Background Primary open-angle glaucoma (POAG) is one of the leading causes of blindness in the United States and worldwide. Three to 6 million people in the United States are at increased risk for developing POAG because of elevated intraocular pressure (IOP), or ocular hypertension. There is no consensus on the efficacy of medical treatment in delaying or preventing the onset of POAG in individuals with elevated IOP. Therefore, we designed a randomized clinical trial, the Ocular Hypertension Treatment Study. Objective To determine the safety and efficacy of topical ocular hypotensive medication in delaying or preventing the onset of POAG. Methods A total of 1636 participants with no evidence of glaucomatous damage, aged 40 to 80 years, and with an IOP between 24 mm Hg and 32 mm Hg in one eye and between 21 mm Hg and 32 mm Hg in the other eye were randomized to either observation or treatment with commercially available topical ocular hypotensive medication. The goal in the medication group was to reduce the IOP by 20% or more and to reach an IOP of 24 mm Hg or less. Main Outcome Measures The primary outcome was the development of reproducible visual field abnormality or reproducible optic disc deterioration attributed to POAG. Abnormalities were determined by masked certified readers at the reading centers, and attribution to POAG was decided by the masked Endpoint Committee. Results During the course of the study, the mean ± SD reduction in IOP in the medication group was 22.5% ± 9.9%. The IOP declined by 4.0%± 11.6% in the observation group. At 60 months, the cumulative probability of developing POAG was 4.4% in the medication group and 9.5% in the observation group (hazard ratio, 0.40; 95% confidence interval, 0.27-0.59; P Conclusions Topical ocular hypotensive medication was effective in delaying or preventing the onset of POAG in individuals with elevated IOP. Although this does not imply that all patients with borderline or elevated IOP should receive medication, clinicians should consider initiating treatment for individuals with ocular hypertension who are at moderate or high risk for developing POAG.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/270953/ecs20045.pdf

The Ocular Hypertension Treatment Study: A Randomized Trial Determines That Topical Ocular Hypotensive Medication Delays or Prevents the Onset of Primary Open-Angle Glaucoma

Objective To provide the results of the Early Manifest Glaucoma Trial, which compared the effect of immediately lowering the intraocular pressure (IOP), vs no treatment or later treatment, on the progression of newly detected open-angle glaucoma. Design Randomized clinical trial. Participants Two hundred fifty-five patients aged 50 to 80 years (median, 68 years) with early glaucoma, visual field defects (median mean deviation, −4 dB), and a median IOP of 20 mm Hg, mainly identified through a population screening. Patients with an IOP greater than 30 mm Hg or advanced visual field loss were ineligible. Interventions Patients were randomized to either laser trabeculoplasty plus topical betaxolol hydrochloride (n = 129) or no initial treatment (n = 126). Study visits included Humphrey Full Threshold 30-2 visual field tests and tonometry every 3 months, and optic disc photography every 6 months. Decisions regarding treatment were made jointly with the patient when progression occurred and thereafter. Main Outcome Measures Glaucoma progression was defined by specific visual field and optic disc outcomes. Criteria for perimetric progression were computer based and defined as the same 3 or more test point locations showing significant deterioration from baseline in glaucoma change probability maps from 3 consecutive tests. Optic disc progression was determined by masked graders using flicker chronoscopy plus side-by-side photogradings. Results After a median follow-up period of 6 years (range, 51-102 months), retention was excellent, with only 6 patients lost to follow-up for reasons other than death. On average, treatment reduced the IOP by 5.1 mm Hg or 25%, a reduction maintained throughout follow-up. Progression was less frequent in the treatment group (58/129; 45%) than in controls (78/126; 62%) ( P =.007) and occurred significantly later in treated patients. Treatment effects were also evident when stratifying patients by median IOP, mean deviation, and age as well as exfoliation status. Although patients reported few systemic or ocular conditions, increases in clinical nuclear lens opacity gradings were associated with treatment ( P = .002). Conclusions The Early Manifest Glaucoma Trial is the first adequately powered randomized trial with an untreated control arm to evaluate the effects of IOP reduction in patients with open-angle glaucoma who have elevated and normal IOP. Its intent-to-treat analysis showed considerable beneficial effects of treatment that significantly delayed progression. Whereas progression varied across patient categories, treatment effects were present in both older and younger patients, high- and normal-tension glaucoma, and eyes with less and greater visual field loss.

http://bmec.swbh.nhs.uk/wp-content/uploads/2013/03/Early-Manifest-Glaucoma-Trial.pdf

Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial.

Objective: To assess factors for progression in the Early Manifest Glaucoma Trial (EMGT), including the effect of EMGT treatment. Setting/Participants: Two hundred fifty-five open-angle glaucoma patients randomized to argon laser trabeculoplasty plus topical betaxolol or no immediate treatment (129 treated; 126 controls) and followed up every 3 months. Methods: Progression was determined by perimetric and photographic optic disc criteria. Patient-based risk of progression was evaluated using Cox proportional hazard regression models and was expressed as hazard ratios (HR) with 95% confidence intervals (95% CI). Results: After 6 years, 53% of patients progressed. In multivariate analyses, progression risk was halved by treatment (HR=0.50; 95% CI, 0.35-0.71). Predictive baseline factors were higher intraocular pressure (IOP) (ie, the higher the baseline IOP, the higher the risk), exfoliation, and having both eyes eligible (each of the latter 2 factors doubled the risk), as well as worse mean deviation and older age. Progression risk decreased by about 10% with each millimeter of mercury of IOP reduction from baseline to the first follow-up visit (HR=0.90 per millimeter of mercury decrease; 95% CI, 0.86-0.94). The first IOP at that visit (3 months' follow-up) was also related to progression (HR=1.11 per millimeter of mercury higher; 95% CI, 1.06-1.17), as was the mean IOP at follow-up (HR=1.13 per millimeter of mercury higher; 95% CI, 1.07-1.19). The percent of patient follow-up visits with disc hemorrhages was also related to progression (HR=1.02 per percent higher; 95% CI, 1.01-1.03). No other factors were identified. Conclusions: Patients treated in the EMGT had half of the progression risk of control patients. The magnitude of initial IOP reduction was a major factor influencing outcome. Progression was also increased with higher baseline IOP, exfoliation, bilateral disease, worse mean deviation, and older age, as well as frequent disc hemorrhages during follow-up. Each higher (or lower) millimeter of mercury of IOP on follow-up was associated with an approximate 10% increased (or decreased) risk of progression.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/415002/ecs20139.pdf

Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial.

ContextPrevious studies indicate that industry-sponsored trials tend to draw
proindustry conclusions.ObjectiveTo explore whether the association between funding and conclusions in
randomized drug trials reflects treatment effects or adverse events.DesignObservational study of 370 randomized drug trials included in meta-analyses
from Cochrane reviews selected from the Cochrane Library, May 2001. From a
random sample of 167 Cochrane reviews, 25 contained eligible meta-analyses
(assessed a binary outcome; pooled at least 5 full-paper trials of which at
least 1 reported adequate and 1 reported inadequate allocation concealment).
The primary binary outcome from each meta-analysis was considered the primary
outcome for all trials included in each meta-analysis. The association between
funding and conclusions was analyzed by logistic regression with adjustment
for treatment effect, adverse events, and additional confounding factors (methodological
quality, control intervention, sample size, publication year, and place of
publication).Main Outcome MeasureConclusions in trials, classified into whether the experimental drug
was recommended as the treatment of choice or not.ResultsThe experimental drug was recommended as treatment of choice in 16%
of trials funded by nonprofit organizations, 30% of trials not reporting funding,
35% of trials funded by both nonprofit and for-profit organizations, and 51%
of trials funded by for-profit organizations (P<.001; χ2 test). Logistic regression analyses indicated that funding, treatment
effect, and double blinding were the only significant predictors of conclusions.
Adjusted analyses showed that trials funded by for-profit organizations were
significantly more likely to recommend the experimental drug as treatment
of choice (odds ratio, 5.3; 95% confidence interval, 2.0-14.4) compared with
trials funded by nonprofit organizations. This association did not appear
to reflect treatment effect or adverse events.ConclusionsConclusions in trials funded by for-profit organizations may be more
positive due to biased interpretation of trial results. Readers should carefully
evaluate whether conclusions in randomized trials are supported by data.

https://jamanetwork.com/journals/jama/articlepdf/197132/JOC30680.pdf

Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events?

Early Manifest Glaucoma Trial: design and baseline data.

Clinical ability of Heidelberg retinal tomograph examination to detect glaucomatous visual field changes.

• A systematic quantitative and qualitative overview of published randomized clinical trials was undertaken to assess the yield of medical treatment on the outcome of patients with primary open angle glaucoma. Reports of 102 randomized clinical trials were published between 1975 and 1991, totaling about 5000 patients. Only 16% (16/102) of the trials were, however, properly designed (ie, comparing an active treatment with a placebo-treated or untreated control group) to answer the question of whether any medical treatment can effectively cure patients with primary open angle glaucoma. Pooled analysis showed a moderate yet statistically significant reduction in mean intraocular pressure (−4.9 mm Hg; 95% confidence interval [Cl], −7.3 to −2.5 mm Hg); however, data on long-term visual field changes were available in only three randomized clinical trials, and their statistical combination failed to show a significant protective effect of active treatment (odds ratio, 0.75; 95% CI, 0.42 to 1.35). All of the remaining 86 randomized clinical trials looked at the effectiveness of one drug vs another in lowering intraocular pressure and were thus of no use in the overview. Practicing ophthalmologists should be aware that the effectiveness of pressure-lowering agents in the treatment of primary open angle glaucoma is still to be determined and that the vast majority of published trials are not appropriate to guide clinical practice. It is urgent to plan trials with end-point and follow-up duration that is fully relevant for the health of patients.

Randomized clinical trials on medical treatment of glaucoma. Are they appropriate to guide clinical practice

Heart rate variability to monitor performance in elite athletes: Criticalities and avoidable pitfalls

Randomized clinical trials on medical treatment of glaucoma: Are they appropriate to guide clinical practice?

OBJECTIVE The aim of this study was to assess critically the published literature concerning medical treatment of primary open-angle glaucoma (POAG), and to see whether trial methodologic quality was related to a clinically relevant outcome measure. METHODS We identified and reviewed the methodologic quality of 102 published randomized clinical trials (RCTs) on treatment of POAG using an explicit protocol and explored the association between selected aspects of design and conduct and the studies' clinical relevance. RESULTS Our analysis revealed serious methodologic problems with the trials reviewed. Areas of major concern were: use of unsatisfactory or unspecified methods of randomization (89% of the trials reported no information), exclusion of some patients from the analysis (53% of the studies), failure to provide evidence of having estimated the number of patients needed to detect a prespecified treatment difference (96% failed to provide such an estimate), and incomplete description of patient characteristics (in 39% of the RCTs information on this item was insufficient). Within this generally unsatisfactory picture we found, however, that those studies adopting a double-masked design and those not excluding patients after randomization followed patients for longer periods of time and assessed treatment effectiveness using a clinically relevant outcome (that is, visual field changes) compared to other studies. CONCLUSIONS For clinicians to make use of the results of clinical trials, future studies must be adequately designed and conducted. In particular, proper method of randomization, masking of the observers, and inclusion of all randomized patients in the analysis must be used. Of perhaps even greater importance is the need for trials to measure clinically relevant outcomes.

Is proper methodology associated with the use of a clinically relevant outcome measure? The case of randomized clinical trials on medical treatment of open-angle glaucoma.

Ilaria Marchetti

Papers

Clinical ability of Heidelberg retinal tomograph examination to detect glaucomatous visual field changes.

Randomized clinical trials on medical treatment of glaucoma. Are they appropriate to guide clinical practice

Heart rate variability to monitor performance in elite athletes: Criticalities and avoidable pitfalls

Randomized clinical trials on medical treatment of glaucoma: Are they appropriate to guide clinical practice?

Is proper methodology associated with the use of a clinically relevant outcome measure? The case of randomized clinical trials on medical treatment of open-angle glaucoma.