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Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs
special report
Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs Nathan G. Congdon, MD, MPH, Oliver D. Schein, MD, MPH, Petra von Kulajta, MD, Lisa H. Lubomski, PhD, Donna Gilbert, Joanne Katz, ScD ABSTRACT Purpose: To explore the potential association between adverse corneal events and the use of topical nonsteroidal antiinflammatory drugs (NSAIDs). Setting: Practice-based reports. Methods: A detailed case-reporting form and request for medical records were sent to all practices reporting cases of corneal or conjunctival pathology in association with the use of topical NSAIDs to the American Society of Cataract and Refractive Surgery. Cases were classified as “mild,” “moderate,” or “severe” according to predetermined clinical criteria. Results: Records of 140 eyes (129 patients) were reviewed; 51 cases (36.4%) were mild, 55 (39.3%) moderate, and 34 (24.3%) severe. An association with a specific topical NSAID was confirmed in 117 cases (81.8%). Most confirmed cases (53.8%) involved generic diclofenac (Falcon). Cases associated with brand diclofenac (Voltaren姞, CIBA Vision) and ketorolac (Acular姞, Allergan) were more likely to have ocular comorbidity and to have received significantly higher total doses of NSAIDs. Neither “off-label” use nor use of any specific agent was associated with severe compared to mild or moderate disease. However, patients with more severe adverse events were more likely to have a history of diabetes, previous surgery in the affected eye, and surgery other than cataract. Cases not occurring in the perioperative period had significantly worse outcomes, had significantly more ocular comorbidities, and received nearly 3 times the dose of NSAIDs. Conclusions: While topical NSAIDs as a class may be associated with severe adverse events, such events appeared to require potentiation in the form of high total doses, ocular comorbidities, or both with Acular and Voltaren. Severe adverse events might have been more likely to occur at lower doses and in routine postoperative settings with generic diclofenac. J Cataract Refract Surg 2001; 27:622– 631 © 2001 ASCRS and ESCRS
© 2001 ASCRS and ESCRS Published by Elsevier Science Inc.
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SPECIAL REPORT: CORNEAL COMPLICATIONS ASSOCIATED WITH NSAID USE
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onsteroidal antiinflammatory drugs (NSAIDs) inhibit the production of prostaglandins and can be used topically in the eye to reduce inflammation and pain.1 Over the past decade, the use of these agents has increased dramatically as clinical studies have supported their use in the treatment or prevention of postoperative cystoid macular edema (CME),2–5 allergic conjunctivitis,6,7 surgically induced miosis,8 inflamed pterygia and pinguecula,9 and in the management of pain and inflammation associated with corneal abrasions,10,11 argon laser trabeculoplasty,12 and surgery for cataract,13–15 glaucoma,16 refractive error,17,18 and strabismus.19 While extensive clinical experience has generally shown the use of topical ocular NSAIDs to be welltolerated, side effects have been reported; these include impaired corneal sensation,20 persistent epithelial defects,21 superficial punctate keratitis,22 stromal infiltrates,23 and subepithelial infiltrates.24 Recently, more severe lesions, including corneal stromal ulceration requiring treatment with tissue adhesive, patch grafting, and penetrating keratoplasty (PKP), have been described25 in association with the topical use of brand diclofenac 0.1% (Voltaren威, Ciba Vision) or its generic equivalent, diclofenac 0.1% (Falcon). Voltaren was introduced in the United States in 1991, and generic diclofenac was approved for use in this country by the Food and Drug Administration on May 4, 1998. Falcon introduced the drug to the U.S. Accepted for publication February 8, 2001. From The Wilmer Eye Institute, Dana Center for Preventive Ophthalmology (Congdon, Schein, Lubomski, Gilbert, Katz), Cornea and Anterior Segment Service (Schein, von Kulajta), and Johns Hopkins University School of Hygiene and Public Health, Division of Disease Control (Congdon, Schein, von Kulajta, Lumbowski, Gilbert), Baltimore, Maryland, USA. Supported under a contractual agreement with the American Society of Cataract and Refractive Surgery; a K-23 Award (K-23 EY00388) from the National Eye Institute and a Career Development Award from Research to Prevent Blindness (Congdon); and a K-24 Award (K-24 EY00395) from the National Eye Institute and the Burton E. Grossman Fund for Preventive Ophthalmology (Schein). None of the authors has a financial or proprietary interest in any product mentioned. Dr. Schein is a paid consultant to Alcon, Inc., on research related to dry eye. Reprint requests to Dr. Oliver D. Schein, 116 Wilmer Building, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. E-mail: [email protected].
market in August 1998 (Stella Robertson, PhD, Alcon Pharmaceuticals, personal communication, August 20, 2000). Between late 1998 and early 1999, there were numerous reports of adverse events associated with the topical ocular use of NSAIDs in non-peer-reviewed ophthalmic publications.26 On July 27, 1999, the American Society of Cataract and Refractive Surgery (ASCRS) initiated a survey of its membership. The survey was sent to 5500 members of ASCRS, of whom 1033 (18.8%) responded; 106 physicians indicated that they had “cared for one or more patients who developed significant corneal changes . . . in the setting of topical NSAID use.” A total of 200 such cases were reported. The results of the survey were released to members on August 3 (telefax: “Alert to ASCRS Members—NSAID Adverse Reaction Report”). Members were advised against the routine use of topical NSAIDs, in particular generic diclofenac, since preliminary analysis suggested that a preponderance of cases had involved this agent. A letter was sent to ASCRS members on August 11, outlining an apparent association between generic diclofenac and corneal adverse events (“NSAID Update”). One week later, on August 19, 1999, Alcon suspended distribution of generic diclofenac, announcing that adverse events were “more prevalent” in patients with preexisting corneal problems (Western Union mailgram: S.M. Robertson, “Alcon Takes Action on NSAID Distribution and Labeling”). Distribution of the drug was discontinued the next day, and on September 24, 1999, Alcon and its affiliate, Falcon Pharmaceuticals, Ltd., conducted a voluntary recall of Falcon diclofenac sodium ophthalmic solution 0.1% (S.M. Robertson, “Urgent Drug Recall”). Many questions remained about the potential association between generic diclofenac in particular and topical NSAIDs in general and severe corneal events: What was the range of severity of the adverse events? What was their outcome in terms of need for further surgery, time to resolution, and final best corrected visual acuity in the affected eye? Did adverse events occur only in association with generic diclofenac or with other topical NSAID products? Did serious adverse events affect primarily or exclusively patients with ocular and systemic comorbidities or off-label/unapproved use of the drug that placed them at increased risk? Did other factors relating to surgery (type of operation, location of inci-
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sion), anesthetic agent, or postoperative treatment (use of topical steroids) play a role in determining the severity of outcome? To address these questions, we conducted a detailed review and synthesis of the cases that were reported to ASCRS in response to the telefax survey. This report presents data regarding outcomes, patterns of topical NSAID use, and other potential risk factors in 140 eyes of 129 patients identified in response to our request for additional information.
Patients and Methods A detailed case-reporting form and request for medical records were sent to all practices that reported cases of corneal or conjunctival pathology in association with the use of topical NSAIDs to ASCRS. The form sought information regarding a number of demographic, ocular, medical, surgical, and postoperative factors that were considered potential risk factors for adverse events or that might help quantify the severity of outcomes. Detailed information was also requested about the identity, dosage, and period of use of all ocular NSAIDs and other topical medications used during the period surrounding the reported event. Patient identifiers were removed from the medical records prior to their being sent from each practice. Treating physicians were asked which NSAID they prescribed and which NSAID the patient used. When a diclofenac product was prescribed and reported to have been used, the physician was asked whether the identity of the product used had been verified by direct inspection of the medication or by calling the pharmacy. The use of a specific diclofenac product was defined as “confirmed” when corroboration by direct inspection or contact with the pharmacy was reported. In the absence of such confirmation, but in the presence of consistency between the case report form and the medical records, the use of a particular diclofenac product was defined as “unconfirmed.” For Acular (for which no generic product existed during the time of the study), the drug identity was “confirmed” when there was consistency between the case report form and the medical record, with both indicating that this drug had been prescribed and used. Case-report forms and medical records next underwent systematic abstraction by 1 of 3 ophthalmologists 624
(N.C., O.S., P.v.K.). The key elements of this process included resolution of omissions and inconsistencies between the questionnaire and the medical record; abstraction of potential premorbid ocular and systemic risk factors and relevant clinical information (eg, size of the corneal lesion, total number of NSAID drops, and surgical methods); and classification of each case as “mild,” “moderate,” or “severe.” A mild case was defined as a condition limited to the corneal epithelium (punctate keratitis, persistent epithelial defect); a moderate case was characterized by loss or inflammation of corneal stromal substance (eg, stromal infiltration, ulceration, suppuration, or thinning) or by conjunctival loss; a severe case had at least 1 of the following—wound leak, descemetocele, corneal perforation, use of tissue adhesive, tectonic graft, PKP, keratoprosthesis, or enucleation. Cases in which the topical NSAID was used as part of acute perioperative management and the complication occurred within 60 days of surgery in the affected eye were considered “surgical.” All other cases (eg, chronic use of NSAIDs for CME) were classified as “nonsurgical.” Practices identified by ASCRS as having reported events but that failed to respond to the initial inquiry or failed to provide complete documents were contacted up to 3 times by a combination of telefaxes and telephone calls. A final review of all cases identified as “severe” was carried out by 1 of the 2 senior investigators (O.S., N.C.). During this process, the identity of the confirmed or suspected agent and evidence of its use was reviewed, as was evidence of the severity of the outcome. Statistical Methods Analyses of risk factors that might be associated with severity of outcome were performed using linear regression, in which severity was coded 0 for mild, 1 for moderate, and 2 for severe; severity was regressed against a variety of risk factors. Identification of categorical risk factors associated with the type of NSAID was done using the chi-square test or the Fisher exact test, where appropriate. For comparison of continuous but not normally distributed data, a nonparametric test (Wilcoxon rank sum) was used. The comparison of surgical and nonsurgical cases was done using the chi-square test for categorical data and the t test for continuous data.
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Results Summary and Demographic Information Sixty-three practices responded to the inquiries, reporting 140 eyes of 129 patients, with 11 bilateral cases. Of these cases, 51 (36.4%) were mild, 55 (39.3%) moderate, and 34 (24.3%) severe. Men comprised 40% of cases. The mean age of all cases was 73.3 years ⫾ 11.8 (SD). Confirmed cases (n ⫽ 117) comprised 81.8% of the total. Most cases (118 or 84.2%) occurred within 60 days of ocular surgery. Among the surgical cases, 106 (89.8%) involved cataract surgery, 5 (4.3%) refractive surgery, 4 (3.4%) intraocular lens (IOL) exchange or secondary IOL, 2 (1.8%) PKP, and 1 (0.9%) glaucoma surgery. Among the cases classified as severe, reported complications included 5 wound leaks, 4 descemetoceles, and 22 perforations; reported interventions included the use of corneal tissue adhesive in 9 eyes, 5 tectonic grafts, and 14 PKPs. Figure 1 illustrates the time line of the confirmed cases reported. Use of Topical NSAIDs Tables 1A and 1B summarize the data on NSAID use and severity of disease. Table 1A presents data on all cases and Table 1B, on the 106 patients who had cataract surgery within 60 days of the onset of corneal complications. As shown in Table 1A, 22 confirmed cases (18.8%) received Acular or preservative-free Acular (Acular PF), 32 (27.4%) received Voltaren,
Figure 1. (Congdon) Time course of all confirmed cases of corneal pathology with the associated NSAIDs.
and 63 (53.8%) received generic diclofenac. Three patients received 2 different NSAIDs, so the total number of confirmed and unconfirmed cases (n ⫽ 143) is greater than the number of eyes in the study (N ⫽ 140). Two patients received both Voltaren and Acular, and the third received Voltaren and generic diclofenac. Neither confirmed nor unconfirmed use of any of the 3 topical NSAID agents was correlated with severity of outcome. Six confirmed severe cases received Acular, 7 received Voltaren, and 18 received generic diclofenac (Table 1A). As shown in Table 1B, a regimen outside that described in the product labeling (ie, 4 times daily for 2 weeks beginning 1 day postoperatively) was used in 55 (51.9%) of all cases involving cataract surgery. However, such off-label use was not associated with more severe outcomes nor was the maximum number of drops used per day, days using NSAID, or the total number of drops used (Table 1B). A more detailed examination of the use patterns of the 3 NSAIDs among confirmed cases revealed that the proportion of surgical cases was significantly lower for Voltaren and Acular than for generic diclofenac (P ⬍ .001, chi-square) (Table 2). All 6 of the severe cases associated with Acular occurred when the drug was being used in a nonsurgical setting. Cases involving Acular and Voltaren also tended to have more ocular comorbidities (P ⫽ .01, chi-square) and to have received a higher total dose of topical NSAIDs (P ⫽ .02, Wilcoxon rank sum) than cases involving generic diclofenac (Table 2). Surgery-Related Indicators Cases associated with cataract surgery (n ⫽ 106) were less likely to be severe than those associated with other forms of surgery (n ⫽ 11) (Table 3). Other potential operative and perioperative risk factors that were not associated with severity of outcome included postoperative use of steroids, location of incision, type of anesthetic agent, use of medications in the immediate preoperative period, type of cataract surgery (eg, phacoemulsification, extracapsular cataract extraction), use of cautery, and postoperative patching of the operated eye. When the location of the lesion with respect to the cataract surgical incision was examined (incision involved, incision not involved, incision and adjacent tissue involved), no association with severity of outcome was
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Table 1A. Topical ocular NSAID and severity of lesion (all cases). Drug
Mild
Moderate
Severe
Total
n ⫽ 41
n ⫽ 45
n ⫽ 31
n ⫽ 117
Acular/Acular PF
10 (24.4)
6 (13.3)
6 (19.4)
22 (18.8)
Voltaren
10 (24.4)
15 (33.3)
7 (22.6)
32 (27.4)
Generic diclofenac
21 (51.4)
24 (53.3)
18 (58.1)
63 (53.8)
n ⫽ 10
n ⫽ 11
n⫽5
n ⫽ 26
Voltaren
5 (50.0)
6 (54.6)
4 (80.0)
15 (57.7)
Generic diclofenac
5 (50.0)
5 (45.5)
1 (20.0)
11 (42.3)
Confirmed cases
Unconfirmed cases
P Value*
.61
.15
Values are number of eyes (%). *Nonsignificant P values showed that the 3 NSAIDs did not differ significantly from one another in severity of outcome and corneal lesions.
Table 1B. Use of topical ocular nonsteroidal medication (NSAID) by severity of lesion in 106 patients having cataract extraction. Severity of Lesion Mild (n ⴝ 46)
Moderate (n ⴝ 42)
Severe (n ⴝ 18)
Total (n ⴝ 106)
P Value*
Exceeding label directions moderately, n (%)†
7 (15.2)
16 (38.1)
5 (27.8)
28 (26.4)
.25
Exceeding label directions significantly, n (%)‡
14 (30.4)
11 (26.2)
2 (11.1)
27 (25.5)
.19§
Max NSAID drops/day (mean ⫾ SD)
5.4 ⫾ 4.60
5.6 ⫾ 4.70
Other Factors
Drops/day ⬎ 4, n (%) Days using NSAID (mean ⫾ SD) Days of use ⬎ 30, n (%) Total NSAID drops (mean ⫾ SD) Total drops ⬎ 150, n (%)
7 (15.2) 18.5 ⫾ 14.9
6 (14.3) 25.9 ⫾ 34.3
9 (19.6) 71.8 ⫾ 54.4
5 (11.9) 93.9 ⫾ 107.1
2 (4.4)
2 (4.8)
4.7 ⫾ 2.8 1 (5.6) 32.4 ⫾ 84.0
5.3 ⫾ 4.29
.66
14 (13.2)
.42§
24.7 ⫾ 46.6
1 (5.6)
15 (14.2)
99.8 ⫾ 181.0
87.1 ⫾ 114.7
1 (5.6)
5 (4.7)
.44 .26§ .51 .99§
*For comparison of mild with severe. All P values reflect chi-square testing (categorical variables) and t tests (continuous variables) unless specified. The nonsignificant P values show that none of these factors describing frequency of use or total dose of NSAIDs is associated with severity of outcome. Only subjects having cataract surgery are included in this table (n ⫽ 106). † Cases in which topical ocular NSAIDs were used more frequently than 4 times per day and/or for longer than 14 consecutive days but less frequently and for a shorter period than for cases “significantly” exceeding label directions as outlined below ‡ Cases in which topical ocular NSAIDs were used more frequently than 6 times per day and/or for longer than 30 consecutive days § Fisher exact test
found nor were there differences with respect to the NSAID used. Medical and Ocular History Indicators The presence of any systemic disease was significantly associated with a more severe outcome (P ⫽ .02, chi-square). Although the chi-square test for trend did not show a significant association between diabetes and severity of outcome, the prevalence of diabetes was significantly higher among patients with severe outcomes than those with mild or moderate outcomes. The presence of other systemic diseases, including rheumatoid 626
arthritis, was not associated with outcome, even when the analysis was restricted to comorbidities identified prior to the diagnosis of an ocular lesion (Table 3). Neither previous use of systemic or ocular medications nor a history of ocular disease in the affected eye was associated with severity of outcome. However, patients with previous surgery in the affected eye had worse outcomes (0.06 test for trend) (Table 3). Comparison of Surgical and Nonsurgical Cases Indications for the use of NSAIDs in a nonoperative setting in our series included CME, allergic conjuncti-
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Table 2. Characteristics of confirmed cases by NSAID agent used.
Characteristic
Voltaren (n ⴝ 32)
Generic Diclofenac (n ⴝ 63)
Acular (n ⴝ 22)
Total
Surgical cases, n (%)
26 (81.3)
60 (95.2)
12 (54.5)
98 (83.8)
Systemic comorbidity, n (%) Ocular comorbidity, n (%) Max NSAID drops/day (mean ⫾ SD) Drops/day ⬎ 4, n (%)
9 (28.1)
17 (27.0)
10 (45.5)
36 (30.8)
.53
18 (29.0)
15 (68.2)
48/116 (41.4)
.01
5.8 ⫾ 4.53
5.7 ⫾ 5.20
4.15 ⫾ 1.14
5.3 ⫾ 4.29
.58†
25.4 ⫾ 35.36
Days of use ⬎ 30, n (%)
7 (11.1)
88.1 ⫾ 72.96
4 (18.2)
15.1 ⫾ 10.87
8 (25.0)
Total NSAID Drops (mean ⫾ SD)
.001
15 (46.9)
7 (21.9)
Days using NSAID (mean ⫾ SD)
P Value*
27.1 ⫾ 19.66
5 (7.9)
6 (27.3)
57.6 ⫾ 34.85
98.8 ⫾ 74.3
18 (15.4)
.38‡
24.7 ⫾ 46.6
.02†
19/117 (16.2)
.04
87.1 ⫾ 115.0
.02†
Total drops ⬎ 150, n (%)
3 (9.4)
1 (1.6)
5 (22.7)
9/117 (7.7)
0.01‡
No off-label use and no systemic or ocular comorbidities
4 (12.5)
13 (20.6)
1 (4.5)
18/117 (15.4)
0.23‡
*Chi-square test comparing characteristics between the 3 agents, unless otherwise specified. A significant P value in this table indicates that the 3 NSAIDs differed significantly from one another in this characteristic. A nonsignificant P value suggests they did not differ from one another significantly. Only confirmed cases are included (n ⫽ 117). † Wilcoxon rank sum test ‡ Fisher exact test
Table 3. Association of ocular and medical history and severity of lesion. Outcome Descriptor Had cataract surgery (%) Presence of any systemic disease
†
Mild (n ⴝ 47)
Moderate (n ⴝ 49)
Severe (n ⴝ 2)
Total
P Value*
46 (97.9)
42 (85.7)
18 (81.8)
106/118 (89.8)
.001
11 (21.6)
12 (21.8)
16 (47.1)
39 (27.9)
.02
Presence of diabetes
7 (13.7)
4 (7.3)
10 (30.3)
21 (15.1)
.08
Taking systemic medications‡
6 (12.5)
6 (11.8)
1 (3.1)
13/131 (9.9)
.20
20 (39.2)
22 (40.0)
18 (54.6)
60/139 (43.2)
.20
7 (13.7)
6 (10.9)
11 (33.3)
24/139 (17.3)
.06
History of ocular disease§ History of prior surgery in affected eye
All values are number of eyes (%) *A significant P value indicates that the factor is significantly associated with severity of outcome. Factors with nonsignificant P values are not associated. Only subjects with postoperative lesions (n ⫽ 118) are included in the first row. All patients (n ⫽ 140) are included in subsequent rows, although numbers may total less than 140 due to missing data. † Includes diabetes, Sjo¨gren’s syndrome, rosacea, rheumatoid arthritis, and other collagen vascular disease. Analysis was carried out separately using all reported history of systemic disease and only those cases documented in the medical record prior to the onset of the lesion. The results of the 2 analyses were identical; only the analysis for all reported history is presented. ‡ Includes oral steroids, oral NSAIDs, and other oral immunosuppression therapy § Includes preoperative contact lens wear, dry eye, history of HSZ/HZV, history of ocular trauma, atopic eye disease, prior corneal disease, and “other”; when all the comorbidities in 10 or more individuals were analyzed separately, the following factors were not significantly associated with severity of outcome: dry eye, “other” ocular comorbidity, and prior corneal disease.
vitis, and ocular pain typically in association with ocular surface abnormalities. Nonsurgical cases had significantly worse outcomes than did surgical cases. Nonsurgical cases were also significantly younger, less likely to
be using steroids, and more likely to have a preexisting ocular comorbidity; they received an almost 3-fold greater total dose of topical NSAIDs than the surgical cases (Table 4).
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Table 4. Comparison of surgical and nonsurgical cases of NSAID-associated corneal pathology.
Characteristic Mean age ⫾ SD, years
Surgical (n ⴝ 118)
Nonsurgical (n ⴝ 22)
P Value*
74.7 ⫾ 10.7
66.3 ⫾ 14.8
.02
Male gender, n (%)
44 (37.3)
12 (54.6)
.13
Presence of systemic comorbidity, n (%)
29 (24.6)
10 (45.5)
.05
Presence of ocular comorbidity, n (%)
41 (35.0)
19 (86.4)
.001
Presence of diabetes, n (%)
17 (14.5)
4 (18.2)
.75†
107 (90.7)
9 (56.3)
.001
Total days of NSAID use (mean ⫾ SD)
18.8 ⫾ 20.5
59.3 ⫾ 107.6
.002‡
Total drops of NSAID (mean ⫾ SD)
69.0 ⫾ 51.8
193.8 ⫾ 253.6
.0004‡
Drops/day of NSAID (mean ⫾ SD)
5.42 ⫾ 4.51
4.70 ⫾ 2.56
Use of postoperative topical steroids, n (%)
.98‡
*A significant P value indicates that surgical and nonsurgical cases differed significantly in this characteristic. † Fisher exact test ‡ Wilcoxon rank sum test
Discussion Generic diclofenac was used in most confirmed cases with severe outcomes, but Acular and Voltaren were implicated in some severe, confirmed cases. In the case of Acular, all the severe events occurred in nonsurgical settings. The severity of outcome did not differ significantly among the 3 agents studied. Analysis of the timing of cases revealed a significant increase within months of the introduction of generic diclofenac, an observation consistent with our finding that most cases occurred in association with this agent. Confirmed cases in which Acular or Voltaren were used were more likely to be nonsurgical, to have ocular comorbidities, and to have received significantly higher doses of NSAIDs. All 3 factors might tend to produce more severe outcomes, although it should be noted that neither a higher total dose of NSAIDs nor the presence of ocular comorbidities was associated with a worse outcome among all cases. Such additional factors may be necessary to potentiate corneal complications with Voltaren and Acular, while such complications are more likely to occur in the absence of identifiable risk factors with generic diclofenac. It is also possible that generic diclofenac is associated with a low total dose because the event itself might occur earlier, resulting in a change in medical management and a cessation of the drug. Although off-label use of NSAIDs was common in this series, this behavior was not associated with severity of outcome. As discussed below, the case-series design of 628
this study, without controls, does not allow us to determine whether off-label use is a risk factor for corneal complications per se. Certain systemic and ocular comorbidities did emerge as risk factors for severe events. Dry eye and rheumatoid arthritis were not associated with outcome, even when only the cases in which the comorbidity had been identified prior to presentation of the ocular lesion (thought to be potentially more reliable diagnoses) were considered. However, a history of diabetes mellitus and prior surgery in the affected eye were associated with a worse outcome. Individuals with diabetes are known to be at increased risk for corneal disorders such as epithelial defects, recurrent erosions, abnormal wound repair, and increased susceptibility to injury.27,28 Postulated mechanisms for this include increased basement membrane thickness,29 decreased hemidesmosome numbers,30 and alterations in the corneal extracellular matrix and epithelial basement membrane.31 Little if any literature exists documenting rates of postoperative corneal complications in patients who had previous surgery in the eye. However, a history of previous surgery in the eye may be a marker for other ocular or systemic conditions that could make adverse events more likely. Patients having cataract extraction had significantly better outcomes than did surgical cases in general. Other surgeries included in our series were refractive surgery, PKP, and glaucoma tube shunts. It is not entirely clear why the cataract surgeries had better outcomes, but it may be that patients having other procedures such as
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PKP and tube shunt were more likely to have other ocular conditions that placed them at increased risk for adverse outcomes. Nonsurgical cases had significantly worse outcomes than did surgical cases. They were also significantly younger, more likely to have ocular comorbidities, and less likely to be using topical steroids; they received significantly higher doses of topical NSAIDs. While age, presence of ocular comorbidities, use of topical steroids, and NSAID dose were not significantly correlated with outcome among all cases, the total dose of NSAIDs was nearly 3 times higher in the nonsurgical cases, nearly 200 total drops. Doses in this range may be associated with a greater risk of corneal adverse outcomes. It is also possible that the finding of more severe outcomes among nonsurgical cases represents bias of ascertainment. Perhaps in the nonsurgical setting, a more severe presentation was required to attract the attention of the physician and to be considered worthy of reporting. Reports in the peer-reviewed literature of severe corneal complications in association with the use of topical NSAIDs have been relatively infrequent. One recent series of 5 cases, 4 of which had corneal perforation, implicated generic diclofenac in 3 of the eyes that perforated and brand diclofenac in 1.25 The actual medication used was confirmed by inspection or telephone contact with the pharmacy (J. Lin, MD, personal communication, September 18, 2000). Data regarding these 5 cases are included in the current report. Animal1 and human32,33 data suggest that topical NSAIDs may interfere with normal corneal healing, perhaps secondary to suppression of keratocyte proliferation, a necessary component in corneal remodeling.34 Still, there are no clear explanations for severe corneal complications such as those described in the current report or for the apparent increase in such cases in the months following the introduction of generic diclofenac. The preservatives (sorbic acid and edetate sodium, Voltaren; polyquad polyquaternium 1, generic diclofenac) and emollients (polyoxyl-35, Voltaren; tocophersolan and mannitol, generic diclofenac) differ between the Ciba Vision and Falcon products, but the implications of this for corneal toxicity are not clear. Further work has to be done to elucidate the mechanisms underlying severe corneal complications in association with the use of topical ocular NSAIDs.
This study has several limitations that are inherent in its design. In the initial ASCRS survey, physicians were asked to report adverse outcomes thought to be associated with the use of topical ocular NSAIDs. Thus, all cases included in this study are reported to have used these medications. As a result, we cannot compare rates of corneal complications between those using and those not using ocular NSAIDs and thus can make no estimates of the risk that may be associated with such use. We do not have data regarding patterns of use of NSAIDs among the population at large. Since we cannot state whether patients with ocular complications in our series differed significantly in the NSAIDs they received from all users of NSAIDs or the NSAID users who did not develop complications, we are unable to state with certainty whether persons using a particular agent are at greater risk of complications. The generic versus brand status of other topical medications (steroids, antibiotics, glaucoma medications) used by patients in this study was not ascertained. Thus, we cannot exclude the possibility that use of other generic medications may have affected the severity of the outcome, although we saw no evidence to suggest this was a factor. It should also be pointed out that the confirmation process for use of Acular, which required only that this medication be recorded as used on the reporting form and in the medical records, does not exclude the possibility that generic diclofenac or another NSAID was substituted. However, none of the 140 records we reviewed showed evidence of such a substitution. Furthermore, the more stringent confirmation process applied with respect to Voltaren did not reveal major differences between confirmed and unconfirmed cases. Finally, the analysis did find that the context of disease was very different for Acular, suggesting that significant misclassification was unlikely. Specifically, not a single severe postoperative case was observed in association with this medication. The time course of the reporting of the adverse events and clinical experience suggest that the association is real, although this study cannot quantify the strength of the association. Sterile corneal ulceration in the early postoperative period is a rare event and has historically been associated with Mooren’s ulceration or related syndromes in patients with evidence of systemic collagen vascular disease or vasculitis.
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It has been postulated that geographic variation could be a factor in determining the distribution of cases of NSAID-associated corneal pathology, with such cases being more common in states in which the dispensing of generic products is required by statute. It is also possible that such requirements vary greatly within states according to the policies of different health care maintenance organizations. Unfortunately, available databases do not allow us to examine this hypothesis. We also lack data on batch numbers of the various drugs implicated in specific cases, which might have allowed us to pinpoint particular batches as being more likely to be associated with adverse outcomes. In conclusion, these data point toward a recent significant increase in severe corneal events related chronologically to the introduction of generic diclofenac. Use of this product was implicated in most confirmed cases in our series, particularly those that occurred in the early postoperative setting. Although our data are consistent with the idea that topical NSAIDs as a class have the potential for significant corneal complications, it would appear that such events otherwise occur at a low rate and usually in the presence of high doses of medication, other potentiating factors such as ocular comorbidities, or both. Generic diclofenac may be an exception to this, as a number of the severe cases in our series involved relatively limited use of the drug in the postoperative setting. Severe cases associated with Acular occurred in nonsurgical settings in patients with coexisting ocular disease treated for long periods. Many of the nonsurgical cases occurred in patients with abnormalities of the ocular surface (eg, conjunctivitis and superficial keratitis). The chronic use of topical NSAIDs in such patients may pose an increased risk of corneal ulceration.
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long-term cystoid macular edema. J Cataract Refract Surg 1997; 23:1183–1189 Weisz JM, Bressler NM, Bressler SB, Schachat AP. Ketorolac treatment of pseudophakic cystoid macular edema identified more than 24 months after cataract extraction. Ophthalmology 1999; 106:1656 –1659 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; 44:58 – 67 Tinkelman DG, Rupp G, Kaufman H, et al. Doublemasked, paired-comparison clinical study of ketorolac tromethamine 0.5% ophthalmic solution compared with placebo eyedrops in the treatment of seasonal allergic conjunctivitis. Surv Ophthalmol 1993; 38:133–140 Tauber J, Raizman MB, Ostrov CS, et al. A multicenter comparison of the ocular efficacy and safety of diclofenac 0.1% solution with that of ketorolac 0.5% solution in patients with acute seasonal allergic conjunctivitis. J Ocular Pharmacol Ther 1998; 14:137–145 Stewart R, Grosserode R, Cheetham JK, Rosenthal A. Efficacy and safety profile of ketorolac 0.5% ophthalmic solution in the prevention of surgically induced miosis during cataract surgery. Clin Ther 1999; 21:723–732 Frucht-Pery J, Siganos CS, Solomon A, et al. Topical indomethacin solution versus dexamethasone solution for treatment of inflamed pterygium and pinguecula: a prospective randomized clinical study. Am J Ophthalmol 1999; 127:148 –152 Kaiser PK, Pineda R II. A study of topical nonsteroidal anti-inflammatory drops and no pressure patching in the treatment of corneal abrasions. Ophthalmology 1997; 104:1353–1359 Szucs PA, Nashed AH, Allegra JR, Eskin B. Safety and efficacy of diclofenac ophthalmic solution in the treatment of corneal abrasions. Ann Emerg Med 2000; 35: 131–137 Goethals M, Missotten L. Efficacy and safety of indomethacin 0.1% versus flurbiprofen 0.03% eyedrops in inflammation after argon laser trabeculoplasty. Doc Ophthalmol 1994; 85:287–293 Flach AJ, Dolan BJ, Donahue ME, et al. Comparative effects of ketorolac 0.5% or diclofenac 0.1% ophthalmic solutions on inflammation after cataract surgery. Ophthalmology 1998; 105:1775–1779 Heier J, Cheetham JK, Degryse R, et al. Ketorolac tromethamine 0.5% ophthalmic solution in the treatment of moderate to severe ocular inflammation after cataract surgery: a randomized, vehicle-controlled clinical trial. Am J Ophthalmol 1999; 127:253–259 Simone JN, Pendelton RA, Jenkins JE. Comparison of the efficacy and safety of ketorolac tromethamine 0.5%
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and prednisolone acetate 1% after cataract surgery. J Cataract Refract Surg 1999; 25:699 –704 Kent AR, Dubiner HB, Whitaker R, et al. The efficacy and safety of diclofenac 0.1% versus prednisolone acetate 1% following trabeculectomy with adjunctive mitomycin-C. Ophthalmic Surg Lasers 1998; 29:562–569 Weinstock VM, Weinstock DJ, Weinstock SJ. Diclofenac and ketorolac in the treatment of pain after photorefractive keratectomy. J Refract Surg 1996; 12:792–794 Rajpal RK, Cooperman BB. Analgesic efficacy and safety of ketorolac after photorefractive keratectomy. J Refract Surg 1999; 15:661– 667 Apt L, Voo I, Isenberg SJ. A randomized clinical trial of the nonsteroidal eyedrop diclofenac after strabismus surgery. Ophthalmology 1998; 105:1449 –1452; discussion by SP Kraft, 1453–1454 Sun R, Gimbel HV. Effects of topical ketorolac and diclofenac on normal corneal sensation. J Refract Surg 1997; 13:158 –161 Shimazaki J, Saito H, Yang H-Y, et al. Persistent epithelial defects following penetrating keratoplasty: an adverse effect of diclofenac eyedrops. Cornea 1995; 14:623– 627 Gills JP. Voltaren associated with medication keratitis (letter). J Cataract Refract Surg 1994; 20:110 Sher NA, Krueger RR, Teal P, et al. Role of topical corticosteroids and nonsteroidal antiinflammatory drugs in the etiology of stromal infiltrates after excimer photorefractive keratectomy (letter). J Refract Corneal Surg 1994; 10:587–588 Probst LE, Machat JJ. Corneal subepithelial infiltrates following photorefractive keratectomy (letter). J Cataract Refract Surg 1996; 22:281 Lin JC, Rapuano CJ, Laibson PR, et al. Corneal melting associated with use of topical nonsteroidal anti-inflam-
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Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs Nathan G. Congdon, MD, MPH, Oliver D. Schein, MD, MPH, Petra von Kulajta, MD, Lisa H. Lubomski, PhD, Donna Gilbert, Joanne Katz, ScD ABSTRACT Purpose: To explore the potential association between adverse corneal events and the use of topical nonsteroidal antiinflammatory drugs (NSAIDs). Setting: Practice-based reports. Methods: A detailed case-reporting form and request for medical records were sent to all practices reporting cases of corneal or conjunctival pathology in association with the use of topical NSAIDs to the American Society of Cataract and Refractive Surgery. Cases were classified as “mild,” “moderate,” or “severe” according to predetermined clinical criteria. Results: Records of 140 eyes (129 patients) were reviewed; 51 cases (36.4%) were mild, 55 (39.3%) moderate, and 34 (24.3%) severe. An association with a specific topical NSAID was confirmed in 117 cases (81.8%). Most confirmed cases (53.8%) involved generic diclofenac (Falcon). Cases associated with brand diclofenac (Voltaren姞, CIBA Vision) and ketorolac (Acular姞, Allergan) were more likely to have ocular comorbidity and to have received significantly higher total doses of NSAIDs. Neither “off-label” use nor use of any specific agent was associated with severe compared to mild or moderate disease. However, patients with more severe adverse events were more likely to have a history of diabetes, previous surgery in the affected eye, and surgery other than cataract. Cases not occurring in the perioperative period had significantly worse outcomes, had significantly more ocular comorbidities, and received nearly 3 times the dose of NSAIDs. Conclusions: While topical NSAIDs as a class may be associated with severe adverse events, such events appeared to require potentiation in the form of high total doses, ocular comorbidities, or both with Acular and Voltaren. Severe adverse events might have been more likely to occur at lower doses and in routine postoperative settings with generic diclofenac. J Cataract Refract Surg 2001; 27:622– 631 © 2001 ASCRS and ESCRS
© 2001 ASCRS and ESCRS Published by Elsevier Science Inc.
0886-3350/01/$–see front matter PII S0886-3350(01)00801-X
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N
onsteroidal antiinflammatory drugs (NSAIDs) inhibit the production of prostaglandins and can be used topically in the eye to reduce inflammation and pain.1 Over the past decade, the use of these agents has increased dramatically as clinical studies have supported their use in the treatment or prevention of postoperative cystoid macular edema (CME),2–5 allergic conjunctivitis,6,7 surgically induced miosis,8 inflamed pterygia and pinguecula,9 and in the management of pain and inflammation associated with corneal abrasions,10,11 argon laser trabeculoplasty,12 and surgery for cataract,13–15 glaucoma,16 refractive error,17,18 and strabismus.19 While extensive clinical experience has generally shown the use of topical ocular NSAIDs to be welltolerated, side effects have been reported; these include impaired corneal sensation,20 persistent epithelial defects,21 superficial punctate keratitis,22 stromal infiltrates,23 and subepithelial infiltrates.24 Recently, more severe lesions, including corneal stromal ulceration requiring treatment with tissue adhesive, patch grafting, and penetrating keratoplasty (PKP), have been described25 in association with the topical use of brand diclofenac 0.1% (Voltaren威, Ciba Vision) or its generic equivalent, diclofenac 0.1% (Falcon). Voltaren was introduced in the United States in 1991, and generic diclofenac was approved for use in this country by the Food and Drug Administration on May 4, 1998. Falcon introduced the drug to the U.S. Accepted for publication February 8, 2001. From The Wilmer Eye Institute, Dana Center for Preventive Ophthalmology (Congdon, Schein, Lubomski, Gilbert, Katz), Cornea and Anterior Segment Service (Schein, von Kulajta), and Johns Hopkins University School of Hygiene and Public Health, Division of Disease Control (Congdon, Schein, von Kulajta, Lumbowski, Gilbert), Baltimore, Maryland, USA. Supported under a contractual agreement with the American Society of Cataract and Refractive Surgery; a K-23 Award (K-23 EY00388) from the National Eye Institute and a Career Development Award from Research to Prevent Blindness (Congdon); and a K-24 Award (K-24 EY00395) from the National Eye Institute and the Burton E. Grossman Fund for Preventive Ophthalmology (Schein). None of the authors has a financial or proprietary interest in any product mentioned. Dr. Schein is a paid consultant to Alcon, Inc., on research related to dry eye. Reprint requests to Dr. Oliver D. Schein, 116 Wilmer Building, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. E-mail: [email protected].
market in August 1998 (Stella Robertson, PhD, Alcon Pharmaceuticals, personal communication, August 20, 2000). Between late 1998 and early 1999, there were numerous reports of adverse events associated with the topical ocular use of NSAIDs in non-peer-reviewed ophthalmic publications.26 On July 27, 1999, the American Society of Cataract and Refractive Surgery (ASCRS) initiated a survey of its membership. The survey was sent to 5500 members of ASCRS, of whom 1033 (18.8%) responded; 106 physicians indicated that they had “cared for one or more patients who developed significant corneal changes . . . in the setting of topical NSAID use.” A total of 200 such cases were reported. The results of the survey were released to members on August 3 (telefax: “Alert to ASCRS Members—NSAID Adverse Reaction Report”). Members were advised against the routine use of topical NSAIDs, in particular generic diclofenac, since preliminary analysis suggested that a preponderance of cases had involved this agent. A letter was sent to ASCRS members on August 11, outlining an apparent association between generic diclofenac and corneal adverse events (“NSAID Update”). One week later, on August 19, 1999, Alcon suspended distribution of generic diclofenac, announcing that adverse events were “more prevalent” in patients with preexisting corneal problems (Western Union mailgram: S.M. Robertson, “Alcon Takes Action on NSAID Distribution and Labeling”). Distribution of the drug was discontinued the next day, and on September 24, 1999, Alcon and its affiliate, Falcon Pharmaceuticals, Ltd., conducted a voluntary recall of Falcon diclofenac sodium ophthalmic solution 0.1% (S.M. Robertson, “Urgent Drug Recall”). Many questions remained about the potential association between generic diclofenac in particular and topical NSAIDs in general and severe corneal events: What was the range of severity of the adverse events? What was their outcome in terms of need for further surgery, time to resolution, and final best corrected visual acuity in the affected eye? Did adverse events occur only in association with generic diclofenac or with other topical NSAID products? Did serious adverse events affect primarily or exclusively patients with ocular and systemic comorbidities or off-label/unapproved use of the drug that placed them at increased risk? Did other factors relating to surgery (type of operation, location of inci-
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sion), anesthetic agent, or postoperative treatment (use of topical steroids) play a role in determining the severity of outcome? To address these questions, we conducted a detailed review and synthesis of the cases that were reported to ASCRS in response to the telefax survey. This report presents data regarding outcomes, patterns of topical NSAID use, and other potential risk factors in 140 eyes of 129 patients identified in response to our request for additional information.
Patients and Methods A detailed case-reporting form and request for medical records were sent to all practices that reported cases of corneal or conjunctival pathology in association with the use of topical NSAIDs to ASCRS. The form sought information regarding a number of demographic, ocular, medical, surgical, and postoperative factors that were considered potential risk factors for adverse events or that might help quantify the severity of outcomes. Detailed information was also requested about the identity, dosage, and period of use of all ocular NSAIDs and other topical medications used during the period surrounding the reported event. Patient identifiers were removed from the medical records prior to their being sent from each practice. Treating physicians were asked which NSAID they prescribed and which NSAID the patient used. When a diclofenac product was prescribed and reported to have been used, the physician was asked whether the identity of the product used had been verified by direct inspection of the medication or by calling the pharmacy. The use of a specific diclofenac product was defined as “confirmed” when corroboration by direct inspection or contact with the pharmacy was reported. In the absence of such confirmation, but in the presence of consistency between the case report form and the medical records, the use of a particular diclofenac product was defined as “unconfirmed.” For Acular (for which no generic product existed during the time of the study), the drug identity was “confirmed” when there was consistency between the case report form and the medical record, with both indicating that this drug had been prescribed and used. Case-report forms and medical records next underwent systematic abstraction by 1 of 3 ophthalmologists 624
(N.C., O.S., P.v.K.). The key elements of this process included resolution of omissions and inconsistencies between the questionnaire and the medical record; abstraction of potential premorbid ocular and systemic risk factors and relevant clinical information (eg, size of the corneal lesion, total number of NSAID drops, and surgical methods); and classification of each case as “mild,” “moderate,” or “severe.” A mild case was defined as a condition limited to the corneal epithelium (punctate keratitis, persistent epithelial defect); a moderate case was characterized by loss or inflammation of corneal stromal substance (eg, stromal infiltration, ulceration, suppuration, or thinning) or by conjunctival loss; a severe case had at least 1 of the following—wound leak, descemetocele, corneal perforation, use of tissue adhesive, tectonic graft, PKP, keratoprosthesis, or enucleation. Cases in which the topical NSAID was used as part of acute perioperative management and the complication occurred within 60 days of surgery in the affected eye were considered “surgical.” All other cases (eg, chronic use of NSAIDs for CME) were classified as “nonsurgical.” Practices identified by ASCRS as having reported events but that failed to respond to the initial inquiry or failed to provide complete documents were contacted up to 3 times by a combination of telefaxes and telephone calls. A final review of all cases identified as “severe” was carried out by 1 of the 2 senior investigators (O.S., N.C.). During this process, the identity of the confirmed or suspected agent and evidence of its use was reviewed, as was evidence of the severity of the outcome. Statistical Methods Analyses of risk factors that might be associated with severity of outcome were performed using linear regression, in which severity was coded 0 for mild, 1 for moderate, and 2 for severe; severity was regressed against a variety of risk factors. Identification of categorical risk factors associated with the type of NSAID was done using the chi-square test or the Fisher exact test, where appropriate. For comparison of continuous but not normally distributed data, a nonparametric test (Wilcoxon rank sum) was used. The comparison of surgical and nonsurgical cases was done using the chi-square test for categorical data and the t test for continuous data.
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Results Summary and Demographic Information Sixty-three practices responded to the inquiries, reporting 140 eyes of 129 patients, with 11 bilateral cases. Of these cases, 51 (36.4%) were mild, 55 (39.3%) moderate, and 34 (24.3%) severe. Men comprised 40% of cases. The mean age of all cases was 73.3 years ⫾ 11.8 (SD). Confirmed cases (n ⫽ 117) comprised 81.8% of the total. Most cases (118 or 84.2%) occurred within 60 days of ocular surgery. Among the surgical cases, 106 (89.8%) involved cataract surgery, 5 (4.3%) refractive surgery, 4 (3.4%) intraocular lens (IOL) exchange or secondary IOL, 2 (1.8%) PKP, and 1 (0.9%) glaucoma surgery. Among the cases classified as severe, reported complications included 5 wound leaks, 4 descemetoceles, and 22 perforations; reported interventions included the use of corneal tissue adhesive in 9 eyes, 5 tectonic grafts, and 14 PKPs. Figure 1 illustrates the time line of the confirmed cases reported. Use of Topical NSAIDs Tables 1A and 1B summarize the data on NSAID use and severity of disease. Table 1A presents data on all cases and Table 1B, on the 106 patients who had cataract surgery within 60 days of the onset of corneal complications. As shown in Table 1A, 22 confirmed cases (18.8%) received Acular or preservative-free Acular (Acular PF), 32 (27.4%) received Voltaren,
Figure 1. (Congdon) Time course of all confirmed cases of corneal pathology with the associated NSAIDs.
and 63 (53.8%) received generic diclofenac. Three patients received 2 different NSAIDs, so the total number of confirmed and unconfirmed cases (n ⫽ 143) is greater than the number of eyes in the study (N ⫽ 140). Two patients received both Voltaren and Acular, and the third received Voltaren and generic diclofenac. Neither confirmed nor unconfirmed use of any of the 3 topical NSAID agents was correlated with severity of outcome. Six confirmed severe cases received Acular, 7 received Voltaren, and 18 received generic diclofenac (Table 1A). As shown in Table 1B, a regimen outside that described in the product labeling (ie, 4 times daily for 2 weeks beginning 1 day postoperatively) was used in 55 (51.9%) of all cases involving cataract surgery. However, such off-label use was not associated with more severe outcomes nor was the maximum number of drops used per day, days using NSAID, or the total number of drops used (Table 1B). A more detailed examination of the use patterns of the 3 NSAIDs among confirmed cases revealed that the proportion of surgical cases was significantly lower for Voltaren and Acular than for generic diclofenac (P ⬍ .001, chi-square) (Table 2). All 6 of the severe cases associated with Acular occurred when the drug was being used in a nonsurgical setting. Cases involving Acular and Voltaren also tended to have more ocular comorbidities (P ⫽ .01, chi-square) and to have received a higher total dose of topical NSAIDs (P ⫽ .02, Wilcoxon rank sum) than cases involving generic diclofenac (Table 2). Surgery-Related Indicators Cases associated with cataract surgery (n ⫽ 106) were less likely to be severe than those associated with other forms of surgery (n ⫽ 11) (Table 3). Other potential operative and perioperative risk factors that were not associated with severity of outcome included postoperative use of steroids, location of incision, type of anesthetic agent, use of medications in the immediate preoperative period, type of cataract surgery (eg, phacoemulsification, extracapsular cataract extraction), use of cautery, and postoperative patching of the operated eye. When the location of the lesion with respect to the cataract surgical incision was examined (incision involved, incision not involved, incision and adjacent tissue involved), no association with severity of outcome was
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Table 1A. Topical ocular NSAID and severity of lesion (all cases). Drug
Mild
Moderate
Severe
Total
n ⫽ 41
n ⫽ 45
n ⫽ 31
n ⫽ 117
Acular/Acular PF
10 (24.4)
6 (13.3)
6 (19.4)
22 (18.8)
Voltaren
10 (24.4)
15 (33.3)
7 (22.6)
32 (27.4)
Generic diclofenac
21 (51.4)
24 (53.3)
18 (58.1)
63 (53.8)
n ⫽ 10
n ⫽ 11
n⫽5
n ⫽ 26
Voltaren
5 (50.0)
6 (54.6)
4 (80.0)
15 (57.7)
Generic diclofenac
5 (50.0)
5 (45.5)
1 (20.0)
11 (42.3)
Confirmed cases
Unconfirmed cases
P Value*
.61
.15
Values are number of eyes (%). *Nonsignificant P values showed that the 3 NSAIDs did not differ significantly from one another in severity of outcome and corneal lesions.
Table 1B. Use of topical ocular nonsteroidal medication (NSAID) by severity of lesion in 106 patients having cataract extraction. Severity of Lesion Mild (n ⴝ 46)
Moderate (n ⴝ 42)
Severe (n ⴝ 18)
Total (n ⴝ 106)
P Value*
Exceeding label directions moderately, n (%)†
7 (15.2)
16 (38.1)
5 (27.8)
28 (26.4)
.25
Exceeding label directions significantly, n (%)‡
14 (30.4)
11 (26.2)
2 (11.1)
27 (25.5)
.19§
Max NSAID drops/day (mean ⫾ SD)
5.4 ⫾ 4.60
5.6 ⫾ 4.70
Other Factors
Drops/day ⬎ 4, n (%) Days using NSAID (mean ⫾ SD) Days of use ⬎ 30, n (%) Total NSAID drops (mean ⫾ SD) Total drops ⬎ 150, n (%)
7 (15.2) 18.5 ⫾ 14.9
6 (14.3) 25.9 ⫾ 34.3
9 (19.6) 71.8 ⫾ 54.4
5 (11.9) 93.9 ⫾ 107.1
2 (4.4)
2 (4.8)
4.7 ⫾ 2.8 1 (5.6) 32.4 ⫾ 84.0
5.3 ⫾ 4.29
.66
14 (13.2)
.42§
24.7 ⫾ 46.6
1 (5.6)
15 (14.2)
99.8 ⫾ 181.0
87.1 ⫾ 114.7
1 (5.6)
5 (4.7)
.44 .26§ .51 .99§
*For comparison of mild with severe. All P values reflect chi-square testing (categorical variables) and t tests (continuous variables) unless specified. The nonsignificant P values show that none of these factors describing frequency of use or total dose of NSAIDs is associated with severity of outcome. Only subjects having cataract surgery are included in this table (n ⫽ 106). † Cases in which topical ocular NSAIDs were used more frequently than 4 times per day and/or for longer than 14 consecutive days but less frequently and for a shorter period than for cases “significantly” exceeding label directions as outlined below ‡ Cases in which topical ocular NSAIDs were used more frequently than 6 times per day and/or for longer than 30 consecutive days § Fisher exact test
found nor were there differences with respect to the NSAID used. Medical and Ocular History Indicators The presence of any systemic disease was significantly associated with a more severe outcome (P ⫽ .02, chi-square). Although the chi-square test for trend did not show a significant association between diabetes and severity of outcome, the prevalence of diabetes was significantly higher among patients with severe outcomes than those with mild or moderate outcomes. The presence of other systemic diseases, including rheumatoid 626
arthritis, was not associated with outcome, even when the analysis was restricted to comorbidities identified prior to the diagnosis of an ocular lesion (Table 3). Neither previous use of systemic or ocular medications nor a history of ocular disease in the affected eye was associated with severity of outcome. However, patients with previous surgery in the affected eye had worse outcomes (0.06 test for trend) (Table 3). Comparison of Surgical and Nonsurgical Cases Indications for the use of NSAIDs in a nonoperative setting in our series included CME, allergic conjuncti-
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Table 2. Characteristics of confirmed cases by NSAID agent used.
Characteristic
Voltaren (n ⴝ 32)
Generic Diclofenac (n ⴝ 63)
Acular (n ⴝ 22)
Total
Surgical cases, n (%)
26 (81.3)
60 (95.2)
12 (54.5)
98 (83.8)
Systemic comorbidity, n (%) Ocular comorbidity, n (%) Max NSAID drops/day (mean ⫾ SD) Drops/day ⬎ 4, n (%)
9 (28.1)
17 (27.0)
10 (45.5)
36 (30.8)
.53
18 (29.0)
15 (68.2)
48/116 (41.4)
.01
5.8 ⫾ 4.53
5.7 ⫾ 5.20
4.15 ⫾ 1.14
5.3 ⫾ 4.29
.58†
25.4 ⫾ 35.36
Days of use ⬎ 30, n (%)
7 (11.1)
88.1 ⫾ 72.96
4 (18.2)
15.1 ⫾ 10.87
8 (25.0)
Total NSAID Drops (mean ⫾ SD)
.001
15 (46.9)
7 (21.9)
Days using NSAID (mean ⫾ SD)
P Value*
27.1 ⫾ 19.66
5 (7.9)
6 (27.3)
57.6 ⫾ 34.85
98.8 ⫾ 74.3
18 (15.4)
.38‡
24.7 ⫾ 46.6
.02†
19/117 (16.2)
.04
87.1 ⫾ 115.0
.02†
Total drops ⬎ 150, n (%)
3 (9.4)
1 (1.6)
5 (22.7)
9/117 (7.7)
0.01‡
No off-label use and no systemic or ocular comorbidities
4 (12.5)
13 (20.6)
1 (4.5)
18/117 (15.4)
0.23‡
*Chi-square test comparing characteristics between the 3 agents, unless otherwise specified. A significant P value in this table indicates that the 3 NSAIDs differed significantly from one another in this characteristic. A nonsignificant P value suggests they did not differ from one another significantly. Only confirmed cases are included (n ⫽ 117). † Wilcoxon rank sum test ‡ Fisher exact test
Table 3. Association of ocular and medical history and severity of lesion. Outcome Descriptor Had cataract surgery (%) Presence of any systemic disease
†
Mild (n ⴝ 47)
Moderate (n ⴝ 49)
Severe (n ⴝ 2)
Total
P Value*
46 (97.9)
42 (85.7)
18 (81.8)
106/118 (89.8)
.001
11 (21.6)
12 (21.8)
16 (47.1)
39 (27.9)
.02
Presence of diabetes
7 (13.7)
4 (7.3)
10 (30.3)
21 (15.1)
.08
Taking systemic medications‡
6 (12.5)
6 (11.8)
1 (3.1)
13/131 (9.9)
.20
20 (39.2)
22 (40.0)
18 (54.6)
60/139 (43.2)
.20
7 (13.7)
6 (10.9)
11 (33.3)
24/139 (17.3)
.06
History of ocular disease§ History of prior surgery in affected eye
All values are number of eyes (%) *A significant P value indicates that the factor is significantly associated with severity of outcome. Factors with nonsignificant P values are not associated. Only subjects with postoperative lesions (n ⫽ 118) are included in the first row. All patients (n ⫽ 140) are included in subsequent rows, although numbers may total less than 140 due to missing data. † Includes diabetes, Sjo¨gren’s syndrome, rosacea, rheumatoid arthritis, and other collagen vascular disease. Analysis was carried out separately using all reported history of systemic disease and only those cases documented in the medical record prior to the onset of the lesion. The results of the 2 analyses were identical; only the analysis for all reported history is presented. ‡ Includes oral steroids, oral NSAIDs, and other oral immunosuppression therapy § Includes preoperative contact lens wear, dry eye, history of HSZ/HZV, history of ocular trauma, atopic eye disease, prior corneal disease, and “other”; when all the comorbidities in 10 or more individuals were analyzed separately, the following factors were not significantly associated with severity of outcome: dry eye, “other” ocular comorbidity, and prior corneal disease.
vitis, and ocular pain typically in association with ocular surface abnormalities. Nonsurgical cases had significantly worse outcomes than did surgical cases. Nonsurgical cases were also significantly younger, less likely to
be using steroids, and more likely to have a preexisting ocular comorbidity; they received an almost 3-fold greater total dose of topical NSAIDs than the surgical cases (Table 4).
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Table 4. Comparison of surgical and nonsurgical cases of NSAID-associated corneal pathology.
Characteristic Mean age ⫾ SD, years
Surgical (n ⴝ 118)
Nonsurgical (n ⴝ 22)
P Value*
74.7 ⫾ 10.7
66.3 ⫾ 14.8
.02
Male gender, n (%)
44 (37.3)
12 (54.6)
.13
Presence of systemic comorbidity, n (%)
29 (24.6)
10 (45.5)
.05
Presence of ocular comorbidity, n (%)
41 (35.0)
19 (86.4)
.001
Presence of diabetes, n (%)
17 (14.5)
4 (18.2)
.75†
107 (90.7)
9 (56.3)
.001
Total days of NSAID use (mean ⫾ SD)
18.8 ⫾ 20.5
59.3 ⫾ 107.6
.002‡
Total drops of NSAID (mean ⫾ SD)
69.0 ⫾ 51.8
193.8 ⫾ 253.6
.0004‡
Drops/day of NSAID (mean ⫾ SD)
5.42 ⫾ 4.51
4.70 ⫾ 2.56
Use of postoperative topical steroids, n (%)
.98‡
*A significant P value indicates that surgical and nonsurgical cases differed significantly in this characteristic. † Fisher exact test ‡ Wilcoxon rank sum test
Discussion Generic diclofenac was used in most confirmed cases with severe outcomes, but Acular and Voltaren were implicated in some severe, confirmed cases. In the case of Acular, all the severe events occurred in nonsurgical settings. The severity of outcome did not differ significantly among the 3 agents studied. Analysis of the timing of cases revealed a significant increase within months of the introduction of generic diclofenac, an observation consistent with our finding that most cases occurred in association with this agent. Confirmed cases in which Acular or Voltaren were used were more likely to be nonsurgical, to have ocular comorbidities, and to have received significantly higher doses of NSAIDs. All 3 factors might tend to produce more severe outcomes, although it should be noted that neither a higher total dose of NSAIDs nor the presence of ocular comorbidities was associated with a worse outcome among all cases. Such additional factors may be necessary to potentiate corneal complications with Voltaren and Acular, while such complications are more likely to occur in the absence of identifiable risk factors with generic diclofenac. It is also possible that generic diclofenac is associated with a low total dose because the event itself might occur earlier, resulting in a change in medical management and a cessation of the drug. Although off-label use of NSAIDs was common in this series, this behavior was not associated with severity of outcome. As discussed below, the case-series design of 628
this study, without controls, does not allow us to determine whether off-label use is a risk factor for corneal complications per se. Certain systemic and ocular comorbidities did emerge as risk factors for severe events. Dry eye and rheumatoid arthritis were not associated with outcome, even when only the cases in which the comorbidity had been identified prior to presentation of the ocular lesion (thought to be potentially more reliable diagnoses) were considered. However, a history of diabetes mellitus and prior surgery in the affected eye were associated with a worse outcome. Individuals with diabetes are known to be at increased risk for corneal disorders such as epithelial defects, recurrent erosions, abnormal wound repair, and increased susceptibility to injury.27,28 Postulated mechanisms for this include increased basement membrane thickness,29 decreased hemidesmosome numbers,30 and alterations in the corneal extracellular matrix and epithelial basement membrane.31 Little if any literature exists documenting rates of postoperative corneal complications in patients who had previous surgery in the eye. However, a history of previous surgery in the eye may be a marker for other ocular or systemic conditions that could make adverse events more likely. Patients having cataract extraction had significantly better outcomes than did surgical cases in general. Other surgeries included in our series were refractive surgery, PKP, and glaucoma tube shunts. It is not entirely clear why the cataract surgeries had better outcomes, but it may be that patients having other procedures such as
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PKP and tube shunt were more likely to have other ocular conditions that placed them at increased risk for adverse outcomes. Nonsurgical cases had significantly worse outcomes than did surgical cases. They were also significantly younger, more likely to have ocular comorbidities, and less likely to be using topical steroids; they received significantly higher doses of topical NSAIDs. While age, presence of ocular comorbidities, use of topical steroids, and NSAID dose were not significantly correlated with outcome among all cases, the total dose of NSAIDs was nearly 3 times higher in the nonsurgical cases, nearly 200 total drops. Doses in this range may be associated with a greater risk of corneal adverse outcomes. It is also possible that the finding of more severe outcomes among nonsurgical cases represents bias of ascertainment. Perhaps in the nonsurgical setting, a more severe presentation was required to attract the attention of the physician and to be considered worthy of reporting. Reports in the peer-reviewed literature of severe corneal complications in association with the use of topical NSAIDs have been relatively infrequent. One recent series of 5 cases, 4 of which had corneal perforation, implicated generic diclofenac in 3 of the eyes that perforated and brand diclofenac in 1.25 The actual medication used was confirmed by inspection or telephone contact with the pharmacy (J. Lin, MD, personal communication, September 18, 2000). Data regarding these 5 cases are included in the current report. Animal1 and human32,33 data suggest that topical NSAIDs may interfere with normal corneal healing, perhaps secondary to suppression of keratocyte proliferation, a necessary component in corneal remodeling.34 Still, there are no clear explanations for severe corneal complications such as those described in the current report or for the apparent increase in such cases in the months following the introduction of generic diclofenac. The preservatives (sorbic acid and edetate sodium, Voltaren; polyquad polyquaternium 1, generic diclofenac) and emollients (polyoxyl-35, Voltaren; tocophersolan and mannitol, generic diclofenac) differ between the Ciba Vision and Falcon products, but the implications of this for corneal toxicity are not clear. Further work has to be done to elucidate the mechanisms underlying severe corneal complications in association with the use of topical ocular NSAIDs.
This study has several limitations that are inherent in its design. In the initial ASCRS survey, physicians were asked to report adverse outcomes thought to be associated with the use of topical ocular NSAIDs. Thus, all cases included in this study are reported to have used these medications. As a result, we cannot compare rates of corneal complications between those using and those not using ocular NSAIDs and thus can make no estimates of the risk that may be associated with such use. We do not have data regarding patterns of use of NSAIDs among the population at large. Since we cannot state whether patients with ocular complications in our series differed significantly in the NSAIDs they received from all users of NSAIDs or the NSAID users who did not develop complications, we are unable to state with certainty whether persons using a particular agent are at greater risk of complications. The generic versus brand status of other topical medications (steroids, antibiotics, glaucoma medications) used by patients in this study was not ascertained. Thus, we cannot exclude the possibility that use of other generic medications may have affected the severity of the outcome, although we saw no evidence to suggest this was a factor. It should also be pointed out that the confirmation process for use of Acular, which required only that this medication be recorded as used on the reporting form and in the medical records, does not exclude the possibility that generic diclofenac or another NSAID was substituted. However, none of the 140 records we reviewed showed evidence of such a substitution. Furthermore, the more stringent confirmation process applied with respect to Voltaren did not reveal major differences between confirmed and unconfirmed cases. Finally, the analysis did find that the context of disease was very different for Acular, suggesting that significant misclassification was unlikely. Specifically, not a single severe postoperative case was observed in association with this medication. The time course of the reporting of the adverse events and clinical experience suggest that the association is real, although this study cannot quantify the strength of the association. Sterile corneal ulceration in the early postoperative period is a rare event and has historically been associated with Mooren’s ulceration or related syndromes in patients with evidence of systemic collagen vascular disease or vasculitis.
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It has been postulated that geographic variation could be a factor in determining the distribution of cases of NSAID-associated corneal pathology, with such cases being more common in states in which the dispensing of generic products is required by statute. It is also possible that such requirements vary greatly within states according to the policies of different health care maintenance organizations. Unfortunately, available databases do not allow us to examine this hypothesis. We also lack data on batch numbers of the various drugs implicated in specific cases, which might have allowed us to pinpoint particular batches as being more likely to be associated with adverse outcomes. In conclusion, these data point toward a recent significant increase in severe corneal events related chronologically to the introduction of generic diclofenac. Use of this product was implicated in most confirmed cases in our series, particularly those that occurred in the early postoperative setting. Although our data are consistent with the idea that topical NSAIDs as a class have the potential for significant corneal complications, it would appear that such events otherwise occur at a low rate and usually in the presence of high doses of medication, other potentiating factors such as ocular comorbidities, or both. Generic diclofenac may be an exception to this, as a number of the severe cases in our series involved relatively limited use of the drug in the postoperative setting. Severe cases associated with Acular occurred in nonsurgical settings in patients with coexisting ocular disease treated for long periods. Many of the nonsurgical cases occurred in patients with abnormalities of the ocular surface (eg, conjunctivitis and superficial keratitis). The chronic use of topical NSAIDs in such patients may pose an increased risk of corneal ulceration.
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