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Heparin in COVID-19 Patients Is Associated with Reduced In-Hospital Mortality: The Multicenter Italian CORIST Study[*]Funding None.
Introduction A hypercoagulable condition was described in patients with coronavirus disease 2019 (COVID-19) and proposed as a possible pathogenic mechanism contributing to disease progression and lethality.
Aim We evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients.
Methods In a retrospective observational study, 2,574 unselected patients hospitalized in 30 clinical centers in Italy from February 19, 2020 to June 5, 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection were analyzed. The primary endpoint in a time-to event analysis was in-hospital death, comparing patients who received heparin (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores.
Results Out of 2,574 COVID-19 patients, 70.1% received heparin. LMWH was largely the most used formulation (99.5%). Death rates for patients receiving heparin or not were 7.4 and 14.0 per 1,000 person-days, respectively. After adjustment for propensity scores, we found a 40% lower risk of death in patients receiving heparin (hazard ratio = 0.60; 95% confidence interval: 0.49–0.74; E-value = 2.04). This association was particularly evident in patients with a higher severity of disease or strong coagulation activation.
Conclusion In-hospital heparin treatment was associated with a lower mortality, particularly in severely ill COVID-19 patients and in those with strong coagulation activation. The results from randomized clinical trials are eagerly awaited to provide clear-cut recommendations.
Prof. Iacoviello and Di Castelnuovo had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Di Castelnuovo, Costanzo, Iacoviello, and De Caterina. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: Iacoviello, Di Castelnuovo and Costanzo. Critical revision of the manuscript for important intellectual content: Iacoviello, Di Castelnuovo, De Caterina, and de Gaetano Donati. Statistical analysis: Costanzo, Di Castelnuovo, and Arboretti. Administrative, technical, or material support: all authors. Supervision: Iacoviello and Di Castelnuovo.
* THE COVID-19 RISK and Treatments (CORIST) collaboration.
** These authors contributed equally to this work.
Received: 14 December 2020
Accepted: 06 January 2021
07 January 2021 (online)
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
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- 1 Lippi G, Favaloro EJ. D-Dimer is associated with severity of coronavirus disease 2019: a pooled analysis. Thromb Haemost 2020; 120 (05) 876-878
- 2 Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
- 3 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
- 4 Gazzaruso C, Paolozzi E, Valenti C. et al. Association between antithrombin and mortality in patients with COVID-19. A possible link with obesity. Nutr Metab Cardiovasc Dis 2020; 30 (11) 1914-1919
- 5 Marongiu F, Grandone E, Barcellona D. Pulmonary thrombosis in 2019-nCoV pneumonia?. J Thromb Haemost 2020; 18 (06) 1511-1513
- 6 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
- 7 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 (16) 1815-1826
- 8 Tremblay D, van Gerwen M, Alsen M. et al. Impact of anticoagulation prior to COVID-19 infection: a propensity score-matched cohort study. Blood 2020; 136 (01) 144-147
- 9 Wang T, Chen R, Liu C. et al. Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19. Lancet Haematol 2020; 7 (05) e362-e363
- 10 Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association?. Eur Heart J 2020; 41 (19) 1858
- 11 Rotzinger DC, Beigelman-Aubry C, von Garnier C, Qanadli SD. Pulmonary embolism in patients with COVID-19: time to change the paradigm of computed tomography. Thromb Res 2020; 190: 58-59
- 12 Cattaneo M, Morici N. Is thromboprophylaxis with high-dose enoxaparin really necessary for COVID-19 patients? A new “prudent” randomised clinical trial. Blood Transfus 2020; 18 (03) 237-238
- 13 Cattaneo M, Bertinato EM, Birocchi S. et al. Pulmonary embolism or pulmonary thrombosis in COVID-19? Is the recommendation to use high-dose heparin for thromboprophylaxis justified?. Thromb Haemost 2020; 120 (08) 1230-1232
- 14 World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. WHO/2019-nCoV/clinical/2020.4. 2020 . Accessed February 1, 2021 at: https://www.who.int/docs/default-source/coronaviruse/clinical-management-of-novel-cov.pdf
- 15 CDC. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). Published 2020. Updated April 13, 2020. Accessed September10, 2020 at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html
- 16 Matos R, Chung K. DoD COVID-19 practice management guide: clinical management of COVID-19. DoD. Published 2020. Updated March 23, 2020. Accessed September 10, 2020 at: https://asprtracie.hhs.gov/technical-resources/resource/7899/dod-covid-19-practice-management-guide-clinical-management-of-covid-19
- 17 Marietta M, Ageno W, Artoni A. et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus 2020; 18 (03) 167-169
- 18 Bikdeli B, Madhavan MV, Jimenez D. et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC State-of-the-Art Review. J Am Coll Cardiol 2020; 75 (23) 2950-2973
- 19 Thachil J, Tang N, Gando S. et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020; 18 (05) 1023-1026
- 20 Gerotziafas GT, Catalano M, Colgan MP. et al; Scientific Reviewer Committee. Guidance for the management of patients with vascular disease or cardiovascular risk factors and COVID-19: position paper from VAS-European Independent Foundation in Angiology/Vascular Medicine. Thromb Haemost 2020; 120 (12) 1597-1628
- 21 Di Castelnuovo A, De Caterina R, de Gaetano G, Iacoviello L. Controversial relationship between renin-angiotensin system inhibitors and severity of COVID-19: announcing a large multicentre case-control study in Italy. Hypertension 2020; 76 (02) 312-313
- 22 Di Castelnuovo A, Bonaccio M, Costanzo S. et al. Common cardiovascular risk factors and in-hospital mortality in 3,894 patients with COVID-19: survival analysis and machine learning-based findings from the multicentre Italian CORIST Study. Nutr Metab Cardiovasc Dis 2020; 30 (11) 1899-1913
- 23 Di Castelnuovo A, Costanzo S, Antinori A. et al. Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study. Eur J Intern Med 2020; 82: 38-47
- 24 WHO. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: interim guidance, 28 January 2020. Accessed September 10, 2020 at: https://apps.who.int/iris/bitstream/handle/10665/330893/WHO-nCoV-Clinical-2020.3-eng.pdf?sequence=1&isAllowed=y
- 25 Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York, NY: John Wiley; 1987
- 26 Glidden DV, Vittinghoff E. Modelling clustered survival data from multicentre clinical trials. Stat Med 2004; 23 (03) 369-388
- 27 Garrido MM, Kelley AS, Paris J. et al. Methods for constructing and assessing propensity scores. Health Serv Res 2014; 49 (05) 1701-1720
- 28 VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med 2017; 167 (04) 268-274
- 29 Di Gennaro F, Marotta C, Storto M. et al. SARS-CoV-2 transmission and outcome in neuro-rehabilitation patients hospitalized at neuroscience hospital in Italy. Mediterr J Hematol Infect Dis 2020; 12 (01) e2020063
- 30 Maugeri N, de Gaetano G, Barbanti M, Donati MB, Cerletti C. Prevention of platelet-polymorphonuclear leukocyte interactions: new clues to the antithrombotic properties of parnaparin, a low molecular weight heparin. Haematologica 2005; 90 (06) 833-839
- 31 Maugeri N, Di Fabio G, Barbanti M, de Gaetano G, Donati MB, Cerletti C. Parnaparin, a low-molecular-weight heparin, prevents P-selectin-dependent formation of platelet-leukocyte aggregates in human whole blood. Thromb Haemost 2007; 97 (06) 965-973
- 32 Billett HH, Reyes-Gil M, Szymanski J. et al. Anticoagulation in COVID-19: effect of enoxaparin, heparin, and apixaban on mortality. Thromb Haemost 2020; 120 (12) 1691-1699
- 33 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
- 34 Pesavento R, Ceccato D, Pasquetto G. et al. The hazard of (sub)therapeutic doses of anticoagulants in non-critically ill patients with Covid-19: The Padua province experience. J Thromb Haemost 2020; 18 (10) 2629-2635
- 35 Ionescu F, Jaiyesimi I, Petrescu I. et al. Association of anticoagulation dose and survival in hospitalized COVID-19 patients: a retrospective propensity score-weighted analysis. Eur J Haematol 2020; 106 (02) 165-174
- 36 Bidar F, Hékimian G, Martin-Toutain I, Lebreton G, Combes A, Frère C. Heparin-induced thrombocytopenia in COVID-19 patients with severe acute respiratory distress syndrome requiring extracorporeal membrane oxygenation: two case reports. J Artif Organs 2020; 24 (02) 277-281
- 37 Lingamaneni P, Gonakoti S, Moturi K, Vohra I, Zia M. Heparin-induced thrombocytopenia in COVID-19. J Investig Med High Impact Case Rep 2021; 13 (01) 8857
- 38 Ayerbe L, Risco C, Ayis S. The association between treatment with heparin and survival in patients with Covid-19. J Thromb Thrombolysis 2020; 50 (02) 298-301
- 39 Albani F, Sepe L, Fusina F. et al. Thromboprophylaxis with enoxaparin is associated with a lower death rate in patients hospitalized with SARS-CoV-2 infection. A cohort study. EClinicalMedicine 2020; 27: 100562