Comparative Effectiveness of First-Line Medications for Primary Open-Angle Glaucoma: A Systematic Review and Network Meta-analysis

Abstract

Topic: Primary open-angle glaucoma (POAG) is a highly prevalent condition worldwide and the most common cause of irreversible sight loss. The objective is to assess the comparative effectiveness of first-line medical treatments in patients with POAG or ocular hypertension through a systematic review and network meta-analysis, and to provide relative rankings of these treatments.

Clinical relevance: Treatment for POAG currently relies completely on lowering the intraocular pressure (IOP). Although topical drops, lasers, and surgeries can be considered in the initial treatment of glaucoma, most patients elect to start treatment with eye drops.

Methods: We included randomized controlled trials (RCTs) that compared a single active topical medication with no treatment/placebo or another single topical medication. We searched CENTRAL, MEDLINE, EMBASE, and the Food and Drug Administration's website. Two individuals independently assessed trial eligibility, abstracted data, and assessed the risk of bias. We performed Bayesian network meta-analyses.

Results: We included 114 RCTs with data from 20 275 participants. The overall risk of bias of the included trials is mixed. The mean reductions (95% credible intervals) in IOP in millimeters of mercury at 3 months ordered from the most to least effective drugs were as follows: 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 3.70 (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).

Conclusions: All active first-line drugs are effective compared with placebo in reducing IOP at 3 months. Bimatoprost, latanoprost, and travoprost are among the most efficacious drugs, although the within-class differences were small and may not be clinically meaningful. All factors, including adverse effects, patient preferences, and cost, should be considered in selecting a drug for a given patient.

Figure 1. Selection of studies

POAG: primary open angle glaucoma FDA: Food and Drug Administration RCT: Randomized controlled trial Our search was broad and included all medical interventions for glaucoma. We reviewed a large number of full text articles because some of them will be used in different but related systematic reviews, for example, combination drug therapy for glaucoma.

Figure 2

Risk of bias figure

Figure 3. Network graph

Each node represents one drug. The drugs are color-coded by class. The size of the node is proportional to the number of participants randomized to that drug. The edges represent direct comparisons, that is, when there is a line connecting two drugs, the two drugs have been compared directly to each other in a trial. The width of the edge is proportional to the number of trials. Total number studies =114 Number of published studies =104 (11 three-arm studies) Number of FDA studies =10 (1 three-arm study, 1 four-arm study) Total number of patients contributing to this network =20,275 Color coding: White: Placebo/vehicle/no treatment Purple: Alpha-2 adrenergic agonist Yellow: Beta-blocker Orange: Carbonic anhydrase inhibitor Turquoise: Prostaglandin analog

Figure 4

Ranking probabilities for any drug at any position

Figure 5. Cumulative ranking probabilities for each drug

The SUCRA value (SUrface under the Cumulative RAnking curve) represents the surface underneath the cumulative ranking curve and is the posterior probabilities for each drug to be among the n-best options (15, 16). The larger the SUCRA value, the higher the ranking probabilities for the drug among the drugs compared. Rankings based on SUCRA values account better for the uncertainly in the estimated treatment effects (15, 16). SUCRA values normalized to %: Placebo (0.01), Apraclonidine (30.55), Brimonidine (57.09), Betaxolol (21.62), Carteolol (53.44), Levobunolol (77.96), Timolol (60.39), Levobetaxolol (31.56), Brinzolamide (27.67), Dorzolamide (30.36), Bimatoprost (99.66), Latanoprost (86.56), Travoprost (85.76), Tafluprost (74.79), Unoprostone (12.44)