How Anatomical Factors Can Affect Anti-VEGF Outcomes in AMD

OCT can play a crucial role.

Avnish Deobhakta, MD • Jason S. Slakter, MD

Given the historical propensity for the neovascular form of age-related macular degeneration to result in devastating vision loss,^1-2 much of the emphasis of treatment has focused on its management.³

Prior to the advent of advanced imaging, initial studies of neovascular AMD suggested that while generally resulting in severe vision loss if untreated, the type (fluorescein angiographic designation of classic, minimally classic, or occult) and location (extrafoveal, juxtafoveal, or subfoveal) of the neovascular lesion itself was significant in predicting future clinical outcomes.^4-8

Virtually all historical treatment studies for neovascular AMD, whether with thermal laser,^5,9,17 photodynamic therapy,^10,11 or surgery, or the current anti-VEGF therapy,^13-16 have respected the idea that lesion type and location can alter clinical outcomes.

The proliferation of newer modalities of imaging, such as spectral-domain OCT, which allows for better views of retinal architecture in vivo (and consequently, the precise location of neovascular tissue), has only underscored the prevailing wisdom that differences in retinal architecture can significantly affect future clinical outcomes.

BEFORE ANTI-VEGF: FLUORESCEIN, LASERS, AND SURGERY

The initial studies of treatments for neovascular AMD focused on thermal laser modalities. The Moorfields Macular Study Group,¹⁷ and the Macular Photocoagulation Study (MPS) Group^5,9 studies investigated thermal laser treatment vs untreated cohorts.

In both the Moorfields study and the analyses tested within the MPS, patients were restricted to having classic, extrafoveal (greater than 200 μm from the foveal avascular zone) CNV lesions and were randomized to treatment with argon laser photocoagulation or no treatment.

The MPS additionally investigated krypton laser photocoagulation, as well as the effects of laser photocoagulation on juxtafoveal (between 1 and 199 μm from the foveal avascular zone) and subfoveal CNV.¹⁸

The results of these studies suggested that patients with extrafoveal classic CNV derived the greatest benefit from macular photocoagulation; however, persistent and recurrent CNV often occurs in up to 60% of patients.¹⁹

Given that laser photocoagulation was limited to a small population of patients with neovascular AMD, PDT with verteporfin was investigated as a possible treatment modality. The procedure involved injection and preferential CNV localization of a photosensitive drug (verteporfin), with subsequently controlled activation using a targeted laser light, which caused closure of the CNV without damage to surrounding tissue. Thus, it was hypothesized that this treatment could be efficacious in lesions closer to the FAZ or even beneath the fovea itself.

The TAP investigation,¹⁰ the Visudyne In Minimally Classic CNV Trial,²⁰ and the VIP trial11 all attempted to assess this potential in patients with subfoveal CNV with a classic component (TAP), in those with subfoveal CNV with a minimally classic component (Visudyne in Minimally Classic CNV), and in patients with subfoveal CNV with an occult component (VIP).

The results of the TAP trial were encouraging: Treated patients were far less likely to suffer vision loss than their placebo counterparts. They were far more likely to retain their visual outcomes over five years, and they were far less likely to have lesion growth.¹⁰

The VIP trial demonstrated that patients undergoing PDT with verteporfin with this lesion type had less robust results, although compared to placebo, they were more likely to retain visual acuity over two years and were less likely to have lesion growth as well.²⁰

Also, the VIP trial, while demonstrating abatement of visual loss relative to placebo, like the two studies preceding it, showed verteporfin/PDT to be effective only in patients with occult CNV with smaller lesions and in patients with poor vision initially.¹¹

Taken in total, the clinical studies of PDT clearly demonstrated that specific characteristics of the neovascular complex (type and size of CNV lesion) had a direct impact on the effectiveness and safety of the treatment.

Figure 1A. Fluorescein angiography of a small classic type of neovascularization.

Figure 1B. Fluorescein angiography of a small minimally classic type of neovascularization.

Figure 1C. Early fluorescein angiography of a large occult type of neovascularization.

Figure 1D. Late fluorescein angiography of a large occult type of neovascularization.

SUBMACULAR SURGERY

Submacular surgery has also been tested as treatment for specific types of neovascular AMD, particularly in eyes with subfoveal CNV.¹² While the results of the Submacular Surgery Trials were equivocal with regard to overall visual acuity outcomes in treated vs untreated cohorts, they did demonstrate that patients with predominantly hemorrhagic subfoveal CNV experienced a reduction in severe vision loss (defined as a loss of greater than 6 lines at two years).¹²

Notably, meta-analyses of the untreated cohorts of all these trials were also performed to assess the natural history of the various angiographic types and locations of neovascular AMD lesions.²¹

These analyses found that the natural course of extrafoveal classic CNV results in vision loss of 3 lines or greater in more than half of all patients and that extrafoveal occult CNV results in slower progression of visual loss.

Juxtafoveal CNV was found to have a greater than 80% chance of resulting in more than 2 lines of vision loss at two years, with more than a 90% chance of conversion to subfoveal CNV.

Subfoveal CNV, of either the classic or occult variety, results in rapid vision loss, and in some studies, there was an 80% chance of 3 lines or more of vision loss in two years.²¹

Given the devastating nature of vision loss in this disease and the lack of a treatment modality with demonstrable visual gains, most clinicians continued to hope for a better solution.

AFTER ANTI-VEGF: OCTS AND INJECTIONS

The advent of OCT and anti-VEGF therapy induced a paradigm shift in the treatment of neovascular AMD. As the previously referenced studies demonstrate, anatomic factors were of paramount importance in both the natural history of the disease and the treatment outcomes for various patient cohorts.

However, the widespread use of OCT enabled clinicians to conduct a de facto optical biopsy of the retina, permitting a heretofore unprecedented depiction of where the CNV was located and how much of the overlying retina was affected.

Considering that the pathogenesis of neovascular AMD was hypothesized to be strongly mediated by vascular trophic factors,²² a particularly salient target to inhibit was VEGF.

One of the first attempts to subvert the function of VEGF was the use of the drug pegaptanib sodium, a pegylated aptamer that inhibits a specific VEGF isoform, VEGF165. The VISION study²³ included two phase 3 clinical trials that demonstrated that intravitreal administration of pegaptanib at six-week intervals over two years reduced the likelihood of moderate and severe vision loss in patients with all forms of neovascular AMD–mediated CNV.

Specifically, 70% of patients lost fewer than 15 letters of visual acuity, compared with 55% among the control group, and more patients receiving pegaptanib maintained or gained visual acuity, compared to those receiving sham injections.

Most notably, patients who continued on pegaptanib during the second year of the VISION study lost less visual acuity compared to even those who remained on PDT.²³

MORE POWERFUL VEGF INHIBITORS

Although the ability to inhibit a specific isoform of VEGF was useful, far more powerful inhibitors of VEGF were identified — in particular, ranibizumab and bevacizumab. Ranibizumab is an antibody fragment that inhibits all identified VEGF isoforms, and initial studies regarding its efficacy prompted future studies on these types of VEGF inhibitors.

While studies dealing with colorectal cancer treatment also demonstrated anti-VEGF efficacy,²⁴ systemic bevacizumab, a recombinant humanized IgG antibody with only VEGF-A specificity, was found to leak from choroidal CNV in animal models.²⁵

The SANA study²⁶ was subsequently launched. Patients with subfoveal CNV, many of whom were previously treated with pegaptanib or PDT, or both, received bevacizumab infusions and were found to have an average of 14 letters of visual gain, compared to control cohorts after 24 months.

Subsequent studies ensued to assess the safety and repeat efficacy of intravitreal bevacizumab, and they had similar success.²⁷ Of note, OCT was now being used to assess changes in the retina due to treatment, with bevacizumab treatment inducing a reduction in retinal thickness. ²⁸

Next, the MARINA trial²⁹ evaluated the efficacy and safety of ranibizumab for the treatment of minimally classic or occult with no classic CNV associated with AMD. This study demonstrated vastly lower rates of severe vision loss relative to sham injection and a mean gain in visual acuity from baseline to 24 months of 6.6 letters in the 0.5-mg group and 5.4 letters in the 0.3-mg group, compared with a loss of 14.9 letters in the shaminjection group.

The ANCHOR trial30 subsequently evaluated the efficacy and safety of ranibizumab vs the previous standard treatment of PDT/verteporfin in patients with predominantly classic CNV associated with neovascular AMD.

The mean change in visual acuity from baseline to 12 months was a gain of 11.3 letters in the 0.5-mg group and a gain of 8.5 letters in the 0.3-mg group, compared with a loss of 9.5 letters in the verteporfin group.

IDENTIFYING CORRECT DOSING

The extraordinary success of the newly created anti-VEGF therapies, not only in preventing vision loss but also enabling recovery of vision, spawned a large set of clinical trials designed to identify the correct dosing and timing of each drug, with an emphasis on qualitative and quantitative analysis of OCT findings.^31-34

Specifically, the PrONTO study³³ investigated how OCT-guided anatomic factors could allow for variable dosing of ranibizumab. The results suggested that if mean central retinal thickness and the presence of intraretinal fluid were used to guide treatment, equivalent visual outcomes could be achieved with fewer injections.³⁵

At this point, it could be seen that a paradigm shift had taken place in the management of CNV. No longer were fluorescein angiography and analysis of lesion characteristics playing crucial roles in treatment decision-making. Instead, OCT had become the key determinant in identifying and managing the disease.

A recent meta-analysis of the data from the HARBOR, ANCHOR, and MARINA studies revealed useful information regarding lesion size and angiographic subtype related to treatment outcomes. Specifically, while patients who received either 0.5 mg or 2.0 mg of ranibizumab ultimately had global lesion size reduction, those who received monthly doses (as opposed to those on a PRN treatment dosing schedule) showed larger reductions in mean total lesion size as assessed by FA. This finding also held for mean total CNV size changes.

Notably, patients who received 2.0 mg ranibizumab on a monthly dosing schedule, while having a statistically similar visual outcome to the other patient cohorts (ie, those receiving 0.5 mg monthly, 0.5 mg PRN, and 2.0 mg PRN doses), had the largest reductions in both mean lesion size and mean CNV size.³⁶

However, while dosing schedule was shown to affect mean changes in lesion size, lesion size itself was found to have a significant effect on visual outcomes as well. In particular, a regression analysis performed on data from the ANCHOR, MARINA, and HARBOR trials demonstrated that for lesions smaller than 4.34 disc areas (approximately 11.02 mm²), there was a statistical trend toward better visual outcomes.³⁶

Figure 2A. Early indocyanine green angiography of an anti-VEGF nonresponse in a patient with PCV. Note the increased hyperfluorescence in the inferotemporal macula, corresponding to a polyp in the late frame.

Figure 2B. Late indocyanine green angiography of an anti-VEGF nonresponse in a patient with PCV. Note the increased hyperfluorescence in the inferotemporal macula, corresponding to a polyp in the late frame.

SMALLER LESIONS FARED BETTER

Moreover, lesions of the predominantly classic variety were found to have the best visual outcomes, followed by minimally classic lesions, with occult lesions having the least gains in visual acuity. Further analysis of these groups on the basis of lesion size demonstrated that in all angiographic subtypes, smaller lesions fared better than larger lesions in terms of visual outcomes.

Interestingly, when lesion size, angiographic subtype, and dosing schedule (monthly vs. PRN) were analyzed together, patients with classic CNV-containing lesions (predominantly classic or minimally classic) on PRN dosing schedules with larger lesions (greater than 4.34 disc areas) showed a greater drop-off in visual acuity due to lesion size than patients who were on a monthly dosing schedule; patients with occult-only lesions showed fairly similar decreases in visual acuity based on lesion size, regardless of dosing schedule. It is believed that, given the natural history of classic lesions to undergo far more rapid growth and subsequent visual decline,²¹ these lesions may require more frequent treatment to reduce their disease burden effectively.³⁶

The advent of aflibercept, a protein consisting of extracellular components of both VEGF receptors 1 and 2 fused to the constant region of an IgG1 molecule, has provided a separate treatment modality, as it has been shown to be noninferior to monthly ranibizumab (VIEW-1 and VIEW-2 studies).¹⁶

Given its increased half-life relative to ranibizumab and its increased affinity for VEGF relative to bevacizumab,³⁵ it is possible that the addition of aflibercept, with OCT guidance, could assist in patients who are recalcitrant to therapy.

However, despite the development of these new therapies and the usefulness of OCT in viewing anatomic changes to modify treatment, as many as 10% of patients do not respond to standard therapy.³⁰ Patients often present with persistent macular fluid, disciform scarring, hemorrhage, atrophy, and, ultimately, vision loss.

Indeed, in many of these cases, lesion type is of paramount importance in guiding therapy. In particular, the use of FA and indocyanine green angiography can reveal the certain disease entities that are refractory to treatment, such as central serous chorioretinopathy and polypoidal choroidal vasculopathy.

In these cases, the options include alternating bevacizumab and ranibizumab every two weeks, to allow for sustained anti-VEGF inhibition, or combination therapies, including PDT, intravitreal corticosteroids, or both.^34,35

CONCLUSION

The treatment of neovascular AMD has undergone a radical change over the last three decades. Pending a complete treatment overhaul, the paradigmatic shift from photocoagulation and surgery to injectable anti-VEGF therapies, with their relatively better outcomes, is likely here to remain for the near future.

Lesion composition and size continue to play important roles in treatment, and the use of FA and indocyanine green angiography can be indispensible in assisting practitioners with regard to lesion classification.

Moreover, given the ease with which OCT enables physicians to identify anatomical changes, as well as the potential imaging advances currently being developed, treatment methods that extensively leverage multimodal imaging techniques are likely the best course of action. RP

REFERENCES

1. Attebo K, Mitchell P, Smith W. Visual acuity and the causes of visual loss in Australia. The Blue Mountains Eye Study. Ophthalmology. 1996;103:357-364.

2. Klaver CC, Wolfs RC, Vingerling JR, et al. Age-specific prevalence and causes of blindness and visual impairment in an older population: the Rotterdam Study. Arch Ophthalmol. 1998;116:653-658.

3. Ferris III FL, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol. 1984;102:1640-1642.

4. The Moorfields Macular Study Group. Treatment of senile disciform macular degeneration: a single-blind randomized trial by argon laser photocoagulation. Br J Ophthalmol. 1982;66:745-753.

5. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy. Five-year results from randomized clinical trials. Arch Ophthalmol. 1991;109:1109-1114.

6. Coscas G, Soubrane G. Argon laser photocoagulation of subretinal neovascularization in senile macular degeneration. Results of a randomized study of 60 cases. Bull Mem Soc Fr Ophthalmol. 1983;94:149-154.

7. Soubrane G, Coscas G, Francais C, Koenig F. Occult subretinal new vessels in age-related macular degeneration. Natural history and early laser treatment. Ophthalmology. 1990;97:649-657.

8. Bressler SB, Bressler NM, Fine SL, et al. Natural course of choroidal neovascular membranes within the foveal avascular zone in senile macular degeneration. Am J Ophthalmol. 1982;93:157-163.

9. Macular Photocoagulation Study Group. Krypton laser photocoagulation for neovascular lesions of age-related macular degeneration. Results of a randomized clinical trial. Arch Ophthalmol. 1990;108:816-824.

10. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials - TAP report 2. Arch Ophthalmol. 2001;119:198-207.

11. Verteporfin In Photodynamic Therapy (VIP) Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization - Verteporfin In Photodynamic Therapy report 2. Am J Ophthalmol. 2001;131:541-560.

12. Submacular Surgery Trials (SST) Research Group. Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: ophthalmic findings: SST report no. 13. Ophthalmology. 2004;111:1993-2006.

13. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.

14. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006;114:363-400.

15. Rosenfeld PJ, Brown DM, Heier JS, et al.; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.

16. Schmidt-Erfurth U, Chong V, Kirchhof B, et al. Primary results of an international phase III study using intravitreal VEGF Trap-Eye compared to ranibizumab in patients with wet AMD (VIEW 2). Paper presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; Fort Lauderdale, FL; May 1-5, 2011.

17. The Moorfields Macular Study Group. Treatment of senile disciform macular degeneration: a single-blind randomized trial by argon laser photocoagulation. Br J Ophthalmol. 1982;66:745-753.

18. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials. Arch Ophthalmol. 1993;111:1200-1209.

19. Macular Photocoagulation Study Group. Persistent and recurrent neovascularization after laser photocoagulation for subfoveal choroidal neovascularization of age-related macular degeneration. Arch Ophthalmol. 1994;112:489-499.

20. Visudyne In Minimally Classic Choroidal Neovascularization Study Group. Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration: 2-year results of a randomized clinical trial. Arch Ophthalmol. 2005;123:448-457.

21. Pauleikhoff D. Outcomes of neovascular AMD. Retina. 2005;25:1065-1084.

22. Grossniklaus HE, Green WR. Choroidal neovascularization. Am J Ophthalmol. 2004;137:496-503.

23. VISION Clinical Trial Group. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology. 2006;113:1508-1521.

24. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3:391-400.

25. Tolentino MJ, Husain D, Theodosiadis P, et al. Angiography of fluoresceinated anti-vascular endothelial growth factor antibody and dextrans in experimental choroidal neovascularization. Arch Ophthalmol. 2000;118:78-84.

26. Moshfeghi AA, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration. twentyfour-week results of an uncontrolled open-label clinical study Ophthalmology. 2006;113:2002-2011.

27. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006; 114:363-400.

28. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005; 36:331-335.

29. Rosenfeld PJ, Brown DM, Heier JS, et al.; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.

30. Brown DM, Kaiser PK, Michels M, et al.; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.

31. Abraham P, Yue H, Wilson L. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2. Am J Ophthalmol. 2010;150:315-324.

32. Schmidt-Erfurth U, Eldem B, Guymer R, et al.; EXCITE Study Group. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration. the EXCITE study. Ophthalmology. 2010;118:831-839.

33. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO study. Am J Ophthalmol. 2009;148:1-3.

34. Kovach JL, Schwartz SG, Flynn HW Jr, Scott IU. Anti-VEGF treatment strategies for wet AMD. J Ophthalmol. 2012;2012:786870.

35. Slakter JS. What to do when anti-VEGF therapy “fails.” Retin Physician. 2010;7(5):35-40.

36. Slakter JS. Update on ranibizumab. Paper presented at: 8th Annual Retinal Physician Symposium; Miami, FL; March 28-31, 2012.