As the third leading preventable cause of blindness, glaucoma affects approximately 105 million people worldwide.1
The findings of this analysis should therefore be of interest to patients, clinicians, policy makers and health insurance funders. We found that all three PGA drugs produce similar efficacy, as measured by response rate and IOP-lowering, across a diverse population of POAG and ocular hypertension patients. The practical clinical importance of this finding is important as clinicians consult with patients about optimal interventions and consider issues of safety, long-term efficacy and cost.
This analysis has several strengths and limitations. Strengths include the extensive searches and contact with authors of the primary trial reports, as well as searches and data abstraction by three independent reviewers. Our analysis is limited as there may still be unpublished trials. We believe it is possible, and perhaps even likely, that negative studies have remained unpublished. It is possible that contacting companies may have identified unpublished studies; however, in our experience, companies do not openly share unpublished data. Another limitation is that reporting of methodological criteria was very inconsistent and definitions were not uniform. For example, responder outcomes were often not reported; of 16 included trials, only 9 reported responders, but used 7 different criteria for evaluating response rates. We found moderate heterogeneity in several analyses and were unable to explain it using a priori explanations, thus our inferences on the completeness of these estimates are weakened.
Some may disagree with our inclusion of a trial evaluating timolol plus travoprost versus timolol alone.33
We believe that such an evaluation meets our inclusion criteria of a prostaglandin versus an inert control as the prostaglandin effect here is the same relative effect as if it were prostaglandin versus nothing. We have conducted a sensitivity analysis to examine if our findings would differ on the primary outcome of IOP-lowering effects. When we examined travoprost versus latanoprost, we found a weighed mean difference of −0.17 (95% CI, −0.90 to 0.54, P
= 0.63, I2
= 61%) mmHg, indicating no difference.
Interpreting noninferiority and equivalence studies may be challenging for readers. displays the recommended interpretation of confidence intervals for equivalence. Only 7 trials reported their analysis as intent-to-treat. As these trials were continuous outcomes and reported their changes by group, we were unable to calculate the intent-to-treat outcomes for each trial. This issue is now receiving debate within the trial community and some argue that only studies reporting intent-to-treat be included.43
Without access to individual data, it is impossible to calculate intent-to-treat outcomes.
Figure 5 Interpreting non-inferiority and equivalence trials.20 Error bars indicate 2-sided 95% confidence intervals (CI). Tinted area indicates zone of inferiority. A, If the CI lies wholly to the left of zero, the new treatment is superior. B and C, If the CI (more ...)
Our meta-analysis found equivalence across all three included drugs. Our findings stand in contrast to claims of superiority in the included studies. We are concerned with the general poor quality of included studies and the biased claims of superiority observed in the published reports. We found several instances where the primary outcomes were not significantly different, but the authors reported them as clinically important in their conclusions.33
Further, on average, the trials included in our analysis were small. There is a clear need for minimum sample sizes in equivalence trials of PGAs to avoid wasted resources and potentially spurious outcomes.
Initially, when the PGAs arrived on the market, beta-adrenergic blockers were widely considered first-line therapy in POAG and clinicians at that time decided to reserve the PGAs for cases where beta-blockers failed to reduce the IOP adequately.44
However over the past 10 years the PGAs have emerged as the most popular first-line IOP-lowering class of drugs in the developed world.45
This approach is widely supported by international glaucoma societies. Guidelines generally advocate that if the first-choice therapy is not measurably effective on IOP, it is then preferable to change the initial therapy rather than switch to a different class drug. The issue of cost, however, still compels developing countries to reserve this class of drug for post-primary therapy or add-on treatment. As this study confirms equivalence between the three brands of PGAs, policy makers, especially in developing countries, may base their selection of a particular drug for public health programs on other practical issues such as cost alone.
As noncompliance with therapy plays a large role in progression to blindness, confirmation that all three drugs are equally effective is encouraging. The favorable dosing schedule (once a day), acceptable side-effect profile and IOP-lowering efficacy make the PGAs highly favored among ophthalmologists and patients alike. Because dosing schedule, cost and treatment side-effects all have to be taken into account when choosing a therapy, the comparative conjunctival hyperemia side-effect of this class is important. Side-effects of the three different drugs are generally identical except for conjunctival hyperemia.
We found increased rates of conjunctival hyperemia associated with especially travoprost but also with bimatoprost as compared to latanoprost. Conjunctival hyperemia is of concern to clinicians for two main reasons: hyperemia may compromise the outcome of filtration surgery, and it may represent a cosmetic problem to the patient thereby likely to lead to poor treatment adherence.46
The extent that hyperemia contributes to poor adherence and the effect of administration of the prostaglandin derivatives on outcome filtration surgery remains to be determined. However, a recent evaluation examining reasons for patient discontinuation and poor adherence of PGA therapy found that hyperemia impacted almost two-thirds of patients with adverse events.47
Given that these evaluations come from head-to-head trials, they provide strong inferences regarding clinical efficacy and public health implications. Conjunctival hyperemia appears to occur via a secondary mechanism, unrelated to the increased uveoscleral outflow mechanism induced by PGA therapy. While this effect may lessen over time,48
it may represent a cosmetic concern to the patient, that may lead to poor treatment adherence and thus poor outcomes.46
In general, PGAs have few systemic adverse events and local ones are mainly transitory or reversible, supporting their use as first line therapy. Beta-blockers on the other side have a greater risk of systemic adverse events, but fewer local and cosmetic side-effects.46
Of note, adherence to treatment may depend on side-effects, but also on the frequency of instillation of the drops and the presence of preservative agents, the latter inducing a local reaction, that can have a negative effect on surgery, making the rate of success lower.49