Clinical Consultations

ANSWERING TODAY’S TOP QUESTIONS ON MANAGING PATIENTS WITH WET AMD

Introduction

The treatment of neovascular age-related macular degeneration (AMD) has rapidly evolved with the use of anti-vascular endothelial growth factor (VEGF) therapy. In 2013, anti-VEGF therapy is firmly established as the primary method of preserving vision for patients with wet AMD. Clinicians rely on data from relevant clinical trials for guidelines on who and how to treat wet AMD but such guidelines apply to only a narrow range of patients and often cannot be used in “real-world” situations. Novel approaches by clinicians can provide effective long-term management of wet AMD with varying degrees of evidence-based data. As with any evolving management strategies, questions arise as treatment strategies are refined over time. This continuing medical education program was designed specifically to address the top questions that retina specialists who treat patients with wet AMD across the United States are asking. The answers reflect the current evidence-based and/or consensus understanding of the issues relevant to managing patients with wet AMD in real-world settings.

The primary goal of this educational activity is to provide insight into the intricacies of clinical care in a setting where all of the information needed to optimize patient outcomes is not yet available.

Question 1. How do the anti-VEGF agents compare with each other in terms of efficacy, duration, safety, and cost?

There are 4 inhibitors of VEGF currently available in the US marketplace. Aflibercept (Eylea^®, Regeneron) is a VEGF trap molecule that is FDA-approved for neovascular AMD. Bevacizumab (Avastin^®, Genentech) is an antibody that is not approved by the US Food and Drug Administration (FDA) for AMD therapy but is widely used off-label for this purpose. Ranibizumab (Lucentis^®, Genentech) is an antibody fragment that is FDA-approved for the treatment of neovascular AMD and other retinal disorders. These 3 agents are pan-VEGF inhibitors: They block the effects of all isoforms of VEGF, of which there are several. The fourth agent is pegaptanib (Macugen^®, Valeant), a nucleic acid-based aptamer that selectively inhibits only 1 isoform of VEGF (VEGF165). In practical terms, pegaptanib is not commonly used because of its clinical inferiority to the pan-VEGF inhibitors so it has no significant role in the current treatment approach to neovascular AMD.

To date, no data exist that compare all 3 anti-VEGF agents in a single, contemporaneous, head-to-head trial. However, many studies have compared various pairings of these agents (Table 1).

To assess the relative efficacy, safety, and duration of action of these agents, cross-study comparisons are generally required. However, limitations exist with cross-study comparisons. The study populations are often different based on various eligibility criteria. In addition, dosing regimens typically vary from study to study, the interpretation of optical coherence tomography (OCT) images can be disparate, and clinical endpoints may also be different for each study. Despite these limitations, useful insights can be gained from carefully reviewing the major trials of anti-VEGF agents for neovascular AMD.

How Anti-VEGF Agents Compare on Efficacy

The first major study to compare bevacizumab and ranibizumab was the Comparison of AMD Treatments Trials (CATT),^1,2 which was designed with 4 arms: administration of bevacizumab monthly or as needed, and administration of ranibizumab monthly or as needed. Patients in the as-needed dosing groups received a single treatment at enrollment and were then followed monthly; only those patients in which visual acuity worsened or had evidence of active neovascularization on clinical exam, OCT, or fluorescein angiography were treated subsequently. The main outcome measure was the mean change in best-corrected visual acuity (BCVA) at 1 year. At the end of the first year, bevacizumab was deemed noninferior to ranibizumab when dosed monthly, while as-needed dosing of bevacizumab was not found to be noninferior to either agent dosed monthly. This is an important point and has been confirmed consistently in other large trials. No matter what anti-VEGF agent is studied, monthly dosing provides the best BCVA outcomes. The as-needed dosing groups required 7 to 8 injections (compared to 12 injections in the monthly treated groups) in the first year of CATT, with slightly more treatments needed in the bevacizumab as-needed dosing group than the ranibizumab as-needed dosing group. This unexpected finding established that these 2 agents have similar duration of action. Previously, it was a commonly held belief that bevacizumab lasted longer than ranibizumab, due to its longer half-life, but this was not evident in CATT based on the number of treatments in the as-needed dosing groups.

In year 2 of CATT, those patients on monthly dosing during the first year were randomly assigned to remain on monthly dosing or move to as-needed dosing. Those patients maintained on monthly dosing for the full 2 years had the best outcomes, establishing that the as-needed dosing regimen was inferior to the monthly dosing regimen with both agents (Figure 1).² Interestingly, those who switched from monthly to as-needed dosing for year 2 finished the year with BCVA measures comparable to those who had been receiving as-needed dosing from the start. These data reinforce the point that monthly dosing may lead to best outcomes over the first 2 years from a visual acuity perspective, and there may be a slight visual acuity cost to reducing the frequency of injections to less than monthly dosing with bevacizumab and ranibizumab. Another important conclusion from these observations is that no matter how long clinicians treat patients with AMD on a monthly basis, there is no permanent structural change regarding the effect of the anti-VEGF agent on the choroidal vascular membrane that is conferred to ease the treatment burden.

Figure 1. Two-year outcomes in CATT.²
Adapted from CATT Research Group et al, 2012.²

Although as-needed dosing may be statistically slightly inferior, it may be an attractive option in clinical practice. The actual outcome difference between the monthly and as-needed dosing arms in CATT was only an average of 2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. These 2 letters represented a statistically significant difference between the groups, but the clinical significance of 2 letters is more difficult to assess. It may merely be a “smudge in the glasses.” In some or most patients, it may be reasonable to give up those 2 letters in exchange for a reduced treatment burden, with fewer visits, fewer injections, and a reduced risk of complications. This is a discussion that clinicians and their patients must have on an individualized basis. However, it must be pointed out that the difference between monthly and as-needed dosing was an average of 2 letters overall; the real difference per patient may be more or less than 2 letters.

The Inhibit VEGF in Age-related Choroidal Neovascularization (IVAN) study, conducted in the United Kingdom, was the first international version of CATT with the treatment groups defined in the same way as CATT. Only a few differences were made in the study design for IVAN; the most notable change was the as-needed groups received 3 monthly loading doses of bevacizumab or ranibizumab and then were reloaded with every episode of recurrence.³ The IVAN results confirmed the CATT results in both years. Bevacizumab was not found to be noninferior to ranibizumab, and the discontinuous (as-needed dosing) arms were not noninferior to the monthly arms. Furthermore, results from the Groupe d’Evaluation Français Avastin versus Lucentis (GEFAL) study—which was conducted in France and followed the study design of both CATT and IVAN—confirmed through the first year similar findings that these 2 larger studies have shown.⁴

The VEGF Trap-Eye Investigation of Efficacy and Safety in Wet AMD (VIEW 1) and VIEW 2 studies compared the outcomes of patients who received ranibizumab with the outcomes of patients who received aflibercept.⁵ The VIEW studies were registration trials for aflibercept and had 4 arms: aflibercept, 0.5. mg or 2.0 mg, monthly, aflibercept, 2.0 mg, every other month (after 3 monthly loading doses), or ranibizumab monthly. The first year followed this fixed-dose regimen; in the second year all study arms required capped as-needed dosing, with 1 injection given every 3 months and additional retreatment given during the intervening months based on OCT and vision criteria. In year 1 of VIEW, the 4 groups had nearly identical visual acuity gains ranging from 8.3 to 9.3 letters in the pooled VIEW 1 and VIEW 2 data set.

How Anti-VEGF Agents Compare on Activity

No study has demonstrated a definitive difference in efficacy or durability between these 3 anti-VEGF agents, despite previous theoretical studies. For example, in vitro studies and pharmacokinetic modeling suggest that aflibercept has more anti-VEGF activity than ranibizumab or bevacizumab.⁶ Another study suggests that the amount of fluid on OCT is a surrogate for VEGF levels.⁷ If true, then the variable “drying effect of the 3 agents” suggests that aflibercept has more anti-VEGF activity than ranibizumab, which, in turn, has more anti-VEGF activity than bevacizumab.^1,2,5 These theoretical assertions regarding ultimate visual acuity outcomes have not been supported by large clinical trials. None of the comparative studies has demonstrated better vision with any of the 3 agents.

How Anti-VEGF Agents Compare on Duration of Action

CATT, IVAN, and GEFAL compared the outcomes of patients who received bevacizumab with the outcomes of patients who received ranibizumab, which reached consistent results on efficacy. There were no apparent differences in duration of action of these drugs in these studies. VIEW 1 and 2 compared aflibercept to ranibizumab. Interestingly, some study arms had substantially different outcomes between VIEW 1 and VIEW 2, varying by as much as 40%. Given that these patients met the same eligibility criteria, received the same treatment, and were followed with the same evaluation schedule, this finding underscores how variable neovascular AMD can be and why individualized patient care is recommended by the vast majority of US retinal specialists. In year 2, there was a small diminution of visual acuity with the transition to as-needed dosing, but all 4 groups still demonstrated remarkably similar outcomes (Figure 2).⁸ The mean number of injections in year 2 was only slightly less in the aflibercept arms compared to the ranibizumab arm (but both arms were still between 4 and 5 injections during the year). In other words, there was a level playing field for a head-to-head comparison in year 2 of VIEW between ranibizumab and aflibercept. Yet, neither efficacy nor durability comparisons showed any significant differences, although trends favored aflibercept in duration of action.

Figure 2. Two-year mean change in visual acuity outcomes of the VIEW studies.⁸
Adapted from Schmidt-Erfurth et al, 2013.⁸

As previously noted, limitations exist with cross-study comparisons. However, given the available data without the benefit of head-to-head comparisons of all anti-VEGF agents, these agents appear to have a similar duration of action in practice for treating neovascular AMD (Figure 3).

Figure 3. Comparison of number of doses in as-needed dosing arms of major anti-VEGF agents in (not head-to-head) trials for AMD.
RBZ=ranibizumab; BVZ= bevacizumab; AFL=aflibercept

How Anti-VEGF Agents Compare on Safety

In general, these anti-VEGF agents are viewed as safe. However, safety concerns include various ocular issues and systemic issues.

With respect to ocular safety concerns, questions about both the injection process and the specific agent that is injected have been raised. To date, there have been no reports of ocular safety issues conclusively and exclusively attributable to the anti-VEGF actions of any of these agents. Some injection-related concerns include endophthalmitis, traumatic cataract, and retinal detachment, although the risk of these problems has decreased in the years since intravitreal injections became commonplace in the vitreoretinal practice, mostly due to both experience and the refinement of protocols. However, there remains no standard protocol for intravitreal injection technique—the use of a lid speculum, mask, and even sterile gloves differs among clinicians. One interesting theory regarding endophthalmitis involves oral flora. Another issue that has arisen in recent times is the potential risk of contamination associated with aliquoting bevacizumab from the vial used for systemic cancer therapy into single-dose syringes for intraocular injection (see sidebar on Preventing Endophthalmitis).

The development and progression of underlying dry macular degeneration in the form of worsening geographic atrophy has been observed in some studies and seems to be associated with frequent injections and anti-VEGF activity in which the surrogate marker is “complete” drying of the macula.² It is unclear if this process is the same as the geographic atrophy seen in the dry form of AMD. Atrophy has been seen in association with all of the anti-VEGF agents. Analysis of some data has suggested atrophy occurs more often when patients receive high or frequent anti-VEGF dosing,^2-4 but keep in mind that these are the patients who tend to be the driest. More recently, atrophy has also been seen in patients with low exposure to anti-VEGF agents in other studies.⁹ Its frequency in eyes with dry AMD suggests that it may be part of the natural history of eyes that achieve dryness rather than being caused by exposure to anti-VEGF agents. Anti-VEGF therapy may address the neovascular component but not the non-neovascular component of this disease, and this progressive atrophy is most commonly associated with long-term vision loss in AMD, according to the SEVEN-UP study,⁹ which was a 7-year study of outcomes in ranibizumab-treated patients in the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial, the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) trial, and the Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (HORIZON). Further study is necessary to clarify this concern, particularly since anti-VEGF therapy is now being used for patients with diabetic macular edema who are younger than those we typically see with wet AMD and may have a greater exposure to these agents over their lifetime.

Elevations in intraocular pressure (IOP) are recognized as an uncommon but potentially serious consequence of long-term intravitreal anti-VEGF therapy. The cause of these IOP elevations remains unknown. Short-term IOP elevations can be attributed to the volume expansion associated with the injection. Long-term IOP elevations have also been reported and may be due to aggregates of molecules within the formulation and/or contamination from the syringes in which the drug is stored, among other possible causes.¹⁰ These IOP elevations are more common in people with preexisting glaucoma, and the risk also increases with a greater number of injections.⁸

Systemic safety is an additional consideration with these anti-VEGF agents. Patients with AMD are typically older than patients with diabetic macular edema (DME) and often have serious comorbidities. Patients with DME being younger may require longer courses of therapy with anti-VEGF agents. Therefore, the systemic safety profiles are important. Characterizing the relative safety of these medications is difficult for several reasons: (1) none of the studies have been powered sufficiently to establish systemic risk, (2) no head-to-head safety trials with all 3 anti-VEGF agents have been conducted, and (3) the sample size required to compare the rates of uncommon events in such head-to-head safety trials is prohibitively high and consequently they are unlikely to be performed.

Nonetheless, the systemic safety profiles of the 3 pan-VEGF inhibitors may be an important differentiator of these agents. Variations in safety profiles may potentially be due to structural differences among the different agents. The 2 larger molecules (aflibercept and bevacizumab) have the Fc component, unlike ranibizumab. Does the Fc component matter? Animal studies have shown that molecules containing the Fc component do tend to remain in the systemic circulation longer. This finding has been recently confirmed in humans. Human data on patients with wet AMD and retinal vein occlusion showed that plasma-free VEGF was lowered below the lowest level of quantification for bevacizumab and aflibercept.¹¹ In the IVAN study, bevacizumab was associated with significantly more systemic VEGF suppression than ranibizumab.¹² Whether or not this is a clinically relevant observation is unknown. In CATT, there were more serious systemic safety events in the bevacizumab groups than in the ranibizumab groups in both year 1 and year 2.^1,2 When this same trend was seen in the first year of the IVAN study,³ the IVAN data safety monitoring committee elected to inform all patients in the IVAN study of this potential risk and have them re-sign their consent forms if they wished to remain in the study.

Aflibercept’s systemic safety compared to ranibizumab was assessed in the VIEW studies, and the safety profiles were noted to be similar.⁷ Recently, the European equivalent of the FDA issued a report based on additional analysis of the raw data from VIEW and found some interesting trends.¹³ Their analysis stratified patients by age and looked separately at cerebrovascular events, such as strokes, and cardiovascular events, such as myocardial infarctions. The age stratification was conducted specifically to look at older people, who tend to have more comorbidities and generally frailer health. These researchers found that patients aged 85 years or older had a higher risk of cerebrovascular events in the aflibercept-treated groups and a higher rate of cardiovascular events in the ranibizumab-treated group than patients under 85 years of age during the first year of VIEW. Data at the end of year 2 pertaining to patients 85 years and older showed a cardiovascular event rate of 10.3% in ranibizumab-treated patients versus 7.4% in aflibercept-treated patients. The cerebrovascular event rate in this age group at the end of year 2 was 9.5% for those treated with aflibercept versus 3.4% for those treated with ranibizumab.

This apparent increased risk for cerebrovascular events in patients who are 85 years or older and who had a previous history of a cerebrovascular or cardiovascular event is not unique to aflibercept. In ranibizumab studies, patients with a prior history of stroke had a higher risk of stroke and death while receiving ranibizumab than patients who had no history of stroke.¹⁴ Similarly, a prior history of diabetes, hypertension, hyperlipidemia, or cardiac arrhythmias increased the risk of both strokes and cardiovascular events in patients who participated in the ranibizumab trials.¹⁴

These safety signals are seen consistently across studies for all anti-VEGF agents, and likely point to a real phenomenon. There may be a slightly increased risk of cerebrovascular or cardiovascular events with these anti-VEGF agents, particularly in vulnerable or high-risk patients such as those described. Fortunately, the increased risk is small and does not generally outweigh the benefits of these agents in recovering and maintaining vision for patients with neovascular AMD. Most patients with neovascular AMD would opt for treatment and accept the small risk rather than not receive anti-VEGF therapy and lose their sight from this disease. The risk of stroke or cardiovascular events should not alter the decision to offer anti-VEGF therapy, but it might alter which anti-VEGF agent is chosen for these potentially at-risk patients. The specific case of approaching therapy in a patient who has had a prior stroke is discussed later in this monograph.

How Anti-VEGF Agents Compare on Cost

Significant cost differences exist between these anti-VEGF agents, with the cost of bevacizumab therapy approximately 40 times less than therapy with ranibizumab or aflibercept. In fact, ranibizumab accounted for almost 10% of the total US Medicare Part B drug budget in 2010.²

Question 2. What are the roles of laser photocoagulation or photodynamic therapy (PDT) today?

Laser photocoagulation was the sole intervention for patients with neovascular AMD for many years, and numerous studies demonstrated that, despite its destructive and negative impact on visual acuity, laser photocoagulation led to better patient outcomes than the untreated natural history of the disease. In the modern era of anti-VEGF agents, there is little room left for laser photocoagulation, which may still have a role in rare situations for patients who present with a well-defined and entirely extrafoveal choroidal neovascular membrane.

PDT with verteporfin bridged the gap between photocoagulation and the development of anti-VEGF therapy as a reasonable intervention for smaller, predominantly classic lesions, but has since largely fallen out of favor. The MONT BLANC study, a double-masked, multicenter trial in Europe, was conducted to determine whether or not PDT combined with ranibizumab could reduce the anti-VEGF treatment burden of ranibizumab alone by decreasing the frequency of required injections.¹⁵ Patients with new-onset neovascular AMD were randomly assigned either to ranibizumab as needed or PDT plus ranibizumab as needed. By the end of 12 months, both groups required the same number of as-needed ranibizumab injections (about 5 injections), and the ranibizumab monotherapy group had better visual acuity outcomes than the group treated with PDF plus ranibizumab as needed.

PDT may be of value in patients with polypoidal choroidal vasculopathy (PCV). In the EVEREST study, patients with PCV were randomized to receive either PDT with verteporfin, ranibizumab, 0.5 mg, or the combination of both interventions.¹⁶ At month 6, PDT alone or combined with ranibizumab was found to be superior to ranibizumab monotherapy in achieving complete polyp regression (71.4% and 77.8% vs 28.6%, respectively; P=.01).

Another potential role of PDT is for patients who are refractory to therapy with anti-VEGF agents. If patients fail to achieve drying of the macula with anti-VEGF agents, adding PDT may stabilize some of these eyes by reducing the anti-VEGF treatment burden. As such, PDT is usually reserved for eyes with a relatively poor prognosis. A recent study based in southern California evaluated this approach in 26 eyes with persistent subretinal or intraretinal fluid despite 3 or more anti-VEGF injections.¹⁷ Researchers found significant improvements in visual acuity 1 and 3 months after rescue PDT (P=0.01), reductions in central subfield retinal thickness at 1, 3, and 6 months (P≤.0003), and an increase in the proportion of fluid-free eyes from 0.5% to 41% (P=.00001)—all while increasing the interval between required anti-VEGF injections from 1.6 to 2.7 months (P=.002).

Question 3. What is the role of imaging, and how does it guide clinical decision-making in caring for patients with neovascular AMD?

OCT remains the primary imaging modality for neovascular AMD in terms of monitoring the effect of therapy. Virtually every major study has used OCT-based treatment criteria, and most of these studies have used time-domain OCT. To date, only the Study of Ranibizumab Administered Monthly or on an As-Needed Basis in Patients With Subfoveal Neovascular AMD (HARBOR) has evaluated outcomes of as-needed therapy guided by spectral-domain OCT.¹² Certainly more retinal detail can be seen on spectral-domain OCT than time-domain OCT. It is unclear what the clinical significance is of seeing additional details such as small pockets of fluid. Some patients have residual fluid, especially subretinal and subretinal pigment epithelium, on spectral-domain OCT but have good and stable visual acuity. Treating them to dryness might be unnecessary and impossible; attempting to do so might represent unnecessary overtreatment. It is sometimes difficult to know when to stop treating the test results and focus on treating the patient.

Fluorescein angiography was once the only imaging modality for the diagnosis of AMD. It remains useful in establishing the diagnosis of neovascular AMD. In terms of following the response to anti-VEGF treatment, its role is more limited. Angiography can help distinguish between neovascular AMD and masquerade syndromes such as central serous chorioretinopathy or pseudovitelliform macular dystrophies. These entities should be considered whenever there is little or no response to initial anti-VEGF therapy. Angiography can also be helpful for patients with AMD who show a little fluid on OCT images but still have good visual acuity—it can help the clinician decide if the lesion is actively leaking or not. Similarly, angiography can reveal leakage in eyes with dry OCT images but declining visual acuity.

Indocyanine green angiography is less often used than fluorescein angiography in the clinical management of patients with AMD. Its primary role is in identifying PCV, and its routine use on all new patients with neovascular AMD remains controversial. It is also useful in helping to differentiate neovascular AMD from central serous chorioretinopathy.

Question 4. Do angiographic lesion classification and location matter anymore with anti-VEGF therapy?

Before the advent of anti-VEGF therapy, fluorescein angiography was routinely used to determine the lesion’s size, location, and angiographic subtype (predominantly or minimally classic or occult). These characteristics mattered in the era of photocoagulation and PDT because different lesion types responded differently to the various treatments available.

In ANCHOR, the majority of patients had predominantly classic lesions whereas in MARINA, they were typically minimally classic or occult.^18,19 Outcomes in these 2 studies were comparable, supporting the finding that lesion subtype is not important from the standpoint of anti-VEGF therapy. Both of these studies did show, however, that baseline lesion size was a predictor of outcomes, and HARBOR also showed that the area of leakage was predictive of acuity outcomes.¹²

Question 5. How often should the patient with neovascular AMD be retreated? When initiating therapy, should the dosing schedule be on a monthly, as-needed, or treat-and-extend basis?

There is little or no significant difference in visual outcomes of patients with neovascular AMD between monthly and as-needed dosing schedules in the first year of treatment, according to the major clinical studies, as long as these patients were monitored on a monthly basis. Patient outcomes in CATT, IVAN, and HARBOR (Figure 4) demonstrated that good visual acuity results can be achieved using as-needed therapy with a mean of 7 to 8 injections in the first year.^1,3,12 Interestingly, in as-needed dosing studies published to date in which the mean number of treatments of anti-VEGF therapy dropped below 5.5 injections in year 1, such as the Study to Evaluate Ranibizumab in Subjects With Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (SAILOR),¹⁴ the visual acuity results did tend to be suboptimal. Data from large claims databases suggest that clinicians are undertreating patients with wet AMD in clinical practice, with an average of 4 to 6 injections in the first year and far fewer in the subsequent years (Table 2).^20,21

Figure 4. Two-year outcomes of the HARBOR study.¹² Adapted from Busbee et al, 2013.¹²

The SEVEN-UP study was an extension of the MARINA, ANCHOR, and HORIZON studies and looked at patients treated with anti-VEGF therapy for a mean of 7.3 years, including an average follow-up period of 3.4 years since the completion of HORIZON.⁹ In that 3.4-year period, an average of 6.8 injections was given to each eye—2 injections per year. Not surprisingly, only 37% of the patients maintained visual acuity ≥20/70, and 23% of the patients had visual acuity ≥20/40 at the completion of SEVEN-UP. Another reason for this decline in visual acuity was the high incidence of atrophy seen with long-term follow-up.

The best approach proven to maximize long-term visual acuity is frequent, fixed-interval continuous therapy. While this approach—such as treatment with monthly bevacizumab or ranibizumab or every 2 months with aflibercept—is backed up with results from large clinical trials, it represents an enormous treatment burden for both patients and clinical practices, leading to overtreatment for some patients with AMD. In practice, clinicians favor individualized therapy with either as-needed treatment as previously described or a variable, continuous approach called the “treat-and-extend” approach. The latest practice pattern surveys indicated the treat-and-extend style of anti-VEGF therapy is now what the majority of retinal specialists favor. One reason for the shift away from as-needed dosing regimens is that the results in year 2 of CATT and IVAN did not show the as-needed dosing arms performed as well as the monthly treatment arms. By the end of year 2 in these studies, the as-needed dosing arms with bevacizumab and ranibizumab were not statistically noninferior to monthly treatment arms.

The treat-and-extend approach maintains continuous therapy—patients receive an injection at every visit regardless of their structural or functional status—but is variable in terms of time between visits. Typically, a patient with AMD who remains stable on monthly therapy may be extended to a 6-week follow-up schedule and treated on return visits. If still stable at that 6-week visit, the next visit may be pushed to 8 weeks, again with treatment at the 8-week visit regardless of the patient’s progress. In this way, many patients can be treated and extended to visits sometimes as far apart as every 10 or 12 weeks. On average, most patients with AMD make office visits every 6 to 8 weeks in the maintenance phase of therapy in year 1 and year 2 of treatment.

At this time, there is no level 1 evidence comparing the treat-and-extend style of therapy to either fixed, continuous (eg, monthly) or as-needed regimens. However, several compelling retrospective studies have found good visual outcomes over the course of about 1 year or so of treatment. Retinal specialists at the Wills Eye Hospital conducted a retrospective analysis of patients treated with either ranibizumab or bevacizumab and followed on a treat-and-extend regimen for a mean of 1.5 years.^22,23 The mean number of injections in the first year was in 7 to 8 injections to gain an average of 2.0 to 2.5 lines, and 96% to 98% of these eyes experienced a loss <3 lines while 32% to 33% of these eyes experienced a gain of ≥3 lines. These values are entirely consistent with outcomes reported in clinical trials with monthly therapy for patients with AMD and were not different between the 2 anti-VEGF agents studied.

A second study evaluated the treat-and-extend approach with ranibizumab in a prospective fashion. In this study, 45 patients received 3 monthly loading doses, after which the follow-up was increased or reduced by 2 weeks based on clinical examination and OCT findings.²⁴ At 12 months, mean visual acuity gains were 1.3 lines, with 95% of these eyes losing <3 lines and 26% of these eyes gaining ≥3 lines, which are outcomes consistent with monthly therapy in major trials.

A third study compared outcomes using the treat-and-extend (a total of 38 eyes) versus as-needed dosing (a total of 52 eyes) approaches.²⁵ At year 1, the eyes that received the treat-and-extend regimen had received a mean of 7.8 injections and had gained an average of 10.8 letters; the eyes in the as-needed dosing group had received an average of 5.2 injections and had gained 2.3 letters.

Several larger, prospective trials are now under way to evaluate the treat-and-extend approach. Some of the studies also include as-needed dosing groups and are designed to assess the potential benefits of spectral-domain OCT in improving outcomes with as-needed dosing as suggested by HARBOR findings. Until these data become available, the guiding principle is to achieve the best possible visual acuity outcomes using the least possible treatment.

It is also interesting to consider the patient’s perspective when determining treatment frequency. A recent survey of 150 patients with AMD who had received an average of about 12 injections over a 2.5-year period revealed that patients do not mind the process.²⁶ Almost 90% of these patients said they would agree to lifetime monthly therapy if that was necessary to preserve their vision. As noted, clinicians are probably undertreating patients with AMD and likely tend to minimize the injection rate because they think these patients want as few injections as possible. This is only half true—patients with AMD want as few injections as possible to achieve excellent outcomes. This finding supports the following underlying philosophy: Give only as many injections as are necessary to optimize outcomes, but be sure to give enough.

Question 6. If using an as-needed dosing treatment approach with an anti-VEGF agent, does the patient with AMD have to be seen monthly?

The major studies that included as-needed dosing treatment arms required monthly evaluations, and even under those optimal circumstances the visual outcomes in the as-needed dosing groups consistently fell below those in the monthly dosing arms. It seems clear that keeping the macula dry is better than letting it become wet and then drying it out over and over. It is likely that if the patient on an as-needed dosing regimen is seen less than monthly, the visual acuity outcomes will be inferior, as indicated in the findings from SAILOR.

Question 7. How many recurrences of fluid can be tolerated by patients with AMD before a change in therapy is warranted?

In general, smaller or less frequent recurrences are better tolerated than larger or more frequent recurrences. Clinicians need to make every effort to minimize the frequency and magnitude of recurrences because, in the long run, there may be incomplete recovery and vision loss with many recurrences over time. A more continuous style of therapy—either fixed and frequent or variable such as with the treat-and-extend approach—may be preferred over an as-needed dosing regimen when recurrences with the as-needed dosing approach are frequent.

In various head-to-head trials, these 3 anti-VEGF agents—bevacizumab, ranibizumab, and aflibercept—have been found to be similar in efficacy, on average. But within individuals, there is the possibility of differential responses, although the proportion of patients who would have a significantly different response to various anti-VEGF agents is likely to be low.²⁷

Furthermore, issues such as tolerance or tachyphylaxis, in which the chronic use of 1 agent may limit future response to that agent but not to other agents, may apply in certain patients with AMD, which may be the basis for the differences seen in switch studies. One study that evaluated 26 patients with AMD switched either from treatment with bevacizumab to ranibizumab (10 patients) or from ranibizumab to bevacizumab (16 patients) found 81% of these patients demonstrated some improvement.²⁸ Similarly, in patients with inadequate responses to treatment with either bevacizumab or ranibizumab and then switched to aflibercept (28 patients), 89% of these patients had a meaningful anatomic response within 1 month.²⁹

The bottom line is that when treatment with anti-VEGF agents for patients with AMD fails to perform as expected, it is reasonable to try something different.

Question 8. Can anti-VEGF agents be given every 2 weeks, or can the dose be doubled in patients who are inadequately controlled on standard dosing administered monthly?

In patients who are suboptimal responders, have developed tolerance to anti-VEGF agents, or have refractory disease, it is tempting to consider intensifying therapy by either increasing the dosing or decreasing the frequency of injections. HARBOR evaluated the relative efficacy of standard ranibizumab, 0.5 mg, dosing compared to a quadruple dose of ranibizumab, 2.0 mg.¹² Both doses had monthly and as-needed (after 3 monthly loading doses) arms. There was no significant difference in the groups receiving monthly doses of ranibizumab, 0.5 mg, (mean 10.1 letters gained at 12 months) or ranibizumab, 2.0 mg, (9.2 letters gained). The as-needed dosing groups gained 8.2 to 8.6 letters on average. So there appears to be no advantage in giving higher doses of anti-VEGF agents on average. However, this study did not focus on patients inadequately controlled on monthly dosing, so there may be a benefit to administering higher or more frequent doses in a specific subgroup of patients with refractory or more aggressive disease.

Question 9. If a patient with AMD has had a recent stroke, should that affect the selection of anti-VEGF therapy?

Some safety signals have been raised regarding the risk of stroke with anti-VEGF therapy. In the VIEW studies, more cerebrovascular events (strokes and transient ischemic attacks [TIAs]) occurred in the aflibercept-treated groups than in the ranibizumab-treated groups when looking at the vulnerable group of patients who are 85 years or older.¹³ In the head-to-head studies of bevacizumab versus ranibizumab, there were trends toward higher rates of systemic serious adverse events in the bevacizumab-treated groups that were not necessarily stroke-related.^2,3 The bottom line is that clinicians have more unanswered than answered questions regarding the risk of stroke with anti-VEGF therapy. Is there a causal relationship between anti-VEGF therapy and cerebrovascular events? Is the risk of cerebrovascular events different between these anti-VEGF agents? Are a prior stroke and a prior TIA considered equal risk factors for subsequent stroke while using anti-VEGF therapy? Does it matter how recently the stroke occurred? Clinicians cannot answer these questions with scientific confidence.

However, these patients who have experienced cerebrovascular events do exist in clinical practices, and clinicians have to manage their care based on the best available evidence. These patients warrant a cautious approach. First, there should be a candid discussion about the risk of cerebrovascular events, acknowledging all of the unknowns but involving the patient in the decision-making process. Whether or not it is appropriate at this time to have a conversation about strokes with all patients before initiating anti-VEGF therapy is unresolved; sometimes it is better for patients to hear it from the retina specialist up front than to hear it later from their cardiologist, neurologist, or their technology-savvy, Web-browsing children.

Once the decision is made to treat the patient’s AMD with anti-VEGF therapy—and these patients should be treated because the risk of blindness is real and imminent while the risk of cerebrovascular events is relatively small—several adjustments can be made to the typical treatment regimen. The most conservative interpretation of the available data suggests that ranibizumab may have the lowest cerebrovascular events rate, so this might be the preferred agent for a patient with AMD at high risk of cerebrovascular events. Regardless of the anti-VEGF agent chosen, an as-needed dosing or treat-and-extend approach might be preferable to monthly therapy, particularly if both eyes require treatment. Likewise, if the disease is bilateral, treating 1 eye at a time would reduce the total systemic exposure compared to simultaneous bilateral treatment. Ranibizumab is also available in a 0.3 mg dose for DME (as opposed to the standard 0.5 mg dose for AMD), and it is reasonable to consider using the lower dose in patients at risk for stroke—in fact, there was relatively little difference in efficacy outcomes in the phase 3 trials that compared these doses for AMD.^18,19 Smaller volumes of the other anti-VEGF agents can also be given by removing a bit of the dose from the syringe before injecting.

For example, a patient with AMD who is currently receiving treatment with anti-VEGF therapy may report having had a stroke or TIA since his or her last visit. In this case, discussion with the patient about the risk for stroke with anti-VEGF therapy is warranted. Options might include transitioning to ranibizumab or reducing the frequency of injections, either by transitioning from monthly to a treat-and-extend approach or, if already using a treat-and-extend approach, extending the treatment regimen further between injections.

Finally, in a patient who already has poor vision and is unlikely to recover significant vision but still warrants treatment, PDT might be a viable alternative to anti-VEGF therapy. Steroids could also be considered but the efficacy results in small studies have not been encouraging.

Question 10. Does a history of blindness from AMD in 1 eye alter your approach when the fellow eye needs treatment for AMD?

In theory, every eye is treated the best way possible, so there should technically be no difference in the management of the fellow eye. However, there is a psychological component for the patient—and often for the clinician—as well as other considerations. Monthly therapy would be the best approach to preserving vision in the second eye, although it comes with increased risks and treatment burden compared to as-needed dosing or treat-and-extend regimens. The bottom line is that clinicians must discuss the risks and benefits of anti-VEGF therapy and allow the patient to be an active participant in the decision-making process. Clinicians must individualize treatment based on each patient’s needs. •

Post Test

To obtain AMA PRA Category 1 Credit™ for this activity, complete the CME Post Test online at http://tinyurl.com/TopQuestionsWetAMD and receive an instant certificate of credit upon successful completion of the post test and evaluation.

References