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ByDavid F. Chang, MD
February 15, 2006
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NSAIDs for the prevention and treatment of postoperative CME

ByDavid F. Chang, MD

Topical nonsteroidal anti-inflammatory drugs have been proven to be invaluable medications for cataract surgeons and their patients. As a class, these drugs prevent intraoperative miosis and are effective as both intraoperative and postoperative analgesics. Their potent anti-inflammatory effects make NSAIDs useful in controlling postoperative iritis. Yet of all the clinical benefits, the primary reason that most cataract surgeons use NSAIDs is for the prevention and management of postoperative cystoid macular edema (CME).

Incidence of clinical and subclinical CME

Clinically significant CME is symptomatic. The patient will typically have a decline in vision to below 20/40 and perifoveal cysts in the macula can often be seen with the slit lamp biomicroscope and a Goldmann contact lens. Conversely, patients with subclinical CME are usually asymptomatic with vision of 20/40 or better. Consequently, an objective measure such as fluorescein angiography or optical coherence tomography (OCT) is usually needed to detect subclinical CME. For this reason, it is often referred to as “angiographic” CME. Prospective studies using angiography or OCT have demonstrated that the incidence of subclinical CME may be as high as 20% to 30% following cataract surgery, whereas the incidence of clinically significant CME following cataract surgery ranges from 0.5% to 3%.

Figure: NSAIDs Reduce CME Incidence
Figure

In separate studies, Kensaku Miyake, MD, has established that NSAIDs are superior to steroids at reducing the incidence of angiographic CME after cataract surgery.

(Figure courtesy of David F. Chang, MD.)

The incidence of clinical CME has been a concern throughout the history of intracapsular and manual extracapsular surgical techniques. However, since phacoemulsification with foldable IOLs involves smaller incisions and less iris trauma, some ophthalmic surgeons may perceive CME to be an extremely infrequent problem. However, recent investigations have confirmed that angiographic CME is still a frequent occurrence following uncomplicated phacoemulsification.

Two studies published in 1999 reported the incidence of subclinical CME following uncomplicated phacoemulsification procedures. In the first study, patients treated postoperatively with only topical steroids underwent angiography at 2 months and the results showed a 19% incidence of CME. In the second study, OCT was used preoperatively and up to 60 days postoperatively in patients treated with indomethacin following surgery. The results showed that 11 of 41 eyes (27%) developed an increase in postoperative macular thickness.

In 2004, OCT data from 71 uncomplicated eyes were presented at the European Society of Cataract and Refractive Surgeons (ESCRS) Congress. All patients were treated with a topical steroid and were evaluated both preoperatively and postoperatively with OCT. The findings revealed an increase in average macular thickness at 1 week, 4 weeks and 8 weeks following surgery.

Pathogenesis of postoperative CME

Much of our understanding of the pathogenesis of CME following uncomplicated cataract surgery can be attributed to Kensaku Miyake, MD. Dr. Miyake hypothesized that surgical trauma triggers the release of inflammatory mediators from lens epithelial cells (LECs) and other intraocular cell membranes. These inflammatory mediators cause a prolonged breakdown of the blood-aqueous barrier, leading to aqueous flare and cell. This process eventually leads to disruption of the blood-retinal barrier, causing increased permeability of perifoveal capillaries, ultimately resulting in CME.

Corticosteroids reduce inflammation by inhibiting phospholipase A2, the enzyme that converts phospholipids released from a traumatized cell membrane into arachidonic acid. By blocking this enzyme, steroids inhibit the production of both prostaglandins and leukotrienes. NSAIDs, however, act at a later point in the cyclooxygenase pathway by inhibiting the COX-2 enzyme and blocking production of inflammatory prostaglandins. Thus, the concurrent use of steroids and NSAIDs provide an additive benefit and suppress inflammation more efficiently than either agent alone.

Treatment of postoperative CME

Prospective clinical trials using fluorescein angio-graphy to objectively measure CME have shown that both steroids and NSAIDs are effective in the treatment of chronic and acute CME. In addition, both classes of anti-inflammatory agents are effective when administered via the oral or topical route. While it is important to note that acute CME following uncomplicated surgery is a self-limiting condition, treatment is usually administered to hasten resolution of the symptoms.

In a trial published in 2000, 28 patients who underwent cataract surgery who had developed postoperative CME were randomized to receive ketorolac alone, prednisolone alone or ketorolac and prednisolone. Treatment was administered four times a day for 3 months or until the CME resolved. Ketorolac was more effective than prednisolone, and the combination was found to be slightly more effective than either agent alone, which suggests that the effects of the two drugs are additive.

A 2004 randomized study compared the combination of ketorolac and prednisolone against ketorolac and placebo in 10 patients who developed acute or chronic clinical CME following cataract surgery.The results revealed no significant differences in outcomes between the two groups indicating that the addition of the steroid to the regimen provided no additional therapeutic benefit in reversing CME.

In another randomized study, ketorolac was directly compared with diclofenac in 34 postoperative cataract patients with chronic CME. Both agents were equally effective in resolving CME.

Risk factors for CME
David F. Chang, MD

Following cataract surgery, the risk for developing cystoid macular edema varies according to a number of factors. For otherwise uncomplicated cataract surgery, these include general patient risk factors such as diabetes, and ocular risk factors such as uveitis, prior ocular surgery and the chronic use of topical medications that contain preservatives (i.e., glaucoma medications or artificial tears). Retinal risk factors include the occurrence of CME following contralateral cataract surgery and anatomic risk factors such as an epiretinal membrane or pre-existing macular edema associated with retinal vascular disease. Examples of the latter include diabetic retinopathy, branch retinal vein occlusion, central retinal vein occlusion and idiopathic macular telangectasis.

Surgical risk factors might include larger incisions, prolonged surgical time and iris trauma, such as with iris prolapse or extensive surgical manipulation. Finally, complications during surgery elevate the risk of CME. Examples would include posterior capsule rupture, vitreous loss, retained lens material, intraocular bleeding and exaggerated inflammation such as with toxic anterior segment syndrome.

Prophylactic therapy for CME

The next important issue related to the development of CME following cataract surgery is prophylaxis. As cataract surgeons, it is important to decide whether just high-risk patients, or all patients should be treated with an anti-inflammatory agent to prevent the development of postoperative CME.

A meta-analysis of 36 articles assessed the effects of prophylactic therapy with topical steroids or NSAIDs on the incidence of postoperative CME. Active treatment groups had a much lower incidence of CME than did the placebo groups, regardless of whether the condition was detected clinically (4.9% vs. 10.1%) or angiographically (11.1% vs. 31.9%). The investigators concluded that the incidence of postoperative CME can be reduced by routinely treating patients with anti--inflammatory agents following cataract surgery.

Randomized prospective trials have shown a benefit to NSAID prophylaxis in angiographic CME. A 1989 study comparing diclofenac with placebo in 179 patients who underwent intracapsular extraction with an anterior chamber IOL demonstrated a significant protective effect with diclofenac. A study published in 1990 assessed the effects of ketorolac versus placebo in 50 patients following manual extracapsular cataract extraction with a posterior chamber IOL and reported a significantly greater reduction in CME in ketorolac-treated patients compared with placebo-treated patients.

Finally, a 1995 prospective trial compared flurbiprofen, indomethacin and placebo in 681 patients who underwent manual extracapsular cataract extraction with a posterior chamber IOL. Results showed that the incidences of angiographic CME were comparable in the groups treated with flurbiprofen (16.8%) and indomethacin (12.4%) and were significantly lower than in the placebo group (32.2%). Flurbiprofen exhibited a protective effect despite the fact that it is considered to be less potent than other NSAIDs.

Prophylaxis in uncomplicated phaco

What is the risk of CME following uncomplicated phacoemulsification? The following studies to evaluate NSAID prophylaxis were randomized prospective comparisons using an objective measure of CME.

Diclofenac therapy in a randomized trial of 88 patients following uncomplicated phacoemulsification significantly reduced the incidence of angiographic CME following cataract surgery compared to placebo. In a later trial, diclofenac exerted a protective effect against CME compared to placebo in two groups of patients who had also been treated with concomitant steroids.

Dr. Miyake and colleagues compared diclofenac to the topical steroid fluorometholone in two prospective randomized trials and found a significantly lower incidence of angiographic CME in patients treated with the NSAID (Figure). In one study, angiographic evaluation of 106 patients at 5 weeks demonstrated CME in 54.7% of 53 patients treated with fluorometholone compared with 5.7% of 53 patients treated with diclofenac.

Michael Raizman, MD, directly compared topical prednisolone alone to the combination of prednisolone and diclofenac in a randomized prospective study of 50 patients following uncomplicated cataract surgery. The incidence of CME by OCT was significantly higher in the steroid-only group. These results seem to confirm the benefit of adding a topical NSAID to a topical steroid in preventing CME following uncomplicated cataract surgery.

Glaucoma medications and CME risk

David F. Chang, MD

The glaucoma medication latanoprost, a prostaglandin analogue, has been associated with the development of clinically significant CME. In a prospective clinical trial published in 1999, postoperative cataract patients were randomized to receive diclofenac and latanoprost, diclofenac alone, fluorometholone alone or fluorometholone and latanoprost. All patients had ocular hypertension, normal-tension glaucoma or primary open-angle glaucoma. In the fifth week following surgery, fluorescein angiography was used to detect CME. The results showed that latanoprost-treated patients had a much higher incidence of CME compared to those not on latanoprost. However, diclofenac was protective and actually blunted the CME producing-effects of latanoprost.

In his Brinkhorst lecture in 2002, Kensaku Miyake, MD, presented an overview of his clinical and cell culture studies of medication-induced CME. Using randomized trials to evaluate preserved latanoprost and timolol, non-preserved timolol, and the preserved and non-preserved vehicles for these drugs, Dr. Miyake concluded that it was the preservative benzalkonium chloride that produced CME via lens epithelial cell toxicity, and not the active drug itself. The results of these studies suggest that a topical NSAID should be concurrently administered to patients on chronic therapy with topical preserved ocular medications, such as for glaucoma.

References

  • 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.
  • 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.
  • Miyake K, Ibaraki N, Goto Y, et al. ESCRS Binkhorst lecture 2002: Pseudophakic preservative maculopathy. J Cataract Refract Surg. 2003;29(9):1800-1810.

Conclusion

Ophthalmic topical NSAIDS are a valuable addition to a cataract surgeon’s pharmacologic arsenal. The efficacy of these agents in preventing postoperative CME is the most compelling reason for using a topical NSAID.

The disadvantages of topical NSAIDs include a certain degree of discomfort or stinging upon instillation, and the inconvenience of using an additional medication. Drug cost is another issue, especially when one considers the large volume of cataract surgery performed in the United States. Finally, compliance is a concern because this class of medication may require dosing of up to four times daily. Nevertheless, the scientific evidence of their CME protective effect is convincing, and forms the basis for their routine use in my cataract practice.

References

  • 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.
  • Sourdille P, Santiago PY. Optical coherence tomography of macular thickness after cataract surgery. J Cataract Refract Surg. 1999;25(2):256-261.
  • Biro Z, Balla Z, Kovacs B. Thickness change of the foveal and perifoveal region measured by optical coherence tomography after cataract surgery. Presented at the European Society of Cataract and Refractive Surgeons Congress; Sept. 18-22, 2004; Paris, France.
  • Miyake K. Prostaglandins as a causative factor of the cystoid macular edema after lens extraction. Nippon Ganka Gakkai Zasshi. 1977;81(9):1449-1464.
  • 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.
  • Singal N, Hopkins J. Pseudophakic cystoid macular edema: Ketorolac alone vs. ketorolac plus prednisolone. Can J Ophthalmol. 2004;39(3):245-250.
  • Rho DS. Treatment of acute pseudophakic cystoid macular edema: Diclofenac vs. ketorolac. J Cataract Refract Surg. 2003;29(12):2378-2384.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Raizman M. Macular Edema After Cataract Surgery. Presented at the Royal Hawaiian Eye Meeting; Jan. 24-29, 1999; Waikoloa, Hawaii.

Discussion

David F. Chang, MD: Do you routinely prescribe NSAIDs for uncomplicated, non-high risk cataract patients?

Deepinder K. Dhaliwal, MD: I use a steroid and a nonsteroidal four times daily for 1 week. At that time I stop the antibiotic and start tapering the steroid on a weekly basis. The nonsteroidal is continued for as long as the bottle lasts, which is generally 4 weeks following routine cases. In a high-risk patient I will continue the nonsteroidal for about 2 to 3 months.

I use nonsteroidals after every intraocular surgery except corneal transplantation because I want the corneal epithelium to heal quickly, and I do not want to add an agent with an additional preservative. In corneal transplants I use an antibiotic until the epithelium heals. In these patients I am more worried about the ocular surface than potential cystoid macular edema (CME), but if the transplant was a complicated procedure, I would use a nonsteroidal after the epithelium had completely healed.

William B. Trattler, MD: I have a similar regimen for cataract cases. For postoperative care, my patients are prescribed a latest-generation fluoroquinolone, a nonsteroidal and a steroid. At 1 week, I discontinue the fluoroquinolone and continue both the steroid, without a taper, and the nonsteroidal four times daily for 1 month.

Roy S. Chuck, MD: In routine cases I prescribe a steroid for 2 to 3 weeks postoperatively and a nonsteroidal for 4 weeks. In high-risk patients, the nonsteroidal is continued for several additional weeks. In some uncomplicated cases, I have prescribed bromfenac without a steroid due to its increased efficacy and potency.

I agree with Dr. Dhaliwal. I add an NSAID any time the iris needs to be manipulated and some iris prolapse is present. However, I routinely use NSAIDs during corneal transplants, and I have not seen many complications in terms of surface healing.

Dhaliwal: I use bandage contact lenses in patients with significant epithelial defects for increased comfort. I usually do not use NSAIDs in these patients.

Monte S. Dirks, MD: We perform cataract surgery in a similar manner. We administer a fluoroquinolone four times daily for a couple of weeks, a steroid four times daily for approximately 1 month and a nonsteroidal (in the case of bromfenac twice daily administration is sufficient) for about 4 weeks. If we opt for a trabeculectomy, the dosing regimen changes significantly, and steroids and nonsteroidals are given for 2 to 3 months.

Chang: It sounds like we are all routinely using topical NSAIDs and steroids following uncomplicated cataract extraction. For years, I thought I was getting excellent results using only topical steroids post-cataract surgery. It was inexpensive and simple. However, it was Dr. Raizman’s randomized prospective study that impacted me the most. He showed using ocular coherence tomography that sub-clinical CME was relatively common when steroids alone were used, but that combination therapy eliminated this problem. As I look back, there were always patients who had crisp 20/20 vision at 1 week, but had dropped a line or two by one month. Because of the improved refractive error and elimination of their cataract, these patients were happy and asymptomatic, but they probably had subclinical CME.

At that point I began adding topical ketorolac routinely. To simplify compliance, I kept my patients on ketorolac and prednisolone acetate four times daily for 1 week, three times daily for 1 week, twice daily for 1 week and then once daily for the final week to taper the steroid. Compared to when I used steroids alone, I saw a convincing decrease in the incidence of clinically-significant CME and rebound iritis with the combination therapy.

With the introduction of bromfenac, a twice-daily agent, it is somewhat challenging to develop a dosing frequency that is not confusing for patients. My approach is to administer both the steroid and the NSAID twice daily for 1 month, after which both medications are stopped without tapering.

Schechter: What have been your results been so far?

Chang: Based upon purely subjective experience, this regimen seems to be working just as well. Have any of you tried just an NSAID alone? Is the addition of a topical steroid really necessary?

Schechter: A nonsteroidal agent alone is sufficient for most uncomplicated surgeries. Many of the postoperative kits now come with a steroid included, which is easier for the patient. I have stopped routine use of a latest-generation fluoroquinolone after 1 week, and patients are comfortable.

Chuck: Dr. Chang, you presented limited clinical studies on fluorometholone alone, or a steroid plus the NSAID, and there is compelling data for both using combination therapy or using the steroid alone. It is hard to know which way to go.

Chang: I tried ketorolac alone for a while because it is appealing to have just one anti-inflammatory agent, and NSAIDs seem to be superior at preventing CME to other agents. However, a certain number of patients treated with an NSAID alone still had significant anterior chamber cells after 1 week of treatment. I think that the steroids eliminate the inflammatory cells more effectively than the NSAID. It is for this reason that I still prescribe topical combination therapy with both a steroid and an NSAID.

Dirks: A 10% drop in compliance is expected for every drop per day. Therefore, if a patient is taking an eye drop four times daily, he or she may receive treatment needing to be administered only 75% of the time. Now, if two drugs are added four times daily and an NSAID is subsequently added, the patient may be receiving less than half of the medication on a daily basis.

Dhaliwal: Now that lens removal occurs not only for cataract surgery, but also for refractive purposes, I think it is even more critical to suppress inflammation that could be present. Postoperative CME would be devastating in patients who did not start out with any pathology except refractive error.

Chang: That is a good point. These are refractive patients who are expecting a “wow” result with their multifocal IOL. If less than 50% of the light is focused at near, then reading well without glasses requires a perfect macula. Even mild temporary CME may be problematic for this demanding group of patients.

Reference

  • Raizman M. Macular Edema After Cataract Surgery. Presented at the Royal Hawaiian Eye Meeting; Jan. 24-29, 1999; Waikoloa, Hawaii.