Timing Is Everything Clock Concept

Treat-and-Extend Maintains Vision Gains Long-term in Clinical Trials and Real-world Practice

In general, studies of anti-VEGF treatment outcomes in patients with neovascular age-related macular degeneration (nAMD) have not consistently shown maintenance of vision gains beyond two years, with undertreatment compared with strict clinical trial regimens a common explanation.1-3 Recent efficacy outcomes using a proactive treat-and-extend (T&E) approach for nAMD, however, suggest that initial vision gains can be maintained long-term and may help decrease the frequency of injections and visits over time. 

CANTREAT 36-month Extension Results

The CANTREAT randomized controlled trial demonstrated that the T&E regimen resulted in clinically meaningful improvement in best-corrected visual acuity (BCVA) that was not worse than monthly treatment using ranibizumab (Lucentis®, Novartis, Basel, Switzerland) for nAMD.4 At 2 years of follow-up in the CANTREAT study, more than 40% of patients in the T&E arm were able to be extended to the maximum treatment interval of 12 weeks. That was achieved using a T&E protocol that did not tolerate the presence of any retinal fluid.4 

The study was then extended to 36 months, with participants treated exclusively with a ranibizumab T&E dosing regimen. A total of 139 patients (73 in the T&E arm and 66 from the once-monthly arm) entered the extension phase and 121 patients completed the 12-month extension.5 

Dr. Peter J. Kertes, from Sunnybrook Health Sciences Centre in Toronto, Canada, discussed the CANTREAT extension study results at the recent American Society of Retina Specialists Virtual Annual Scientific Meeting (ASRS 2020).5 

Mean (SD) changes from baseline in BCVA at 36 months were 6.3 (11.61) letters for the T&E group and 3.9 (13.91) letters for the monthly dosing group switched to T&E. During the extension period, a mean (SD) of 7.3 (2.73) and 7.1 (2.80) injections were administered in the T&E and once-monthly T&E arms, respectively. Gains in vision and reductions in central retinal thickness at month 12 were sustained at both 2- and 3-year follow-up. 

Asked to highlight the main take-home message, Dr. Kertes commented: “Three-year extension data from the CANTREAT study further demonstrates that a treat-and-extend approach is a durable treatment strategy, where the visual acuity gains in year one can be maintained long term.”

He added: “It is also a ‘hard sell’ to suggest that newer agents may be significantly more durable than established anti-VEGF agents administered using a flexible treat-and-extend approach.”

Good Real-world Visual Outcomes Over 4 Years’ Follow-up of Anti-VEGF for nAMD 

Treat-and-Extend Maintains Vision Gains Long-term in Clinical Trials and Real-world Practice

Good 4-year functional and morphological outcomes using aflibercept (Eylea®, Bayer, Leverkusen, Germany) for treatment-naïve patients with nAMD in a real-life clinical setting were recently reported by clinicians at Moorfields Eye Hospital, London (Figure 1).6 

Patients were treated at fixed dosing intervals in year one followed by a personalized T&E dosing approach, with 94 eyes of 89 patients completing 4-year follow-up. 

From a mean ± SD visual acuity (VA) of 54.1 ± 15.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, mean VA improved by 7.8 letters to 61.9 letters at year one. At 4 years of follow-up, the mean ± SD VA was 60.4 ± 20.0 ETDRS letters (p < 0.0001), showing an overall mean VA improvement from baseline of 6.4 ETDRS letters. Central subfield thickness decreased most in year one and continued to decrease each year through follow-up.  

Thirty-three percent of eyes gained ≥15 ETDRS letters from baseline and 70% (n=66) were fluid free. Overall, 35% of eyes were 20/40 or better, a positive outcome considering that those with more advanced nAMD features such as central atrophy and fibrosis were not excluded. The mean number of aflibercept injections over 4 years was 19.32, with 7.41, 4.91, 4.21 and 2.29 injections in years 1, 2, 3 and 4, respectively. 

Dr. Praveen J. Patel, a consultant ophthalmologist at Moorfields Eye Hospital in London, explained in a telephone interview with the author: “We were pleased to see that excellent long-term treatment outcomes for nAMD can be obtained, even looking at four years after commencing treatment. Moreover, approaching 75% of the patients were being treated less frequently than every 8 weeks with aflibercept at 4 years of follow-up.

“Historically, long-term nAMD follow-up studies generally have not consistently shown maintenance of VA gain out to four or five years.2,3 One of the reasons that these studies have not reported the success that we have reported in our study is potentially due to using a pro re nata (PRN, as needed) approach rather than a T&E dosing regimen. We therefore advocate adopting a proactive treatment paradigm for treatment of nAMD with anti-VEGF therapy.”

Asked about current approaches to anti-VEGF maintenance therapy, Dr. Patel said: “The main shift has been in the first year of aflibercept treatment where we are happier to move into a T&E paradigm after the third loading injection, and to extend or intensify the treatment interval from the time of the first bimonthly injection. Treatment intervals are adjusted in 2-weekly increments but we have changed the aflibercept T&E protocol, by adopting a recommendation from the ALTAIR study, to extend treatment intervals potentially out to a maximum of 16 weeks.7 

“Also, we are increasingly more tolerant of subretinal fluid in the context of stable vision. If there is persistent fluid and stable vision, we are more likely now to maintain the treatment interval between injections.”

Editor’s Note: Rod McNeil is an independent medical journalist.

Treat-and-Extend Maintains Vision Gains Long-term in Clinical Trials and Real-world Practice


  1. Rofagha S, Bhisitkul RB, Boyer DS, et al, SEVEN-UP Study Group. Seven-year Outcomes in Ranibizumab-Treated Patients in ANCHOR, MARINA, and HORIZON: A Multicenter Cohort Study (SEVEN-UP). Ophthalmology. 2013;120(11):2292-9. 
  2. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group; 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.
  3. Gillies MC, Campain A, Barthelmes D, et al, Fight Retinal Blindness Study Group. Long-term outcomes of treatment of neovascular age-related macular degeneration: data from an observational study. Ophthalmology. 2015;122(9):1837-1845.
  4. Kertes PJ, Galic IJ, Greve M, et al. Efficacy of a treat-and-extend regimen with ranibizumab in patients with neovascular age-related macular disease: a randomized clinical trial. JAMA Ophthalmol. 2020;138(3):244-250.
  5. Kertes PJ. Canadian treat-and-extend trial with ranibizumab in nAMD patients: CANTREAT 36-month extension results. Presentation at the American Society of Retina Specialists 2020 Virtual Annual Meeting, July 26-28, 2020. 
  6. Lukic M, Eleftheriadou M, Hamilton RD, et al. Four-year outcomes of aflibercept treatment for neovascular age-related macular degeneration: Results from real-life setting. Eur J Ophthalmol. 2020. Article first published online: June 25, 2020.
  7. Ohji M, Takahashi K, Okada AA, et al. Efficacy and safety of intravitreal aflibercept treat-and-extend regimens in exudative age-related macular degeneration: 52- and 96-week findings from ALTAIR. Adv Ther. 2020;37(3):1173-1187.
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