Several clinical trials have examined anti-inflammatory treatments for the prevention of cystoid macular edema (CME) after uneventful cataract surgery, but the optimal preventive regimen is still up for debate. A recent study published in the American Journal of Ophthalmology evaluating tried-and-true and newer therapies found that although NSAID use—and pretreatment, in particular—may speed up visual recovery, evidence does not point toward improved long-term visual acuity (VA) outcomes. 

Additionally, the authors reported limitations in published reports that included unbalanced dosing, which precluded any determination on whether an NSAID used in combination with a steroid can provide a synergistic effect.

Considering newer treatment options, such as the recently approved dropless delivery systems, including Dexycu (dexamethasone intraocular suspension 9%, EyePoint Pharmaceuticals) and Dextenza (dexamethasone ophthalmic insert 0.4mg, Ocular Therapeutics), the research paper noted these options may improve compliance, but trials examining long-term vision loss due to CME, as well as economic analysis for these costly drugs, are needed prior to widespread adoption.

“While prescribing both NSAIDs and corticosteroids for cataract surgery is common, these classes have overlapping mechanisms. Combination therapy may speed visual recovery, but there remains little evidence for improved long-term visual outcomes from NSAIDs,” the researchers wrote in their paper. “The last two decades have seen increasing data on potential benefits of pretreatment with NSAIDs one to three days prior to cataract surgery. Simultaneously, newly approved ‘dropless’ delivery systems hold promise, and clinical trials are ongoing to assess outcomes of such formulations.”

The paper wasn’t a systematic review or meta-analysis, but instead an opinion based on experience, viewpoints, a review of current evidence and original research by the authors.

NSAIDs’ Drawbacks

Several meta-analyses have concluded that NSAIDs decrease the incidence of postoperative CME. However, these meta-analyses have their own limitations, including disparate studies using different definitions of CME, variable corticosteroid formulations and unbalanced dosing schedules. Additionally, a number of studies were industry-sponsored, the authors explained.

Given the lack of evidence that NSAIDs improve long-term VA, with or without concomitant steroid use, routine use for cataract surgery is not recommended at this time, the researchers said. 

“Not only have NSAIDs not demonstrated clear benefits for visual function, but costs are substantial,” they wrote in their paper.

Controlled studies are needed to assess the effect of NSAIDs compared with and in addition to corticosteroids with good aqueous penetration, such as 1% prednisolone acetate or 0.05% difluprednate, and balanced dosing schedules, the investigators said. Such studies should track VA, not only CME, as a primary outcome, they added.

PREMED Study Findings

Pretreatment before surgery also remains controversial, the authors said. Their paper cited the findings of the Prevention of Macular Edema after cataract surgery (PREMED) study, a multicenter

randomized clinical trial funded by the European Society of Cataract and Refractive Surgery. In PREMED, patients received either bromfenac twice daily for two days preoperatively and for two weeks postoperatively or 0.1% dexamethasone four times daily for two days preoperatively and for one week postoperatively followed by weekly taper, or a combination of these regimens. 

The study concluded that patients in the combination group had the lowest central subfield thickness at the six-week follow-up, followed by the bromfenac group and then the dexamethasone group. The study also found a lower incidence of CME as well as more clinically significant macular edema at the six-week follow-up, though there was no statistical difference between treatment arms.

While the authors said the large PREMED study was a welcome addition to the literature, they noted that there were no significant differences in VA outcomes between groups, and, because of methodological limitations, there was still insufficient evidence for the routine use of NSAIDs alone or in combination with topical steroid therapy after cataract surgery.

Dropless Steroid Formulations

Two recent drug delivery systems for sustained-release anti-inflammatory medication have garnered FDA-approval: Dexycu and Dextenza. The anti-inflammatory effects of both medications have been encouraging, with Dexycu seeming to demonstrate better performance in the literature cited, the authors suggested. 

In a Phase III trial for Dexycu, 66% of patients had resolution of anterior chamber cell eight days after surgery, while i. In two Phase III trials of Dextenza, only between 33% and 52% had a resolved anterior chamber 14 days after surgery.  

The majority of the Phase III trials for the two medications were placebo-controlled, which the authors said made it difficult to assess whether these dropless delivery systems are better than standard care with topical steroids, topical NSAIDs or dual topical therapy.

Additionally, between 14% and 17% of patients receiving Dextenza in one study required rescue topical anti-inflammatory therapy.

Costs are also a concern with these medications, the researchers added. In the United States, the wholesale cost for a single dose of Dexycu is $595 and $538 for Dextenza.

Final Thoughts

A consensus definition for clinically significant CME may facilitate the comparison of anti-inflammatory drugs, the authors concluded, and a need remains for well-designed trials examining both topical and extended-release drug delivery systems to refine the treatment paradigm., the researchers concluded.

Taubsenslag KJ, Kim SJ, Grzybowski A. Anti-inflammatory pharmacotherapy for the prevention of cystoid macular edema after cataract surgery. Am J Ophthalmol. June 19, 2021. [Epub ahead of print].