Model-based assessment of the benefits and risks of recombinant tissue plasminogen activator treatment in acute ischaemic stroke

Jinju Guk, Dongwoo Chae, Hankil Son, Joonsang Yoo, Jihoe Heo, Kyungsoo Park

Research output: Contribution to journalArticle

Abstract

Aims: Recombinant tissue plasminogen activator (rt-PA) is the only first-line agent approved by the US Food and Drug Administration to treat acute ischaemic stroke. However, it often causes the serious adverse event (AE) of haemorrhagic transformation. The present study developed a pharmacometric model for the rt-PA treatment effect and AE and, using the developed model, proposed a benefit-to-risk ratio assessment scheme as a supportive tool to optimize treatment outcome. Methods: The data from 336 acute ischaemic stroke patients were used. The treatment effect was assessed based on an improvement in National Institutes of Health Stroke Scale (NIHSS) scores, which were described using an item response theory (IRT)-based disease progression model. Treatment failure and AE probabilities, and their occurrence times, were described by incidence and time-to-event models. Using the developed model, benefit-to-risk ratios were simulated under various scenarios using the global benefit-to-risk trade-off ratio (GBR). Results: High initial NIHSS score and middle cerebral artery (MCA) stroke were risk factors for treatment failure, where the failure rate with MCA stroke was 2.87-fold higher than with non-MCA stroke. The haemorrhagic transformation time was associated with longitudinal changes in NIHSS scores. The benefit-to-risk ratio simulated was highest in minor stroke severity, with GBR >1 in all scenarios, and the ratio with non-MCA stroke was 2–3 fold higher than with MCA stroke. Conclusions: The study demonstrated the feasibility of applying an IRT model to describing the time course of the rt-PA treatment effect and AE. Benefit-to-risk ratio analyses showed that the treatment was optimal in non-MCA stroke with minor stroke severity.

Original languageEnglish
Pages (from-to)2586-2599
Number of pages14
JournalBritish Journal of Clinical Pharmacology
Volume84
Issue number11
DOIs
Publication statusPublished - 2018 Nov 1

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Tissue Plasminogen Activator
Stroke
Odds Ratio
Cerebral Arteries
Middle Cerebral Artery Infarction
National Institutes of Health (U.S.)
Therapeutics
Treatment Failure
Feasibility Studies
United States Food and Drug Administration
Disease Progression
Incidence

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Guk, Jinju ; Chae, Dongwoo ; Son, Hankil ; Yoo, Joonsang ; Heo, Jihoe ; Park, Kyungsoo. / Model-based assessment of the benefits and risks of recombinant tissue plasminogen activator treatment in acute ischaemic stroke. In: British Journal of Clinical Pharmacology. 2018 ; Vol. 84, No. 11. pp. 2586-2599.
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abstract = "Aims: Recombinant tissue plasminogen activator (rt-PA) is the only first-line agent approved by the US Food and Drug Administration to treat acute ischaemic stroke. However, it often causes the serious adverse event (AE) of haemorrhagic transformation. The present study developed a pharmacometric model for the rt-PA treatment effect and AE and, using the developed model, proposed a benefit-to-risk ratio assessment scheme as a supportive tool to optimize treatment outcome. Methods: The data from 336 acute ischaemic stroke patients were used. The treatment effect was assessed based on an improvement in National Institutes of Health Stroke Scale (NIHSS) scores, which were described using an item response theory (IRT)-based disease progression model. Treatment failure and AE probabilities, and their occurrence times, were described by incidence and time-to-event models. Using the developed model, benefit-to-risk ratios were simulated under various scenarios using the global benefit-to-risk trade-off ratio (GBR). Results: High initial NIHSS score and middle cerebral artery (MCA) stroke were risk factors for treatment failure, where the failure rate with MCA stroke was 2.87-fold higher than with non-MCA stroke. The haemorrhagic transformation time was associated with longitudinal changes in NIHSS scores. The benefit-to-risk ratio simulated was highest in minor stroke severity, with GBR >1 in all scenarios, and the ratio with non-MCA stroke was 2–3 fold higher than with MCA stroke. Conclusions: The study demonstrated the feasibility of applying an IRT model to describing the time course of the rt-PA treatment effect and AE. Benefit-to-risk ratio analyses showed that the treatment was optimal in non-MCA stroke with minor stroke severity.",
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Model-based assessment of the benefits and risks of recombinant tissue plasminogen activator treatment in acute ischaemic stroke. / Guk, Jinju; Chae, Dongwoo; Son, Hankil; Yoo, Joonsang; Heo, Jihoe; Park, Kyungsoo.

In: British Journal of Clinical Pharmacology, Vol. 84, No. 11, 01.11.2018, p. 2586-2599.

Research output: Contribution to journalArticle

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T1 - Model-based assessment of the benefits and risks of recombinant tissue plasminogen activator treatment in acute ischaemic stroke

AU - Guk, Jinju

AU - Chae, Dongwoo

AU - Son, Hankil

AU - Yoo, Joonsang

AU - Heo, Jihoe

AU - Park, Kyungsoo

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Y1 - 2018/11/1

N2 - Aims: Recombinant tissue plasminogen activator (rt-PA) is the only first-line agent approved by the US Food and Drug Administration to treat acute ischaemic stroke. However, it often causes the serious adverse event (AE) of haemorrhagic transformation. The present study developed a pharmacometric model for the rt-PA treatment effect and AE and, using the developed model, proposed a benefit-to-risk ratio assessment scheme as a supportive tool to optimize treatment outcome. Methods: The data from 336 acute ischaemic stroke patients were used. The treatment effect was assessed based on an improvement in National Institutes of Health Stroke Scale (NIHSS) scores, which were described using an item response theory (IRT)-based disease progression model. Treatment failure and AE probabilities, and their occurrence times, were described by incidence and time-to-event models. Using the developed model, benefit-to-risk ratios were simulated under various scenarios using the global benefit-to-risk trade-off ratio (GBR). Results: High initial NIHSS score and middle cerebral artery (MCA) stroke were risk factors for treatment failure, where the failure rate with MCA stroke was 2.87-fold higher than with non-MCA stroke. The haemorrhagic transformation time was associated with longitudinal changes in NIHSS scores. The benefit-to-risk ratio simulated was highest in minor stroke severity, with GBR >1 in all scenarios, and the ratio with non-MCA stroke was 2–3 fold higher than with MCA stroke. Conclusions: The study demonstrated the feasibility of applying an IRT model to describing the time course of the rt-PA treatment effect and AE. Benefit-to-risk ratio analyses showed that the treatment was optimal in non-MCA stroke with minor stroke severity.

AB - Aims: Recombinant tissue plasminogen activator (rt-PA) is the only first-line agent approved by the US Food and Drug Administration to treat acute ischaemic stroke. However, it often causes the serious adverse event (AE) of haemorrhagic transformation. The present study developed a pharmacometric model for the rt-PA treatment effect and AE and, using the developed model, proposed a benefit-to-risk ratio assessment scheme as a supportive tool to optimize treatment outcome. Methods: The data from 336 acute ischaemic stroke patients were used. The treatment effect was assessed based on an improvement in National Institutes of Health Stroke Scale (NIHSS) scores, which were described using an item response theory (IRT)-based disease progression model. Treatment failure and AE probabilities, and their occurrence times, were described by incidence and time-to-event models. Using the developed model, benefit-to-risk ratios were simulated under various scenarios using the global benefit-to-risk trade-off ratio (GBR). Results: High initial NIHSS score and middle cerebral artery (MCA) stroke were risk factors for treatment failure, where the failure rate with MCA stroke was 2.87-fold higher than with non-MCA stroke. The haemorrhagic transformation time was associated with longitudinal changes in NIHSS scores. The benefit-to-risk ratio simulated was highest in minor stroke severity, with GBR >1 in all scenarios, and the ratio with non-MCA stroke was 2–3 fold higher than with MCA stroke. Conclusions: The study demonstrated the feasibility of applying an IRT model to describing the time course of the rt-PA treatment effect and AE. Benefit-to-risk ratio analyses showed that the treatment was optimal in non-MCA stroke with minor stroke severity.

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