results to the major ranibizumab trials, which was better than in the control group of previous submacular surgery trials. Dense sub-foveal haemorrhage also appeared to respond well in another study of 12 patients [56].

15.2.3What Parameters Define Whether NV-AMD Is Active and Would Likely Benefit from Anti-VEGF Therapy, and Which Features Suggest that Treatment

Would be Futile?

The International Advisory Group report [33] addressed the concept that anti-VEGF therapy should be reserved for NV-AMD cases that were ‘active’ level III evidence, and that ‘inactive’ or extremely advanced, irreversible, lesions should not be treated. Because anti-VEGF therapy specifically targets angiogenesis and vascular permeability [16, 57], the active disease concept was developed for NV-AMD to encompass the hallmarks of the evolution of neovascularization to endstage lesions, and its response to anti-VEGF therapy. This concept included signs indicating the presence of persistent or recurrent extracellular fluid, which include:

1.Increased retinal thickness due to intraretinal, subretinal or sub-retinal pigment epithelial fluid accumulation (ideally confirmed by OCT)

2.Presence (or recurrence) of intraretinal or sub-retinal haemorrhage

3.New or persistent leakage (or CNV enlargement) shown on FA.

The RCOphth guidelines also state that ‘Treatment

is indicated with ranibizumab when: There is active sub-foveal neovascularization of any lesion type’…

Patients with ‘active’ disease, but for whom treatment is not generally recommended (i.e., because it would likely be futile), were defined by the International Advisory Group, by the presence of the following lesions or signs:

1.Structural foveal damage

2.Advanced sub-retinal fibrosis or significant geographic atrophy involving the foveal centre, particularly if long-standing, as functional benefit from treatment of these cases is unlikely.

3.Confounding severe ocular disease. This includes vitreous or pre-retinal haemorrhage that obscures

the central macula, or rhegmatogenous retinal detachment. These conditions will generally need other types of treatment, though ranibizumab may still be used [33].

The RCOphth guidelines [34] also stress that there should be no permanent structural damage to the fovea. This was defined as long-standing fibrosis or atrophy in the fovea, or a significant chronic disciform scar, which in the opinion of the clinician, would prevent the patient deriving functional benefit, or prevention of further vision loss, from treatment.

Retinal pigment epithelial tears involving subfoveal sites, frequently reported after intravitreal ranibizumab [58–65], were initially considered a relative contraindication. However, no data have yet suggested that continuing ranibizumab in these cases causes any harm (level III evidence). However, this guidance is based only on expert opinion (level III evidence) and some clinical trial evidence, and no trials have examined this question.

15.2.4Do Flexible Therapy Regimens Provide as Satisfactory Visual Outcomes as Monthly Therapy? How Should Treatment be Started? What Flexible Approaches

Are Reported?

15.2.4.1 Results with Continuous Monthly Treatment

VA rapidly improved in the first 3 months of ranibizumab therapy in the pivotal MARINA and ANCHOR trials, and was then sustained over a full 2-year period (Fig. 15.1a, b) [33]. Ranibizumab also demonstrated angiographic and morphologic responses, with improvements in total CNV area and CNV leakage (FA), and in foveal centre-point thickness (OCT) [66]. Clinically, meaningful improvements in patient-reported vision-related function were observed with 0.5 mg ranibizumab, compared with progressively reduced function with sham (MARINA) [67] and verteporfin PDT (ANCHOR) [68]. These improvements were maintained over the 24-month study period, paralleling the objective VA improvements, and importantly occurred with treatment of only one eye.

-25

0

Ranibizumab injections

0

Ranibizumab injections

Ranibizumab 0.3 mg

Ranibizumab 0.5 mg

Verteporfin PDT

Ranibizumab 0.3 mg quarterly

Ranibizumab 0.5 mg quarterly

Ranibizumab 0.3 mg monthly

Individualised dosing with monthly visits

Fig. 15.1 Mean change from baseline in best-corrected visual acuity by month for (a) MARINA, (b) ANCHOR, (c) PIER, (d) EXCITE, (e) PrONTO, (f) SUSTAIN. (a) Copyright © 2006 Massachusetts Medical Society. All rights reserved; (b) Reprinted

from Brown et al. [85], Copyright 2009, with permission from Elsevier; (c) Reprinted from Regillo et al. [86]; (e) Reprinted from Fung et al. [74], Copyright 2007, with permission from Elsevier