal of Thrombosis and Thrombolysis, (0123456789). https://doi.org/10.1007/s11239-021-02552-x

Flumingnan, R., Tinoco, J., Pascoal, P., Areias, L., Cossi, M., Fernandes, M., … Matar, C. (2020). Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database of Systematic Reviews, (10). https://doi.org/10.1002/14651858.CD013739.www.cochranelibrary.com

Gómez-Mesa, J. E., Galindo-Coral, S., Montes, M. C., & Muñoz Martin, A. J. (2021). Thrombosis and Coagulopathy in COVID-19. Current Problems in Cardiology, 46(3). https://doi.org/10.1016/j.cpcardiol.2020.100742

Grandone, E., Tiscia, G., Pesavento, R., De Laurenzo, A., Ceccato, D., Sartori, M. T., … Vescovi, A. (2021). Use of low-molecular-weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation. Journal of Thrombosis and Thrombolysis, (0123456789). https://doi.org/10.1007/s11239-021-02429-z

Helms, J., Severac, F., Merdji, H., Schenck, M., Clere-Jehl, R., Baldacini, M., … Meziani, F. (2021). Higher anticoagulation targets and risk of thrombotic events in severe COVID-19 patients: bi-center cohort study. Annals of Intensive Care, 11(1). https://doi.org/10.1186/s13613-021-00809-5

Hippensteel, J. A., LaRiviere, W. B., Colbert, J. F., Langou t-Astri, C. J., & Schmidt, E. P. (2020). Heparin as a therapy for COVID-19: Current evidence and future possibilities. American Journal of Physiology - Lung Cellular and Molecular Physiology, 319(2), L211–L217. https://doi.org/10.1152/AJPLUNG.00199.2020

Jenner, W. J., Kanji, R., Mirsadraee, S., Gue, Y. X., Price, S., Prasad, S., & Gorog, D. A. (2021). Thrombotic complications in 2928 patients with COVID-19 treated in intensive care: a systematic review. Journal of Thrombosis and Thrombolysis, 51(3), 595–607. https://doi.org/10.1007/s11239-021-02394-7

Jonmarker, S., Hollenberg, J., Dahlberg, M., Stackelberg, O., Litorell, J., Everhov, Å. H., … Cronhjort, M. (2020). Dosing of thromboprophylaxis and mortality in critically ill COVID-19 patients. Critical Care, 24(1), 1–10. https://doi.org/10.1186/s13054-020-03375-7

Kamel, A. M., Sobhy, M., Magdy, N., Sabry, N., & Farid, S. (2021). Anticoagulation outcomes in hospitalized Covid-19 patients: A systematic review and meta-analysis of case-control and cohort studies. Reviews in Medical Virology, 31(3). https://doi.org/10.1002/rmv.2180

Khan, A., Althunayyan, S., Alsofayan, Y., Alotaibi, R., Mubarak, A., Arafat, M., … Jokhdar, H. (2020). Risk factors associated with worse outcomes in COVID-19: A retrospective study in Saudi Arabia. Eastern Mediterranean Health Journal, 26(11), 1371–1380.https://doi.org/10.26719/emhj.20.130

Kim, S. Y., Jin, W., Sood, A., Montgomery, D. W., Grant, O. C., Fuster, M. M., … Linhardt, R. J. (2020). Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions. Antiviral Research, 181(May). https://doi.org/10.1016/j.antiviral.2020.104873

Klok, F. A., Kruip, M. J. H. A., Meer, N. J. M. van der, Arbous, M. S., Gommers, D. A. M. P. J., Kant, K. M., … Endeman, H. (2020). Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res, (January). https://doi.org/https://doi.org/10.1016/j.thromres.2020.04.013

Langer, F., Kluge, S., Klamroth, R., & Oldenburg, J. (2020). Coagulopathy in COVID-19 and Its Implication for Safe and Efficacious Thromboprophylaxis. Hamostaseologie, 40(3), 264–269. https://doi.org/10.1055/a-1178-3551

Martinelli, I., Ciavarella, A., Abbattista, M., Aliberti, S., De Zan, V., Folli, C., … Peyvandi, F. (2021). Increasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19. Internal and Emergency Medicine, 16(5), 1223–1229. https://doi.org/10.1007/s11739-020-02585-9

Mennuni, M. G., Renda, G., Grisafi, L., Rognoni, A., Colombo, C., Lio, V., … Patti, G. (2021). Clinical outcome with different doses of low-molecular-weight heparin in patients hospitalized for COVID-19. Journal of Thrombosis and Thrombolysis, (0123456789). https://doi.org/10.1007/s11239-021-02401-x

Mycroft-West, C. J., Su, D., Pagani, I., Rudd, T. R., Elli, S., Gandhi, N. S., … Skidmore, M. A. (2020). Heparin Inhibits Cellular Invasion by SARS-CoV-2: Structural Dependence of the Interaction of the Spike S1 Receptor-Binding Domain with Heparin. Thrombosis and Haemostasis, 120(12), 1700–1715. https://doi.org/10.1055/s-0040-1721319

Nadkarni, G. N., Lala, A., Bagiella, E., Chang, H. L., Moreno, P., Pujadas, E., … Fuster, V. (2020). Anticoagulation, Mortality, Bleeding and Pathology Among Patients Hospitalized with COVID-19: A Single Health System Study. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2020.08.041

Neyeloff, J. L., Fuchs, S. C., & Moreira, L. B. (2012). Meta-analyses and Forest plots using a Microsoft Excel spreadsheet: Step-by-step guide focusing on descriptive data analysis. BMC Research Notes, 5(Mix). https://doi.org/10.1186/1756-0500-5-52

Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., … Moher, D. (2021). The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. The BMJ, 372. https://doi.org/10.1136/bmj.n71

Patel, N. G., Bhasin, A., Feinglass, J. M., Belknap, S. M., Angarone, M. P., Cohen, E. R., … Bashyam, M. D. (2020). Clinical Outcomes of Hospitalized Patients with COVID-19 on Therapeutic Anticoagulants. medRxiv, 1–30. https://doi.org/10.1101/2020.08.22.20179911

Pesavento, R., Ceccato, D., Pasquetto, G., Monticelli, J., Leone, L., Frigo, A., … Vettor, R. (2020). The hazard of (sub)therapeutic doses of anticoagulants in noncritically ill patients with Covid-19: The Padua province experience. Journal of Thrombosis and Haemostasis, 18(10), 2629–2635. https://doi.org/10.1111/jth.15022

Pluta, J., Cieniewicz, A., & Trzebicki, J. (2021). COVID-19: Coagulation disorders and anticoagulant treatment in patients hospitalised in ICU. Anaesthesiology Intensive Therapy, 53(2), 153–161. https://doi.org/10.5114/ait.2021.105783

Rentsch, C. T., Beckman, J. A., Tomlinson, L., Gellad, W. F., Alcorn, C., Kidwai-Khan, F., … Freiberg, M. S. (2021). Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: Cohort study. The BMJ, 372. https://doi.org/10.1136/bmj.n311

Shen, L., Qiu, L., Liu, D., Wang, L., Huang, H., Ge, H., … Zhou, N. (2021). The Association of Low Molecular Weight Heparin Use and In-hospital Mortality Among Patients Hospitalized with COVID-19. Cardiovascular Drugs and Therapy. https://doi.org/10.1007/s10557-020-07133-3

Tang, N., Bai, H., Chen, X., Gong, J., Li, D., & Sun, Z. (2020). Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. Journal of Thrombosis and Haemostasis, 18(5), 1094–1099. https://doi.org/10.1111/jth.14817

Thachil, J., Tang, N., Gando, S., Falanga, A., Cattaneo, M., Levi, M., … Iba, T. (2020). ISTH interim guidance on recognition and management of coagulopathy in COVID-19. Journal of Thrombosis and Haemostasis, 18(5), 1023–1026. https://doi.org/10.1111/jth.14810

Tree, J. A., Turnbull, J. E., Buttigieg, K. R., Elmore, M. J., Coombes, N., Hogwood, J., … Carroll, M. W. (2021). Unfractionated heparin inhibits live wild type SARS-CoV-2 cell infectivity at therapeutically relevant concentrations. British Journal of Pharmacology, 178(3), 626–635. https://doi.org/10.1111/bph.15304

von Elm, E., Altman, D. G., Egger, M., Pocock, S. J., Gøtzsche, P. C., & Vandenbroucke, J. P. (2014). The strengthening the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting observational studies. International Journal of Surgery, 12(12), 1495–1499. https://doi.org/10.1016/j.ijsu.2014.07.013

Weeks, L. D., Pharmd, K. W. S., Connors, J. M., & Connell, N. T. (2021). Management of therapeutic unfractionated heparin in 19 patients : A retrospective cohort study. (March), 1–11. https://doi.org/10.1002/rth2.12521

Zheng, R., Zhou, J., Song, B., Zheng, X., Zhong, M., Jiang, L., … Sang, L. (2021). COVID-19-associated coagulopathy: thromboembolism prophylaxis and poor prognosis in ICU. Experimental Hematology and Oncology, 10(1), 1–11. https://doi.org/10.1186/s40164-021-00202-9

Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., … Cao, B. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet, 395(10229), 1054–1062. https://doi.org/10.1016/S0140-6736(20)30566-3

Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., … Tan, W. (2020). A Novel Coronavirus from Patients with Pneumonia in China, 2019. New England Journal of Medicine, 382(8), 727–733. https://doi.org/10.1056/nejmoa2001017

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