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Benefits of NSAIDs for CME prevention in cataract surgery

ByDavid F. Chang, MD

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The benefits of nonsteroidal anti-inflammatory drugs for cataract surgery include their ability to prevent intraoperative miosis and to act as intraoperative and postoperative analgesics. The anti-inflammatory properties of NSAIDs provide protection against postoperative cystoid macular edema (CME) and iritis.

Clinically significant CME is defined as that with a symptomatic drop in vision to worse than 20/40 and the presence of visible perifoveal cysts in the macula. The incidence of perifoveal cysts ranges from 0.5% to 3%. In contrast, angiographic CME may be asymptomatic — patients will generally have vision that is 20/40 or better. Therefore, fluorescein angiography or optical coherence tomography (OCT) must be used to diagnose CME in these cases. Historically, studies have suggested that the incidence of angiographic CME after uncomplicated cataract surgery may be as high as 20% to 30%.

A fair question to ask is whether modern phacoemulsification methods reduce the incidence of angiographic CME compared with intracapsular and extracapsular surgical techniques. However, a study performed by Paul G. Ursell, MD, MBBS, FRCOphth, in 1999 showed that, even after uncomplicated phacoemulsifacation, the incidence of angiographic CME was still 19%.¹

Philippe Sourdille, MD, performed a study of CME as diagnosed by OCT after routine cataract surgery and found that 11 of 41 eyes had an increase in macular thickness postoperatively.²

Data on 71 eyes that were treated with a steroid for uncomplicated cataract surgery were presented at the European Society of Cataract and Refractive Surgeons (ESCRS) Congress in 2004. OCT measurements were taken preoperatively and postoperatively. The study found that the average macular thickness increased at 1, 4 and 8 weeks postoperatively.³

Pathogenesis of CME after cataract surgery

Kensaku Miyake, MD, first proposed in the 1970s that surgical trauma causes the release of inflammatory mediators from cell membranes, most notably, the prostaglandins and leukotrienes.⁴ Lens epithelial cells (LECs) may be the most important contributors to these mediators, which lead to the breakdown of the blood-aqueous barrier, resulting in aqueous flare and cell. Because the blood-aqueous barrier requires a significant amount of time to become re-established, a breakdown of the blood-retinal barrier occurs. Increasing capillary permeability around the fovea results in either angiographic or clinically significant CME.

Within the arachidonic acid pathway, steroids and NSAIDs work at different points in the inflammation cascade. Steroids work at the top of the chain by blocking phospholipase A. Steroids block both subsequent arms of the pathway, including prostaglandin synthesis and leukotriene production, whereas NSAIDs come into play later and block prostaglandin synthesis.

Treatment of CME

When I am beginning treatment of patients with CME, one important consideration is whether an NSAID should be used concurrently with a steroid. While postoperative CME following uncomplicated surgery is a self-limited condition, treatment of symptomatic CME is commonly initiated in order to speed up the resolution. Many studies have shown that both NSAIDs and steroids, whether oral or topical, are effective in treating CME.

Jeffrey S. Heier, MD, performed a randomized prospective study on the effect of ketorolac alone, prednisolone alone or a combination of the two drugs for the treatment of CME. He found that ketorolac alone and the combination therapy were significantly more effective than prednisolone alone, with the combination being slightly superior to the NSAID alone.⁵ A more recent study of 10 patients did not find the combination to be better but, rather, found that ketorolac alone and ketorolac combined with prednisolone were equally effective.⁶ A large prospective study by David S. Rho, MD, compared ketorolac and diclofenac and found no difference with respect to efficacy for treating CME.⁷ All of these studies were prospective randomized studies utilizing fluorescein angiography to objectively evaluate CME.

Figure Several patient and surgical risk factors predispose eyes to CME following cataract surgery. NSAIDs are indicated in these cases. (Figure courtesy of David F. Chang, MD)

Prophylaxis for CME

Luca Rossetti, MD, and colleagues performed a meta-analysis of 36 studies on CME prophylaxis published through 1998. Prophylactically treated eyes had an average incidence of 11% of angiographic CME, compared to 32% incidence of angiographic CME in untreated eyes. Treated eyes had a 5% incidence of clinical CME, compared to 10% in untreated eyes. However, most of these studies were not randomized prospective trials.⁸

Following Dr. Rosetti’s meta-analysis, several randomized prospective trials evaluating the ability of NSAIDs to prevent angiographic CME have been published. Claus-Dieter Quentin, MD, performed an early study comparing diclofenac vs. placebo and found that diclofenac had a protective effect against CME in patients undergoing intracapsular surgery with anterior chamber IOLs.⁹ Allan J. Flach, MD, and Leon Solomon, MD, found a similar protective effect with ketorolac and flurbiprofen vs. placebo in two studies evaluating manual extracapsular surgery with posterior chamber IOLs.^10,11

Clinicians may wonder whether the issue of CME is still relevant in light of less traumatic, small-incision phaco techniques. However, a number of randomized prospective trials have demonstrated that angiographic CME still occurs frequently enough following uncomplicated phaco. Two Italian randomized prospective studies showed that diclofenac was protective against angiographic CME compared to placebo both with or without concomitant steroid.^12,13

Even more compelling were Dr. Miyake’s prospective randomized angiographic studies demonstrating a greater CME protective effect of diclofenac compared to fluorometholone.^14,15 In one study, at 5 weeks postoperatively, angiographic CME was present in 5.7% of eyes treated with diclofenac only, compared to 54.7% of eyes treated with fluorometholone only.¹⁵

Postoperative NSAIDs for high-risk eyes

Several risk factors predispose eyes to CME following uncomplicated cataract surgery, and topical NSAIDs are indicated for these cases. Patient risk factors for CME include diabetes, uveitis or previous ocular surgery and the chronic use of preserved topical medications, such as for glaucoma. Additional patient risk factors for CME include pre-existing macular edema from retinal vascular disease, the presence of an epiretinal membrane and previous postoperative CME in the fellow eye.

Surgical risk factors for CME include large incisions, prolonged surgical time, iris trauma and residual cortex. CME is more likely to occur following complications such as posterior capsular rupture, vitreous loss, retained lens material, placement of anterior chamber IOLs and sulcus-fixated posterior chamber IOLs.intraocular bleeding and toxic anterior segment syndrome (Figure).

Many patients who undergo cataract surgery are also taking glaucoma medications, and increased incidence of subclinical and symptomatic CME has been discovered in these eyes. Dr. Miyake published a landmark randomized prospective study in 1999 in which patients were stratified into four groups: latanoprost plus diclofenac, latanoprost plus fluorometholone, diclofenac only and fluorometholone only.¹⁶ In comparing the two fluorometholone groups, concomitant latanoprost was associated with a statistically higher rate of angiographic CME. However, when comparing the two latanoprost groups, there was a statistically lower rate of angiographic CME when diclofenac was used. In other words, the NSAID blocked the CME-inducing effect of latanoprost.

In 2002, Patrick C. Yeh, MD, and colleagues reported a strong association between latanoprost and clinically significant CME after routine cataract surgery in a retrospective study of 162 eyes.¹⁷ This also seemed to confirm surgeons’ concerns about using a prostaglandin analogue after cataract surgery.

However, in his 2002 ESCRS Binkhorst lecture, Dr. Miyake proposed a completely different mechanism, labeling the phenomenon pseudophakic preservative maculopathy.¹⁸ Using LEC cultures, he compared latanoprost, preserved and nonpreserved timolol and preserved and nonpreserved vehicle. From these comparisons, he concluded that the preservative benzalkonium chloride was toxic to the LECs. Randomized prospective clinical trials with these agents (latanoprost and preserved vs. nonpreserved timolol or vehicle) subsequently confirmed that angiographic CME was associated with the preservative rather than the drugs.¹⁸ Based upon these often overlooked studies, NSAIDs should be used whenever patients are taking chronic topical preserved medications.

Postoperative NSAIDs for routine cataract surgery

I began using postoperative NSAIDs routinely in 1999, based upon a randomized prospective study by Michael Raizman, MD.¹⁹ He used OCT to identify increased macular thickness following uncomplicated phacoemulsification. Patients receiving prednisolone had approximately a 25% incidence of CME diagnosed by OCT, compared with 0% of patients who received prednisolone with diclofenac.¹⁹ This was convincing objective evidence that NSAIDs prevent sub-clinical CME following uncomplicated cataract surgery.

For a time, I tried using NSAIDs without prednisolone following surgery, but a number of eyes exhibited significant inflammatory cells in the anterior chamber after 1 week, compelling me to prescribe both agents after routine surgery, despite the added cost and inconvenience.

Objective evidence from randomized clinical trials indicates that NSAIDs prevent both clinical and angiographic CME following routine or complicated cataract surgery. It is on this basis that I routinely use NSAIDs postoperatively, regardless of the presence of risk factors for CME.

References

1. Ursell PG, Spalton DJ, Whitcup SM, Nussenblatt RB. Cystoid macular edema after phacoemulsification: Relationship to blood-aqueous barrier damage and visual acuity. J Cataract Refract Surg. 1999;24(11):1492-1497.
2. Sourdille P, Santiago PY. Optical coherence tomography of macular thickness after cataract surgery. J Cataract Refract Surg. 1999;25(2):256-261.
3. Binder. Presented at the European Society of Cataract and Refractive Surgeons Congress; Sept. 18-22, 2004; Paris, France.
4. Miyake K. Prostaglandins as a causative factor of the cystoid macular edema after lens extraction. Nippon Ganka Gakkai Zasshi. 1977;81(9):1449-1464.
5. Heier JS, Topping TM, Baumann W, Dirks MS, Chern S. Ketorolac versus prednisolone versus combination therapy in the treatment of acute pseudophakic cystoid macular edema. Ophthalmology. 2000;107(11):2034-2028;discussion:2039.
6. Singal N, Hopkins J. Pseudophakic cystoid macular edema: Ketorolac alone vs. ketorolac plus prednisolone. Can J Ophthalmol. 2004;39(3):245-250.
7. Rho DS. Treatment of acute pseudophakic cystoid macular edema: Diclofenac vs. ketorolac. J Cataract Refract Surg. 2003;29(12):2378-2384.
8. Rossetti L, Chaudhuri J, Dickerson K. Medical prophylaxis and treatment of cystoid macular edema after cataract surgery. The results of a meta-analysis. Ophthalmology. 1998;105(3):397-405.
9. Behrens-Baumann W, Quentin CD, Eckhardt B, Vogel M. Incidence of cystoid macular edema after cataract extraction [article in German]. Fortchr Ophthalmol. 1989;86(3):195-196.
10. Flach AJ, Stegman RC, Graham J, Kruger LP. Prophylaxis of aphakic cystoid macular edema without corticosteroids. A paired-comparison, placebo-controlled double-masked study. Ophthalmology. 1990;97(10):1253-1258.
11. Solomon LD. Efficacy of topical flurbiprofen and indomethacin in preventing pseudophakic cystoid macular edema. Flurbiprofen-CME Study Group I. J Cataract Refract Surg. 1995;21(1):73-78.
12. Rossetti L, Bujtar E, Castoldi D, Torrazza C, Orzalesi N. Effectiveness of diclofenac eyedrops in reducing inflammation and the incidence of cystoid macular edema after cataract surgery. J Cataract Refract Surg. 1996;22(Suppl 1):794-799.
13. Rossetti L, Bellucci R, Cillino S, et al. Efficacy and safety of combined diclofenac 0.1% and gentamicin 0.3% eyedrops after phacoemulsification. J Cataract Refract Surg. 1997;23(5):745-749.
14. Miyake K, Ota I, Maekubo K, Ichihashi S, Miyake S. Latanoprost accelerates disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema in early postoperative pseudophakias. Arch Ophthalmol. 1999;117(9):1265-1266.
15. Miyake K, Masuda K, Shirato S, et al. Comparison of diclofenac and fluorometholone in preventing cystoid macular edema after small incision cataract surgery: a multicentered prospective trial. Jpn J Ophthalmol. 2000;44(1):58-67.
16. Miyake K, Ota I, Maekubo K, Ichihashi S, Miyake S. Latanoprost accelerates disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema in early postoperative pseudophakias. Arch Ophthalmol. 1999;117(1):34-40.
17. Yeh PC, Ramanathan S. Latanoprost and clinically significant cystoid macular edema after uneventful phacoemulsification with intraocular lens implantation. J Cataract Refract Surg. 2002;28(10):1814-1818.
18. Miyake K, Ibaraki N, Goto Y, et al. ESCRS Binkhorst lecture 2002: Pseudophakic preservative maculopathy. J Cataract Refract Surg. 2003;29(9):1800-1810.
19. Raizman M. Macular Edema After Cataract Surgery. Presented at the Royal Hawaiian Eye Meeting; Jan. 24-29, 1999; Waikoloa, Hawaii.

Discussion Eric D. Donnenfeld, MD: One of the challenges encountered in the clinical trials for Xibrom (bromfenac sodium 0.1%, Ista Pharmaceuticals) was that the bar was raised higher in the clinical approval process than other nonsteroidal anti-inflammatory drugs previously approved by the Food and Drug Administration. In the past, Voltaren (diclofenac sodium, Novartis) and Acular (ketorolac tromethamine 0.5%, Allergan) were required to achieve a score of 1 on the postoperative inflammation chart, whereas the FDA required a score of 0 for Xibrom. Sixty-four percent of the 356 patients taking bromfenac achieved ocular inflammation scores of 0, compared to 43% of 171 patients on placebo. Additionally, the FDA also evaluated resolution of pain after cataract surgery, a measure that had not been reviewed previously. Patients taking bromfenac showed complete resolution of pain in fewer than 2 days after surgery vs. patients taking placebo, who took longer to experience pain resolution (Figure 1). Postoperative photophobia was also significantly decreased with bromfenac in the FDA trials, showing that this NSAID is clinically effective. It is difficult to compare NSAIDs because there are few head-to-head studies. However, there are clinical differences between them. Preventing and managing CME Donnenfeld: Dr. Chang, how do you define CME? Please differentiate between angiographic and clinical CME. David F. Chang, MD: Clinical CME produces a symptomatic decrease in vision, which may be slight or very dramatic. In this context, angiographic CME refers to an asymptomatic patient in whom sub-clinical CME is detected by fluorescein angiography or optical coherence tomography (OCT). While some of these eyes may be 20/25 or 20/30, Snellen acuity testing may not be sensitive enough to detect the functional change in other eyes. Testing contrast sensitivity or reading speed might better detect the more subtle impairment of sub-clinical CME. Henry Perry, MD: In terms of CME diagnosis, there is no question that OCT has improved the clinician’s ability to detect CME. With improved diagnoses, I believe that surgeons will be more prone to use NSAIDs to prevent the occurrence of CME. Donnenfeld: I think that Snellen visual acuity may be the worst way to test postoperative results in cataract surgery. Low-contrast sensitivity and glare testing are equally important to measure the visual acuity of patients who have undergone cataract surgery. Under these conditions, CME will cause significant visual degradation. Figure 1 In phase 3 of the U.S. FDA clinical trials, 80.5% of patients taking bromfenac showed complete resolution of pain 2 days after beginning treatment, compared to 32.7% taking placebo. Patients in both groups initiated treatment with a baseline summed ocular inflammation score of 3.7. Bromfenac is not indicated for the relief of ocular pain. (Figure courtesy of Eric D. Donnenfeld, MD.) Dr. Chang, please comment on the data on the incidence of CME after cataract surgery without use of NSAIDs that Michael Raizman, MD, presented at Hawaii 1999: The Royal Hawaiian Eye Meeting.1 Chang: Dr. Raizman’s study addressed the obvious question of whether routinely adding a postoperative NSAID to the usual topical steroid regimen is necessary following uncomplicated cataract surgery. Using OCT in a prospective randomized study, he demonstrated that combination therapy prevented CME compared to steroids alone.1 Based upon his study, I began routinely prescribing combination therapy in 1999. This has dramatically decreased the incidence of clinical CME, which previously I would occasionally see following steroid cessation. The prevention of clinical and sub-clinical CME justifies the added cost and inconvenience of NSAIDs in my mind.