Association between Heparin Dose and 6-Week Mortality in Patients with COVID-19

Claire Coutureau1,2, Philippe Nguyen3, Maxime Hentzien2,4, Peter Joe Noujaim1, Sarah Zerbib1, Damien Jolly1,2 and Lukshe Kanagaratnam1,2.

1 Department of Research and Public Health, Reims University Hospital, 51092 Reims, France.
2 UR 3797 Vieillissement, Fragilité (VieFra), faculty of medicine, University of Reims Champagne-Ardenne, 51092 Reims, France.
3 Department of Hematology Laboratory, Reims University Hospital, 51092 Reims, France.
4 Department of Internal Medicine, Clinical Immunology and Infectious Diseases, Reims University Hospital, 51092 Reims, France.

Correspondence to: Dr Claire Coutureau. Reims University Hospitals, Robert Debré Hospital, Department of Research and Public Health, Rue du Général Koenig - F51092 Reims, France. Telephone Number : +33 3 26 78 45 21. E-mail: ccoutureau@chu-reims.fr

Published: May 1, 2022
Received: March 1, 2022
Accepted: April 10, 2022
Mediterr J Hematol Infect Dis 2022, 14(1): e2022036 DOI 10.4084/MJHID.2022.036

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background: Severe forms of SARS-CoV-2 infections are associated with high rates of thromboembolic complications. Professional societies and expert consensus reports have recommended anticoagulants for COVID-19 hospitalized patients. Our study aimed to compare the effect of therapeutic, intermediate and prophylactic doses of heparin on 6-week survival in patients hospitalized for COVID-19.
Methods. The study sample is a French cohort of COVID-19 patients hospitalized between Feb 25th and Apr 30th 2020. Patients were assigned to one of 3 anticoagulation dose groups based on the maximum dose they received for at least three days (prophylactic, intermediate or therapeutic). The main outcome was survival up to 42 days after hospital admission. Multivariate Cox regression models were performed to adjust analyses for confounding factors.
Results. A total of 323 patients were included. The mean age of the study sample was 71.6 ± 15 years, and 56.3% were men. Treatment with the intermediate versus prophylactic dose of anticoagulation (HR = 0.50, 95%CI = [0.26; 0.99], p = 0.047) and with therapeutic versus prophylactic dose (HR = 0.58 95%CI = [0.34; 0.98], p = 0.044) was associated with a significant reduction in 6-week mortality, after adjustment for potential confounding factors. Comparison of therapeutic versus intermediate doses showed no significant difference in survival.
Conclusions. Our results reported a significant positive effect of intermediate and therapeutic doses of heparin on 6-week survival for hospitalized COVID-19 patients compared with a prophylactic dose.


Introduction

The coronavirus disease 2019 (COVID-9), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been responsible for the deaths of several million persons worldwide.[1] The range of severity of COVID-19 is broad, and most patients who require hospitalization suffer from respiratory failure and/or sepsis. In the most severe cases, acute respiratory distress syndrome (ARDS), multi-organ failure and death can ensue.[2]
The cytokine storm, an excessive systemic inflammatory response,[3] is considered one of the major causes of ARDS in COVID-19 patients.[4] It is now well established that interaction between inflammation and coagulation exists.[5] It has been observed that severe forms of SARS-CoV-2 infection are associated with elevated levels of D-dimers and fibrinogene with high rates of thromboembolic complications, such as pulmonary embolism.[6]
In a meta-analysis, Malas et al. estimated that the overall rate of venous thromboembolism was 21%, ranging from 5% among patients hospitalized in conventional wards to 31% in patients admitted to the intensive care unit (ICU).[7] In addition, autopsy studies from deceased COVID-19 patients have also shown the presence of fibrinous thrombi in small pulmonary arterioles, confirming the important role of coagulation abnormalities.[8]
Anticoagulant treatments are used to prevent and treat thromboembolic events.[9] Moreover, heparin also has anti-inflammatory effects[10] that may benefit patients with severe forms of SARS-CoV-2 infection. Professional societies and expert consensus reports have recommended anticoagulants as part of the treatment of hospitalized COVID-19 patients.[11–13] However, vascular complications, occurring even in patients receiving prophylactic doses of anticoagulants, led to intensified prophylactic doses (called intermediate doses) and therapeutic doses,[14,15] with changing indications over time. Since April 2020,  the French Society of Thrombosis and Haemostasis recommends intensified doses depending on the patient's state (e.g. requirement for supplemental oxygen therapy, D-dimer levels) and characteristics.[16]
Observational studies have reported encouraging results regarding the mortality reduction in patients treated with anticoagulants.[17–20] However, to the best of our knowledge, no cohort study has investigated the effect of 3 different anticoagulant doses on 6-week mortality. In this context, we aimed to compare the effect of therapeutic, intermediate and prophylactic doses of anticoagulants on 6-week survival among a cohort of patients hospitalized for COVID-19 during the first wave of the pandemic in France.   

Methods

Population. The study sample is a prospective cohort of adult patients diagnosed with COVID-19 and admitted to Reims University Hospital, France, between Feb 25th and Apr 30th 2020. This study received approval from the Ethics Committee (number 3838-RM), and informed consent was obtained for each patient. The study was registered on Clinicaltrials.gov under the number NCT04553575.
Patients were included if they were hospitalized with a diagnosis of COVID-19, defined as a positive reverse transcriptase-polymerase chain reaction (RT-PCR) test or the presence of characteristic findings on a computed tomography scan associated with a typical clinical history.
Patients were excluded if they did not receive anticoagulant treatment or were already hospitalized for another condition before their COVID-19 diagnosis. Patients with a length of stay shorter than five days were also excluded to prevent immortality bias[21] since they were unlikely to receive the studied doses of treatment in such a short stay.
Anticoagulation treatments were unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Examples of prophylactic, intermediate and therapeutic doses of different anticoagulants are presented in Table S1 (Supplementary material).
We assigned each patient to one of the three following anticoagulant dose groups: (1) prophylactic, (2) intermediate or (3) therapeutic. The patient had to receive the corresponding dose for at least three days to be assigned to a group.
Patients who received anticoagulation at different doses during their hospital stay were assigned to the group corresponding to the maximum dose received. If a patient received more than three days of anticoagulation but less than three days of intermediate or therapeutic dose in total, they were assigned to the prophylactic dose group since there is evidence that therapeutic levels are not reached for most patients in this short timeframe.[22] Similarly, patients with less than three days of anticoagulation at any dose were excluded from the study since the treatment duration was too short of ensuring a real anticoagulation effect.
Variables and outcome. For each patient, we recorded socio-demographic characteristics, co-morbidities, clinical and biological data regarding the initial severity of COVID-19, as well as treatments and outcomes. We defined cardiovascular disease as the presence of high blood pressure, a history of cerebral stroke, coronary heart disease, cardiac surgery or heart failure of New York Heart Association (NYHA) class III or IV. The updated version of the Charlson co-morbidity index by Quan et al. was used to measure the co-morbidity status.[23] To evaluate the severity of infection at admission, we measured and recorded the early warning score (EWS), a modified version of the National Early Warning Score 2 with age ≥ 65 years old as an additional parameter.[24] Each patient was classified as low (EWS ≤ 4), medium (EWS > 4 and ≤ 6) or high risk (EWS > 6) of acute deterioration. In addition, we noted whether the patient received systemic corticosteroid therapy, as it is a recommended treatment for severe forms of COVID-19.[25] Since Mar 27th 2020, the treatment protocol in our hospital has included corticosteroids for all patients with COVID-19 pneumonia, at a dose of 1 mg/kg equivalent per day of prednisone or methylprednisolone for 3 to 4 weeks, depending on the severity of the disease.
Information on potential complications of anticoagulation was extracted from the program for the medicalization of information systems (PMSI) of our hospital. This database contains information on diagnoses, co-morbidities, and complications for each hospital stay.
The main outcome of our analysis was survival up to 6 weeks (42 days) after hospital admission.
Statistical analysis. Quantitative variables are described as mean ± standard deviation (SD) or median and interquartile range (IQR), and qualitative variables as numbers (percentage). Comparisons by anticoagulant dose group were performed using the ANOVA test for quantitative variables and the Chi2 test for qualitative variables. In addition, validity conditions for these tests were verified.
We constructed survival curves using the Kaplan Meier method to compare the effect of the 3 anticoagulant doses on 6-week survival. Curves were compared using the log-rank test.
Multivariate Cox regression analysis was performed to adjust for potential confounders, which were identified in the bivariate analyses or recognized confounding or prognostic factors from the literature. The choice of variables also took into account the risk of multicollinearity. Thus, the following adjustment variables were chosen for our analyses: socio-demographic characteristics (age and sex), co-morbidities evaluated with the Charlson co-morbidity index, anticoagulant as part of regular treatment, the severity of COVID-19 (O2 therapy needed at hospital arrival and hospitalization in ICU) and treatment of SARS-CoV-2 infection with systemic corticosteroids. Results are expressed as hazard ratios (HR) with a 95% confidence interval (95% CI).
All analyses were performed using R software, version 4.0.5 (R Core Team (2019). R Foundation for Statistical Computing, Vienna, Austria). A p-value <0.05 was considered statistically significant.

Results

A total of 479 patients were included in the cohort between Feb 25th and Apr 30th. Thirty-seven patients were not treated with anticoagulants, 111 patients were hospitalized for other reasons before their COVID-19 diagnosis or were hospitalized for less than five days, and eight patients did not receive at least three days of any anticoagulant dose. Therefore, 323 patients were included in our analysis: 34.1% in the prophylactic group, 25.4% in the intermediate group and 40.6% in the therapeutic group (Figure 1).
Figure 1 Figure 1. Flow chart of the study population. Abbreviations: P, prophylactic; I, intermediate; T, therapeutic.
Overall, the mean age of the population was 71.6 ± 15 years, and 56.3% were men. Fifty-nine (18.3%) patients received anticoagulants, and 114 (35.3%) had an antiplatelet agent in their regular treatment before admission.
Information on baseline D-dimer levels was missing for 91 patients. Among those with available data, the median D-dimer level was 0.9 mg/L (IQR = [0.7; 2.0]) in the prophylactic group, 0.8 mg/L (IQR = [0.4; 1.1]) in the intermediate group and 1.6 mg/L (IQR = [0.6; 5.7]) in the therapeutic group. Nineteen patients (5.9%) suffered pulmonary embolism during their hospital stay. The characteristics of the three groups are presented in Table 1.
Table 1 Table 1. Characteristics of the study population according to the dose of anticoagulant received (prophylactic, intermediate or therapeutic) during hospitalization for COVID-19.
Independently of the treatment duration, and thus of the assigned group, we also explored the different anticoagulant doses received by each patient in chronological order. Nearly two thirds (209) of included patients received only one type anticoagulant regimen, 79 (24.5%) received two regimens, 15 (4.6%) received three regimens, and 20 (6.2%) had more complicated treatment regiments comprising several dose changes that did not fit with any other regimen (Table 2).
Table 2 Table 2. Schemes of anticoagulant doses received by each patient.
At 6 weeks post-admission, 31 (28.2%) patients in the prophylactic group, 12 (14.6%) in the intermediate group and 31 (23.7%) in the therapeutic group had died. The Kaplan-Meier curves depicting survival across the three groups are shown in Figure 2. There was no significant difference between groups (p = 0.066) (Figure 2). The results of the bivariate analysis investigating the impact of patient characteristics on 6-week survival are presented in Table S2 (Supplementary material).
Figure 2 Figure 2. Comparison of Kaplan-Meier survival curves with 95% confidence intervals.
A total of 319 patients were included in the multivariate analyses; 4 were excluded because of missing data on one of the adjustment variables.
Treatment with intermediate dose of anticoagulation was associated with a significant reduction in the risk of 6-week mortality, compared to prophylactic dose (HR = 0.50, 95%CI = [0.26; 0.99], p = 0.047). Similarly, therapeutic dose of heparin, compared to prophylactic dose, was associated with a significant reduction in the risk of mortality (HR = 0.58, 95%CI = [0.34; 0.98], p = 0.044). When comparing the therapeutic versus the intermediate dose, no significant difference was found (HR = 1.14, 95%CI = [0.57; 2.29], p = 0.704).
Four patients, 1 in the prophylactic group, 1 in the intermediate group and 2 in the therapeutic group, presented a minor complication of anticoagulant treatment (i.e. asymptomatic overdose, oral or nasal bleeding) and 3 patients of the therapeutic group presented an intramuscular hematoma.

Discussion

The results of our study highlight the positive impact of intermediate and therapeutic doses of heparin on 6-week survival among hospitalized COVID-19 patients, as compared with prophylactic dose of anticoagulant therapy.
It has been well established that severe SARS-CoV-2 infection is associated with a high prevalence of pulmonary thrombosis and macro-vascular thromboembolic events. Besides its anticoagulant activity, heparin also has anti-inflammatory and immunomodulatory properties that may explain its beneficial effects on the outcomes of COVID-19 patients.[26]
Our results are consistent with other observational studies[22,27] reporting that patients receiving therapeutic doses had a higher survival probability than those receiving only prophylactic doses. A further study by Meizlish et al.[28] reported a significantly lower cumulative incidence of in-hospital death for patients receiving intermediate doses of anticoagulant compared to prophylactic doses. 
Due to the observational design of our study, our results remain subject to hidden confounding factors. The association between anticoagulation and survival in SARS-CoV-2 infected patients warrants evaluation in interventional studies. Randomized controlled trials (RCTs) in hospitalized COVID-19 patients have found contrasting results. Two RCTs testing the effects of full dose anticoagulant therapy showed no beneficial effect on clinical outcomes compared to prophylactic doses.[29,30] One trial had to stop enrolment of critically ill patients prematurely due to futility and safety concerns.[31] Nevertheless, results in non-critically ill patients showed that therapeutic doses of heparin increased the probability of survival to hospital discharge, with reduced use of cardiovascular and respiratory organ support compared to prophylactic doses.[32] Another recent study concluded that therapeutic doses of heparin reduced major thromboembolism and death among in-patients with elevated D-dimers, but no treatment effect was seen in ICU patients.[33] Regarding the comparison between intermediate and prophylactic doses of anticoagulants, two RCTs, including only patients with severe COVID-19, found no significant difference.[34,35] There are still many on-going RCTs that will provide further evidence to determine the optimal anticoagulation doses.[36]
To the best of our knowledge, this study is the first prospective, observational study to compare the effect of 3 types of anticoagulant doses on 6-week mortality. Our cohort included adult patients hospitalized with COVID-19 independently of the severity of the disease, the need for mechanical ventilation and the presence of coagulation disorders. Moreover, patients were followed for 6 weeks, whereas most published observational studies and trials focused only on in-hospital or short-term mortality.
The precision of the data collected enabled us to study the different dose regimens received by the patients. Accordingly, we noted that more than a third of the study population received at least two types of regimen (from among prophylactic, intermediate and therapeutic doses). This could be explained by the lack of consensus on anticoagulant treatment before April 2020 in France, but above all, by the constant adaptation of the treatment doses by the clinicians in response to the patient's state and any potential complications of the disease.
Our results also provide interesting findings as regards the comparison of therapeutic versus intermediate doses. Indeed, we found no significant advantage of therapeutic anticoagulation in terms of survival. While therapeutic and intermediate doses were both found to be superior to prophylactic doses, the use of intermediate anticoagulation may have the advantage of reducing the risk of bleeding complications. Indeed, it has previously been shown that therapeutic doses of anticoagulant increase the risk of bleeding in COVID-19 patients.[37]
Our study presents several limitations. Firstly, we did not have precise data on the start and end dates of each dose for each patient. As a result, we were not able to perform a time-dependent analysis, which would have been a more appropriate approach to correctly classify the immortal time in pharmacoepidemiology.[38] We partially took this risk of bias into account by excluding patients with a length of stay less than 5 days, because there was a high risk that these patients were not hospitalized long enough to receive intermediate or therapeutic doses of anticoagulant. Secondly, the fact that patients with less than 3 days of intermediate or therapeutic doses were assigned to the prophylactic group could induce classification bias. Since the reason for the short duration of treatment was unknown, we may have overlooked potential complications due to higher doses of anticoagulation. However, as highlighted by Ionescu et al., assigning patients with less than 3 days of treatment in the intermediate or therapeutic  group could induce other biases, as therapeutic levels are often not reached in such a short timeframe.[27] Thirdly, our study may suffer from a lack of statistical power due to the small sample size. Finally, the external validity of our results might be affected by the fact that this was a single-centre study.


Conclusions

Our study reports a significant positive effect of intermediate and therapeutic doses of heparin, compared to prophylactic doses, on 6-week survival in hospitalized COVID-19 patients. Results of on-going RCTs will be helpful to determine the optimal anticoagulation doses.

Acknowledgements

Reims COVID Study Group : Ailsa ROBBINS, Kévin DIDIER, Pauline ORQUEVAUX, Violaine NOEL, Paola MARIANETTI, Juliette ROMARU, Dorothée LAMBERT, Jean Luc BERGER, Sandra DURY, Maxime DEWOLF, Jean Hugues SALMON, Jérôme COSTA, Julia SIMON, Natacha NOEL, Sara BARRAUD, Marion BARROIS, Hédia BRIXI, Quentin LAURENT-BADR, Manuelle VIGUIER, Clélia VANHAECKE, Laurence GUSDORF, Isabelle QUATRESOUS, Aline CARSIN-VU, Véronique BRODARD, Antoine HUGUENIN, Morgane BONNET, Aurore THIERRY.
We extend our sincere thanks to Fiona CAULFIELD for her assistance in editing this manuscript.

References   

  1. WHO Coronavirus (COVID-19) Dashboard [Internet]. [cited 2021 Dec 1]. Available from: https://covid19.who.int
  2. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. 2020 Mar;395(10229):1054-62. https://doi.org/10.1016/S0140-6736(20)30566-3
  3. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020 Dec 3;383(23):2255-73. https://doi.org/10.1056/NEJMra2026131 PMid:33264547 PMCid:PMC7727315
  4. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19. J Infect. 2020 Jun;80(6):607-13. https://doi.org/10.1016/j.jinf.2020.03.037 PMid:32283152 PMCid:PMC7194613
  5. Connors JM, Levy JH. Thromboinflammation and the hypercoagulability of COVID-19. J Thromb Haemost. 2020;18(7):1559-61. https://doi.org/10.1111/jth.14849 PMid:32302453
  6. Semeraro N., Colucci M.The prothrombotic state associated with SARS-CoV-2 infection: pathophysiological aspects. Mediterr J Hematol Infect Dis 2021, 13(1): e2021045 https://doi.org/10.4084/MJHID.2021.045 PMid:34276914 PMCid:PMC8265369
  7. Malas MB, Naazie IN, Elsayed N, Mathlouthi A, Marmor R, Clary B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: A systematic review and meta-analysis. EClinicalMedicine. 2020 Dec;29:100639. https://doi.org/10.1016/j.eclinm.2020.100639 PMid:33251499 PMCid:PMC7679115
  8. Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, da Silva LFF, de Oliveira EP, Saldiva PHN, Mauad T, Negri EM. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost JTH. 2020 Jun;18(6):1517-9. https://doi.org/10.1111/jth.14844 PMid:32294295 PMCid:PMC7262093
  9. Amaral F, Baptista-Silva J, Nakano L, Flumignan R. Pharmacological interventions for preventing venous thromboembolism in patients undergoing bariatric surgery. Cochrane Database Syst Rev [Internet]. 2020;(7).   https://doi.org/10.1002/14651858.CD013683 PMCid:PMC7386840
  10. Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res. 2008;122(6):743-52. https://doi.org/10.1016/j.thromres.2006.10.026 PMid:17727922
  11. Rico-Mesa JS, Rosas D, Ahmadian-Tehrani A, White A, Anderson AS, Chilton R. The Role of Anticoagulation in COVID-19-Induced Hypercoagulability. Curr Cardiol Rep. 2020 Jun 17;22(7):53-53. https://doi.org/10.1007/s11886-020-01328-8 PMid:32556892 PMCid:PMC7298694
  12. Task Force for the management of COVID-19 of the European Society of Cardiology. ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 2-care pathways, treatment, and follow-up. Eur Heart J. 2021 Nov 16;ehab697.
  13. Castelli R, Gidaro A. Abnormal Hemostatic Parameters and Risk of Thromboembolism Among Patients With COVID-19 Infection. J Hematol. 2020 Apr;9(1-2):1-4. https://doi.org/10.14740/jh636 PMid:32362977 PMCid:PMC7188381
  14. Pesavento R, Ceccato D, Pasquetto G, Monticelli J, Leone L, Frigo A, Gorgi D, Postal A, Marchese GM, Cipriani A, Saller A, Sarais C, Criveller P, Gemelli M, Capone F, Fioretto P, Pagano C, Rossato M, Avogaro A, Simioni P, Prandoni P, Vettor R. The hazard of (sub)therapeutic doses of anticoagulants in non-critically ill patients with Covid-19: The Padua province experience. J Thromb Haemost JTH. 2020 Oct;18(10):2629-35. https://doi.org/10.1111/jth.15022 PMid:32692874 PMCid:PMC7404507
  15. Dobesh PP, Trujillo TC. Coagulopathy, Venous Thromboembolism, and Anticoagulation in Patients with COVID-19. Pharmacotherapy. 2020/11/03 ed. 2020 Nov;40(11):1130-51. https://doi.org/10.1002/phar.2465 PMid:33006163 PMCid:PMC7537066
  16. Susen S, Tacquard CA, Godon A, Mansour A, Garrigue D, Nguyen P, Godier A, Testa S, Levy JH, Albaladejo P, Gruel Y, GIHP and GFHT. Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring. Crit Care Lond Engl. 2020 Jun 19;24(1):364. https://doi.org/10.1186/s13054-020-03000-7 PMid:32560658 PMCid:PMC7303590
  17. Ayerbe L, Risco C, Ayis S. The association between treatment with heparin and survival in patients with Covid-19. J Thromb Thrombolysis. 2020;50(2):298-301. https://doi.org/10.1007/s11239-020-02162-z PMid:32476080 PMCid:PMC7261349
  18. Nadkarni GN, Lala A, Bagiella E, Chang HL, Moreno PR, Pujadas E, Arvind V, Bose S, Charney AW, Chen MD, Cordon-Cardo C, Dunn AS, Farkouh ME, Glicksberg BS, Kia A, Kohli-Seth R, Levin MA, Timsina P, Zhao S, Fayad ZA, Fuster V. Anticoagulation, Bleeding, Mortality, and Pathology in Hospitalized Patients With COVID-19. J Am Coll Cardiol. 2020 Oct 20;76(16):1815-26. https://doi.org/10.1016/j.jacc.2020.08.041 PMid:32860872 PMCid:PMC7449655
  19. Paranjpe I, Fuster V, Lala A, Russak AJ, Glicksberg BS, Levin MA, Charney AW, Narula J, Fayad ZA, Bagiella E, Zhao S, Nadkarni GN. Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19. J Am Coll Cardiol. 2020 Jul 7;76(1):122-4. https://doi.org/10.1016/j.jacc.2020.05.001 PMid:32387623 PMCid:PMC7202841
  20. Rentsch CT, Beckman JA, Tomlinson L, Gellad WF, Alcorn C, Kidwai-Khan F, Skanderson M, Brittain E, King JT, Ho Y-L, Eden S, Kundu S, Lann MF, Greevy RA, Ho PM, Heidenreich PA, Jacobson DA, Douglas IJ, Tate JP, Evans SJW, Atkins D, Justice AC, Freiberg MS. 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 Feb 11;372:n311. https://doi.org/10.1136/bmj.n311 PMid:33574135 PMCid:PMC7876672
  21. Lévesque LE, Hanley JA, Kezouh A, Suissa S. Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes. BMJ. 2010 Mar 12;340:b5087. https://doi.org/10.1136/bmj.b5087 PMid:20228141
  22. Trinh MA, Chang DR, Govindarajulu US, Kane E, Fuster V, Kohli-Seth R, Ahmed S, Levin MA, Chen MD. Therapeutic Anticoagulation Is Associated with Decreased Mortality in Mechanically Ventilated COVID-19 Patients. medRxiv. 2020 Jun 3;2020.05.30.20117929. https://doi.org/10.1101/2020.05.30.20117929
  23. Holler JG, Eriksson R, Jensen TØ, van Wijhe M, Fischer TK, Søgaard OS, Israelsen SB, Mohey R, Fabricius T, Jøhnk F, Wiese L, Johnsen S, Søborg C, Nielsen H, Kirk O, Madsen BL, Harboe ZB. First wave of COVID-19 hospital admissions in Denmark: a Nationwide population-based cohort study. BMC Infect Dis. 2021 Jan 9;21(1):39. https://doi.org/10.1186/s12879-020-05717-w PMid:33421989 PMCid:PMC7794638
  24. Liao X, Wang B, Kang Y. Novel coronavirus infection during the 2019-2020 epidemic: preparing intensive care units-the experience in Sichuan Province, China. Intensive Care Med. 2020;46(2):357-60. https://doi.org/10.1007/s00134-020-05954-2 PMid:32025779 PMCid:PMC7042184
  25. World Health Organization. Corticosteroids for COVID-19: living guidance, 2 September 2020 [Internet]. Geneva: World Health Organization; 2020. Available from: https://apps.who.int/iris/handle/10665/334125
  26. Gozzo L, Viale P, Longo L, Vitale DC, Drago F. The Potential Role of Heparin in Patients With COVID-19: Beyond the Anticoagulant Effect. A Review. Front Pharmacol. 2020 Aug 21;11:1307.
    https://doi.org/10.3389/fphar.2020.01307 PMid:32973526 PMCid:PMC7472559
  27. Ionescu F, Jaiyesimi I, Petrescu I, Lawler PR, Castillo E, Munoz-Maldonado Y, Imam Z, Narasimhan M, Abbas AE, Konde A, Nair GB. Association of anticoagulation dose and survival in hospitalized COVID-19 patients: A retrospective propensity score-weighted analysis. Eur J Haematol. 2021 Feb;106(2):165-74. https://doi.org/10.1111/ejh.13533 PMid:33043484 PMCid:PMC7675265
  28. Meizlish ML, Goshua G, Liu Y, Fine R, Amin K, Chang E, DeFilippo N, Keating C, Liu Y, Mankbadi M, McManus D, Wang SY, Price C, Bona RD, Ochoa Chaar CI, Chun HJ, Pine AB, Rinder HM, Siner JM, Neuberg DS, Owusu KA, Lee AI. Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: A propensity score-matched analysis. Am J Hematol. 2021 Apr 1;96(4):471-9. https://doi.org/10.1002/ajh.26102 PMid:33476420 PMCid:PMC8013588
  29. Lopes RD, Silva PGM de B e, Furtado RHM, Macedo AVS, Bronhara B, Damiani LP, Barbosa LM, Morata J de A, Ramacciotti E, Martins P de A, Oliveira AL de, Nunes VS, Ritt LEF, Rocha AT, Tramujas L, Santos SV, Diaz DRA, Viana LS, Melro LMG, Chaud MS de A, Figueiredo EL, Neuenschwander FC, Dracoulakis MDA, Lima RGSD, Dantas VC de S, Fernandes ACS, Gebara OCE, Hernandes ME, Queiroz DAR, Veiga VC, Canesin MF, Faria LM de, Feitosa-Filho GS, Gazzana MB, Liporace IL, Twardowsky A de O, Maia LN, Machado FR, Soeiro A de M, Conceição-Souza GE, Armaganijan L, Guimarães PO, Rosa RG, Azevedo LCP, Alexander JH, Avezum A, Cavalcanti AB, Berwanger O. 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. The Lancet. 2021 Jun 12;397(10291):2253-63. https://doi.org/10.1016/S0140-6736(21)01203-4
  30. Sholzberg M, Tang GH, Rahhal H, AlHamzah M, Kreuziger LB, Áinle FN, Alomran F, Alayed K, Alsheef M, AlSumait F, Pompilio CE, Sperlich C, Tangri S, Tang T, Jaksa P, Suryanarayan D, Almarshoodi M, Castellucci LA, James PD, Lillicrap D, Carrier M, Beckett A, Colovos C, Jayakar J, Arsenault M-P, Wu C, Doyon K, Andreou ER, Dounaevskaia V, Tseng EK, Lim G, Fralick M, Middeldorp S, Lee AYY, Zuo F, da Costa BR, Thorpe KE, Negri EM, Cushman M, Jüni P, RAPID trial investigators. 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 randomized clinical trial. BMJ. 2021 Oct 14;375:n2400. https://doi.org/10.1136/bmj.n2400  PMid:34649864 PMCid:PMC8515466
  31. REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Goligher EC, Bradbury CA, McVerry BJ, Lawler PR, Berger JS, Gong MN, Carrier M, Reynolds HR, Kumar A, Turgeon AF, Kornblith LZ, Kahn SR, Marshall JC, Kim KS, Houston BL, Derde LPG, Cushman M, Tritschler T, Angus DC, Godoy LC, McQuilten Z, Kirwan B-A, Farkouh ME, Brooks MM, Lewis RJ, Berry LR, Lorenzi E, Gordon AC, Ahuja T, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen J-T, Cheng AC, Chkhikvadze T, Coiffard B, Contreras A, Costantini TW, de Brouwer S, Detry MA, Duggal A, Džavík V, Effron MB, Eng HF, Escobedo J, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Froess JD, Fu Z, Galanaud JP, Galen BT, Gandotra S, Girard TD, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Haniffa R, Hegde SM, Hendrickson CM, Higgins AM, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Huang DT, Hudock K, Hunt BJ, Husain M, Hyzy RC, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski A, King AJ, Knudson MM, Kornblith AE, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Gallego Lima F, Linstrum K, Litton E, Lopez-Sendon J, Lother SA, Marten N, Saud Marinez A, Martinez M, Mateos Garcia E, Mavromichalis S, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nicolau JC, Nunez-Garcia B, Park JJ, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Pompilio M, Quigley JG, Rosenson RS, Rost NS, Rowan K, Santos FO, Santos M, Santos MO, Satterwhite L, Saunders CT, Schreiber J, Schutgens REG, Seymour CW, Siegal DM, Silva DG, Singhal AB, Slutsky AS, Solvason D, Stanworth SJ, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Widmer RJ, Wilson JG, Yuriditsky E, Zhong Y, Berry SM, McArthur CJ, Neal MD, Hochman JS, Webb SA, Zarychanski R. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):777-89.
  32. ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Lawler PR, Goligher EC, Berger JS, Neal MD, McVerry BJ, Nicolau JC, Gong MN, Carrier M, Rosenson RS, Reynolds HR, Turgeon AF, Escobedo J, Huang DT, Bradbury CA, Houston BL, Kornblith LZ, Kumar A, Kahn SR, Cushman M, McQuilten Z, Slutsky AS, Kim KS, Gordon AC, Kirwan B-A, Brooks MM, Higgins AM, Lewis RJ, Lorenzi E, Berry SM, Berry LR, Aday AW, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen J-T, Cheng AC, Chkhikvadze T, Coiffard B, Costantini TW, de Brouwer S, Derde LPG, Detry MA, Duggal A, Džavík V, Effron MB, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Galanaud JP, Galen BT, Gandotra S, García-Madrona S, Girard TD, Godoy LC, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Hamburg NM, Haniffa R, Hanna G, Hanna N, Hegde SM, Hendrickson CM, Hite RD, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Hudock K, Hunt BJ, Husain M, Hyzy RC, Iyer VN, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski AL, King AJ, Knudson MM, Kornblith AE, Krishnan V, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Lima FG, Linstrum K, Litton E, Lopez-Sendon J, Lopez-Sendon Moreno JL, Lother SA, Malhotra S, Marcos M, Saud Marinez A, Marshall JC, Marten N, Matthay MA, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Moore SC, Morillo Guerrero R, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nunez-Garcia B, Pandey A, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Pérez González YS, Pompilio M, Prekker ME, Quigley JG, Rost NS, Rowan K, Santos FO, Santos M, Olombrada Santos M, Satterwhite L, Saunders CT, Schutgens REG, Seymour CW, Siegal DM, Silva DG, Shankar-Hari M, Sheehan JP, Singhal AB, Solvason D, Stanworth SJ, Tritschler T, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Wells BJ, Widmer RJ, Wilson JG, Yuriditsky E, Zampieri FG, Angus DC, McArthur CJ, Webb SA, Farkouh ME, Hochman JS, Zarychanski R. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):790-802.
  33. Spyropoulos AC, Goldin M, Giannis D, Diab W, Wang J, Khanijo S, Mignatti A, Gianos E, Cohen M, Sharifova G, Lund JM, Tafur A, Lewis PA, Cohoon KP, Rahman H, Sison CP, Lesser ML, Ochani K, Agrawal N, Hsia J, Anderson VE, Bonaca M, Halperin JL, Weitz JI, HEP-COVID Investigators. 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 Oct 7;
  34. Perepu US, Chambers I, Wahab A, Ten Eyck P, Wu C, Dayal S, Sutamtewagul G, Bailey SR, Rosenstein LJ, Lentz SR. Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: A multi-center, open-label, randomized controlled trial. J Thromb Haemost JTH. 2021 Sep;19(9):2225-34. https://doi.org/10.1111/jth.15450 PMid:34236768 PMCid:PMC8420176
  35. INSPIRATION Investigators, Sadeghipour P, Talasaz AH, Rashidi F, Sharif-Kashani B, Beigmohammadi MT, Farrokhpour M, Sezavar SH, Payandemehr P, Dabbagh A, Moghadam KG, Jamalkhani S, Khalili H, Yadollahzadeh M, Riahi T, Rezaeifar P, Tahamtan O, Matin S, Abedini A, Lookzadeh S, Rahmani H, Zoghi E, Mohammadi K, Sadeghipour P, Abri H, Tabrizi S, Mousavian SM, Shahmirzaei S, Bakhshandeh H, Amin A, Rafiee F, Baghizadeh E, Mohebbi B, Parhizgar SE, Aliannejad R, Eslami V, Kashefizadeh A, Kakavand H, Hosseini SH, Shafaghi S, Ghazi SF, Najafi A, Jimenez D, Gupta A, Madhavan MV, Sethi SS, Parikh SA, Monreal M, Hadavand N, Hajighasemi A, Maleki M, Sadeghian S, Piazza G, Kirtane AJ, Van Tassell BW, Dobesh PP, Stone GW, Lip GYH, Krumholz HM, Goldhaber SZ, Bikdeli B. 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 Clinica Trial. JAMA. 2021 Apr 27;325(16):1620-30. https://doi.org/10.1001/jama.2021.4152 PMid:33734299 PMCid:PMC7974835
  36. Talasaz AH, Sadeghipour P, Kakavand H, Aghakouchakzadeh M, Kordzadeh-Kermani E, Van Tassell BW, Gheymati A, Ariannejad H, Hosseini SH, Jamalkhani S, Sholzberg M, Monreal M, Jimenez D, Piazza G, Parikh SA, Kirtane AJ, Eikelboom JW, Connors JM, Hunt BJ, Konstantinides SV, Cushman M, Weitz JI, Stone GW, Krumholz HM, Lip GYH, Goldhaber SZ, Bikdeli B. Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19. J Am Coll Cardiol. 2021 Apr 20;77(15):1903-21. https://doi.org/10.1016/j.jacc.2021.02.035 PMid:33741176 PMCid:PMC7963001
  37. Musoke N, Lo KB, Albano J, Peterson E, Bhargav R, Gul F, DeJoy R, Salacup G, Pelayo J, Tipparaju P, Azmaiparashvili Z, Patarroyo-Aponte G, Rangaswami J. Anticoagulation and bleeding risk in patients with COVID-19. Thromb Res. 2020 Dec;196:227-30. https://doi.org/10.1016/j.thromres.2020.08.035 PMid:32916565 PMCid:PMC7444469
  38. Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol. 2008 Feb 15;167(4):492-9. https://doi.org/10.1093/aje/kwm324 PMid:18056625

Supplementary data
Table S1 Table S1. Examples of anticoagulant doses 


Table S2 Table S2. Bivariate analysis of the effects of patient characteristics on 6-week survival. 

[TOP]