Stroke Treatment Academic Industry Roundtable Recommendations for Individual Data Pooling Analyses in Stroke

Abstract

Pooled analysis of individual patient data from stroke trials can deliver more precise estimates of treatment effect, enhance power to examine pre-specified subgroups, and facilitate exploration of treatment-modifying influences. Analysis plans should be declared, and preferably published, before trial results are known. For pooling trials that used diverse analytic approaches, an ordinal analysis is favoured, with justification for considering deaths and severe disability jointly. Since trial pooling is an incremental process, analyses should follow a sequential approach, with statistical adjustment for iterations. Updated analyses should be published when revised conclusions have a clinical implication. However, caution is recommended in declaring pooled findings that may prejudice ongoing trials, unless clinical implications are compelling. All contributing trial teams should contribute to leadership, data verification, and authorship of pooled analyses. Development work is needed to enable reliable inferences to be drawn about individual drug or device effects that contribute to a pooled analysis, versus a class effect, if the treatment strategy combines two or more such drugs or devices. Despite the practical challenges, pooled analyses are powerful and essential tools in interpreting clinical trial findings and advancing clinical care.

Classification of Different Degrees of Disability Following Intracerebral Hemorrhage: A Decision Tree Analysis from VISTA-ICH Collaboration

“…Finally, there has been discussion on appropriate partition of the Rankin disability scale, particularly with regard to the threshold for moderate disability on the mRS. Based on recommendations to keep the ordinal structure of the mRS, we had chosen the partition as mild (mRS 0–2), moderate (mRS 3–4), and severe disability and death (mRS 5–6) ( 22 ). This partition severe disability and death as mRS 5–6 had been used in stroke trials ( 30 , 31 ) and studies on prediction ( 32 ) and is consistent with recommendation by panel of experts ( 33 ). Nevertheless, we had also performed the analysis with the revised threshold for moderate disability as mRS equals to 3.…”

Utility-Weighted Modified Rankin Scale as Primary Outcome in Stroke Trials

“…The modified Rankin Scale (mRS) is the most widely used primary outcome measure in trials for acute stroke interventions. 1 , 2 The mRS is an ordinal scale ranging from 0 (no symptoms) to 6 (death) measuring the degree of disability or dependence in everyday life. 3 Previously, dichotomizing the mRS into dead or dependent (mRS, 3–6) versus independent (mRS, 0–2) was common, but this results in a reduction in statistical power to detect relevant treatment effects.…”

“… 9 – 11 For the mRS to reflect both treatment effect and patient perception, the utility-weighted mRS (UW-mRS) has been proposed and used as primary end point. 2 , 12 , 13 In the UW-mRS, utilities based on the EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D-3L) values are assigned to the mRS health states. Two prior studies reported utility weights for the mRS health states: 1 representing the values of patients and 1 representing the values of clinicians.…”

Utility-weighted modified Rankin Scale: Still too crude to be a truly patient-centric primary outcome measure?

“…The misclassification matrix showed excellent statistical agreement between the ''actual'' and ''matched'' mRS categories at 3 months (kappa, 0.81; CI, 0.79-0.84) and 12 months (kappa, 0.86; CI, 0.85-0.87) ( Figure 2). However, based on the AQoL-4D utility values, good discrimination between sequential pairs of mRS categories was only observed for mRS 3 vs. 4…”

“…1 It is an emerging outcome measure which aims to reflect patient perception of quality of life to improve interpretability of the mRS. 2,3 The UW-mRS also claims to improve statistical efficiency by providing a continuous alternative to either an ordinal or dichotomized analysis of the mRS. 3 The development of a UW-mRS has been advocated by several associations including the Stroke Therapy Academic Industry Roundtable. 4 Utility, centered on health-related quality of life, is a widely accepted measure of a patient's preference for a specific health outcome. 5,6 UW-mRS values are obtained by assigning a mean utility weight to each mRS category based on patient, clinician, or societal valuation of various disability health states.…”