Progressive retinal nerve fiber layer (RNFL) thinning as a biomarker to guide intraocular pressure (IOP) lowering treatment in ocular hypertensives (OHT)

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Glaucoma is a leading cause of irreversible blindness, afflicting 21.8 million patients in China by 2020. While the Ocular Hypertension Treatment Study (OHTS) established the effectiveness of lowering the IOP in decreasing the risk of glaucoma development, <10% of the untreated patients worsened and developed glaucoma in 5 years. Treating non- progressing patients not only incurs unnecessary costs to patients and health-care providers, but also induces adverse effects that can compromise visual function and quality of life. Risk stratification using the OHTS-EGPS (European Glaucoma Prevention Study) prediction model has been proposed to identify high risk OHT (5-year risk >15%) for IOP-lowering treatment to prevent glaucoma development. Notably, the risk calculated by the OHTS-EGPS model relies on five biometric parameters measured cross sectionally, which can be highly variable during follow-up. The ability to distinguish high-risk from low-risk OHT remains imprecise and it is largely unclear when to initiate IOP-lowering treatment. Identifying biomarkers indicative of disease deterioration behavior to guide IOP-lowering treatment for prevention of visual impairment is an unmet need in the management of OHT. We hypothesize progressive RNFL thinning to be a biomarker predictive of subsequent visual field (VF) progression and that IOP-lowering treatment initiated upon detection of progressive RNFL thinning is an effective approach to direct OHT at risk of VF progression for treatment. We propose a 5-year prospective study, randomizing 310 OHT patients into two management paradigms with IOP-lowering treatment initiated upon detection of (I) progressive RNFL thinning, as determined by spectral-domain optical coherence tomography Trend-based Progression Analysis of serial RNFL thickness maps; or (II) a 5-year glaucoma conversion risk >15% calculated from the OHTS-EGPS model. All patients will undergo clinical examination, RNFL imaging and perimetry 4-monthly for 5 years. The objectives are to compare the proportion of patients requiring IOP-lowering treatment and the proportion of patients developing VF progression within the two management paradigms. We expect that the proportion of patients requiring treatment is smaller for patients randomized to management paradigm I with a comparable/smaller proportion of patients developing VF progression compared with those randomized to management paradigm II. The finding of the study will transform the management of OHT. Specifically, we would be able to target treatment to OHT at risk of VF progression based on a biomarker indicative of disease deterioration behavior. It also would minimize both costs and adverse effects, and enhance the rational re-allocation of resources within the healthcare system to those at most need.

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