Clinicians say studies, experience support safety of Voltaren, Acular

Long-term use, as in CME prevention and treatment, would have revealed serious corneal problems, say NSAID users. But they saw none.

Despite the withdrawal of one topical ophthalmic nonsteroidal anti-inflammatory drug (NSAID) from the market, many surgeons continue to use others in the class to prevent inflammation after cataract surgery.

Many also endorse off-label use of NSAIDs to prevent and treat cystoid macular edema (CME).

The endorsement follows a debate touched off by the American Society of Cataract and Refractive Surgery (ASCRS), which questioned the use of NSAIDs after its members reported 134 cases of keratitis, corneal erosions and perforations that they associated with the postop use of NSAID drops.

ASCRS reported that the survey linked corneal complications to three NSAIDs — Voltaren (diclofenac sodium, CIBA Vision); Acular (ketorolac tromethamine, Allergan); and DSOS (diclofenac (diclofenac sodium ophthalmic solution, Alcon). The society issued a warning on Aug. 3, 1999, to avoid using them until the problem could be studied.

But the warning may have unfairly implicated two of those NSAIDs, according to surgeons who are sticking by their brand of choice.

According to Mark Abelson, MD, “There’s a lot of fear engendered without information right now. The epidemiological studies that ASCRS are doing right now should be applauded. But getting to the answer requires finer tools epidemiologically and evaluation of these cases on a case-by-case basis.”

According to Richard L. Lindstrom, MD, “I use both [steroidals and NSAIDs] and I’ve never had a melt of any kind.”

Melts explained

When surgeons create an incision, Dr. Lindstrom said, the cornea responds by cleaning up dead cells from the trauma of surgery and then rebuilding the tissue by bringing in new collagen. NSAIDs shut down the arachidonic acid pathway to prostaglandins and allow leukotrienes to fill those receptors. This brings in white blood cells, which carry lytic enzymes and coagulases.

This throws off the balance between cleaning out dead cells and building new ones, which triggers the erosions and melting.

“It does appear that the NSAIDs, by bringing in too many white cells, can get out of balance,” Dr. Lindstrom said. “You are overloaded with white cells and have too much of the lytic side faster than the rebuilding side can happen.”

Difference studied

Frank A. Bucci Jr., MD, of Wilkes-Barre, Pa., started a prospective controlled study of the two drugs before the controversy sprang up. Dr. Bucci was completing his study as anecdotal reports arose about NSAIDs and the DSOS brand of the drug.

“I was doing the comparison that someone would want to do after hearing about the controversy, but I was doing it before the controversy started,” he said. “My study more or less proves what everyone suspected, that DSOS [generic diclofenac] causes this corneal infiltrative keratitis and possibly corneal melting.”

Dr. Bucci’s study, which CIBA funded, randomized 64 patients into two groups treated with Voltaren or DSOS.

Dr. Bucci followed the Food and Drug Administration approved product labeling in all aspects except one — he started the drops immediately postoperatively instead of waiting one day.

“Alcon has been saying that these difficulties arose from improper use of the drug,” Dr. Bucci said. “But in this study they were used four times a day.”

He used a Kowa cell and flare meter to assess the corneas at 1 day, 1 week and 2 weeks. A masked observer noted conjunctival injection at the same time periods.

At 1 day no substantial difference existed between the two groups. But at 1 week and 2 weeks, there was anywhere from 25% to 35% more cell and flare in the DSOS group and almost twice as much conjunctival injection in the DSOS group compared with the Voltaren group, Dr. Bucci said.

He recorded four adverse events in the DSOS group (12%) and none in the Voltaren group. One patient experienced so much postop iritis and corneal folds at 1 week that Dr. Bucci withdrew the eye from further participation in the study. Another three eyes had extremely dense, opaque corneal infiltrates at the temporal clear corneal wound incision and at the paracentesis site.

“I was lucky that in the protocol of my study, I was seeing the patients at 1 week and 2 weeks,” he said. “I normally see my cataract patients 2 to 3 weeks later and that corneal infiltrate is the perfect set-up for a corneal melt. I caught the patients at 1 week, but it’s amazing that an infiltrate that severe can occur at the 1 week period. That’s a very severe event.”

The dense infiltrates occur when white blood cells are recruited to the cornea, and the anti-inflammatory medicine cannot handle the overload, Dr. Bucci said.

“There must be something in the vehicle of the DSOS that is inflaming the ocular surface,” Dr. Bucci said. “So you have inflammation of the ocular surface and the eye is raw and irritated, which is causing an epithelial problem, such as punctate epithelial keratitis. The conjunctival cells and the corneal cells, the ocular surface, is being irritated, which decreases the epithelial healing over the cornea.”

Panel stands up for NSAIDs

At the American Academy of Ophthalmology meeting, Allergan hosted an “Ask the Experts” panel on ophthalmic NSAIDs at their booth.

“There’s a perception that maybe nonsteroidals are not as safe as we thought,” said panel moderator Kerry Solomon, MD, in opening the discussion. “Maybe we should be rethinking how we’re dosing and using nonsteroidals.”

“Is there a safety issue to the use of nonsteroidals?” Calvin Roberts, MD, asked rhetorically. “There’s a safety issue with every medication we use, and no medicine is 100% safe. However, we learn to raise the safety profile and apply medicine to our patients judiciously.”

“Good point,” Dr. Solomon said. “No surgery is going to be complication-free, and no medicine is going to be complication-free. But there have been a lot of studies looking at steroids and nonsteroidals in allergy, CME and/or postoperative inflammation following cataract surgery. While any medicine has the potential to cause a problem — especially in predisposed patients with diabetes, dry eye, etc. — the published studies have certainly shown that the nonsteroidals are equivalent to or safer than topical steroids.”

“Over the years we have developed confidence in nonsteroidals,” Dr. Roberts said. “What has happened recently has shaken a lot of people’s confidence in the class, which really isn’t deserved. The class is safe. It was a problem with a specific product.”

Dr. Solomon agreed that some statements being made about NSAIDs as a class were unclear.

“Are there differences between the different nonsteroidals,” he asked, “and even more specifically between the diclofenac products?”

“There is a difference between the vehicle of the Voltaren form of diclofenac and the ‘generic’ form, which, to the best of my understanding, was the source of the problem,” Dr. Roberts said.

Lessons from long use

“There has been some suggestion that corneal melts and side effects have to do with physicians abusively dosing nonsteroidals,” Dr. Solomon said. “Most of us on the panel have had experience with thousands of patients treated with topical ophthalmic NSAIDs, and some of them were treated over long periods for allergy or CME. Has anyone on the panel seen a corneal melt?”

Jeffrey S. Heier, MD, said, “It is not uncommon to have CME patients on NSAIDs for upwards of 4 or 5 months, often with complicated eyes. Some patients have been on them for 6 months to a year, and I have never seen a corneal melt.”

Dr. Solomon asked panelists, “Is starting the drops immediately at the end of your cataract surgery or dosing them preoperatively being too aggressive?”

“Let’s start with on-label use,” Dr. Roberts replied. “On-label use for nonsteroidals in cataract surgery is four times a day starting 24 hours after surgery for a period of 2 weeks. My experience has been with nonsteroidals four times a day beginning 3 days prior to surgery. The study published in the September 1996 issue of Ophthalmology showed that patients who were treated 3 days prior to surgery had a statistically significant decrease in the amount of inflammation that was present on the first postoperative day. I always continue my patients on nonsteroidals for at least a month.”

“Most of our anterior segment surgeons have patients on nonsteroidals for roughly 4 weeks and then actually taper it to twice a day for the next 2 weeks,” Dr. Heier said. “That is in the routine, standard cataract patient. There are a lot of patients at much higher risk: diabetics, patients who have had CME in the fellow eye. In those patients I recommend treating prophylactically for at least 3 days. Depending on how their surgery went and how the postoperative inflammation resolved, we could have them on NSAIDs for 6 weeks or 2 months.”

“I also use nonsteroidals to prevent not only inflammation but cystoid macular edema,” said Michael B. Raizman, MD. “I start the drops at least 2 days, sometimes 3 days before surgery. I continue the drops for at least 4 weeks after surgery. I think patients who have lost vitreous should be on NSAIDs for 12 weeks, maybe longer.

“We have very good data that show this does in fact prevent cystoid macular edema. And in my studies and all the studies of CME prevention that I’ve read in the literature, there have been no problems with corneal toxicity.”

Why NSAIDs for CME?

Dr. Solomon asked, “Can you review why nonsteroidals decrease the incidence of CME?”

“It has been shown in a number of studies that they stabilize the blood-retinal barrier,” Dr. Heier said. “While no body can say for certain what causes cystoid macular edema, the prevailing thought is that it’s the release of prostaglandins because of inflammation at the time of surgery. The prostaglandins lead to capillary dilation and increased vascular permeability. Nonsteroidals stabilize that pathway, so you don’t get the release of prostaglandins.”

Dr. Solomon concluded the panel discussion with a recommendation for his colleagues in the audience.

“I disagree strongly with some of what I’ve seen written about the safety and efficacy of nonsteroidals,” he said. “These are safe drugs. In my own experience and that of my colleagues, NSAIDs’ track record is proven. I would encourage you to use them as you have been using them in the past.”

Dr. Abelson told Ocular Surgery News that NSAIDs still have a place in controlling pain, photophobia, cell and flare and probably for CME.

“Because cataract surgery has become so successful, the number one adverse outcome is CME, which occurs in 1% of patients. That’s permanent, chronic macular edema with visual impairment. Maybe 20% [of patients] have a temporary decrease in vision because of CME,” he said.

He added that NSAIDs decrease cell and flare in patients, and the combination of steroids and NSAIDs decrease the likelihood of CME.

Dr. Abelson speculated that the erosion and melting may stem from patients who use multiple medications — steroids, NSAIDs, antibiotics and maybe glaucoma medication.

“What we have is almost a stress test to see how many anti-inflammatory drops certain eyes can tolerate,” Dr. Abelson said.

“This is an important drug category,” he said. “We shouldn’t stop using them because in their exaggerated use and situations, they cause occasional problems. It makes more sense to shorten the usage of the drugs and develop proper models to maximize the efficacy.”