Glaucoma treatment: by the highest level of evidence

50 years ago, ophthalmologists thought glaucoma and increased intraocular pressure to be synonymous.1Leydhecker W Akiyama K Neumann HG Der introkulare Druck gesunder menschlichen Augen.Klin Monbl Augenheilk. 1958; 133: 662-670Google Scholar In 1958, Wolfgang Leydhecker defined healthy limits for intraocular pressure1Leydhecker W Akiyama K Neumann HG Der introkulare Druck gesunder menschlichen Augen.Klin Monbl Augenheilk. 1958; 133: 662-670Google Scholar and patients with intraocular pressure of 21 mm Hg or higher received a diagnosis of glaucoma, irrespective of whether there were any signs of glaucomatous damage. They were given intraocular-pressure-lowering eye drops, and were told to use these drops three to four times a day or they would go blind. Patients with pressures of 20 mm Hg or lower were told that they did not have glaucoma. The problem was that increased intraocular pressure and glaucoma are not synonymous. The first epidemiological study of glaucoma, done in Wales, UK in the 1960s, showed that many patients with glaucoma had intraocular pressure measurements within Leydhecker's healthy range; these patients were said to have normal-tension glaucoma.2Leske MC The epidemiology of open-angle glaucoma: a review.Am J Epidemiol. 1983; 118: 166-191Crossref PubMed Scopus (427) Google Scholar These findings have been confirmed in dozens of other epidemiological studies, and it is now accepted that about half of all patients with glaucoma have normal-tension glaucoma—a proportion as high as 90% in Japan.3Hollows FC Graham PA Intra-ocular pressure, glaucoma and glaucoma suspects in a defined population.Br J Ophthalmol. 1966; 50: 570-586Crossref PubMed Scopus (551) Google Scholar Equally confusingly, there were many patients with pressures of 21 mm Hg or higher without glaucomatous damage, and when these patients were monitored without treatment for up to 20 years, most of them developed no signs of glaucomatous damage.4Lundberg L Wettrell K Linnér E Ocular hypertension: a prospective twenty-year follow-up study.Acta Ophthalmol. 1987; 65: 705-708Crossref PubMed Scopus (61) Google Scholar Thus, ophthalmologists realised that the relation between increased intraocular pressure and glaucoma was not clear, which led to doubts about the efficacy of intraocular-pressure-lowering therapy. Because this uncertainty was an obstacle to clinical decision making and to allocation of sufficient resources for glaucoma care, clinical studies were needed. The problem was first addressed in four randomised clinical trials in the 1980s5Kass MA Gordon MO Hoff MR et al.Topical timolol administration reduces the incidence of glaucomatous damage in ocular hypertensive individuals. A randomized, double-masked, long-term clinical trial.Arch Ophthalmol. 1989; 107: 1590-1598Crossref PubMed Scopus (152) Google Scholar, 6Schulzer M Drance SM Douglas GR A comparison of treated and untreated glaucoma suspects.Ophthalmology. 1991; 98: 301-307Summary Full Text PDF PubMed Scopus (97) Google Scholar, 7Epstein DL Krug Jr, JH Hertzmark E Remis LL Edelstein DJ A long-term clinical trial of timolol therapy versus no treatment in the management of glaucoma suspects.Ophthalmology. 1989; 96: 1460-1467Summary Full Text PDF PubMed Scopus (147) Google Scholar, 8Heijl A Bengtsson B Long-term effects of timolol therapy in ocular hypertension: a double-masked, randomised trial.Graefes Arch Clin Exp Ophthalmol. 2000; 238: 877-883Crossref PubMed Scopus (35) Google Scholar that investigated whether a reduction of intraocular pressure in patients with increased pressure in the absence of glaucomatous damage (ocular hypertension) could reduce the incidence of glaucoma damage. Results were inconclusive,5Kass MA Gordon MO Hoff MR et al.Topical timolol administration reduces the incidence of glaucomatous damage in ocular hypertensive individuals. A randomized, double-masked, long-term clinical trial.Arch Ophthalmol. 1989; 107: 1590-1598Crossref PubMed Scopus (152) Google Scholar, 6Schulzer M Drance SM Douglas GR A comparison of treated and untreated glaucoma suspects.Ophthalmology. 1991; 98: 301-307Summary Full Text PDF PubMed Scopus (97) Google Scholar, 7Epstein DL Krug Jr, JH Hertzmark E Remis LL Edelstein DJ A long-term clinical trial of timolol therapy versus no treatment in the management of glaucoma suspects.Ophthalmology. 1989; 96: 1460-1467Summary Full Text PDF PubMed Scopus (147) Google Scholar, 8Heijl A Bengtsson B Long-term effects of timolol therapy in ocular hypertension: a double-masked, randomised trial.Graefes Arch Clin Exp Ophthalmol. 2000; 238: 877-883Crossref PubMed Scopus (35) Google Scholar and a 1989 report commissioned by the US Congress concluded that there was no proof that lowering of intraocular pressure reduced glaucomatous damage. Investigators then started two randomised controlled studies of patients with manifest glaucoma. The Collaborative Normal-Tension Glaucoma Study (CNTGS) enrolled only patients with normal-tension glaucoma, whereas the Early Manifest Glaucoma Trial (EMGT) studied patients with glaucoma who had normal and increased pressures; both trials compared pressure-lowering treatment with no treatment. The intention-to-treat analysis in CNGTS did not report significant effects, but after correction for the increased incidence of cataract in the treated group, the researchers reported positive treatment effects.9Collaborative Normal-Tension Glaucoma Study GroupThe effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma.Am J Ophthalmol. 1998; 126: 498-505Summary Full Text Full Text PDF PubMed Scopus (1153) Google Scholar Findings from EMGT showed that pressure lowering had positive effects, irrespective of patients' initial intraocular pressures.10Heijl A Leske MC Bengtsson B Hyman L Bengtsson B Hussein M Early Manifest Glaucoma Trial GroupReduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial.Arch Ophthalmol. 2002; 120: 1268-1279Crossref PubMed Scopus (2619) Google Scholar In The Lancet, David Garway-Heath and colleagues11Garway-Heath DF Crabb DP Bunce C et al.Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial.Lancet. 2014; (published online Dec 19.)http://dx.doi.org/10.1016/S0140-6736(14)62111-5PubMed Google Scholar report results of the United Kingdom Glaucoma Treatment Study (UKGTS), a randomised clinical trial to investigate the effects of intraocular pressure lowering in glaucoma patients with healthy pressures. UKGTS involved ten centres in the UK, in which 516 patients were randomly assigned. In some ways, UKGTS was modelled on the EMGT—eg, the original primary outcome (which was later amended), but the two studies also differed in several respects. First, UKGTS was placebo controlled and EMGT was not. Second, UKGTS used monotherapy in the treatment group—prostaglandin analogue eye drops (latanoprost 0·005%), the most commonly used antiglaucoma therapy in high-income countries. The authors also aimed to use a study design from which conclusions could be drawn in a relatively short time—patients were followed up for only 2 years. To achieve this, 11 visual field tests were obtained during this period, since it is well known that identification of visual field progression or measurement of rate of progression needs several field tests, and that the time needed to identify progression strongly depends on the frequency of testing. Garway-Heath and colleagues' study11Garway-Heath DF Crabb DP Bunce C et al.Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial.Lancet. 2014; (published online Dec 19.)http://dx.doi.org/10.1016/S0140-6736(14)62111-5PubMed Google Scholar is important in many ways, perhaps most importantly because it is the second to show the positive treatment effects of intraocular pressure reduction in manifest glaucoma. For the highest level of medical evidence, more than one study is usually required and this has been absent in the area until now. Since modern glaucoma treatment is based on reduction of intraocular pressure, and because glaucoma management uses about 25% of all ophthalmology resources, this is a fundamental issue in ophthalmic care. That the study was placebo controlled is a further strength. The magnitude of treatment effects is also important. The intraocular pressure difference between the treated and the placebo groups after 24 months was slight (2·9 mm Hg), due to the fact that untreated pressures at study entry were quite low. Intraocular-pressure-reducing drugs produce much smaller pressure reductions in eyes that start with low pressures than in eyes in which pressure is high. Still, the risk of progression was substantially lower in the treated group than in the group receiving placebo drops (adjusted hazard ratio [HR] 0·44 [95% CI 0·28–0·69]). From this HR, the risk reduction could be about 19% per mm Hg, confirming results from the EMGT and Canadian Glaucoma Study, and showing that intraocular pressure reduction is highly effective, and that every mm of pressure counts.12Leske MC Heijl A Hyman L Bengtsson B Dong L Yang Z EMGT GroupPredictors of long-term progression in the early manifest glaucoma trial.Ophthalmology. 2007; 114: 1965-1972Summary Full Text Full Text PDF PubMed Scopus (1031) Google Scholar, 13Chauhan BC Mikelberg FS Balaszi AG LeBlanc RP Lesk MR Trope GE Canadian Glaucoma Study GroupCanadian Glaucoma Study 2: risk factors for the progression of open-angle glaucoma.Arch Ophthalmol. 2008; 126: 1030-1036Crossref PubMed Scopus (182) Google Scholar These results should motivate careful clinical follow-up and monitoring of disease progression in patients with glaucoma, and should also serve as a stimulus to the pharmaceutical industry to continue development of new and even more potent drugs. It is important that Garway-Heath and colleagues11Garway-Heath DF Crabb DP Bunce C et al.Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial.Lancet. 2014; (published online Dec 19.)http://dx.doi.org/10.1016/S0140-6736(14)62111-5PubMed Google Scholar documented very significant treatment effects after only 24 months; in fact, the first differences were seen after 12 months (adjusted HR 0·47; 95% CI 0·23–0·95). Certainly, the UKGTS took a lot longer than 2 years to complete, but only because recruitment took several years. Measurement of glaucomatous progression with visual field status is the gold standard, and visual field sensitivity is also important to patients. Nevertheless, in recent years some researchers have stated that studies using visual field endpoints take too long, and that it is too difficult to assess the effects of new drugs or other treatments. Garway-Heath and colleagues clearly show that this view is pessimistic, and that, with frequent testing with widely available clinical instruments, important studies can be completed within a very reasonable time. I expect this to be the first of a series of papers reporting UKGTS results; additional findings will be reported in future, notably those that compare the results obtained with visual field testing with those of ophthalmic image analysis. I consult for Carl Zeiss Meditec and Allergan, and have received honoraria for speaking from Allergan, Merck Sharp & Dohme, and Santen. Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trialThis is the first randomised placebo-controlled trial to show preservation of the visual field with an intraocular-pressure-lowering drug in patients with open-angle glaucoma. The study design enabled significant differences in vision to be assessed in a relatively short observation period. 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