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The News Magazine of the American Society of Cataract & Refractive Surgery
Anti-inflammation:
Perfecting cataract surgery
Supplement to EyeWorld August 2012
Supported by an educational grant from ISTA Pharmaceuticals
Moderator
Uday Devgan, M.D., in private
practice, Devgan Eye Surgery,
Los Angeles and Beverly Hills,
Calif., and chief of ophthalmology,
Olive View UCLA Medical Center,
Los Angeles, performs the full
spectrum of corneal and lenticular
refractive surgery
Johnny L. Gayton, M.D., adjunct
professor of ophthalmology,
Mercer Medical School, and
chief executive officer and chief
surgeon, Eye Associates of Middle
Georgia, Warner Robins, Ga., has
practiced ophthalmology for over
25 years
nflammation remains a significant
challenge to modern cataract
surgery. Left untreated, inflammation can ruin even the most
consummately performed surgery
utilizing the most advanced techniques
and technology.
Experts gathered to discuss “Ocular
Anti-Inflammation: Prevention, Diagnosis,
and Curative Treatment Options” at an
EyeWorld Educational Symposium held at
the 2012 ASCRS•ASOA Symposium &
Congress. The event was supported
by an educational grant from ISTA
Pharmaceuticals (Irvine, Calif.).
I
“Cataract surgery is evolving,” said Dr.
Katsev. According to Dr. Katsev, patients’
standards have been increasing in the last
decade in part thanks to the increasing
role of premium IOLs in cataract surgery.
In that time, the use of premium IOLs
has increased dramatically, he said, but
the promise of great vision these IOLs
make does not necessarily mean happy
patients; surgeons need to give them
more. Surgeons need to take the extra
step and give their patients great vision
that is also free of complications such as
cystoid macular edema (CME).
More than 20 years ago, Dr. Katsev
started using Ocufen (flurbiprofen sodium
0.3%, Allergan, Irvine, Calif.) based on
studies that showed that the drug
prevented miosis in all cases. More
importantly, he said, the prevention of
miosis was most effective in patients with
small pupils.
NSAID issues 2012
Douglas A. Katsev, M.D.,
chairman of ophthalmology,
Sansum Clinic, Santa Barbara,
Calif., is the lead ophthalmologist
in a large group performing over
2,500 cataract/refractive cases a
year
Terry Kim, M.D., professor of
ophthalmology, Duke University
School of Medicine, Durham, N.C.,
has published over 200 journal
articles, textbook chapters, and
scientific abstracts in peerreviewed literature and has
delivered over 200 national and
international invited lectures
A study he co-authored with Robert
C. Drews, M.D., showed as much as a
30% decrease in pupil surface area in
small pupils when the non-steroidal antiinflammatory drug (NSAID) was not used.1
The benefits of using NSAIDs during
cataract surgery have long been established. Inflammation as indicated by
increased anterior chamber cells and flare
is known to slow visual recovery.2,3 Topical
NSAIDs have been shown to reduce postop inflammation and pain after surgery and
have typically been used in place of or in
addition to topical corticosteroids.
Other suspected benefits in peer
Keith A. Walter, M.D.,
associate professor of
ophthalmology, Wake Forest
University, Winston-Salem,
N.C., has published several
landmark articles on the effects
of humidity on LASIK, IOL
calculations after LASIK,
and small incision DSAEK
review include decreasing CME and
maintaining pupil dilation during surgery.
There are many reasons to use
NSAIDs, but CME prevention is the
biggest “stay out of trouble” factor, said Dr.
Katsev, adding that it only takes a few loud
patients suffering from this complication to
negatively influence a practice.
A large-scale study comparing ketorolac 0.4% and steroid with steroid alone
after cataract surgery found that anywhere
from 2.4-6.1% of healthy eyes develop
CME without NSAIDs.4 This percentage,
while small, is not insignificant. In practice
terms, said Dr. Katsev, these patients
provide “the best advertisement.”
The increasing utilization of premium IOLs is indicative of an increasing standard for post-op
outcomes in cataract surgery
August 2012 1
Anti-inflammation: Perfecting cataract surgery
In September 2011, pharmaceutical
companies began releasing generics into
the market. At the time, generic ketorolac
comprised 27.9% of NSAIDs used in
cataract surgery.
Generic NSAIDs were first introduced
with generic diclofenac. Not long after the
introduction of the drug, ASCRS reported
an increase in the number of corneal
melts, and all NSAIDs were pulled from the
market for a period of time.
This, said Dr. Katsev, created a fear of
using NSAIDs still felt by some surgeons
today.
Dr. Devgan reported a corneal melt
with a generic NSAID; since then there
have been several cases reported in the
literature.
Importantly, said Dr. Katsev, these
reports show cases of corneal melt
occurring with generic NSAIDs, but not
with branded NSAIDs.
There are additional challenges
regarding these generic drugs that go
beyond the clinical, said Dr. Katsev. In
June 2011, the Supreme Court came out
with a ruling that essentially freed generics
manufacturers from the responsibilities for
updating their labeling held over branded
product manufacturers. Branded product
manufacturers need to protect their
names; with generics, they are not
beholden to protecting that name.
Dr. Katsev’s first encounter with low
quality generics was in a patient with
diabetes in whom he had implanted
bilateral premium IOLs. He initially started
the patient on Bromday (bromfenac
sodium, ISTA Pharmaceuticals). However,
at the pharmacy, the patient was instead
given generic ketorolac.
The patient did not return until he
had CME. By going back on Bromday, his
vision was restored to 20/25. According to
the patient, he needed to stop using the
generic ketorolac due to discomfort and
did not use any NSAID until his follow-up
consult, by which time it was almost too
late.
“We as surgeons need to be vigilant
about the quality of the drugs we use in
our patients,” said Dr. Katsev. With generics, he said, the medication is supposed to
be the same, but the bottle, the pH, all of
these things are different and may have an
effect on the quality of the drug.
“There may be great generics, but
there are also bad generics, and it is up to
us to keep watch over these drugs to
maintain a high standard for cataract
surgery in our patients.”
2 August 2012
group of proteases or collagenolytic
enzymes called matrix metalloproteinases
(MMPs).
The MMP family is very large;
to date, studies have identified 20 MMPs
expressed in humans. These enzymes
have multiple functions and are known to
degrade extracellular matrix (ECM) and
enhance cell-cell, cell-matrix communications. Rarely detected in normal tissues,
MMPs are typically expressed in tissues
undergoing rapid turnover, such as during
tumor breakout, normal bone and joint
formation, and wound healing.
In the eye, MMPs are involved in
Corneal melts/toxicity:
many physiologic and pathophysiologic
Is there still an issue?
processes, said Dr. Kim. These include
The reported complications following the
disease conditions like macular
use of NSAIDs in cataract surgery vary in
degeneration and diabetic retinopathy
severity, according to Dr. Kim. These
and processes such as IOP regulation.
cases range from things as innocuous as
In the cornea specifically, MMPs
superficial punctate keratitis, to stromal
have been detected in corneal ulcers,
infiltrates, immune rings, and persistent
keratoconus, and after PRK surgery.
epithelial defects, to the most dreaded
NSAIDs have been potentially linked
complication: corneal melts.
to corneal melts through the upregulation
Dr. Kim said this was the major issue
of MMPs, resulting in an imbalance
back in 1999, when the ASCRS survey
between ECM deposition and degradation.
came out looking at observations of
NSAIDs may cause excessive MMP
corneal melt after routine anterior segment
expression, and various MMPs have been
surgery.
found in NSAID-related melts.
The survey pinpointed the use of
Clinically, topical NSAIDs decrease
topical generic diclofenac, which was
normal corneal sensation1,2 and can affect
voluntarily identified and recalled by the
corneal epithelial healing.3,4
manufacturer. There have been many
To avoid complications, NSAIDs
similar reports with other NSAIDs, said
should be used properly. “I believe it is
Dr. Kim.
very important to follow the label dosing,”
“There is still a lot of fear among
said Dr. Kim. “If you look at case series
cataract surgeons when using NSAIDs
that are reported in the literature, compliduring cataract surgery,” he said.
cations like corneal melt usually occur
The deleterious effect of NSAIDs on
when NSAIDs are not dosed properly.”
the cornea is thought to be related to a
With improper
dosing, he said,
NSAIDs can cause
complications within
2 hours of use. “I
would also recommend avoiding longterm use of topical
NSAIDs,” he added.
It is important to
also examine patient
characteristics,
looking at risks for
corneal melt.
Patients with epithelial keratopathy or
severe dry eyes, bacterial keratitis, herpes
simplex or zoster keratitis, ocular surface
Since the 1999 ASCRS survey, several cases of NSAID-related corneal melt have
disease, concurrent
been reported
topical steroids, or
References
1. Drews RC, Katsev DA. Ocufen and pupillary dilation
during cataract surgery. J Cataract Refract Surg.
1989;15(4):445-448.
2. Kim SJ, Flach AJ, Jampol LM. Nonsteroidal antiinflammatory drugs in ophthalmology. Surv Ophthalmol.
2010;55:108-133.
3. O’Brien TP. Emerging guidelines for use of NSAID
therapy to optimize cataract surgery patient care.
Curr Med Res Opin. 2005;21:1131-1137.
4. Wittpenn JR, Silverstein S, Heier J, et al. Acular LS for
Cystoid Macular Edema (ACME) Study Group. A randomized, masked comparison of topical ketorolac 0.4% plus
steroid vs. steroid alone in low-risk cataract surgery
patients. Am J Ophthalmol. 2008;146:554-560.
systemic disorders predisposing them to
corneal melts such as diabetes and
rheumatoid arthritis need to be followed
more closely. In addition, “Always make
sure there is no active infection in patients
undergoing topical NSAID therapy,” said
Dr. Kim.
Established safety profiles are a very
important consideration, he added; for
instance, there have been no reports of
corneal melt in clinical trials using
Bromday. The once-daily dosing of
Bromday, which has been reportedly used
for up to 3 or 4 months and longer, is
particularly relevant for patients at high
risk for corneal melt, but also an important
consideration for the routine patient.
Complications with NSAIDs are fairly
uncommon, but it’s important to pay
attention to high-risk patients.
“Multiple factors are involved in
corneal melt and NSAID toxicity,” said Dr.
Kim. “We need further studies to elucidate
the mechanisms that are involved and the
specific role of MMPs.”
References
1. Szerenyi K, Sorken K, Garbus JJ, et al. Decrease in
normal human corneal sensitivity with topical diclofenac
sodium. Am J Ophthalmol. 1994;118:312-315.
2. Sun R, Gimbel HV. Effects of topical ketorolac and
diclofenac on normal corneal sensation. J Refract Surg.
1997 Mar-Apr; 13:158-161.
3. Hersh PS, Rice BA, Baer JC, et al. Topical nonsteroidal
agents and corneal wound healing. Arch Ophthalmol.
1990;108:577-583.
4. Assouline M, Renard G, Arne JL, et al. A prospective
randomized trial of topical soluble 0.1% indomethacin
versus 0.1% diclofenac versus placebo for the control of
pain following excimer laser photorefractive keratectomy.
Ophthalmic Surg Lasers. 1998;29:365-374.
My routine Rx: Insights on
compliance and dosing
The medical literature strongly indicates
that non-compliance ranges up to 50% of
various dosing regimens.1 Significantly,
compliance worsens with increasing age.2
“There are three signs of getting old,”
said Dr. Gayton. “One is losing your
memory, and I can’t remember what the
other two are. The truth is, you do tend to
forget. That’s just a fact.”
According to Dr. Gayton, as shown
by previous studies, one thing that can
improve compliance is less frequent
dosing.3,4
In a survey of Dr. Gayton’s own patients comparing Pred Forte (prednisolone,
Allergan) and Durezol (difluprednate,
Alcon, Fort Worth, Texas), most of them
said they preferred Durezol because of its
less frequent dosing.
There are many factors that correlate
with compliance, including dosing regimen,
patient lifestyle routines, use of other
medication, and side effects. “We are
used to hearing that if a medication
doesn’t burn or taste bad, it isn’t good
for you,” said Dr. Gayton. “The truth is,
patients don’t like a drop that burns,
and they will tend not to use it.”
Bromday, he noted, is a comfortable
drop to use. “It isn’t sticky and it does not
burn.”
The number of drops a patient has to
use each day is another factor; studies have
shown that drops used just once or twice a
day may improve compliance over more frequent dosing.3 Meanwhile, non-compliance
in glaucoma patients who tend to need two
or more instillations of various drops per day
has been noted to go up to 59%.5
Looking into compliance in post-op
cataract surgery patients revealed that all
were non-compliant at some point in terms
of total dose, time intervals, and premature
discontinuation of therapy.6
Different therapies have different
advantages and disadvantages.
Studies have shown that use of
steroids alone for long-term treatment has
a greater risk of IOP rise and is attended
by a definite increase in macular thickening or CME.7,8
On the other hand, steroids reduce
the amount of arachidonic acid available
for the cox enzymes to convert
prostaglandins, and it is reasonable to
believe, said Dr. Gayton, that using
NSAIDs alone may lose some efficacy
by missing the lipoxygenase pathway.
“Combined therapy can be very
efficacious in safely controlling acute and
chronic inflammation,” he said. “And
because we know that the peak incidence
of CME is 4-6 weeks,9 it makes sense to
use therapy for at least that amount of
time.”
It’s very important to use your NSAIDs
long enough especially in high-risk cases,
he said.
Dr. Gayton switched to using Bromday
(at the time marketed as Xibrom) on the
basis of results from rabbit and rat studies
that demonstrated that the drug remained
at stable concentrations in ocular tissues
for more than 24 hours. These studies, he
said, showed that the drug could be safely
used with once-a-day dosing.10,11
In Dr. Gayton’s practice, he begins
instillation of drops including NSAIDs and
antibiotics several days before surgery.
On the question of using generics or
branded drugs, “we strongly prefer
Bromday,” he said. “In fact, we tell our
patients that if they have to choose
between all of the different medications
and can only pick one branded drug, we
ask them to make that branded drug the
NSAID. The NSAID carries the greatest
risk and the greatest benefit.”
In Dr. Gayton’s clinic, they use antibiotics three times a day 6 days before
surgery and Bromday 7 days before
surgery; the antibiotics are continued out
to 14 days because of research that’s
shown the peak incidence of endophthalmitis is 10-14 days.
“We’ll use NSAIDs at least 6 weeks if
possible,” he said. “That’s one of the big
advantages of a drop that’s used one time
a day because people are much more
likely to comply.”
Dr. Gayton combines NSAID therapy
with a steroid, although in non-diabetic
patients, the steroid is discontinued much
earlier, stopping anywhere from 2-3 weeks.
“Patients who are at high risk will continue
the steroid for a significantly longer period
of time, maybe going out as long as 6
weeks; [we recognize] that we have to
follow those patients more closely because
of the increased risk of sequela such as
ocular surface issues,” he added.
To help with regard to compliance, Dr.
Gayton suggested keeping in mind what
he calls the Cs: “You need to have good
corneal penetration, you need excellent
cox enzyme binding, you need rapid and
total clearance of inflammation, and you
need to have a drop that’s comfortable and
convenient to use.”
References
1. Koberlein J, Kothe AC, Schaffert C. Determinants of
patient compliance in allergic rhinoconjunctivitis.
Curr Opin Allergy Clin Immunol. 2011;11(3):192-199.
2. Hoy SM, Keam SJ, Keating GM. Travoprost/Timolol.
Drugs Aging. 2006;23(7):587-597.
3. Ikeda H, Sato M, Tsukamoto H, et al. Evaluation and
multivariate statistical analysis of factors influencing
patient adherence to ophthalmic solutions. Yakugaku
Zasshi. 2001;121(11):799-806.
4. Cremer J. Medicine Partnerships. Heart. 2003;89
(suppl II):ii19-ii21.
5. Patel SC, Spaeth GL. Compliance in patients prescribed
eyedrops for glaucoma. Ophthalmic Surg.
1995;26(3):233-236.
6. Hermann MM, Ustundag C, Diestelhorst M. Compliance
with topical therapy after cataract surgery using a new
microprocessor-controlled eye drop monitor. Invest
Ophthalmol Vis Sci. 2005;46. E-abstract 3832.
7. Raizman M. Macular edema after cataract surgery.
Presented at the Royal Hawaiian Eye Meeting; Jan 24-29,
1999; Waikoloa, Hawaii.
8. Wittpenn JR, Silverstein S, Heier J, et al. Acular LS for
Cystoid Macular Edema (ACME) Study Group. A randomized, masked comparison of topical ketorolac 0.4% plus
August 2012 3
Anti-inflammation: Perfecting cataract surgery
IOP proved to be an interesting endpoint for Dr. Walter, with significantly more eyes experiencing IOP elevation
with Pred Forte than with Bromday
steroid vs. steroid alone in low-risk cataract surgery
patients. Am J Ophthalmol. 2008;146:554-560.
9. Asano S, Miyake K, Ota I, et al. Reducing angiographic
cystoid macular edema and blood-aqueous barrier
disruption after small-incision phacoemulsification and
foldable intraocular lens implantation: Multicenter
prospective randomized comparison of topical diclofenac
0.1% and betamethasone 0.1%. J Cataract Refract Surg.
2008;34(1):57-63.
10. Baklayan GA, Patterson HM, Song CK, et al. 24-hour
evaluation of the ocular distribution of (14) c-labeled
bromfenac following topical instillation into the eyes of
New Zealand white rabbits. J Ocul Pharmacol Ther.
2008;24:392-398.
11. Data on file, ISTA Pharmaceuticals.
NSAID alone vs.
NSAID + steroid
Are steroids really necessary in routine
cataract surgery? asked Dr. Walter.
In October 2010, he said that steroids
stopped being a routine part of his cataract
kits. “At the time, I was frustrated by how
ineffective generic steroids were, and I was
hesitant to write a prescription for yet
another eye drop,” he said.
Since then, Dr. Walter said that he
only uses Bromday. He begins therapy 2
days before surgery and has the patient
use it until the bottle runs out, an offlabel—but effective, in his experience—
use of the drug.
This supplement was produced by EyeWorld
and supported by an educational grant from
ISTA Pharmaceuticals. Copyright 2012 ASCRS
Ophthalmic Corporation. All rights reserved.
The views expressed here do not necessarily reflect
those of the editor, editorial board, or the publisher and
in no way imply endorsement by EyeWorld or ASCRS.
4 August 2012
“I believe I could always add a steroid
if I need to,” he said.
Dr. Walter used this protocol on all his
patients, and he recently published data
from his experience in U.S. Ophthalmic
Review.1
In this study, Dr. Walter and his
colleagues looked retrospectively at 200
consecutive eyes in which he had used
Pred Forte 1% four times a day for about 5
weeks. About 12% of those patients
received Bromday as well.
They also looked at 200 consecutive
eyes where he only used Bromday; none
of those patients had supplemental
steroids.
Dr. Walter performed surgery on most
of the eyes, leaving about 20% to two
different fellows. They included “all
comers”—their patients with diabetes,
floppy iris, and hard nuclei. They looked at
pain, inflammation, BCVA, CME, and
post-op IOP as endpoints.
They had follow-up in 178 eyes with
Pred Forte and 169 eyes with Bromday.
The vision between the two groups of
patients was about the same, with BCVA 1
month post-op at 20/27.2 and 20/26.6,
respectively.
At 2 weeks post-op, inflammation was
seen in 16 (8%) Pred Forte group eyes
and 24 (12%) Bromday eyes. Of note, Dr.
Walter said that two out of the 24 eyes in
the Bromday group had retained nuclear
fragments.
They had 44 patients respond to a
survey. These patients rated pain
intraoperatively and post-op at around 1
on a scale from 0 to 10, indicating very low
pain either intra- or post-op.
Only 2 (1%) eyes in the Pred Forte
group and 1 (0.5%) in the Bromday group
had CME, detected clinically and
confirmed with OCT.
IOP elevation proved to be an interesting endpoint, said Dr. Walter. The total
number of eyes with IOP elevations of 5
mm Hg or higher from pre-op baseline was
16 (8%) in the Pred Forte group and 7
(3.5%) in the Bromday group (p=0.08).
Note that the eyes with elevated IOP in the
Bromday group included the two eyes with
retained nuclear fragments.
Looking at eyes with a history of
glaucoma, 8 out of 25 (32%) in the Pred
Forte group and none out of 17 in the
Bromday group had IOP elevation.
Remember that these are all comers,
including patients with floppy irises,
diabetes, and dense nuclei. “Why haven’t
we needed to add a steroid in any of my
last 900 cases [including the 200 who were
part of this study]?” wondered Dr. Walter.
“I think it comes down to this: It may
be that we are so engrained to use a
steroid that it’s impossible to consider
doing otherwise in these cases,” he said.
It must also have to do with the
advances in pharmaceutical technology.
“NSAIDs have gotten better and better with
each additional newcomer on the block,”
said Dr. Walter. “Bromday is a better
NSAID than any we’ve had before.
“It’s made my life simpler because
now my patients have a much simpler drop
table,” he continued. “Compliant patients
have had no CME yet, and we have not
had any corneal complications.”
Reference
1. Walter K, Estes A, Watson S, Ellingboe M. Management
of Ocular Inflammation following Routine Cataract
Surgery—Topical Corticosteroid (Prednisolone) versus
Topical Non-steroidal (Bromfenac). US Ophthalmic
Review, 2011;4(2):97-100.
2. Duong HQ, Westfield KC, Singleton IC. Comparing Three
Post-Op Regiments for Management of Inflammation Post
Uncomplicated Cataract Surgery. “Are Steroids Really
Necessary?” J Clinic Experiment Ophthalmol 2011; 2:6.
3. Cable M. Clinical Outcomes of Bromfenac Ophthalmic
Solution 0.09% QD vs. Nepafenac 0.1% TID for Treatment
of Ocular Inflammation Associated with Ocular Surgery.
Presented at ARVO 2012.
Contact information
Devgan: [email protected]
Gayton: [email protected]
Katsev: [email protected]
Kim: [email protected]
Walter: [email protected]