Based on our extensive literature review, this is the first documented systematic review of RCTs specifically evaluating ketorolac for prevention of acute pseudophakic CME. The current medical literature suggests that a consensus has not been reached regarding the appropriate methods in preventing acute pseudophakic CME. There are still opposing views regarding whether patients should be treated prophylactically with an NSAID or not given any medication.
After pooling the results, it was found that treatment with ketorolac significantly reduced the risk of CME development compared with control, two of which compared ketorolac with no treatment and two of which evaluated ketorolac vs
placebo, at the end of treatment (typically at 4 weeks) (P
=0.008; 95% confidence interval (CI), 0.03–0.58) (). Three of four trials were estimable, though nonstatistical inclusion of the Chatziralli study11
made no difference to the overall results when re-analyzed in a subgroup analysis.
Forest plot displaying pooled summary estimates of CME development in patients treated with ketorolac compared with control at the end of the treatment period.
However, the authors stress caution with the interpretation of these results. When analyzed individually, each individual study was statistically nonsignificant in its findings, with the exception of the Wittpenn study.9
When the pooled relative risk was calculated, the large sample size of this systematic review led to overall statistical significance. The authors attribute this to the review's large sample size and not to the individual studies themselves. Furthermore, the included studies were all determined to be significantly underpowered based on a power of 80% and an α
significance of 0.05. The Almeida, Donnenfeld, and Wittpenn studies were determined to have a statistical power of 2.5%, 45.1%, and 53.1%, respectively.9, 10, 12
The power of the Chatiziralli study11
was inestimable because of the fact that there were no incidents of CME in either group.
In the risk of bias summary, most of the trials were considered essentially devoid of any major biases related to the study execution (). Publication bias was adjudged to be fairly nonexistent according to visual inspection of a funnel plot. However, this conclusion should be taken with caution given the number of included studies.
Risk of bias summary across all studies. (‘+': low risk of bias, ‘−': high risk of bias).
Nevertheless, there is a questionable risk of additional biases in the Donnenfeld and Wittpenn studies because of their paid consultancies for Allergan, Inc., at the time of their study investigations.9, 10
This compromise of objectivity raises concerns when interpreting these trials. As shown in a review of 370 RCTs, studies funded by for-profit organizations were 5.3 times more likely (95% CI, 2.0–14.4) than non-profit organizations to recommend the experimental drug as the treatment of choice.19, 20
The authors decided not to conduct a meta-analysis in the four included trials owing to their substantial heterogeneity:
- Two RCTs used ketorolac tromethamine 0.4% whereas the other two employed ketorolac tromethamine 0.5%
- Two RCTs utilized placebo drops as their control group compared with the other two RCTs using only a steroid and antibiotic
- Variation in sample size
- Differences in time when ketorolac was administered (pre-, peri-, and/or postoperatively)
- Only one RCT analyzed contrast sensitivity9
- Two RCTs assessed CME via OCT9, 12
- All but Almeida et al12 evaluated best-corrected visual acuity.
There is a need for more long-term trials evaluating ketorolac in large groups in order to strengthen the evidence in favor of ketorolac to prevent acute pseudophakic CME development. Moreover, ketorolac should be compared head-to-head with other NSAIDs if the ophthalmologic community deems NSAIDs as an integral component of surgical cataract care. Given the large number of cataract procedures performed annually (1.8 million were performed on Medicare beneficiaries alone in 2004), the use of any NSAID in this setting without legitimate justification would result in significant costs to Medicare and insurance plans, as well as to uninsured patients.21
Ideally, future trials should compare ketorolac with both placebo drops and with no treatment within the same trial. These trials should be sufficiently large and with longer follow-up periods in order to achieve the power necessary to illustrate any potential difference in outcome among these preventive strategies for acute pseudophakic CME. If future studies support Flach's22
findings that outcomes at 7 years suggest that the natural history of CME is spontaneous resolution, the question of whether or not ketorolac should be used for acute pseudophakic CME would be rendered moot.