TITLE: Corneal Cross Linking with Riboflavin for Keratoconus: Clinical and Cost-

Effectiveness

DATE: 21 April 2010

RESEARCH QUESTIONS:

1. What is the clinical effectiveness of corneal cross linking with riboflavin for keratoconus?

2. What is the cost-effectiveness of corneal cross linking with riboflavin for keratoconus?

METHODS:

A limited literature search was conducted on key health technology assessment resources,
including PubMed, the Cochrane Library (Issue 4, 2010), University of York Centre for Reviews
and Dissemination (CRD) databases, ECRI (Health Devices Gold), EuroScan, international
health technology agencies, and a focused Internet search. The search was limited to English
language articles published between 2005 and April 12, 2010. No filters were applied to limit the
retrieval by study type. Internet links were provided, where available.

The summary of findings was prepared from the abstracts of the relevant information. Please
note that data contained in abstracts may not always be an accurate reflection of the data
contained within the full article.

RESULTS:

HTIS reports are organized so that the higher quality evidence is presented first. Therefore,
randomized controlled trials are presented first. These are followed by controlled clinical trials,
observational studies, and evidence-based guidelines.

One randomized controlled trial, one controlled clinical trial, six observational studies, and one
evidence-based guideline related to the clinical effectiveness of corneal cross linking with
riboflavin for keratoconus were identified. No studies of the cost-effectiveness of corneal cross

Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing
health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews.
The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts
within the time allowed. HTIS responses should be considered along with other types of information and health care considerations.
The information included in this response is not intended to replace professional medical advice, nor should it be construed as a
recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality
evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for
which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation
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linking with riboflavin for keratococnus were identified, nor were any relevant health technology
assessments, systematic reviews or meta-analyses. Studies that combined corneal cross linking
with riboflavin and an additional procedure were placed in the appendix. Additional articles of
potential interest can also be found in the appendix.

OVERALL SUMMARY OF FINDINGS:

Eight studies1-8 that assessed the clinical effectiveness of corneal cross linking with riboflavin for
the treatment of keratoconus were indentified. Study characteristics and conclusions can be
found in Table 1. All eight included studies1-8 concluded corneal cross linking with riboflavin was
an effective treatment for keratoconus. A National Institute for Health and Clinical Excellence
guideline for the use of corneal cross linking with riboflavin and ultraviolet A recommended that
the procedure only be performed in special circumstances, as there was insufficient higher
quality evidence to recommend the procedure for all patients with keratoconus.9

Table 1: Study results – Corneal collagen cross linking with riboflavin

Author Number of eyes treated Follow-up Conclusion
Randomized controlled trials
Wittig-Silva et al.1 66 eyes of 49 patients 12 months Temporary stabilization of all eyes
in CXL treatment group
Controlled clinical trials
Coskunseven et 38 eyes of 19 patients 9 +/- 2 months CXL effective for inhibiting
al.2 keratoconus progression
Observational studies
Agrawal et al.3 68 eyes of 41 patients 12 months* Keratoconus improved and
stabilized after CXL
Arbelaez et al.4 20 eyes of 19 patients 12 months CXL is safe and effective for
progressive keratoconus
Grewal et al.5 NR 12 months No keratoconus progression one
year after CXL. Lens and macula
not affected by treatment.
Vinciguerra et al.6 28 eyes 12 months Improved UCVA and BSCVA in
eyes with progressive keratoconus
after CXL
Raiskup-Wolf et 480 eyes of 272 patients Up to 6 years Long-term stabilization and
al.7 improvement. CXL is an effective
therapy for progressive
keratoconus
Caporossi et al.8 10 eyes of 10 patients 6 months 2.5 D reduction in mean spherical
equivalent. Improvement in
symmetry with significant reduction
in comatic aberrations
BSCVA = best spectacle-corrected visual acuity; CXL = Corneal collagen crosslinking; D = diopter; NR = not reported; UCVA =
uncorrected visual acuity
* 12 month follow-up data were available for 37 of the 68 eyes

Corneal Cross Linking with Riboflavin for Keratoconus 2

REFERENCES SUMMARIZED:

Health technology assessments

No literature identified

Systematic reviews and meta-analyses

No literature identified

Randomized controlled trials

1. Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR. A

randomized controlled trial of corneal collagen cross-linking in progressive keratoconus:
preliminary results. J Refract Surg. 2008 Sep;24(7):S720-S725. PubMed: PM18811118

Controlled clinical trials

2. Coskunseven E, Jankov MR, Hafezi F. Contralateral eye study of corneal collagen cross-
linking with riboflavin and UVA irradiation in patients with keratoconus. J Refract Surg.
2009 Apr;25(4):371-6. PubMed: PM19431928

Observational studies

3. Agrawal VB. Corneal collagen cross-linking with riboflavin and ultraviolet - a light for
keratoconus: results in Indian eyes. Indian J Ophthalmol. 2009 Mar;57(2):111-4. Available
from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684426 PubMed: PM19237783

4. Arbelaez MC, Sekito MB, Vidal C, Choudhury SR. Collagen cross-linking with riboflavin
and ultraviolet-A light in keratoconus: one-year results. Oman Journal of Ophthalmology
[Internet] 2009 [cited 2010 Apr 12]; 2(1):33-38. Available from:
http://www.muscateye.com/publication/files/04%20OmanJOphthalmol2133-
3660906_101009.pdf

5. Grewal DS, Brar GS, Jain R, Sood V, Singla M, Grewal SP. Corneal collagen crosslinking
using riboflavin and ultraviolet-A light for keratoconus: one-year analysis using
Scheimpflug imaging. J Cataract Refract Surg. 2009 Mar;35(3):425-32. PubMed:
PM19251133

6. Vinciguerra P, Albe E, Trazza S, Rosetta P, Vinciguerra R, Seiler T, et al. Refractive,

topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing
corneal cross-linking. Ophthalmology. 2009 Mar;116(3):369-78. PubMed: PM19167087

7. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and
ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008
May;34(5):796-801. PubMed: PM18471635

8. Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Parasurgical therapy for

keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of corneal collagen:

Corneal Cross Linking with Riboflavin for Keratoconus 3

 preliminary refractive results in an Italian study. J Cataract Refract Surg. 2006
May;32(5):837-45. PubMed: PM16765803

Economic evaluations
No literature identified

Guidelines and recommendations

9. Photochemical corneal collagen cross-linkage using riboflavin and ultraviolet A for

keratoconus [Internet]. London: National Institute Health and Clinical Excellence; 2009
Nov. [cited 2010 Apr 12]. Available from:
http://www.nice.org.uk/nicemedia/pdf/IPG320Guidance.pdf Interventional procedure
guidance 320.

PREPARED BY:
Health Technology Inquiry Service
Email: htis@cadth.ca
Tel: 1-866-898-8439

Corneal Cross Linking with Riboflavin for Keratoconus 4

APPENDIX – FURTHER INFORMATION:

Health technology assessments

10. Medical Advisory Secretariat. Intrastromal corneal ring implants for corneal thinning
disorders: an evidence-based analysis. Ontario Health Technology Assessment series
[Internet]. 2009 Apr [cited 2010 Dec 4];9(1):1-90. Available from:
http://www.health.gov.on.ca/english/providers/program/mas/tech/reviews/pdf/rev_intacs_2
0090401.pdf
Note: see Collagen Cross-Linking, page 45 and Use of Adjunct therapies With INTACS,
page 52

Randomized controlled trials

11. Coskunseven E, Jankov MR, Hafezi F, Atun S, Arslan E, Kymionis GD. Effect of treatment
sequence in combined intrastromal corneal rings and corneal collagen crosslinking for
keratoconus. J Cataract Refract Surg. 2009 Dec;35(12):2084-91. PubMed: PM19969212

Observational studies

12. Goldich Y, Barkana Y, Morad Y, Hartstein M, Avni I, Zadok D. Can we measure corneal
biomechanical changes after collagen cross-linking in eyes with keratoconus?--a pilot
study. Cornea. 2009 Jun;28(5):498-502. PubMed: PM19421050

13. Kanellopoulos AJ. Collagen cross-linking in early keratoconus with riboflavin in a

femtosecond laser-created pocket: initial clinical results. J Refract Surg. 2009
Nov;25(11):1034-7. PubMed: PM19731884

14. Kymionis GD, Kontadakis GA, Kounis GA, Portaliou DM, Karavitaki AE, Magarakis M, et
al. Simultaneous topography-guided PRK followed by corneal collagen cross-linking for
keratoconus. J Refract Surg. 2009 Sep;25(9):S807-S811. PubMed: PM19772256

15. Raiskup F, Hoyer A, Spoerl E. Permanent corneal haze after riboflavin-UVA-induced

cross-linking in keratoconus. J Refract Surg. 2009 Sep;25(9):S824-S828. PubMed:
PM19772259

16. Tu KL, Aslanides IM. Orbscan II anterior elevation changes following corneal collagen
cross-linking treatment for keratoconus. J Refract Surg. 2009 Aug;25(8):715-22. PubMed:
PM19714796

17. Mazzotta C, Traversi C, Baiocchi S, Caporossi O, Bovone C, Sparano MC, et al. Corneal
healing after riboflavin ultraviolet-A collagen cross-linking determined by confocal laser
scanning microscopy in vivo: early and late modifications. Am J Ophthalmol. 2008
Oct;146(4):527-33. PubMed: PM18672225

18. Mencucci R, Mazzotta C, Rossi F, Ponchietti C, Pini R, Baiocchi S, et al. Riboflavin and
ultraviolet A collagen crosslinking: in vivo thermographic analysis of the corneal surface. J
Cataract Refract Surg. 2007 Jun;33(6):1005-8. PubMed: PM17531694

Corneal Cross Linking with Riboflavin for Keratoconus 5

19. Mazzotta C, Traversi C, Baiocchi S, Sergio P, Caporossi T, Caporossi A. Conservative
treatment of keratoconus by riboflavin-uva-induced cross-linking of corneal collagen:
qualitative investigation. Eur J Ophthalmol. 2006 Jul;16(4):530-5. PubMed: PM16952090

Review articles

20. Karmel M. Clinical update: tools and techniques. Eyenet [Internet]. 2009 Apr [cited 2010
Apr 12];29-31. Collagen crosslinking: research offers promise and poses questions.
Available from: http://www.aao.org/publications/eyenet/200904/upload/CU-Cornea.pdf

Corneal Cross Linking with Riboflavin for Keratoconus 6