European Glaucoma Prevention Study

Abstract

If placebo eyedrops lower intraocular pressure (IOP), the history of glaucoma needs to be rewritten. Yet, the European Glaucoma Prevention Study (EGPS) report1European Glaucoma Prevention Study (EGPS) GroupResults of the European Glaucoma Prevention Study.Ophthalmology. 2005; 112: 366-375Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar states: “This result can be explained mainly by a clinically significant effect of the placebo on IOP,” and a “placebo also significantly and consistently lowered IOP.” An examination of the findings of the EGPS study leads one to a different interpretation of their data. It is quite important to know whether lowering of IOP is beneficial to those at risk for developing or progressively worsening from open-angle glaucoma (OAG). Recent clinical trials have shown definitively the benefit of achieving a target IOP lowering to decrease progressive OAG damage.2Kass M.A. Heuer D.K. Higginbotham E.J. et al.The Ocular Hypertension Treatment Study A randomized trial determines that topical ocular hypertensive medication delays or prevents the onset of primary open-angle glaucoma.Arch Ophthalmol. 2002; 120: 701-713Crossref PubMed Scopus (2770) Google Scholar, 3Heijl A. Leske M.C. Bengtsson B. Early Manifest Glaucoma Trial GroupReduction of intraocular pressure and glaucoma progression results from the Early Manifest Glaucoma Trial.Arch Ophthalmol. 2002; 120: 1268-1278Crossref PubMed Scopus (2448) Google Scholar, 4Collaborative Normal-Tension Glaucoma Study GroupComparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressure.Am J Ophthalmol. 1998; 126: 487-497Abstract Full Text Full Text PDF PubMed Scopus (1305) Google Scholar Why did 3 studies of ocular hypertension (OHT) or OAG find that IOP-lowering therapy slowed the progression of the disease, whereas the EGPS seemingly did not? Answers are found in the design and implementation of the study. The EGPS was similar to the Ocular Hypertension Treatment Study (OHTS) in that both were randomized clinical trials among OHT patients with no defined visual field (VF) loss. Both evaluated the effect of lowering IOP, using change in optic disc photographs and automated VFs as end point determinations. The distribution of entry IOP in both studies was similar, from 22 to 23 mmHg at the low end to 29 to 32 mmHg at the high end. However, 3 significant differences with the OHTS may explain the failure of the EGPS to find a therapy benefit: (1) its commitment to dorzolamide therapy alone, regardless of IOP lowering with placebo control; (2) a major regression to the mean in IOP at 6 months; and (3) selective loss to follow-up of persons with higher IOP. First, each OHTS subject who was randomized to treatment was to achieve a target IOP lowering at least 20% below baseline, whereas controls received no therapy. In the EGPS, treated subjects received dorzolamide eyedrops 3 times daily, regardless of their effect, and no other agents were allowed.5European Glaucoma Prevention Study (EGPS) GroupThe European Glaucoma Prevention Study design and baseline description of the participants.Ophthalmology. 2002; 109: 1612-1621Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar In the EGPS, a placebo eyedrop was given to controls, and the study was double masked. In a placebo-controlled study, no IOP target can be set without unmasking. If the chosen single medication is relatively ineffective at IOP lowering, the study will have an uninterpretable result. Indeed, the difference between the mean IOP in treated and placebo EGPS groups was only about 1 mmHg (5% lower). Intraocular pressure was lowered about 25% by treatment in the OHTS and Early Manifest Glaucoma Trial. The EGPS report states that “the overall magnitude of the IOP-lowering effect of dorzolamide” was “15% to 22%,” but this is the IOP value of the treatment group relative to pretreatment, not the net effect when placebo data are taken into account. Second, the IOP was 3 mmHg lower in both drug and placebo EGPS groups at 6 months. Can we accept the authors’ conclusion that buffered mannitol with benzalkonium chloride lowers IOP nearly as well as dorzolamide? Clearly, because placebos have shown no past lowering of IOP in a study cited by the EGPS authors themselves,6Strahlman E. Tipping R. Vogel R. Dorzolamide dose-response study group A six-week dose-response study of the ocular hypotensive effect of dorzolamide with a one-year extension.Am J Ophthalmol. 1996; 122: 183-194Abstract Full Text PDF PubMed Scopus (63) Google Scholar there must be another explanation. The EGPS patients had to have at least 2 IOP measurements above 21 mmHg, but these could be 2 hours apart on the same day. That might have been the high point of the IOP fluctuation range, and because therapy was started apparently without other visits, the next IOP would be, on average, more likely lower than baseline. This is called regression to the mean, and can be minimized by having separate qualifying examinations, later baseline examinations on a different day, then initiation of therapy. The OHTS required separate eligibility and baseline IOP visits,7Gordon M.O. Kass M.A. Ocular Hypertension Treatment Study GroupThe Ocular Hypertension Treatment Study design and baseline description of the participants.Arch Ophthalmol. 1999; 117: 573-583Crossref PubMed Scopus (332) Google Scholar as have other glaucoma clinical trials. Even with this safeguard, regression to the mean can still occur (in the OHTS it averaged 0.6 mmHg (Gordon MO, personal communication, 2005). The EGPS authors agree that the 3 mmHg IOP fall at 6 months in both placebo and drug groups “could have been explained by a regression to the mean” (p. 372). Third, the apparent lowering of IOP by both dorzolamide and a placebo in the EGPS increased over time. Most ophthalmologists do not observe that drugs get more effective with time—if anything, they lose effect. Thus, we are asked to believe not only that a placebo works, but that it gets progressively better. The EGPS authors mention a more likely cause of decreasing IOP over time: they lost many subjects to follow-up, with “those patients with a higher IOP being more likely to withdraw from the trial” (p. 373). Each EGPS group started with over 500 persons, but only about 200 per group remained at 5 years. Those who fluctuated to higher IOP possibly were removed from the study by their ophthalmologists to use different eyedrops. Hence, the mean IOP of the remaining persons decreased, but not because the IOP fell in each retained study subject. The OHTS study found a small decline of IOP over time, but it was associated with coincidental use of systemic β-antagonist pills (Gordon MO, personal communication, 2005). If both the placebo and the treated subjects in the EGPS had minimal true IOP lowering, we would expect that the rate at which they developed damage would be the rate of untreated OHT in the OHTS. Indeed, the EGPS subjects reached damage end points at 2.2% per year, whereas untreated OHTS subjects did so at 1.9% per year. Treatment that lowers IOP by ≥20% reduces this rate to ≤1%.2Kass M.A. Heuer D.K. Higginbotham E.J. et al.The Ocular Hypertension Treatment Study A randomized trial determines that topical ocular hypertensive medication delays or prevents the onset of primary open-angle glaucoma.Arch Ophthalmol. 2002; 120: 701-713Crossref PubMed Scopus (2770) Google Scholar Both the Early Manifest Glaucoma Trial and the Normal-Tension Glaucoma Study4Collaborative Normal-Tension Glaucoma Study GroupComparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressure.Am J Ophthalmol. 1998; 126: 487-497Abstract Full Text Full Text PDF PubMed Scopus (1305) Google Scholar found that IOP lowering improves the outcome in OAG. The logical conclusion is that the EGPS is closer to a natural history study of OHT than a clinical trial that tests for therapy benefit. To evaluate IOP lowering, one has to lower the IOP. It would be truly unfortunate if those who read the EGPS report’s abstract failed to recognize that lack of target IOP, regression to the mean, and selective loss to follow-up are the likely explanations for this study’s results. The EGPS authors feel that their results “strongly support the need to evaluate or reevaluate the efficacy of long-term medical therapy of OHT.” I find more reason to question the interpretation of the EGPS data. Ophthalmologists should feel confident in telling OHT suspects and OAG patients that lowering IOP to 20% to 25% below baseline is an effective means to reduce progressive worsening. European Glaucoma Prevention Study: Author replyOphthalmologyVol. 112Issue 9PreviewWe are thankful for Dr Quigley’s thoughtful remarks on the rather unexpected results of the European Glaucoma Prevention Study (EGPS), in which we could not detect a protective effect of intraocular pressure (IOP) lowering on the development of glaucoma by treatment with dorzolamide because the difference in IOP lowering between dorzolamide and its placebo was only 1 mmHg during the course of the study. Dr Quigley offers several explanations for this effect, and we thank him for this. Dr Quigley suggests that possible explanations may be (1) commitment of the EGPS to dorzolamide therapy alone, regardless of IOP lowering; (2) a major regression to the mean in IOP at 6 months; and (3) selective loss of follow-up of patients with higher IOPs. Full-Text PDF