Reassessment of the Collaborative Normal-Tension Glaucoma Study: Statistical Evidence and Implications for Current Management

INTRODUCTION: The Collaborative Normal-Tension Glaucoma Study (CNTGS) is frequently cited as evidence that a 30% reduction in intraocular pressure (IOP) slows progression in normal-tension glaucoma (NTG). This study re-examines the statistical methodology of CNTGS to assess how its conclusions are supported by the data. METHODS: This study reviews the CNTGS design with emphasis on survival analysis methodology, including the definition of time zero, censoring rules, and intention-to-treat (ITT) versus per-protocol comparisons. Particular attention is given to the post hoc redefinition of baseline and the handling of cataract-related visual decline, assessing their impact on the reported treatment effect. RESULTS: CNTGS shifted the analytical baseline for the treatment group to the point of IOP stabilization, thereby excluding early progression events and introducing immortal time bias. Additionally, cataract-related visual decline, more frequent in the treatment group, was censored rather than treated as a competing risk or time-dependent covariate. These methodological choices reduced the number of counted progression events in the treatment arm. Although the adjusted per-protocol analysis yielded a statistically significant treatment effect, this effect disappeared under the original ITT analysis, which included all randomized eyes from time zero and all progression events. CONCLUSION: The potential treatment benefit reported in CNTGS depended largely on post hoc analytical modifications, whereas the original ITT analysis did not support a statistically significant effect of IOP reduction. These findings highlight the importance of transparent survival analysis methods and strict adherence to ITT principles in future NTG trials. Well-designed prospective studies that avoid immortal time bias and model treatment-related events appropriately are needed to clarify the true role of IOP reduction on NTG management.