WSO - April 2024 - 420

420
International Journal of Stroke 19(4)
among the non-impaired (for global PSCI), protective
effect was evident within 170 days. One possible explanation
for this finding is pioglitazone dosing fluctuations during
follow-up. Medication adherence taking ⩾ 80% of
maximum dose as stipulated by protocol decreased from
61% to 55% from first to the second, and to 52% on the
third year.5 It is possible that higher doses of pioglitazone
were more protective for non-impaired patients while PSCI
required lower doses. It is also possible that non-impaired
patients benefited from higher doses in earlier phases due
to improved blood glucose metabolism, while patients with
memory and global PSCI required longer periods of time. It
may also be possible that this finding, while statistically
significant in our study, may be due to chance.
Since IR is associated with a systemic inflammatory
state increasing risk of both stroke and dementia,16,17 one
may argue that the observed pioglitazone treatment effect
modification by PSCI is related to IR. However, given that
our final model (Model 4) was adjusted for the HOMA-IR
index, it is likely that reported association was independent
of IR severity and likely was associated with vascular
pathology and inflammation.
Pioglitazone treatment effect modification by PSCI was
observed not only for recurrent stroke but also for MI prevention.
Interestingly, as opposed to the recurrent stroke endpoint,
there was no evidence of violations of the proportional
hazards assumption in models for time to MI. One possible
explanation for this finding is the fact that MI is secondary to
single etiology-coronary artery disease, while etiology of
recurrent stroke is multifactorial (including large artery atherosclerosis,
small vessel disease, cardioembolic, other etiologies,
and cryptogenic). Although we adjusted for baseline
stroke etiology (TOAST), no data were available on recurrent
stroke etiology. Therefore, it is possible that the observed
time dependency of pioglitazone effect modification by
PSCI is related to recurrent stroke etiology.
The strengths of the study include its relatively large
sample size with high-quality outcome ascertainment.
However, this study has some limitations. One limitation of
the study is the type of cognitive test used, given that the
3MS battery is focused more on memory and language
impairments and may have reduced sensitivity for other
cognitive domains (such as frontal/executive functions). In
addition, we may not have the power to detect potential
associations with other domains PSCI, given the low rates
of recurrent stroke. Also, as this was an exploratory analysis,
we did not adjust p-values for the number of hypothesis
tests that we conducted. Finally, the IRIS trial enrolled
patients with stroke and IR based on specific criteria, and
therefore, our findings may not be generalizable to the
wider population of persons with stroke.
The novel associations reported in this analysis are
hypothesis generating. Our findings warrant further
study to see if they are reproducible. There is biological
plausibility that PSCI represents a biomarker of elevated
International Journal of Stroke, 19(4)
vascular risk. Therefore, future trials of secondary stroke
prevention may benefit from enrollment of high-risk
patients identified based on baseline PSCI.
Author contributions
Z.N. researched literature and conceived the study. K.S., M.C.P.,
A.C., and Z.N. were involved in protocol development. K.S. and
A.C. conducted data analysis. K.S. and Z.N. wrote the first draft
of the article, while A.C. and M.C.P. provided significant intellectual
contributions while editing the article. All authors reviewed
and edited the article and approved the final version of the article.
Drs A.C. and Z.N. contributed equally as senior authors.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Ethical approval
An Institutional Review Board (IRB) has approved the use of
humans for this study. De-identified data from the study were
acquired with approval from the National Institute of Neurological
Disorders and Stroke (NINDS)/National Institutes of Health
(NIH), and the study was ruled not human subjects research by the
George Washington University IRB.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: The
Insulin Resistance Intervention after Stroke (IRIS) was supported
by NINDS/NIH (grant #U01NS044876).
Informed consent
All participants in the IRIS trial provided written informed consent,
and the IRIS trial was approved by the local IRBs of all participating
centers.
Data availability
Data available on request from the authors.
ORCID iDs
Kat Schmidt
https://orcid.org/0000-0002-1240-6767
Zurab Nadareishvili
https://orcid.org/0000-0002-5526-1342
Supplemental material
Supplemental material for this article is available online.
References
1. El Husseini N, Katzan IL, Rost NS, et al. Cognitive impairment
after ischemic and hemorrhagic stroke: a scientific statement
from the American Heart Association/American Stroke
Association. Stroke 2023; 54: e272-e291.
2. Schmidt K, Power MC, Ciarleglio A, Nadareishvili Z and
IRIS Study Group. Post-stroke cognitive impairment and
https://www.orcid.org/0000-0002-1240-6767 https://www.orcid.org/0000-0002-5526-1342
WSO - April 2024

Table of Contents for the Digital Edition of WSO - April 2024
