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Figure 1.
PRISMA Flowchart of Identification and Screening of Studies
PRISMA Flowchart of Identification and Screening of Studies
Figure 2.
Forest Plots of Risk for Death With Anti–Vascular Endothelial Growth Factor (VEGF) Treatment
Forest Plots of Risk for Death With Anti–Vascular Endothelial Growth Factor (VEGF) Treatment

Different data marker sizes indicate weight. See Table 1 for definition of the abbreviations.

Table 1.  
Characteristics of Included Studiesa
Characteristics of Included Studiesa
Table 2.  
Summary of the Main Findingsa
Summary of the Main Findingsa
1.
Solomon  SD, Lindsley  K, Vedula  SS, Krzystolik  MG, Hawkins  BS.  Anti–vascular endothelial growth factor for neovascular age-related macular degeneration.  Cochrane Database Syst Rev. 2014;8:CD005139.PubMedGoogle Scholar
2.
Virgili  G, Parravano  M, Menchini  F, Evans  JR.  Anti–vascular endothelial growth factor for diabetic macular oedema.  Cochrane Database Syst Rev. 2014;10:CD007419.PubMedGoogle Scholar
3.
Jampol  LM, Bressler  NM, Glassman  AR.  Revolution to a new standard treatment of diabetic macular edema.  JAMA. 2014;311(22):2269-2270.PubMedGoogle ScholarCrossref
4.
Braithwaite  T, Nanji  AA, Lindsley  K, Greenberg  PB.  Anti–vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion.  Cochrane Database Syst Rev. 2014;5:CD007325.PubMedGoogle Scholar
5.
Mintz-Hittner  HA, Kennedy  KA, Chuang  AZ; BEAT-ROP Cooperative Group.  Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity.  N Engl J Med. 2011;364(7):603-615.PubMedGoogle ScholarCrossref
6.
Ranpura  V, Hapani  S, Chuang  J, Wu  S.  Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials.  Acta Oncol. 2010;49(3):287-297.PubMedGoogle ScholarCrossref
7.
Schutz  FA, Je  Y, Azzi  GR, Nguyen  PL, Choueiri  TK.  Bevacizumab increases the risk of arterial ischemia: a large study in cancer patients with a focus on different subgroup outcomes.  Ann Oncol. 2011;22(6):1404-1412.PubMedGoogle ScholarCrossref
8.
Rosenfeld  PJ, Brown  DM, Heier  JS,  et al; MARINA Study Group.  Ranibizumab for neovascular age-related macular degeneration.  N Engl J Med. 2006;355(14):1419-1431.PubMedGoogle ScholarCrossref
9.
Heier  JS, Brown  DM, Chong  V,  et al; VIEW 1 and VIEW 2 Study Groups.  Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration.  Ophthalmology. 2012;119(12):2537-2548.PubMedGoogle ScholarCrossref
10.
Brown  DM, Nguyen  QD, Marcus  DM,  et al; RIDE and RISE Research Group.  Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE.  Ophthalmology. 2013;120(10):2013-2022.PubMedGoogle ScholarCrossref
11.
Nguyen  QD, Brown  DM, Marcus  DM,  et al; RISE and RIDE Research Group.  Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE.  Ophthalmology. 2012;119(4):789-801.PubMedGoogle ScholarCrossref
12.
Korobelnik  JF, Do  DV, Schmidt-Erfurth  U,  et al.  Intravitreal aflibercept for diabetic macular edema.  Ophthalmology. 2014;121(11):2247-2254.PubMedGoogle ScholarCrossref
13.
Do  D. VIVID/VISTA for DME: two-year results. PowerPoint presented at: 2014 American Academy of Ophthalmology Meeting; October 14, 2014; Chicago, IL.
14.
Preiss  D, Sattar  N, McMurray  JJ.  A systematic review of event rates in clinical trials in diabetes mellitus: the importance of quantifying baseline cardiovascular disease history and proteinuria and implications for clinical trial design.  Am Heart J. 2011;161(1):210-219.e1.PubMedGoogle ScholarCrossref
15.
Ford  JA, Lois  N, Royle  P, Clar  C, Shyangdan  D, Waugh  N.  Current treatments in diabetic macular oedema: systematic review and meta-analysis.  BMJ Open. 2013;3(3):e002269.PubMedGoogle ScholarCrossref
16.
Mitry  D, Bunce  C, Charteris  D.  Anti–vascular endothelial growth factor for macular oedema secondary to branch retinal vein occlusion.  Cochrane Database Syst Rev. 2013;1:CD009510.PubMedGoogle Scholar
17.
Ueta  T, Noda  Y, Toyama  T, Yamaguchi  T, Amano  S.  Systemic vascular safety of ranibizumab for age-related macular degeneration: systematic review and meta-analysis of randomized trials.  Ophthalmology. 2014;121(11):2193-2203.e1, 7.PubMedGoogle ScholarCrossref
18.
Avery  RL, Francom  S, Lai  P, Melson  C, Cha  SB, Tuomi  L.  Meta-analysis examining the systemic safety profile of intravitreal ranibizumab injections in AMD, RVO and DME [ARVO Abstract].  Invest Ophthalmol Vis Sci. 2013;54:1535.Google ScholarCrossref
19.
Thulliez  M, Angoulvant  D, Le Lez  ML,  et al.  Cardiovascular events and bleeding risk associated with intravitreal antivascular endothelial growth factor monoclonal antibodies: systematic review and meta-analysis.  JAMA Ophthalmol. 2014;132(11):1317-1326.PubMedGoogle ScholarCrossref
20.
Yanagida  Y, Ueta  T.  Systemic safety of ranibizumab for diabetic macular edema: meta-analysis of randomized trials.  Retina. 2014;34(4):629-635.PubMedGoogle ScholarCrossref
21.
Avery  RL, Castellarin  AA, Steinle  NC,  et al.  Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD.  Br J Ophthalmol. 2014;98(12):1636-1641.PubMedGoogle ScholarCrossref
22.
Chakravarthy  U, Harding  SP, Rogers  CA,  et al; IVAN Study Investigators.  Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial.  Ophthalmology. 2012;119(7):1399-1411.PubMedGoogle ScholarCrossref
23.
Wang  X, Sawada  T, Sawada  O, Saishin  Y, Liu  P, Ohji  M.  Serum and plasma vascular endothelial growth factor concentrations before and after intravitreal injection of aflibercept or ranibizumab for age-related macular degeneration.  Am J Ophthalmol. 2014;158(4):738-744.e1.PubMedGoogle ScholarCrossref
24.
Zehetner  C, Kralinger  MT, Modi  YS,  et al.  Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age-related macular degeneration: a randomised, prospective trial.  Acta Ophthalmol. 2015;93(2):e154-e159.PubMedGoogle ScholarCrossref
25.
Harding  SP. IVAN outcomes [abstract]. Presented at: 2013 Meeting of the Association for Research in Vision and Ophthalmology; May 7, 2013; Seattle, WA.
26.
Yoshida  I, Shiba  T, Taniguchi  H,  et al.  Evaluation of plasma vascular endothelial growth factor levels after intravitreal injection of ranibizumab and aflibercept for exudative age-related macular degeneration.  Graefes Arch Clin Exp Ophthalmol. 2014;252(9):1483-1489.PubMedGoogle ScholarCrossref
27.
Bressler  NM, Boyer  DS, Williams  DF,  et al.  Cerebrovascular accidents in patients treated for choroidal neovascularization with ranibizumab in randomized controlled trials.  Retina. 2012;32(9):1821-1828.PubMedGoogle Scholar
28.
Antiplatelet Trialists’ Collaboration.  Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients.  BMJ. 1994;308(6921):81-106.PubMedGoogle ScholarCrossref
29.
Higgins  JPT, Altman  DG, Sterne  JAC; Cochrane Statistical Methods Group. Cochrane Bias Methods Group, eds. Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0. Updated March 2011. http://handbook.cochrane.org. Accessed June 28, 2015.
30.
Guyatt  GH, Oxman  AD, Vist  GE,  et al; GRADE Working Group.  GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.  BMJ. 2008;336(7650):924-926.PubMedGoogle ScholarCrossref
31.
Deeks  JJHJ, Altman  DG; Cochrane Statistical Methods Group, eds. Analysing data and undertaking meta-analyses. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Updated March 2011. http://handbook.cochrane.org. Accessed June 28, 2015.
32.
Paccola  L, Costa  RA, Folgosa  MS, Barbosa  JC, Scott  IU, Jorge  R.  Intravitreal triamcinolone versus bevacizumab for treatment of refractory diabetic macular oedema (IBEME study).  Br J Ophthalmol. 2008;92(1):76-80.PubMedGoogle ScholarCrossref
33.
Faghihi  H, Roohipoor  R, Mohammadi  SF,  et al.  Intravitreal bevacizumab versus combined bevacizumab-triamcinolone versus macular laser photocoagulation in diabetic macular edema.  Eur J Ophthalmol. 2008;18(6):941-948.PubMedGoogle Scholar
34.
Ahmadieh  H, Ramezani  A, Shoeibi  N,  et al.  Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema: a placebo-controlled, randomized clinical trial.  Graefes Arch Clin Exp Ophthalmol. 2008;246(4):483-489.PubMedGoogle ScholarCrossref
35.
Soheilian  M, Ramezani  A, Obudi  A,  et al.  Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema.  Ophthalmology. 2009;116(6):1142-1150.PubMedGoogle ScholarCrossref
36.
Nguyen  QD, Shah  SM, Khwaja  AA,  et al; READ-2 Study Group.  Two-year outcomes of the Ranibizumab for Edema of the Macula in Diabetes (READ-2) study.  Ophthalmology. 2010;117(11):2146-2151.PubMedGoogle ScholarCrossref
37.
Elman  MJ, Bressler  NM, Qin  H,  et al; Diabetic Retinopathy Clinical Research Network.  Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.  Ophthalmology. 2011;118(4):609-614.PubMedGoogle ScholarCrossref
38.
Sultan  MB, Zhou  D, Loftus  J, Dombi  T, Ice  KS; Macugen 1013 Study Group.  A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema.  Ophthalmology. 2011;118(6):1107-1118.PubMedGoogle ScholarCrossref
39.
Lim  JW, Lee  HK, Shin  MC.  Comparison of intravitreal bevacizumab alone or combined with triamcinolone versus triamcinolone in diabetic macular edema: a randomized clinical trial.  Ophthalmologica. 2012;227(2):100-106.PubMedGoogle ScholarCrossref
40.
Soheilian  M, Garfami  KH, Ramezani  A, Yaseri  M, Peyman  GA.  Two-year results of a randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus laser in diabetic macular edema.  Retina. 2012;32(2):314-321.PubMedGoogle ScholarCrossref
41.
Rajendram  R, Fraser-Bell  S, Kaines  A,  et al.  A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3.  Arch Ophthalmol. 2012;130(8):972-979.PubMedGoogle Scholar
42.
Elman  MJ, Qin  H, Aiello  LP,  et al; Diabetic Retinopathy Clinical Research Network.  Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results.  Ophthalmology. 2012;119(11):2312-2318.PubMedGoogle ScholarCrossref
43.
Sivaprasad  S, Crosby-Nwaobi  R, Esposti  SD,  et al.  Structural and functional measures of efficacy in response to bevacizumab monotherapy in diabetic macular oedema: exploratory analyses of the BOLT study (report 4).  PLoS One. 2013;8(8):e72755.PubMedGoogle ScholarCrossref
44.
Nepomuceno  AB, Takaki  E, Paes de Almeida  FP,  et al.  A prospective randomized trial of intravitreal bevacizumab versus ranibizumab for the management of diabetic macular edema.  Am J Ophthalmol. 2013;156(3):502-510.e2.PubMedGoogle ScholarCrossref
45.
Lang  GE, Berta  A, Eldem  BM,  et al; RESTORE Extension Study Group.  Two-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema: interim analysis of the RESTORE extension study.  Ophthalmology. 2013;120(10):2004-2012.PubMedGoogle ScholarCrossref
46.
Comyn  O, Sivaprasad  S, Peto  T,  et al.  A randomized trial to assess functional and structural effects of ranibizumab versus laser in diabetic macular edema (the LUCIDATE study).  Am J Ophthalmol. 2014;157(5):960-970.PubMedGoogle ScholarCrossref
47.
Ip  MS, Domalpally  A, Hopkins  JJ, Wong  P, Ehrlich  JS.  Long-term effects of ranibizumab on diabetic retinopathy severity and progression.  Arch Ophthalmol. 2012;130(9):1145-1152.PubMedGoogle ScholarCrossref
48.
Wells  JA, Glassman  AR, Ayala  AR,  et al; Diabetic Retinopathy Clinical Research Network.  Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.  N Engl J Med. 2015;372(13):1193-1203.PubMedGoogle ScholarCrossref
49.
Schmidt-Erfurth  U, Lang  GE, Holz  FG,  et al; RESTORE Extension Study Group.  Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study.  Ophthalmology. 2014;121(5):1045-1053.PubMedGoogle ScholarCrossref
50.
Virgili  G, Parravano  M, Menchini  F, Brunetti  M.  Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for diabetic macular oedema.  Cochrane Database Syst Rev. 2012;12:CD007419.PubMedGoogle Scholar
51.
Kitchens  J. Systematic review of safety across the phase 2 and 3 clinical trials of intravitreal aflibercept injection in neovascular age-related macular degeneration, macular edema following retinal vein occlusion, and diabetic macular edema. Poster presented at: 2015 Meeting of the Association for Research in Vision and Ophthalmology; May 6, 2015; Denver, CO.
52.
Avery  RL.  What is the evidence for systemic effects of intravitreal anti-VEGF agents, and should we be concerned?  Br J Ophthalmol. 2014;98(suppl 1):i7-i10.PubMedGoogle ScholarCrossref
53.
Boyer  D. Systemic safety of intravitreal anti-VEGF therapy in select patient populations. Paper presented at: 46th Annual Scientific Meeting of the Retina Society; September 28, 2013; Beverly Hills, CA.
54.
Bekelman  JE, Li  Y, Gross  CP.  Scope and impact of financial conflicts of interest in biomedical research: a systematic review.  JAMA. 2003;289(4):454-465.PubMedGoogle ScholarCrossref
55.
Chakravarthy  U, Harding  SP, Rogers  CA,  et al; IVAN Study Investigators.  Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.  Lancet. 2013;382(9900):1258-1267.PubMedGoogle ScholarCrossref
56.
Elman  MJ, Ayala  A, Bressler  NM,  et al; Diabetic Retinopathy Clinical Research Network.  Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results.  Ophthalmology. 2015;122(2):375-381.PubMedGoogle ScholarCrossref
Original Investigation
January 2016

Systemic Safety of Prolonged Monthly Anti–Vascular Endothelial Growth Factor Therapy for Diabetic Macular EdemaA Systematic Review and Meta-analysis

Author Affiliations
  • 1California Retina Consultants and Research Foundation, Santa Barbara
JAMA Ophthalmol. 2016;134(1):21-29. doi:10.1001/jamaophthalmol.2015.4070
Abstract

Importance  Anti–vascular endothelial growth factor (VEGF) therapy is commonly used to treat numerous retinal conditions and appears safe, yet controversy remains regarding systemic safety.

Objective  To evaluate the systemic safety of intravitreous anti-VEGF injections in high-risk patients with diabetic macular edema (DME) and to investigate separately the subgroup of these patients with the highest level of exposure to anti-VEGF monthly treatment for 2 years.

Data Sources  A search of MEDLINE, Cochrane Central Register of Controlled Trials, clincaltrials.gov, and ophthalmology congress abstracts January 1, 1947, to May 19, 2015.

Study Selection  Randomized clinical trials were selected that evaluated monthly anti-VEGF injections for DME for 2 years and reported the outcome measures of cerebrovascular accidents, myocardial infarctions, arteriothrombotic events, and mortality.

Data Extraction and Synthesis  Two reviewers collected data independently from each study for the meta-analysis. Data were pooled using a fixed-effects model and analyzed from November 6, 2014, to June 28, 2015. Peto odds ratios with 95% CIs were calculated.

Main Outcomes and Measures  Primary end points included cerebrovascular accidents and all-cause mortality in the highest-dose arms. Secondary outcomes included myocardial infarctions, arteriothrombotic events, and vascular-related death.

Results  Of 1126 articles reviewed, 598 were removed as duplicate studies and 524, for lack of monthly treatment data for 2 years, leaving 4 studies for the meta-analysis that met the search criteria: 2 trials using monthly aflibercept and 2 using monthly ranibizumab, representing 1328 patients. The primary evaluation (1078 patients) combined the monthly aflibercept and the 0.5-mg ranibizumab arms and yielded an increased risk for death compared with sham and laser treatments (odds ratio [OR], 2.98; 95% CI, 1.44-6.14; P = .003). Analysis including monthly aflibercept and 0.5-mg ranibizumab yielded an increased risk for cerebrovascular accidents (OR, 2.33; 95% CI, 1.04-5.22; P = .04) and vascular death (OR, 2.51; 95% CI, 1.08-5.82; P = .03). No definitive increased risk for myocardial infarctions and arteriothrombotic events was seen with all dose combinations.

Conclusions and Relevance  In this meta-analysis of anti-VEGF agents for patients with DME, assessment of the highest-level exposure group (those high-risk patients with DME who received 2 years of monthly treatment) revealed a possible increased risk for death and potentially for cerebrovascular accidents. Consideration of total exposure to anti-VEGF agents when treating those at high risk for vascular disease may be important.

Introduction

The intravitreous use of anti–vascular endothelial growth factor (VEGF) agents has transformed the treatment of many retinal diseases.15 Despite systemic safety concerns of these agents when used intravenously for cancer treatment, the much smaller intravitreous dose has been found to be safe in numerous registered trials.612 However, these trials are not powered to evaluate the safety risks of uncommon events, and many trials10,1214 have excluded patients at highest risk of systemic adverse effects of these agents (ie, those with recent cerebrovascular accident [CVA] or myocardial infarction [MI]) from enrollment. Meta-analyses have been performed to evaluate larger populations of patients and have demonstrated safety when evaluating the entire study population; however, there may be increased risk in certain high-risk subgroups.1,2,4,1520 Data demonstrate a reduction in circulating VEGF levels after intravitreous injection of these agents, providing biological plausibility for possible systemic effects.2126

Epidemiologists often look for factors associated with an outcome in high-risk groups by studying the groups with the highest levels of exposure. Because systemic administration of these agents for cancer is associated with increased risks for arteriothrombotic events (ATEs), we first chose persons with diabetes mellitus as a high-risk group given their propensity for ATEs. This choice was also supported by a recent meta-analysis of ranibizumab treatment for age-related macular degeneration (AMD), retinal vascular occlusion, and diabetic macular edema (DME)18 that found imbalances in the risks for death, CVA, and impaired wound healing, but only in DME. Second, several meta-analyses of ranibizumab treatment for AMD17,27 have identified an increased risk for CVA but only in the higher-dose (0.5 mg) arm or only with monthly instead of as-needed dosing. A recent Cochrane meta-analysis of anti-VEGF for DME2 analyzed 15 trials and showed no increased risk for ATEs or death. The intent of the present analysis was to evaluate the subpopulation of patients with DME who had the highest levels of exposure to anti-VEGF agents, specifically, monthly injections for 2 years.

Box Section Ref ID

At a Glance

  • Because of controversy regarding the systemic safety of anti–vascular endothelial growth factor (VEGF) commonly used to treat diabetic macular edema (DME), this study evaluated a pooled analysis on systemic safety of intensive intravitreous anti-VEGF injections for DME for 2 years.

  • Although several meta-analyses evaluating the entire population of patients in anti-VEGF trials with different treatment regimens have not shown safety signals, patients receiving maximum monthly doses had an increased risk for death compared with those receiving sham and laser treatments.

  • In an analysis of pooled patients receiving monthly aflibercept and different doses of monthly ranibizumab (0.5 mg, 0.3 mg, or both), the Peto odds ratios (95% CI) were 2.98 (1.44-6.14; P = .003), 2.56 (1.17-5.57; P = .02), and 2.57 (1.31-5.05; P = .006), respectively, for an increased risk for death.

  • These data suggest an increased risk for death in a select, intensively treated population receiving monthly anti-VEGF treatment for 2 years.

Methods
Sources and Search Methods

We conducted a systematic search without language restrictions of MEDLINE, the Cochrane Central Register of Controlled Trials, and clinicaltrials.gov from January 1, 1947 (start date for MEDLINE) through May 19, 2015, for randomized clinical trials evaluating anti-VEGF agents for DME. In addition, we reviewed ophthalmology congress abstracts (Association for Research in Vision and Ophthalmology, American Academy of Ophthalmology, and European Society of Retina Specialists) and contacted representatives from Genentech, Novartis, and Regeneron to determine whether unpublished studies met selection criteria. Search details of the predefined protocol are available in the eMethods in the Supplement and further described in the PRISMA diagram in Figure 1. Randomized clinical trials were included if they met the eligibility criteria of 2 years of monthly anti-VEGF therapy for DME and reported the safety outcomes of CVAs, MIs, ATEs, and mortality.

Data Collection and Risk for Bias Assessment

Data regarding study quality, drug dosing, incidence of CVAs, MIs, ATEs, and all-cause and vascular-related deaths were collected from each study independently by 2 reviewers (R.L.A. and G.M.G.). When the causes of death were provided, we applied the definition of vascular death used by the Antiplatelet Trialists’ Collaboration (APTC): “definitely or possibly vascular, which includes all deaths attributed to cardiac, cerebral, hemorrhagic, embolic, other vascular, or unknown causes.”28(p83) Most disparities were resolved by communication with trial sponsors; alternative calculations for potential interpretations were performed to address unresolved disparities. The assessment of risk for bias followed the recommendations of the Cochrane Collaboration.29

Data Synthesis and Analysis

Data were analyzed from November 6, 2014, to June 28, 2015. The clinical and methodological characteristics of the included trials were evaluated following Cochrane Collaboration guidelines, and statistical analysis was performed using RevMan 5.3 software.29 We used a fixed-effects method with the Peto odds ratio (OR) and 95% CI, which has been reported to have superior statistical properties to analyze uncommon events.29 The ranibizumab trials used 2 different monthly doses: 0.3 mg, approved in the United States and 0.5 mg, approved outside the United States. The prespecified primary analysis included the 0.5-mg arms (high dose) with monthly aflibercept; however, given the importance of both doses, secondary analyses combined monthly aflibercept treatment with the 0.3-mg ranibizumab arms (low dose) or with the 0.3- and 0.5-mg ranibizumab arms (combined dose). Both drugs are presented in the same forest plot to test for subgroup differences. Because several prior studies17,18,20,27 had raised concern about an increased risk for CVA and death, these constituted the primary outcome measures. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system to assess the quality of the evidence.30 Heterogeneity was assessed by calculating the I2 statistic and χ2 tests.31

Results
Literature Search for Risk in Persons With DME

Evaluation of recent meta-analyses of the safety of anti-VEGF use in DME2,4,15,20 has not shown a safety signal in the entire population. The most recent Cochrane analysis of 15 trials2 showed no increased risk for ATEs or death.

Literature Search for Persons With DME at the Highest Level of Exposure to Anti-VEGF

The database query concerning persons with DME at the highest level of exposure to anti-VEGF revealed 1126 titles, 598 of which were duplicates. After we reviewed 528 titles and abstracts, we evaluated 20 full-length articles and 1 presentation, which yielded 4 reports of 4 studies that met the inclusion criteria (Figure 1). A review of abstracts allowed exclusion of the majority of studies and was followed by a full-text review of the remaining titles.1013,3248 Two studies had been published with 1-year results only, but the 2-year follow-up had been presented, and a detailed summary of 2-year results is available from Regeneron (Intravitreal aflibercept injection for diabetic macular edema: primary results [unpublished data; December 4, 2014]).12,13 The excluded studies, including all studies of pegaptanib sodium and bevacizumab, did not have monthly treatment for 2 years.

Qualitative Synthesis

Table 1 shows the characteristics of the 4 included trials, representing 1328 patients.1013 They were all randomized, registered trials sponsored by pharmaceutical companies with 2-year completion rates ranging from 105 of 135 (77.8%) to 110 of 127 (86.6%) for individual study arms. Two essentially identical studies, RISE (Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema [ME] With Center Involvement Secondary to Diabetes Mellitus)10,11 and RIDE (Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema [ME] With Center Involvement Secondary to Diabetes Mellitus),10,11 evaluated 2 monthly doses of ranibizumab vs a sham injection or laser treatment (sham/laser treatment), and 2 essentially identical studies, VISTA (Study of Intravitreal Aflibercept Injection in Patients With DME)12,13 and VIVID (Intravitreal Aflibercept Injection in Vision Impairment Due to DME),12,13 evaluated several dosing regimens of aflibercept vs sham/laser treatment. The entry criteria were similar except that the ranibizumab trials excluded patients with MI or CVA within 3 months of entry; the aflibercept trials excluded patients if the event was within 6 months of entry. No individual trial reported a significantly increased risk for ATE, MI, CVA, or death.

Risk for Bias Assessment

All trials were deemed of low risk with respect to allocation, blinding, selective outcome reporting, and other potential sources of bias. Attrition was deemed unclear in the aflibercept trials because the second year is unpublished, and details of incomplete outcome data remain unclear.13 However, the trial design is well documented in the 1-year publication12 (eTable in the Supplement).

Summary of Findings

Table 2 summarizes the findings for the main comparison, which included the monthly aflibercept and 0.5-mg ranibizumab doses. Figure 2 shows all-cause mortality in the 3 analyses combining monthly aflibercept and 0.5-mg, 0.3-mg, and combined monthly ranibizumab doses. The risk for death (OR; 95% CI) in aflibercept-ranibizumab treatment compared with sham/laser treatment increased in the 0.5-mg (2.98; 1.44-6.14; P = .003), 0.3-mg (2.56; 1.17-5.57; P = .02), and combined (2.57; 1.31-5.05; P = .006) ranibizumab injection groups. The subgroups receiving monthly 0.5-mg doses of ranibizumab with aflibercept individually demonstrated increased mortality (OR, 3.24; 95% CI, 1.12-9.36; P = .03) when compared with those groups receiving sham/laser treatment (OR, 2.76; 95% CI, 1.02-7.46; P = .05) (Figure 2A).

We identified no definitive difference when we compared monthly ranibizumab and aflibercept subgroups for death or any other outcome in this study. In all analyses within this study, outcome measures were consistent across all trials without significant heterogeneity as measured by the I2 statistic and χ2 tests.

Vascular Mortality

The evaluation of vascular mortality is shown in eFigure 1 in the Supplement. For this analysis, the APTC definition of vascular death was applied to the reported causes of death. A disparity was noted in the VISTA findings. Three vascular deaths were reported in the monthly aflibercept arm; however, in another part of the report, causes of death of 6 patients in this arm were listed as cardiac arrest, acute cardiac failure, MI, pulseless electrical activity, CVA, and “death.”13 After discussion with the VISTA sponsors, part of the disparity is explained by their prespecified definition requiring that treatment-emergent events must occur within 30 days of the previous injection. Only treatment-emergent events were presented in their safety analysis set and, apparently, 2 patients had vascular deaths more than 30 days after the last aflibercept injection despite being in the monthly arm. In addition, the VISTA Study team and Regeneron will reclassify 1 patient as having a vascular-related death.13 For our analysis, we considered these 6 deaths to be vascular per the APTC definition, but alternative calculations are discussed in the Sensitivity Analyses subsection below. The treatment-emergent ATEs reported in the ranibizumab trials included events throughout the trials, including those occurring more than 30 days after an injection. The meta-analysis including monthly aflibercept and the 0.5-mg or combined ranibizumab dose arms showed an increased risk for vascular-related death in the 0.5-mg ranibizumab group (OR, 2.51; 95% CI, 1.08-5.82; P = .03) and in the combined-dose ranibizumab group (OR, 2.23; 95% CI, 1.01-4.89; P = .05) compared with sham/laser treatment.

Cerebrovascular Accident

The analysis of CVAs is shown in eFigure 2 in the Supplement. In the VIVID study, one patient died of brain herniation, which was confirmed to have been related to a CVA. Analysis of monthly aflibercept and the 0.5-mg ranibizumab dose revealed an increased risk for CVA compared with laser/sham treatment (OR, 2.33; 95% CI, 1.04-5.22; P = .04).

MI and ATEs

The meta-analysis with respect to MI and ATEs is shown in eFigures 3 and 4 in the Supplement. In the groups receiving 0.5-mg, 0.3-mg, and combined doses, no definitive increase in the risk for MI or ATE compared with sham/laser treatment was identified.

Sensitivity Analyses

Outcome measures were consistent across all trials; however, in the RISE study, 1 patient assigned to sham/laser treatment was mistakenly treated with 1 dose of ranibizumab. This patient had a CVA and later died of an unknown cause that was classified as a vascular-related death. For safety purposes, the RISE study included this patient in the 0.5-mg ranibizumab arm. However, we also repeated the analysis placing this patient in the sham/laser treatment arm and found an increased risk for death (OR, 2.60; 95% CI, 1.26-5.38; P = .01) for the 0.5-mg dose group (eFigure 5A in the Supplement), whereas the risk for CVA had an OR of 1.97 (95% CI, 0.88-4.42; P = .10) (eFigure 6A in the Supplement) and the risk for vascular death had an OR of 2.09 (95% CI, 0.90-4.86; P = .09) (eFigure 7A in the Supplement).

Given the disparity in the number of vascular-related deaths in the VISTA study, we applied the APTC criteria to the listed cause of death. However, if fewer of these deaths had vascular causes, the analysis of the increased risk for vascular-related death decreases. If there are only 5 vascular-related deaths in the VISTA monthly arm instead of 6, the increased risk for vascular-related death in the high-dose analysis is an OR of 2.37 (95% CI, 1.00-5.63; P = .05). If only 4 deaths have vascular causes, the OR is 2.24 (95% CI, 0.93-5.41; P = .07). Also, if all 3 deaths in the sham/laser treatment arm are considered vascular related, including the patient with multiple-organ failure, the risk for vascular-related death has an OR of 2.21 (95% CI, 0.97-5.04; P = .06) (eFigure 8 in the Supplement). No other changes in results were noted among the remaining comparisons.

Discussion

This study was designed to evaluate prolonged monthly anti-VEGF therapy in a high-risk group of patients to assess any potential systemic safety signal. We started by evaluating a group of patients at high risk for arteriothrombotic disease—those with diabetes mellitus. No excess risk for arteriothrombotic disease or mortality was seen in the recent overall Cochrane meta-analysis of patients with DME.2 However, when we focused on the group with the highest level of exposure, that is, a monthly injection of ranibizumab or aflibercept for 2 years, we found an increased risk for death when the analysis included aflibercept and the 0.3- or 0.5-mg ranibizumab dose. In the main high-dose analysis, we also found a borderline increased risk for CVA and vascular-related death. The authors of the RISE and RIDE studies10,11 noted that deaths and CVAs were numerically higher in ranibizumab groups but that this imbalance had not been seen in other studies, such as the Diabetic Retinopathy Clinical Research Network protocol I,42 which evaluated ranibizumab, laser, and triamcinolone for DME, or the RESTORE Extension Study, which compared ranibizumab injections with laser treatment for DME.11,45,49 However, these other trials did not require monthly injections, and the present analysis implies that this difference could be related to overall drug exposure. In fact, several meta-analyses of anti-VEGF agents for DME2,15,50 have not demonstrated a definitive safety signal, but these studies have predominantly evaluated trials with less frequent dosing or of shorter duration and thereby with less drug exposure. The recent Cochrane DME analysis2 did not use the monthly dosing arms from the VIVID or VISTA studies in the main analysis, and only 1-year data were available. Another meta-analysis of ranibizumab for DME20 did not find an increased risk for CVA, MI, ATEs, or mortality across all trials but noted a dose-dependent increased risk for mortality in the largest trial that used monthly ranibizumab. A recent meta-analysis of phase 2 and 3 aflibercept trials for multiple diseases,51 which accounted for duration of treatment, found the risk for death in treated patients with DME to be 1.70 per 100 patient-years at risk vs 0.55 per 100 patient-years at risk for sham/laser treatment.

In patients with AMD, 2 meta-analyses17,27 have observed an increased risk for CVA with the higher dose of ranibizumab. This increase was only seen in the high-risk patients when stratified for baseline CVA risk by Bressler et al.27 In the study by Ueta et al,17 the increased risk was seen not only with the higher dose but also with monthly dosing vs less frequent or as-needed treatment, although no increased risk for mortality was seen.

One potential explanation for the finding of an increased mortality risk in the present analysis but not in other larger meta-analyses is that this analysis focuses on a population with DME receiving monthly injections for 2 years, who thereby have a much higher level of drug exposure than patients in other studies. The finding of a possibly increased risk for CVA and vascular-related death in the higher-dose arm provides biological plausibility that the increased risk for all-cause mortality could be related to systemic vascular effects of the small doses of these agents rather than random events. Several studies21,2326 have documented that these agents pass into the bloodstream after intravitreous injection and reduce systemic VEGF levels, sometimes for prolonged periods. In 1 AMD study, 2 years of ranibizumab or bevacizumab injections significantly reduced serum VEGF levels, but more so in the monthly treatment arms.25 Persons with diabetes mellitus are particularly susceptible to ATEs, and long-term blockade of VEGF in the bloodstream could exacerbate this susceptibility and increase the risk for CVA and death.14,52 Concern over a potential safety signal in this population is not new because both trial sponsors14,52 excluded patients with recent ATEs from enrollment, the VISTA study12,13 stratified randomization by history of MI or CVA, and Genentech presumably sought approval of the lower ranibizumab dose for DME to lower the risk for a safety issue. Furthermore, any risk could be increased in patients undergoing intensive bilateral treatment.

This study has several limitations. First, we studied a subgroup of a subgroup (patients with diabetes mellitus), and only 4 trials are included. Individually, the trials are not large enough to show a difference in ATEs or death. However, in the meta-analysis of those with the highest levels of anti-VEGF exposure, increased risks are suggested. Although the risk for death was higher in this select subpopulation, in the evaluation of the risk for CVA or vascular-related death, only a borderline difference was found, and reclassification of a single patient can alter the confidence in the difference identified. Second, the 2-year data from 2 of the 4 studies have not yet been published. Fortunately, the first-year data have been published, including a detailed description of the study design. The main results of the second year have been presented and are available from the sponsor (Regeneron, unpublished data, December 4, 2014), who is submitting the study for publication.

Third, only study-level data are available rather than patient-level data. Therefore, we cannot adjust for baseline patient characteristics, which may not be balanced, leading to possible confounding. In addition, calculations of time to death cannot be performed; however, these imbalances did not materialize in the trials at 1 year, and Kaplan-Meier calculations have shown the separation of curves for CVA and death mostly during year 2 of the RISE and RIDE trials.2,12,53 Hence, most of the deaths occurred after a full year of monthly drug exposure, although this finding could be related to selection of patients in better health at study entry, such as excluding those with recent arteriothrombotic disease.

Fourth, all studies were sponsored by pharmaceutical companies and could have an increased risk for bias.54 Fifth, we compared across 2 different anti-VEGF agents. However, this comparison is common in meta-analyses, including those by the Cochrane Collaboration.2,19,50,55 In the current meta-analysis, the trials were similarly designed and registered with the US Food and Drug Administration, and outcomes were consistent across all trials as measured by heterogeneity tests. In all trials, patients with a recent MI or CVA were excluded, although with a different definition of recent (3 vs 6 months), which could introduce bias.11,12

This study looked at a limited subset of patients in clinical practice—the subgroup of a high-risk group with the highest level of anti-VEGF exposure and specifically persons with diabetes mellitus receiving monthly injections for 2 years. Many studies have shown excellent effects on DME with far fewer injections, such as 2 to 3 in the second year of protocol I in the Diabetic Retinopathy Clinical Research Network Study.42,56 Although patients in protocol T, which compared aflibercept, bevacizumab, and ranibizumab for DME, received 9 to 10 injections in the first year, year 2 will likely have fewer injections.48 The concern about a potential increased risk for death may not apply to most of the patients who are undergoing less intensive therapy, which is the standard of care in many clinical practices.

Conclusions

This study suggests a safety signal for patients at high risk for vascular disease who received intensive treatment for DME with monthly anti-VEGF therapy for 2 years. Further evaluation of these studies with patient-specific data and future larger studies are needed to better evaluate this signal. These increased risks were noted although patients with uncontrolled diabetes mellitus, hypertension, or recent CVA or MI were excluded from these trials. Furthermore, patients enrolling in clinical trials tend to be healthier and more adherent to treatment regimens than the general population. Hence, as clinicians, we should be increasingly cognizant of our patients’ medical histories when we decide how to treat them. Because these data provide possible evidence of a systemic adverse effect in aggressive treatment of at-risk patients, further studies of other at-risk populations, such as patients with AMD and previous CVAs, are indicated to assess whether this biologically plausible risk is seen in other high-risk, high-exposure groups.

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Article Information

Corresponding Author: Robert L. Avery, MD, California Retina Consultants and Research Foundation, 525 E Micheltorena, Ste A, Santa Barbara, CA 93103 (bobave@gmail.com).

Submitted for Publication: March 20, 2015; final revision received August 28, 2015; accepted September 3, 2015.

Published Online: October 29, 2015. doi:10.1001/jamaophthalmol.2015.4070.

Author Contributions: Drs Avery and Gordon had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Avery.

Acquisition, analysis, or interpretation of data: Both authors.

Drafting of the manuscript: Avery.

Critical revision of the manuscript for important intellectual content: Both authors.

Statistical analysis: Both authors.

Administrative, technical, or material support: Gordon.

Study supervision: Avery.

Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Avery reported receiving personal fees from Alcon, Allergan, and Bausch and Lomb; personal fees and other from Alimera, Novartis, and Replenish; grants, personal fees, and nonfinancial support from Genentech; and grants, personal fees, and other from Regeneron, outside the submitted work. In addition, Dr Avery reports a patent intravitreous drug delivery licensed to Replenish. No other disclosures were reported.

Previous Presentations: This paper was presented in part at the 2015 Meeting of the Association for Research in Vision and Ophthalmology; May 4, 2015; Denver, Colorado; and at the annual meeting of the American Society of Retinal Specialists; July 14, 2015; Vienna, Austria.

Additional Contributions: Maureen Maguire, PhD, Perelman School of Medicine, University of Pennsylvania, Philadelphia, provided expertise in critically reviewing this manuscript. She did not receive any compensation for this role.

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