Results of literature search
Our first and second search produced 35,207 and 97,523 abstracts respectively. The third and final search (search #1 AND #2 pooled) produced 1144 abstracts. After thorough assessment, 215 abstracts were excluded since they were review articles. Another 549 abstracts were excluded as they were not relevant to present study. Overall, 380 full text papers were retrieved for possible inclusion. Upon careful review of the 380 full text articles, we included 47 full text articles in our analysis (Phi = 0.88). Figure presents details of the exclusion criteria at the various stages during the study selection process.
Flow diagram of included studies
Table outlines the characteristics of all 47 included publications. Of these, 31 reported conducting comparisons of treatments (e.g., travoprost vs. latanoprost) that were duplicated in at least one other included study. More specifically, five trials compared bimatoprost to latanoprost [11
]. Four trials compared bimatoprost and timolol [16
]. Three trials compared bimatoprost to a fixed combination (FC) treatment that contained timolol [20
Characteristics of included publications
Six trials compared latanoprost to timolol [13
]. Three studies compared latanoprost to brimonidine (or brimonidine-containing fixed combination) [28
]. Two studies compared FC latanoprost/timolol vs FC dorzolamide/timolol [31
]. Two studies compared FC latanoprost/timolol versus its individual components (i.e. latanoprost and timolol) [33
]. Two studies compared FC latanoprost/timolol versus latanoprost and timolol administered concomitantly [35
Four studies compared travoprost and latanoprost [12
]. Two studies compared travoprost and timolol [23
]. Two studies compared travoprost or FC-containing travoprost versus latanoprost (or FC-containing latanoprost) [39
] and three studies compared travoprost or FC-containing travoprost versus timolol (or FC-containing timolol) [39
]. Finally, 16 publications contained other comparisons of treatment types that were not duplicated with any other included study. [42
Characteristics of trials
Table shows the characteristics of the trials as well as the quality of reporting. The average sample size was 311 (SD 33), although on average, only 86% of patients were included in the final analyses. Seventeen out of the included 47 trials (36%, 95% CI: 24–51) were crossover designs.
Methodological quality and reporting
Of the 47 trials, 36 were noninferiority trials (77%, 95% CI: 63–86) and 11 (23%, 95% CI: 14–37) were designed for equivalence. In the final interpretations of the studies, 16/47 (34%, 95% CI: 22–48) trials claimed noninferiority, 14/47 (30%, 95% CI: 19–44) claimed equivalence and 17/47 (36%, 95% CI: 24–51) claimed superiority. For the trials claiming noninferiority, 33/36 (92%, 95% CI: 78–92) were accurate within their noninferiority margin. For those claiming equivalency, 10/11 (90%, 95% CI: 62–98) were accurate within their a priori margins. Seventeen percent of trials (8/47, 95% CI: 9–30) employed a combined test of noninferiority and superiority.
Sequence generation was reported in 22/47 trials (47%, 95% CI: 33–61). Allocation concealment was reported in only 10/47 (21%, 95% CI: 12–35) of the trials. Thirty-five studies (74%, 95% CI: 60–85) employed masking of at least two groups, 4/47 (9%, 95% CI: 3–20) masked only patients and 8/47 (17%, 95% CI: 9–30) were open label studies.
Only 6 of the 47 (13%, 95% CI: 6–25) studies specified that the trial was a noninferiority or equivalence trial in the title or abstract. The background or introduction section of 5/47 (11%, 95% CI: 5–23) articles contained a rationale for using a noninferiority or equivalence trial design. Thirteen articles (28%, 95% CI: 17–42) had a clear objective or hypothesis pertaining to noninferiority or equivalence. Thirty-four trials (72%, 95% CI: 58–83) properly described the method applied in the sample size determination and set appropriate boundaries on noninferiority or equivalence. The pre-stated noninferiority/equivalence in all the trials lied between the ranges of -1 to 2.5. Primary outcome measure was the mean intraocular pressure which was mostly measured as a mean difference or as a mean reduction from baseline.
Only 3/47 (6%, 95% CI: 2–17) studies reported and presented results of both ITT and PP populations. Two studies (4%, 95% CI: 1–14) presented only PP results but mentioned that ITT population had similar results. Twelve studies (26%, 95% CI: 15–39) presented only ITT results but mentioned that PP population had similar results. Thirteen trials (28%, 95% CI: 17–42) presented only PP results with no mention of ITT population results while 17/47 (36%, 95% CI: 24–51) studies presented only ITT results with no mention of PP population results.
From the 47 trials reported in this study, only one (2%, 95% CI: 0.5–11) diagrammatically presented its results by use of a figure showing the confidence intervals and pre-specified margins of equivalence or noninferiority. Handling of losses to follow-up was not addressed in 33 of the 47 trials (70%, 95% CI: 56–81). Loss to follow-up was mentioned but unaddressed in 10 trials (21%, 95% CI: 12–35), while 3/47 (6%, 95% CI: 2–17) were addressed in the statistics and 1/47 (2%, 95% CI: 0–11) had a zero loss to follow-up.
Measurement of hyperemia
We found large heterogeneity of measuring hyperemia. Two of the 47 (4%, 95% CI: 1–14) included studies used a severity scale based on non-serious, mild, moderate, and serious. Six studies (13%, 95% CI: 6–25) used a severity scale based on none, mild, moderate, and serious. Five (11%, 95% CI: 5–23) used a scale that recorded only mild, moderate, and severe. One (2%, 95% CI: 0.5–11) used a scale that included only non-serious and serious. One (2%, 95% CI: 0.5–11) used a four-point scale from 1–4 stating minimum and maximum as the scale endpoints. Six (13%, 95% CI:6–25) studies used a 5 point scale with 0 = none, 0.5 = trace, 1 = mild, 2 = moderate, and 3 severe. A further 26/47 (55%, 95% CI: 41–69) did not report their method of measuring hyperemia, of which 5/26 (19%, 95% CI: 9–38) did not report on hyperemia outcomes.