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Risk-stratified monitoring for thiopurine toxicity in immune-mediated inflammatory diseases: prognostic model development, validation, and, health economic evaluation.

Nakafero, Georgina; Card, Tim; Grainge, Matthew J; Williams, Hywel C; Taal, Maarten W; Aithal, Guruprasad P; Fox, Christopher P; Mallen, Christian D; van der Windt, Danielle A; Stevenson, Matthew D; Riley, Richard D; Abhishek, Abhishek

Authors

Georgina Nakafero

Tim Card

Matthew J Grainge

Hywel C Williams

Maarten W Taal

Guruprasad P Aithal

Christopher P Fox

Matthew D Stevenson

Richard D Riley

Abhishek Abhishek



Abstract

BackgroundPatients established on thiopurines (e.g., azathioprine) are recommended to undergo three-monthly blood tests for the early detection of blood, liver, or kidney toxicity. These side-effects are uncommon during long-term treatment. We developed a prognostic model that could be used to inform risk-stratified decisions on frequency of monitoring blood-tests during long-term thiopurine treatment, and, performed health-economic evaluation of alternate monitoring intervals.MethodsThis was a retrospective cohort study set in the UK primary-care. Data from the Clinical Practice Research Datalink Aurum and Gold formed development and validation cohorts, respectively. People age ≥18 years, diagnosed with an immune mediated inflammatory disease, prescribed thiopurine by their general practitioner for at-least six-months between January 1, 2007 and December 31, 2019 were eligible. The outcome was thiopurine discontinuation with abnormal blood-test results. Patients were followed up from six-months after first primary-care thiopurine prescription to up to five-years. Penalised Cox regression developed the risk equation. Multiple imputation handled missing predictor data. Calibration and discrimination assessed model performance. A mathematical model evaluated costs and quality-adjusted life years associated with lengthening the interval between blood-tests.FindingsData from 5982 (405 events over 16,117 person-years) and 3573 (269 events over 9075 person-years) participants were included in the development and validation cohorts, respectively. Fourteen candidate predictors (21 parameters) were included. The optimism adjusted R2 and Royston D statistic in development data were 0.11 and 0.76, respectively. The calibration slope and Royston D statistic (95% Confidence Interval) in the validation data were 1.10 (0.84-1.36) and 0.72 (0.52-0.92), respectively. A 2-year period between monitoring blood-test was most cost-effective in all deciles of predicted risk but the gain between monitoring annually or biennially reduced in higher risk deciles.InterpretationThis prognostic model requires information that is readily available during routine clinical care and may be used to risk-stratify blood-test monitoring for thiopurine toxicity. These findings should be considered by specialist societies when recommending blood monitoring during thiopurine prescription to bring about sustainable and equitable change in clinical practice.FundingNational Institute for Health and Care Research.

Journal Article Type Article
Acceptance Date Oct 3, 2023
Online Publication Date Sep 14, 2023
Publication Date 2023-10
Deposit Date Oct 9, 2023
Publicly Available Date Oct 9, 2023
Journal EClinicalMedicine
Print ISSN 2589-5370
Electronic ISSN 2589-5370
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 64
Article Number 102213
DOI https://doi.org/10.1016/j.eclinm.2023.102213
Keywords Inflammatory Bowel Disease, Thiopurine, Drug Toxicity Prediction
PMID 37745026

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