1. Update on Anti-VEGF Therapy in Diabetic Macular Edema, Neovascular AMD, and Retinal Vein Occlusion
Jonathan S. Chang, MD
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida
A REPORT FROM THE 2012 ANNUAL MEETING OF THE ASSOCIATION FOR RESEARCH IN VISION AND OPHTHALMOLOGY
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2. A New Focus on Ophthalmic Disease
Use of anti-vascular endothelial growth factor (anti-VEGF) agents has become a mainstay in treating several common retinal diseases.
This drug class initially was used to manage neovascular age-related macular degeneration (AMD).1–3
Its value recently was affirmed for treating both branch retinal vein occlusion (BRVO)4 and central retinal vein occlusion (CRVO).5
Further clinical data support their use in managing diabetic macular edema (DME).6
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3. Novel Drugs for Ophthalmic Indications
Ranibizumab has been approved by the US Food and Drug Administration (FDA):
To treat patients with neovascular AMD
For macular edema following retinal vein occlusion (RVO)
For DME (August 2012)
Aflibercept (VEGF Trap-Eye) is approved by the FDA for treating neovascular AMD.
Intravitreal bevacizumab is widely used off-label for the treatment of these conditions, especially neovascular AMD.
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4. Clinical Trials of VEGF Inhibitors
Several recent studies offered additional insight into the use of anti-VEGF agents.
The READ,3,7 RISE,8 and RIDE8 trials involved the use of ranibizumab in patients with DME.
The DA VINCI trial9 demonstrated the effect of aflibercept therapy in DME patients.
The 2-year results of the CATT trial10 compared use of bevacizumab with ranibizumab therapy in AMD patients.
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5. Clinical Trials of VEGF Inhibitors
Investigators involved in the VIEW 1 and VIEW 2 studies11 reported on the use of aflibercept in patients with neovascular AMD.
The management of RVO changed after analysis of the CRUISE4 and BRAVO5 study results.
Further information has been gathered in the HORIZON study.12
Questions about the management of patients diagnosed with retinal disease remain.
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6. Issues Involved in Using VEGF inhibitors
Monthly versus as-needed dosing
The choice of an anti-VEGF agent for treating each condition
Corticosteroid and laser therapy in patients affected by RVO and DME
The safety of intravitreal injections of VEGF inhibitors
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7. Diabetic Macular Edema
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8. Diabetic Macular Edema: DRCR Trial
In the Diabetic Retinopathy Clinical Research Network (DRCR) protocol I,6,13 investigators compared sham therapy plus prompt focal laser treatment with:
Ranibizumab plus prompt laser therapy
Ranibizumab plus deferred laser treatment
Triamcinolone plus prompt laser therapy
Two-year follow-up data recently showed improved visual acuity and central foveal thickness in both ranibizumab groups as compared with those receiving sham plus laser therapy or triamcinolone plus laser therapy.14
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9. Diabetic Macular Edema: RISE and RIDE Trials
RISE8 and RIDE8 were two parallel studies comparing the use of 0.3 or 0.5 mg of ranibizumab given monthly with sham therapy for DME.
In the RIDE trial, patients receiving 0.3 and 0.5 mg of ranibizumab gained 8.6 and 9.7 letters of visual acuity, respectively.
Similar results were reported in the RISE trial, with patients given 0.3 mg of ranibizumab gaining 10.0 letters and those given 0.5 mg gaining 9.3 letters.
Patients receiving ranibizumab at either dose level showed improvement in visual acuity and retinal thickness and a reduction in diabetic retinopathy.
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10. Diabetic Macular Edema: READ 3 Trial
The READ 3 trial7 compared two different ranibizumab doses in patients with DME.
Patients were randomized to groups receiving 0.5 or 2.0 mg of ranibizumab monthly for 6 months.
At month 6, patients in the 0.5-mg group gained a mean of 8.72 letters, whereas those in the 2.0-mg group gained a mean of 7.35 letters.
At month 12, patients in the 0.5-mg group gained letters as compared with the 7.39 letters gained by the 2.0-mg group (P = 0.03).
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11. Diabetic Macular Edema: BOLT Study
The BOLT study15 compared the use of bevacizumab with focal laser therapy in patients with DME.
Patients were randomized to groups receiving either bevacizumab or macular laser therapy and were followed for 2 years.
Patients in the bevacizumab group gained a mean of 8.6 letters, whereas those in tThe macular laser therapy group lost a mean of 0.5 letters.
Central foveal thickness also was reduced in the bevacizumab group as compared with the laser treatment group.
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12. Diabetic Macular Edema: DA VINCI Study
Results from the DA VINCI trial9 demonstrated improvement in the eyes of patients with DME who used aflibercept as compared with patients who underwent focal laser therapy.
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13. Diabetic Macular Edema: Treatment Considerations
Many ophthalmologists prefer to administer treatment at regular intervals instead of as needed in patients affected with a chronic process like DME.
Persistent edema appears to be more common among patients with DME than in those with neovascular AMD, even in eyes treated regularly.
The clinician’s threshold for residual edema may be greater, because the two diseases have different natural histories.
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14. Diabetic Macular Edema: Treatment Considerations
Patients with DME tend to be young:
They may receive a considerable number of injections over their lifetime.
Frequent office visits can interrupt their daily lives.
The current VIVID-DME (ClinicalTrials.gov NCT ) and VISTA DME (ClinicalTrials.gov NCT ) trials are examining use of a loading dose of aflibercept every month for 6 months followed by dosing every 6 months.
Data on these phase III trials should be available in the coming years.
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15. Diabetic Macular Edema: Corticosteroid Therapy
Corticosteroid therapy continues to be an option for patients with DME.
However, it tends to be used now in individuals who do not respond to anti-VEGF treatment.
Increased intraocular pressure and cataracts continue to be the main adverse effects related to the use of corticosteroids.
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16. Diabetic Macular Edema: FAME Trial
The FAME trial16 examined the use of a fluocinolone acetonide implant in patients with DME.
The results demonstrated efficacy with both a 0.2 and 0.5 µg/d implant.
At 2 years, a greater than 15-letter improvement in visual acuity was achieved in:
28.7% of patients receiving 0.2 µg/d of fluocinolone
28.6% of patients receiving 0.5 µg/d of fluocinolone
16.2% of the sham treatment group (P = for each)
62% of patients receiving 0.2 µg/d did not require treatment for increased intraocular pressure.
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17. Diabetic Macular Edema: Corticosteroid Therapy
The FDA has not approved the use of fluocinolone acetonide implants for treating DME because of insufficient safety data.
Marketing of the implant for this indication is approved in Europe. In selected patients, corticosteroid treatment remains an option.
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18. Neovascular AMD
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19. Neovascular AMD: Clinical Data and Options
AMD is the leading cause of blindness in the United States and in other developed countries.17
During the past few months, data from several large trials have impacted treatment options.
Use of ranibizumab for neovascular (exudative) AMD was first reported in the MARINA2 and ANCHOR3 studies.
Frequency of ranibizumab dosing has been examined in the PIER,18 PrONTO,19 SUSTAIN,20 EXCITE,21 and HORIZON22 trials.
As anti-VEGF treatment alternatives have expanded, ophthalmologists now have 3 options: ranibizumab, aflibercept, and off-label bevacizumab.
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20. Neovascular AMD: The VIEW Trials
Results from the VIEW 1 and VIEW 2 trials, which compared the use of aflibercept with ranibizumab therapy for exudative AMD, were reported recently.11
These parallel, noninferiority trials randomized a total of 1,217 North American patients to one of four treatment groups:
0.5 mg of ranibizumab monthly
0.5 mg of aflibercept monthly
2 mg of aflibercept monthly
Three monthly 2-mg aflibercept injections given as a loading dose followed by 2 mg of aflibercept every 2 months
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21. Neovascular AMD: The VIEW Trials
In 94%–96% of patients, moderate vision loss was prevented.
The three aflibercept groups had results that were noninferior to those observed in the ranibizumab group.
Patients receiving 2.0 mg of aflibercept monthly experienced a 10.9-letter gain as compared with an 8.1-letter gain observed in patients given monthly ranibizumab.11
This difference was statistically significant.
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22. Neovascular AMD: The VIEW Trials
The VIEW 2 trial enrolled 1,240 patients in Europe, Asia, and Latin America and had outcomes similar to those of the VIEW 1 trial.11
Both studies had adverse event rates that were similar to each other and to those of prior studies of anti-VEGF therapy.
Aflibercept may be an option in patients who do not respond well to ranibizumab or bevacizumab.
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23. Neovascular AMD: The CATT Trial
Two-year results of the CATT trial,10 a study funded by the National Eye Institute, recently were presented at the 2012 ARVO meeting.
A total of 1,185 patients with neovascular AMD were randomly assigned to one of four treatment groups:
0.5 mg of ranibizumab monthly
1.25 mg of bevacizumab monthly
0.5 mg of ranibizumab as needed
1.25 mg of bevacizumab as needed
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24. Neovascular AMD: The CATT Trial
The as-needed groups were seen every 4 weeks and received injections when:
New fluid was present on optical coherence tomography (OCT)
New or persistent hemorrhage occurred
Decreased visual acuity or new leakage was seen on fluorescein angiography
After 1 year, the monthly groups were divided into monthly and as-needed treatment cohorts for 1 year.
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25. Neovascular AMD: The CATT Trial
After 2 years of therapy:
The monthly ranibizumab group demonstrated a gain of 8.8 letters.
The monthly bevacizumab group gained 7.8 letters.
The ranibizumab as-needed group gained 6.7 letters.
The bevacizumab as-needed group gained 5 letters.
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26. Neovascular AMD: The CATT Trial
Patients receiving monthly injections gained 2.4 letters more than did those given ranibizumab or bevacizumab as needed (P = 0.046).
Mean retinal thickness on OCT was 29 μm less in the monthly treatment groups than in patients receiving ranibizumab or bevacizumab as needed
This difference also was statistically significant.
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27. Neovascular AMD: The CATT Trial
No evidence of fluid was found on OCT in:
45.5% of the monthly ranibizumab group
30.2% of the monthly bevacizumab group
22.3% of the as-needed ranibizumab group
13.9% of the as-needed bevacizumab group
Over 2 years, the mean number of injections in the monthly ranibizumab and bevacizumab groups was 22.4 and 23.4, respectively.
The as-needed ranibizumab and bevacizumab groups received a mean of 12.6 and 14.1 injections, respectively.
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28. Neovascular AMD: The CATT Trial
Based on the results of the CATT trial, there is a 2.4-letter difference between monthly dosing and as-needed dosing in patients with neovascular AMD.
The results also affirmed the effectiveness of off-label bevacizumab in treating neovascular AMD.
It is not known whether differences in results between groups given monthly or as-needed dosing would increase further after 2 years.
Given that many patients with neovascular AMD are treated for longer than 2 years, clinicians are greatly interested in the long-term effects of therapy.
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29. Neovascular AMD: The CATT Trial
Geographic atrophy increased in the monthly dosing groups when compared with the as-needed dosing groups.
It is not clear whether this finding is related to improved visualization of geographic atrophy due to a decreased amount of fluid or to a process associated with chronic anti-VEGF therapy.
Geographic atrophy is a factor to consider in future trials of VEGF inhibitors.
Other imaging may be useful in this regard.
The study also did not address the efficacy of the commonly used “treat-and-extend” protocol for administering ranibizumab or bevacizumab.
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30. Retinal Vein Occlusion
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31. Retinal Vein Occlusion: FDA-Approved Drugs for Treating RVO
In 2009, the FDA approved the use of a dexamethasone intravitreal implant for the treatment of macular edema following RVO.
The following year, it approved the use of intravitreal ranibizumab for the same indication.
In the past, RVO initially would have been treated with observation.
Now, based on data from the CRUISE and BRAVO studies,4,5 prompt treatment of RVO with ranibizumab has become commonplace.
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32. Retinal Vein Occlusion: Clinical Trials
Investigators involved in the COPERNICUS study23 reported data showing an improvement in macular edema after 6 months of monthly aflibercept therapy in patients with CRVO.
Treatment regimens for RVO now typically start with monthly injections of anti-VEGF agents before patients are switched to as-needed dosing with monthly monitoring.
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33. Retinal Vein Occlusion: Clinical Trials
Based on data from the HORIZON trial,12,22 in which patients initially enrolled in CRUISE or BRAVO continued therapy with as-needed treatment, fewer injections were required after the initial 12 months of therapy.
Focal laser therapy often is used adjunctively after 5–6 months of initial therapy.
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34. Retinal Vein Occlusion: Monitoring Retinal Nonperfusion
Patients with CRVO or BRVO who are given anti-VEGF therapy have shown differences in central nonperfusion.
However, these discrepancies have not been fully evaluated in clinical trials.
Peripheral retinal nonperfusion also may recover with anti-VEGF therapy.
This finding, however, also has not been fully studied.
Retinal nonperfusion often is a precursor to neovascularization and may be a measure for future studies.
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35. Retinal Vein Occlusion: Monitoring Retinal Nonperfusion
Retinal hemorrhage resolution improves with anti-VEGF therapy.
The mechanism for this clearance is not fully understood.
The use of scatter and focal laser photocoagulation also is important in these patients.
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36. Safety of Anti-VEGF Therapy
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37. Safety of Anti-VEGF Therapy
In recent clinical trials evaluating VEGF inhibition in patients with DME, exudative AMD, or RVO, endophthalmitis occurred in about 1% of patients, about the same frequency as reported in prior studies.
As previously mentioned, increased geographic atrophy has been observed in patients with neovascular AMD receiving monthly injections of ranibizumab or bevacizumab.10
However, this finding has not been reported in patients who were treated with VEGF inhibitors for DME or RVO.
It is not clear whether this increase in geographic atrophy is directly related to anti-VEGF therapy.
Systemic adverse effects in patients with neovascular AMD previously were evaluated in the SAILOR trial.24
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38. Safety of Anti-VEGF Therapy
Systemic adverse effects in patients with neovascular AMD previously were evaluated in the SAILOR trial.24
In the CATT trial, % of the bevacizumab group and 31.7% of those receiving ranibizumab developed one or more serious systemic adverse events, a statistically significant difference (P = 0.004).10
Serious adverse events included:
Death (6.1% for bevacizumab vs 5.3% for ranibizumab)
Arterial thrombotic events (5.0% vs 4.7%)
Venous thrombotic events (1.7% vs 0.5%)
Hypertension (0.7% vs 0.5%)
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39. Conclusion
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40. Conclusion
The use of anti-VEGF therapy continues to be a mainstay of medical retina therapy.
Increased use of VEGF inhibitors for retinal diseases has led to questions about:
Their efficacy and safety
Frequency of treatment
The possible application of “treat-and-extend” therapy
The potential role of corticosteroid implants in treating DME and RVO
A better understanding of the VEGF pathways and ways that VEGF affects normal physiology will increase our knowledge of these diseases.
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41. Conclusion
In DME, there appears to be a role for anti-VEGF agents.6–8,13–15
Regular monthly injections of these agents seem to produce greater benefit than does as-needed dosing.
Recent data from several large AMD trials demonstrated the efficacy of aflibercept11 and validated the off-label use of bevacizumab for neovascular AMD, albeit at the risk of a greater frequency of serious systemic adverse events when compared with ranibizumab.10
Monthly dosing also appeared to produce better outcomes in AMD than did as-needed dosing.10
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42. Conclusion
For RVO, anti-VEGF agents have changed treatment planning from observation to earlier intervention.
Further investigation is needed to determine long-term treatment strategies for these patients.
Recent trials have not demonstrated any higher frequency of adverse systemic effects or additional adverse events from VEGF-inhibitor therapy.
Future studies will supply greater details on the safety and efficacy of these agents and optimal dosing schedules.
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43. References
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Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419–1431.
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Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117:1102–1112.
Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. BRAVO Investigators. Ophthalmology. 2010;117:1124–1133.
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44. References
Heier JS. VEGF Trap-Eye for AMD: VIEW 1/VIEW 2 studies. Presented at the 2011 Annual Meeting of the American Academy of Ophthalmology (AAO) Retina Subspecialty Day; October 21, 2011; Orlando, Florida. Abstract 21.
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45. References
Holz FG, Amoaku W, Donate J, et al. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study. Ophthalmology. 2011;118:663–671.
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