Therapeutic-dose anticoagulation or thromboprophylaxis with low-molecular-weight heparin for moderate Covid-19: meta-analysis of randomized controlled trials
Tóm tắt
We carried out a meta-analysis since there is not enough evidence to recommend for or against therapeutic-dose anticoagulation compared with thromboprophylaxis in noncritically ill patients hospitalized with Covid-19.
We performed a systematic literature search using PubMed, Embase, Cochrane Library, and MedRxiv for randomized trials that included therapeutic-dose with low-molecular-weight heparin (LMW) or thromboprophylaxis with LMW heparin in noncritically ill patients admitted to the hospital with Covid-19. We identified five open-label studies for analysis with a total of 3220 patients. Two independent researchers selected, assessed, and extracted the data in duplicate. The outcomes evaluated were all-cause mortality, progression to invasive mechanical ventilation, incidence of venous thromboembolism, and major bleeding. The studies did not show risk for selection, detection, attrition, or reporting bias. Therapeutic-dose anticoagulation with LMW heparin compared with thromboprophylaxis with LMW heparin had no significant effect of all-cause death (risk ratio [RR] 0.85; 95% confidence interval [CI] 0.67–1.07; P = 0.16; I2 = 48%), or progression to invasive mechanical ventilation (RR 0.89; CI 0.73–1.08; P = 0.24; I2: 0%). Therapeutic-dose anticoagulation significantly reduced the risk of venous thromboembolic disease (RR 0.42; 95% CI 0.28–0.62; P = 0.0001; I2 = 0%) [Number needed to treat = 37]. Major bleeding occurred in 1.79% of the patients receiving therapeutic-dose anticoagulation and in 0.97% of those receiving thromboprophylaxis [Number needed to harm 125]. Therapeutic-dose anticoagulation in noncritically ill patients with Covid-19 could be indicated for patients at high risk of venous thromboembolic disease and low risk of bleeding.
Tài liệu tham khảo
Zhang L, Feng X, Zhang D, Jiang C, Mei H, Wang J, et al. Deep vein thrombosis in hospitalized patients with COVID-19 in Wuhan, China: prevalence, risk factors, and outcome. Circulation. 2020;142(2):114–28. https://doi.org/10.1161/CIRCULATIONAHA.120.046702.
Piazza G, Campia U, Hurwitz S, Snyder JE, Rizzo SM, Pfeferman MB, Morrison RB, Leiva O, Fanikos J, Nauffal V, Almarzooq Z, Goldhaber SZ. Registry of arterial and venous thromboembolic complications in patients with COVID-19. J Am Coll Cardiol. 2020;76(18):2060–72. https://doi.org/10.1016/j.jacc.2020.08.070.
Wichmann D, Sperhake JP, Lütgehetmann M, Steurer S, Edler C, Heinemann A, et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med. 2020;173(4):268–77. https://doi.org/10.7326/M20-2003.
Zhan H, Chen H, Liu C, Cheng L, Yan S, Li H, Li Y. Diagnostic value of D-dimer in COVID-19: a meta-analysis and meta-regression. Clin Appl Thromb Hemost. 2021;27:10760296211010976. https://doi.org/10.1177/10760296211010976.
Jirjees F, Saad AK, Al Hano Z, Hatahet T, Al Obaidi H, Dallal Bashi YH. COVID-19 treatment guidelines: do they really reflect best medical practices to manage the pandemic? Infect Dis Rep. 2021;13(2):259–84. https://doi.org/10.3390/idr13020029.
Santoliquido A, Porfidia A, Nesci A, De Matteis G, Marrone G, Porceddu E, et al. Incidence of deep vein thrombosis among non-ICU patients hospitalized for COVID-19 despite pharmacological thromboprophylaxis. J Thromb Haemost. 2020;18(9):2358–63. https://doi.org/10.1111/jth.14992.
Franco-Moreno A, Muñoz-Rivas N, Mestre-Gómez B, Torres-Macho J. Tromboembolismo pulmonar y COVID-19: un cambio de paradigma [Pulmonary embolism and COVID-19: a paradigm change]. Rev Clin Esp. 2020;220(7):459–61. https://doi.org/10.1016/j.rce.2020.05.006 (Spanish).
Ionescu F, Jaiyesimi I, Petrescu I, Lawler PR, Castillo E, Munoz-Maldonado Y, et al. Association of anticoagulation dose and survival in hospitalized COVID-19 patients: a retrospective propensity score-weighted analysis. Eur J Haematol. 2021;106(2):165–74. https://doi.org/10.1111/ejh.13533.
Hutton B, Salanti G, Caldwell DM, Chairman A, Schmid CH, Cameron C, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777–84. https://doi.org/10.7326/M14-2385.
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;18(343): d5928. https://doi.org/10.1136/BMJ.d5928.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719–48.
Sterne JA, Jüni P, Schulz KF, Altman DG, Bartlett C, Egger M. Statistical methods for assessing the influence of study characteristics on treatment effects in “meta-epidemiological” research. Stat Med. 2002;21(11):1513–24. https://doi.org/10.1002/sim.1184.
ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators, Lawler PR, Goligher EC, Berger JS, et al. Therapeutic anticoagulation with heparin in noncritically Ill patients with Covid-19. N Engl J Med. 2021;385(9):790–802. https://doi.org/10.1056/NEJMoa2105911.
Marcos-Jubilar M, Carmona-Torre F, Vidal R, Ruiz-Artacho P, Filella D, Carbonell C, et al. Therapeutic versus prophylactic Bemiparin in hospitalized patients with nonsevere COVID-19 pneumonia (BEMICOP Study): an open-label, multicenter, randomized. Controlled Trial Thromb Haemost. 2022;122(2):295–9. https://doi.org/10.1055/a-1667-7534.
Muñoz-Rivas N, Aibar J, Gabara-Xanco C, Trueba-Vicente A, Urbelz-Perez A, Gomez-del Olmo V, et al. Optimal thromboprophylaxis in noncritically ill patients with COVID-19 pneumonia, the PROTHROMCOVID randomized controlled trial. medRxiv. 2022. https://doi.org/10.1101/2022.05.03.22274594.
Sholzberg M, Tang GH, Rahhal H, AlHamzah M, Kreuziger LB, Áinle FN, et al. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;14(375): n2400. https://doi.org/10.1136/BMJ.n2400.
Spyropoulos AC, Goldin M, Giannis D, Diab W, Wang J, Khanijo S, et al. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med. 2021;181(12):1612–20. https://doi.org/10.1001/jamainternmed.2021.6203.Erratum.In:JAMAInternMed.2022Feb1;182(2):239.
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;3(4):692–4. https://doi.org/10.1111/j.1538-7836.2005.01204.x.
Perepu US, Chambers I, Wahab A, Ten Eyck P, Wu C, Dayal S, et al. Standard prophylactic versus intermediate-dose enoxaparin in adults with severe COVID-19: a multicenter, open-label, randomized controlled trial. J Thromb Haemost. 2021;19(9):2225–34. https://doi.org/10.1111/jth.15450.
Bikdeli B, Talasaz AH, Rashidi F, Bakhshandeh H, Rafiee F, Rezaeifar P, et al. Intermediate-dose versus standard-dose prophylactic anticoagulation in patients with COVID-19 Admitted to the intensive care unit: 90-day results from the INSPIRATION randomized trial. Thromb Haemost. 2022;122(1):131–41. https://doi.org/10.1055/a-1485-2372.
REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACK Investigators, Goligher EC, Bradbury CA, McVerry BJ, et al. Therapeutic anticoagulation with heparin in critically Ill patients with Covid-19. N Engl J Med. 2021;385(9):777–789. https://doi.org/10.1056/NEJMoa2103417.
Giossi R, Menichelli D, Pani A, Tratta E, Romanini A, Roncato R, Nani A, et al. A systematic review and a meta-analysis comparing prophylactic and therapeutic low molecular weight heparins for mortality reduction in 32,688 COVID-19 patients. Front Pharmacol. 2021;2(12): 698008. https://doi.org/10.3389/fphar.2021.698008.
Jorda A, Siller-Matula JM, Zeitlinger M, Jilma B, Gelbenegger G. Anticoagulant treatment regimens in patients with covid-19: a meta-analysis. Clin Pharmacol Ther. 2022;111(3):614–23. https://doi.org/10.1002/cpt.2504.
Kow CS, Ramachandram DS, Hasan SS. The effect of higher-intensity dosing of anticoagulation on the clinical outcomes in hospitalized patients with COVID-19: a meta-analysis of randomized controlled trials. J Infect Chemother. 2022;28(2):257–65. https://doi.org/10.1016/j.jiac.2021.11.008.
Sholzberg M, da Costa BR, Tang GH, Rahhal H, AlHamzah M, Baumann KL. Randomized trials of therapeutic heparin for COVID-19: a meta-analysis. Res Pract Thromb Haemost. 2021;5(8): e12638. https://doi.org/10.1002/rth2.12638.
Pilia E, Belletti A, Fresilli S, Finco G, Landoni G. Efficacy and safety of heparin full-dose anticoagulation in hospitalized non-critically ill COVID-19 patients: a meta-analysis of multicenter randomized controlled trials. J Thromb Thrombolysis. 2022. https://doi.org/10.1007/s11239-022-02681-x.
Barnes GD, Burnett A, Allen A, Ansell J, Blumenstein M, Clark NP, et al. Thromboembolic prevention and anticoagulant therapy during the COVID-19 pandemic: updated clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2022;17:1–14. https://doi.org/10.1007/s11239-022-02643-3.
COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/.
Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of coronavirus disease 2019. Crit Care Med. 2020;48(9):1358–64. https://doi.org/10.1097/CCM.0000000000004458.
Mirsadraee S, Gorog DA, Mahon CF, Rawal B, Semple TR, Nicol ED, et al. Prevalence of thrombotic complications in ICU-treated patients with coronavirus disease 2019 detected with systematic CT scanning. Crit Care Med. 2021;49(5):804–15. https://doi.org/10.1097/CCM.0000000000004890.
Raj K, Chandna S, Doukas SG, Watts A, Jyotheeswara Pillai K, Anandam A, et al. Combined use of wells scores and D-dimer levels for the diagnosis of deep vein thrombosis and pulmonary embolism in COVID-19: a retrospective cohort study. Cureus. 2021;13(9): e17687. https://doi.org/10.7759/cureus.17687.