Incidence and risk factors for post-penetrating keratoplasty glaucoma: A systematic review and meta-analysis

Methodological quality of the review: High confidence

Authors: Wu S and Xu J

Geographical coverage: UK, China, Israel, Germany, India, Turkey, Singapore, Saudi Arabia, Australia, USA, France, Brazil, Canada, Poland,

Sector: Glaucoma

Sub-sector: Incidence and risk factors for postpenetrating keratoplasty glaucoma

Equity focus:  No

Review type: Other review

Quantitative synthesis method: Systematic review and meta-analysis

Background:

Glaucoma continues to be a frequent complication of penetrating keratoplasty (PK) and has been determined to be a primary cause of graft failure, with yet unexplained determinants. It has also been reported to be one of the three most common causes for graft failure along with rejection and infection. the factors that contribute to clinically significant glaucoma after PK have not been fully established and are currently a matter of vital importance, which emphasizes the need for further investigation and to identify variables that can be modified to control intraocular pressure (IOP) after PK.

Objectives:

The objective of this meta-analysis was to identify all currently published literature to establish the incidence of post-penetrating keratoplasty glaucoma (PPKG), along with its major confounding factors, and its risk factors.

Main findings:

Thirty studies reporting on 27,146 patients were included in the analysis of the incidence and risk factors for PPKG. Exact PPKG definitions used in the literature could be classified in to three subgroups:

• ocular hypertension (> 21mmHg) after PK;
• more than four weeks medical treatment required;
• treatment escalation among patients with pre-existing glaucoma.

Overall (Definition 1) pooled incidence in all studies was 21.5% (95% CI 17.8%, 25.7%), I2 = 97.4%. The value varied according to different filtering criteria, including the three definitions that were presented previously. The lowest incidence reported was 5.3% in a study from China using the Definition 1 criteria, while the highest incidence was 60%, which was reported in a UK survey that used the Definition 1 criteria. In addition, the incidence was similar between prospective and retrospective study groups.

The research for predictors of PPKG identified 18 publications on eight major factors. The pooled incidence was much higher in those with pre-existing glaucoma and in aphakic individuals, and was slightly higher in those with PK, pseudophakia, regrafting and preoperative diagnosis as trauma. The combination procedure of PK with extra capsular cataract extraction (ECCE) + intraocular lens (IOL) implantation seemed to be insignificantly associated with the increasing incidence of PPKG. Notably, the results remain similar when only high quality (using multivariate regression) studies were included. The pooled OR for trauma with PPKG became insignificant on removal of the studies by Kirkness et al. Nevertheless, there was a trend toward an increased incidence.

Methodology: 

Inclusion criteria: Studies were included if the following criteria applied:

1) reported on incidence or risk factors for PPKG;

2) reported to have included consecutive patients;

3) performed a minimum of 30 PK procedures; and

4) enrollment for PK was based on existing and accepted guidelines.

When two or more publications were based on the same population, the publication with a larger sample size was included in the analysis. For the purpose of our current search and analysis, PPKG was defined as ocular hypertension (> 21mmHg) after PK.

Outline of search: A systematic review of the published literature on PPKG was conducted following the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A computerized search was performed to identify all relevant studies published from January 1, 1947, to March 1, 2016, in the Medline, EMBASE and Cochrane Library database. The following search terms were used: penetrating keratoplasty and corneal transplantation. Citations were screened at the title and abstract level and retrieved as a full report if they reported on outcomes after PK. The full texts and bibliography of all potential articles were also reviewed in detail to search for additional relevant studies. In addition, a Google search was performed to locate relevant publications from national corneal transplantation registry web sites.

Data extraction and quality assessment: Data were independently extracted from eligible studies by two reviewers. Relevant information was collected and included but was not limited to, year and journal of publication, first author, study design, inclusion and exclusion criteria, IOP measurement methods, definition of endpoints, number of subjects included, study population demographics, follow-up period, and outcomes. The study quality was also assessed in terms of prospective study design (prospective versus retrospective) and multivariate statistical analyses (univariate versus multivariate logistic regression).

Analysis: The proportion of individuals with PPKG in each study was logit transformed, meta-analyzed and back-transformed to obtain a pooled incidence of PPKG for all studies. The incidence of PPKG was compared according to preexisting glaucoma, bullous keratopathy (BK), aphakia, pseudophakia, triple procedure, regrafting, and surgical indications including herpes simplex keratitis (HSK) and trauma, using an odd ratio (OR) with a 95% CI. Statistical significance was set at p < 0.05 (2-tailed). Heterogeneity was assessed by H2 and I2 test. The robustness of our findings was also analyzed by omitting one study at a time. In addition, publication bias was monitored and tested using funnel plots and fail-safe N (Rosenthal’s for incidence analysis and Orwin’s for risk factor analysis) when more than 10 studies were involved. In risk factor analysis, criterion for a ‘trivial’ OR was set as 1.05, and the mean OR for missing studies was set as 1.00. If a publication bias was observed, the corresponding incidence or OR along with the CI was subsequently adjusted by Duval and Tweedie’s trim and fill [15]. Data analysis was performed using comprehensive meta-analysis Version 2 (Biostat Inc., Englewood, NJ), except the confidence intervals for I2 which were calculated manually using the formulae from Higgins et al.

Applicability/external validity:

The authors discussed the generalizability of the results of their review by acknowledging some limitation that prevents tis external applicability of the results. The authors reported that, all studies included were single-centered, except the Australian Corneal Graft Registry Report, decreasing the generalizability and increasing the likelihood of environmental and socio-economic bias. They further added that, From the global perspective, the absence of studies that have reported on the incidence and risk factors for PPKG for some geographical regions, such as Africa and Central America, is another limitation for the generalizability of this meta-analysis. In addition, as mentioned, diverse IOP-measuring methods contributed to PPKG identification bias.

Geographic focus:

This review just focuses on high-income countries because of the absence of articles published on this particular topic in Africa and central America.

Summary of quality assessment:

There is high confidence in the conclusions about the effects of this study. The authors used appropriate methods to conduct literature searches, screen studies for inclusion and extract data of include studies. This review is very interesting in the sense that it highlights the absence of data on this topic in Africa and America and call for more study on this topic in these two regions.