Therapeutic Anticoagulation in Non-Critically Ill Patients with Covid-19

  1. The ATTACC, ACTIV-4a, and REMAP-CAP Investigators
  2. Patrick R. Lawler
  3. Ewan C. Goligher
  4. Jeffrey S. Berger
  5. Matthew D. Neal
  6. Bryan J. McVerry
  7. Jose C. Nicolau
  8. Michelle N. Gong
  9. Marc Carrier
  10. Robert S. Rosenson
  11. Harmony R. Reynolds
  12. Alexis F. Turgeon
  13. Jorge Escobedo
  14. David T. Huang
  15. Charlotte Ann Bradbury
  16. Brett L. Houston
  17. Lucy Z. Kornblith
  18. Anand Kumar
  19. Susan R. Kahn
  20. Mary Cushman
  21. Zoe McQuilten
  22. Arthur S. Slutsky
  23. Keri S. Kim
  24. Anthony C. Gordon
  25. Bridget-Anne Kirwan
  26. Maria M. Brooks
  27. Alisa M. Higgins
  28. Roger J. Lewis
  29. Elizabeth Lorenzi
  30. Scott M. Berry
  31. Lindsay R. Berry
  32. Derek C. Angus
  33. Colin J. McArthur
  34. Steven A. Webb
  35. Michael E. Farkouh
  36. Judith S. Hochman
  37. Ryan Zarychanski

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Abstract

Background

Thrombo-inflammation may contribute to morbidity and mortality in Covid-19. We hypothesized that therapeutic-dose anticoagulation may improve outcomes in non-critically ill patients hospitalized for Covid-19.

Methods

In an open-label adaptive multiplatform randomized controlled trial, non-critically ill patients hospitalized for Covid-19, defined by the absence of critical care-level organ support at enrollment, were randomized to a pragmatic strategy of therapeutic-dose anticoagulation with heparin or usual care pharmacological thromboprophylaxis. The primary outcome combined survival to hospital discharge and days free of organ support through 21 days, which was evaluated with Bayesian statistical models according to baseline D-dimer.

Results

The trial was stopped when prespecified criteria for superiority were met for therapeutic-dose anticoagulation in groups defined by high (≥2-fold elevated) and low (<2-fold elevated) D-dimer. Among 2219 participants in the final analysis, the probability that therapeutic anticoagulation increased organ support-free days compared to thromboprophylaxis was 99.0% (adjusted odds ratio 1.29, 95% credible interval 1.04 to 1.61). The adjusted absolute increase in survival to hospital discharge without organ support with therapeutic-dose anticoagulation was 4.6% (95% credible interval 0.7 to 8.1). In the primary adaptive stopping groups, the final probabilities of superiority for therapeutic anticoagulation were 97.3% in the high D-dimer group and 92.9% in the low D-dimer group. Major bleeding occurred in 1.9% and 0.9% of participants randomized to therapeutic anticoagulation and thromboprophylaxis, respectively.

Conclusions

In non-critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increases the probability of survival to hospital discharge with reduced use of organ support.

Trial registration numbers: NCT02735707 , NCT04505774 , NCT04359277 , NCT04372589

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  1. ScreenIT

    SciScore for 10.1101/2021.05.13.21256846: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: 16 The trial was approved by relevant ethics committees and conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.
    Consent: Written or verbal informed consent, in accordance with regional regulations, was obtained from all participants or their surrogates.
    Sex as a biological variablenot detected.
    RandomizationTrial Design and Oversight: To accelerate evidence generation, three adaptive randomized controlled trial protocols evaluating therapeutic-dose anticoagulation with heparin in patients hospitalized for Covid-19 were integrated into a single mpRCT.
    BlindingThe ATTACC and REMAP-CAP designs specified the possibility for response-adaptive randomization, whereby blinded randomization allocation ratios could be modified during the trial based on adaptive analyses to favor allocation of participants to the treatment arm demonstrating greater benefit.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    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:
    Although the open-label design of the mpRCT represents a potential limitation, the primary outcome involving survival and receipt of organ support was selected to minimize bias and to function across a spectrum of illness severity. The potential for ascertainment bias cannot be excluded for the secondary outcomes of major bleeding or thrombosis. This, along with the absence of protocolized screening for venous thrombosis, exclusion of patients at increased bleeding risk, and changing disease epidemiology over time may have contributed to lower thrombotic event rates than have been previously reported.35 The treatment effect was attenuated in the final analysis relative to the adaptive stopping results; nevertheless, a high probability of benefit persisted in all D-dimer groups. In conclusion, in hospitalized, non-critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin improves organ support-free days. Therapeutic-dose anticoagulation increases the probability of survival to hospital discharge with reduced use of critical care-level organ support.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT02735707RecruitingRandomized, Embedded, Multifactorial Adaptive Platform Trial…
    NCT04505774RecruitingAnti-thrombotics for Adults Hospitalized With COVID-19 (ACTI…
    NCT04359277TerminatedA Randomized Trial of Anticoagulation Strategies in COVID-19
    NCT04372589Active, not recruitingAntithrombotic Therapy to Ameliorate Complications of COVID-…

    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.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2021.05.13.21256846v1 on medRxiv