Vitrectomy Timing for Retained Lens Fragments After Surgery for Age-Related Cataracts: a Systematic Review and Meta-Analysis

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Vitrectomy Timing for Retained Lens Fragments After Surgery for Age-Related Cataracts: A Systematic Review and Meta-Analysis

ELIZABETH A. VANNER AND MICHAEL W. STEWART

● PURPOSE: To evaluate the effect of vitrectomy timing ● CONCLUSIONS: This systematic review and meta-anal- on outcomes for patients with crystalline retained lens ysis found significantly better outcomes (visual acuity, -fragments receiving vitrectomy 3؉ days after cataract retinal detachment, increased intraocular pressure, intra surgery. ocular infection/inflammation) with earlier vitrectomy ● DESIGN: Systematic review and meta-analysis of retro- for retained lens fragments. Reduced vitrectomy delays spective interventional cases series. may yield better patient outcomes. (Am J Ophthalmol ● METHODS: Searches of MEDLINE (English, 1/1/85 2011;152:345–357. © 2011 by Elsevier Inc. All rights through 7/30/2010) and article reference lists. Articles reserved.) were screened for patients with crystalline retained lens fragments after surgery for age-related cataracts, discussion of vitrectomy timing, and, for the meta-analysis, NTRAVITREAL RETAINED LENS FRAGMENTS, WITH AN patient totals for at least 1 outcome and multiple time incidence rate between 0.1% and 1.6%,1–5 are a rare but ,periods, 10؉ patients, and mean follow-up >3 months. I potentially serious complication of cataract surgery Outcomes included visual acuity, retinal detachment, which can result in poor visual acuity (VA) and other increased intraocular pressure, intraocular infection/in- serious ocular complications.1–14 Patients are often referred flammation, cystoid macular edema, and corneal edema. to a vitreoretinal surgeon for treatment, usually including Data extraction was performed twice and quality as- a pars plana vitrectomy (PPV)2 to improve visual acuity sessed. Logistic regression estimated study-level odds and reduce intraocular inflammation and pressure,10–19 but ratios for each additional 1-week vitrectomy delay. Meta- some are treated medically.1,4,14,16,20 Optimal vitrectomy analysis estimated summary odds ratios using random- timing is unknown, and the effect of timing on outcomes effects models. is controversial.1–7,21 Some favor early vitrectomy within ● RESULTS: Of 257 articles identified, there were 43 a week or two of, or even the same day as, cataract unique studies (53 articles) for the systematic review, surgery.9,19,22 Others prefer to wait and see, performing an including 27 (31 articles) for the meta-analysis. Early early PPV only when clinically indicated—for example, if vitrectomies were statistically significantly associated the patient had increased intraocular pressure (IOP) un- with better outcomes for not good visual acuity (odds responsive to medication and/or a severe inflammatory ؍ ratio: 1.13; 95% CI: 1.04–1.22, P .005); bad visual response.1,2,6,7 However, many avoid the first few days after ؍ acuity (odds ratio: 1.05; 95% CI: 1.01–1.09, P .009); cataract surgery to permit the eye to recover.17,19,20,23 previtrectomy retinal detachment (odds ratio: 1.29; 95% The literature contains mixed results: some studies show ؍ CI: 1.01–1.65, P .038); postvitrectomy retinal de- statistically significant results indicating early vitrectomy ؍ tachment (odds ratio: 1.13; 95% CI: 1.02–1.26, P leads to better outcomes,24,25 while other studies do .024); increased intraocular pressure (odds ratio: 1.23; not,8,18,26–29 but many show a nonsignificant trend favor- -and intraocular infec ;(003. ؍ CI: 1.07–1.41, P 95% ing early vitrectomy.1–6,10–17,19–21,24,30–47 In addition, it is tion/inflammation (odds ratio: 1.20; 95% CI: 1.01– likely that selection bias has confounded these results, Results were robust to sensitivity .(041. ؍ P ,1.42 since patients with more serious ocular complications were analyses. more likely to receive an early vitrectomy.6,7,36 If meta- analysis indicated that outcomes were better with early Supplemental Material available at AJO.com. vitrectomy, despite selection bias favoring later vitrec- 9 Accepted for publication Feb 4, 2011. tomy, a hypothesis that early vitrectomy might result in From the Departments of Preventive Medicine and Health Care Policy better outcomes seems reasonable. & Management (E.A.V.), Health Sciences Center, Stony Brook Univer- sity, Stony Brook, New York; and the Department of Ophthalmology Most studies reported visual acuity results in 3 catego- (M.W.S.), Mayo Clinic College of Medicine, Jacksonville, Florida. ries: good VA (Ն/Ͼ 0.5 or 20/40), moderate VA (0.5–0.1 Inquiries to Elizabeth A. Vanner, Health Sciences Center Level 2 or 20/40 to 20/200), and bad VA (Յ/Ͻ 0.1 or 20/200). School of Health Technology and Management, Stony Brook University, 27,48 100 Nicolls Rd, Stony Brook, NY, 11794-8204; e-mail: evanner@ Retinal detachment (RD), IOP/glaucoma, intraocu- notes.cc.sunysb.edu lar inflammation/infection,43,49 cystoid macular edema

0002-9394/$36.00 © 2011 BY ELSEVIER INC.ALL RIGHTS RESERVED. 345 doi:10.1016/j.ajo.2011.02.010 FIGURE 1. Flow chart of literature search for studies on vitrectomy timing for crystalline retained lens fragments (adapted from Moher et al.62).

(CME), and corneal edema44,50 are ocular complications of PATIENTS AND METHODS retained lens fragments6 that often result in visual loss.19,29 These were the outcomes for this systematic review and THE MEDLINE DATABASE WAS SEARCHED ELECTRONICALLY meta-analysis. All were assessed postvitrectomy or final, and additional articles identified from reference lists. except RD, which was analyzed separately for pre- and Search strategy details may be found in the Appendix (see post-PPV. This study explored the effects of vitrectomy Supplemental Material, available at AJO.com). All study timing on outcomes, for patients with retained lens frag- designs were considered, and no previous systematic review ments managed surgically, after an initial wait for the eye or meta-analysis on this topic was found. Articles passed to recover from cataract surgery. the initial screen if at least 80% of patients (or identifiable

346 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 2011 subgroups) had intravitreal crystalline retained lens frag- provided data for the meta-analysis. Figure 1 provides a ments from cataract surgery for an age-related cataract or if summary of the search results. the article contained the same patients as another included To do a capture-recapture assessment of the search’s article.51 The meta-analysis required counts for at least 1 thoroughness, reference lists of all 66 articles were searched, outcome, 2 time periods (cataract surgery to vitrectomy), and the Web of Science was searched for all articles (N ϭ 10 patients, and 3 months mean follow-up. 228) that referenced any of these. It estimated56 the total Data were extracted twice, about 3 months apart, and relevant articles at 66 (95% CI, 62–70), indicating that, at discrepancies were resolved by reexamination of the arti- most, 4 articles might have been missed. cle. For each study/outcome combination, the number of patients who had received a vitrectomy was recorded, ● SYSTEMATIC REVIEW OF THE LITERATURE: Table 1 separately for those who did and did not experience that contains details for the 53 systematic review articles, pub- outcome, for each time period. Data were eliminated for lished from 1986 through 2010. Geographic distribution was patients who received a vitrectomy before day 3 post 28 in the United States/Canada, 16 in Europe, 8 in Asia, and cataract surgery or any group of patients whose average 1 in Australia. Patients were treated from 1977 through 2008, vitrectomy time post cataract surgery was less than 3 days. with a mean of 6.0 years of elapsed time between the earliest Using SAS for Windows, version 9.2 (TS Level 1MO, and latest vitrectomies included in the article (range, 1–23 2006; SAS Institute Inc, Cary, North Carolina, USA), years). The 43 unique studies tended to be small, with 37 exact logistic regression was used to estimate the odds (86.0%) including fewer than 100 patients (range, 2–343) ratio, one for each study/outcome combination, for each with data for 2380 eyes (mean ϭ 55.3 eyes per study). Of additional 1-week vitrectomy delay (after day 3 post these, 2323 (97.6%) received a PPV and 57 (2.4%) received cataract surgery). All odds ratios (from the individual medical management. Patient age averaged 73.8 years, and studies) for each outcome were then used to estimate a 54.1% (1078/1994) were female. Average time between summary odds ratio for that outcome, using Comprehen- cataract surgery and vitrectomy was just over 3 weeks, and sive Meta Analysis, version 2.2 (Biostat Inc, Englewood, average follow-up was estimated at 15.6 months. For studies New Jersey, USA). Random-effects models were fit be- with available data, Table 2 shows, for each outcome, cause of differences in the case-mix and clinical practices whether early or later vitrectomy seemed better. The litera- of the surgeons who authored the studies and the goal of ture clearly contained more results, albeit many not statisti- the meta-analysis, which was to generalize the estimated cally significant, favoring early vitrectomy. summary effects to other patient populations.52 Study quality was assessed using a checklist adapted from First week analysis. One issue is whether to attempt a validated sources53 and a method proposed by Minckler.54 vitrectomy on the same day as cataract surgery. While 3,8,22,23,31,40 Reporting and publication biases were assessed using “trim recommended by some, others stress that this & fill” and “fail safe N” analyses.52 Heterogeneity was precludes moving the patient or waiting until later the same 9,38 assessed for all significant effects if the I2 statistic was day. However, some authors indicated that cataract sur- greater than 0.52,55 A subgroup analysis52,55 assessed how gery anesthesia may make a same-day vitrectomy more difficult,3,5 and another felt same-day vitrectomy was not the results differed between studies that included patients 21 with only nuclear fragments from studies that also included necessary. 52,55 One author suggested vitrectomy the day after cataract patients with cortical fragments. Sensitivity analyses 23 were performed to assess the effects of: 1) setting the cutoff surgery, but many suggested avoiding this time to wait until the eye recovers from cataract surgery (to clear ocular con- for vitrectomies at day 3 post cataract surgery, 2) removing 8,9,35,36 1 study at a time, and 3) assuming that all significant gestion, inflammation, and corneal edema). Emergent effects were at the low end of their confidence intervals. vitrectomy, within 3 days of cataract surgery, was associated with reduced visual acuity and retinal tears in 1 study17 and hypopyon and possible endophthalmitis in another.20 In a third study, of 3 patients who had a vitrectomy for retained RESULTS lens fragments within 72 hours of cataract surgery, 1 patient had CME, another had choroidal detachment, and all 3 had A TOTAL OF 257 ARTICLES WERE IDENTIFIED, WITH 104 moderate to severe inflammation.23 eliminated by reading the title and abstract. Full text of the The first few days after cataract surgery may not be remaining 153 articles was retrieved and reviewed. A total optimal for a vitrectomy. This time might best be avoided, of 66 articles, comprising 56 unique study (patient) co- except in extraordinary circumstances, when any delay is horts, passed the initial screen, but 13 did not report or impossible. Using individual patient data from stud- discuss results for different vitrectomy timings (3ϩ days ies3,8,10–14,32,33,35,41,46 (n ϭ 12) that provided the exact after cataract surgery). The remaining 53 articles, compris- day, post cataract surgery, of each patient’s vitrectomy, ing 43 unique cohorts, were included in the systematic Table 3 shows visual acuity outcomes for each day of the review, and 31 articles, comprising 27 unique cohorts, first week. Rates changed for both good and bad visual

VOL. 152,NO. 3 VITRECTOMY TIMING FOR RETAINED LENS FRAGMENTS:META-ANALYSIS 347 TABLE 1. Description of Studies for Systematic Review and Meta-analysis of Vitrectomy Timing for Retained Lens Fragments

Study No.a Study Use Study IDb Study Location (#L) IPY-FPY (Inclusive)

1 MA Fastenberg 199117 New York (1) — 2 MA Blodi 199230 Florida, Iowa, Illinois (3) 1981–1990 2a SR Flynn 198659 Florida (1) 1980–1983 2b SR Smiddy 199664 Florida (1) 1981–1992 3 MA Gilliland 199218 Texas (1) 1979–1991 4 MA Pollet 199519 Belgium (1) 1991–1994 5 MA Tommila 199531 Finland (1) 1991–1994 6 MA Borne 199621 Pennsylvania (1) 1991–1994 7 MA Ross 199616 British Columbia (1) 1990–1994 7a MA Ross 199332 British Columbia (1) — 8 MA Margherio 19972 Michigan (1) 1986–1996 9 MA Stilma 19974 Netherlands (11) 1988–1994 10 MA Bessant 199820 England (1) 1991–1995 11 MA Stenkula 19983 Sweden (2) 1994–1994 12 MA Watts 200011 Wales (1) 1995–1998 13 MA Al-Khaier 200125 England (1) 1993–1998 13a MA Wong 199733 England (1) 1993–1994 14 MA Oruc 200147 Missouri (1) 1990–1998 15 MA Hansson 200234 Sweden (1) 1997–2000 16 MA Yang 200235 Taiwan (2) 1992–1998 17 MA Scott 200336 Florida (1) 1990–2001 17a MA Moore 200337 Florida (1) 1990–2001 17b MA Kim 199438 Florida (1) 1990–1992 17c SR Vilar 199739 Florida (1) 1993–1995 17d SR Smiddy 200365 Florida (1) 1994–2001 17e SR Irvine 199266 Florida (1) 1991–1991 17f SR Kim 199649 Florida (1) 1990–1994 18 MA Stefaniotou 200340 Greece (1) — 19 MA van der Meulen 200412 Netherlands (1) 1996–2000 20 MA Ruiz-Moreno 200613 Spain (1) — 21 MA Ho SF 200715 England (1) 2000–2006 22 MA Merani 20076 Australia (1) 1998–2003 23 MA Romero-Aroca 20075 Spain (1) 1997–2005 24 MA Tajunisah 20078 Malaya (1) 2001–2005 25 MA Chen 200824 Taiwan (1) 2000–2006 26 MA Schaal 20091 Kentucky (2) 2000–2006 27 MA Ho LY 201041 Michigan (1) 2005–2008 28 SR Lambrou 199210 Florida (1) 1988–1990 29 SR Greve 199342 Louisiana (6) 1989–1992 30 SR Kapusta 199626 Quebec (1) 1991–1995 31 SR Terasaki 199714 Japan (1) 1995–1998 32 SR Boscher 199850 France (1) 1993–1996 33 SR Joondeph 199943 Michigan (1) — 34 SR Lu 199923 China (—) — 35 SR Yeo 19997 England (1) 1995–1996 36 SR Verma 200144 India (1) 1997–1999 37 SR Wilkinson 200160 Maryland (1) 1977–1999 38 SR Kwok 200227 Hong Kong (1) 1993–1999 39 SR Schwartz 200245 Texas (2) 1995–1999 40 SR Murat Uyar 200328 Turkey (1) 1998–2000 41 SR Greven 200429 North Carolina (2) 1994–2000 42 SR Kiss 200846 Massachusetts (1) 2007–2007 43 SR Ho LY 200948 Pennsylvania (1) 2001–2007

#L ϭ number of study locations; #PPV ϭ number of eyes that received a PPV; CS ϭ cataract surgery; FPY ϭ final patient year; IPY ϭ initial patient year; M ϭ mean; MA ϭ meta-analysis; Max ϭ maximum; Md ϭ median; Min ϭ minimum; PPV ϭ pars plana vitrectomy; PPV % ϭ percentage of eyes that received a PPV; — ϭ missing data; SR ϭ systematic review. aPatients in a study whose number includes a letter are a subset of the patients in the correspondingly numbered study (ie, patients in study 7a are also in study 7). bStudy identified by first author and publication year. Continued on next page

348 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 2011 TABLE 1. Description of Studies for Systematic Review and Meta-analysis of Vitrectomy Timing for Retained Lens Fragments (Continued)

# Eyes # PPV (PPV %) Patients’ Ages M/Md/Min/Max Days CS to PPV M/Md/Min/Max Follow-up (Months) M/Md/Min/Max

13 11 (85) —/—/27/88 —/—/—/— —/—/7/30 36 32 (89) —/—/—/— —/—/—/— 14/—/1/60 2 2 (100) —/81/75/86 —/50/45/55 —/5/—/— 6 6 (100) —/—/—/— —/14/2/480 23/—/6/50 65 56 (86) 73/—/40/90 —/—/—/— 20/—/—/— 21 21 (100) 68/—/39/86 —/20/0/10950 10/—/—/— 23 23 (100) 75/—/56/89 —/7/0/53 11/—/3/20 121 121 (100) 75/—/43/92 19/30/0/120 17/—/3/— 54 46 (85) 74/—/41/94 —/—/0/— 14/—/6/48 12 10 (83) 77/76/53/94 20/12/0/93 16/16/6/26 126 126 (100) 77/—/24/96 —/—/—/— 19/—/6/— 70 63 (90) 75/—/47/88 —/—/0/— —/—/3/— 44 34 (77) 68/—/20/87 —/—/0/105 7/—/1/26 19 19 (100) 76/79/58/89 21/20/0/60 11/8/0/24 18 18 (100) 74/76/62/87 10/5/0/77 14/12/6/34 89 89 (100) 77/—/47/94 —/15/0/357 6/—/1/60 19 19 (100) 64/—/—/— 29/20/2/192 —/—/2/— 85 85 (100) 74/—/—/— —/—/—/— 10/—/2/72 66 66 (100) —/80/41/94 —/3/0/255 —/8/0/30 25 24 (96) 70/72/40/90 25/17/0/97 10/6/3/44 343 343 (100) —/76/24/100 —/12/0/— —/8/1/96 343 343 (100) —/76/24/100 —/13/0/— —/8/1/96 62 62 (100) 75/—/51/91 —/—/0/365 —/—/—/— 126 126 (100) 74/—/40/94 —/—/0/225 12/—/1/36 101 101 (100) 76/—/—/— 22/8/0/366 14/9/3/82 4 4 (100) —/81/74/90 —/103/50/368 —/5/2/8 5 5 (100) —/77/73/84 —/17/5/198 —/10/3/21 26 26 (100) 67/—/59/90 —/—/—/— —/—/3/9 13 13 (100) 77/77/63/84 14/9/2/50 29/28/3/69 18 18 (100) 71/71/58/87 8/7/0/24 34/45/6/53 82 82 (100) —/78/48/85 —/—/—/— —/27/4/48 223 223 (100) 76/78/53/93 10/4/0/132 21/15/0/66 47 47 (100) 73/—/57/86 —/—/—/— 63/—/12/106 22 22 (100) 69/68/52/84 11/5/0/60 9/—/1/24 78 78 (100) 70/—/24/92 —/—/—/— 14/—/5/47 42 27 (64) 71/—/59/85 —/—/—/— 12/12/12/12 17 17 (100) 73/—/58/85 7/—/2/17 5/—/1/16 8 8 (100) 77/78/64/88 8/3/1/36 12/10/2/22 17 17 (100) 74/—/56/91 —/—/—/— 13/—/0/8 25 25 (100) 77/—/60/94 —/—/0/90 —/6/2/— 15 14 (93) 74/76/56/86 3/3/0/7 —/—/—/— 21 21 (100) 75/—/45/96 15/—/1/120 21/—/7/37 14 14 (100) —/—/42/90 —/—/1/56 —/—/—/— 3 3 (100) —/—/—/— —/—/—/3 —/—/—/— 22 22 (100) —/—/—/— —/—/0/97 —/—/3/9 24 24 (100) 54/—/40/77 29/—/0/99 —/—/3/— 135 135 (100) —/—/42/89 —/—/0/6935 —/—/—/— 27 27 (100) 74/—/54/85 10/—/0/70 31/—/3/60 26 26 (100) —/—/—/— —/6/1/77 6/6/6/6 43 43 (100) 65/—/46/79 15/—/0/90 8/—/2/27 42 42 (100) 73/73/39/89 —/—/—/— 30/25/6/— 6 6 (100) —/—/—/— 19/19/2/30 —/—/—/— 166 166 (100) —/75/37/98 —/4/0/139 20/—/3/69

VOL. 152,NO. 3 VITRECTOMY TIMING FOR RETAINED LENS FRAGMENTS:META-ANALYSIS 349 TABLE 2. Results of Systematic Review of Vitrectomy Timing for Retained Lens Fragments on Outcomesa

Study No.b Study IDc VA RD Pre RD Post IOP IOI CME CE

1 Fastenberg 199117 — — — E-nSS E-nSS — — 2 Blodi 199230 no infl — no infl E-SS E-nSS no infl no infl 3 Gilliland 199218 no infl — — no infl — — — 4 Pollet 199519 — — — E-nSS — — — 5 Tommila 199531 E-nSS — — E-nSS — — — 6 Borne 199621 E-nSS — — — — — — 7 Ross 199616 E-nSS — — E-nSS — — — 7a Ross 199332 no infl E-nSS E-nSS — — L-nSS — 8 Margherio 19972 E-nSS E-nSS no infl E-nSS no infl L-nSS no infl 9 Stilma 19974 E-nSS — — — — — — 10 Bessant 199820 E-nSS — E-nSS L-nSS — — — 11 Stenkula 19983 E-nSS — — no infl no infl — — 12 Watts 200011 E-nSS — — E-nSS E-nSS — — 13 Al-Khaier 200125 E-SS — — no infl — — — 13a Wong 199733 — — E-nSS — — — — 14 Oruc 200147 M-nSS — — — — — — 15 Hansson 200234 E-nSS — — no infl — — — 16 Yang 200235 E-nSS E-nSS — — E-nSS — — 17 Scott 200336 E-nSS — — E-nSS — — — 17a Moore 200337 — no infl E-nSS — — — — 17b Kim 199438 E-nSS — — E-nSS — — — 17c Vilar 199739 no infl — E-nSS no infl — — — 18 Stefaniotou 200340 E-nSS E-nSS E-nSS E-nSS no infl — — 19 van der Meulen 200412 M-nSS — — no infl — E-nSS — 20 Ruiz-Moreno 200613 no infl — no infl E-nSS — — — 21 Ho SF 200715 E-SS — E-nSS E-nSS — — — 22 Merani 20076 E-nSS E-nSS E-nSS no infl no infl E-nSS unclear 23 Romero-Aroca 20075 E-SS — — E-SS — E-SS — 24 Tajunisah 20078 no infl — — — — — — 25 Chen 200824 E-SS E-nSS E-nSS E-SS no infl E-nSS — 26 Schaal 20091 M-nSS Excl — E-nSS — no infl — 27 Ho LY 201041 no infl E-nSS — — — — — 28 Lambrou 199210 E-nSS — — — — — — 29 Greve 199342 — — — E-nSS — — — 30 Kapusta 199626 no infl — — — — — — 31 Terasaki 199714 E-nSS — — — — — — 32 Boscher 199850 L-nSS — — — — — — 33 Joondeph 199943 — — — E-nSS — — — 35 Yeo 19997 E-SS — — E-SS — — — 36 Verma 200144 E-nSS — — — — — — 38 Kwok 200227 no infl — — no infl — — — 39 Schwartz 200245 E-nSS — — — — — — 40 Murat Uyar 200328 no infl — — no infl — — — 41 Greven 200429 no infl — — — — — — 42 Kiss 200846 no infl — — E-nSS — — E-nSS 43 Ho LY 200948 unclear — unclear E-SS — unclear —

— ϭ no data provided and no estimate possible; CE ϭ corneal edema; CME ϭ cystoid macular edema; E-SS ϭ statistically significant result favoring early vitrectomy (Pb Յ .05); E-nSS ϭ nonsignificant result favoring early vitrectomy (.5 Ͼ Pb Ͼ .05); Excl ϭ patients excluded from analysis; IOI ϭ intraocular inflammation/infection; IOP ϭ increased intraocular pressure/glaucoma; L-nSS ϭ nonsignificant result favoring later vitrectomy (.5 Ͼ Pb Ͼ .05); M-nSS ϭ nonsignificant mixed results; no infl ϭ no influence of vitrectomy timing (Pb Ͼ .5); post ϭ after the PPV; pre ϭ before/during the PPV; RD ϭ retinal detachment; unclear ϭ unclear effect of vitrectomy timing (Pb Ͼ .5); VA ϭ visual acuity. aP values are approximate and may be based on the article and/or logistic regression estimates (which were done for the meta-analysis). bPatients in a study whose number includes a letter are a subset of the patients in the correspondingly numbered study (ie, patients in study 7a are also in study 7). cStudy identified by first author and publication year.

350 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 2011 TABLE 3. Final/Post-Vitrectomy Visual Acuity by Day of Vitrectomy (Days 0–7) for Retained Lens Fragmentsa

Day of Vitrectomy After Cataract Surgery Aggregated

Visual Acuityb 01234567TOTAL 0–2 3–7

Number of Patients Good 12 3936486 512427 Moderate 42642112 221210 Bad 74710110 21183 TOTAL 23 9 22 8 8 6 10 8 94 54 40 Percentage of Patients Good 52.2 33.3 40.9 37.5 75.0 66.7 80.0 75.0 44.4 67.5 Moderate 17.4 22.2 27.3 50.0 25.0 16.7 10.0 25.0 22.2 25.0 Bad 30.4 44.4 31.8 12.5 0.0 16.7 10.0 0.0 33.3 7.5

aData are from 12 articles3,8,10–14,32,33,35,41,46 that provided the necessary detailed individual patient data for this analysis. bVisual acuity (VA) good ϭ VA Ն/Ͼ0.5 or 20/40; VA moderate ϭ VA 0.5 to 0.1 or 20/40 to 20/200; VA bad ϭ VA Յ/Ͻ0.1 or 20/200.

FIGURE 2. Forest plot for not good visual acuity (

acuity, with days 3 through 7 having more good and fewer more days (on average, for grouped data) after cataract bad results (Mantel-Haenszel ␹2 test for trend,57 P ϭ .006). surgery. The hypothesis of a constant odds ratio from one Table 3 also shows these data aggregated into days 0 week to the next, for each additional 1 week of vitrectomy through 2 and 3 through 7, which also indicated a delay, would not have been valid if data for the eye’s signiﬁcant trend toward better visual acuity outcomes for recovery time remained in the analysis. vitrectomies on days 3 through 7 (Mantel-Haenszel ␹2 test for trend, P ϭ .004). Based on this analysis, days 0 through Power analysis. Many authors indicted that nonsignif- 2 were considered as recovery time, and the meta-analysis icant results might have been attributable to small was limited to patients who received a vitrectomy 3 or samples and low power, but no author reported a power

VOL. 152,NO. 3 VITRECTOMY TIMING FOR RETAINED LENS FRAGMENTS:META-ANALYSIS 351 TABLE 4. Meta-analysis Results of Vitrectomy Timing (Day 3 Post Cataract Surgery and Later) for Retained Lens Fragments

OR From OR CI OR CI Total # First Week First 3 Weeksa First 3 Weeksa Adverse Outcomeb # Studies MA Low High P Value I-Squared Eyes PERR PERR NNT

VA not good 22 1.13 1.04 1.22 0.005 36.2 1272 4.5% 13.8% 8 VA bad 16 1.05 1.01 1.09 0.009 0.0 1007 0.9% 2.7% 37 RD - pre-PPV 7 1.29 1.01 1.65 0.038 76.6 737 1.1% 4.2% 24 RD - post-PPV 11 1.13 1.02 1.26 0.024 22.1 861 0.7% 2.4% 43 IOP/glaucoma 18 1.23 1.07 1.41 0.003 59.0 992 3.3% 11.2% 9 IOI 7 1.20 1.01 1.42 0.041 0.0 230 1.2% 4.2% 25 CME 7 1.05 0.74 1.49 0.770 20.7 347 NI: MA results not signiﬁcant Corneal edema 2 1.09 0.88 1.35 0.434 0.0 165 NI: MA results not signiﬁcant Composite adverse event (any 1 of 5 events: not good VA, pre-/post-PPV RD, IOP, and/or IOI) 10.3% 31.4% 4

CI ϭ confidence interval; CME ϭ cystoid macular edema; I-squared ϭ a measure of heterogeneity; IOI ϭ intraocular infection/inflammation; IOP ϭ increased intraocular pressure/glaucoma; MA ϭ meta-analysis; NI ϭ not included; NNT ϭ number needed to treat to avoid 1 additional adverse outcome; OR ϭ odds ratio; PERR ϭ positive event reduction rate (indicates the decrease in the percentage of patients without an adverse event); post ϭ after PPV; PPV ϭ pars plana vitrectomy; pre ϭ before/during PPV; RD ϭ retinal detachment; VA ϭ visual acuity; VA not good ϭ VA Յ/Ͻ0.5 or 20/40; VA bad ϭ VA Յ/Ͻ0.1 or 20/200. aApproximate average wait time before PPV (after a 3-day wait for the eye to recover from cataract surgery). bAll outcomes are post-PPV or final, except as noted.

FIGURE 3. Estimated decrease in the number of positive outcomes with increased waiting time before vitrectomy for crystalline visual acuity, good VA (>/>0.5 or 20/40), bad ؍ retained lens fragments (RLF), for a hypothetical cohort of 1000 patients. VA ؍ after the vitrectomy; IOP ؍ before/during the vitrectomy; post ؍ retinal detachment; pre ؍ VA (

analysis. Each study’s power for comparing outcomes was Quality analysis. No study in the meta-analysis was estimated,57 and the results (mean ϭ 23%, median ϭ prospective or randomized, but unbiased inclusion/exclu- 13%) indicated that, indeed, many studies had low sion criteria were clearly described. Data collection was power. not masked since all who assessed outcomes and risk

352 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 2011 factors were aware of treatment status, but all risk factors Analyses of biases. There was little evidence of publica- were recorded before outcomes occurred in medical re- tion bias since many small studies with nonsignificant cords, which lack research biases.58 In 19 of 27 studies results were published. However, studies exhibited report- (70%), patients were a consecutive series (a representative ing bias, and it is possible that authors were more likely to sample),41 and 24 studies (89%) stated years of service. In report significant results. Data availability for the 27 24 studies (89%), patients’ characteristics at presentation meta-analysis studies ranged from 22 (82%) for not good were reported, but only 7 studies (26%) reported pre- visual acuity; 18 (67%) for increased IOP; 16 (59%) for existing ocular comorbidities. In 25 studies (93%), all bad visual acuity; 11 (41%) for postvitrectomy RD; and 7 patients were accounted for, while reasons were given for (26%) for previtrectomy RD, intraocular inflammation/ all lost/excluded patients in 26 studies (96%), but in only infection, and CME to 2 (7%) for corneal edema, with 20 studies (74%) was information reported on all patients overall availability of 42%. Also, there were 12 studies in excluded for missing data or lost to follow-up. In 19 studies the systematic review and 9 that passed the initial screen, (70%), authors indicated their criteria for treatment each with more than 10 patients, that did not report choice and/or vitrectomy timing, but in only 13 studies useable timing data for any outcome. (48%) was a standardized assessment of outcomes specified The “trim & fill” estimates’ revised odds ratios (data not and actual probabilities reported. shown) for the significant effects were not appreciably Using the Minckler54 evidence-based rating system, for different from the actual results (in Table 4) and still clinical importance 23 studies were rated A, 1 rated B, and suggested that early vitrectomy produced better outcomes. 2 rated C; and for strength of evidence all were rated III The “fail safe N” analysis’s number of additional, nonre- (weak). One study reported data for all 8 outcomes, 2 for porting studies, which would have needed to report neutral 6 outcomes, 3 for 5 outcomes, 5 for 4 outcomes, 4 for 3 results for the meta-analysis to indicate that there was no outcomes, 9 for 2 outcomes, and 3 for 1 outcome. Three vitrectomy timing effect,52 for each outcome was 17 of 35 studies had an average follow-up time between 3 and 6 (49%) for bad visual acuity, 27 of 44 (61%) for pre-PPV months, 11 between 6 and 12 months, 9 between 12 and RD, 29 of 40 (73%) for post-PPV RD, and 3 of 44 (7%) for 24 months, and 4 greater than 24 months. intraocular inflammation/infection. For good visual acuity and increased IOP, there were not enough nonreporting ● META-ANALYSIS: The 27 studies with data for the studies to change the results to indicate that there was no meta-analysis included 1730 vitrectomized eyes. Results vitrectomy timing effect.52 indicated that earlier vitrectomy (day 3ϩ post cataract Therefore, for publication and reporting bias, only the surgery) may be better for all outcomes, with significant intraocular inflammation/infection outcome result was effects for not good visual acuity (odds ratio: 1.13; 95% CI: tenuous. Seven studies reported these results, but the “trim 1.04–1.22; P ϭ .005); bad visual acuity (odds ratio: 1.05; & fill” analysis added 4 studies, reducing the estimated 95% CI: 1.01–1.09; P ϭ .009); previtrectomy RD (odds effect of intraocular inflammation/infection from 1.20 to ratio: 1.29; 95% CI: 1.01–1.65, P ϭ .038); postvitrectomy 1.11. The “fail safe N” was 3, so only 7% of the nonre- RD (odds ratio: 1.13; 95% CI: 1.02–1.26; P ϭ .024); porting studies would have needed to be neutral for the increased IOP (odds ratio: 1.23; 95% CI: 1.07–1.41; P ϭ meta-analysis to have indicated that there was no intraoc- .003); and intraocular inflammation/ infection (odds ratio: ular inflammation/infection PPV timing effect. However, 1.20; 95% CI: 1.01–1.42; P ϭ .041). Effects for CME (odds even if the intraocular inflammation/infection effect had ratio: 1.05; 95% CI: 0.74–1.49; P ϭ .770) and corneal not been significant, the overall results and conclusions of edema (odds ratio: 1.09; 95% CI: 0.88–1.35; P ϭ .434) this meta-analysis would not have changed. were not significant. Figure 2 shows a sample forest plot summarizing the results of a meta-analysis. Heterogeneity and subgroup analysis. We attempted to The last line in Table 4 represents a composite of 5 explain the summary effects’ (odds ratios) observed heter- adverse events: not good visual acuity, pre-PPV RD, ogeneity (I-squared Ͼ 0, Table 4) with subgroup analyses post-PPV RD, increased IOP, and intraocular inflamma- and meta-regressions,52 but none proved satisfactory. Sub- tion/infection. The model estimated that, at day 3 group analysis did indicate larger effects for studies that post-cataract surgery, a 1-week vitrectomy delay in- included eyes with only nuclear lens material (as opposed creases the probability of a patient’s experiencing 1 or to studies that also included eyes with cortical material),13 more adverse events by 10.3%; and that if no vitrecto- with significant differences only for increased IOP mies were delayed past 3 days (mean delay ϭ 3ϩ weeks), (P ϭ .006), but also marginally significant differences for the composite adverse event rate would decrease by not good visual acuity (P ϭ .105) and bad visual acuity 31.4%. This indicates a number needed to treat57 of (P ϭ .062). only 4 patients. For a hypothetical cohort of 1000, for all outcomes with significant effects, Figure 3 displays Sensitivity analyses. We assessed the decision to deter- positive outcomes decreasing with greater vitrectomy mine the effect of delaying vitrectomy, beginning with day delay. 3 post-cataract surgery, by adding vitrectomies performed

VOL. 152,NO. 3 VITRECTOMY TIMING FOR RETAINED LENS FRAGMENTS:META-ANALYSIS 353 on day 2 back into the analysis. Results were less favorable others’ were not as good4,31 (data not shown). Reasons for for early vitrectomy, confirming that the eye was typically this dichotomy were unclear, and further studies are still recovering on day 2. Additionally, a 1-study-removed necessary. analysis assessed how the results would change if a single There were indications that the first few days after study had been omitted:52 for not good VA, bad VA, and cataract surgery were not optimal for a vitrectomy, and increased IOP, the significance of the estimated effects that this time should be avoided, except when any delay is remained robust, but for RD (pre- and postvitrectomy) and impossible.17,19,20,23 Scott recommended waiting until the intraocular inflammation/infection, removing any 1 of 4 cornea clears.36 Recovery from cataract surgery can im- studies resulted in a nonsignificant effect. Also, in the prove the vitreoretinal surgeon’s view of the posterior highly unlikely scenario that all significant effects were at segment and reduce the chance of choroidal hemorrhage the low end of their confidence intervals, the model still (Bolt HC, personal communication, 2004). We found that estimated that a 1-week vitrectomy delay would increase PPV performed 0 to 2 days after cataract surgery (elimi- the probability of a patient’s experiencing 1 or more of the nated from this meta-analysis) produced inferior outcomes 5 adverse events (Table 4) by 3.2%, and estimated a compared with days 3 to 7 (Table 3), and concur with composite adverse event rate decrease of 9.6% if no existing recommendations that, except when a SD-PPV is vitrectomies were delayed. These sensitivity analyses indi- possible, PPV be delayed until the eye has recovered from cated that this study’s conclusions were generally robust. cataract surgery.8,17,20,23 Many previously published vitrectomy timing analyses did not achieve statistical significance (often reported as indicat- DISCUSSION ing no effect) when, in fact, there were many nonsignificant effects in favor of early vitrectomy1–6,10–17,19–21,24,30–47 and WHEN CONFRONTED WITH A PATIENT’S RETAINED LENS very few in favor of later vitrectomy2,20,32,47,50 (Table 2). fragments, a vitreoretinal surgeon must decide whether to With so many studies and outcomes, a few nonsignificant attempt medical management or when to schedule a results, in favor of later vitrectomy, could occur by chance, vitrectomy, often depending on how the eye has re- even if early vitrectomy were actually the better option. In acted.20,59 Authors indicated that worse post–cataract addition, studies may not have achieved statistically sig- surgery complications such as poor VA, retinal tears or nificant results in favor of early vitrectomy for several detachment, increased IOP, intraocular inflammation/in- reasons, including small samples and the fact that patients’ fection, CME, and a larger percentage of the crystalline results were grouped into discrete time periods (eg, 0-7 lens retained were criteria for vitrectomy, and that patients days, 8-30 days), which might have masked differences in with these complications were more likely to receive a outcomes within these time periods. One limitation of this prompt referral and/or an early PPV.1,2,4,6,7,16–18,29,31–36,39 meta-analysis was that most studies’ data were presented in Although there is no consensus on the optimal time for a these discrete time periods, which limited the model’s PPV,1,5–7 several sites have established clinical guide- precision. lines,3,4,13,20,21,31,36,45 generally for early vitrectomy within Therefore, these meta-analyses’ results do not indicate 1 to 2 weeks, and this meta-analysis supports those guide- that a vitrectomy on day 3 post-cataract surgery alone is lines when a PPV is necessary. optimal, because day-3 outcomes cannot be distinguished Studies have shown that some eyes may be successfully from outcomes for days 4 through 7, since these times were managed with medical therapy alone.1,17,32 Anti-inflam- usually grouped together. Therefore, we conclude that the matory medications and aqueous suppressants successfully optimal timing for vitrectomy may begin 3 days after control intraocular inflammation and pressure, in the short cataract surgery and extend through day 7. Also, outcomes term, in most eyes,36 and some eyes with retained lens for days 8 through 30 tended to be grouped together, so it fragments can maintain good VA without major compli- is possible that week-2 results are more like days 3 through cations with these medications indefinitely.1,6,32 This 7 than like weeks 3 and 4. meta-analysis was limited to eyes that surgeons determined The reasons that vitrectomy on days 3 through 7 required vitrectomy, and did not include eyes managed indicated superior results are not entirely clear. However, exclusively with medical therapy. Further studies are nec- macrophage-related inflammation, an important risk factor essary to determine under what circumstances medical for increased IOP and prolonged uveitis, are reported to therapy for retained lens fragments should be considered. begin after day 3.7,60 This could help explain why, al- One issue among vitreoretinal surgeons is whether or though a few days’ delay is acceptable to allow the eye to not to perform a vitrectomy on the same day as the recover from cataract surgery,8,9,35,36 shortly after that, cataract surgery. Same-day vitrectomy (SD-PPV) has been before the immunologic response becomes advanced,43,60 recommended by some,8,19,23 but others indicated that the could be the optimal time for a vitrectomy. cataract surgery anesthesia may make this difficult.3,5 Other limitations of this study include English-only Interestingly, when examining results for SD-PPV, we articles and that many studies did not report data for all 8 found that some facilities had good VA results while outcomes. Data that are more precise (providing patient-

354 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 2011 level detail and the exact time between cataract surgery Overall, despite this selection bias, results indicated, for and vitrectomy) and complete (for all patients and out- early vitrectomy: 1) 6 statistically significantly better comes including other pre- and postvitrectomy outcomes outcomes (good VA, bad VA, previtrectomy RD, post- not considered here) could be analyzed to gain a more vitrectomy RD, increased IOP, and intraocular inflam- thorough understanding of the prognosis and treatment of mation/infection); 2) effects that were generally robust; retained lens fragments. With such data, future studies and 3) a clinically significant composite effect. There- could attempt to 1) provide a more precise estimate of fore, for patients who did not receive a same-day optimal vitrectomy timing, 2) explore the dichotomy in vitrectomy, this meta-analysis indicates that the best same-day vitrectomy results to determine when a same-day time to remove retained lens fragments might be during vitrectomy might be performed, and 3) compare medically the latter part of the first week (days 3-7), although the managed and surgically managed patients to determine possibility of the second week cannot be eliminated. when medical management might be considered. Earlier vitrectomy might improve visual acuity out- All of these studies were retrospective interventional comes and reduce rates of RD, increased IOP, and case series, which is a weaker level of evidence than is intraocular inflammation/infection. often included in a meta-analysis.61 Therefore, these meta- We believe that vitreoretinal surgeons have known (or analysis results should not be interpreted as if they were at least strongly suspected) these results for many years. based on randomized controlled trials, which provide the Recommendations for early vitrectomy are repeated preferred and highest level of evidence.61 However, no throughout the literature19,36 even by authors with non- randomized controlled trials about retained lens fragments, assessing the effect of vitrectomy timing on outcomes, were significant results. However, for vitreoretinal surgeons to found, although we concur with the many authors who adopt this strategy of early vitrectomy, several things called for one.9,20,24,28,35 Notwithstanding, data from ret- would need to occur: 1) corneal edema must have suffi- rospective interventional case series studies can be valu- ciently cleared to allow unimpeded visualization of the able for meta-analyses because such studies’ outcomes were vitreous and retina, 2) the patient must not have devel- not defined or assessed for research purposes, but were oped a complication (eg, endophthalmitis or early retinal conditions with objective, standard assessments, recorded detachment) that required an immediate vitrectomy before before the study in a patient’s record, as part of contempo- day 3, and 3) the cataract surgeon must have referred the rary ophthalmologic practice. This would reduce informa- patient in a timely manner to a vitreoretinal surgeon for tion and observer biases and patient misclassification, evaluation.3,4,9,22,31 We hope that this systematic review which sometimes occur during research studies.58 and meta-analysis has brought some order to the multitude Also, the widely acknowledged selection bias favoring of individual, seemingly conflicting statistics, from so many later vitrectomy6,9,22,36,50 was consistent among studies. separate studies.

THE AUTHORS INDICATE NO FUNDING SUPPORT. M.W.S. REPORTS RESEARCH SUPPORT FROM REGENERON, TARRYTOWN, New York; Alcon, Fort Worth, Texas; and Bayer, Leverkusen, Germany. Involved in design (E.A.V.) and conduct of the study (E.A.V., M.W.S.); collection (E.A.V.), management (E.A.V.), analysis (E.A.V., M.W.S.), and interpretation of the data (E.A.V., M.W.S.); and preparation (E.A.V.), review (E.A.V., M.W.S.), or approval (E.A.V., M.W.S.) of the manuscript. This study adhered to the tenets of the Declaration of Helsinki and all state and federal laws of the United States of America. The authors conﬁrm that they are in compliance with their Institutional Review Boards and HIPAA requirements. IRB approval and informed consent are not required for a systematic review and meta-analysis and was not sought for this manuscript.

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VOL. 152,NO. 3 VITRECTOMY TIMING FOR RETAINED LENS FRAGMENTS:META-ANALYSIS 357 APPENDIX: SEARCH METHODS TO 8. “visual acuity” IDENTIFY STUDIES (MEDLINE/PUBMED) 9. “visual outcome” FOR “VITRECTOMY TIMING FOR 10. “retinal detachment” RETAINED LENS FRAGMENTS AFTER 11. “retina detachment” SURGERY FOR AGE-RELATED 12. “glaucoma” CATARACTS: A SYSTEMATIC REVIEW 13. “intraocular pressure” AND META-ANALYSIS” 14. “intra-ocular pressure” 15. “intra-ocular inflammation” November 1, 2009: Initial Search 16. “intraocular inflammation” 1. “retained lens” 17. “uveitis” 2. “dropped nucleus” 18. “vitritis” 3. “dislocated lens” 19. “AC inflammation” 4. “intravitreal lens” 20. “anterior chamber inflammation” 5. “posterior dislocation of lens” 21. “intraocular infection” 6. #1 OR #2 OR #3 OR #4 OR #5 22. “intra-ocular infection” Limits: English, January 1, 1985 (year of the initial journal 23. “endophthalmitis” article on this subject) to October 31, 2009, with updates 24. “hypopyon” weekly through the “My NCBI” service of PUBMED. 25. “corneal edema” Outcomes were not included based on recommendations 26. “cornea edema” for search strategies in the Cochrane Handbook for Sys- 27. “cystoid macular edema” tematic Review of Interventions.63 28. #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 January 30, 2010: Second Search36 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 1. “lens fragments” OR #27 2. “dropped nuclei” 29. #7 AND #28 3. “retained nuclei” 4. “nuclear fragments” Limits: English, January 1, 1985 through July 30, 2010. 5. “lens dislocation” Outcomes were included here because the term “nuclear 6. “lens material” fragments” returned too many nonrelevant studies about 7. #1 OR #2 OR #3 OR #4 OR #5 OR #6 cell nuclei.

357.e1 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 2011 Biosketch

Elizabeth Vanner graduated from Harvard College with a degree in biochemistry and Harvard School of Public Health with an MS in Biostatistics, Health Policy & Management. She is Vice Chair and Clinical Assistant Professor, Department of Health Care Policy and Management and earning a PhD in Clinical Outcomes Research, Department of Preventive Medicine, School of Medicine; Health Sciences Center, Stony Brook University, Stony Brook, NY. Her interests include biostatistics and clinical outcomes research in ophthalmology. (Photo by Jeanne Neville).

VOL. 152,NO. 3 VITRECTOMY TIMING FOR RETAINED LENS FRAGMENTS:META-ANALYSIS 357.e2 Biosketch

Michael W. Stewart graduated from Harvard College with a degree in chemistry and received his medical degree from McGill University, Montreal, Quebec. He completed his residency at Emory University and vitreoretinal fellowships at Touro Inﬁrmary in New Orleans and the University of California, Davis. He is Assistant Professor of Ophthalmology and Chairman of Ophthalmology at the Mayo Clinic in Jacksonville, Florida. His research interests include pharmacokinetics, and the treatment of retinal vascular diseases and infectious retinopathies.

357.e3 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 2011