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Age-related macular degeneration (AMD) is still referred to as the leading cause of severe and irreversible visual loss world-wide. The disease has a profound effect on quality of life of affected individuals and represents a major socioeconomic challenge for societies due to the exponential increase in life expectancy and environmental risks. Advances in medical research have identified vascular endothelial growth factor (VEGF) as an important pathophysiological player in neovascular AMD and intraocular inhibition of VEGF as one of the most efficient therapies in medicine. The wide introduction of anti-VEGF therapy has led to an overwhelming improvement in the prognosis of patients affected by neovascular AMD, allowing recovery and maintenance of visual function in the vast majority of patients. However, the therapeutic benefit is accompanied by significant economic investments, unresolved medicolegal debates about the use of off-label substances and overwhelming problems in large population management. The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance. Simultaneously, ground-breaking innovations in diagnostic technologies, such as optical coherence tomography, allows unprecedented high-resolution visualisation of disease morphology and provides a promising horizon for early disease detection and efficient therapeutic follow-up. However, definite conclusions from morphologic parameters are still lacking, and valid biomarkers have yet to be identified to provide a practical base for disease management. The European Society of Retina Specialists offers expert guidance for diagnostic and therapeutic management of neovascular AMD supporting healthcare givers and doctors in providing the best state-of-the-art care to their patients. Trial registration number NCT01318941.
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Guidelines for the management of neovascular
age-related macular degeneration by the European
Society of Retina Specialists (EURETINA)
Ursula Schmidt-Erfurth,
1
Victor Chong,
2
Anat Loewenstein,
3
Michael Larsen,
4
Eric Souied,
5
Reinier Schlingemann,
6
Bora Eldem,
7
Jordi Monés,
8
Gisbert Richard,
9
Francesco Bandello
10
For numbered afliations see
end of article.
Correspondence to
Professor Ursula Schmidt-
Erfurth, Department of
Ophthalmology, Medical
University of Vienna,
Waehringer Guertel 18-20,
Wien 1090, Austria; ursula.
schmidt-erfurth@meduniwien.
ac.at
Received 20 June 2014
Accepted 23 June 2014
To cite: Schmidt-Erfurth U,
Chong V, Loewenstein A,
et al. Br J Ophthalmol
2014;98:11441167.
ABSTRACT
Age-related macular degeneration (AMD) is still referred
to as the leading cause of severe and irreversible visual
loss world-wide. The disease has a profound effect on
quality of life of affected individuals and represents a
major socioeconomic challenge for societies due to the
exponential increase in life expectancy and
environmental risks. Advances in medical research have
identied vascular endothelial growth factor (VEGF) as
an important pathophysiological player in neovascular
AMD and intraocular inhibi tion of VEGF as one of the
most efcient therapies in medicine. The wide
introduction of anti-VEGF therapy has led to an
overwhelming improvement in the prognosis of patients
affected by neovascular AMD, allowing recovery and
maintenance of visual function in the vast majority of
patients. However, the therapeutic benetis
accompanied by signicant economic investments,
unresolved medicolegal debates about the use of off-
label substances and overwhelming problems in large
population management. The burden of disease has
turned into a burden of care with a dissociation of
scientic advances and real-world clinical performance.
Simultaneously, ground-breaking innovations in
diagnostic technologies, such as optical coherence
tomography, allows unprecedented high-resolution
visualisation of disease morphology and provides a
promising horizon for early disease detection and
efcient therapeutic follow-up. However, denite
conclusions from morphologic parameters are still
lacking, and valid biomarkers have yet to be identied to
provide a practical base for disease management. The
European Society of Retina Specialists offers expert
guidance for diagnostic and therapeutic management of
neovascular AMD supporting healthcare givers and
doctors in providing the best state-of-the-art care to
their patients.
Trial registration number NCT01318941.
INTRODUCTION
Age-related macular degeneration (AMD) has been
described as the leading cause of legal blindness,
affecting 10%13% of adults over 65 years of age
in North America, Europe, Australia and, recently,
Asia.
12
AMD is a major medical and socio-
economic challenge worldwide and, based on
increased life expectancy and a growing negative
impact of environmental risk factors, particularly
arteriosclerosis, obesity and smoking, its incidence
is expected to at least double by 2020.
37
The
Global Burden of Disease Study 2010 reported an
exponential increase of 160% in vision-related
years lived with disability due to AMD, highlight-
ing the overwhelming burden for societies overall.
8
Moreover, with an impact similar to AIDS, renal
failure and stroke, AMD has a profound effect on
the quality of life of those affected.
9
Fortunately, progress in AMDs diagnosis and
therapy, based on advances in medical research has
recently wrought a substantial paradigm shift in the
management of neovascular AMD. Identication of
a major pathogenetic feature, that is, the inuence of
vascular endothelial growth factor (VEGF), has
opened an easily accessible therapeutic window.
1012
Landmark clinical trials proved that intravitreal
inhibition of VEGF-A can efciently block the
pathophysiological process of AMD, restore retinal
morphology and increase/maintain neurosensory
function in most patients with neovascular
AMD.
13 14
Since the approval of anti-VEGF pharma-
cotherapy in 2006, the prevalence of legal blindness
and visual impairment due to AMD has been consid-
erably reduced, removing neovascular AMD from
the list of incurable diseases.
1517
The impressive benet of antiangiogenic therapy
has since been widely recognised. However, real-life
outcomes have consistently been found to be less
favourable than clinical trial results.
1820
The com-
munity faces a huge dilemma in the management of
AMD, with substantial controversies over the ef-
cacy of substances, choice of therapeutic regimens
and adequate monitoring needs. This is further
aggravated by exponentially growing costs resulting
from highly priced drugs, increasing patient
numbers and long-term disease chronicity.
21 22
At
the same time, one of the most successful thera-
peutic break-throughs in ophthalmology is currently
at the centre of an array, of unresolved issues and
the standard-of-care is vastly inconsistent.
Evidently, there are enormous variations in clin-
ical practice, and considerable uncertainty about
how the scientic evidence should be reduced to
clinical practice in widely varying settings. The
EURETINA community has, therefore, taken
responsibility for bringing together experts in the
eld to develop a working guidance based on the
best available scientic and clinical knowledge.
The goal is to provide clinically sound, economic-
ally acceptable and unbiased diagnostic and thera-
peutic recommendations to brighten the horizon
for patients and physicians worldwide.
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Diagnostic procedures
Patients history, clinical examination and self-monitoring
Rationale
Neovascular AMD is an acute onset and rapidly progressing
disease which impacts central vision. Early detection of disease
onset and continuous follow-up are mandatory because, visual
loss becomes irreversible with delayed diagnosis and treatment.
General ophthalmologic examination procedures, such as deter-
mination of best-corrected visual acuity (BCVA), stereoscopic
ophthalmoscopy and home monitoring between routine visits
should be implemented. Whenever neovascular AMD is sus-
pected, advanced diagnostic measures such as uorescein angio-
graphy (FA) and optical coherence tomography (OCT) must
follow to conrm the diagnosis. Numerous clinical trials have
shown that better nal outcomes can be achieved with better
initial visual acuity (VA). Unfortunately, in most trials as well as
in real life, lesions nowadays are usually detected when there is
already considerable visual loss. Therefore, awareness must be
raised in individuals aged 50 years and older, and physicians
should perform AMD screenings regularly.
Evidence
The reduced efcacy of anti-VEGF therapy compared with aca-
demic trial results is commonly associated with poor initial diag-
nosis and/or discontinuous follow-up in routine clinical care.
Compared with treatment paradigms validated by clinical trials,
patients with neovascular AMD received too few injections and
only infrequent monitoring in US clinical practice from 2006 to
mid-2011. Holecamp et al, found 8767 patients were treated
with a mean annual number of 4.7 bevacizumab or 5.0 ranibizu-
mab injections between 2006 and 2007. The mean annual
number of injections increased slightly from 2008 to 2010, with
10 259 patients divided between six cohorts receiving 4.6, 5.1
and 5.5, bevacizumab or 6.1, 6.6 and 6.9, ranibizumab injec-
tions, but mean numbers of visits to an ophthalmologist and
OCT examinations remained low.
23
In a Germany-based, multi-
centre, retrospective review of data from patients with suspected
neovascular AMD visiting ophthalmology clinics over
18 months in 20082010, 10 sites collected data from 2498
patients with a mean VA of 0.4±0.3 at the time of diagnosis.
The most frequent pathological ndings detected by routine
ophthalmic examination were brotic lesions, indicating late
diagnosis of choroidal neovascularisation (CNV).
24
A conrmed
diagnosis of neovascular AMD was most frequently based on
funduscopy (67.3%) or FA (39.6%).
Disease activity in neovascular AMD is lifelong. Long-term
outcomes 78 years after initiation of intensive ranibizumab
therapy were assessed in patients originally treated with ranibi-
zumab in landmark phase 3 trials (SEVEN-UP). Approximately
7 years after initiation of ranibizumab therapy in the ANCHOR
or MARINA trials, one-third of patients had good visual out-
comes, whereas another third had poor outcomes.
25
Compared
with baseline, almost half the eyes were stable, whereas
one-third had declined by 15 letters or more. Hence, even at
this late stage in the therapeutic course, exudative AMD patients
remain at risk for substantial additional visual decline. Active
exudative disease was detected by spectral-domain OCT in 68%
of study eyes, and 46% were receiving ongoing intraocular
anti-VEGF treatments.
The AMD Detection of Onset of New Choroidal
Neovascularisation Study (AMD DOC Study) evaluated the sen-
sitivity of time-domain (TD) OCT relative to FA, in detecting
new-onset neovascular AMD within 2 years from onset. The
sensitivity of Amsler grid testing, preferential hyperacuity
perimetry (PHP), OCT, and FA for detection of CNV was 0.40
for OCT ((95% CI (0.16 to 0.68)), 0.42 for supervised Amsler
grid (95% CI 0.15 to 0.72) and 0.50 for PHP (95% CI 0.23 to
0.77)). The AMD DOC Study demonstrated that FA is still the
best method for detecting new-onset CNV.
26
Nevertheless, self-
monitoring with regular Amsler grid testing is suggested
between ophthalmological visits. PHP telemonitoring is a more
standardised self-monitoring tool. The HOME study, a pro-
spective, randomised clinical trial found that participants rando-
mised to the home monitor had less vision loss at the time of
CNV detection than those in standard care with about 90%
maintaining a VAof 20/40 or better at the time of CNV detec-
tion.
27
The study also showed that when using the home moni-
toring device with standard care, CNV detection rates increased
statistically signicantly, and with smaller lesion size VA at detec-
tion was better than standard care alone. With subjective
symptom realisation, BCVA at the time of detection was statistic-
ally signi cantly worse than an alert by the device, with a 11.5
letter loss. Increased intraocular pressure (IOP) is another issue
in prolonged anti-VEGF therapy.
28 29
In 528 eyes receiving
1796 intravitreal injections of bevacizumab, IOP was persistently
elevated in 19 eyes (3.6%, 19/528) of 18 patients (4.2%, 18/
424) with IOP elevated 3070 mm Hg, 330 days after injec-
tion. Mean IOP was 42.6 mm Hg (range 3070); IOP elevations
occurred after an average of 7.8 injections of bevacizumab
(range 313). Injected eyes (19/528) had a signicantly higher
incidence of elevated IOP than non-injected eyes (fellow eyes),
1/328, p<0.001. Identical observations were published for IOP
increases with ranibizumab.
29
Doctors should be aware that IOP
might increase after repeated treatments.
Recommendation
Doctors should initially ask patients who present with an onset
of decreased vision or metamorphopsia, if they have a family
history of AMD, and for their social history including smoking
habits. Their complete history should be examined to identify
systemic risk factors for anti-VEGF therapy and current
medications. Standardised BCVA testing and stereoscopic
biomicroscopy/ophthalmoscopy of the macula of both eyes is
mandatory, as well as measurement of IOP at least every
6 months. Patients should be instructed to self-monitor their
vision between routine ofce visits. By contrast with current
home monitoring strategies, those with intermediate AMD
(large drusen in one or both eyes) could benet from home
monitoring with PHP, whenever the device is available. Patients
who have received treatment should be monitored at regular
intervals, according to a standardised strategy, either monthly or
following an individualised pro-re-nata (PRN) or treat-
and-extend regimen. Follow-up visits should include examin-
ation for new onset of a decrease in vision and nes or
persistent metamorphopsia, changes in medical or social history
and, most importantly, BCVA tests should be repeated using
identical procedures. Further examination by OCT is required if
stereoscopic fundus examination reveals clinical signs of retinal
oedema, detachment of the retinal pigment epithelium (RPE) or
haemorrhage. These recommendations are based on the
Age-Related Eye Disease Study and HOME study (evidence
level I) and levels II/III data for clinical management of early
AMD.
Angiography
Rationale
FA was the main, and for many years, the only diagnostic and
follow-up tool for AMD patients.
30
Nowadays, many non-
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invasive techniques (such as spectral domain (SD) OCT, auto-
uorescence imaging) can provide detailed anatomical informa-
tion and precise functional data. In spite of this, FA continues to
play a key role in the diagnostic process, for example, providing
the base for its clinical classication and the initiation of thera-
peutic management. The role of FA is to visualise retinal vascu-
lature and neovascular retinal/choroidal proliferations as well as
its dynamic features, such as perfusion and exudation. FA has
been used in all phase 3 clinical trials for the initial diagnosis of
neovascular AMD.
Evidence
In the case of neovascular AMD, leakage of dye from patho-
logical new vessels, into retinal structures appears as hyperuor-
escence, which increases in intensity and extension throughout
the examination duration.
30
This leakage is classied by its loca-
tion (subfoveal, juxtafoveal, or extrafoveal) and by its features
(classic, occult, or mixed). Classic CNV represents a lesion that
has penetrated the RPE layer and is located in the subretinal
space (gure 1), whereas occult CNV refers to a neovascular
lesion located underneath the RPE (gure 2). In the case of dry
AMD, the angiogram will show various grades of drusen
(usually seen as early, intensely hyperuorescence spots) and
atrophy (a well-demarcated, hyperuorescent areas resulting
from increased visualisation of the adjacent choroidal
uorescence).
When assessing a patient with clinical suspicion of neovascu-
lar AMD, FA evaluation, if not contraindicated for systemic
risks, is routinely mandatory.
26 31
In fact, it is the only examin-
ation that can conrm the mere existence of a CNV, and is also
used to evaluate the location and extent of classic and occult
forms, particularly when it is coupled with indocyanine green
angiography (ICGA). In addition to the location and the area of
leakage, FA provides information about the dynamic exudative
activity of the lesion. These features, particularly lesion size,
have a well-recognised prognostic value and should be claried
in order to plan an appropriate treatment strategy.
3234
An angiogram is also essential to detect specic forms of
AMD that present a more aggressive natural history and requires
modication of the therapeutic approach. Retinal angiomatous
proliferation (RAP) is characterised clinically by focal haemor-
rhage, oedema and lipid exudates within retinal layers. In more
advanced stages, a serous or vascularised pigment epithelial
detachment (PED) is detectable.
35
ICGA reveals the area of
focal hyperuorescence arising from the deep capillary plexus
forming the initial angiomatous lesion, which subsequently will
form an anastomosis with the choroidal circulation (gure 3).
ICGA is therefore vital to distinguish this lesion presentation
and should be followed by SD-OCT focused on the lesion site.
The other relevant example of a different subtype of exudative
AMD is polypoidal choroidal vasculopathy (PCV). It is difcult
to distinguish this entity clinically from other forms of occult
CNV, even though, it presents more commonly with recurrent
serous and haemorrhagic PED.
36 37
The FA shows an ill-dened
occult leakage pattern, whereas ICGA is able to delineate the
polypoidal lesions in distinct detail (gure 4). As PCV is more
common in patients of Asian and African descent, it should be
considered in these patients.
Recommendation
Once the initial diagnosis of CNV is established by FA, the
effect of anti-VEGF therapy can be efciently monitored by
Figure 1 Classic choroidal neovascularisation is located above, the retinal pigment epithelium layer and is associated with intraretinal cystoid
spaces and/or subretinal uid. Due to its subretinal location, the neovascular net is delineated with distinct margins. Leakage in late-phase
angiography conrms the biologic activity of the lesion (ophthalmoscopy, spectral domain-optical coherence tomography, early uorescein
angiography (FA), late FA).
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non-invasive SD-OCT alone.
3841
Nonetheless, FA may be advis-
able, especially where OCT fails to provide reliable information,
such as in high myopia, extrafoveal lesions or when dealing
with fresh CNV reactivation at the borders of a brotic lesion.
Additionally, FA and ICGA should be repeated in the case of a
sudden clinical worsening, or in occurrence of haemorrhage or
new PED. These recommendations are based on evidence levels
II/III.
Optical coherence tomography
Rationale
OCT, rst used in the 1990s, is based on the properties of light
waves reected from and scattered by ocular tissues, which
allows anatomical changes associated with exudative AMD to be
visualised and measured.
42 43
Since its introduction with the
initial time-domain technology, the modality has continued to
improve, with high-denition SD technology and swept source
(SS) OCT, achieving greater resolution, repeatability and applic-
ability than earlier OCT devices.
44 45
Advanced OCT permits
high-speed retina scanning that allows complete coverage of the
macular area and generation of three-dimensional retinal
images. Within a few years, of its introduction, OCT became a
major element in both initial diagnosis and management of
patients with exudative AMD. TD-OCT has been used in most
of the phase 3 clinical trials for antiangiogenic therapy in AMD
either as a second outcome examination for central retinal thick-
ness (CRT) or for retreatment indications in trials with a exible
regimen. SD-OCT has so far been used exclusively in the
HARBOR study comparing ranibizumab therapy in a xed
monthly and a exible PRN regimen. OCT visualises structural
changes of the retina and RPE as a high-resolution optical hist-
ology, in a static mode, however, without identication of vas-
cular features or any representation of dynamic processes such
as perfusion or leakage.
Evidence
OCT supports the diagnosis of exudative AMD at initial presen-
tation. Type 1 CNV (also called occult CNV) may have several
manifestations in OCT (gure 5): The neovascular membrane is
localised behind the RPE, creating a vascularised brovascular
or serous PED. Subretinal uid (SRF) presents as a dark virtual
space between the retina and the RPE, often with disruption of
the external limiting membrane-photoreceptor complex in the
outer retina. Intraretinal exudation appears as round, dark,
cystoid spaces within the retinal layers, but not all cystoid spaces
are exudative features. Persistent cystoid spaces mostly have an
irreversible degenerative nature. Pigment epithelium detach-
ments are characterised by elevations of the RPE (gure 6).
Serous PED present as a smooth regular and sharply demar-
cated, dome-shaped hyporeective RPE elevation, whereas
brovascular PED appears to be lled with solid layers of mater-
ial of medium or high reectivity, separated by hyporeective
clefts. On OCT, RPE tears are typically seen as a discontinuity
in a large PED, with the free edge of the RPE often curled
under the PED. Type 2 CNV (also called classic CNV) is loca-
lised in the subretinal space (gure 7 ). Most eyes with type 2
CNV present a small discrete PED associated with the highly
reective subretinal lesions (mainly located beneath the
Figure 2 Occult choroidal neovascularisation is located underneath the retinal pigment epithelium layer. By uorescein angiography (FA), an area
of stippled, or pinpoint hyperuorescence with leakage in late phases, are seen. Indocyanine green angiography (ICGA) (right lower image) may
visualise the neovascular pattern of the occult lesion (ophthalmoscopy, early FA, late FA, ICGA).
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subretinal lesion). Increased thickness of the retina, SRF, cystoid
spaces and PED are commonly observed.
46
RAP (also called
type 3 CNV) is described as small erosion or elevated RPE, a
ap sign, or, later, a focal funnel-shaped defect in the RPE,
called kissing sign, accompanied by subretinal and/or intraret-
inal uid (gure 8).
47
In PCV, the branching vascular network
appears as RPE elevations, while the polypoidal lesions appear
as sharper, dome-shaped protuberances, often associated with
exudative ndings (gure 9).
OCT is currently the most frequently used tool in the long-
term management of exudative AMD. Comparisons of macular
thickness and morphology over time allow a patients response
to treatment to be assessed. In the MARINA and ANCHOR
studies, anti-VEGF intravitreal injections were based on a xed
regimen every 4 weeks
13 14
and CRT measured by OCT was
only a secondary outcome. Subsequently, individualised regi-
mens based on the concept of treating patients only when neces-
sary have since been investigated. Most subsequent clinical trials
of anti-VEGF agents have used some variation on a PRN
regimen, usually involving three consecutive monthly loading
injections followed by further injections as needed, according to
predened retreatment criteria.
4851
This concept of individua-
lised or evaluation-based, as-needed therapy is reportedly the
most commonly used treatment regimen in current clinical prac-
tice in Europe. The most frequent morphologic criterion for
retreatment decisions has been dened as an increase in CRT.
52
Recent analyses revealed that CRT does not correlate with
BCVA in AMD, because the structure/function correlation is lost
during follow-up as early as at month 3.
53
The Comparison of
Age-Related Macular Degeneration Treatments Trials (CATT)
study, therefore, suggested patients should be retreated in a no
tolerance mode, that is, whenever any uid was seen on
TD-OCT.
54
The same principle of tight retreatment based on
any change in OCT was adopted in the HARBOR trial, but,
using SD-OCT which usually leads to a higher retreatment fre-
quency due to the increased number of scans potentially reveal-
ing intraretinal uid or SRF.
55
A comprehensive subgroup
analysis of the VIEW study correlation of functional and ana-
tomical data revealed that OCT biomarkers, which are generally
correlated with reduced vision in neovascular AMD, were
intraretinal cystoid spaces (IRC) at baseline, and persistent
cystoid spaces at the end of the loading dose.
56
Whenever IRC
were present initially, BCVA, and the therapeutical gain in BCVA
were limited, while eyes with SRF showed the best visual prog-
nosis. Prognostic for the therapeutic benet were IRC and bro-
vascular PED at initial presentation, where RPE detachment is
the primary pathognomonic feature, and secondary cyst forma-
tion under discontinued treatment is the biomarker associated
with vision loss.
56
These features were independent of the sub-
stance and the regimen used.
Recommendation
BCVA alone is insufcient to detect a recurrence of activity of
the neovascular membranes in neovascular AMD. FA can also
be useful, in addition to OCT, in some ambiguous cases, par-
ticularly for type 2 CNV. New haemorrhage on fundus examin-
ation is also a sign of CNV activity. Nevertheless, OCT is
actually the most useful tool for evaluating morphological
Figure 3 A retinal angiomatous proliferation is characterised by an early hyperuorescent spot at the level of the retinal vasculature, mostly at the
site of a focal haemorrhage and progressive intraretinal leakage. The concomitant optical coherence tomography scan reveals a pigment epithelium
detachment and intraretinal cystoid expansions.
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changes because it best reects recurrence of neovascular
activity. Two types of assessment for neovascular activity can be
distinguished: measurements and qualitative OCT observa-
tions.
57
CRT has been the most common measurement used in
clinical studies, however, PRN treatment based on these mea-
surements was invariably associated with reduced therapeutical
benet compared with a xed continuous regimen.
54 58
There is
a large body of evidence that supports qualitative morphology-
based OCT data as more sensitive than measurements for
detecting of CNV activity. IRC, SRF and RPE detachments are
important signs of activity in the neovascular membrane,
independent of CRT. In a real life PRN protocol, all these fea-
tures are usually considered as criteria for reinjection of
anti-VEGF substances. Compared with the former TD-OCT
technology, current SD-OCT or SS-OCT technologies which
provide raster-scanning imaging, are more sensitive for detecting
of subtle morphological changes and, thus, permit early treat-
ment of exudative recurrence.
59 60
The common recommenda-
tion is, therefore, to monitor disease activity using SD-OCT,
and on a monthly base. The concept of a zero tolerance on
OCT criteria is emerging, because of the rapid progression of
exudative features and progressive loss of vision when initiation
Figure 4 Marked intraretinal exudates and/or haemorrhage seen clinically are associated with multiple hyperuorescent polyps angiographically in
polypoidal chorioidopathy. Indocyanine green angiography (ICGA) is often helpful in delineating the polypoidal components despite haemorrhage
(ophthalmoscopy, early uorescein angiography (FA), ICGA, late FA).
Figure 5 Spectral domain-optical coherence tomography (SD-OCT) rev eals a bro vascular pigment epithelial detachment and a ser ous retinal detachment
in a patient with age-related macular degenera tion a ffected by a type 1 choroidal neovascularisa tion (scanning laser ophthalmoscopy, SD-OCT).
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of treatment is delayed.
61
However, persistent IRC should be
considered signs of irreversible retinal degeneration and should
not trigger further retreatment. These recommendations are
based on evidence levels I (CATT, VIEW, HARBOR) and evi-
dence levels II.
THERAPEUTIC STRATEGIES
Intravitreal pharmacotherapy
Pegaptanib
Rationale
VEGF increases vascular permeability, enhances the inamma-
tory response and induces angiogenesis.
62
The isoform VEGF
165 has been particularly implicated in bloodretinal barrier
breakdown and pathological intraocular neovascularisation.
Pegaptanib sodium, Macugen, is a short RNA oligonucleotide,
an aptamer that binds with high specicity and afnity only to
the isoform VEGF165. The rationale is to selectively inhibit
pathological leakage and angiogenesis.
63
Pegaptanib is well tol-
erated in humans and has a mean intravitreal half-life of
10 days.
Evidence
The VEGF Inhibition Study in Ocular Neovascularisation
(VISION) Study completed at the end of 2004 marked a new
era for the treatment of neovascular AMD. The study showed
the safety and efcacy of intravitreal inhibition of VEGF for the
treatment of neovascular AMD over 1 year.
64
It was a double-
masked, sham-controlled, dose-ranging phase 3 clinical trial
including 0.3, 0.1 and 3.0 mg doses. The control group was
given the usual care including photodynamic therapy (PDT)
monotherapy. Patients received intravitreal injections at 6-week
intervals independent of the neovascular activity. Seventy per
cent of those receiving pegaptanib at 0.3 mg lost fewer than 15
letters of VA, compared with 55% of the control group
(p<0.001). The risk of severe loss of VA (loss of 30 letters or
more) was reduced from 22% in the sham-injection group to
10% in the group receiving 0.3 mg of pegaptanib (p<0.001)(3).
Patients receiving pegaptanib lost a mean of 9 letters over
1 year compared with a loss of 14 letters in the sham-injection
group. Despite continued treatment, progressive growth and
persistent leakage of the neovascular lesion was seen angiogra-
phically in most of the patients. At 54 weeks, every patient in
the pegaptanib groups was re-randomised to continuous further
pegaptanib treatment or sham treatment. Patients from the usual
care group were assigned to continuous usual care, one of the
three groups of pegaptanib doses or the sham-injection group.
At 2 years, 59% of eyes receiving a dose of 0.3 mg lost <15
letters versus 45% of the usual care sham-injected eyes.
65
Six
per cent of eyes in the pegaptanib group improved by three
lines compared with 2% of the sham-injected group. At 2 years,
a mean vision loss of 10 letters was found in all subgroups
treated with pegaptanib at 0.3 mg, with a mean of nine treat-
ments applied per year.
The ocular and systemic safety prole of the drug was very
good. Related to the intravitreal injection procedure, specic
risks, such as endophthalmitis (1.3% of treated cases during the
rst year, 0.7% during the second year), traumatic lens injury
(0.6% during the rst year, 0.2% during the second year) and
Figure 6 Fluorescein angiography (FA) and spectral domain-optical coherence tomography (SD-OCT) identify a minimally classic choroidal
neovascularisation with the classic component in the nasal portion of the macular area and the occult component in the temporal area
(FA, SD-OCT).
Figure 7 Spectral domain-optical coherence tomography (SD-OCT) features of type 2 (classic) choroidal neovascularisation (CNV) associated with
exudative age-related macular degeneration are shown: uorescein angiography (FA) visualises a small type 2 neovascular membrane. On SD-OCT,
CNV appears between the retina and the retinal pigment epithelium, associated with some exudative cystoid spaces and increased central retinal
thickness. (FA, SD-OCT).
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retinal detachment (0.7% during the rst year, 1.2% during the
second year) were reported.
66
This was the rst evidence that
anti-VEGF therapy is effective and safe in AMD.
Recommendatio n
Macugen was approved for all lesion types in neovascular AMD
by the Food and Drug Administration (FDA) for the USA in
December 2004, and by the European Medicines Agency for
countries in the European Union (EU) in January 2006. The
therapeutic benet was favourable compared with the one
obtained with PDT monotherapy, with few treatments needed
with PDT. The chance of a statistically signicant improvement
in VA was relatively low (6%). The visual benets of preventing
visual loss shown in the VISION Study were largely exceeded
by the next anti-VEGF therapy; that is, ranibizumab. This
marked difference in efcacy may be because pegaptanib does
not inhibit other bioactive isoforms of VEGF, such as the
soluble 110 and 121 VEGF fragment in vivo. Therefore, due to
its poorer efcacy compared with other currently available
anti-VEGF drugs, pegaptanib is no longer recommended for the
treatment of exudative AMD. These recommendations are based
on the VISION study data (evidence level I).
66
Ranibizumab
Rationale
Ranibizumab is a recombinant, humanised Fab fragment of a
monoclonal antibody with a high afnity for VEGF A. The
binding site is located at amino acid sites 8889. Ranibizumab
binds and inactivates all isoforms of VEGF, including the
soluble VEGF isoforms 110, 121 and 165 and the tissue-bound
isoforms 189 and 206.
62 66
While bevacizumab was developed
for long systemic retention in the treatment of metastatic cancer,
ranibizumab was designed for rapid systemic clearance by
removing the Fc fragment from the parent molecule.
67
Additionally, the afnity of the compound for VEGF was
enhanced by modication of ve amino acids. In animal models,
intravitreal injection effectively reduced retinal and choroidal
neovascular growth as well as leakage from established vessels.
68
Ranibizumab, with its molecular weight of 76 kDa, was found
to penetrate the retina well after intravitreal injection.
69
With a
short intravitreal half-life time of 24 days, and a rapid systemic
clearance, the systemic safety of ranibizumab is extremely
high.
70
Ranibizumab monotherapy has, therefore, become the
reference standard for treatment of CNV.
Evidence
Fixed regimens were evaluated in the MARINA, ANCHOR,
PIER and EXCITE studies. Seven hundred and sixteen patients
with minimally classic or purely occult CNV, and evidence of
presumed recent disease progression, were included in the
MARINA study, a randomised, multicenter, sham-controlled
phase 3 trial. Patients received monthly injections of 0.3 or
0.5 mg of ranibizumab or sham treatment continuously over
24 months. At 12 months, 95% of ranibizumab-treated eyes
compared with 62% of sham-treated eyes, lost <15 letters in
VA .
13
Visual improvement by >15 letters was found in 34% of
Figure 8 In retinal angiomatous proliferation, uorescein angiography (FA) shows a hot-spot in the macular area. On spectral domain-optical
coherence tomography (SD-OCT), a focal pigment epithelial detachment and intraretinal cystoid spaces are the pathognomonic features. (FA,
SD-OCT).
Figure 9 Spectral domain-optical coherence tomography (SD-OCT) features of polypoidal choroidopathy are shown: Indocyanine green angiography
(ICGA) identies a hyperuorescent polypoidal lesion. A punctuate haemorrhage associated with the hot-spot on angiography suggests a retinal
angiomatous proliferation. SD-OCT shows a dome-shaped elevation, the sign of a polypoidal lesion. (ICGA, scanning laser ophthalmoscopy, SD-OCT).
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Figure 10 MARINA study. (A) Rate
of loss or gain of visual acuity at 12
and 24 months associated with
ranibizumab, as compared with sham
injection. At 12 months, mean
increases in visual acuity were +6.5
letters in the 0.3 mg group and +7.2
letters in the 0.5 mg group, as
compared with a decrease of 10.4
letters in the sham-injection group
(p<0.001 for both comparisons). The
benet in visual acuity was maintained
at 24 months. The average benet
associated with ranibizumab over that
of sham injection was approximately
17 letters in each dose group at
12 months, and 2021 letters at
24 months. (B) Mean (±SE) changes in
choroidal neovascularisation and
leakage. The mean change from
baseline in each of the
ranibizumab-treated groups differed
signicantly from that in the
sham-injection group at 12 and
24 months ( p<0.001 for each
comparison) in favour of ranibizumab
treatment. Printed with permission
from ref 13.
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eyes treated with a dose of 0.5 mg (gure 10A and B). At
24 months, 90% of eyes in the 0.5 mg group had continued to
maintain stable vision without loss of >15 letters compared
with 53% in the control group.
34
A mean improvement of
seven letters was documented at 24-month follow-up.
Thirty-three per cent of eyes in the 0.5 mg dose group improved
by >15 letters with 42% ending up with a VA of 20/40 or
better. Ranibizumab prevented further CNV growth and
decreased the mean area of leakage angiographically in both
dose groups. Typically, the functional and anatomical effects
were seen rapidly within the rst 3 months of intervention, and
were maintained throughout the entire follow-up of 24
months.
34 66
Additionally, patients treated with ranibizumab
reported large improvements in near vision, distance vision and
vision-specic dependency in quality-of-life questionnaires
(NEI-VFQ-25).
16
The ANCHOR study included 423 patients with predomin-
antly classic subfoveal CNV due to AMD in a prospective, ran-
domised phase 3 trial design.
71
Monthly injections of
ranibizumab at 0.3 or 0.5 mg were compared with standard
PDT, which was indicated at 3-month intervals if leakage was
seen angiographically. Ninety per cent of all eyes treated with
ranibizumab at 0.5 mg lost less than 15 letters compared with
66% of eyes maintaining vision with PDT treatment alone at
24 months. Forty-one per cent of eyes in the 0.5ä-mg dose
group improved by >15 letters and 12% improved by >30
letters, compared with 6% of PDT-treated eyes trated with PDT
(gure 11). Additionally, these ranibizumab-treated patients
demonstrated a mean improvement of 11 letters at 24 months,
and 38% had a nal outcome of 20/40 or better. Initial VA, or
lesion size, had no impact on vision prognosis.
66 72
The PIER study, a phase 3b trial, included 182 patients with
all lesion types and evaluated the efcacy and safety of monthly
ranibizumab at three doses followed by dosing every 3 months.
While patients in the sham group lost a mean of 16 letters
during 12 months of follow-up, patients receiving either dose of
ranibizumab remained stable at baseline VA.
66
Ninety per cent
in the group receiving the 0.5 dose lost <15 letters compared
with 49% in the sham group; 13% versus 10% gained >15
letters.
73
As the overall VA, returned to baseline from month 3
to month 12 after switching to quarterly dosing, this reduction
appears to suggest that quarterly dosing is inferior to monthly
dosing. This was subsequently conrmed by the EXCITE
study.
50
Patients (n=353) with all types of CNV were rando-
mised (1:1:1) to receive doses of ranibizumab at 0.3 mg quar-
terly, 0.5 mg quarterly or 0.3 mg monthly. Treatment comprised
a loading phase (3 consecutive monthly injections) followed by
a 9-month maintenance phase (either monthly or quarterly
injection).
50
Mean VA gain over baseline was observed for the
entire 12-month trial in all groups. At month 12 compared with
month 3, the VA gain was slightly decreased with quarterly
dosing (by 2.2 and 3.1 letters with 0.3 mg and 0.5 mg of
ranibizumab, respectively) (gure 12A C).
Flexible regimens were evaluated in the subsequent trials
including PrONTO, CATT, SECURE and HARBOR. The small,
open-label, prospective, non-randomised PrONTO study
assessed three consecutive monthly injections followed by
OCT-guided variable-interval dosing (at >1 month intervals).
48
Retreatment criteria were a 5-letter loss and uid as detected by
OCT; >100 mm increase in CRT; new-onset classic CNV; new
macular haemorrhage; or persistent macular uid detected by
OCT >100 mm increase in central thickness (CRT) new-onset
classic CNV new macular haemorrhage or persistent macular
uid detected by OCT. Although VA outcomes were similar to
those of the MARINA and ANCHOR trials with fewer intravi-
treal injections, substantial trial design differences limit compari-
sons. Despite small and open-label, this study suggested that
exible OCT-guided retreatment could sustain visual gain with
fewer injections, a concept which has since become a popular
model in clinical practice, particularly in Europe.
The investigators in the randomised CATT trials set out to
assess the relative efcacy and safety of ranibizumab and bevaci-
zumab and to determine whether an as-needed regimen, com-
pared with a monthly regimen, would compromise long-term
VA .
54
The treatment protocol was much tighter than used previ-
ously, and is often referred to as zero tolerance. Radial scan-
ning by TD-OCT was used in the trial and any uid on OCT
was added to the usual retreatment criteria. At 12 months,
patients treated with monthly ranibizumab with 11.7 injections,
and with ranibizumab as needed with 6.9 injections, gained
Figure 11 ANCHOR study. Mean
(±SE) changes in the number of letters
read as a measure of visual acuity
from baseline through 12 months. The
tracking of mean changes in visual
acuity scores over time showed that
the values in each of the ranibizumab
groups were signicantly superior to
those in the verteporn group at each
month during the rst year (p<0.001)
(gure 2) On average, visual acuity of
ranibizumab-treated patients increased
by +5.9 letters in the 0.3 mg group
and +8.4 letters in the 0.5 mg group
at 1 month after the rst treatment
and increased further over time to a
gain of +8.5 letters in the 0.3 mg
group and +11.3 letters in the 0.5 mg
group by 12 months. By contrast, the
verteporn group had an average loss
in visual acuity at each month after the
rst month, with a mean loss of 9.5
letters by 12 months. Printed with
permission from ref 13.
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+8.5 and +6.8 letters, respectively.
54
Based on the trial design,
PRN using ranibizumab was considered to be non-inferior.
However, a meta-analysis combining the data from all the
groups, as well as the data from the IVAN study, a similar trial
in the UK with different retreatment protocol, found that dis-
continuous was inferior to continuous treatment.
74
As the latter
also included data from bevacizumab, the ndings might have
been different, if ranibizumab had been used alone, were in this
analysis.
In the CATT year 2 data, when the monthly ranibizumab
group was re-randomised into a continuous monthly treatment
and as-needed treatment, the as-needed group lost 1.8 letters
as compared with those staying with monthly treatment. Over
the entire 2 years, the vision gain was very similar to the year 1
data with +8.8 and +6.7 letters in the monthly and as needed,
respectively.
54
In other words, changing to as needed in year 2
lost all the benet of the monthly treatment from year 1.
SECURE
75
and HORIZON
76
are prospective extension
studies that were designed to assess the long-term safety and
efcacy of intravitreal injections of 0.5 mg of ranibizumab in
patients with neovascular AMD. HORIZON is a multicentre,
open-label, 24-month extension study following patients who
had completed the MARINA, ANCHOR, or FOCUS (RhuFAb
V2 Ocular Treatment Combining the Use of Visudyne to
Evaluate Safety) trials. It is to evaluate long-term safety, toler-
ability and efcacy of multiple intravitreal injections of 0.5 mg
ranibizumab to patients as needed, SECURE is a phase 4.2-year
extension study in patients with AMD who had completed
1 year of treatment with ranibizumab in the EXCITE
75
or
SUSTAIN
77
studies. The results from the SECURE study corrob-
orate the ndings from the HORIZON study,
76
where there was
an incremental decline in the BCVA gains achieved with
monthly ranibizumab treatment in the previous studies, leading
to an overall gradual decline in BCVA by 7.5 letters
(ranibizumab-treated initial group) at the study end. This VA
decline highlights the progressive nature of neovascular macular
disease and shows a strict need for continuous follow-up moni-
toring and rigorous objective retreatment criteria. Continued
follow-up in the SEVEN-UP study also suggested a long-term
persistence of disease activity in the majority of patients.
49
The extension studies have provided further data on the
safety of ranibizumab treatment. Intravitreal injections of ranibi-
zumab were associated with a low incidence of endophthalmitis
(0.9%) in the SECURE study
75
consistent with the rates
reported in the HORIZON study (0.2% for presumed
endophthalmitis).
76
The rates are also consistent with those
reported at 2 years in previous neovascular AMD studies
(MARINA, 1.0%; ANCHOR, 1.1%). In the SECURE study,
arterial thromboembolic events (ATEs) (categorised under
adverse effects (AE) of special interest, and including haemor-
rhagic cerebrovascular conditions, ischaemic cerebrovascular
conditions, myocardial infarction, and arterial embolic and
thrombotic events) occurred in 5.6% of the patients receiving
ranibizumab. These data are similar to the rate of ATEs (accord-
ing to the Anti-platelet Trialists Collaboration criteria) reported
in patients receiving ranibizumab in the ANCHOR and
MARINA studies (4.4%5%) and the HORIZON study (5.3%
in the ranibizumab-treated initial patients).
25
Additionally, the LUMINOUS programme was initiated as
part of an ongoing pharmacovigilance programme for ranibizu-
mab, it was designed to assess long-term safety, efcacy, treat-
ment patterns, and health-related quality-of-life outcomes in a
large number of patients treated with ranibizumab in routine
Figure 12 EXCITE study. (A, B) Proportion of patients with (A) visual
acuity loss (<15 letters) or (B) gain (15 letters) over time in the
intent-to-treat patient population (last observation carried forward
(LOCF)) of EXCITE. Best-corrected visual acuity (BCVA) increased from
baseline to month 12 by +4.9, +3.8, and +8.3 letters in the 0.3 mg
quarterly (104 patients), 0.5 mg quarterly (88 patients), and 0.3 mg
monthly (101 patients) dosing groups, respectively. After three initial
monthly ranibizumab injections, monthly (0.3 mg) and quarterly
(0.3 mg/0.5 mg) ranibizumab treatments maintained BCVA in patients
with choroidal neovascularisation secondary to age-related macular
degeneration. At month 12, BCVA gain in the monthly regimen was
higher than that of the quarterly regimens. The non-inferiority of a
quarterly regimen was not achieved with reference to 5.0 letters.
(C) Mean change from baseline over time of central retinal thickness as
assessed by optical coherence tomography scan in the intent-to-treat
patient population ( LOCF) of EXCITE. Vertical bars represent SE of the
mean. The mean decrease in central retinal thickness from baseline to
month 12 in the intention-to-treat population was 96.0 mm in 0.3 mg
quarterly, 105.6 mm in 0.5 mg quarterly, and 105.3 mm in 0.3 mg
monthly group. Printed with permission from ref 50.
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clinical practice across the world.
25
(ClinicalTrials.gov identier:
NCT01318941).
The HARBOR study is the only trial that has included
SD-OCT monitoring into a PRN regimen compared with
monthly treatment.
55
The study evaluated the 12-month efcacy
and safety of 0.5 and 2.0 mg intravitreal dosing of ranibizumab
monthly and on an as-needed (PRN) basis in treatment-naive
patients with subfoveal neovascular AMD. Patients (n=1098)
were randomised to receive ranibizumab 0.5 or 2.0 mg ranibizu-
mab injections intravitreally, monthly or on a PRN basis after
three monthly loading doses. At month 12, the mean change
from baseline in BCVA for the four groups was +10.1 letters
(0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters
(2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The propor-
tion of patients who gained 15 letters from baseline at month
12 in the four groups was 34.5%, 30.2%, 36.1% and 33.0%.
The mean change from baseline in central foveal thickness at
month 12 was 172, 161.2, 163.3 and 172.4 μm. The
mean number of injections was 7.7 and 6.9 for the 0.5 mg PRN
and 2.0 mg PRN groups. Ocular and systemic safety proles
were consistent with previous ranibizumab trials in AMD and
similar between groups, without any safety risks documented.
At month 12, the ranibizumab 2.0 mg monthly group did not
meet the prespecied non-inferiority (NI) comparison. Vision in
all treatment groups improved clinically meaningfully (+8.2 to
+10.1 letters), and all groups had improved anatomic out-
comes, with the PRN groups requiring approximately four
fewer injections (6.97.7) than the monthly groups (11.211.3).
(gure 13A and B). No new safety events were observed despite
a fourfold dose escalation in the study. Therefore, the HARBOR
study conrmed that 0.5 mg of ranibizumab dosed monthly pro-
vides optimum results in patients with neovascular AMD, and
that there is no great disadvantage in using a PRN regimen
instead of continued monthly injections
55
provided that strict
monthly monitoring is provided using SD-OCT technology.
Treat-and-extend is another exible strategy suggested to
reduce retreatment numbers. After three initial monthly ranibi-
zumab or bevacizumab injections, and then to continue with
monthly injections until there was no CNV activity (subretinal/
intraretinal uid, loss of >5 letters, or persistent/recurrent
retinal haemorrhage) in a prospective cohort study of 120
patients.
78
When there was no leakage activity, the interval to
the next visit/injection was extended by 2 weeks to a maximum
of 12 weeks. When there was CNV activity, this interval was
shortened by 2 weeks. Mean VA change from baseline was
+9.5±10.9 and +8.0±12.9 letters after 12 and 24 months,
respectively, with, on average, 8.6±1.1 visits/injections in the
rst year, and 5.6±2.0 in the second year. After 12 and
24 months, 97.5% and 95.0% of patients, respectively, lost <15
letters. This inject-and-extend protocol with fewer injections
and visits delivered outcomes similar to those of the pivotal clin-
ical trials of monthly ranibizumab with fewer injections and
fewer visits. Treat-and-extend trials are currently underway in
Europe. Although undertreatment is the major issue, complica-
tions from overtreatment should also be considered because,
since a substantially increased rate of geographic atrophy (GA)
was documented with monthly use of ranibizumab had new GA
lesions after 2 years compared with only 15% of eyes treated in
the as-needed arm.
Recommendatio n
Lucentis has been approved by the FDA since July 2006 for all
lesion types in neovascular AMD in the USA since July 2006.
An approval by the European Medicines Agency (EMA) for
countries in the EU was granted in January 2007. The approved
dose is 0.5 mg of ranibizumab. Giving injections continuously
monthly for 2 years on a PRN regimen with strict monthly
monitoring using SD-OCT and retreatment, whenever any evi-
dence of uid is noted by retinal imaging has been found to be
the regimen that secures the optimum results in vision outcome.
The ofcial product label in Europe recommends monthly intra-
vitreal injections continued until maximum VA is achieved for
three consecutive monthly assessments. Thereafter, patients
should be monitored monthly for VA. Treatment is to be
resumed when monitoring indicates loss of VA due to wet
AMD. Monthly injections should then continue until stable VA
is reached again for three consecutive monthly assessments.
Current usage in Europe is based on OCT monitoring and ces-
sation of treatment when uid is absent on OCT.
Figure 13 HARBOR study. (A) Mean change from baseline to month
12 in best-corrected visual acuity (BCVA). *Vertical bars are ±1 SE of
the unadjusted mean. Mean number of injections was analysed for
patients who received at least 1 ranibizumab injection in the study eye.
At month 12, the mean change from baseline in BCVA for the four
groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg
pro-re-nata (PRN)), +9.2 letters (2.0 mg monthly), and +8.6 letters
(2.0 mg PRN). The proportion of patients who gained 15 letters from
baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1% and
33.0%, respectively. The mean number of injections was 7.7 and 6.9
for the 0.5 mg PRN and 2.0 mg PRN groups, respectively. (B) Mean
change from baseline to month 12 in central foveal thickness (CFT) by
spectral-domain optical coherence tomography. Vertical bars are ±1 SE
of the unadjusted mean. The mean change from baseline in CFT at
month 12 in the 4 groups was 172, 161.2, 163.3, and
172.4 μm, respectively. Printed with permission from ref 55.
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Treat-and-extend is being evaluated in prospective clinical trials.
Development of GA should be observed during prolonged
treatment.
The recommendations are based on the ANCHOR,
MARINA, PIER, EXCITE, HARBOR and CATT study data (evi-
dence level I) as well as the SECURE and HORIZON study data
(evidence level II).
Bevacizumab
Rationale
Bevacizumab is a full-length recombinant monoclonal antibody
that binds all VEGF isoforms. It was developed to inhibit patho-
logical angiogenesis in tumours and tumour growth and is
approved by the FDA and EMA for the intravenous treatment
of metastatic colorectal cancer and other cancer types.
79
Cancer
patients receiving systemic bevacizumab are commonly found to
have an increased risk of cardiovascular events, stroke and
gastrointestinal bleeding.
80
A mathematical model comparing
the time-dependent relative elimination of ranibizumab, bevaci-
zumab and aibercept was used to determine the theoretical
peak and binding activities when the drugs were injected every
28 days. The intravitreal half-lives of ranibizumab, bevacizumab,
and aibercept were estimated to be 3.2, 5.6 and 4.8 days,
respectively. The relative molar binding activities of ranibizu-
mab, bevacizumab and aibercept were 1, 0.05 to 0.2, and 140,
respectively, indicating a lower binding afnity for bevacizu-
mab.
81
The systemic retention is prolonged because the
Fc-portion of the substance binds to an endothelial cell receptor
and is recycled. Intravitreal bevacizumab has recurrently been
found to lower systemic VEGF concentrations much more than
ranibizumab. Because bevacizumab and VEGF have similar bind-
ings patterns, it is hypothesised that bevacizumab may be as
effective as ranibizumab in the treatment of neovascular AMD
and other types of intraocular neovascularisation, and may
provide a less expensive alternative to approved substances spe-
cically adapted for intraocular use.
8285
Evidence
Since 2005, many uncontrolled and retrospective case series
have indicated that bevacizumab has a benecial effect in the
treatment of neovascular AMD.
8688
Bevacizumab has been split
from the original vial into single doses containing 1.25 mg in a
volume of 0.05 mL. Intraocular use has incidentally been asso-
ciated with clusters of non-infectious mild to severe ocular
inammation (153 patients reported, no serious sequelae) and a
single cluster of infectious endophthalmitis (12 patients), the
latter associated with inappropriate pharmacy dispensing of the
drug.
89 90
A sterile preparation of single doses is mandatory
with timely usage to prevent contamination spreading and
aggregates forming, which leads to enhanced intraocular inam-
matory reactions.
91
Evidence level I data for bevacizumab are exclusively derived
from NI trials comparing bevacizumab with ranibizumab in the
treatment of neovascular AMD aimed at reducing drug-related
costs in clinical practice. The CATT study was a single-masked,
NI trial, in which 1208 patients with neovascular AMD were
randomised to intravitreal injections of ranibizumab or bevacizu-
mab on either a monthly schedule or as needed, with monthly
evaluation. At 1 year, with a difference of ve letters, monthly
bevacizumab was equivalent to monthly ranibizumab, with +8.0
and +8.5 letters gained.
92
Bevacizumab as needed was equiva-
lent to ranibizumab as needed with +5.9 and +6.8 letters
gained. Nevertheless, the comparison between bevacizumab as
needed and monthly bevacizumab was inconclusive, and NI was
not achieved. The mean decrease in CRTwas greater in the rani-
bizumab monthly group (196 μm) than in the other groups
(152168 μm). Rates of death, myocardial infarction, and stroke
were similar for patients receiving either bevacizumab or ranibi-
zumab (p>0.20). However, the proportion of patients with
serious systemic adverse events (primarily hospitalisations) was
higher with bevacizumab than with ranibizumab (24.1% vs
19.0%; risk ratio, 1.29; 95% CI 1.01 to 1.66). Subsequently,
1107 patients were followed during year 2, and the patients ini-
tially assigned to monthly treatment were reassigned randomly
to monthly or as-needed treatment, without changing the drug
assignment.
54
The mean gain in VA was similar for both drugs
(bevacizumab-ranibizumab difference, 1.4 letters; 95% CI),
but greater for monthly than for as-needed treatment (differ-
ence, 2.4 letters; 95% CI 4.8 to 0.1; p=0.046). The pro-
portion of eyes without uid was 13.9% in the bevacizumab
as-needed group, against 45.5% in the ranibizumab monthly
group (drug, p=0.0003; regimen, p<0.0001 with statistically
signicantly more eyes treated with ranibizumab demonstrating
resolution of uid). Generally, switching from monthly to
as-needed treatment resulted in a greater mean decrease in
vision during year 2 (2.2 letters; p=0.03) and a lower propor-
tion without uid (19%; p<0.0001). Rates of death and arter-
iothrombotic events were similar for both drugs (p>0.60) after
2 years, but the proportion of patients with one or more sys-
temic serious adverse events was again higher with bevacizumab
than with ranibizumab (39.9% vs 31.7%; adjusted risk ratio,
1.30; 95% CI 1.07 to 1.57; p=0.009). Treatment as needed,
generally resulted in less gain in VA, whether instituted at enrol-
ment or after 1 year of monthly treatment. The differences
between BCVA values at 2 years increased compared with the
year 1 outcomes with monthly ranibizumab scoring highest and
as-needed bevacizumab scoring lowest. Retreatment indications
were based on loss in BCVA or morphologic evidence of uid in
the macula based on TD-OCT without clear denition of the
type and localisation of uid no tolerance regimen, and no
clear biomarkers were identied by the protocol (gure 14A-C).
In the IVAN study, 610 patients were assigned randomly to
ranibizumab or bevacizumab, given either every month (con-
tinuous) or as needed (discontinuous), with three consecutive
injection series and monthly review. One year after randomisa-
tion, the comparison between bevacizumab and ranibizumab
was inconclusive and bevacizumab did not meet the NI criteria
(bevacizumab minus ranibizumab 1.99 letters, 95% CI 4.04
to 0.06)
74
. Discontinuous treatment was equivalent to continu-
ous treatment (discontinuous minus continuous 0.35 letters;
95% CI 2.40 to 1.70). There was no difference between drugs
in the proportion of patients experiencing a serious systemic
adverse event (OR, 1.35; 95% CI 0.80 to 2.27; p=0.25).
Serum VEGF was lower with bevacizumab (geometric mean
ratio, 0.47; 95% CI 0.41 to 0.54; p<0.0001) and higher with
discontinuous treatment (geometric mean ratio, 1.23; 95% CI
1.07 to 1.42; p=0.004). After 2 years, bevacizumab similarly
failed to fall within the NI margin (mean difference 1.37
letters, 95% CI 3.75 to 1.01; p=0.26).
93
Moreover, discon-
tinuous treatment also did not reach the NI level (1.63 letters,
4.01 to 0.75; p=0.18), that is, the reduction in the frequency
of retreatment resulted in a small loss of efcacy irrespective of
the chosen drug. Frequency of arterial thrombotic events or hos-
pital admission for heart failure did not differ between groups
given ranibizumab (20 (6%) of 314 participants) and bevacizu-
mab (12 (4%) of 296; OR 1.69, 95% CI 0.80 to 3.57;
p=0.16), or those given continuous (12 (4%) of 308) and dis-
continuous treatment (20 (7%) of 302; 0.56, 0.27 to 1.19;
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Figure 14 CATT study. (A) The mean change in visual acuity from enrolment over time in patients treated with the same dosing regimen for
2 years. While ranibizumab monthly, becacizumab monthly and ranibizumab as needed meet the non-inferiority level, treatment with bevacizumab
as needed led to inconclusive results and non-inferiority was not proven. At 2 years, the mean increase in letters in visual acuity from baseline was
+8.8 in the ranibizumab monthly group, +7.8 in the bevacizumab monthly group, +6.7 in the ranibizumab as-needed group and +5.0 in the
bevacizumab as-needed group. Main gain was greater for monthly than for as-needed treatment. Switching from monthly to as-needed treatment
resulted in greater mean decrease in vision during year 2 with 2.2 letters. (B) Differences in mean change in visual acuity at 2 years and 95% CIs
in patients treated with the same dosing regimen for 2 years. The difference in mean improvements for patients treated with bevacizumab relative to
those treated with ranibizumab was 1.4 letters. The difference in mean improvements for patients treated by an as-needed regimen relative to
those treated monthly was 2.4 letters. (C) The mean change in total foveal thickness from enrolment over time by dosing regimen within drug
group: (A) ranibizumab and (B) bevacizumab. Mean gain was greater for monthly than for as-needed treatment. The proportion without uid ranged
from 13.9% in the bevacizumab as-needed group to 45.5% in the ranibizumab monthly group. Printed with permission from ref 54.
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p=0.13). Mortality was lower with continuous than discontinu-
ous treatment (OR 0.47, 95% CI 0.22 to 1.03; p=0.05), but
did not differ by drug group (0.96, 0.46 to 2.02; p=0.91).
With respect to safety, pooled analyses of the CATT and IVAN
studies showed that mortality was lower with ranibizumab, but
neither outcome differed signicantly between drugs with the
size of the respective study population ( p=0.34 and
p=0.55). Increased odds of experiencing a serious adverse
event with bevacizumab observed in the CATT persisted in the
meta-analysis (p=0.016). Most importantly, the CATT and
IVAN studies were not powered to identify small, but clinically
signicant differences in the safety of the two compounds
(gure 15).
The GEFAL study was a multicenter, prospective, NI, double-
masked, randomised, clinical trial performed at 38 French oph-
thalmology centres.
94
Patients were randomly assigned to
receive intravitreal bevacizumab (1.25 mg) or ranibizumab
(0.50 mg). Hospital pharmacies were responsible for preparing,
blinding and dispensing treatments. Patients were followed for
1 year, with a loading dose of three monthly intravitreal injec-
tions, followed by an as-needed regimen (1 injection in the case
of active disease) for the remaining 9 months with monthly
follow-up. Five hundred and one patients were assigned ran-
domly. In the per protocol analysis, bevacizumab was non-
inferior to ranibizumab (bevacizumab minus ranibizumab +1.89
letters; 95% CI 1.16 to +4.93, p<0.0001). The mean number
of injections was 6.8 in the bevacizumab group and 6.5 in the
ranibizumab group (p=0.39). Both drugs reduced the central
subeld macular thickness, with a mean decrease of 95 μm for
bevacizumab and 107 μm for ranibizumab (p=0.27). There
were no statistically signicant differences in the presence of
subretinal or intraretinal uid at nal evaluation, dye leakage on
angiogram or change in choroidal neovascular area, but ranibi-
zumab tended to have a better anatomic outcome. The propor-
tion of patients with serious adverse events was 12.6% in the
bevacizumab group and 12.1% in the ranibizumab group
(p=0.88). The proportion of patients with serious systemic or
ocular adverse events was similar in both groups.
Safety is a topic of controversy discussed issue in the use of
bevacizumab. Experimental studies revealed that systemic VEGF
inhibition disrupts endothelial homeostasis and accelerates
atherogenesis, suggesting that these events contribute to the clin-
ical cardiovascular adverse events of VEGF-inhibiting therapies.
The recommendation was, therefore, to determine cardiovascu-
lar safety proles to improve patient selection for therapy and
allow close monitoring of patients at increased cardiovascular
risk.
95
In human studies, Avery et al
96
found that the systemic
exposure after the third monthly intravitreal injection was
13-fold greater for aibercept and 70-fold greater for bevacizu-
mab than for ranibizumab. Another report reviewed differences
in both ocular and systemic safety between intravitreal bevacizu-
mab and ranibizumab in the setting of neovascular AMD.
91
Serious adverse events associated with either bevacizumab or
ranibizumab injections are generally rare. Acute intraocular
inammation tends to occur more frequently following bevaci-
zumab injection. Systemic absorption of bevacizumab is greater
than with ranibizumab, and many studies have shown that spe-
cic risk or age groups of patients have an increased risk of sys-
temic adverse events when receiving bevacizumab compared
with those receiving ranibizumab. A systemic review based on
Medline, Embase and the Cochrane Library evaluated whether
bevacizumab is as safe as ranibizumab, and whether bevacizu-
mab can be justiably offered to patients as a treatment for
AMD with robust evidence of no differential risk.
97
Registered
clinical trials that investigated bevacizumab or ranibizumab in
direct comparison, or against any other control group (indirect
comparison), and had a minimum follow-up of 1 year were
included. Direct comparison (3 trials, 1333 patients): The
1-year data show a signicantly higher rate of ocular AE with
bevacizumab than with ranibizumab (relative risk (RR)=2.8;
95% CI 1.2 to 6.5). The proportion of patients with serious
infections and gastrointestinal disorders was also higher with
bevacizumab than with ranibizumab (RR=1.3; 95% CI 1.0 to
1.7). Arterial thromboembolic events were equally distributed
among the groups. Indirect comparison: Ranibizumab versus
any control (5 trials, 4054 patients). The 2-year results of three
landmark trials showed that while absolute rates of serious
ocular AE were low (2.1%), relative harm was signicantly
raised (RR=3.1; 95% CI 1.1 to 8.9). Bevacizumab versus any
control (three trials, 244 patients): the safety prole of bevacizu-
mab could not be judged due to the poor quality of AE moni-
toring and reporting in the trials. In summary, evidence from
head-to-head trials raised concern about an increased risk of
ocular and systemic adverse events with bevacizumab. The need
for studies that are powered not just for efcacy, but also for
dened safety outcomes based on the signals detected in system-
atic reviews must be emphasised.
Recommendation
The CATT and IVAN results indicate that ranibizumab and beva-
cizumab both confer solid visual function benets. With
monthly use of both drugs, NI has been proven with optimal
Figure 15 IVAN study. Mean
differences in best corrected distance
visual acuity at 2 years by drug (top)
and by regimen (bottom). Black dashed
line shows non-inferiority limit of 3.5
letters. Mean differences estimated
with data from visits 0, 3, 6, 9, 12, 15,
18, 21, and 24, adjusted for centre size.
For best-corrected visual acuity,
bevacizumab was neither non-inferior
nor inferior to ranibizumab (mean
difference 1.37 letters, 95% CI 3.75
to 1.01; p=0.26). Discontinuous
treatment was neither non-inferior nor
inferior to continuous treatment (1.63
letters, 4.01 to 0.75; p=0.18). Printed
with permission from ref 93.
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visual outcomes. Direct comparison among as-needed treat-
ments also demonstrated NI, although on a generally lower
level. Bevacizumab, as needed, failed to meet NI equivalence to
monthly ranibizumab, that is, bevacizumab used in a PRN
regimen did not reach the superior visual outcome achievable
with monthly ranibizumab. Therefore, choice of the proper
(xed monthly) regimen is relevant when off-label bevacizumab
is used. How much reduction in ocular efcacy one would be
willing to sacrice for reducing the number of injections and/or
costs might depend on individual circumstances.
No major safety issues have emerged, but conclusive data are
lacking, and none of the trials were powered for safety.
Nevertheless, evidence from head-to-head trials consistently
raises concerns about an increased risk of ocular and systemic
adverse events with bevacizumab. Bevacizumabs impact on
plasma concentrations of VEGF and its prolonged half-life in the
circulation are proven. Therefore, the individual physical condi-
tion of each patient should be considered in the choice of the
adequate therapy with the notion that patients included in clin-
ical trials do not reect the common risk prole of the real-world
population. Bevacizumab is substantially less expensive, but each
treatment decision islegally and medicallybased on an indi-
vidual agreement between treating physician and patient, and
must be the consequence of a comprehensive discussion of treat-
ment alternatives and incalculable risks. Informed consent after
discussing the optimal benet, comfort and risks and the off-label
status of the drug is mandatory.
98
Currently, there is a conict on
Avastin between the cost-conscious health authorities in EU
member states and the EU drug regulators. There are several
examples of cost-cutting solutions by health authorities, which
risk undermining the fundamental principles of the regulatory
framework. Meanwhile patients and doctors shoulder the risk.
These recommendations are based on the CATT and IVAN
data (evidence level I).
Aibercept
Rationale
Aibercept, unlike the monoclonal antibodies, bevacizumab and
ranibizumab, is a soluble decoy receptor fusion protein. In ai-
bercept, the second binding domain of the native VEGF recep-
tor 1 and the third binding domain of VEGF receptor 2 are
attached to the Fc component of human ICG.
99
Therefore, the
binding afnity of aibercept (KDa=0.49 pmol/L) is higher than
that of ranibizumab (KDa=0.46 pmol/L) and bevacizumab
(KDa=0.58 pmol/L).
100 101
The molecular size of aibercept of
115 kDa results in an intravitreal half-life of 7.1 days, a calcu-
lated bioactivity in human eyes of 2.5 months and a serum half-
life of 18 days due to the presence of an Fc portion.
100 101
The
compound binds to all VEGF-A isoforms and VEGF-B, with
higher afnity than their native receptors.
102
Aibercept and
ranibizumab have been found to be equally effective in blocking
endothelial cell proliferation, and 10-fold more potent than bev-
acizumab.
103
Aibercept also binds to placental growth factor
(PlGF) present on endothelial cells and leucocytes.
100
In preclin-
ical studies, the compound suppressed CNV and VEGF-induced
vascular breakdown in mice and rats.
104 105
However, pro-
longed and high-doses administration led to loss of endothelial
cells and pericytes.
106
Intravenous therapy in the rst clinical
trial was associated with systemic toxicity, such as proteinuria
and hypertension.
107
Evidence
The rst intravitreal phase I study showed that aibercept
decreased macular oedema and SRF for at least six weeks and
was well tolerated.
108
A subsequent phase 2 clinical trial,
CLEAR-IT2, compared monthly with quarterly intravitreal ai-
bercept at 0.5 and 2.0 mg. With both doses, monthly treatment
was functionally and anatomically more efcient than quarterly
treatment, initially and after a PRN regimen, until week 52.
109
Approval of aibercept for the treatment of neovascular AMD
was based on two parallel phase 3 pivotal trials, VIEW 1 and
VIEW 2.
110 111
Two thousand four hundred and nineteen
patients with treatment-naive neovascular AMD were included
in these double-masked, multicentre, parallel-group, active-
controlled, randomised trials. Eyes with new-onset subfoveal or
juxtafoveal CNV comprising at least 50% of the total lesion size
and a BCVA level between 20/40 and 20/320 Snellen equiva-
lents were randomised 1:1:1:1 to two doses (0.5 and 2.0 mg)
and two regimen (monthly and eight-weekly with 2.0 mg) of
aibercept. There was one control arm receiving ranibizumab
(0.5 mg) at monthly intervals for 52 weeks. The primary end-
point was dened as NI in the proportion of patients maintain-
ing BCVA. Secondary outcomes were change in BCVA and a
reduction in CRT on OCT. At 52 weeks, all aibercept groups,
independent of doses and regimen, were non-inferior to the
control group with equal maintenance of vision in 95% of
eyes.
110
A mean improvement of +8.7 letters (0.5 mg/q4 ranibi-
zumab) in the control group compared with a mean change in
BCVA of +9.3 letters with 2 mg aibercept every 4 weeks and
+8.4 letters every 8 weeks. In the integrated analysis of VIEW 1
(US centres) and VIEW 2 (centres in Canada, South America,
Europe, Asia, Australia) all regimens were within 0.5 letters of
the reference arm ranibizumab. Notably, in the VIEW 1 study
alone, which included 1217 patients, the four weekly aibercept
regimen provided a benet that was statistically superior to that
seen in the other groups, with a visual gain of +10.9 letters.
110
Lesions in the VIEW 1 trial were primarily smaller and asso-
ciated with higher initial BCVA scores. Anatomically, all treat-
ment groups demonstrated a similar rapid decline in CRT by
130 to 157 mm. In the eight-weekly aibercept groups,
bimonthly uctuations in CRT were seen with recurrent exud-
ation between extended aibercept injections. Ocular and sys-
temic adverse events were similar across all treatment groups
with no statistically signicant differences in Anti-Platelet
Trialists Collaboration (APTC) ATE events or AE rates.
A capped PRN regimen was applied to the 2457 patients in
the complete trial from week 52 to week 96.
111
Criteria for
retreatments were new or persistent uid on OCT, an increase
in CRT of 100 mm or more, or loss of ve Early Treatment
Diabetic Retinopathy Study (ETDRS) letters or more, compared
with the best previous score with uid on OCT, new classic
CNV seen by FA or haemorrhage on ophthalmoscope, and a
mandatory capped injections at an interval of 12 weeks since
the previous treatment. The proportion of maintenance in
BCVA ranged between 91% and 92% at week 96 for all groups.
Mean BCVA gains were between +6.6 (aibercept 0.5 mg) and
+7.9 letters (ranibizumab q4), 7.6 letters (aibercept q4 and
q8) conrming NI for aibercept and the eight-weekly retreat-
ment regimen. (gure 16A and B). Overall, a mean loss of 0.8
1.7 letters was seen in all groups after the switch from a xed to
a capped exible regimen. The retreatment frequency was
similar for both substances during the capped PRN year, with
4.1/4.2 (aibercept 2q4 and 2q8) and 4.7 (ranibizumab) injec-
tions. Less patients with pronounced disease activity requiring at
least six reinjections during the second year received aibercept
(2 mg) (14%16%) than ranibizumab (26.5%) treatments.
Accordingly, more aibercept-treated than ranibizumab-treated
eyes were seen without retinal uid at weeks 52 and 96.
111
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Recent subgroup analyses of the VIEW trials suggested a
superior morphologic efciency of aibercept in reducing intrar-
etinal uid and SRF as well as reducing RPE elevation. One
retrospective assessment of eyes with persistent subfoveal uid,
despite previous treatments with ranibizumab suggested that at
6 months, mean BCVA and CRT improved signicantly upon a
switch to intravitreal aibercept.
112
However, most case series
have indicated that 2.0 mg aibercept leads to anatomic
improvements in patients with long-standing persistent uid,
who have received other anti-VEGF agents, but BCVA condi-
tions usually remained unchanged.
113 114
Most of these analyses
were retrospective in design and did not specify the previous
anti-VEGF regimen and continuity in detail.
Recommendatio n
FDA approval of aibercept for the treatment of neovascular
AMD at a recommended intravitreal dose of 2.0 mg was
granted in 2012. The suggested regimen is monthly injections
for the initial 3 months followed by a xed dosing every eight
weeks. The label also highlights that no additional efcacy was
demonstrated when aibercept was dosed every 4 weeks com-
pared with every 8 weeks. In the VIEW 1 study, however,
monthly aibercept provided statistically superior visual gains.
Many interventional studies suggest a superior anatomic efcacy
of aibercept compared with ranibizumab and bevacizumab.
The EU label recommends three initial injections at monthly
intervals, followed by eight weekly injections without any subse-
quent monitoring. After 12 months of treatment, the injection
intervals may be prolonged, depending on the functional and
anatomical condition of the individual patient. Control intervals
for evaluation may be adjusted at the treating ophthalmologists
discretion. The bimonthly uctuations in BCVA and CRT values
are small when averaged but are more impressive individually.
This suggests patients with more intensive desease activity who
can benet from a monthly regimen, as noted in the VIEW 1
study, should be identied. Beyond the rst year, increased
dosing with continued monthly/bimonthly injections may be
needed in eyes with morphologic signals, such as PED and IRC,
which are likely associated with aggressive progression of CNV
disease. Evidence level I is provided by the VIEW I and II
studies.
110 111
Photocoagulation and PDP for neovascular AMD
Rationale
Photocoagulation relies on the high transparency of the neuro-
sensory retina and the melanin pigment content of the RPE to
exert a selective effect on the outer layers of the retina. Such
photocoagulation can be used to obtain immediate closure of
subretinal neovascular membranes (CNV) resulting in perman-
ent cessation of exudation, haemorrhage and vessel growth. An
alternative method of closing subretinal CNV is PDT, which
combines intravenous infusion of a phot