A systematic review «Burr JM, Botello-Pinzon P, Takwoingi Y ym. Surveil...»1 was undertaken to identify prediction models for development of OAG that include IOP as a predictor, and to critically appraise the construction and validation of the models. Databases were searched from 1987 until January 2011 with no language restriction. Prospective studies and studies in which patients were retrospectively identified but prospectively followed up were included if: only patients with OHT were recruited, they were conducted post 1987, when reliable computerised perimetry became the standard of care, a prediction equation for the development of OAG could be obtained, the reported model included at least two variables, one of which was IOP and the performance of the model was reported in any data set (derivation or validation) of longitudinal follow-up of a cohort initially free of OAG irrespective of the length of follow-up. Adults with OHT (defined as elevated IOP but no evidence of glaucomatous optic nerve damage or visual field loss) aged ≥ 18 years.
The quality of included studies was assessed using a checklist that included assessment of the definition of OAG, the method of measurement of candidate predictors and how continuous predictors were used in the models.
Of 565 articles screened, 54 full-text papers were retrieved for detailed evaluation of eligibility. Forty-nine papers were excluded. Of the five included papers, four were based on the results of two RCTs, the OHTS (Ocular Hypertension Treatment Study) and the European Glaucoma Prevention Study. These provided three models for which prediction equations were available (full and reduced OHTS models and the pooled OHTS-EGPS means model). The fifth paper reported the independent validation study of the OHTS model in the Diagnostic Innovations in Glaucoma Study (DIGS) cohort.
Both the OHTS and EGPS were large prospective studies that included patients with OHT aged ≥ 30 years who had no evidence of glaucomatous damage at baseline. The OHTS randomised 1636 individuals, with an IOP 24-32 mmHg in one eye and an IOP 21-32 mmHg in the other eye, to treatment or observation. The EGPS randomised 1081 individuals with IOP ≥ 22 mmHg in at least one eye to treatment or placebo. The inclusion and exclusion criteria used in the DIGS cohort were very similar to those used by the OHTS (IOP e ≥ 24 mmHg in one eye and ≥ 21 mmHg in the other eye).The original protocols of the OHTS and EGPS did not include CCT and measurements were taken later, 2–3 years after randomisation of the last patient enrolled in the studies. All patients in the DIGS had CCT measurements taken during follow-up.
In univariate analyses of the OHTS or pooled OHTS and EGPS data, statistically significant predictors for development of OAG were age, IOP, CCT, VCD ratio, horizontal cup-to-disc (C/D) ratio, PSD, history of heart disease, gender, race and diabetes mellitus. In both OHTS and EGPS, history of diabetes and heart disease were self-reported and not clinically verified. CCT was a major predictor for the development of OAG over 5 years. For the OHTS-EGPS model, there was an increase in risk per 40-μm decrease in corneal thickness (HR 2.04, 95 % CI 1.70 to 2.45).
Comment: The authors conclude, however, that it is unclear to what extent lower CCT is responsible for the increased risk of OAG. Previous studies have shown that CCT tends to decrease with increasing age. It is also well known that corneal thickness influences the measurement of IOP: IOP is overestimated in thick corneas and underestimated in thin ones. Nevertheless, there is no consensus on the clinical significance of the effect of CCT on IOP measurements. No correlation was found between CCT and IOP in either the OHTS or the EGPS. This may be owing to exclusion of patients with normal or very low IOPs and also those with very high IOPs. In the Early Manifest Glaucoma Trial, CCT was identified as a significant predictive factor for glaucoma progression in patients with higher baseline IOP but not in those with lower baseline IOP.
Racial differences in CCT have been reported in several population studies, with individuals of African ancestry having thinner corneas, on average, than Caucasians, Hispanics or Asians. It has been suggested that black race may not be an independent risk factor because black patients tend to have higher IOP, thinner corneas and higher C/D ratios than other patients with OHT and are therefore generally at a higher risk than white patients. In the OHTS and OHTS-EGPS, when either VCD ratio or CCT was included in the multivariate model, race was no longer statistically significant.
CCT has also been shown to be a highly heritable trait. Because thinner CCT has also been found to predict progression of visual loss in patients with OAG, it is plausible that a biological link exists between aspects of the cornea that regulate its thickness and the physical and structural properties of tissues involved in glaucoma pathogenesis.