Methods for Analyzing the Modified Rankin Scale in Stroke Thrombolysis Trials: A Systematic Review and Methodological Framework

BACKGROUND: Significant heterogeneity in modified Rankin Scale (mRS; a 7-point ordinal scale from 0 to 6) analytical methodologies compromises interpretation and comparability of results in intravenous thrombolysis trials. This study comprehensively reevaluates contemporary mRS analysis methodologies in these trials, aiming to clarify findings and provide insights for future trial design. METHODS: A systematic search of PubMed, Embase, and Cochrane Library was conducted from inception through June 2025 for randomized controlled trials investigating intravenous thrombolysis in acute ischemic stroke using the 90-day mRS as the primary outcome. Two independent reviewers conducted study screening and risk-of-bias assessment and extracted patient characteristics, methodological variables, and treatment parameters. The study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Consensus-Based Standards for the Selection of Health Measurement Instruments reporting guideline and Stroke Therapy Academic Industry Roundtable XI recommendations. RESULTS: A total of 38 randomized controlled trials (n=30 470) were included in this review, of which 5 were at moderate risk. A 90-day mRS score of 0 to 1 was the most frequently selected primary outcome (57.9%). Trials enrolling mild to moderate, younger, or male-dominant participants principally used an mRS score of 0 to 1 as the primary outcome, while those focusing on moderate to severe, older, or female-dominant patients predominantly used ordinal shift analysis. CONCLUSIONS: Primary outcome approaches differed widely across intravenous thrombolysis trials. Although a 90-day mRS score of 0 to 1 remains the most commonly used primary outcome, it is insufficient to capture the full spectrum across diverse thrombolysis populations. A 3-dimensional methodological framework is proposed that integrates severity- and population-stratified outcome strategies with rigorous methodological considerations to advance approaches for analyzing mRS outcomes in stroke thrombolysis trials.