June 2019

ASCRS NEWS

Eyeworld journal club
Review of “Comparative analysis of intravitreal triamcinolone acetonide/moxifloxacin versus standard peri-operative eye drops in cataract surgery”


by Rahul Raghu, MD, Huy Ly, MD, Ashraf Ahmad, MD, Samuel Dresner, MD, Patrick Pham, MD, Linda Ohsie Bajor, MD, Loretta Szczotka-Flynn, OD, PhD, Manasvee Kapadia, MD


Manasvee Kapadia, MD

Residency program director
Case Western Reserve University/University Hospitals Cleveland Medical Center

Although “dropless”surgery is an appealing concept, intravitreal injection of a compounded triamcinolone-moxifloxacin formulation has never undergone an FDA clinical trial. I’ve asked the Case Western residents to review this head-to-head comparison with topical therapy that appears in this month’s JCRS.

—David F. Chang, MD,
EyeWorld Journal
Club editor


Case Western Reserve University residents, from left: Rahul Raghu, MD, Patrick Pham, MD, Samuel Dresner, MD, Huy Ly, MD, Ashraf Ahmad, MD

 

Vision loss secondary to cataract is cited as the most common cause of reversible blindness, globally affecting more than 250 million people1. With the increasing aging population, the current estimate of 3.6 million annual cataract surgeries performed here in the U.S. is only expected to rise2. Numerous advances in phacoemulsification technology have helped to make the procedure safer, more efficient, and contributed to better visual outcomes.
Despite this, innovation in perioperative management has remained relatively stagnant. Prescription of a topical antibiotic, steroid, and NSAID are the standard of care for most surgeons before and/or after cataract surgery. While many patients are able to adhere to postoperative topical drop regimens, these drops do have the potential to be burdensome and difficult to handle for a subset of patients. For this reason, other alternatives are being used. One way of providing medications is the intracameral technique, where the medication is injected through the side port incision at the time of cataract surgery and into the anterior chamber of the eye. However, with this technique, the drug is quickly removed from the anterior chamber due to normal aqueous humor dynamics. Another technique is “dropless” cataract surgery, whereby injection of pharmacologic agents is given into the anterior vitreous at the time of surgery. There are two approaches for delivery, either transzonular or through pars plana. This technique allows the drug to remain in the eye for a prolonged period of time, thereby reducing or even completely eliminating the need for postoperative topical eye drops.
Beyond the increased convenience that dropless cataract surgery may offer patients, there is evidence that injectable agents may also be more cost effective as compared to their topical counterparts3. The ESCRS Endophthalmitis Study Group demonstrated that at least from an infectious standpoint, there is a meaningful reduction in postoperative endophthalmitis4.
In this study, Nassiri et al. retrospectively compared the postoperative outcomes of patients who received 0.2 mL intravitreal triamcinolone acetonide/moxifloxacin (Tri-Moxi, ImprimisRx) and a non-steroidal anti-inflammatory eye drop with those patients who received a standard eye drop regimen. A total of 1,195 eyes from 919 patients operated on by two surgeons at a single institution were included in the study. Although there were no formal criteria for the assignment of patients to each of the two treatment arms, the baseline characteristics of the study groups were statistically comparable, with exception of median age, which showed a small but statistically significant difference.
The patients’ postoperative outcome was reviewed with particular attention paid to intraocular inflammation, corneal edema, and rate of high intraocular pressure, which was defined as 24 mm Hg or higher. Though the Tri-Moxi medication group experienced a greater severity of corneal edema on postoperative day 1, there were no other statistically significant differences between the two groups. As a result, intravitreal therapy was concluded to have shown non-inferiority to standard therapy for the outcomes measured. Of note, intraocular pressure tended to increase from baseline in both groups at postoperative day 1, but this normalized by subsequent follow-up visits and there were no statistically significant differences in intraocular pressure between the two treatment groups at postoperative month 1.
The results and conclusions of this study provide compelling evidence for considering Tri-Moxi as an alternative to standard therapy. By using a large sample size, the study allows for generalizability of its statistical findings. An emphasis was placed on limiting confounding demographic variables. The baseline characteristics of the two groups within the study were relatively comparable, with a minor difference in median age as noted previously.
Additionally, elevated postoperative IOP has been cited as a concern for use of an injectable steroid following cataract surgery. A 2013 meta-analysis found that 32% of patients develop ocular hypertension following 4.0 mg of triamcinolone5. However, this study showed no statistical significant difference between the two groups at final follow-up with regard to IOP. The evidence presented here may help to alleviate concerns surrounding high IOP in a dropless approach involving steroid injection.     
Ultimately, the study set out to compare the effectiveness of Tri-Moxi to standard eye drop regimen in controlling postoperative inflammation, corneal edema, and elevation in IOP. Through its large sample size and similar study groups, the authors successfully demonstrate non-inferiority of Tri-Moxi compared to standard postoperative drug regimens in reducing the degree of intraocular inflammation and corneal edema, without a difference noted in elevated IOP between the two groups.
The authors self-disclose many of the study weaknesses. From a study design perspective, the initial decision of whether a patient received dropless versus standardized therapy was left to discretion of the surgeon. The authors note that the surgeons did take into account patient preferences and almost undeniably patient reliability, introducing an element of selection bias, potentially influencing the ultimate results.
The authors also note the limitations of a 1-month follow-up period, particularly related to the fact that one of the most common postoperative complications of pseudophakic CME classically presents after the 1-month period.
The authors note that the specific NSAID used was non-standard due to issues surrounding insurance. While this is unlikely to have affected outcomes in a significant manner, it is rightfully noted. Also, the authors are ideally seeking to evaluate the effectiveness of dropless cataract surgery’s impact on postoperative inflammation, but both groups still required use of a topical NSAID. As this does not represent truly dropless cataract surgery, some of the strengths noted above, particularly around patient compliance and ability to administer drops, may not be 100% applicable to this study.
In regard to statistical analysis, the authors provide a number of comparisons they made for multiple endpoints (VA, inflammation, IOP, and corneal edema). All of those were also tested at multiple time points. BCVA was analyzed in a logMAR format, IOP was converted to a binary covariate if >24 or not, and inflammation and corneal edema were graded on a 4-point ordinal scale. An odds ratio was determined using ordinal (logistic) regression, and in some circumstances they adjusted for potential confounding variables, therefore some models were multivariate.
Of note, there is lack of accounting for multiplicity; with the repeated testing at different time points, the p values should be adjusted to control for the type 1 error. The authors did perform a repeated measures ANOVA on some of the repeated VA analyses, but there was no adjustment of p values for the multiple looks at the odds ratios and p values in Table 2 of the study. If a simple Bonferroni correction was applied to that table, for each row, some of those findings would no longer be significant.
While the promise of dropless cataract surgery has been demonstrated in the literature, to date it has not been widely adopted in the U.S. At the top of the list of concerns are those surrounding the compounding process, which are subject to human error, such as dilution error or contamination. Additionally, there is concern that dropless cataract surgery with moxifloxacin monotherapy does not provide adequate prophylaxis for endophthalmitis. 
Patel et al.6 presented a retrospective chart review of seven patients who experienced toxic posterior segment syndrome during an outbreak stemming from compounded triamcinolone/moxifloxacin. These patients had immediate decrease in vision after cataract surgery along with other visual complaints. Foveal RPE changes on clinical exam was noted in three patients and ellipsoid zone changes on OCT. ERG changes were noted in five patients. The authors postulated that the retinal damage was due to “poloxamer 407,” which is used in compounded medications for solubility. 
Kishore et al.7 reported four cases of acute onset postoperative endophthalmitis after cataract surgery and transzonular intravitreal Tri-Moxi. The authors express concern that the half-life of the typically injected 200 micrograms of moxifloxacin may be too short, resulting in premature clearance from the vitreous, theoretically preventing useful action in the anterior chamber. From a letter to the study authors, a basic science research lab published an experimental study in rabbits who received triamcinolone/moxifloxacin or triamcinolone/moxifloxacin/vancomycin and were then challenged with intravitreal S. aureus. The triamcinolone/moxifloxacin group did not prevent endophthalmitis against bacteria with high MICs, whereas the group with vancomycin did. This raises the question about the addition of vancomycin to dropless cataract surgery regimens. However, it is well reported that there is a risk of hemorrhagic occlusive retinal vasculitis with injection of vancomycin in the vitreous.8,9
Another consideration is that use of injectable agents may cost less to the patient, however, there is an increased cost for the surgeon/surgery facility. For a surgery center that has a high volume of cataract surgery, the extra cost can add up. While dropless surgery is a nice option for patients from a safety and compliance standpoint, widespread adoption by surgeons may potentially be limited by cost at this time. 
In summary, the study suggests that intravitreal triamcinolone/moxifloxacin, along with a topical NSAID, should be considered a reasonable alternative for standard topical postoperative drops. Despite certain limitations of the study, Tri-Moxi with a topical NSAID can be considered a reasonable alternative to standard therapy following cataract surgery, particularly for those patients who may struggle or be considered unreliable to administer eye drops postoperatively. Additional surveillance with an extended follow-up of the two groups would likely be required for wide scale adoption.

Contact information

Kapadia: Manasvee.Kapadia@UHhospitals.org

References

1. Global Data on Visual Impairments 2010. WHO 2012.
2. Lindstrom R. Thoughts on Cataract Surgery: 2015. Review of Ophthalmology. March 9, 2015.
3. Vandenbroeck S, et al. Prevalence and correlates of self-reported nonadherence with eye drop treatment: the Belgian Compliance Study in Ophthalmology (BCSO). J Glaucoma. 2011;20:414–21.
4. Endophthalmitis Study Group, European Society of Cataract & Refractive Surgeons. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract Surg. 2007;33:978–88.
5. Kiddee W, et al. Intraocular pressure monitoring post intravitreal steroids: a systematic review. Surv Ophthalmol. 2013;58:291–310.
6. Patel SB, et al. Toxic posterior segment syndrome after dropless cataract surgery with compounded triamcinolone-moxifloxacin. Retina. 2019. Epub ahead of print.
7. Kishore K, et al. Acute-onset of postoperative endophthalmitis after cataract surgery and transzonular intravitreal triamcinolone-moxifloxacin. J Cataract Refract Surg. 2018;44:1436–1440.
8. Nicholson LB, et al. Severe bilateral ischemic retinal vasculitis following cataract surgery. Ophthalmic Surg Lasers Imaging Retina. 2014;45:338–42.
9. Witkin AJ, et al. Postoperative hemorrhagic occlusive retinal vasculitis. Expanding the clinical spectrum and possible association with vancomycin. Ophthalmology. 2015;122:1438–51.

Review of “Comparative analysis of intravitreal triamcinolone acetonide/moxifloxacin versus standard peri-operative eye drops in cataract surgery” Review of “Comparative analysis of intravitreal triamcinolone acetonide/moxifloxacin versus standard
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