Abstract
Intracerebral hemorrhage (ICH) is a form of stroke characterized by uncontrolled bleeding into the parenchyma of the brain. There is no approved therapy for ICH and it is associated with very poor neurological outcomes with around half of subjects dying within 1 month and most subjects showing complete or partial disability. A key challenge is to identify subjects who could benefit from intervention using characteristics such as baseline hemorrhage volume and the increase in hemorrhage volume in the first few hours, which have been correlated with final outcomes in ICH. Combined longitudinal models were developed to describe stroke scales using categorical data (Modified Rankin Scale, mRS), continuous bounded data (National Institutes of Health Stroke Scale, NIHSS), and time to death. Covariate effects for baseline hematoma volume and maximum increase in hematoma volume were incorporated to assess the improvement in outcome when hematoma volume increase would be reduced by a potential treatment. The combined model provided an adequate description of stroke scales, with patients split into a Non-survival and a High-survival sub-population, and dropout due to death was well described by a constant hazard survival model. Models were compared indicating that the combined mRS/NIHSS model provided the most information, followed by the NIHSS-only model, and the mRS-only model, and finally the traditional statistical analysis on dichotomized response at 90 days. Simulations showed that substantial reductions in hematoma volume increase were required to increase the probability of a favorable outcome.
Similar content being viewed by others
References
Broderick J et al (2007) Guidelines for the management of spontaneous intracerebral hemorrhage in adults 2007 update. Stroke 38:2001–2023
Mozaffarian D et al (2015) Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 131:e29–e322
Mayer SA et al (2008) Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 358:2127–2137
http://www.virtualtrialsarchive.org/vista-ich/. Accessed 17 July 2018
Lynden P (2017) Using the National Institutes of Health Stroke Scale, A Cautionary tale. Stroke 48:513–519
https://stroke.nih.gov/documents/NIH_Stroke_Scale.pdf. Accessed 17 July 2018
Banks JL, Marotta CA (2007) Outcomes validity and reliability of the modified rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke 38:1091–1096
mRS. http://rankinscale.org/. Accessed 25 May 2016
Sheiner LB (1994) A new approach to the analysis of analgesic drug trials, illustrated with bromfenac data. Clin Pharmacol Ther 56:309–322
Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ (Eds) (1989–2011) NONMEM users guides. Icon Development Solutions, Ellicott City
Lindbom L, Pihlgren P, Jonsson EN (2005) PsN-toolkit—a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Progr Biomed 79:241–257
R Development Core Team (2015) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna
Karlsson MO, Holford N (2008) A tutorial on visual predictive checks. PAGE 17:1434
Ueckert S, Karlsson MO, Hooker AC (2016) Accelerating Monte-Carlo power studies through parametric power estimation. J Pharmacokinet Pharmacodyn 43:223–234
Bruno A et al (2011) Simplified modified rankin scale questionnaire. Reproducibility over the telephone and validation with quality of life. Stroke 42:2276–2279
Savio K et al (2013) Reliability of the modified Rankin Scale applied by telephone. Neurol Int 5:e2
Acknowledgements
The authors would like to thank Bill Denney for his valuable input in early stages of model development. VISTA-ICH Steering Committee: Daniel F. Hanley (Chair), Kenneth S. Butcher, Stephen Davis, Barbara Gregson, Kennedy R. Lees, Patrick Lyden, Stephan Mayer, Keith Muir and Thorsten Steiner.
Author information
Authors and Affiliations
Consortia
Contributions
RS, SN, LH, and MOK wrote the manuscript; RS modelled the data.
Corresponding author
Ethics declarations
Conflict of interest
At the time this manuscript was submitted for publication, L.H. and S.N were full-time employees of Pfizer Ltd, and R.S and M.O.K. were paid consultants for Pfizer Ltd.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The VISTA-ICH Steering Committee are listed in “Acknowledgements”.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Schoemaker, R., Nayak, S., Harnisch, L.O. et al. Modeling and simulation of the modified Rankin Scale and National Institutes of Health Stroke Scale neurological endpoints in intracerebral hemorrhage. J Pharmacokinet Pharmacodyn 46, 473–484 (2019). https://doi.org/10.1007/s10928-019-09653-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10928-019-09653-4