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JAK inhibitors and risk of major cardiovascular events or venous thromboembolism: a self-controlled case series study

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Abstract

Purpose

JAK-inhibitors (JAK-i) might be associated with venous (VTE) and arterial thromboembolic events (ATE). To evaluate the association between JAK-i and the risk of VTE and ATE.

Methods

A self-controlled case series was performed using data from the nationwide French healthcare insurance system database SNDS. We included all patients treated with JAK-i (baricitinib or tofacitinib), and having presented at least one VTE or ATE between November 1, 2017 and June 30, 2019. Associations were estimated using the incident rate ratio (IRR). Two post-exposure periods (until day 30 and until day 60) were individualized.

Results

Among 5870 patients with JAK-i dispensing, 92 had an incident VTE or ATE within the study period. Their median age at JAK-i initiation was 65.7 years [IQR: 56.1–75.8] and 65.2% were female (n = 60). Before event incidence, 65.2% (n = 60) received baricitinib, 32.6% (n = 30) tofacitinib and 2.2% (n = 2) had both medications. Moreover, 41.3% (n = 38) presented a VTE and 58.7% (n = 54) an ATE. The median time-to-onset after JAK-i initiation was 4.6 months [IQR: 2.5–9.2] for VTE and 6.1 months [IQR: 3.0–8.5] for ATE. An IRR of 8.27 (95% CI 3.41–20.04) for VTE was detected during JAK-i treatment and remained increased over the 30-day period of post-exposure (6.52 [2.02–21.11]). An IRR of 9.27 (3.68–23.34) was also found for ATE, which remained increased over the 30-day period of post-exposure (10.12 [3.27–31.37]). No increased risk was detected during long-term post-exposure for either VTE or ATE.

Conclusions

This study shows evidence of an increased risk of VTE and ATE associated with the use of baricitinib and tofacitinib.

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Data availability

The data that support the findings of this study are not publicly available due to restrictions. No additional data is available by the author (French law to access SNDS https://www.snds.gouv.fr).

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Acknowledgements

The authors would like to thank the UMC, which provided and gave permission to use the data analyzed in the present study. The authors are indebted to the National Pharmacovigilance Centers that contributed data. The opinions and conclusions in this study are not necessarily those of the various centers or of the WHO.

Author information

Authors and Affiliations

  1. Team Pharmacoepidemiology, Univ. Bordeaux, INSERM, CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie Médicale, U1219F-33000, Bordeaux, BPH, France

    Amandine Gouverneur & Antoine Pariente

  2. Service de Rhumatologie, Université de Paris, Hôpital Cochin, AP-HP.CUP, Paris, France

    Jérôme Avouac

  3. University Hospital, CHU Minjoz, Rheumatology Unit, Besancon, France

    Clément Prati

  4. Université Grenoble Alpes, INSERM, HP238000, Grenoble, France

    Jean-Luc Cracowski

  5. Department of Rheumatology, National Reference Center for Systemic Autoimmune Rare Diseases, Hopital Pellegrin, Bordeaux, France

    Thierry Schaeverbeke & Marie-Elise Truchetet

  6. Department of Rheumatology, UMR5164 ImmunoConcept, Bordeaux University, Bordeaux University Hospital, CNRS, Raba Leon, Place Amelie, 33076, Bordeaux Cedex, France

    Marie-Elise Truchetet

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  1. Amandine Gouverneur
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Contributions

Amandine Gouverneur, Thierry Schaeverbeke, Antoine Pariente, and Marie-Elise Truchetet had the idea for the study. Amandine Gouverneur, Thierry Schaeverbeke, Antoine Pariente and Marie-Elise Truchetet conceived and planned the study. Amandine Gouverneur performed statistical analyses. Amandine Gouverneur, Antoine Pariente, Thierry Schaeverbeke, and Marie-Elise Truchetet ensured project and study management. All authors (Amandine Gouverneur, Jérôme Avouac, Clément Prati, Jean-Luc Cracowski, Thierry Schaeverbeke, Antoine Pariente, and Marie-Elise Truchetet) contributed to the interpretation of the data and revised the manuscript. Amandine Gouverneur and Marie-Elise Truchetet drafted the manuscript. All authors approved the final manuscript. The corresponding author (Marie-Elise Truchetet) attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Marie-Elise Truchetet is the guarantor.

Corresponding author

Correspondence to Marie-Elise Truchetet.

Ethics declarations

Ethics approval

The study protocol was approved by the Comité d’expertise pour les recherches, les études et les évaluations dans le domaine de la santé (CERESS) and the Commission Nationale de l’Informatique et des Libertés (CNIL).

Informed consent

No informed consent was needed for the use of this anonymized healthcare database or anonymized pharmacovigilance database.

Competing interests

All authors have completed the ICMJE uniform disclosure form at https://ww.icmje.org/coi_disclosure.pdf and declare: Amandine Gouverneur, Clément Prati, and Jean-Luc Cracowski no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work; no support from any organization for the submitted work; Antoine Pariente reports acting as an independent expert towards the French Medicines Agency (Agence Nationale de Securité du Médicament et des Produits de Santé, ANSM) and the European Medicines Agency (EMA). Antoine Pariente coordinates the DRUGS Systematized Assessment in real-liFe EnviRonment (DRUGS-SAFER) program funded by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM); Jérôme Avouac has/had consultancy relationship and/or research funding in the area of potential treatments for rheumatoid arthritis from (last three years): Abbvie, Galapagos, Pfizer, Bristol Myers Squibb, Sanofi, Nordic Pharma, Chugai, and MSD; Thierry Schaeverbeke has/had consultancy and/or research fundings: Abbvie, Lilly, Pfizer, Galapagos, Novartis, BMS, Medac, NordicPharma, Biogen, Mylan, Janssen; Marie-Elise Truchetet has/had consultancy relationship and/or research funding in the area of potential treatments for rheumatoid arthritis and spondyloarthritis and their complications from (last three years): Abbvie, Galapagos, Lilly, Medac, Novartis, Pfizer, and Roche; no other relationships or activities that could appear to have influenced the submitted work.

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Gouverneur, A., Avouac, J., Prati, C. et al. JAK inhibitors and risk of major cardiovascular events or venous thromboembolism: a self-controlled case series study. Eur J Clin Pharmacol 78, 1981–1990 (2022). https://doi.org/10.1007/s00228-022-03402-2

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