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Combination Therapy for Wet Age-related Macular Degeneration
will increasingly use combination therapy to treat patients with ocular Figure 1: The Cascade of Wet Age-related
angiogenesis, including wet AMD.
Macular Degeneration
The Evolution of Combination Therapies
Combination therapy for wet AMD began in earnest after V-PDT was
Oxidative stress
approved for use in 2000. The first dual combinations involved V-PDT
plus intravitreal triamcinolone. When the anti-VEGF agent pegaptanib
became the first agent in its class approved for use, studies of
Inflammatory mediators Biochemical
combination therapies of this drug plus a steroid or V-PDT followed. and pro-angiogenic cytokines factors
Subsequent availability of the anti-VEGF agent ranibizumab generated
considerable excitement because, as noted above, it demonstrated
meaningful vision benefit for the first time in patients with wet AMD.
Inappropriate vessel growth
Combination therapy with ranibizumab or the similar agent
bevacizumab and a steroid, V-PDT, or both, followed.
Therefore, the treatment options have expanded considerably over
Exudation and haemmorhage
Physical
manifestations
the past decade. Currently, combination therapies including
ranibizumab or bevacizumab plus V-PDT with and without a steroid
are being intensely investigated. The overall goal is to produce vision
Choroid scar formation
benefits comparable to those produced with ranibizumab
monotherapy but with a reduced need for re-treatment. A brief review
of the clinical evidence that supports combination therapy in wet and nine; ranibizumab was administered at baseline and at months one,
AMD follows. two and three. Combination therapy was given on the same day. At nine
months all lesions were inactive and all cases of macular oedema and
Combination Therapies subretinal fluid had resolved. Although this study was small (32
Verteporfin Photodynamic Therapy plus patients), it showed that same-day administration of V-PDT plus
Intravitreal Triamcinolone ranibizumab was not associated with severe vision loss or severe ocular
Overall results from two prospective trials favoured this combination inflammation.
26
In a subanalysis of the PROTECT trial, the effects of the
over V-PDT monotherapy. Specifically, combination therapy was above-described regimen on retinal anatomy, choroidal perfusion and
associated with fewer lines of vision lost and a lower rate of moderate visual function were assessed. The vascular effects were immediate
vision loss at one year compared with V-PDT monotherapy.
23
In photothrombosis of the CNV and surrounding choroid. Retinal
addition to maintaining VA, combination therapy was also significantly sensitivity also improved immediately and continued over time,
better than V-PDT monotherapy in reducing lesion size and foveal although some choroidal malperfusion remained.
27
As noted, this study
thickness.
24
Notably, there was a significantly lower re-treatment rate and its subanalysis were small in size and non-comparative;
with combination therapy versus monotherapy (p=0.04).
24
nevertheless, the results showed the safety and efficacy of combination
therapy given on the same day, which would certainly be more
Verteporfin Photodynamic Therapy plus convenient to patients and potentially lower the risk of retinal toxicity.
Anti-vascular Endothelial Growth Factor
Therapies with or without Steroids MONT BLANC is a 24-month randomised, double-blind, European
With the availability of anti-VEGF drugs, clinical trials of dual multicentre trial comparing V-PDT plus ranibizumab with ranibizumab
combinations – V-PDT plus an anti-VEGF agent – and triple alone in 255 subjects. Standard-fluence V-PDT (or placebo) was
combinations – V-PDT plus an anti-VEGF agent plus a steroid – have administered at baseline and then at intervals of at least three months
been carried out or are now under way (see Table 1). Dual as required, based on pre-defined re-treatment criteria. Ranibizumab
combination trials comparing V-PDT plus ranibizumab with either was administered as three ‘loading doses’ followed by monthly
V-PDT or ranibizumab monotherapy include FOCUS, PROTECT, MONT treatment as needed based on pre-defined re-treatment criteria.
28
In
BLANC and DENALI. a preliminary analysis of one-year results, mean VA improvement
from baseline in the combination therapy group (2.5 letters) was
The results of FOCUS, a multicentre, randomised, single-blind, shown to be non-inferior to that in the ranibizumab monotherapy
controlled clinical trial, showed better efficacy with V-PDT plus group (4.4 letters). The percentage of patients with a three-month
ranibizumab than with V-PDT alone.
25
At 12 months, 95 of the 105 treatment-free interval after the last loading dose was similar (96 and
(91%) V-PDT plus ranibizumab-treated patients and 38 of the 56 (68%) 92% in the combination and ranibizumab monotherapy groups,
V-PDT monotherapy patients had lost fewer than 15 letters from respectively). Post hoc analysis showed that 85% of patients in the
baseline VA (p<0.001). Patients treated with combined therapy also combination therapy group, compared with 72% in the ranibizumab
required less V-PDT re-treatment. Ranibizumab was associated with monotherapy group, had a treatment-free interval of at least four
an increased risk of serious intraocular inflammation, possibly related months. Median time to first re-treatment was extended by
to the use of an early formulation of this agent, yet affected patients approximately one month in the combination group (month six)
on average still experienced VA benefit.
25
compared with the monotherapy group (month five). There were no
unexpected safety findings and the adverse event incidence was
In the prospective, multicentre PROTECT study, V-PDT was administered similar between groups.
28
As noted, this is a preliminary analysis; final
at baseline and, if fluorescein leakage was present, at months three, six results are awaited before firm conclusions can be drawn.
EUROPEAN OPHTHALMIC REVIEW 99
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