April 2012


EyeWorld journal club

Casey Eye InstituteOregon Health & Science University residents' review of "Cataract surgery in patients with AMD after anti-VEGF therapy"

by Alan Bengtzen, M.D., Robert J. Courtney, M.D., Jennifer Rose-Nussbaumer, M.D., Shandiz Tehrani, M.D., Daniel Tu, M.D., and Andreas K. Lauer, M.D.

Andreas K. Lauer, M.D.

Director, Ophthalmology Residency Program

This month, I asked the Casey Eye residents to review this important paper on cataract outcomes in patients with wet ARMD.

David F. Chang, M.D., chief medical editor

Age-related macular degeneration (AMD) and cataract are common causes of visual impairment in the aging population. Consideration as to whether cataract surgery has an influence on the visual outcome of AMD patients has been an area of continual contention. In "Outcomes of cataract surgery in patients with neovascular age-related macular degeneration in the era of anti-vascular endothelial growth factor therapy," published in the April issue of the Journal of Cataract and Refractive Surgery, Tabandeh and colleagues1 present their review of cases evaluating the visual outcomes, choroidal neovascular complex status, and adverse events in patients with concurrent visually significant cataract and neovascular age-related macular degeneration (AMD) who have undergone cataract surgery.

In a retrospective review of charts derived from two private retina practices based in California and Connecticut, neovascular AMD patients who met entry criteria were identified in whom cataract surgery was conducted after the initiation of anti-VEGF therapy with bevacizumab or ranibizumab between January 2007 and December 2010. Only patients with a diagnosis of occult or classic neovascular AMD who had phacoemulsification and IOL implantation with 6 months of follow-up or longer were included in the study. Data collected from the medical records included demographic characteristics, ocular history, baseline corrected distance visual acuity (CDVA) measured on Snellen charts, type and frequency of anti-VEGF therapy, adverse events related to cataract surgery, post-cataract surgery CDVA, and neovascular AMD status. Patients with a history of visual loss due to other conditions including diabetic retinopathy, retinal vascular occlusion, retinal detachment, and advanced glaucoma were excluded from the study. Patients with fewer than 6 months of follow-up were excluded from the study.

The neovascular AMD treatment and retreatment protocol for the patients in this study were similar to the method described by the Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intraocular Ranibizumab (Lucentis [Genentech, South San Francisco]) Study (PrONTO).2 The treatment included an induction phase of three consecutive monthly injections followed by optical coherence tomography (OCT)-guided retreatment. The status of the neovascularization was established according to the PrONTO study protocol where the appearance of any amount of macular fluid on OCT was indication for treatment. Intravitreal anti-VEGF injections were withheld if patients had two consecutive visits without signs of activity on OCT and were deemed to have a drug-free phase.

The authors' record review identified 34 potential cases of which 30 eyes of 28 patients met entry criteria. In reviewing their pre- and post-cataract surgery CDVA, perioperative adverse events, and status of the choroidal neovascular complex, the authors reported a mean improvement in CDVA and no adverse macular events at 6 months post-cataract surgery. The authors also reported that there was no significant difference in visual improvement between the patients who were in a drug-free phase before and those who were continuing to receive anti-VEGF therapy for choroidal neovascularization found to be active perioperatively.

The authors concluded that for neovascular AMD patients undergoing regular evaluations and appropriate treatment with anti-VEGF agents, cataract surgery did not appear to be associated with an increased incidence of perioperative complications or macular adverse events.

These findings appear congruent with the current clinical impression of ophthalmologists who treat neovascular AMD patients with intravitreal anti-VEGF agents. In previous years, studies have evaluated the relationship of cataract surgery and neovascular macular degeneration in patients who were treated by modalities other than intravitreal pharmacotherapy or those patients for whom treatment was not available. The study designs have included case series, cross sectional surveys (or prevalence studies), and longitudinal observational studies, all of which were retrospective and not specifically designed to examine the effect of cataract surgery on patients undergoing intravitreal injections for neovascular AMD. Although a retrospective chart review uses a data set that is fraught by having limited pertinent data and heavily relies on the accuracy of written record or recall of individuals,3 the advantages of Tabandeh et al.'s study design are the relative ease with which to access existing data and the low expense for addressing an initial exploratory study question. While a retrospective review of greater than 30 eyes with this clinical scenario may not constitute many subjects, this study design is useful in early description or hypothesis generation of this new clinical problem. Further explanation of the methods by which 34 potential cases were identified from the two practices would have helped us better understand the potential degree of recall, and selection bias exists as an inherent component of a retrospective study. Methods for improving retrospective study design that might be considered for future studies on the impact of cataract surgery in neovascular AMD patients undergoing intravitreal injections could include assigning a control group to the case series (case-control study). Such a study may be made superior if the assigned control subjects are selected so that they resemble or match the cases with regard to certain characteristics (e.g., age, comorbidity, severity of disease). The goal then is to compare case and control patients who have similar characteristics and thereby to adjust for potential confounders and increase the precision of the comparison (matched case-control study). Although this improved methodology could be used, it may still be difficult to establish cause and effect. Indeed, it is difficult to control bias and confounders in selecting cases when randomization or blinding is not employed.

Recently, Rosenfeld et al. evaluated cataract surgery in ranibizumab-treated patients with neovascular age-related macular degeneration.4 In this retrospective analysis of patients who participated in the Phase III ANCHOR and MARINA trials, cataract surgery appeared to be safe and beneficial for all eyes with AMD, including ranibizumab-treated eyes with neovascular AMD. In comparing three groups, study eyes of ranibizumab-treated patients (758 eyes [23 undergoing surgery]), fellow eyes of ranibizumab-treated patients (758 eyes [28 undergoing surgery]), and eyes of non-ranibizumab patients (762 [16 undergoing surgery]) were examined. They concluded that 3 months after cataract surgery, an average VA improvement of more than two lines was typically observed with no significant differences seen between the groups. Since in clinical trials the numbers of subjects are relatively higher and the information is captured and reported according to standardized protocol, retrospective analysis of a multicenter randomized clinical trial such as this may at times provide additional valuable insight. While the follow-up in this study is 3 months, Tabandeh et al.'s work included patients with follow-up of 6 months or more and presently represents the longest follow-up to date concerning this study question. In their discussion, Tabandeh et al. reference Dr. Klein's editorial, which addresses the issues related to study design in better answering the current study question.5 Not surprisingly, a prospectively designed study is suggested. In such a study, the subject patient would need to agree to random assignment of one of his/her eyes for surgery whereas the fellow eye would not for a period of time. Both eyes would be studied according to a predetermined schedule with adequate evaluation of the fundus and surgery site with codified examination procedures. Since the patient would serve as his/her own control, this would permit controlling for the host of differences between people that even very well planned clinical trials of random assignment of subjects cannot precisely adjust for. Since each person serves as his/her own control, many of the confounders of other studies are no longer an issue, and the specifics of the cataract surgery/ AMD incidence and progression can be examined. Dr. Klein suggested that the follow-up would continue for a year or more with specific parameters for pre-op evaluation and post-op follow-up. There could be hard copy imaging (e.g., fundus photography fluorescein, optical coherence tomography) with trained masked graders evaluating the images of both eyes according to specified protocols. While such a study would be feasible from a design perspective and might be the best way to address this important therapeutic problem, conducting a multicenter study to specifically address this question would consume a substantial amount of time and resources. Until the inherent importance of the study question and the potential public health impact of the answer to the study question are carefully considered, such a study may be very difficult to accomplish.

In an era of intravitreal anti-VEGF therapy for neovascular AMD, the earliest studies such as Tabandeh et al.'s and Rosenfeld et al.'s seem to indicate that for patients with neovascular AMD who are undergoing regular evaluations and appropriate treatment, surgery for visually significant cataract may be beneficial and does not appear to be associated with an increased incidence of perioperative complications or macular adverse events.1,4,6-8 Further studies would be helpful to support or refute these early findings. In the meantime, until more retrospective studies or a prospective trial are completed, ophthalmologists should candidly discuss with their patients that inconsistencies remain in the research findings regarding risks of progression of neovascular AMD patients requiring cataract surgery. Ophthalmologists should also continue to encourage regular evaluation and management of their neovascular AMD perioperatively.


1. Tabandeh H, Chaudhry NA, Boyer DS, Kon-Jara VA, Flynn HW. Outcomes of cataract surgery in patients with neovascular age-related macular degeneration in the era of anti-vascular endothelial growth factor therapy. J Cataract Refract Surg. 2012 April; 38:677-682.

2. Fung AE, Lalwani GA, Rosenfeld PJ, Dubovy SR, Michels S, Feuer WJ, Puliafito CA, Davis JL, Flynn HW Jr., Esquiabro M. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007; 143:566-583.

3. Fletcher RH, Fletcher SW. Clinical research in general medical journals: a 30-year perspective. N Engl J Med. 1979; 301(4):180-183. 4. Rosenfeld PJ, Shapiro H, Ehrlich JS, Wong P; MARINA and ANCHOR Study Groups. Cataract surgery in ranibizumab-treated patients with neovascular age-related macular degeneration from the phase 3 ANCHOR and MARINA trials. Am J Ophthalmol. 2011 Nov; 152(5):793-8. 5. Klein BEK. Is the risk of incidence or progression of age-related macular degeneration increased after cataract surgery? [editorial] Arch Ophthalmol. 2009; 127:1528-1529.

6. Dong LM, Stark WJ, Jefferys JL, Al-Hazzaa S, Bressler SB, Solomon SD, Bressler NM. Progression of age-related macular degeneration after cataract surgery. Arch Ophthalmol. 2009; 127:1412-1419.

7. Hooper CY, Lamoureux EL, Lim L, Fraser-Bell S, Yeoh J, Harper CA, Keeffe JE, Guymer RH. Cataract surgery in high-risk age-related macular degeneration: a randomized controlled trial. Clin Exp Ophthalmol. 2009; 37:570-576.

8. Chew EY, Sperduto RD, Milton RC, Clemons TE, Gensler GR, Bressler SB, Klein R, Klein BEK, Ferris FL III. Risk of advanced age-related macular degeneration after cataract surgery in the Age-Related Eye Disease Study; AREDS report 25. Ophthalmology. 2009; 116:297-303.

Contact information

Lauer: lauera@ohsu.edu

Casey Eye Institute Oregon Health & Science University residents' review of "Cataract surgery in patients with AMD after anti-VEGF therapy" Casey Eye Institute Oregon Health & Science University residents' review of "Cataract surgery in patients with
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