Comparative effectiveness of first-line medications for primary open angle glaucoma – a systematic review and network meta-analysis

Methodological quality of the review: High Confidence

Authors: Li T, Lindsley K, Rouse B, Hong H, Shi Q, Friedman DS, Wormald R, Dickersin K

Region: Worldwide

Sector: Glaucoma

Sub-sector: Treatment

Equity focus:  None specified

Review type: Other review

Quantitative synthesis method: Meta-analysis

Qualitative synthesis method: Not applicable

Background:

Glaucoma is an acquired disease of the optic nerve with characteristic optic nerve head changes and associated visual field defects. It is the second leading cause of blindness worldwide. Nearly three quarters of all glaucoma occurs in individuals with open angles, and open-angle glaucoma (OAG) is the most common form of glaucoma in nearly all countries. Primary open-angle glaucoma (POAG) is a highly prevalent condition worldwide and the most common cause of irreversible sight loss.

Objectives:

The objective is to assess the comparative effectiveness of first line medical treatments in patients with POAG or ocular hypertension, and to provide relative rankings of these treatments.

Main findings:

The authors included a total of 114 RCTs in their network meta-analysis. These trials were published between 1983 and 2013, included a total of 20,275 participants. 78 trials were multi-center trials. Of the 85 reporting the regions in which participants were recruited, 47 recruited participants from North America, 20 from Europe, 17 from Asia, four from Latin America, four (5%) from Oceania, and two from Africa (a trial could recruit participants from more than one region). The overall risk of bias of RCTs was mixed as noted by the authors.

Included trials compared 15 interventions (14 active drugs and “placebo/vehicle/no treatment”). Timolol was the most often used comparator and was studied in 70 trials. 101 trials had two treatment arms, 12 trials had three arms, and the remaining trial had four arms.

The authors found that all active drugs to be more effective compared to placebo in lowering IOP at three months. The mean reductions (95% credible intervals) in IOP in mmHg at three months, ordered from the most to least effective drugs based on the SUCRA values were: bimatoprost 5·61 (4·94; 6·29), latanoprost 4·85 (4·24; 5·46), travoprost 4·83 (4·12; 5·54), levobunolol 4·51 (3·85; 5·24), tafluprost 4·37 (2·94; 5·83), timolol 3·7 (3·16; 4·24), brimonidine 3·59 (2·89; 4·29), carteolol 3·44 (2·42; 4·46), levobetaxolol 2·56 (1·52; 3·62), apraclonidine 2·52 (0·94; 4·11), dorzolamide 2·49 (1·85; 3·13), brinzolamide 2·42 (1·62; 3·23), betaxolol 2·24 (1·59; 2·88), and unoprostone 1·91 (1·15; 2·67). The authors noted that bimatoprost, latanoprost, and travoprost are among the most efficacious drugs, although the within-class differences were small and may not be clinically meaningful. Most trials did not measure or report visual field or other patient-centered outcomes, such as visual function and blindness. In addition, the authors mentioned that all factors, including side effects, patient preferences, and cost should be considered in selecting a drug for a given patient.

Methodology:

The authors included trials if they were reported to be randomized parallel group trials if 60% or more of randomized participants had a diagnosis of POAG and/or OH, as defined by the trialists. Trials were eligible if they evaluated first line topical medical interventions from one of four drug classes – beta blockers, carbonic anhydrase inhibitors, alpha-2 adrenergic agonists, and prostaglandin analogs – to reduce intraocular pressure (IOP) or progression of visual field damage; and compared a single active treatment with no treatment/placebo or another single active topical medical treatment. The authors pre-specified difference in mean IOP measured by any method at three months in continuous mmHg as their primary outcome measure. Secondary outcome measure included visual field.

The authors searched Cochrane Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, and EMBASE on November 17, 2009 and updated the search on March 11, 2014. No language restriction was imposed. The authors also searched the US Food and Drug Administration’s website (Drugs@FDA) in April 2014 for drugs potentially eligible studies.

Two authors independently screened studies for inclusion and extracted data of included studies, apart from studies written in languages other than English. Risk of bias was assessed using the Cochrane Risk of Bias Tool.

In the primary analysis, the authors combined different concentrations of the same medication and separated bimatoprost and timolol into two concentrations in an ad hoc sensitivity analysis. In addition, the authors generated probabilities of each treatment taking each possible rank and the cumulative ranking.

Applicability/external validity:

All active first-line drugs are effective compared to placebo in reducing IOP at three months. All factors, including adverse effects, patient preferences, and cost should be considered in selecting a drug for a given patient.

Geographic focus:

The authors did not specify the geographic focus of included studies. However, the authors note in the discussion that the ranking drug in lowering IOP at three months (that is, bimatoprost 0·03%) is no longer sold, being replaced on the market by a lower concentration. The authors also mention that in developing countries, timolol is the only accessible and affordable option among the top ranked drugs, as reflected in prescription patterns.

Summary of quality assessment:

Overall, there is high confidence in the conclusions about the effects of this study. The authors used appropriate methods to identify, appraise and review findings of included studies.