This study investigated the justification for determining glaucoma medication effectiveness using the traditional time-of-day standardized approach. The authors examined the day-to-day repeatability of IOP measurements in a prospective cohort of patients with primary open-angle glaucoma (OAG) or ocular hypertension (OHT). The results indicate that even under ideal conditions, day-to-day variability significantly undermines the precision of IOP measurement and of the estimation of medication effectiveness even when time of day is standardized. The authors conclude that better ways of eliminating the effects of this variability are needed.
All patients were treatment naive and presented with IOP greater than 21 mm Hg. They underwent measurement by masked Goldmann tonometry before treatment at three weekly visits at 08:00, 11:00 and 16:00 and after starting on travaprost 0.004% at three weekly visits at the same times of day. Day-to-day repeatability was estimated before and after commencing medication as the coefficient of repeatability (CR) and coefficient of variability (CV).
Maximum medication effect was achieved after one week in both OAG and OHT patients. Among the 30 patients who completed the study, at the 8:00 time point, mean IOP was 26.1 in the eye with higher pressure before treatment and 17.9 mm Hg after starting treatment. CR was 6.8 mm Hg before treatment and 4.6 mm Hg after, while CV was 10 percent and 10.5 percent, respectively. Therefore, before and after starting medication, IOP lay within a range of ±20 percent of the mean IOP with 95% confidence.
Within-subject CR ranged from 5.3 to 6.9 mm Hg pre-treatment and 4.1 to 4.8 mm Hg post-treatment. A decrease in IOP less than these figures would be indistinguishable from day-to-day fluctuation and measurement error and not directly attributable to the medication's effect. The authors found that repeated IOP measurements at the same time on different days lie within a range of ±14.9 to ±20.5 percent of the mean diurnal value with 95% confidence in untreated patients and ±21.2 to ±23.1 percent in treated patients.
Time-standardized measurements consistently improved IOP measurement reproducibility. The authors also showed that the precision of IOP estimation improved when using the mean of three IOP readings (8:00, 11:00, and 16:00) from an average of ±18.4 to ±13.3 percent pre-treatment and ±20.9 to ±16.1 percent post-treatment.
The results suggest that day-to-day variation in patients with high-tension glaucoma or OHT may be higher than in normal subjects and extrapolation from normal subjects is inappropriate. The authors suggest that since CR becomes tighter after initiating travaprost, treatment may decrease IOP fluctuations. However, they highlight that the variability of ±20 percent they found is sufficiently large to obscure the actual medication effect and make it difficult to distinguish from day-to-day fluctuation.
In order to improve precision of IOP measurement repeatability, the authors suggest taking either multiple IOP measurements pre- and post-treatment on different days, especially if performed at the same time of day, or obtaining diurnal IOP measurements pre- and post-treatment and using the daily diurnal mean to determine the best estimate of IOP and medication effect. While these methods may improve the estimation of medication effect, they are resource-intensive and inconvenient.