Assessing the effectiveness of intraocular pressure-lowering therapy.

monocular drug trial. In this issue, Bhorade et al 1 from the OHTS team report a post hoc analysis of the clinical utility of the monocular drug trial among 206 initially observed OHTS participants who were treated with a prostaglandin analogue at the completion of the first Ocular Hypertension Treatment Study. The monocular trial is a clinical tool designed to try to help distinguish between the IOP change attributable to the trial drug and the IOP change attributable to spontaneous variation. A significant challenge of IOP management is that IOP is a dynamic parameter. Like systemic blood pressure or blood glucose levels, IOP changes over time. Statistically significant and clinically relevant changes in IOP have been described over time frames as brief as 12 to 24 hours, as well as over visits separated by days, weeks, or months. The magnitude of spontaneous IOP variation is large enough to mask or mimic the therapeutic effect of a newly initiated IOP-lowering treatment, and these large spontaneous IOP variations occur at approximately 15% of office visits. 2,3 In the face of spontaneous IOP variation, how are we accurately to assess the effectiveness of newly initiated IOPlowering therapy? Enter the monocular drug trial, which was described specifically to address this clinical challenge. The monocular trial is conceptually elegant in its simplicity: treat one eye and leave the fellow eye untreated. In the treated eye, we observe a combination of therapeutic and spontaneous IOP variation. In the untreated eye, we observe purely spontaneous IOP variation. Subtracting the IOP change in the untreated eye from the IOP change in the treated eye reveals the therapeutic IOP effect attributable to treatment. Elegant, yes, but does the monocular trial work? In recent years, the assumptions underlying the monocular trial, as well as the trial itself, have come under scrutiny. Our group initiated this scrutiny in a 2002 article challenging the dogma that fellow eyes exhibit symmetric spontaneous IOP variation, 3 and in 2004 published the first formal evaluation of the monocular drug trial. 4 In that report, we found that the IOP change in the monocular trial eye did not adequately predict the IOP change observed when the fellow eye received the trial drug. Subsequently, several other groups independently confirmed this finding. 5‐8 However, in retrospect, the authors of most of these early reports (ourselves included) made an important mistake: we asked the wrong question, or at least a question of limited clinical relevance. In managing a chronic and slowly progressive disease such as glaucoma, we should perhaps be less interested in whether the monocular trial can provide an estimate of short-term IOP control in the fellow eye. Rather, perhaps we should be more interested in whether the monocular trial can provide an estimate of long-term IOP control in the trial eye itself. In the summer of 2009, we published the first prospective evaluation of the monocular drug trial in subjects with ocular hypertension or glaucoma. 9 In this study, we examined the monocular trial’s ability to predict long-term IOP reduction in the same eye. We feel that this is a more relevant clinical question and one that could potentially be assessed via the monocular trial. However, as it turned out, we discovered that the monocular trial was a very poor predictor of long-term IOP reduction. We found a coefficient of determination of 0.28. The coefficient of determination (also known as r 2 or the square of the Pearson’s correlation coefficient, r) measures the strength of association between a predictor and an outcome, in this case the monocular trial IOP change and the long-term IOP change. A value of 0.28 means that the long-term mean IOP change is only 28% determined by the monocular trial IOP change and 72% determined by other, unidentified factors. The monocular trial doesn’t seem to tell us very much about long-term IOP control. In this issue, Bhorade and the OHTS team have made a major contribution to the ongoing scrutiny of the monocular trial. They have asked the clinically relevant question: does the monocular trial predict the trial eye’s long-term IOP reduction? To do so, they have essentially replicated our analysis in the large Second Ocular Hypertension Treatment cohort. In their report, they compared the IOP change seen during the monocular trial to the mean change in IOP calculated from up to 3 pretreatment IOP measurements taken before the trial and up to 3 on-treatment IOP measurements taken after the trial. Their analysis revealed a coefficient of determination of 0.17. Again, with 83% of the variance in long-term IOP control unaccounted for, the monocular trial doesn’t seem to be telling us very much about future IOP control. The consistency of the findings between the OHTS analysis and our own is compelling, particularly in light of the differences between our studies. Our study, while adequately powered, was quite small (26 participants total), and all of the participants were white (which reflects the population in West Virginia where the study was conducted). The OHTS data set compensated for these shortcomings with a much larger and more ethnically diverse sample. But the OHTS analysis is also not without a few important limitations. The subjects in OHTS were ocular hypertensive but did not have glaucoma. In OHTS, the eye with the