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Published in: Infection 6/2022

30-03-2022 | Anticoagulant | Original Paper

Efficacy of different anticoagulant doses for patients with COVID-19: a systematic review and network meta-analysis

Authors: Hideto Yasuda, Takuya Mayumi, Hiromu Okano

Published in: Infection | Issue 6/2022

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Abstract

Purpose

As no reported randomized control trials (RCTs) directly compare the three administration doses of anticoagulants (prophylactic dose, treatment dose, and no treatment), the most recommended dose to be administered to patients with coronavirus disease 2019 (COVID-19) remains unclear. The purpose of this study was to examine the effects of anticoagulant doses administered to patients with COVID-19, using a network meta-analysis (NMA) including high-quality studies.

Methods

All eligible trials from the Cochrane Central Register of Controlled Trials, MEDLINE, and Clinicaltrials.gov were included. We included RCTs and observational studies adjusted for covariates for patients aged ≥ 18 years and hospitalized due to objectively confirmed COVID-19. The main study outcome was mortality.

Results

In patients with moderate COVID-19, the prophylactic (relative risk (RR) 0.64 [95% confidence interval (CI) 0.52–0.80]) and treatment dose (RR 0.57 [95% CI 0.45–0.72] were associated with a lower risk of short-term mortality than that with no anticoagulant treatment. However, the prophylactic and treatment dose groups were not significantly different. The hierarchy for efficacy in reducing short-term mortality was treatment dose (P score 92.4) > prophylactic dose (57.6) > no treatment (0.0). In patients with severe COVID-19, due to the absence of trials with the no-treatment group, NMA could not be conducted. However, pairwise comparison did not show a significant difference between the prophylactic and treatment dose groups.

Conclusions

Treatment and prophylactic doses of anticoagulants showed similar effects on mortality; however, the treatment dose is preferred over the prophylactic dose for patients with both moderate and severe COVID-19.

Trial registration number and registration dates

PROSPERO (registration number: CRD42021245308, 05/21/2021).
Appendix
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Literature
1.
go back to reference Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2000;383:120–8.CrossRef Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2000;383:120–8.CrossRef
2.
go back to reference Martines RB, Ritter JM, Matkovic E, et al. Pathology and pathogenesis of SARS-CoV-2 associated with fatal coronavirus disease. United States Emerg Infect Dis. 2020;26:2005–15.CrossRefPubMed Martines RB, Ritter JM, Matkovic E, et al. Pathology and pathogenesis of SARS-CoV-2 associated with fatal coronavirus disease. United States Emerg Infect Dis. 2020;26:2005–15.CrossRefPubMed
4.
go back to reference Maccio A, Madeddu C. Potential role of macrophage activation in mediating thromboticcomplications associated with the different vaccines against COVID-19. Eur Rev Med Pharmacol Sc. 2021;25:6176–8. Maccio A, Madeddu C. Potential role of macrophage activation in mediating thromboticcomplications associated with the different vaccines against COVID-19. Eur Rev Med Pharmacol Sc. 2021;25:6176–8.
5.
go back to reference Godoy LC, Goligher EC, Lawler PR, et al. Anticipating and managing coagulopathy and thrombotic manifestations of severe COVID-19. CMAJ. 2020;192:E1156–61.CrossRefPubMedCentralPubMed Godoy LC, Goligher EC, Lawler PR, et al. Anticipating and managing coagulopathy and thrombotic manifestations of severe COVID-19. CMAJ. 2020;192:E1156–61.CrossRefPubMedCentralPubMed
7.
go back to reference Rentsch CT, Beckman JA, Tomlinson L, et al. Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study. BMJ. 2021;372:n311.CrossRefPubMed Rentsch CT, Beckman JA, Tomlinson L, et al. Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study. BMJ. 2021;372:n311.CrossRefPubMed
8.
go back to reference Ionescu F, Jaiyesimi I, Petrescu I, et al. Association of anticoagulation dose and survival in hospitalized COVID-19patients: a retrospective propensity score-weighted analysis. Eur J Haematol. 2021;106:165–74.CrossRefPubMed Ionescu F, Jaiyesimi I, Petrescu I, et al. Association of anticoagulation dose and survival in hospitalized COVID-19patients: a retrospective propensity score-weighted analysis. Eur J Haematol. 2021;106:165–74.CrossRefPubMed
9.
go back to reference Nadkarni GN, Lala A, Bagiella E, et al. Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19. J Am Coll Cardiol. 2020;76:1815–26.CrossRefPubMedCentralPubMed Nadkarni GN, Lala A, Bagiella E, et al. Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19. J Am Coll Cardiol. 2020;76:1815–26.CrossRefPubMedCentralPubMed
10.
go back to reference REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, et al. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021;385:777–89. REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, et al. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021;385:777–89.
11.
go back to reference REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, et al. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021;385:790–802. REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, et al. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021;385:790–802.
12.
go back to reference Lemos ACB, do EspíritoSanto DA, Salvetti MC, et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized phase II clinical trial (HESACOVID). Thromb Res. 2020;196:359–66.CrossRefPubMedCentralPubMed Lemos ACB, do EspíritoSanto DA, Salvetti MC, et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized phase II clinical trial (HESACOVID). Thromb Res. 2020;196:359–66.CrossRefPubMedCentralPubMed
13.
go back to reference Sholzberg M, Tang GH, Rahhal H, et al. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately illpatients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;375:n2400.CrossRefPubMed Sholzberg M, Tang GH, Rahhal H, et al. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately illpatients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;375:n2400.CrossRefPubMed
14.
go back to reference Lopes RD, de Barros E Silva PGM, Furtado RHM, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397:2253–63. Lopes RD, de Barros E Silva PGM, Furtado RHM, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397:2253–63.
16.
go back to reference Flumignan RL, Tinôco JDS, Pascoal PI, et al. Prophylactic anticoagulants for people hospitalized with COVID-19: systematic review. Cochrane Database Syst Rev. 2020;10:CD013739.PubMed Flumignan RL, Tinôco JDS, Pascoal PI, et al. Prophylactic anticoagulants for people hospitalized with COVID-19: systematic review. Cochrane Database Syst Rev. 2020;10:CD013739.PubMed
19.
20.
go back to reference VanderWeele TJ. Optimal approximate conversions of odds ratios and hazard ratios to risk ratios. Biometrics. 2020;76:746–52.CrossRefPubMed VanderWeele TJ. Optimal approximate conversions of odds ratios and hazard ratios to risk ratios. Biometrics. 2020;76:746–52.CrossRefPubMed
21.
go back to reference Brignardello-Petersen R, Bonner A, Alexander PE, et al. Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis. J Clin Epidemiol. 2018;93:36–44.CrossRefPubMed Brignardello-Petersen R, Bonner A, Alexander PE, et al. Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis. J Clin Epidemiol. 2018;93:36–44.CrossRefPubMed
22.
go back to reference Rhodes KM, Turner RM, Higgins JP. Predictive distributions were developed for the extent of heterogeneity in meta-analyses of continuous outcome data. J Clin Epidemiol. 2015;68:52–60.CrossRefPubMedCentralPubMed Rhodes KM, Turner RM, Higgins JP. Predictive distributions were developed for the extent of heterogeneity in meta-analyses of continuous outcome data. J Clin Epidemiol. 2015;68:52–60.CrossRefPubMedCentralPubMed
24.
go back to reference Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011;64:163–71.CrossRefPubMed Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011;64:163–71.CrossRefPubMed
26.
go back to reference Demelo-Rodriguez P, Farfán-Sedano AI, Pedrajas JM, et al. Bleeding risk in hospitalized patients with COVID-19 receivingintermediate- or therapeutic doses of thromboprophylaxis. J Thromb Haemost. 2021;19:1981–9.CrossRefPubMedCentralPubMed Demelo-Rodriguez P, Farfán-Sedano AI, Pedrajas JM, et al. Bleeding risk in hospitalized patients with COVID-19 receivingintermediate- or therapeutic doses of thromboprophylaxis. J Thromb Haemost. 2021;19:1981–9.CrossRefPubMedCentralPubMed
27.
go back to reference Águila-Gordo D, Martínez-Del Río J, Mazoteras-Muñoz V, Negreira-Caamaño M, Nieto-Sandoval Martín de la Sierra P, Piqueras-Flores J. Mortality and associated prognostic factors in elderly and very elderly hospitalized patients with respiratory disease COVID-19. Rev Esp Geriatr Gerontol. 2021;56:259–67.CrossRefPubMed Águila-Gordo D, Martínez-Del Río J, Mazoteras-Muñoz V, Negreira-Caamaño M, Nieto-Sandoval Martín de la Sierra P, Piqueras-Flores J. Mortality and associated prognostic factors in elderly and very elderly hospitalized patients with respiratory disease COVID-19. Rev Esp Geriatr Gerontol. 2021;56:259–67.CrossRefPubMed
28.
go back to reference Canoglu K, Saylan B. Therapeutic dosing of low-molecular-weight heparin may decrease mortality in patients with severe COVID-19 infection. Ann Saudi Med. 2020;40:462–8.CrossRefPubMedCentralPubMed Canoglu K, Saylan B. Therapeutic dosing of low-molecular-weight heparin may decrease mortality in patients with severe COVID-19 infection. Ann Saudi Med. 2020;40:462–8.CrossRefPubMedCentralPubMed
29.
go back to reference Di Castelnuovo A, Costanzo S, Antinori A, et al. Heparin in COVID-19 patients is associated with reduced in-hospital mortality: the multicenter Italian CORIST study. Thromb Haemost. 2021;121:1054–65.CrossRefPubMed Di Castelnuovo A, Costanzo S, Antinori A, et al. Heparin in COVID-19 patients is associated with reduced in-hospital mortality: the multicenter Italian CORIST study. Thromb Haemost. 2021;121:1054–65.CrossRefPubMed
30.
go back to reference Chocron R, Galand V, Cellier J, et al. Anticoagulation before hospitalization is a potential protective factor for COVID-19: insight from a French multicenter cohort study. J Am Heart Assoc. 2021;10:e018624.CrossRefPubMedCentralPubMed Chocron R, Galand V, Cellier J, et al. Anticoagulation before hospitalization is a potential protective factor for COVID-19: insight from a French multicenter cohort study. J Am Heart Assoc. 2021;10:e018624.CrossRefPubMedCentralPubMed
31.
go back to reference Fauvel C, Weizman O, Trimaille A, et al. Pulmonary embolism in COVID-19 patients: a French multicentre cohort study. Eur Heart J. 2020;41:3058–68.CrossRefPubMed Fauvel C, Weizman O, Trimaille A, et al. Pulmonary embolism in COVID-19 patients: a French multicentre cohort study. Eur Heart J. 2020;41:3058–68.CrossRefPubMed
32.
go back to reference Ferguson J, Volk S, Vondracek T, Flanigan J, Chernaik A. Empiric therapeutic anticoagulation and mortality in critically ill patients with respiratory failure from SARS-CoV-2: a retrospective cohort study. J Clin Pharmacol. 2020;60:1411–5.CrossRefPubMed Ferguson J, Volk S, Vondracek T, Flanigan J, Chernaik A. Empiric therapeutic anticoagulation and mortality in critically ill patients with respiratory failure from SARS-CoV-2: a retrospective cohort study. J Clin Pharmacol. 2020;60:1411–5.CrossRefPubMed
33.
go back to reference Gabara C, Solarat B, Castro P, et al. Anticoagulation strategies and risk of bleeding events in critically ill COVID-19 patients. Med Intensiva (Engl Ed). 2021;S0210–5691(21):00178–9. Gabara C, Solarat B, Castro P, et al. Anticoagulation strategies and risk of bleeding events in critically ill COVID-19 patients. Med Intensiva (Engl Ed). 2021;S0210–5691(21):00178–9.
34.
go back to reference Halaby R, Cuker A, Yui J, et al. Bleeding risk by intensity of anticoagulation in critically ill patients with COVID-19: a retrospective cohort study. J Thromb Haemost. 2021;19:1533–45.CrossRefPubMedCentralPubMed Halaby R, Cuker A, Yui J, et al. Bleeding risk by intensity of anticoagulation in critically ill patients with COVID-19: a retrospective cohort study. J Thromb Haemost. 2021;19:1533–45.CrossRefPubMedCentralPubMed
35.
go back to reference Helms J, Severac F, Merdji H, et al. Higher anticoagulation targets and risk of thrombotic events in severe COVID-19 patients: bi-center cohort study. Ann Intensive Care. 2021;11:14.CrossRefPubMedCentralPubMed Helms J, Severac F, Merdji H, et al. Higher anticoagulation targets and risk of thrombotic events in severe COVID-19 patients: bi-center cohort study. Ann Intensive Care. 2021;11:14.CrossRefPubMedCentralPubMed
36.
go back to reference Hsu A, Liu Y, Zayac AS, Olszewski AJ, Reagan JL. Intensity of anticoagulation and survival in patients hospitalized with COVID-19 pneumonia. Thromb Res. 2020;196:375–8.CrossRefPubMedCentralPubMed Hsu A, Liu Y, Zayac AS, Olszewski AJ, Reagan JL. Intensity of anticoagulation and survival in patients hospitalized with COVID-19 pneumonia. Thromb Res. 2020;196:375–8.CrossRefPubMedCentralPubMed
37.
38.
go back to reference Martinelli I, Ciavarella A, Abbattista M, et al. Increasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19. Intern Emerg Med. 2021;16:1223–9.CrossRefPubMedCentralPubMed Martinelli I, Ciavarella A, Abbattista M, et al. Increasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19. Intern Emerg Med. 2021;16:1223–9.CrossRefPubMedCentralPubMed
39.
go back to reference Melmed KR, Cao M, Dogra S, et al. Risk factors for intracerebral hemorrhage in patients with COVID-19. J Thromb Thrombolysis. 2021;51:953–60.CrossRefPubMed Melmed KR, Cao M, Dogra S, et al. Risk factors for intracerebral hemorrhage in patients with COVID-19. J Thromb Thrombolysis. 2021;51:953–60.CrossRefPubMed
40.
go back to reference Vaughn VM, Yost M, Abshire C, et al. Trends in venous thromboembolism anticoagulation in patients hospitalized with COVID-19. JAMA Netw Open. 2021;4:e2111788.CrossRefPubMedCentralPubMed Vaughn VM, Yost M, Abshire C, et al. Trends in venous thromboembolism anticoagulation in patients hospitalized with COVID-19. JAMA Netw Open. 2021;4:e2111788.CrossRefPubMedCentralPubMed
41.
go back to reference Yu B, Gutierrez VP, Carlos A, et al. Empiric use of anticoagulation in hospitalized patients with COVID-19: a propensity score-matched study of risks and benefits. Biomark Res. 2021;9:29.CrossRefPubMedCentralPubMed Yu B, Gutierrez VP, Carlos A, et al. Empiric use of anticoagulation in hospitalized patients with COVID-19: a propensity score-matched study of risks and benefits. Biomark Res. 2021;9:29.CrossRefPubMedCentralPubMed
43.
go back to reference Kamel AM, Sobhy M, Magdy N, Sabry N, Farid S, et al. Anticoagulation outcomes in hospitalized Covid-19 patients: a systematic review and meta-analysis of case-control and cohort studies. Rev Med Virol. 2021;31:e2180.CrossRefPubMed Kamel AM, Sobhy M, Magdy N, Sabry N, Farid S, et al. Anticoagulation outcomes in hospitalized Covid-19 patients: a systematic review and meta-analysis of case-control and cohort studies. Rev Med Virol. 2021;31:e2180.CrossRefPubMed
44.
go back to reference Egi M, Ogura H, Yatabe T, et al. The Japanese clinical practice guidelines for management of sepsis and septic shock 2020 (J-SSCG 2020). J Intensive Care. 2021;9:53.CrossRefPubMedCentralPubMed Egi M, Ogura H, Yatabe T, et al. The Japanese clinical practice guidelines for management of sepsis and septic shock 2020 (J-SSCG 2020). J Intensive Care. 2021;9:53.CrossRefPubMedCentralPubMed
45.
go back to reference INSPIRATION Investigators, Sadeghipour P, Talasaz AH, et al. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial. JAMA. 2021;325:1620–30.CrossRef INSPIRATION Investigators, Sadeghipour P, Talasaz AH, et al. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial. JAMA. 2021;325:1620–30.CrossRef
46.
go back to reference Uaprasert N, Panrong K, Rojnuckarin P, Chiasakul T. Thromboembolic and hemorrhagic risks after vaccination against SARS-CoV-2: a systematic review and meta-analysis of randomized controlled trials. Thromb J. 2021;19:86.CrossRefPubMedCentralPubMed Uaprasert N, Panrong K, Rojnuckarin P, Chiasakul T. Thromboembolic and hemorrhagic risks after vaccination against SARS-CoV-2: a systematic review and meta-analysis of randomized controlled trials. Thromb J. 2021;19:86.CrossRefPubMedCentralPubMed
47.
go back to reference Varikasuvu SR, Varshney S, Dutt N, et al. D-dimer, disease severity, and deaths (3D-study) in patients with COVID-19: a systematic review and meta-analysis of 100 studies. Sci Rep. 2021;11:21888.CrossRefPubMedCentralPubMed Varikasuvu SR, Varshney S, Dutt N, et al. D-dimer, disease severity, and deaths (3D-study) in patients with COVID-19: a systematic review and meta-analysis of 100 studies. Sci Rep. 2021;11:21888.CrossRefPubMedCentralPubMed
Metadata
Title
Efficacy of different anticoagulant doses for patients with COVID-19: a systematic review and network meta-analysis
Authors
Hideto Yasuda
Takuya Mayumi
Hiromu Okano
Publication date
30-03-2022
Publisher
Springer Berlin Heidelberg
Published in
Infection / Issue 6/2022
Print ISSN: 0300-8126
Electronic ISSN: 1439-0973
DOI
https://doi.org/10.1007/s15010-022-01809-8

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