We noticed you’re blocking ads

Thanks for visiting RetinaToday. Our advertisers are important supporters of this site, and content cannot be accessed if ad-blocking software is activated.

In order to avoid adverse performance issues with this site, please white list https://supplements.retinatoday.com in your ad blocker then refresh this page.

Need help? Click here for instructions.

Digital Supplement | Sponsored by Novartis Pharma AG

Clinical Value of Treat-and-Extend Regimen and the RIVAL Study

This supplement is intended for non-promotional scientific purposes only and may contain information on products or indications currently under investigation and/or that have not been approved by the regulatory authorities. The opinions and views expressed in this supplement are those of the faculty members and do not necessarily constitute the opinions or recommendations of Novartis. The presentations were accurate at the time of presentation. Any data on competitor product(s) are based on publicly available information at the time of presentation. Prescribing information may vary depending on local health authority approval in each country. Before prescribing any product, always refer to the SmPC or product information approved in your local country. Permissions for all content within have been received from each copyright holder for the presentations. Separate use, adaptation, and/or translation requires application for specific use permissions from each copyright holder. All product names, trademarks and registered trademarks are property of their respective owners.

In early clinical trials of ranibizumab in neovascular age-related macular degeneration (nAMD), such as ANCHOR and HARBOR, patients achieved impressive mean gains in vision with monthly dosing (11.3 and 10.1 letters, respectively, at 12 months).1,2 Patients in the 2007 PrONTO study achieved a similar mean gain of 9.3 letters with 5.6 injections given according to a prn regimen.3 These outcomes appear superior to the mean gain at 12 months of 6.2 letters with 8.7 injections reported in the 2018 TREND study of ranibizumab given according to a treat-and-extend (T&E) regimen.4 However, these results should be considered in light of the fact that the profile of patients enrolled into nAMD clinical trials has evolved since anti-VEGF agents first became widely available, with the average patient now having considerably better vision at baseline.

Patients in ANCHOR, HARBOR, and PrONTO had mean baseline VAs of 47.1, 54.5, and 56.2 letters, respectively, compared with 60.7 letters in TREND, meaning patients in the earlier trials had greater scope for improvement upon treatment.1-4 Indeed, comparing the absolute mean VA scores at 12 months in ANCHOR, HARBOR, PrONTO, and TREND (58.4, 62.7, 65.5, and 68.6), it can be seen that the best final mean VA score was seen with the T&E regimen in TREND.1-4 “It’s difficult to tell what matters the most,” said Prof. Patricio Schlottmann. “Is it the number of letters gained, or is it the final vision that the patient achieved? Baseline VA may confuse the comparison between trials.”

In a meta-analysis of 42 real-world observational studies of ranibizumab for nAMD published between 2007 and 2015, patients treated according to a T&E regimen achieved mean VA gains at 12 months of 8.8 letters, compared with 3.5 letters for prn.5 This was with a greater mean number of injections (7.3 vs 5.4), but fewer clinic visits (7.8 vs 8.6).5 More evidence for the benefits of T&E over prn dosing comes from a retrospective study of treatment-naive patients switching from a prn to a T&E regimen during routine clinical practice. A decrease in mean BCVA during prn maintenance therapy was reported following a gain achieved in the initial loading stage, followed by a sustained improvement in mean BCVA following the switch to T&E.6 In addition, greater variability was seen in intraindividual BCVA during prn treatment versus T&E. The mean number of visits was significantly higher during the prn phase (P < .001).6 “This evidence shows that T&E leads to a lower number of injections, greater comfort for the patient, and less burden for the clinician, for the system, and for the patient,” said Prof. Schlottmann.

The RIVAL study is the first randomized clinical trial to compare the two anti-VEGF agents ranibizumab and aflibercept using identical T&E regimens (Figure 1).7,8 This was a 24-month, partially masked, randomized, multicenter, phase 4 trial performed in Australia, with the primary objective being to discover whether a difference exists in the development of macular atrophy between the two agents in terms of growth in macular atrophy area over 24 months. Key secondary outcomes included number of injections and change in BCVA at month 12.7,8

Figure 1. RIVAL study design.

The T&E regimen used in RIVAL mandated three monthly loading injections before entering the T&E phase. During the T&E phase, the treatment interval was reduced by 2 weeks if one out of three prespecified disease activity criterion was present (out of loss of ≥ 5 letters from the best VA recorded since treatment started, new retinal hemorrhage, or the presence of any intra- or subretinal fluid on spectral domain-OCT), or to a 4-week interval if two or more of these criteria were present.7,8 “An important point is that the presence of fluid was detected by the reading center which was fully masked to the randomization of the patients, removing the possibility of bias,” said Prof. Schlottmann.

The 24-month results of RIVAL are now available, and they reveal no statistical difference between ranibizumab and aflibercept in terms of the primary endpoint, change in square root area of macular atrophy (P = 0.24; Figure 2).8 Longer term studies would be required to investigate the long-term effects of anti-VEGF on the development of macular atrophy.

Figure 2. RIVAL primary endpoint: change in square root area of macular atrophy.

Gains in BCVA with ranibizumab and aflibercept at month 24 were similar: 6.5 letters and 5.3 letters, respectively (Figure 3).8 There was some evidence that patients in the aflibercept arm took slightly longer to initially achieve their vision gains, which could not be accounted for by factors such as differences in baseline characteristics or clusters of slow gainers at particular study sites, implying treatment errors.

Figure 3. Mean BCVA change from baseline to 24 months in RIVAL.


  • A T&E regimen provides better VA gains with a reduced number of injections compared with prn.4
  • RIVAL is the first prospective randomized controlled trial comparing ranibizumab 0.5 mg and aflibercept 2.0 mg using a T&E regimen.7,8
  • RIVAL found no statistical difference between ranibizumab and aflibercept in terms of development of macular atrophy in nAMD patients treated over 24 months. Number of injections, VA improvements, and safety profiles were also comparable between agents.8

The mean numbers of injections were very similar between arms, with patients in the ranibizumab group receiving 17.7 over 24 months and those in the aflibercept group receiving 17. A return to monthly dosing at any time over the 24 months was triggered in 64% of the ranibizumab group and 59% of the aflibercept group. The mean injection interval over 24 months was 6.1 in both arms, and the distribution of maximum injection intervals was similar between groups (Figure 4).8 “If there was a myth of extra durability for one agent over the other, these results appear to dispel it: there is no difference between agents in terms of injection frequency,” said Prof. Schlottmann. Safety results showed similar rates of ocular and non-ocular serious adverse events in both groups.8

Figure 4. Maximum injection intervals over 24 months in RIVAL.

Patricio Schlottmann
  • Organización Medica de Investigación, Buenos Aires, Argentina