Is there a place for a one-eyed trial in glaucoma therapy?

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Glaucoma is a leading cause of blindness worldwide and a major public health concern. As intraocular pressure (IOP) is well-recognised as an important risk factor for the occurrence and progression of glaucoma, 1-3 much of glaucoma management is focused on lowering and controlling IOP to reduce the risk of further optic nerve damage and subsequent vision loss.

Lowering IOP with eye-drops may sound simple in theory but in clinical practice, determining the efficacy of therapy can be difficult. One major reason for this difficulty is diurnal IOP fluctuation, which can be as high as 6 mmHg in some individuals. When a patient demonstrates an IOP reduction of 3 mmHg after commencing treatment, clearly the clinician needs to confirm that this is indeed true therapeutic IOP reduction as opposed to background fluctuation. The monocular, or one-eyed, trial of glaucoma therapy has been proposed as one way of overcoming this problem.

In the monocular trial, only one eye is started on therapy while the untreated fellow eye is used as control. At the follow-up visit, any change in IOP in the untreated fellow eye is considered to be the result of fluctuation. The observed IOP reduction in the treated eye is then adjusted to take into account the change in IOP in the untreated fellow eye.

For example, at baseline, the IOPs were 32 mmHg in the right eye and 30 mmHg in the left. Therapy was commenced to the right eye only and after four weeks, the IOPs measured 18 mmHg right and 24 mmHg left. In the treated right eye, the IOP reduction was 14 mmHg (32-18 mmHg). However, in the untreated left eye, there was also a lowering of IOP of 6 mmHg (30-24 mmHg), presumably due to fluctuation. Thus, of the 14 mmHg IOP reduction seen in the treated right eye, 6 mmHg can be attributed to spontaneous variation and the remaining 8 mmHg (14-6 mmHg) to the actual therapeutic IOP-lowering effect.

For the monocular trial to work, several assumptions have to hold true. First, it is assumed that using the medication in one eye will have no crossover or contralateral effect in the fellow eye. For instance, it is known that topical beta blockers do have a crossover effect,4 thus precluding their use in a monocular trial. Another assumption is that the IOP in both eyes of the same individual fluctuate the same amount throughout the day. In this respect, it has been found that there is good correlation in the IOP fluctuation in both eyes in glaucoma patients but not in healthy subjects.5,6

Is the monocular trial valid?

Various studies have been conducted to evaluate the validity and usefulness of the monocular trial, with mixed results and contrasting conclusions. Differences in research design and methodology mean that it is not possible to make direct comparisons between studies. Most were retrospective analyses that were subject to bias and the inability to adequately account for diurnal variation and regression to the mean.7 Additionally, the research question often posed was whether the monocular trial held any predictive value in determining the IOP reduction in the fellow eye, which is not really what the monocular trial is set out to determine.8,9

A prospective, randomised, masked study of 26 patients with open angle glaucoma or ocular hypertension (all previously treated but underwent a four-week wash-out period prior to randomisation) concluded that the monocular trial at one month was a poor predictor of IOP reduction at two to three months after latanoprost treatment was commenced.10

Similarly, when data was analysed from the 206 study participants in the observation arm of the Ocular Hypertension Treatment Study (OHTS) who were subsequently started on prostaglandin analogues, the monocular trial at one month was deemed to poorly determine IOP reduction up to 18 months later. 11 Predicting the medium-term or long-term outcome of therapy is not really the purpose of the monocular trial, either.

King and colleagues published perhaps the best conducted study so far in trying to determine the validity and usefulness of the classic monocular trial.12 In their prospective, masked, intention-to-treat cohort study, 30 treatment-naïve patients with open angle glaucoma or ocular hypertension had their IOPs measured at the initial clinic visit and then subsequently at 11 am (±15 minutes) for seven consecutive weeks. At the third visit, the eye with the higher IOP was commenced on travoprost; at the fourth visit, the fellow eye was also started on travoprost. Visits 1 to 3 were the pre-treatment visits, while visits 5 to 7 were the post-treatment visits.

The adjusted IOP was the IOP change between the initial clinic visit and visit 4 in the treated eye, minus the IOP change in the untreated fellow eye over the same two visits (that is, the monocular trial). The true therapeutic IOP-lowering effect of travoprost was calculated as the difference in IOP between the three pre-treatment and the three post-treatment visits (the IOP at the initial clinic visit was not considered in this instance). By designing the study this way, the problems of diurnal variation, regression to the mean, crossover and selection bias are minimised. The authors found that not adjusting the IOP via the monocular trial meant that the true therapeutic effect was overestimated by a mean of 3.1 mmHg (or 36 per cent); this overestimation was less than 0.1 mmHg after IOP adjustment.

Way forward

The specific design of King and colleagues’ work also means that the results are applicable only to a specific set of circumstances, namely travoprost treatment and IOP measurements at 11 am. It is not known if these results remain valid for IOP measurements at other time points, for instance, at 8 am or 6 pm. To be able to evaluate the monocular trial in a more comprehensive manner, future studies should ideally include IOP measurements at different times throughout the day and night, rendering them almost too impractical and resource consuming to be conducted in the first place.

What does this mean for clinicians? The gold standard in determining the response to glaucoma medication is still measuring the IOP on multiple occasions before and after the decision to commence therapy. There is no doubt that the monocular trial, if performed correctly, can provide an accurate estimate of the actual therapeutic IOP lowering effect. However, both methods may not be practical in the day-to-day clinical setting.

The way forward has to be 24-hour IOP measurement in a way that is easy to administer, safe and accurate. Until then, monitoring of treatment response should be individualised and based on the characteristics of the patient being treated, including age, severity of glaucoma, adherence to treatment, appointment attendance, distance, cost to patient and patient preference.

1. Kass MA, Heuer DK, Higginbotham EJ et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or preventsthe onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120: 701-713.

2. Heijl A, Leske MC, Bengtsson B et al. Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the early Manifest Glaucoma Trial. Arch Ophthalmol 2002; 120: 1268-1279.

3. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7, the relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 2000; 130: 429-440.

4. Realini T, Vickers WR. Symmetry of fellow-eye intraocular pressure responses to topical glaucoma medications. Ophthalmology 2005; 112: 599-602.

5. Sit AJ, Liu JH, Weinreb RN. Asymmetry of right versus left intraocular pressures over 24 hours in glaucoma patients. Ophthalmology 2006; 113: 425-430.

6. Sit AJ, Liu JH, Weinreb RN. Variation of 24-hour intraocular pressure in healthy individuals. Ophthalmology 2005; 112: 1670-1675.

7. Bhorade AM . The monocular trial controversy: a critical review. Curr Opin Ophthalmol 2009; 20: 104-109.

8. Dayanir V, Cakmak H, Berkit I. The one-eye trial and fellow eye response to prostaglandin analogues. Clin Experiment Ophthalmol 2008; 36: 136-141.

9. Chaudhary O, Adelman RA, Shields MB. Predicting response to glaucoma therapy in one eye based on response in the fellow eye: the monocular trial. Arch Ophthalmol 2008; 126: 1216-1220.

10. Realini TD. A prospective, randomized, investigator masked evaluation of the monocular trial in ocular hypertension or open-angle glaucoma. Ophthalmology 2009; 116: 1237-1242.

11. Bhorade AM, Gordon MO, Wilson B et al for the Ocular Hypertension Treatment Study Group. The utility of the monocular trial: data from the Ocular Hypertension Treatment Study. Ophthalmology 2010; 117: 2047-2054.

12. King AJ, Uppal S, Rotchford AP et al. Monocular trial of intraocular pressure-lowering medication:a prospective study. Ophthalmology 2011; 118: 2190-2195

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