The Comparison of AMD Treatments Trails (CATT) multicenter, single-masked, noninferiority trial evaluated 1,208 patients, comparing the safety and efficiency of bevacizumab (Avastin; Genetech) vs ranibizumab (Lucentis; Genetech) in neovascular AMD. The trial also evaluated monthly vs as-needed (discontinuous) administration of these drugs.¹ The CATT study spanned 2 years, with results released in 2011 and 2012.^1,2 While NIH funding was not secured to extend CATT past 2 years, the authors secured funding for the CATT Follow-up Study, which allowed for a single evaluation of patients at 5 years. This included 647 (70.8%) of the 914 living patients enrolled in the initial trial, with results published in 2016.³

1-YEAR CATT RESULTS

In the 1-year results, the authors concluded that administration of bevacizumab was equivalent to ranibizumab for mean number of letters gained and the proportion of patients who maintained stable VA (less than 15 letters lost). In a direct comparison of monthly bevacizumab and ranibizumab, there was an increase of 8.0 letters vs 8.5 letters, respectively. As-needed administration of bevacizumab and ranibizumab resulted in gains of 5.9 letters vs 6.8 letters, respectively.¹ There was no statistical significance between the groups. More than 91% of patients lost fewer than 15 letters from baseline, regardless of which drug or dosing regimen they received, with no statistical significance between the groups.

The authors concluded that VA results were impressive even with as-needed regimens. The results were corroborated by 5 other studies comparing intravitreal bevacizumab to ranibizumab, which found no differences in the effectiveness or safety of either agent.^4-9

In terms of anatomical changes, both drugs produced an impressive decrease in central subfoveal thickness after the initial injection, with the proportion of patients maintaining no fluid on OCT ranging from 19.2% in those treated with as-needed bevacizumab to 43.7% in those treated with monthly ranibizumab (P<.001). The mean lesion size on fluorescein angiography showed no change in the monthly treatment groups, although it increased slightly in the as-needed treatment groups (P=.047). In an analysis of serious adverse events compared to combined dosing regimens, bevacizumab had slightly higher frequency of events compared to ranibizumab, with a relative risk ratio of 1.29 (confidence interval 1.01 to 1.66, P=.04).

Contrastingly, no other study has corroborated this higher incidence of serious adverse events with bevacizumab.^8,9 There was no difference in deaths or arteriothrombotic events. The authors also calculated the average cost per year for each drug regimen, with monthly ranibizumab totaling $23,400, compared to $385 in the bevacizumab as-needed treatment group.

2-YEAR CATT RESULTS

At 2 years, 1,107 patients were included from the original trial. The same general trends were found at 2 years as in year 1 in terms of mean number of letters gained and the proportion of patients maintaining stable VA. The monthly administration of bevacizumab and ranibizumab resulted in an average gain of 7.8 vs 8.8 letters, respectively; while as-needed administration resulted in an average gain of 5.0 and 6.7 letters, respectively (drug, P=.21; regimen, P=.046). In congruence with the 1-year results, more than 88% of patients lost fewer than 15 letters, irrespective of their drug or dosing regimen, with no statistical difference between groups. In comparison to previous studies implementing observation or photodynamic therapy, 60% of patients in all groups maintained vision of 20/40.^10,11

At 2 years, the monthly treatment groups gained 2.4 more letters compared to the as-needed groups, regardless of drug used (P=.046). Interestingly, a small advantage emerged with the monthly ranibizumab group gaining 3.8 more letters compared to the bevacizumab as-needed group. Overall, the authors found that monthly administration of either drug for the first year did not protect against vision loss once switched to as-needed dosing in the second year. Patients switched to an as needed regimen after 1 year of monthly treatments for either drug had an average loss of 2.2 letters, which was equivalent to as needed dosing for the entire 2-year period.²

The proportion of patients without fluid on OCT ranged from 13.9% in the bevacizumab as needed group to 45.5% in the ranibizumab monthly group (P=.0003). However, switching from monthly administration to as-needed administration during year 2 resulted in greater residual fluid on OCT. Similar to the 1-year results, the highest proportion of patients with no fluid on OCT belonged to the monthly ranibizumab group, but this group also had a higher proportion of patients with GA.² In addition, GA was highest in the 2 groups of monthly treatment as compared to the as-needed treatment groups.

The mean increase in lesion area on fluorescein angiography was greatest in the as-needed treatment groups (drug, P=.006; regimen, P=.0003). Higher rates of serious adverse events with bevacizumab were persistent in year 2, with a risk ratio of 1.3 (95% confidence interval, 1.07-1.57; P=.009). The authors concluded that the 2 agents had similar effects on VA over the 2-year period and that administrative regimens should be picked after carefully weighing the advantages and disadvantages associated with each.²

5-YEAR CATT RESULTS

In 2016, the authors of CATT released the data for the 647 patients with available VA (71%), at 5 years.³ It is important to note that after the conclusion of CATT, 60% of the patients were treated with an agent other than the originally assigned medication. In contrast to the gain of letters at the conclusion of CATT, on average, patients lost 3.3 letters from their baseline and 10.8 letters from their year 2 visit. Eyes that had originally been assigned to bevacizumab lost fewer letters at the 5-year visit than their counterparts assigned to ranibizumab (-8.8 vs -12.7 letters, respectively; P=.008). There was no statistically significant difference between these outcomes based on originally assigned treatment regimen.³ In addition, the percentage of eyes with vision of 20/200 or worse had increased to 20% at the follow-up visit, as compared to the initial 5% to 6% in the baseline and 2-year mark of CATT.³ While the VA gains did not persevere through the 5-year follow up visit, a similar percentage (50%) of patients had vision of 20/40 or better.

The authors hypothesized that a decreased frequency of injections may contribute to the inability to maintain VA in the patients after the conclusion of CATT. Similar to previously published reports, increased injection frequency resulted in better maintenance of VA, whereas decreased injection frequency was linked to worsening vision.12-14 Moreover, the authors believe that their previously established association of monthly ranibizumab with GA was likely not meaningful, furthered by published reports in the Inhibit VEGF in Age-related choroidal Neovascularization (IVAN) study reporting a similar incidence of GA in eyes treated with bevacizumab and ranibizumab.¹⁵ However, the authors did acknowledge that monthly injections with either agent are likely more consistent with the development of GA.³ This was further supported by the results of the IVAN study, which also concluded that those receiving monthly treatments were more likely to develop GA than as-needed treatments (34% vs 26%, P=.03).¹⁵

Therefore, it is difficult to elucidate whether overtreatment or undertreatment is the cause of decreased VA in patients after the conclusion of CATT.¹⁶ In terms of serious adverse events, the patients who were originally assigned to ranibizumab had more arteriothrombotic events. However, because these events were equivalent when drug exposure was controlled, the authors concluded that these differences are likely not attributed to the drug assignment themselves.

CATT TODAY

Currently, ranibizumab, in addition to aflibercept (Eylea; Regeneron), have FDA approval for the treatment of neovascular AMD. Phase 3 trials have shown 8-week injections of aflibercept to provide the same visual gains as ranibizumab monthly.^17,18 Although they are FDA approved, multiple studies have pointed out the exponentially higher cost of using ranibizumab or aflibercept in place of bevacizumab.^1,3 In addition, the aforementioned studies demonstrate the equivalent outcomes with intravitreal bevacizumab vs intravitreal ranibizumab at the 1- and 2-year mark in terms of visual gains and maintenance. Moreover, the slight increase in VA in ranibizumab is lost at the 5-year follow up. Therefore, most ophthalmologists opt for bevacizumab as their first-line therapy for neovascular AMD.

These trends were recently captured in the American Society of Retina Specialists (ASRS) Preferences and Trends (PAT) survey. Retina societies around the world were surveyed, with 1,127 members responding in 2016.^19,20 Most retina specialists choose bevacizumab for their first-line treatment in neovascular AMD. In the United States, 65% preferred bevacizumab.²⁰ In contrast to previous studies, which implement stringent monthly or as-needed injections, 78% of US retinal specialists employ a treat-and-extend treatment protocol.^20,21 Interestingly, most retinal specialists believe that VA tends to improve then stabilize in chronic neovascular AMD; this ranged from 44.4% in Europe to 68% in South America. This is in contrast to the 5-year results of CATT, which showed regression to baseline vision. Retina specialists were also asked to explain why the most common treatment protocol was as-needed injections for neovascular AMD; most responded that they felt patients develop the same visual outcomes with either continuous or discontinuous dosing.¹⁹

CATT’S INFLUENCE ON DAILY PRACTICE

Overall, it appears that CATT, along with other clinical trials examining bevacizumab and ranibizumab, have influenced most retinal physicians in choosing bevacizumab as their first-line treatment for neovascular AMD. Both drugs are equivalent at the 2-year mark, but unfortunately, their effects do not persist through 5 years, likely due to a decrease in the frequency of treatment compared to the strict treatment protocols used while the patients were in the study. Further studies are required to determine the exact mechanisms behind the VA loss at extended follow-up. Regardless, these drugs have allowed for much better visual outcomes than previously seen with other treatment modalities for neovascular AMD. RP

REFERENCES

1. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908.
2. Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1398.
3. Maguire MG, Martin DF, Ying GS, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: The Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016;123(8):1751-1761.
4. Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 2012;119(7):1399-1411.
5. Solomon SD, Lindsley KB, Krzystolik MG, Vedula SS, Hawkins BS. Intravitreal bevacizumab versus ranibizumab for treatment of neovascular age-related macular degeneration: findings from a Cochrane systematic review. Ophthalmology. 2016;123(1):70-77.
6. Biswas P, Sengupta S, Choudhary R, Home S, Paul A, Sinha S. Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal neovascular membrane in age-related macular degeneration. Indian J Ophthalmol. 2011;59(3):191-196.
7. Kodjikian L, Souied EH, Mimoun G, et al. Ranibizumab versus bevacizumab for neovascular age-related macular degeneration: Results from the GEFAL noninferiority randomized trial. Ophthalmology. 2013;120(11):2300-2309.
8. Krebs I, Schmetterer L, Boltz A, et al. A randomised double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration. British J Ophthalmol. 2013;97(3):266-271.
9. Subramanian ML, Abedi G, Ness S, et al. Bevacizumab vs ranibizumab for age-related macular degeneration: 1-year outcomes of a prospective, double-masked randomised clinical trial. Eye (Lond). 2010;24(11):1708-1715.
10. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
11. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.
12. Singer MA, Awh CC, Sadda S, et al. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 2012;119(6):1175-1183.
13. Gillies MC, Campain A, Barthelmes D, et al. Long-term outcomes of treatment of neovascular age-related macular degeneration: data from an observational study. Ophthalmology. 2015;122(9):1837-1845.
14. Arevalo JF, Lasave AF, Wu L, et al. Intravitreal bevacizumab for choroidal neovascularization in age related macular degeneration: 5 year results of the pan american collaborative retina study group. Retina. 2016;36(5):859-867.
15. 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):1258-1267.
16. Avery RL, Ho A. CATT 5-year data: our perspective. Retina Today. 2016;July/August.
17. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-2548.
18. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121(1):193-201.
19. Rezaei KA. ASRS International Affairs Preference and Trends (PAT) Survey. American Society of Retina Specialists: 2016.
20. Rezaei KA. ASRS International Affairs Preference and Trends (PAT) Survey. American Society of Retina Specialists: 2014.
21. Agarwal A, Rhoades WR, Hanout M, et al. Management of neovascular age-related macular degeneration: current state-of-the-art care for optimizing visual outcomes and therapies in development. Clin Ophthalmol. 2015;9:1001-1015.