Corneal Collagen Crosslinking for Keratoconus Patients

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; GLUJOVSKY, D.; ALCARAZ, A.; LOPEZ, A.; BARDACH, A.; CIAPPONI, A; ROMANO, M

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2013 p. 1 - 30

1668-2793

Keratoconus is a disorder that causes the thinning and ectasia (frontal protrusion) of the cornealsurface, consequently decreasing visual acuity (VA). It is generally bilateral and progressive. Itsetiology is not defined and it usually affects children and young people. In the generalpopulation, the reported frequency is 1 every 2,000 people. As treatment, hard contact lensesare used for mild cases. Keratoplasty (corneal transplant) may be used for advanced cases.Intrastromal ring implantation (Intacts®) and cross-linking (CXL) are proposed as treatment formoderate keratoconus, isolated or to supplement other treatments.Technology?Cross-linking? (CXL) involves applying a photosensitive product in the cornea, such asriboflavin and then activating it using ultraviolet light-A (UVA) in order to harden the cornea bycreating bridges between the collagen fibrils through phototherapy biochemical action, thusstopping keratoconus progression. The procedure is performed in an ambulatory setting undertopical anesthesia. The corneal epithelium is eroded in order to facilitate riboflavin penetration.Riboflavin drops are placed while the eye is radiated with UVA for about 30 minutes.PurposeTo assess the available evidence on the efficacy, safety and coverage related aspectsregarding corneal collagen crosslinking use in patients with keratoconus.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internetgeneral search engines, in health technology evaluation agencies and health sponsors. Prioritywas given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs);health technology assessments and economic evaluations; clinical practice guidelines andcoverage policies of other health systems.ResultsThree controlled randomized clinical trials (RCTs), two Clinical Practice Guidelines (CPGs),three Health Technology Assessments (HTAs) and two coverage policies were found.In one RCT published in 2011 which included 71 eyes, each eye was randomized to CXLtreatment or riboflavin alone (placebo). The study does not report comparisons between thetreated and untreated groups. In the CXL group, corrected and uncorrected VA improvedsignificantly at 12 months (from 20/137 to 20/117 and from 20/45 to 20/34 respectively, this isthe same as improving one line in the Snellen VA Chart) compared with the patient?s baseline.In the treated group there were also statistically significant improvements in the ketarometryreadings. In the control group (no treatment), no significant differences were observed in VA at12-month-follow up. CXL was effective in improving the VA with and without correction.Another prospective randomized study published in 2011 enrolled 24 patients with mild tomoderate keratoconus with recent progression. One of the patient?s eyes was randomized toCXL and the other to control. Follow up was 18 months in 22 patients. In the treated group, thecorrected VA at 18 months improved (p=0.01), as well as the keratometry readings by simulatedOrbscan II (p<0.001), the keratometry at 3 mm (p=0.008) compared to the patient?s baseline. Inthe untreated group the results remained unchanged at 18 months.Another controlled randomized prospective study published in 2008 included 66 eyes of 49patients with progressive keratoconus to CXL treatment or control. No statistically significantdifferences were observed on VA evaluation. Patients were followed up at 12 months anddecreases in keratometry readings were observed for the treated eyes. No significant changeswere observed in the endothelial epithelium density. The results suggest a temporalstabilization in the CXL treated eyes in this disease.The CPGs published by NICE in 2009 support its use only for patients with progressivekeratoconus with adequate corneal thickness, as well as the ones published by Mexico?sMinistry of Health.Among the HTAs, the Canadian Agency, CADTH, concludes that CXL is effective for patientswith keratoconus, while Ontario?s Agency states that CXL effectiveness is yet to be determined.The Swedish Agency from Sahlgrenska University Hospital considers that there is a very lowlevel evidence to suggest CXL potential benefit to stabilize progressive keratoconus and thatthere is no evidence to suggest that CXL could prevent the future need of corneal transplant.The U.S. Agencies AETNA and CIGNA consider CXL is still experimental and investigational,since its efficacy for this indication has not been determined.The cost in Argentina is estimated to be between AR$ 6,000 and 8,000 (Argentine PesosJanuary/ 2013) equivalent to about U$S 1,250 and 1,650 (U.S. dollars January/2013).ConclusionsLow quality evidence suggests that CXL could slightly improve the VA and disease progressionin patients with progressive keratoconus. The CPGs support its indication. Studies with morepatients and with longer follow up are needed to be more certain whether CXL interventionstops long term disease progression and if the VA benefits obtained persist.