Anit-inflammation Perfecting cataract surgery

 Anit-inflammation Perfecting cataract surgery

EyeWorld Supplement to EyeWorld August 2012

Inflammation 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.).

NSAID issues 2012

“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.

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 anti-inflammatory 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 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.”

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.”

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 anti-inflammatory 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.

Corneal melts/toxicity:

Is there still an issue?

The reported complications following the use of NSAIDs in cataract surgery vary in severity, according to Dr. Kim. These cases range from things as innocuous as superficial punctate keratitis, to stromal infiltrates, immune rings, and persistent epithelial defects, to the most dreaded complication: corneal melts.

Dr. Kim said this was the major issue back in 1999, when the ASCRS survey came out looking at bservations of corneal melt after routine anterior segment surgery.

The survey pinpointed the use of topical generic diclofenac, which was voluntarily identified and recalled by the manufacturer. There have been many similar reports with other NSAIDs, said Dr. Kim.

“There is still a lot of fear among cataract surgeons when using NSAIDs during cataract surgery,” he said.

The deleterious effect of NSAIDs on the cornea is thought to be related to a group of proteases or ollagenolytic 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 many physiologic and pathophysiologic processes, said Dr. Kim. These include disease conditions like macular degeneration and diabetic retinopathy and processes such as IOP regulation.

In the cornea specifically, MMPs have been detected in corneal ulcers, keratoconus, and after PRK surgery.

NSAIDs have been potentially linked to corneal melts through the upregulation of MMPs, resulting in an imbalance between ECM deposition and degradation. NSAIDs may cause excessive MMP expression, and various MMPs have been found in NSAID-related melts.

Clinically, topical NSAIDs decrease normal corneal sensation1,2 and can affect corneal epithelial healing.3,4

To avoid complications, NSAIDs should be used properly. “I believe it is very important to follow the label dosing,” said Dr. Kim. “If you look at case series that are reported in the literature, complications like corneal melt usually occur when NSAIDs are not dosed properly.”

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 disease, concurrent topical steroids, or 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,  on-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  table 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 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

“I believe I could always add a steroid if I need to,” he said. Dr. Walter used this protocol on all hispatients, 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 painintraoperatively 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: devgan@gmail.com

Gayton: JLGayton@aol.com

Katsev: katsev@aol.com

Kim: terry.kim@duke.edu

Walter: kwalter@wfubmc.edu