"Treat and Ignore": The Perils of Anti-VEGF Dosing

Monthly injections may not fit with every patient, but do more lengthy periods between injections ultimately do more harm than good?

"Treat and Ignore": The Perils of Anti-VEGF Dosing

Monthly injections may not fit with every patient, but do more lengthy periods between injections ultimately do more harm than good?

Milan Shah, MD • Philip J. Rosenfeld, MD, PhD

There's no question of the importance of inhibiting VEGF in the treatment of neovascular age-related macular degeneration. Prospective clinical trials, retrospective studies and our extensive experience with bevacizumab (Avastin, Genentech) and ranibizumab (Lucentis, Genentech) have confirmed the beneficial effects of anti-VEGF therapies in AMD. However, there is much confusion and uncertainty concerning the best strategy for dosing patients to achieve the best visual acuity outcome while minimizing the risks and inconvenience of therapy.


The first anti-VEGF drug approved by the Food and Drug Administration was pegaptanib sodium (Macugen, Eyetech) in December 2004.1 Pegaptanib was dosed every six weeks, but to this day, the optimal dosing regimen for this drug is still not known. In 2005, bevacizumab was first used off-label2 and was rapidly adopted worldwide, and retina specialists adopted a variety of dosing regimens into their clinical practices. These strategies included an every month dosing regimen; an every six weeks dosing regimen; a regimen guided by optical coherence tomography imaging requiring monthly follow-up with the goal of maintaining a fluid-free macula with injections given if there was any evidence of recurrent exudation; and a regimen known as treat-and-extend, in which patients are dosed monthly until a fluid-free macula is achieved. Dosing is then continued at each follow-up visit but visits are extended by two weeks if the macula remains fluid-free.

The OCT-guided approach was greatly influenced by the PrONTO study (Figure 1), which was designed to identify the fewest number of injections based on OCT imaging and monthly follow-up,3 while the treat-and-extend strategy was recommended as a way to maintain a fluid-free macula while decreasing the number of clinic visits.4 Of course, the gold-standard for treatment is the two-year monthly dosing regimen used in the phase 3 clinical trials for ranibizumab (Figures 2 and 3), which was FDA-approved in 2006.5-7 While proven to be safe and effective, monthly dosing for two years may not be necessary for most patients based on our clinical experience since the approval of ranibizumab, as suggested by the results of PrONTO and other variable dosing regimens.8 However, while monthly dosing for two years might be excessive, inadequate dosing and follow-up can be detrimental to our patients and must be avoided.

Figure 1. The injection protocol for the PrONTO study over a 24-month period.

Figure 2. Changes in visual acuity over 24 months as seen in the MARINA trial.

Figure 3. Changes in visual acuity over 24 months as seen in the ANCHOR trial.


Retinal physicians are always striving to deliver a treatment benefit while subjecting our patients to the least possible risk and inconvenience. For specialists treating neovascular AMD, this translates to the least number and the lowest frequency of anti-VEGF injections while maintaining the maximal visual benefit. While the PrONTO study was under way, Genentech designed a clinical trial known as the PIER study in an attempt to use fixed dosing intervals longer than one month rather than use OCT-guided therapy as the basis for retreatment.9

PIER was a two-year, phase 3b, randomized, double-masked, controlled trial involving 184 patients with all types of CNV. Subjects underwent 1:1:1 randomization to 0.3 mg or 0.5 mg ranibizumab or sham injections (Figure 4). Treatment was administered once monthly for three consecutive months, followed by subsequent injections every three months (quarterly) in all treatment arms, irrespective of clinical findings. The primary endpoint was the mean change in VA from baseline.

Figure 4. The treatment schedule over 24 month for the PIER trial.

On average there was some decrease in vision in all groups at the one-year interval (Figure 5): −16.3, −1.6, and −0.2 letters for the sham, 0.3 mg, and 0.5 mg groups, respectively (P ≤ .0001, each ranibizumab dose vs sham). While the 0.3-mg and 0.5-mg ranibizumab-treated patients had a better outcome than the sham-treated patients by +14.7 and +16.1 letters, respectively (P < .0001), only 83.3% and 90.2% of the 0.3-mg and 0.5-mg lost fewer than 15 letters of VA, compared with 95 % in the phase 3 clinical trials with monthly dosing, and only 13% experienced a gain of at least 15 letters compared with 35% to 40% in the phase 3 trials. Moreover, after three monthly doses at the start of the study, the mean visual acuity decreased over the ensuing 10 months, which was not observed in the phase 3 trials with monthly dosing.

Figure 5. Changes in visual acuity over 24 months as seen in the PIER trial.

This failure to appreciate the need for more frequent dosing was repeated in the subsequent HORIZON, SAILOR and EXCITE studies. The HORIZON study was the extension study from the phase 3 trails that permitted continued treatment with 0.5 mg ranibizumab once subjects had completed two years in the phase 3 trials.10 In this study, all patients were rolled over into active treatment with ranibizumab, but treatment was at the discretion of the investigator. However, rather than require monthly follow-up, Genentech underfunded the study and only required follow-up every three months. Not surprisingly, the average visual acuity decreased over the subsequent year when patients were ignored. At the Bascom Palmer Eye Institute, we continued to follow our patients monthly, and none of our 37 patients experienced a decrease in their visual acuity (Figure 6).

Figure 6. Changes in visual acuity over 12 months as seen in the HORIZON trial.

Prior to FDA approval of ranibizumab, Genentech offered early access to ranibizumab within a clinical study known as SAILOR.11 However, this one-year, phase 3b, randomized clinical trial suffered from the same flawed study design. After three monthly doses, patients returned at month three and then every three months thereafter for treatment based on a set of criteria that relied heavily on visual acuity testing and OCT imaging.

Both treatment-naïve and previously treated subjects were enrolled in two separate cohorts. Subjects in cohort 1 were randomized 1:1 to receive either 0.3 mg ranibizumab or 0.5 mg ranibizumab. The retreatment criteria for cohort 1 was based on a greater than five-letter decrease in visual acuity compared with the highest visual acuity score at a previous visit and/or >100 μm increase in central foveal thickness compared with the lowest measurement at any previous visit. cohort 2 received the 0.5 mg dose of ranibizumab.

Although the primary endpoint of the study was to evaluate safety, the secondary endpoint evaluated efficacy. All groups in cohort 1 demonstrated an increase in visual acuity after three consecutive injections; at month 3, treatment-naïve patients gained 5.8 letters in the 0.3 mg group and 7.0 letters in the 5.0 mg group. However, from month 3 to 12, there was a demonstrable decrease in this visual acuity improvement down to 0.5 letters in the 0.3-mg group and 2.3 letters in the 0.5-mg group. A similar trend was witnessed in the previously treated patients. The proportion of patients that gained ≥ 15 letters at the 12-month period ranged from 14.6% to19.3% depending on the subgroup analyzed. As with the PIER Study, the visual acuity scores improved over the first three monthly doses and then subsequently declined over the ensuing 10 months.

A similar suboptimal outcome was observed for the EXCITE study, which included monthly follow-up, but in this study, investigators were prevented from treating even when there was unambiguous OCT evidence of fluid in the macula accompanied by vision loss.8 This one-year, phase 3b, randomized, double-masked, active-controlled clinical trial involved 353 patients with all types of neovascular AMD. This was the first prospective study that directly compared the efficacy of monthly vs quarterly dosing of ranibizumab. Patients were randomized 1:1:1 to receive 0.3 mg or 0.5 mg ranibizumab quarterly or 0.3 mg ranibizumab monthly (Figure 7). In all treatment groups, patients received three consecutive monthly ranibizumab injections followed by either monthly or quarterly injections (every three months) for the remainder of the year. The primary endpoints were mean change in visual acuity and central retinal thickness up to one year of follow-up.

Figure 7. Treatment schedule for 12 months used in the EXCITE trial.

The mean change in VA from baseline was measured at 4.0, 2.8, 8.0 letters in the 0.3 mg quarterly, 0.5 quarterly and 0.3 mg monthly groups, respectively (Figure 8). The proportion of patients that lost fewer than 15 letters from baseline was 93.3 % (0.3 mg quarterly), 91.5% (0.5 mg quarterly), and 94.8% (0.3 mg monthly). Moreover, the proportion of patients gaining at least 15 letters from baseline was 14.2% (0.3 mg quarterly), 17.8% (0.5 mg quarterly), and 28.7% (0.3 mg monthly). All three groups showed similar VA gains in the first three months; however, the quarterly groups begin to diverge after month 3, with a drop in visual acuity while the initial gain in visual acuity in the monthly treatment arm was sustained for the duration of the study.

Figure 8. Changes in visual acuity over 12 months as seen in the EXCITE trial.

Although the gains in visual acuity were better than that seen in the PIER and SAILOR studies with quarterly dosed ranibizumab, the EXCITE study clearly demonstrated that quarterly maintenance dosing was inferior to monthly dosing. Not surprisingly, the loss of vision corresponded to the increase in macular fluid seen on OCT.


So what does this level one evidence from clinical trial data tell us about the "ideal" treatment regimen for neovascular AMD? We clearly know from phase 3 studies that three consecutive monthly injections results in a rapid gain in visual acuity that represents the majority of the visual gain with anti-VEGF therapy. This suggests that three consecutive injections on a monthly basis should be considered when treatment is initiated.

Second, the phase 3 trials clearly demonstrated that monthly anti-VEGF dosing provided a sustained visual acuity benefit and serves as our current gold standard. The visual acuity benefits derived from the quarterly dosing regimens in the PIER, HORIZON, SAILOR and EXCITE trials were clearly inferior compared with monthly dosing. But this does not mean that patients must be treated monthly to achieve the best possible visual acuity outcomes. It just means that treat-and-ignore is not a viable treatment option.

Retinal specialists must understand the difference between the failure to follow our patients and the failure of a poorly conceived clinical trial. Genentech failed to learn from the failure of the PIER study and perpetuated this flawed study design in both the SAILOR and HORIZON studies. In Europe, Novartis Pharmaceuticals compounded the mistake by running the EXCITE trial.

One cynical perspective for why this failed quarterly dosing strategy was repeatedly pursued is that it was purposely done to emphasize the importance of monthly dosing at the exclusion of more flexible dosing regimens. Retina specialists should always have the best interests of their patients in mind with the goal of obtaining the best vision possible while minimizing the number of injections. Maintaining an open dialogue with patients is the best way to solve this dosing dilemma. Patients can be told that we really do not know the best dosing regimen, but the evidence is strong that less frequent dosing with close follow-up is a viable option.

After reviewing the global clinical experience with anti-VEGF therapy, a recent paper concluded that an OCT-guided dosing regimen to achieve a fluid-free macula is a viable option in lieu of monthly dosing.8 Some patients would rather avoid an injection and maintain close follow-up, while others would prefer the injection in the hope of extending the retreatment interval. Both strategies are reasonable.


Whether it's monthly dosing, OCT-guided dosing or treat-and-extend dosing, there are advantages and disadvantages for the patient with each regimen, but above all, we should not be treating patients based on financially driven recommendations from industry, whether it is in the form of drug sales or rebates. By mid-2011, we should know for sure whether the outcomes from OCT-guided therapy are comparable to monthly dosing based on the results of the ongoing Comparisons of Age-Related Macular Degeneration Treatment Trials. But until then, we will have to use our clinical judgment and avoid the failed treat-and-ignore strategies used in the PIER, HORIZON, SAILOR and EXCITE trials. RP


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Milan Shah, MD, and Philip J. Rosenfeld, MD, PhD, are on the faculty of the Bascom Palmer Eye Institute of the University of Miami. Neither author reports any financial interest in any products mentioned in this article. Dr. Rosenfeld can be reached via e-mail at