Clinically important effect sizes for clinical trials using infarct growth reduction as the primary outcome: a systematic review.

Background: Infarct growth on multimodal imaging is a common lead outcome in phase 2 proof-of-concept and dose-optimization neuroprotective agent stroke trials. However, the effect size in infarct growth reduction that correlates with clinically meaningful differences in clinical global disability outcomes has not been well delineated.

Methods: A systematic literature search identified all endovascular thrombectomy randomized trials reporting magnitude of treatment effect on both infarct growth reduction and increase in functional independence (modified Rankin Scale (mRS) 0-2). Data aggregation determined the size of infarct growth reductions salient to four types of clinically meaningful effect sizes of increase in functional independence: (1) the minimal clinically important difference (MCID)-outcome specific; (2) the MCID-practice changing; (3) the realistic target difference; and (4) the reasonable comparability effect size.

Results: A systematic search identified four trials enrolling 612 imaged participants. Across the trials, the amount of functional independence (mRS 0-2) increase associated with each 1 mL reduction in infarct growth was mean 2.3±0.6%. An infarct growth reduction of 0.57 mL correlated with the mRS 0-2 increase MCID of 1.3%. Infarct growth reductions of 2.27 mL, 4.35 mL, and 6.53 mL correlated with realistic effect and reasonable comparability effects sizes of mRS 0-2 increases of 5%, 10%, and 15%, respectively.

Conclusion: In formal meta-analysis of randomized treatment trials, every 1 mL reduction in infarct growth was associated with a 2.3% increase in functional independence (mRS 0-2) at 3 months. This conversion factor can inform selection of infarct growth effect size targets for phase 2 trials of neuroprotective agents.