Protocol for a systematic review, meta-analysis, and trial sequential analysis of clinical outcomes following accelerated versus conventional corneal collagen cross-linking for corneal ectasia

BACKGROUND: Collagen cross-linking (CXL) is an evolving procedure that enhances the biomechanical rigidity of the cornea and can slow or halt ectatic disease. CXL requires delivery of 5.4 J/cm(2) of ultraviolet A (UVA) radiation to a cornea saturated with riboflavin in order to induce cross-link formation. The conventional CXL procedure achieves this fluence by exposing the cornea to a 3 mW/cm(2) UVA lamp for 30 min; however, some surgeons have proposed accelerated protocols which achieve the same fluence in a shorter period of time by using a higher power light source. Whether accelerated protocols are as effective in arresting ectasia as the established conventional procedure remains unclear. Accordingly, this study will systematically review and synthesise the evidence on accelerated CXL and compare it to the conventional approach across an array of clinical outcomes. METHODS: We will search 16 electronic databases, including MEDLINE, Embase, and the Cochrane Library, from inception to February 1, 2019. We will include all randomised controlled trials comparing accelerated and conventional CXL for any corneal ectatic disease. Two reviewers will independently screen search results to identify eligible articles, complete data collection, and conduct quality assessment. The quality of individual trials will be assessed using the Cochrane Collaboration’s Risk of Bias Assessment Tool. Our primary outcome will be the change in maximal keratometry (K(max)) at 12 months following treatment. Additional outcomes will include: incidence of disease progression, incidence of serious adverse events, as well as change in K(max) at longest follow-up, mean stromal demarcation line depth, mean uncorrected distance visual acuity, mean corrected distance visual acuity, mean K(max), mean endothelial cell density, mean central corneal thickness, mean spherical equivalent, mean intraocular pressure, and mean corneal power, at 12 months following treatment. We will calculate relative risks and 95% confidence intervals (CIs) for dichotomous outcomes and weighted mean differences and corresponding 95% CIs for continuous outcomes. Prespecified subgroup analyses will be performed to investigate heterogeneity. We will rate the overall quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. DISCUSSION: This review will provide a comprehensive evaluation of the evidence on accelerated and conventional CXL approaches and serve to inform clinical practice, medical device design, and future research. Evaluating variations of the CXL protocol aimed at reducing treatment duration is of critical importance and a prerequisite to expanding treatment availability to more patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018104151