Core Messages

›Three recent guidelines have addressed management of neovascular AMD (NV-AMD) with anti-VEGF agents, covering diagnosis, selection including classification of lesions as ‘active’ or ‘inactive’, and approaches to treatment with anti-VEGF agents, using monthly or flexible regimens. Most data from large randomized clinical trials has accumulated for ranibizumab therapy.

›A mandatory role for baseline fluorescein angiography in diagnosis is argued, as well as an ongoing critical place for optical coherence tomography (OCT), which detects VEGFinduced permeability changes. Newer spectral domain technology is now dominant. All NV-AMD lesion types and visual acuity (VA) categories are suitable for treatment, with smaller lesion size a consistent predictor of better VA outcomes. Parameters defining lesion ‘activity’ have been proposed as an important indicator of lesions that will benefit from treatment,

P. Mitchell (*) • S. Foran

Department of Ophthalmology, University of Sydney, Sydney, Australia

e-mail: paul.mitchell@sydney.edu.au; suriya.foran@sydney.edu.au

as well as acknowledging late signs indicating a poor/ futile outcome.

›Approaches and documented treatment outcomes are summarized, principally for the use of ranibizumab, including: (1) continuous monthly therapy; (2) initial ‘loading’ regimen of three injections followed by ‘as needed’ or ‘prn’ injections; and (3) a more recent ‘treat- and-extend’ regimen that has become increasingly popular, and appears to be a logical way to maximize gains, short of continuing monthly therapy, that still has the best documented outcomes. Achieving treatment for the earliest (and smallest) baseline lesions is stressed.

15.1Introduction

Age-related macular degeneration (AMD) is the principal cause of severe, irreversible vision loss and legal blindness in most Western countries, including Europe [1], North America [2–4], Australia [5, 6] and parts of Asia [7]. It has three manifestations, an early stage (early AMD), characterized by the appearance of large (soft) drusen or retinal pigmentary changes (either hyperpigmentation or hypopigmentation), and two alternate late stages, neovascular AMD (NV-AMD), characterized by the growth of choroidal new vessels beneath the neurosensory retina or retinal pigment epithelium (RPE), and geographic atrophy (GA), in which progressive loss of RPE becomes evident [8].

NV-AMD results in a considerable economic burden, estimated in Australia to cost approximately $5 billion

annually [9], an economic cost which is expected to rise with population ageing, and is now the focus for anti-VEGF (vascular endothelial growth factor) therapy.

Documented NV-AMD risk factors include increasing age, genetic and environmental factors. Considerable advances have occurred in the elucidation of key gene variants, including single nucleotide polymorphisms (SNPs) at complement factor H (CFH) and at the ARMS2 site, the LOC/HTRA complex [10, 11]. To date, over ten risk or protective SNPs have been identified that influence the development of NV-AMD [12]. Although it has been speculated that NV-AMD gene variants could influence the response to antiVEGF therapy, but to date data are conflicting, with some studies showing an influence [13–15], and others not confirming this. Among environmental factors, cigarette smoking is the most well established. Smoking increases the risk of NV-AMD (by around threefold) in all races so far examined, and also appears to induce its development at an earlier age.

15.1.1 Anti-VEGF Therapies for NV-AMD

Vascular endothelial growth factor-A (VEGF-A) is now the key target for various pharmacotherapies designed to inhibit choroidal neovascularization (CNV) and potentially arrest the progression of NV-AMD [16–18].

The first major phase III randomised controlled trial (RCT) of anti-VEGF therapy for NV-AMD was the VISION trial of pegaptanib sodium (Macugen®; EyeTech, New York, NY), a selective antagonist of the 165 VEGF-A isoform, which showed superior efficacy to verteporfin or sham [19], when given intravitreally at 6-weekly intervals. Although pegaptanib was then approved by the Food and Drug Administration (FDA) in December 2004, its routine use was supplanted to some extent by the substantially greater efficacy of ranibizumab. A recent open-label collaborative European study of 253 patients [20] showed somewhat better overall retention of vision (>90% of patients lost <15 letters from baseline, compared with 70% in the VISION trial [19] at 1 year).

The next major RCTs were for ranibizumab (Lucentis®; Novartis Pharma AG, Basel, Switzerland, and Genentech Inc., South San Francisco, CA, USA), which was developed as a recombinant, humanized, monoclonal antibody Fab fragment that inhibits all biologically

active VEGF-A isoforms [21]. The two largest studies to assess anti-VEGF therapy up to this time were the MARINA [22] and ANCHOR [23] phase III RCTs. They assessed monthly intravitreal ranibizumab for treatment of all types of NV-AMD. Both trials demonstrated substantial preservation of vision compared with sham intravitreal injections or intravenous photodynamic therapy with verteporfin; 94% of patients lost fewer than 15 letters (3 LogMAR lines) after 1 and 2 years, and over in one-third of patients, vision improved by at least 15 letters (3 LogMAR lines), after 1 and 2 years [22, 23]. Ranibizumab was approved by the FDA in June 2006 (as monthly 0.5 mg intravitreal injection), and has been the major anti-VEGF agent used worldwide for treatment of NV-AMD in the period since.

A pilot trial of an oncology product, bevacizumab (Avastin®; Genentech Inc., South San Francisco, CA, USA) which is a full-length monoclonal antibody active against all VEGF-A isoforms, was reported in 2005 [24] demonstrating apparent efficacy in NV-AMD. This drug had been approved by the FDA for colorectal cancer in 2004. It has subsequently been used extensively worldwide as an off-label intravitreal therapy for neovascular AMD [25, 26], and in one small, phase III randomised controlled trial [27], which showed somewhat similar efficacy to the pivotal ranibizumab RCTs.

Some large clinic series have shown somewhat similar efficacy for bevacizumab to ranibizumab [28], head-to-head trials comparing ranibizumab to bevacizumab are needed to provide more definitive information about the comparative effectiveness and safety of these two drugs [29]. Such studies are currently underway (Table 15.1) but are not scheduled to report until early in 2011 or in 2012. Included are the CATT (USA), IVAN (UK), VIBERA (Germany), MANTA (Austria), LUCAS (Norway), GEFAL (France), BRAMD (Netherlands) and EQUAL (Netherlands) trials, totalling over 4,000 patients. The CATT trial of 1,200 patients randomized 1:1:1:1 to four treatment groups: ranibizumab 0.5 mg fixed monthly injections, bevacizumab 1.25 mg fixed monthly injections, ranibizumab 0.5 mg 1+pro-re-nata (PRN), and bevacizumab 1.25 mg 1+PRN, is the largest. This trial will re-randomize half of the patients in the fixed regimens to the PRN regimen after 12 months.

A fourth agent (the oncology product, aflibercept, termed VEGF Trap-Eye; Regeneron Inc., Tarrytown,

Table 15.1 Head to head trials comparing ranibizumab and bevacizumab

NY, USA and Bayer Healthcare, Leverkusen, Germany) functions as a VEGF-A receptor decoy with a high affinity for all VEGF-A isoforms as well as placental growth factors (PIGF-1 and -2) [30, 31]. Positive data from the VIEW I and VIEW II phase III RCTs in almost 2,500 patients with NV-AMD have been reported in a press release (November 2010), but are not yet published.

15.1.2Evidence-Based Guidelines for Managing Diseases

Evidence-based guidelines for managing disease are systematically developed statements that are based on robust scientific evidence of the clinical effectiveness and safety of different therapies. While expert consensus often forms part of the process of developing guidelines, expert opinion by itself, even when in agreement, is no substitute for carefully assembled evidence, particularly those derived from the findings of major phase III RCTs, or from meta-analyses of multiple trial data.

A hierarchy of levels of evidence for therapeutic decisions is apparent. The strongest evidence (level I) is that derived from well-designed RCTs addressing

Table 15.2 Currently available guidelines for managing neovascular (NV-) AMD

the issue in question. These RCTs are often referred to as ‘pivotal’ trials, and form the basis for registration of products by regulators. The evidence they provide about the magnitude of therapeutic efficacy compared with previous standards of care, is often used in cost effectiveness analyses employed by payers in deciding reimbursement for new therapies. Substantial evidence (level II), however, may also be derived from less rigorous RCTs (e.g., those without a control group or with less than optimal follow-up), particularly if these studies answer specific questions about treatment that were not addressed in the pivotal studies. Finally, noncomparative studies without controls, descriptive studies, recommendations from panel consensus groups without specific evidence, or ‘expert opinion’ is regarded as relatively weak evidence (level III) [32].

Well-developed evidence-based guidelines have the potential to improve the quality of patient care in clinical practice, by assisting in decision making, improving the standard of diagnosis and treatment of particular conditions, reducing variability in practice, and pointing to the need for further research.

15.1.3Existing Guidelines for Managing NV-AMD with Anti-VEGF Agents

A number of guideline documents are currently available for the use of anti-VEGF therapies in the management of NV-AMD, as shown in Table 15.2 [26, 32–34, 36, 37]. In addressing five specific questions relating to the use of anti-VEGF therapy to manage NV-AMD, this review will focus on recommendations from the three most recent ‘guidelines’, published between February

2009 and October 2010 [32–34]. However, a number of other individual publications have also provided useful guidance to anti-VEGF therapy (particularly for ranibizumab) [35, 38, 39] and this literature is growing.

15.2Five Key Questions Addressed in NV-AMD Guidelines

These cover the following areas of clinical practice, in more or less detail:

1.How should NV-AMD be diagnosed?

2.Which NV-AMD lesions should be considered for anti-VEGF treatment?

3.What parameters define whether NV-AMD is active and would likely benefit from anti-VEGF therapy, and which features suggest that treatment would be futile?

4.Monthly therapy provides good visual outcomes for most – is there evidence that flexible therapy regimens also provide satisfactory visual outcomes? What flexible approaches are reported?

5.What are the long-term considerations in antiVEGF therapy of NV-AMD?

15.2.1How Should Neovascular AMD be Diagnosed?

Accurate diagnosis and classification of NV-AMD using recommended criteria is critical. Assessment should include: history (duration and characteristics of visual symptoms); visual acuity (VA); stereoscopic biomicroscopic slit lamp fundus examination (using a 78D or similar lens); fluorescein angiography (FA); and, where possible, OCT [33] (Table 15.3).

Logarithm of the minimum angle of resolution (logMAR) VA is strongly preferred to Snellen VA because of its greater sensitivity, ordered letter size progression, with five equally readable letters per line, reproducibility, and ability to compare with published trial data [40]. Non-geometric letter size progression and variable number of letters per line prevent Snellen outcomes from being easily equated to letters or lines of VA change [41].

In all three recent guideline documents, baseline FA was regarded as mandatory both to detect CNV as well as to exclude non-AMD causes (e.g., neovascularization due to myopic degeneration, pseudo-xanthoma elasticum, multifocal choroiditis, etc.), and to determine CNV extent, type, size, location, extent of leak, and the proportion of various lesion components [38, 42]. Indocyanine green angiography (ICG) may also be indicated when either polypoidal choroidal vasculopathy (PCV) [43, 44] or retinal angiomatous proliferation (RAP) is suspected [45], or if the extent of CNV in occult lesions is unclear [33].

A baseline OCT assessment was recommended by two of the three guidelines in order to define the extent of retinal thickening, its localization, and the qualitative pattern of extracellular fluid accumulation. OCT clearly detects VEGF-induced permeability changes in the retina, and the newer spectral domain (SD) OCT devices and software now permit a greatly enhanced view of early qualitative signs indicating NV-AMD activity, and a compartmental distribution of components [46], compared with the Stratus time domain model (TD-OCT). There may however be some differences between the various SD-OCT machines in their resolution of certain NV-AMD features [47].

15.2.2Which NV-AMD Lesions Should be Considered for Anti-VEGF Treatment?

The AAO guidelines recommend anti-VEGF therapy using either ranibizumab or bevacizumab for subfoveal CNV, and laser for extrafoveal classic CNV [32]. RCOphth guidelines emphasize focal laser for extrafoveal CNV, or anti-VEGF therapy when the clinician considers that the laser-induced scotoma would likely interfere with visual function [34]. For subfoveal/ juxtafoveal CNV, the RCOphth recommended anti-VEGF therapy, while also recommending PDT or combination treatment as possibilities, if regular clinic attendance is difficult [34]. For juxtafoveal lesions, anti-VEGF (‘retinal sparing’) therapy was recommended in the RCOphth guidelines in order to prevent direct foveal laser damage or later encroachment of the laser scar [34]. Inclusion of both sub-foveal and juxtafoveal lesions for recommended ranibizumab (antiVEGF) therapy was also confirmed by the worldwide advisory group paper [33].

All three major CNV subtypes (predominantly classic, occult [with no classic component], and minimally classic) were shown to respond to ranibizumab [22, 23, 33, 48] over 2 years, and are recommended for treatment with this agent. Although considerably lower patient numbers were included in the ABC trial, this study also suggested that all three lesion types also responded to 6-weekly intravitreal bevacizumab treatment [27].

Retrospective analyses of 24-month MARINA data showed that ranibizumab was superior to sham across all AMD lesion subgroups based on patient age, gender, CNV lesion type, lesion size, baseline VA and AMD duration [49]. The VA outcomes were predicted by CNV lesion size (greater VA benefit was observed in treatment of smaller CNV lesions), baseline VA level (greater VA gains occurred in patients with somewhat worse baseline VA, suggesting a ceiling effect in patients with better baseline VA) and age (slightly lower VA gains were found in patients in the oldest age groups), all level I evidence. As in a recent UK case series, poorer baseline VA was a predictor of maximum VA gain, but eyes with better initial VA had a substantially better final VA [50].

The finding that smaller CNV lesions had a better visual prognosis than larger lesions is important, and was

confirmed in the 12-month subgroup analysis of the ANCHOR data [51]. This outcome, which was also confirmed in the SUSTAIN and EXCITE [52] trials, indicates the need for the earliest referral, and emphasizes the need to start anti-VEGF treatment as soon as possible after diagnosis of an active CNV lesion [33, 34].

Although clinical data are only available for baseline VA levels between 20/40 (6/12) and 20/320 (6/72), the initial baseline VA did not limit the response to ranibizumab in ANCHOR and MARINA. All baseline VA subgroups gained with treatment [49, 51]. For example, cases with active sub-foveal/ juxtafoveal CNV and VA better than 20/40 (6/12) should always be considered for treatment, as these have the potential to retain the best possible vision outcomes, particularly for tasks such as reading and driving [33]. A recent UK report (level II evidence) in 14 patients addressed this issue. All patients with a baseline VA better than 6/12 maintained posttreatment VA of 6/12 or better, and there was a mean LogMAR VA improvement from 0.182 to 0.129 at 12 months (average 7.5 injections) [53].

Although the pivotal ranibizumab trials did not include cases with the following criteria, no evidence suggests withholding ranibizumab in these patients (level III evidence) [33]:

1.Haemorrhage or serous pigment epithelial detachment (PED) involving over half the CNV lesion, particularly if CNV can be documented (e.g., using ICG)

2.Glaucoma or elevated intraocular pressure

3.Major cataract: cataract surgery should generally follow ranibizumab therapy.

Lesion characteristics such as isolated serous PED

without documented CNV [54], RAP or PCV have not been investigated sufficiently in ranibizumab or other anti-VEGF therapy trials. These cases may be considered for ranibizumab therapy, but may not respond as well, or may respond more slowly [43], than would be expected from the average trial outcomes of other occult lesions [33]. Trials have investigated certain subtypes (e.g., ranibizumab phase IV EVEREST PCV trial; clinical trials’ identifier NCT00674323).

RCOphth guidelines indicate that ranibizumab therapy should not be withheld in cases with haemorrhage involving >50% of the total CNV lesion, even though these patients would not have been included in the pivotal trials [34]. A small case series of seven patients addressed this question recently [55], and found similar