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Sex differences in thromboprophylaxis of the critically ill: a secondary analysis of a randomized trial

Différences entre les sexes en matière de thomboprophylaxie chez les patients en état critique : analyse secondaire d’un essai randomisé

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Abstract

Purpose

Venous thromboembolism (VTE) is a common complication of critical illness. Sex- or gender-based analyses are rarely conducted and their effect on outcomes is unknown. We assessed for an effect modification of thromboprophylaxis (dalteparin or unfractionated heparin [UFH]) by sex on thrombotic (deep venous thrombosis [DVT], pulmonary embolism [PE], VTE) and mortality outcomes in a secondary analysis of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT).

Methods

We conducted unadjusted analyses using Cox proportional hazards analysis, stratified by centre and admission diagnostic category, including sex, treatment, and an interaction term. Additionally, we performed adjusted analyses and assessed the credibility of our findings.

Results

Critically ill female (n = 1,614) and male (n = 2,113) participants experienced similar rates of DVT, proximal DVT, PE, any VTE, ICU death, and hospital death. In unadjusted analyses, we did not find significant differences in treatment effect favouring males (vs females) treated with dalteparin (vs UFH) for proximal leg DVT, any DVT, or any PE, but found a statistically significant effect (moderate certainty) favouring dalteparin in males for any VTE (males: hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52 to 0.96 vs females: HR, 1.16; 95% CI, 0.81 to 1.68; P = 0.04). This effect remained after adjustment for baseline characteristics (males: HR, 0.70; 95% CI, 0.52 to 0.96 vs females: HR, 1.17; 95% CI, 0.81 to 1.68; P = 0.04) and weight (males: HR, 0.70; 95% CI, 0.52 to 0.96 vs females: HR, 1.20; 95% CI, 0.83 to 1.73; P = 0.03). We did not identify a significant effect modification by sex on mortality.

Conclusions

We found an effect modification by sex of thromboprophylaxis on VTE in critically ill patients that requires confirmation. Our findings highlight the need for sex- and gender-based analyses in acute care research.

Résumé

Objectif

La maladie thromboembolique veineuse (MTEV) est une complication fréquente au cours des maladies critiques. Des analyses basées sur le sexe ou le genre sont rarement effectuées et leur effet sur les critères d’évaluation est inconnu. Nous avons évalué une modification de l’effet de la thromboprophylaxie (daltéparine ou héparine non fractionnée [HNF]) selon le sexe sur la maladie thrombotique (thrombose veineuse profonde [TVP], embolie pulmonaire [EP], MTEV) et sur les critères de mortalité au cours d’une analyse secondaire de l’étude PROTECT (essai de prophylaxie de la thromboembolie en soins critiques).

Méthode

Nous avons réalisé des analyses non ajustées au moyen d’une analyse des risques proportionnels de Cox, stratifiées par site et catégorie diagnostique à l’admission, incluant le sexe, le traitement et un terme d’interaction. Nous avons aussi réalisé des analyses ajustées et avons évalué la crédibilité de nos constatations.

Résultats

Les participant·es dans un état critique de sexe féminin (n = 1 614) et masculin (n = 2 113) ont présenté des taux semblables de TVP, EP, et MTEV de tout type, de décès en soins intensifs et de décès en milieu hospitalier. Nous n’avons pas trouvé de différences significatives dans les analyses non ajustées en faveur des hommes (par rapport aux femmes) traités par la daltéparine (par rapport à l’HNF) pour la TVP de la cuisse, la TVP de tout type, ou tout type d’EP; en revanche, nous avons trouvé un effet statistiquement significatif (certitude modérée) en faveur de la daltéparine pour la MTEV de tout type (hommes : rapport de risque [RR], 0,71; intervalle de confiance [IC] à 95 %, 0,52 à 0,96 par rapport aux femmes : RR, 1,16; IC 95 %, 0,81 à 1,68; P = 0,04). Cet effet a persisté après ajustement pour les caractéristiques à l’inclusion (hommes : RR, 0,70; IC 95 %, 0,52 à 0,96 par rapport aux femmes : RR, 1,17; IC 95 %, 0,81 à 1,68; P = 0,04) et le poids (hommes : RR, 0,70; IC 95 %, 0,52 à 0,96 par rapport aux femmes : RR, 1,20; IC 95 %, 0,83 à 1,73; P = 0,03). Nous n’avons pas identifié de modification significative de l’effet en fonction du sexe sur la mortalité.

Conclusion

Nous avons trouvé une modification de l’effet en fonction du sexe sur la thromboprophylaxie sur la MTEV chez les patient·es en état critique; cette constatation nécessite une confirmation. Nos constatations soulignent le besoin d’analyses en fonction du sexe et du genre dans la recherche sur les soins aigus.

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Author contributions

Karen E. A. Burns, Diane Heels-Ansdell, and Deborah J. Cook contributed to study design. Diane Heels-Ansdell and Lehana Thabane contributed to data analysis and presentation. All authors contributed to data interpretation and manuscript preparation.

Acknowledgements

We would like to thank the patient and families who provided consent to participate in PROTECT. In addition, we would like to thank Dr. Aimee J. Sarti for her review of our manuscript for the Grants and Manuscripts Committee of the Canadian Critical Care Trials Group. We also wish to acknowledge the investigators and research coordinators around the world who participated in this trial. PROTECT was supported by the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group. The list of PROTECT collaborators is provided in the Data Online Supplement to the original trial report (2).

Disclosures

Mark A. Crowther declares that in the last 24 months he has provided educational materials and/or presented on behalf Bayer, Pfizer, and CSL Behring, and he has served in an advisory capacity to Hemostasis Reference Laboratories and Syneos Health. The other authors declare that they have no financial or nonfinancial conflicts of interest to declare.

Funding statement

This study was not funded. The original PROTECT trial was funded by the Canadian Institutes of Health Research and the Australian and New Zealand College of Anesthetists Research Foundation. Prophylactic dalteparin was provided by Pfizer Inc. and Esai Co., Ltd. None of these agencies played a role in the design, conduct, analysis, interpretation, or write-up of the original trial or this study. K. Burns was supported in this work by the Physician Services Incorporated of Ontario Mid-Career Research Award. D. Cook and S. Kahn were supported by Tier-1 Research Chairs from the Canadian Institutes of Health Research. M. Crowther was supported by the Leo Chair in Thrombosis of McMaster University. S. Kahn is an investigator of the CanVECTOR Network, which holds grant funding from the Canadian Institutes of Health Research (Funding Reference: CDT142654) and from the Fonds de recherche du Québec – Santé (File # 309911).

Data availability statement

The data will be made available upon written request to Drs Cook and Burns.

Editorial responsibility

This submission was handled by Dr. Stephan K. W. Schwarz, Editor-in-Chief, Canadian Journal of Anesthesia/ Journal canadien d’anesthésie.

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Authors and Affiliations

  1. Interdepartmental Division of Critical Care, Department of Medicine, University of Toronto, Toronto, ON, Canada

    Karen E. A. Burns MD, FRCPC, MSc & Sangeeta Mehta MD

  2. Li Ka Shing Knowledge Institute, Unity Health Toronto–St. Michael’s Hospital, 30 Bond Street, 4-045 Donnelly Wing, Toronto, ON, M5B 1W8, Canada

    Karen E. A. Burns MD, FRCPC, MSc

  3. Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada

    Karen E. A. Burns MD, FRCPC, MSc, Diane Heels-Ansdell MSc, Lehana Thabane PhD & Deborah J. Cook MD

  4. St. Joseph’s Healthcare Hamilton, McMaster University, Hamilton, ON, Canada

    Lehana Thabane PhD, Mark A. Crowther MD & Deborah J. Cook MD

  5. Department of Medicine, McGill University, Montreal, QC, Canada

    Susan R. Kahn MD

  6. Research Center of the CHU de Québec-Université Laval, Population Health and Optimal Practices Research Unit (Trauma-Emergency-Critical Care Medicine), Quebec City, QC, Canada

    Francois Lauzier MD

  7. Mount Sinai Hospital, Toronto, ON, Canada

    Sangeeta Mehta MD

  8. Department of Critical Care and Nephrology, King’s College London, Guy’s and St Thomas’ Hospital, London, UK

    Marlies Ostermann MD, PhD, FRCP

  9. Department of Pharmacy, Unity Health Toronto–St. Michael’s Hospital, Toronto, ON, Canada

    Pulkit Bhuptani PharmD

  10. Department of Medicine, McMaster University, Hamilton, ON, Canada

    Mark A. Crowther MD & Deborah J. Cook MD

  11. Clinical Trials Unit, The George Institute, Sydney, NSW, Australia

    Simon Finfer MD

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Burns, K.E.A., Heels-Ansdell, D., Thabane, L. et al. Sex differences in thromboprophylaxis of the critically ill: a secondary analysis of a randomized trial. Can J Anesth/J Can Anesth 70, 1008–1018 (2023). https://doi.org/10.1007/s12630-023-02457-8

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