Corneal collagen cross-linking for treating ke

ratoconus: a cochrane interventional review

Presenter: Dr.Arushi Goyal

Moderator: Dr. R.R.Sudhir

Corneal collagen cross-linking for

treating keratoconus: a cochrane interv
entional review
Sykakis E, Karim R, Evans JR, Bunce C, Amissah-Arthur KN, Patwary S,
McDonnell PJ,
Hamada S, Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.:
CD010621.

Review content assessed as up-to-date: 28

August 2014

Cochrane review
Cochrane Reviewsare
systematicreviewsof primary rese
arch in human health care and health
reviewis a type of
policy,Asystematic
and are internationally
recognis
literaturereviewthat collects
ed as the
standard
in evidence
andhighest
critically analyzes
multiple
-based health
care.
They
investigate th
research
studies
or papers
e effects of interventions for preventio
n, treatment and rehabilitation.

Background

Keratoconus : Bilateral noninflammatory

corneal ectasia
Incidence : 1 in 2000 people
Collagen cross-linking (CXL):
Treatment to slow or halt progression of
keratoconus

Significance
CXL :only treatment to halt progression of
keratoconus
Robust evidence on long term results of
efficacy and safety of this procedure lacking
Standardised criteria for selection of ideal
patient lacking
Review is evidence based reference point for
people with keratoconus for validated infor
mation regarding the efficiency of this treatm
ent.

OBJECTIVE

To assess whether there is evidence that CXL

is an effective and safe treatment for halting t
he progression of keratoconus compared to n
o treatment.

METHODS AND RESULTS

INCLUSION AND EXCLUSION CRITERIA

Type of studies:
Randomised controlled trials (RCTs) where patients are
diagnosed with keratoconus.
Type of participants:
Included: All age participants
Excluded: with history of some other treatment.
Type of intervention:
Studies that compared CXL with the epithelium off technique
to no treatment
Exclusion: Studies comparing different ways of doing CXL
Studies with no control group
Use of CXL for ectasias other that keratoconus

METHODS and RESULTS(cont.)

Search methods for identification of studies:

Electronic searches: All electronic databases till
28th august 2014
2 review authors: ES and RK reviewed all studies

METHODS and RESULTS(cont.)

Included studies:
3 RCTS
219 eyes 119 cases and 100 controls
Australia (Wittig-Silva 2008), the United
Kingdom (OBrart 2011), and the United State
s (Hersh 2011).

METHODS and RESULTS(cont.)

Type of intervention (CXL with epithelium off
technique)
Epithelium removed under
topical anaesthesia

Isotonic riboflavin solution of

0.1% applied
Cornea treated with UVA
radiation (370 nm at 3
mW/cm2) for 30 minutes.

METHODS and RESULTS(cont.)

Assessment of risk of bias in included
studies
Using cochranes tool for assessing risk of bias (as a
percentage) having the following criterias:

Randomisati
onis the best
method
removing
selection bias
between two
groups of
patients

Attritionrefers to the
reduction of
experimentalparticipants
leaving an experiment or
study for reasons,

BIAS

Selective reporting

Concealed allocationis
a procedure implemented
in a randomized control
trial where the individuals
screening and separating
the candidates into two
(or more) arms of a study
are blinded.

METHODS and RESULTS(cont.)

Outcome measures:
Primary outcome: Disease progression at 12
months after treatment
Increase Kmax >1.5 D
Worsening in uncorrected VA > 0.2 logMAR

METHODS and RESULTS(cont.)

Secondary Measures(12 months after
treatment):
Mean average corneal power
Mean corneal pachymeter at thinnest part
of cornea
Mean spherical equivalent
Contact lens intolerance
Adverse effects of CXL included in these
studies
Quality of life outcomes
Economic data

METHODS and
RESULTS(cont.)

Measure of treatment effect

Primary outcomes (dichotomous data) : risk

ratio(RR)
Secondary outcomes (continuous data) :
Dichotomousvariabl
Therisk ratio(or
Mean
difference
es are nominal
variables which have
only two categories
or levels. For
example, if we were
looking at gender,
we would most
probably categorize
somebody as either
"male" or "female".

relativerisk) is
theratioof
theriskof an event
in the two groups, a
value of 1 indicates
that the estimated
effects are the same
for both
interventions.

METHODS and RESULTS(cont.)

Primary outcome analysis
Progression at 12 months of Kmax
Study
CXL
Control
Risk
group
ratio

Confidenc
e interval

OBrart
2011

0/22

3/22

0.14

0.01,2.61

Wittig Silva
2008

0/9

4/10

0.12

0.01,2.00

Progression at 36 months of Kmax

Wittig Silva
2008

0/46

19/48

0.03

0.00,0.43

No study took the other primary outcome i.e

UCVA as their outcome

METHODS and
RESULTS(cont.)

Secondary outcome analysis

Mean Kmax at 12 months after treatment

Study

Mean difference

Confidence
interval

Witting Silva
2008

-1.92

-2.54,-1.30

Mean UCVA at 12 months after treatment

Witting Silva
2008

-0.2

-0.31,-0.09

Change in mean thinnest pachymetry at 12 months

Witting Silva
2008

8.93

-0.60, 18.46

OBrart 2011

-2

-33.01, 29.01

Mean average corneal power at 12 months

OBrart 2011

-0.8

-1.24, -0.36

METHODS and
RESULTS(cont.)

Adverse outcomes
Study

participa
nts

Adverse event

Witting Silva
2008 ( 36
months)

1. Corneal edema with

paracentral infiltrate
2. Peripheral corneal
vascularisation,
3. Subepithelial infiltrates with
ac
Inflammation

OBrart 2011
(12 months)

Corneal edema, ac
inflammation, recurrent corneal
erosion

Quality of life
Hersh 2011

Reported it for treated eye but

METHODS and RESULTS(cont.)

Overall quality of evidence using GRADE classification for

each outcome: Very low ( We are uncertain of the
estimate)
The main reasons for downgrading the evidence

included risk of bias in the included

studies, imprecision, indirectness and publication bias.

Summary of main results

Only 3 RCTs, out of which 1 (Hersh 2011) had very little

usable data.
Not possible to pool data due to differences in measuring
and reporting outcomes
High overall risk of bias
80-90% reduction in relative risk for progression of
keratoconus but this result is very uncertain
Adverse effects not uncommon
Small sample size
Risk of visual acuity loss, quality of life outcomes and
economic data not reported
Only 1 study followed up for more than 1 year
Children not included in any of the studies
Quality of evidence low, the main reasons being risk of bias ,
imprecision, indirectness and publication bias.

This systematic review is not a metaanlysis:

as few studies
Studies did not report required outcomes in correct
format to enable data to be pooled
Therefore it is a qualitative analysis not
quantitative(metaanalysis)

DISCUSSION

Other systematic reviews:

Study: NICE 2013 : CXL is effective in

halting progression
Flaw
Increase in Kmax With use of different
of 1 D is defined
topography instruments,
as progression
error is more
Repeatability and
measurement errors of most
topographers is well known
A study by
Random allocation of
Henriquez 2011
treatment not done

AUTHORSCONCLUSIONS

Despite the numerous prospective and retrospective studies

available in the literature and the fact that CXL seems to be
accepted worldwide as a breakthrough treatment in the manage
ment of keratoconus, evidence is limited due to the lack of prope
rly conducted RCTs. If strict criteria are used and only data from
RCTs accepted, then there is a lack of evidence that CXL is indeed
an effective treatment in halting the progression of keratoconus.
Higher-quality studies are needed before an appropriate
metaanalysis can be conducted to confirm the importance of this
treatment

Why is study significant

Major positives and

negatives

years previously were

examined. The main
outcome measures were
refractive error, visual
acuity, corneal
topographic
keratometry, ultrasonic
pachymetry, and
topography-derived
corneal wavefront.
RESULTS:
At 7 years compared to
preoperative values,
mean spherical
equivalent refractive
error (SEQ) increased

Futur
e
resea
rch

Gap in literature

Existing
Literature