Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study

  1. Christopher T Rentsch
  2. Joshua A Beckman
  3. Laurie Tomlinson
  4. Walid F Gellad
  5. Charles Alcorn
  6. Farah Kidwai-Khan
  7. Melissa Skanderson
  8. Evan Brittain
  9. Joseph T King
  10. Yuk-Lam Ho
  11. Svetlana Eden
  12. Suman Kundu
  13. Michael F Lann
  14. Robert A Greevy
  15. P Michael Ho
  16. Paul A Heidenreich
  17. Daniel A Jacobson
  18. Ian J Douglas
  19. Janet P Tate
  20. Stephen J W Evans
  21. David Atkins
  22. Amy C Justice
  23. Matthew S Freiberg

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Abstract

Objective

To evaluate whether early initiation of prophylactic anticoagulation compared with no anticoagulation was associated with decreased risk of death among patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United States.

Design

Observational cohort study.

Setting

Nationwide cohort of patients receiving care in the Department of Veterans Affairs, a large integrated national healthcare system.

Participants

All 4297 patients admitted to hospital from 1 March to 31 July 2020 with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without a history of anticoagulation.

Main outcome measures

The main outcome was 30 day mortality. Secondary outcomes were inpatient mortality, initiating therapeutic anticoagulation (a proxy for clinical deterioration, including thromboembolic events), and bleeding that required transfusion.

Results

Of 4297 patients admitted to hospital with covid-19, 3627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3600) of treated patients received subcutaneous heparin or enoxaparin. 622 deaths occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospital stay. Using inverse probability of treatment weighted analyses, the cumulative incidence of mortality at 30 days was 14.3% (95% confidence interval 13.1% to 15.5%) among those who received prophylactic anticoagulation and 18.7% (15.1% to 22.9%) among those who did not. Compared with patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30 day mortality (hazard ratio 0.73, 95% confidence interval 0.66 to 0.81). Similar associations were found for inpatient mortality and initiation of therapeutic anticoagulation. Receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion (hazard ratio 0.87, 0.71 to 1.05). Quantitative bias analysis showed that results were robust to unmeasured confounding (e-value lower 95% confidence interval 1.77 for 30 day mortality). Results persisted in several sensitivity analyses.

Conclusions

Early initiation of prophylactic anticoagulation compared with no anticoagulation among patients admitted to hospital with covid-19 was associated with a decreased risk of 30 day mortality and no increased risk of serious bleeding events. These findings provide strong real world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial treatment for patients with covid-19 on hospital admission.

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  1. Version published to 10.1136/bmj.n311
  2. ScreenIT

    SciScore for 10.1101/2020.12.09.20246579: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: Ethics: This study was approved by the institutional review boards of VA Connecticut Healthcare System and Yale University.
    Consent: It has been granted a waiver of informed consent and is Health Insurance Portability and Accountability Act compliant.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    We used Microsoft SQL Server Management Studio v17.4 for data management and SAS version 9.4 (SAS Institute, Cary, NC, US) and Stata 16 MP for statistical analyses.
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Strengths and limitations: While this study had many strengths, including the availability of detailed, longitudinal, electronic health record data on a nationwide cohort of patients hospitalized with COVID-19, rigorous methodology and findings that were robust to sensitivity analyses, we recognize possible limitations. First, due to the observational nature of the study, a degree of uncertainty persists that can only be addressed through randomized trials. Nonetheless, we took several steps to mitigate potential confounding. We comprehensively accounted for chronic and acute health conditions at hospital admission in addition to other potential COVID-19 treatments to achieve balance of these potential confounders between treatment groups. Further, we showed that our results were robust to unmeasured confounding using quantitative bias analysis, which demonstrated that a confounder would need to be strongly associated with receipt of prophylactic anticoagulation and each of the outcomes considered to explain the observed effects. Second, we did not have available a validated algorithm to identify thromboembolic events as an outcome. However, the use of therapeutic anticoagulation may occur as a result of many reported complications of COVID-19 including venous thromboembolism, arterial thromboembolism, cardiac arrhythmia, and disseminated intravascular coagulation.51–58 We surmised that an intensification of anticoagulation indicated an adverse change in clinical condition. T...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a protocol registration statement.

    About SciScore

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  3. Version published to 10.1101/2020.12.09.20246579v1 on medRxiv