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

BACKGROUND: Patients 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 inf...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10514402/
https://www.ncbi.nlm.nih.gov/pubmed/37745026
http://dx.doi.org/10.1016/j.eclinm.2023.102213
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author 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
author_facet 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
author_sort Nakafero, Georgina
collection PubMed
description BACKGROUND: Patients 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. METHODS: This 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. FINDINGS: Data 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 R(2) 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. INTERPRETATION: This 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. FUNDING: 10.13039/501100000272National Institute for Health and Care Research.
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spelling pubmed-105144022023-09-23 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 eClinicalMedicine Articles BACKGROUND: Patients 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. METHODS: This 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. FINDINGS: Data 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 R(2) 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. INTERPRETATION: This 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. FUNDING: 10.13039/501100000272National Institute for Health and Care Research. Elsevier 2023-09-14 /pmc/articles/PMC10514402/ /pubmed/37745026 http://dx.doi.org/10.1016/j.eclinm.2023.102213 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Articles
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
Risk-stratified monitoring for thiopurine toxicity in immune-mediated inflammatory diseases: prognostic model development, validation, and, health economic evaluation
title Risk-stratified monitoring for thiopurine toxicity in immune-mediated inflammatory diseases: prognostic model development, validation, and, health economic evaluation
title_full Risk-stratified monitoring for thiopurine toxicity in immune-mediated inflammatory diseases: prognostic model development, validation, and, health economic evaluation
title_fullStr Risk-stratified monitoring for thiopurine toxicity in immune-mediated inflammatory diseases: prognostic model development, validation, and, health economic evaluation
title_full_unstemmed Risk-stratified monitoring for thiopurine toxicity in immune-mediated inflammatory diseases: prognostic model development, validation, and, health economic evaluation
title_short Risk-stratified monitoring for thiopurine toxicity in immune-mediated inflammatory diseases: prognostic model development, validation, and, health economic evaluation
title_sort risk-stratified monitoring for thiopurine toxicity in immune-mediated inflammatory diseases: prognostic model development, validation, and, health economic evaluation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10514402/
https://www.ncbi.nlm.nih.gov/pubmed/37745026
http://dx.doi.org/10.1016/j.eclinm.2023.102213
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