BACKGROUND: Treatment group imbalances in baseline stroke severity in the NINDS intravenous t-PA for acute stroke treatment trial led to controversy regarding the efficacy of tissue plasminogen activator (t-PA) in the treatment of acute ischemic stroke. PURPOSE: Describe the steps used to independently re-evaluate this trial. METHODS: NIH appointed an independent multidisciplinary committee that gained access to the original data. We undertook analyses of t-PA efficacy accounting for this imbalance, as well as analyses to identify subgroups that experienced additional harm or benefit from t-PA. Analyses of time from stroke onset to treatment (OTT), blood pressure, and intracerebral hemorrhage are given as illustrations. RESULTS: Despite subgroup imbalances in baseline stroke severity, when t-PA was administered to acute ischemic stroke patients according to study protocol, there was a statistically significant and clinically important benefit of t-PA treatment resulting in a higher likelihood of having a favorable clinical outcome at 3 months. Moreover, we were unable to identify subgroups of patients between which t-PA treatment effect differed, albeit these analyses had low power. These data failed to support the NINDS investigators' conclusion that effect of t-PA therapy diminished with increasing values of OTT within the protocol-specified 3 h time limit. In addition, the blood pressure measurements were highly variable and inconsistently determined so as to be too unreliable for inclusion in analysis. CONCLUSION: With new NIH requirements for data-sharing, the frequency of re-analysis of clinical trial data may increase substantially. This re-evaluation provides a blueprint for future re-evaluations of other trials. These best practices include re-analysis of the study data, after suitable replication, by an independent multidisciplinary committee, including a skilled statistical programmer analyst. Primary investigators should address significant errors determined in such re-analyses.
BACKGROUND: Treatment group imbalances in baseline stroke severity in the NINDS intravenous t-PA for acute stroke treatment trial led to controversy regarding the efficacy of tissue plasminogen activator (t-PA) in the treatment of acute ischemic stroke. PURPOSE: Describe the steps used to independently re-evaluate this trial. METHODS: NIH appointed an independent multidisciplinary committee that gained access to the original data. We undertook analyses of t-PA efficacy accounting for this imbalance, as well as analyses to identify subgroups that experienced additional harm or benefit from t-PA. Analyses of time from stroke onset to treatment (OTT), blood pressure, and intracerebral hemorrhage are given as illustrations. RESULTS: Despite subgroup imbalances in baseline stroke severity, when t-PA was administered to acute ischemic strokepatients according to study protocol, there was a statistically significant and clinically important benefit of t-PA treatment resulting in a higher likelihood of having a favorable clinical outcome at 3 months. Moreover, we were unable to identify subgroups of patients between which t-PA treatment effect differed, albeit these analyses had low power. These data failed to support the NINDS investigators' conclusion that effect of t-PA therapy diminished with increasing values of OTT within the protocol-specified 3 h time limit. In addition, the blood pressure measurements were highly variable and inconsistently determined so as to be too unreliable for inclusion in analysis. CONCLUSION: With new NIH requirements for data-sharing, the frequency of re-analysis of clinical trial data may increase substantially. This re-evaluation provides a blueprint for future re-evaluations of other trials. These best practices include re-analysis of the study data, after suitable replication, by an independent multidisciplinary committee, including a skilled statistical programmer analyst. Primary investigators should address significant errors determined in such re-analyses.
Authors: Jody D Ciolino; Renee' H Martin; Wenle Zhao; Edward C Jauch; Michael D Hill; Yuko Y Palesch Journal: Contemp Clin Trials Date: 2014-03-07 Impact factor: 2.226
Authors: Jody D Ciolino; Reneé H Martin; Wenle Zhao; Michael D Hill; Edward C Jauch; Yuko Y Palesch Journal: Stat Methods Med Res Date: 2011-08-24 Impact factor: 3.021
Authors: Jody D Ciolino; Renée H Martin; Wenle Zhao; Edward C Jauch; Michael D Hill; Yuko Y Palesch Journal: J Biopharm Stat Date: 2013 Impact factor: 1.051