Systematic review of intra-ocular pressure-lowering effects of adjunctive medications added to latanoprost

Methodological quality of the review: Medium confidence

Author: Cheng JW, Li Y, Wei RL

Geographical coverage: Not reported

Sector: Glaucoma

Sub-sector: Treatment efficacy

Equity focus: None specified

Review type: Effectiveness review

Quantitative synthesis method: Meta-analysis

Qualitative synthesis method: Not applicable

Background: To increase the possibility of lowering intra-ocular pressure (IOP), several commonly used IOP-lowering drugs have been added to latanoprost. The degree of additional reduction in IOP that can be achieved with different drugs is still controversial between different studies. There is a lack of an adequate systematic review to summarise the results of individual clinical trials.

Objectives: To evaluate the lowering effects of adjunctive medications on IOP when added to 0.005% latanoprost taken once daily.

Main findings: In this study, nine randomised controlled trails (RCTs) were included. In general, the quality of the included studies was high. The mean total quality score for all studies was 15.3 (range 13-17). Authors did not identify heterogeneity in funnel plots; p values or absolute reductions from baseline Egger’s measure of publication bias were 0.63 at peak, 0.44 at trough and 0.54 at diurnal curve. No publication bias was identified.

The mean pooled IOP reductions were 3.3 mm Hg (95% CI: 2.1-4.5) at trough and 4.4 mm Hg (95% CI: 3.4-5.4) at peak when adding 0.5% Timolol once daily, 2.6 mm Hg (95% CI: 1.9-3.3) at trough and 3.8 mm Hg (95% CI: 2.5-5.2) at peak when adding 0.1/0.15% Brimonidine twice daily, 2.6 mm Hg (95% CI: 1.7-3.4) at trough and 3.1 mm Hg (95% CI: 2.6-3.6) at peak when adding 2% Dorzolamide twice daily, 2.4 mm Hg (95% CI: 2.0-2.8) at trough and 2.7 mm Hg (95% CI: 2.2-3.2) at peak when adding 0.5% Timolol twice daily, and 2.8 mm Hg (95% CI: 1.5-4.1) at trough and 1.8 mm Hg (95% CI: 1.2-2.3) at peak when adding 1% Brinzolamide twice daily.

Based on these findings, authors conclude that the addition of Brimonidine, Dorzolamide, Timolol or Brinzolamide can further lower IOP in eyes being treated with latanoprost. Timolol 0.5% once daily might be the most effective adjunctive medication.

Authors highly recommend a randomised controlled trial directly comparing single dosing with twice-daily dosing of Timolol as an adjunctive therapy in patients with low responsiveness to latanoprost to further evaluate their true efficacy.

Methodology: PUBMED, EMBASE and the Cochrane Controlled Trials Register were searched for randomised clinical trials using the following key word(s): latanoprost, Xalatan, glaucoma and ocular hypertension. For additional materials and information, Google and Yahoo search engines and references lists were reviewed, and manufacturers of relevant pharmaceutical agents were also contacted. The following studies were selected for inclusion: randomised clinical trials with over 85% of patients presenting with primary open-angle glaucoma or ocular hypertension who were treated with the combination treatment of latanoprost. Two reviewers conducted searches independently which were checked by another reviewer; the same approach was used to extract data of included studies and to assess the methodological quality of included studies. It is not clear, however, whether study selection for inclusion was conducted by two reviewers independently.

The authors performed meta-analysis using a random-effects model on an intention-to-treat basis. To detect publication biases, authors explored asymmetry in funnel plots, which were examined visually; in addition Egger’s measure of publication bias was calculated.

Applicability/external validity: The authors did not discuss the applicability/external validity of the results.

Geographic focus: Authors did not specify which countries were covered by included studies.

Summary of quality assessment: Overall, there is medium confidence in the conclusions about the effects of this study. Authors conducted a comprehensive search of the literature, however the timeframe of the search was not clear. The likelihood of bias of the included studies was addressed and the methodological quality of the included randomised control trials was appropriately assessed. Using this scale, all studies were rated ‘high quality’, meaning methodologically sound. Authors clearly described the method of analysis and addressed issues of heterogeneity in the review.