Prostaglandin analogues and timolol-fixed versus unfixed combinations or monotherapy for open angle glaucoma: a systematic review and meta-analysis

Methodological quality of the review: High confidence

Author: Quaranta L, Biagioli E, Riva I, Rulli E, Poli D, Katsanos A, Floriani I

Geographical coverage: Not reported

Sector: Glaucoma

Sub-sector: Open angle glaucoma

Equity focus: None specified

Review type: Effectiveness review

Quantitative synthesis method: Meta-analysis

Qualitative synthesis method: Not applicable

Background: Multi-drug therapy is frequently used for the management of glaucoma, and prostaglandin analogues (PGAs) in combination with beta blockers are frequently used. Several years ago, PGA fixed combinations (FCs) were introduced to improve adherence to chronic topical medical therapy in patients with ocular hypertension (OHT) and open angle glaucoma (OAG). Therefore, it is important to assess the efficacy and tolerability of these combinations.

Objectives: To estimate the intra-ocular pressure (IOP)-lowering effect of PGAs administered in combination with beta blockers.

Main findings: In this meta-analysis, 18 eligible trials involved 23 comparisons of FC versus monotherapy (Mt), and five of FC versus unfixed (UC) were included. The methodological quality of studies was overall good. Authors noted that selection bias could not be excluded in 14 studies and attrition bias could not be excluded in six studies. Authors noted that no asymmetry in the funnel plot was detected as such, suggesting low risk of publication of bias.

Findings from the meta-analysis suggested that FCs were less efficacious than UCs (MeD: 0.69, 95% CI: 0.29 to 1.08). In comparison with timolol Mt, the latanoprost/timolol FC led to a greater IOP reduction (MeD: −2.74, 95% CI: −3.24 to −2.23) than the bimatoprost/timolol FC (MeD: −1.49, 95% CI: −1.86 to −1.12) or the travoprost/timolol FC (MeD: −1.93, 95%CI: −2.98 to −0.88). Results from the pooled analysis suggested that FCs led to a lower hyperemia risk than UCs [relative risk (RR): 0.70, 95% CI: 0.43 to 1.14] and PGA Mt (RR: 0.61, 95% CI: 0.53 to 0.70). Based on these findings, authors concluded that fixed combinations are more effective than their individual components, but less effective than their respective UCs. FCs lead to a lower hyperemia risk than their respective UCs PGA Mt.

Authors noted that future studies for direct comparison of FCs will be helpful to draw definite conclusions.

Methodology: Authors searched MEDLINE and EMBASE databases for randomised trials comparing topical therapies with PGAs and timolol administered as Mt, or in FC or UC to patients with glaucoma or ocular hypertension. The efficacy endpoint was the mean difference (MeD) in the reduction in IOP from baseline; the tolerability endpoint was the incidence of hyperemia.

Although no language restrictions were applied to searches when sifting studies for inclusion, studies written in languages other than English were excluded. Authors also reviewed reference lists of trial reports and narrative and systematic reviews to identify additional trials. Sifting of studies for inclusion was independently conducted by three reviewers.

Data extraction, as well as quality assessment of studies, was independently conducted by two reviewers. Quality assessment was conducted using a modified version of the Delphi list. Additional items were included to avoid bias most frequently highlighted in ophthalmology studies.

Authors conducted a systematic review and meta-analysis of included studies. Pooled MeD estimates were calculated using the two-step method for the random-effects model proposed by DerSimonian and Laird. Tolerability was only evaluated on the basis of the incidence of conjunctival hyperemia as an overall assessment of other adverse events.

Statistical heterogeneity was quantified using the I2 statistic, and Chi-squared tests for homogeneity were also used. Sub-group analyses were made by the type of PGA and the time of administration of the same Mt (timolol or PGA) The chi-squared test and I2 statistics were calculated to compare the differences between sub-groups. To detect publication bias or small-study effect, authors examined funnel plot asymmetry.

Applicability/external validity: No methods were used either to assess the applicability/external validity of the results or to discuss how generalizable the results are. Despite the lack of detail of included studies, authors noted not restricting the search based on sex, age, race or gender.

Geographic focus: This review focuses on all countries. It is not clear if studies from low/middle-income countries were included or not.


Summary of quality assessment: Overall, there is high confidence in the conclusions about the effects of this study as minor limitations were identified. Authors conducted a partially comprehensive search of the literature, restricting to the inclusion on studies written in English only. However, authors used appropriate methods to sift studies for inclusion, extract data and assess methodological quality of included studies, minimising the risk of bias. Authors appropriately acknowledged limitations and biases of included studies. No strong policy conclusions were drawn based on included studies.

Publication source: Quaranta L, Biagioli E, Riva I, Rulli E, Poli D, Katsanos A, Floriani I. Prostaglandin analogues and timolol-fixed versus unfixed combinations or monotherapy for open angle glaucoma: a systematic review and meta-analysis. J Ocul Pharmacol Ther. 2013 May;29(4):382-9. Source