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  • The Monocular Trial Debate

    Comprehensive Ophthalmology, Glaucoma
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    The Primary Open-Angle Glaucoma Preferred Practice Pattern (2005) from the American Academy of Ophthalmology recommends the use of a monocular therapeutic trial to determine intraocular pressure (IOP) response to topical hypotensive medications. In a monocular trial, clinicians typically begin a topical hypotensive medication in one eye (usually the eye with the higher pressure) while the untreated eye serves as a control for nontherapeutic IOP fluctuations. The patient returns for follow-up in 4-6 weeks to determine the IOP response of the medication in the treated eye. If the IOP in the treated eye is lowered substantially more than that in the untreated eye compared to results from the prior visit, then the monocular trial is deemed successful. The medication is instituted bilaterally and the patient returns for follow-up. The usefulness of the monocular therapeutic trial has long been accepted; however, its validity has recently been challenged, and recommendations have been made to abandon the monocular trial or alter the way it is implemented. Is this long-standing method of evaluation still clinically useful? To answer this question, this article reviews the data from recent studies and assesses whether the assumptions underlying the monocular trial are indeed true.

    The Predictive Accuracy of the Monocular Trial

    Realini et al (Ophthalmology. 2004;111:421-426) recently reported that the IOP-lowering response of topical medications in the first (or treated) eye of a monocular trial correlated poorly with the IOP response in the second (or untreated) eye (r=0.13). Based on these results, Realini argues that the monocular trial does not provide useful information and should not be used in clinical practice. The sample size used for this study, however, was small (n=52 patients) and the data were retrospective, which may have introduced bias and error. Furthermore, baseline IOP measurements of each eye were taken at separate visits, possibly introducing error due to diurnal variation and regression to the mean.

    Data from monocular trials using topical beta-blockers conducted in the Ocular Hypertension Treatment Study (OHTS) suggest a stronger positive correlation in IOP-lowering response between the first and second eye than shown in Realini’s study (Table 1). Among the 590 ocular hypertensive participants on topical beta-blockersin the OHTS, there was a moderate correlation (r=0.48) of IOP response between the first eye after one month of treatment and the second eye after 5 months of treatment (unpublished data, OHTS). Preliminary analysis of prostaglandin analogue trials is currently underway.

    Table 1. Results from recent monocular trial studies
      

    Baseline IOP in mm Hg
    Mean + SD

    Post-treatment IOP
    in mm Hg
    Mean + SD

    IOP Difference
    Baseline
    Post-treatment
    in mm Hg (%)

    Correlation of IOP-lowering response between eyes

    Realini1

    First Eye

    22.4 + 5.2

    16.7 + 4.3

    5.7 (25%)

    r = 0.13

     

    Second Eye

    19.7 + 4.2

    16.9 + 3.7

    2.8 (14%)

    		 

    OHTS (beta-blockers)

    First Eye

    25.9 + 2.8

    19.1 + 2.5

    6.8 (26%)

    r = 0.48

     

    Second Eye

    24.2 + 2.7

    19.3 + 2.9

    4.9 (20%)

    		 

    The overall post-treatment IOP in the first and second eyes were nearly identical, 19.1 mm Hg and 19.3 mm Hg, respectively. The scatter plot, however, shows that post-treatment IOPs frequently differ between the first and second eyes of individuals (Figure 1). This variation explains why the correlation between the eyes is only moderate despite similar mean values. Possible explanations for such variation in post-treatment IOP may include nontherapeutic factors such as diurnal variation, inter-eye asymmetry, regression to the mean, and measurement variability.

    OHTS Scatter Plot
    Figure 1. Scatter plot of post-treatment IOP in first and second eyes from the OHTS (unpublished data).
     

    Assumptions of the Monocular Trial

    There are several underlying assumptions of the monocular trial which must be validated prior to accepting or rejecting this method as a useful tool in clinical practice.3,4

    Assumption 1. IOP response to topical hypotensive medications (therapeutic effects) is similar in both eyes.
    This assumption was recently supported by a retrospective study by Realini et al (Ophthalmology. 2005;112:599-602) who report a strong correlation (r=0.84) between eyes undergoing bilateral simultaneous treatment with topical hypotensive medications. The 43 patients with bilateral glaucoma or ocular hypertension had an IOP-lowering response of 5.0 mm Hg (26.9%) and 4.3 mm Hg (23.7%) in the right and left eyes respectively, suggesting that medication-lowering effects are similar between eyes.

    Data from the OHTS also support this assumption. There was a strong correlation of IOP between both eyes at a baseline visit prior to treatment (r=0.78) (unpublished data). The correlation between eyes remained strong (r=0.78) after bilateral treatment with at least a 20% reduction in IOP 5 months later. These remarkably similar correlations pre-and post-treatment suggest a similar IOP-lowering response of both eyes to the medications, thus further supporting this assumption.

    Assumption 2. Nontherapeutic effects on IOP are similar in both eyes.
    Nontherapeutic influences on the monocular trial can be both intrinsic and extrinsic. Examples of intrinsic effects of the eye include diurnal fluctuations of IOP during separate visits and asymmetric diurnal fluctuations of IOP between eyes during the same visit. Extrinsic factors influencing IOP may include measurement error (observer and instrument), body position, fluid intake, caffeine or alcohol intake, Valsalva, and other factors.

    The monocular trial was designed to control for nontherapeutic influences by using the untreated eye as a control. The assumption that nontherapeutic influences are symmetrical between the two eyes is supported by an earlier study which found fairly symmetric IOPs between eyes over a 24-hour period in normal, ocular hypertensive, and glaucoma patients (Am J Ophthalmol. 1975;79:557-56). More recently, Sit et al showed a lack of a significant difference in mean, peak, or trough IOPs in fellow eyes in the sitting and supine positions (Ophthalmology. 2006;113:425-430).

    The argument against this assumption arises from an earlier study which suggests dissimilar shapes of diurnal curves for fellow eyes (Acta Ophthalmol. 1964;78:1-131). Dissimilar diurnal curves between fellow eyes was found in 36% of glaucoma and 6% of normal patients in a study by Wilensky et al (Ophthalmology. 1993;100:940-944). In a more recent study, spontaneous IOP fluctuations between eyes were found to occur in 16% of visits (1 in 6 visits) for glaucoma patients (Ophthalmology. 2002;109:1367-1371). Supporting and dissenting studies make it unclear whether this assumption is true.

    Assumption 3. Treatment in one eye will not affect IOP in the untreated eye.
    This assumption was proven false after Zimmerman and Kaufman introduced the concept that unilaterally instilled topical beta-blockers lower IOP in the fellow eye through systemic absorption (Arch Ophthalmol. 1977;95:601-4). This contralateral IOP-lowering effect of topical beta-blockers was found to be 1.5 mm Hg or 5.8% of the treated IOP response in the OHTS (Am J Ophthalmol. 2000;130:441-453). The magnitude of the effect was correlated with the magnitude of IOP reduction in the treated eye as well as the baseline IOP in the untreated eye.

    In an attempt to minimize contralateral effects, prostaglandins have been studied for their assumed minimal crossover effect. Realini et al analyzed a subset of patients on latanoprost and still found a poor correlation (r=0.16) in IOP-lowering response between eyes (Ophthalmology. 2004;111:421-6). This poor correlation therefore is likely due to nontherapeutic influences. The OHTS is currently analyzing trials using prostanglandin analogues.

    Is the Monocular Trial Useful In Clinical Practice?

    Predicting the accuracy of the monocular trial may not be as straightforward as once believed. There is a strong correlation between fellow eyes in their response to IOP-lowering medications: if one eye responds, the other eye will likely respond in kind. The problem lies in determining whether the IOP response of the first eye after treatment is attributable to therapeutic or nontherapeutic factors.

    Recommendations have been made to measure several pre- and post-treatment IOP readings to better understand an individual’s IOP range and diurnal variability.3,12,13 Although ideal in theory, this may not be practical. Additional readings would require multiple diurnal curves resulting in increased time and economic burden, compromise to follow-up, decreased patient compliance, and prolonged delay until treatment. Additional methods to reduce nontherapeutic influences include measuring IOP at several times to reduce measurement error, ensuring proper patient positioning, and scheduling follow-up visits at a consistent time of day.

    Future studies and modifications of this therapeutic trial are likely necessary to increase the accuracy of our treatment decisions. Analysis using data from eyes with similar baseline IOPs or comparisons of diurnal variation between eyes in the untreated control group in the OHTS may provide further insight. When using the monocular trial in clinical practice, one should keep in mind the nontherapeutic influences which may affect the results. Future studies may clarify the validity of the monocular trial.

    References

    1. American Academy of Ophthalmology. Primary Open-Angle Glaucoma, Preferred Practice Pattern. San Francisco: American Academy of Ophthalmology, 2005. Available at: https://www.aao.org/ppp.
    2. Realini T, Fechtner RD, Atreides SP, Gollance S. The uniocular drug trial and second-eye response to glaucoma medications. Ophthalmology. 2004;111:421-6.
    3. Realini T, Vickers WR. Symmetry of fellow-eye intraocular pressure responses to topical glaucoma medications. Ophthalmology. 2005;112:599-602.
    4. Smith J, Wandel T. Rationale for the one-eye therapeutic trial. Ann Ophthalmol. 1986;18:8.
    5. Kitazawa Y, Horie T. Diurnal variation of intraocular pressure in primary open-angle glaucoma. Am J Ophthalmol. 1975;79:557-56.
    6. Sit AJ, Liu JH, Weinreb R. Asymmetry of right versus left intraocular pressures over 24 hours in glaucoma patients. Ophthalmology. 2006;113:425-430.
    7. Katavisto M. The diurnal variation of ocular tension in glaucoma. Acta Ophthalmol (Suppl). 1964;78:1-131.
    8. Wilensky JT, Gieser DK, Dietsche ML, et al. Individual variability in the diurnal intraocular pressure curve. Ophthalmology.1993;100:940-4.
    9. Realini T, Barber L, Burton D. Frequency of asymmetric intraocular pressure fluctuations among patients with and without glaucoma. Ophthalmology. 2002;109:1367-71.
    10. Zimmerman TJ, Kaufman HE. Timolol. A beta-adrenergic blocking agent for the treatment of glaucoma. Arch Ophthalmol. 1977;95:601-4.
    11. Piltz J, Gross R, Shin DH, et al. Contralateral effect of topical beta-adrenergic antagonists in initial one-eyed trials in the Ocular Hypertension Treatment Study. Am J Ophthalmol. 2000;130:441-53.
    12. Piltz-Seymour J, Jampel H. The one-eye drug trial revisited. Ophthalmology. 2004;111:419-20.
    13. DeBry PW. Prospective validation of the monocular trial as a test to determine medication effectiveness. Paper presented at: American Glaucoma Society Annual Meeting; March 6, 2004; Sarasota, Fl.

    Author Disclosure

    The author discloses her receipt of clinical research funding from Pfizer and the National Institutes of Health (NIH). She is also on the speaker panel for Alcon. Dr. Bhorade has no proprietary interest in any of the practices or medications discussed in this article.