Efficacy and Safety of Intensified Versus Standard Prophylactic Anticoagulation Therapy in Patients With Coronavirus Disease 2019: A Systematic Review and Meta-Analysis

  1. Nicola K Wills
  2. Nikhil Nair
  3. Kashyap Patel
  4. Omaike Sikder
  5. Marguerite Adriaanse
  6. John Eikelboom
  7. Sean Wasserman

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Abstract

Background

Randomized controlled trials (RCTs) have reported inconsistent effects from intensified anticoagulation on clinical outcomes in coronavirus disease 2019 (COVID-19). We performed an aggregate data meta-analysis from available trials to quantify effect on nonfatal and fatal outcomes and identify subgroups who may benefit.

Methods

We searched multiple databases for RCTs comparing intensified (intermediate or therapeutic dose) vs prophylactic anticoagulation in adults with laboratory-confirmed COVID-19 through 19 January 2022. We used random-effects meta-analysis to estimate pooled risk ratios for mortality, thrombotic, and bleeding events (at end of follow-up or discharge) and performed subgroup analysis for clinical setting and dose of intensified anticoagulation.

Results

Eleven RCTs were included (N = 5873). Intensified vs prophylactic anticoagulation was not associated with a mortality reduction up to 45 days (risk ratio [RR], 0.93 [95% confidence interval {CI}, .79–1.10]). There was a possible signal of mortality reduction for non–intensive care unit (ICU) patients, although with low precision and high heterogeneity (5 studies; RR, 0.84 [95% CI, .49–1.44]; I2 = 75%). Risk of venous thromboembolism was reduced (RR, 0.53 [95% CI, .41–.69]; I2 = 0%), with effect driven by therapeutic rather than intermediate dosing (interaction P = .04). Major bleeding was increased with intensified anticoagulation (RR, 1.73 [95% CI, 1.17–2.56]) with no interaction for dosing and clinical setting.

Conclusions

Intensified anticoagulation has no effect on mortality among hospitalized adults with COVID-19 and is associated with increased bleeding risk. The observed reduction in venous thromboembolism risk and trend toward reduced mortality in non-ICU settings requires exploration in additional RCTs.

Clinical Trials Registration. CRD42021273449 (PROSPERO).

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  1. Version published to 10.1093/ofid/ofac285
  2. ScreenIT

    SciScore for 10.1101/2022.03.05.22271947: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    RandomizationRisk of bias in individual studies was independently assessed by KP, MA and NW using version 2 of the Cochrane risk-of-bias tool for randomized trials (https://training.cochrane.org/handbook/current/chapter-08), with respect to the key outcome of interest (mortality).
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Search strategy: An electronic search was conducted on 19 September 2021 and repeated on 19 January 2022 using MEDLINE (PubMed), Scopus, the World Health Organization (WHO) COVID-19 database (https://search.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/), and the Cochrane Library.
    MEDLINE
    suggested: (MEDLINE, RRID:SCR_002185)
    Cochrane Library
    suggested: (Cochrane Library, RRID:SCR_013000)
    We also screened the WHO Trial Registry Network (https://trialsearch.who.int/) and ClinicalTrials.gov (https://clinicaltrials.gov/) for ongoing/recently completed trials, and PROSPERO (https://www.crd.york.ac.uk/PROSPERO/) for ongoing or recently completed systematic reviews.
    https://clinicaltrials.gov/
    suggested: (ClinicalTrials.gov, RRID:SCR_002309)
    Record management and data extraction: Records from the primary search were entered into Mendeley Reference Management Software Version 1.19.8 (https://www.mendeley.com/) and duplicates removed.
    https://www.mendeley.com/
    suggested: (Mendeley Data, RRID:SCR_002750)
    After consensus on studies meeting criteria for inclusion, variables of interest (supplementary Table S3) were extracted on a Microsoft Excel spreadsheet by NH and OS with independent verification by MA and NW.
    Microsoft Excel
    suggested: (Microsoft Excel, RRID:SCR_016137)
    Risk of bias in individual studies was independently assessed by KP, MA and NW using version 2 of the Cochrane risk-of-bias tool for randomized trials (https://training.cochrane.org/handbook/current/chapter-08), with respect to the key outcome of interest (mortality).
    Cochrane
    suggested: (Cochrane Library, RRID:SCR_013000)

    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:
    This review has several limitations. First, we analysed trial-level data, limiting the extent to which we could explore differences in subgroups by important baseline prognostic variables such as age, comorbidity, and markers of disease severity and inflammation. Second, although we performed subgroup analysis by clinical setting (as a surrogate for disease severity), criteria for severe disease and ICU eligibility were institution and study-specific, limiting generalisability. This may have contributed to the extreme heterogeneity (I2 = 75%) observed among non-ICU-based studies in the risk ratios for mortality. Third, the relatively small number of events limited precision of effect estimates, especially for the non-critically ill subgroup where there was possibly a signal for reduced mortality. We were not able to analyse effect of intensified anticoagulation on need for, and duration of, organ support since these outcomes were not consistently reported. Fourth, we identified 2 studies to be at high risk of bias and with some concerns, chiefly with regards trials using non-objective methods in defining and detecting thrombosis events. This serves to emphasise the limitation using of thrombotic events as an outcome in anticoagulation trials. Fifth, asymmetry in the funnel plots indicates possibility of publication bias, but the small number of included trials limits accuracy. Finally, although sensitivity analysis showed no effect modification on the primary outcome with omi...

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

    IdentifierStatusTitle
    NCT04483960RecruitingAustralasian COVID-19 Trial (ASCOT) ADAptive Platform Trial
    NCT04730856RecruitingStandard vs High Prophylactic Doses or Anticoagulation in Pa…
    NCT04427098RecruitingEnoxaparin in COVID-19 Moderate to Severe Hospitalized Patie…
    NCT04640181CompletedFactor Xa Inhibitor Versus Standard of Care Heparin in Hospi…
    NCT04324463RecruitingAnti-Coronavirus Therapies to Prevent Progression of Coronav…
    NCT04512079RecruitingFREEDOM COVID-19 Anticoagulation Strategy

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2022.03.05.22271947 on medRxiv