April 2016




Pharmaceutical focus

New focus on NSAIDs for cataract surgery

by Maxine Lipner EyeWorld Senior Contributing Writer


OCT image

OCT image of a patient who underwent uncomplicated cataract surgery and developed CME postoperatively.

Source: William Trattler, MD

Physicians discuss prophylactic use of NSAIDs in cataract patients

Does the use of topical NSAIDs make sense for cataract patients? Among the primary uses for many is to keep cystoid macular edema (CME), which sometimes plagues patients after cataract surgery, at bay. Determining how frequently CME occurs depends upon what parameters are considered, according to Neal Shorstein, MD, ophthalmologist and associate chief of quality, Kaiser Permanente, Walnut Creek, California. In a study1 published in the December 2015 issue of Ophthalmology, which Dr. Shorstein led, investigators compared the effectiveness of 3 different prophylactic strategies in preventing CME after phacoemulsification. Based on this study, Dr. Shorstein estimates that the rate of CME runs between 1 and 3%. It can go as high as 40% if you are calling it CME primarily based on OCT evidence of fluid, Dr. Shorstein said. In the recent study, investigators used visually significant CME, as determined by OCT evidence of CME, as well as a visual acuity of 20/40 or worse.

When it comes to prophylaxis, in Dr. Shorsteins view, NSAIDs may have a role to play. In our study of more than 16,000 eyes, we saw a 55% reduction in the incidence of visually significant CME when topical NSAIDs were added to topical prednisolone, he said, adding that the results were statistically significant and were consistent with a number of other studies. The practice of the surgeons included in the study was to prescribe NSAIDs for application 4 times a day for 4 weeks after cataract surgery. While none of the surgeons included in this retrospective study were prescribing the NSAIDs preoperatively, Dr. Shorstein thinks this may have value. Some studies have shown that theres an additional benefit from preoperative administration, he said.

John Wittpenn, MD, partner, Ophthalmic Consultants of Long Island, who led an earlier NSAID cataract study, agrees that prophylaxis with these is helpful. In this study,2 appearing in October 2008 in the American Journal of Ophthalmology, investigators compared use of topical ketorolac 0.4% in combination with steroid to steroid alone for staving off post-phacoemulsification complications. While at the time, Acular LS (ketorolac, Allergan, Dublin) was the nonsteroidal being used, few people today are using this because the brand formulation is not available, Dr. Wittpenn pointed out. Theyre using either bromfenac as Prolensa [Bausch + Lomb, Bridgewater, New Jersey] or nepafenac as Ilevro [Alcon, Fort Worth, Texas], he said.

While full-blown CME was the endpoint of his study, other studies have considered macular thickening as an indication of this, Dr. Wittpenn said, adding that with this kind of study the same statistical difference that was found for ketorolac has been seen for Nevanac (nepafenac, Alcon, Fort Worth, Texas). In his study, the prophylaxis included having the NSAID on board beginning 3 days preoperatively. This has the added advantage of maintaining pupillary dilation, as well as decreasing pain with surgery, Dr. Wittpenn pointed out. We have patients use the NSAID postoperatively for 4 to 5 weeks. William Trattler, MD, Center for Excellence in Eye Care, Miami, who also participated in this study, agreed that use of NSAIDs can be helpful for patients undergoing cataract surgery. Typically, he puts patients on newer generation NSAIDs, such as Ilevro and Prolensa, for a month postoperatively. But for some he may use NSAIDs longer. There are some patients who are at higher risk for CME than others or who have more inflammation in general, so we may extend it to 68 weeks, he said. However, one has to be careful with the generic NSAIDs, as there can be ocular surface issues. There can be a big difference between brand name NSAIDs and generics, he finds. When my patients get switched at the pharmacy, they typically have more ocular irritation with the generic, especially if there is preexisting dry eye, he said. Patients will experience more ocular surface irritation and staining with generic NSAIDs versus the brand names, which results in blurred vision. Dr. Trattler pointed out that a few corneal melts have been reported with the topical NSAIDs in the past few years. They seem to be mostly occurring with the generics, he said, adding that if a patient has a compromised ocular surface, surgeons have to be careful in how they prescribe nonsteroidals. Such patients may not be the best candidates for nonsteroidals. If they have severe ocular surface disease, any NSAID may cause ocular irritation, he said. But overall, the brand name nonsteroidals are better tolerated. Dr. Wittpenn likewise finds that the brand name NSAIDs are more likely to spare the ocular surface. Prolensa and Ilevro are gentler on the ocular surface than the generics, he said. With the generic ketorolac, which many people are now getting because thats all thats on the formulary, its not uncommon to have to stop or reduce the drop after a week because of increasing punctate keratopathy. If the patient is complaining of increasing stinging or burning from the drops, its a sign to look carefully at the cornea for punctate keratopathy and stop the drop if necessary, Dr. Wittpenn said.

Cost factor Not everyone is convinced that prophylactic use of NSAIDs is of value. William Myers, MD, health system clinician, Feinberg School of Medicine, Northwestern University, Evanston, Illinois, and in private practice, Skokie, Illinois, said that when he underwent his training, around 1980, no one pretreated with topical agents for CME. If a patient had a problem in the first eye, an oral NSAID might be used, but for the most part this wasnt treated until there was an actual issue. Treatment generally solved the problem, Dr. Myers said. Within 6 months, a high percentage would usually get better whether they were treated or not, but more would respond when they were treated. Thats the basis for why all nonsteroidals are used today, Dr. Myers said.

My personal feeling is that all of these topical nonsteroidals are incredibly expensive, he said, adding that even for generics its not uncommon for them to cost close to $100 a bottle, with most patients ultimately needing 2 bottles. Meanwhile, he thinks that oral NSAIDs are as effective as the topical ones, if not more so. In Dr. Myers view, oral agents are not inferior to topical ones and are safer for the surface of the eye. They might be riskier in patients who have gastrointestinal disease, but the vast majority of patients dont have a history of gastritis or ulcers, he said. Those people have low rates of trouble taking medicines like naproxen. Such medicines would cost under $10 a bottle and would last for awhile, he pointed out.

Intraoperative use In addition to using prophylactic drops, the intracameral NSAID Omidria (phenylephrine and ketorolac, Omeros, Seattle) is making inroads. Omidria is now the only FDA-approved product where you can put the nonsteroidal in the eye, Dr. Wittpenn said. It got approved based on its ability to maintain pupillary dilation combined with phenylephrine and decreased pain. While the studies dont sort out which element does which, they did show that the combination of the 2 products enhanced both of these features. He finds that Omidria maintains good pupillary dilation. Dr. Wittpenn thinks this could potentially reduce or eliminate the need for topical NSAIDs because the levels of ketorolac measured in the animal studies are much greater than what could be achieved topically. Many of the newer agents such as Prolensa and Ilevro are currently being dosed once a day, but this schedule has nothing to do with preventing macular thickening. He pointed out that studies done on the prevention of CME or macular thickening utilized ketorolac dosed 4 times a day or nepafenac dosed 3 times a day. These agents block prostaglandin synthesis by binding to the COX enzymes. When there are insufficient molecules to block all the enzymes, production of prostaglandins resumes. These prostaglandins cannot be eliminated when additional medicine is dosed at a later time. Unlike with an antibiotic where you can hope to kill what you missed with the next, with prostaglandin synthesis, once it is made it remains in the eye tissue to elicit inflammation, pain, and macular changes. With this in mind, he currently doses topical brand NSAIDs twice a day and is uncertain whether even that is enough. Now perhaps Omidria will let me get down to once-a-day dosing or even eliminate topical NSAIDs, Dr. Wittpenn said.

Others are looking to perhaps decrease the number of drops patients are taking by eliminating the use of steroids from the postoperative mix. However, its currently a fluid question as to whether or not topical NSAIDs can be used alone. Dr. Trattler pointed out that while most nonsteroidals are FDA approved for control of the inflammation after cataract surgery without a steroid, the 2 together have a synergistic effect because these work on different parts of the inflammatory pathway. There are surgeons who prefer just using a nonsteroidal and thats appropriate, but I like the combination, Dr. Trattler said. Overall, in Dr. Trattlers view, NSAIDs will continue to be an important part of the cataract regimen. I think we will continue to work toward lowering the amount of drops used for patients in and around cataract surgery, Dr. Trattler said. But we need a nonsteroidalits a very important part of postoperative care for cataract surgery. EW


1. Shorstein NH, et al. Comparative effectiveness of three prophylactic strategies to prevent clinical macular edema after phacoemulsification surgery. Ophthalmology. 2015;122:24502456.

2. Wittpenn JR, et al. A randomized, masked comparison of topical ketorolac 0.4% plus steroid vs. steroid alone in low-risk cataract surgery patients. Am J Ophthalmol. 2008;146:554560.

Editors note: Dr. Shorstein has no financial interests related to his comments. Dr. Trattler has financial interests with Alcon, Allergan, Bausch + Lomb, and Omeros. Dr. Myers has no financial interests related to his comments. Dr. Wittpenn has financial interests with Bausch + Lomb and Omeros.

Contact information
Myers: wmyers2020@gmail.com
Shorstein: nshorstein@eyeonsight.org
Trattler: wtrattler@gmail.com
Wittpenn: jrwittpenn@aol.com

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