Supplementary Online Content - JAMA · Ophthalmology. 2012;119(4):789-801. 2 Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular

© 2015 American Medical Association. All rights reserved.

Supplementary Online Content

Avery RL, Gordon GM. Systemic safety of prolonged monthly anti–vascular endothelial growth factor therapy for diabetic macular edema: a systematic review and meta-analysis. JAMA Ophthalmol. Published online October 29, 2015. doi: 10.1001/jamaophthalmol.2015.4070.

eMethods. Parameters Used for Online Literature Search

eTable. Risk for Bias Assessment.

eFigure 1. Anti-VEGF Treatment and Vascular Deaths

eFigure 2. Anti-VEGF Treatment and Cerebrovascular Accidents (CVAs)

eFigure 3. Anti-VEGF Treatment and Myocardial Infarction (MI)

eFigure 4. Anti-VEGF Treatment and Arteriothrombotic Events (ATEs)

eFigure 5. Anti-VEGF Treatment and Death Excluding a RISE Protocol Violation Patient

eFigure 6. Anti-VEGF Treatment and Cerebrovascular Accidents (CVAs) Excluding a RISE Protocol Violation Patient

eFigure 7. Anti-VEGF Treatment and Vascular Death Excluding a RISE Protocol Violation Patient

eFigure 8. Anti-VEGF Treatment and Vascular Death When All 3 Deaths Are Vascular in VISTA Sham Arm

This supplementary material has been provided by the authors to give readers additional information about their work.

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eMethods. Parameters Used for Online Literature Search

Systemic Safety of Intensive Use of Intravitreal Anti-VEGF Agents for Diabetic Macular Edema

Systematic Review and Meta-analysis of Randomized Trials

Robert L Avery, MD

California Retina Consultants and Research Foundation

Santa Barbara, CA

Background:

DME is one of the leading causes of blindness in the industrialized world1. Anti-VEGF therapy has revolutionized our treatment of many retinovascular diseases, and is now the mainstay of therapy for DME, in part because it is associated with fewer ocular side effects than steroid injections2. However, the systemic safety of these injections remains controversial3, 4. Fortunately, there is increasing evidence that the small doses of these agents are safe5-7. When much larger doses are used intravenously to treat cancer patients, there is an increased risk of ATEs8, 9. But these agents get into the bloodstream after intravitreal injection, and can affect systemic VEGF levels10-14. A meta-analysis of ranibizumab in AMD trials showed an increased risk for CVA only if patients were stratified as to their baseline risk of CVA15. A more recent meta-analysis of 6,500 AMD patients demonstrated an increased risk of CVA with more intensive ranibizumab therapy – higher doses or more frequent (monthly) treatment, but not an increased risk of death16. Patients with diabetic retinopathy may have a higher baseline risk for ATEs; hence, most DME trials have excluded patients with recent CVA or MI from inclusion into the study17-19. Nevertheless, a meta-analysis preformed jointly by Genentech and Novartis of 6,504 patients in ranibizumab trials of AMD, RVO, and DME where pair-wise comparisons were possible revealed imbalances only in the DME patients, and were observed in wound healing, CVA, and death20. Two recent meta-analyses of DME patients did not show a statistically significant increased risk of ATEs or death across all treatment regimens, but one raised concern about a dose-dependent increased risk of death in a subset of patients5, 21.

Review Objectives:

To conduct a meta-analysis of randomized trials to evaluate the use of intensive prolonged monthly anti-VEGF therapy in diabetics with macular edema

Methods:

The study will be conducted and reported according to PRISMA guidelines.

Population:

Patients treated with monthly anti-VEGF agents for at least 2 years in randomized clinical trials.

Selection Criteria:

Inclusion criteria: (both required)



Randomized trials of patients receiving anti-VEGF with at least one arm of monthly treatment for at least 2 years.

Randomized trials reporting of the following safety outcomes: CVA, MI, ATEs, and mortality.

Exclusion Criteria

Concomitant use of other anti-VEGF agents

Database search:

Medline, Cochrane Central Register of Controlled Trials, clinical trials.gov and congress abstracts will be searched. The following strategy will be used for the MEDLINE search without language restrictions:

1 randomized controlled trial 2 controlled clinical trial 3 randomized 4 placebo 5 drug therapy 6 randomly 7 trial 8 groups 9 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 10 macular edema 11. macular oedema 12. 10 or 11 13. diabetic 14. diabetes 15. 13 or 14 16. 12 and 15 17. pegaptanib 18. bevacizumab 19. ranibizumab 20. aflibercept 21. 17 or 18 or 19 or 20 22. 9 and 16 and 21Screening of titles and abstracts will be carried out independently by two investigators, and obviously irrelevant articles will be rejected. Full reports of residual articles will be evaluated independently for eligibility. Any disagreements will be resolved by discussion between investigators. In addition, the pharmaceutical companies making the agents will be contacted in an attempt to find unpublished reports.

Data extraction:

Study characteristics:

Data relating to study design, the number of participants, the mean age, regimens of anti-VEGF treatment including dose, follow-up, completion rate of follow-up, support from manufactures, and exclusion criteria due to baseline systemic vascular conditions will be extracted.

Study quality:

Risk of bias will be assessed per Cochrane Collaboration recommendations.



Outcome data:

Interventions and comparators:

Monthly intravitreal injection of anti-VEGF agents will be compared with and sham injections. Laser therapy is not considered to influence the risk of systemic vascular events. If the treatment regimen changes during the course of the study, data until the protocol switch will be used.

Outcome measures:

The number of APTC defined events of CVA, MI, ATE, overall death, and vascular death.

Meta-analysis:

Peto odds ratio will be used to estimate the risk ratio with 95% confidence interval. Both ranibizumab doses (0.5 and 0.3 mg) will be evaluated alone, and also in combination to increase the power of the study; however, the primary outcome of the study is to assess the 0.5 mg dose as higher exposure has been possibly implicated in death and CVA in earlier studies16, 21. Heterogeneity will be assessed by calculating the I2 statistic and Chi2 tests22.

References

1. Frank RN. Diabetic retinopathy. N Engl J Med 2004;350(1):48-58. 2. Thomas BJ, Shienbaum G, Boyer DS, Flynn HW, Jr. Evolving strategies in the management of diabetic macular edema: clinical trials and current management. Can J Ophthalmol 2013;48(1):22-30. 3. 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:i7-10. 4. Beaumont PE, Petocz P, Kang HK. Is there risk of stroke with aflibercept? Ophthalmology 2014;121(1):e4. 5. 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. 6. Solomon SD, Lindsley K, Vedula SS, et al. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev 2014;8:CD005139. 7. Cheng JW, Cheng SW, Lu GC, Wei RL. Effect of intravitreal anti-vascular endothelial growth factor therapy on the risk of arterial thromboembolic events: a meta-analysis. PLoS One 2012;7(7):e41325. 8. 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):287-97. 9. Schutz FA, Je Y, Azzi GR, et al. 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):1404-12. 10. Chakravarthy U, Harding SP, Rogers CA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet 2013;382(9900):1258-67. 11. 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):1636-41. 12. Wang X, Sawada T, Sawada O, et al. 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):738-44 e1.



13. 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):1483-9. 14. 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 2014. 15. 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):1821-8. 16. Ueta T, Noda Y, Toyama T, et al. Systemic Vascular Safety of Ranibizumab for Age-Related Macular Degeneration: Systematic Review and Meta-analysis of Randomized Trials. Ophthalmology 2014;121(11):2193-203 e7. 17. Ip MS, Domalpally A, Hopkins JJ, et al. Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol 2012;130(9):1145-52. 18. Brown DM, Nguyen QD, Marcus DM, et al. 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):2013-22. 19. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology 2014;121(11):2247-54. 20. Avery RL, Francom SF, 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. Seattle, WA2013; v. 1535 - C0025. 21. Yanagida Y, Ueta T. Systemic safety of ranibizumab for diabetic macular edema: meta-analysis of randomized trials. Retina 2014;34(4):629-35. 22. The Cochrane Collaboration. Chapter 9: Analysing data and undertaking meta-analyses. In: Deeks JJ HJ, Altman DG, ed. Cochrane Handbook for Systematic Reviews of Interventions Version 510 (updated March 2011): Higgins JPT, Green S, 2011.



eTable. Risk for Bias Assessment No. of

Patients by Study

Random Sequence Generatio

n (selection

bias)

Allocation Concealment (selection

bias)

Blinding of Participants

and Personnel

(performance bias)

Blinding of Outcome

Assessment

(detection bias)

Incomplete

Outcome Data

(attrition bias)

Selective Reportin

g (reporting bias)

Other

Bias

RISE1,2 L L L L L L L

RIDE1,2 L L L L L L L

VISTA3,4 L L L L U L L

VIVID3,4 L L L L U L L

H=High Risk; L=Low Risk; U=Unclear Risk

1Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.

2Brown DM, Nguyen QD, Marcus DM, et al. 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

3Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254.

4Do D. VIVID/VISTA for DME: Two-Year Results. Powerpoint presentation presented at AAO subspecialty day; Oct 18, 2014; Chicago, IL.





eFigure 1. Anti‐VEGF Treatment and Vascular Death

Comparison between different monthly treatments and sham. A: Ranibizumab 0.5 mg arms. B:

Ranibizumab 0.3 mg arms. C: Combined ranibizumab 0.3 & 0.5 mg arms. CI = confidence interval.





eFigure 2. Anti‐VEGF Treatment and Cerebrovascular Accidents (CVAs)







eFigure 3. Anti‐VEGF Treatment and Myocardial Infarction (MI)







eFigure 4. Anti‐VEGF Treatment and Arteriothrombotic Events (ATEs)







eFigure 5. Anti‐VEGF Treatment and Death Excluding a RISE Protocol Violation Patient

One death was moved into the the sham/laser arm. Comparison between different monthly treatments

and sham. A: Ranibizumab 0.5 mg arms. B: Ranibizumab 0.3 mg arms. C: Combined ranibizumab 0.3 &

0.5 mg arms. CI = confidence interval.





eFigure 6. Anti‐VEGF Treatment and Cerebrovascular Accidents (CVAs) Excluding a RISE Protocol

Violoation Patient

One death was moved into the sham/laser arm. Comparison between different monthly treatments and

sham. A: Ranibizumab 0.5 mg arms. B: Ranibizumab 0.3 mg arms. C: Combined ranibizumab 0.3 & 0.5

mg arms. CI = confidence interval.





eFigure 7. Anti‐VEGF treatment and vascular death Excluding a RISE Protocol Violation Patient

One death was moved into the sham/laser arm: Comparison between different monthly treatments and

sham. A: Ranibizumab 0.5 mg arms. B: Ranibizumab 0.3 mg arms. C: Combined ranibizumab 0.3 & 0.5

mg arms. CI = confidence interval.





eFigure 8. Anti‐VEGF Treatment and Vascular Death When All 3 Deaths Are Vascular in VISTA Sham Arm




Documents

Supplementary Online Content - JAMA · Ophthalmology. 2012;119(4):789-801. 2 Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular