January 2010 Volume 94 Issue 1
`
`Shawnee Mission Medical Center Medical Library
`FEB 0 1 2010
`
`Library Date Received
`
`Ophthalmology
`
`British journal of
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`bjo.bmj.com
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`BMJI Journals
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`Contents
`
`Volume 94 Number 1 | BJO January 2010
`
`Editorial
`1 Ocular anaesthesia and the never-ending story
`P Atlianasiov, T Henderson
`
`Review
`2 Ranibizumab (Lucentis) in neovascular
`age-related macular degeneration: evidence
`from clinical trials
`P Mitchell, J-F Korohelnik, P Lanzetta, F C Holz,
`C Priinte, U Schmidt-Erfurth, Y Tano, S Wolf
`
`Global issues
`14 Mapping trachoma in Nasarawa and Plateau
`States, central Nigeria
`J D King, N JifT, Y S Jugu, Othman,
`A F Rodgers, D Y Dai'om, E Miri, P M Emerson
`
`20 Increased hyperopia with ageing based on
`cycloplegic refractions in adults: the Tehran Eye
`Study
`H Hashemi, R Iribarren, I C Morgan, Ad
`KhabazKhooh, K Mohammad, >1 Fotouhi
`
`Innovations
`24 Computer simulation-assisted rotational
`autokeratoplasty with pupillary enlargement for
`management of cases with partial corneal
`opacification
`T Agarwal, N Sharma, V Jhanji, R B Vajpayee
`
`Cover illustration
`26 All for a drop: Undines and drop bottles
`R Keeler, A D Singh, H S Dua
`
`Original articles
`Clinical science
`28 A novel Ocular Anaesthetic Scoring System,
`OASS, tool to measure both motor and sensory
`function following local anaesthesia
`J Cehajic-Kapetanovic, P N Bishop, S Liyanage,
`T King M Muldoon, IM Wearne
`33 Intraocular pressures after ketamine and
`sevoflurane in children with glaucoma
`undergoing examination under anaesthesia
`L Jones, V Sung G Lascaratos, H Nagi,
`R Holder
`36 A pilot randomised controlled trial comparing
`the post-operative pain experience following
`vitrectomy with a 20-gauge system and the
`25-gauge transconjunctival system
`L Wickham, C Bunce, A S Kwan, J Bainbridge,
`G W Aylward
`
`Courtesy of Mr Richard Keeler, Curator,
`Museum of the Royal College of
`Ophthalmologists. See p 28.
`
`•
`
`Editors-in-Chief
`Harminder S Dua (UK)
`Arun 0 Singh (USA)
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`Website Editor
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`José Gomes (Brazil) : :
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`
`41 Macular morphology and visual acuity after
`macular hole surgery with or without internal
`limiting membrane peeling
`LI C Christensen, K Kreyer, B Sander,
`T M Jorgensen, Ad Larsen, M la Cour
`48 Subretinal coapplication of recombinant tissue
`plasminogen activator and bevacizumab for
`neovascular age-related macular degeneration
`with submacular haemorrhage
`F Treumer, C Klatt, J Raider, J Hillenkamp
`54 New patterns of retinal collateral circulation are
`exposed by a retinal functional imager (RFI)
`G Landa, R B Rosen
`CHOICE
`59 Relationship between different fluorescein and
`indocyanine green angiography features in
`multiple evanescent white dot syndrome
`R dell'Omo, R Wong Ai Aiarino,
`K Konstantopoulou, C Pavesio
`64 A comparison between microperimetry and
`standard achromatic perimetry of the central
`visual field in eyes with glaucomatous
`paracentral visual-field defects
`V C Lima, T S Prata, C C V De Moraes, J Kim,
`W Seiple, R B Rosen, J Ad Liebmann, R Pitch
`68 The sensitivity and specificity of Heidelberg
`Retina Tomograph parameters to glaucomatous
`progression in disc photographs
`V Saarela, A Falck, P J Airaksinen, A Tuulonen
`74 Efficacy and tolerability of bimatoprost versus
`©travoprost in patients previously on latanoprost:
`a 3-month, randomised, masked-evaluator,
`multicentre study
`J A Kammer, B Katzman, S L Ackerman,
`D A Hollander
`80 Using diurnal intraocular pressure fluctuation to
`assess the efficacy of fixed-combination
`latanoprost/timolol versus latanoprost or timolol
`- monotherapy
`R Varma, L-J Hwang J W Gründen, G W Bean
`
`MORE CONTENTS k
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`This article has been chosen by the Editor to be of special interest
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`

`Contents
`
`Volume 94 Number 1 | BJO January 2010
`
`85 The effect of socio-economic deprivation on
`severity of glaucoma at presentation
`W S Ng, P K Agarwal, S Sidiki, L McKay,
`J Townend, A Azuara-Blanco
`88 Visual training of cerebral blindness patients
`gradually enlarges the visual field
`D P Bergsma, G van der Wildi
`97 Scope of super-resolution in central vision
`L Frisen
`101 Evaluation of the impact of intracorneal ring
`segments implantation on the quality of life of
`patients with keratoconus using the NEI-RQL
`(National Eye Institute Refractive Error Quality
`of life) instrument
`J de Freitas Santos Paranhos, M P Avila,
`A Paranhos Jr, P Schor
`106 Evaluation of the Lenstar LS 900 non-contact
`biometer
`L P J Crtiysherg, M Doors, F Verbakel,
`T T J M Berendschot, J De Brabander,
`R M M A Nuijts
`111 Endophthalmitis following open globe injury
`Y A4 N Zhang C H Jiang Y Yao,
`K Zhang
`
`115 Peripapillary retinal nerve fibre layer thickness
`profile in subjects with myopia measured using
`the Stratus optical coherence tomography
`MJ Kim, E J Lee, T-W Kim
`121 Ophthalmological findings in children and young
`adults with genetically verified mitochondrial
`disease
`A'l A Gronlund, A K Seyedi Honarvar,
`S Andersson, A R Moslem!, A Oldfors, E Holme,
`AL Tulinius, N Darin
`Mi A prospective comparison of fine-needle
`aspiration cytopathology and histopathology in
`the diagnosis of orbital mass lesions
`Z A Karcioglu, J C Fleming B C Haik
`
`Education
`131 Papilloedema and vision loss with elevated
`cerebrospinal fluid protein in a patient with
`systemic lupus erythematosus: diagnosis and
`management challenges
`£ K Deschler, N R ALiller, P S Subramanian
`
`PostScript
`133 Letters
`139 Mailbox
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`

`Review
`
`’ Department of Ophthalmology,
`University of Sydney, Sydney,
`Australia; Department of
`Ophthalmology, Centre
`Hospitaller Universitaire de
`Bordeaux, Bordeaux, France;
`’ Department of Ophthalmology,
`University of Udine, Udine, Italy;
`'' Department of Ophthalmology,
`University of Bonn, Bonn,
`Germany; Department of
`Ophthalmology and Optometry,
`Medical University of Vienna,
`Vienna, Austria; ® Department of
`Ophthalmology, Osaka University
`Medical School, Osaka, Japan;
`' Department of Ophthalmology,
`Inselspital, University of Bern,
`Bern, Switzerland
`
`Correspondence to:
`Professor P Mitchell, Eye Clinic
`(B4A), Westmead Hospital,
`Hawkesbury Hoad, Westmead,
`NSW, 2145, Australia;
`paul_mitchell@wmi.usyd.edu.
`au
`
`Accepted 29 April 2009
`Published Online First
`20 May 2009
`
`Ranibizumab (Lucentis) in neovascular age-related
`macular degeneration: evidence from clinical trials
`P Mitchell/ J-F Korobelnik/ P Lanzetta? F G Holz/ C Priinte/ U Schmidt-Erfurth/
`Y Tano,® S Wolf
`
`ABSTRACT
`Background: Neovascular age-related macular degen­
`eration (AMD) has a poor prognosis if left untreated,
`frequently resulting in legal blindness. Ranibizumab is
`approved for treating neovascular AMD. However, further
`guidance is needed to assist ophthalmologists in clinical
`practice to optimise treatment outcomes.
`Methods: An international retina expert panel assessed
`evidence available from prospective, multicentre studies
`evaluating different ranibizumab treatment schedules
`(ANCHOR, MARINA, PIER, SAILOR, SUSTAIN and EXCITE)
`and a literature search to generate evidence-based and
`consensus recommendations for treatment indication and
`assessment, retreatment and monitoring.
`Results: Ranibizumab is indicated for choroidal neovas­
`cular lesions with active disease, the clinical parameters
`of which are outlined. Treatment initiation with three
`consecutive monthly injections, followed by continued
`monthly injections, has provided the best visual-acuity
`outcomes in pivotal clinical trials. If continued monthly
`injections are not feasible after initiation, a flexible
`strategy appears viable, with monthly monitoring of lesion
`activity recommended. Initiation regimens of fewer than
`three injections have not been assessed. Continuous
`careful monitoring with flexible retreatment may help
`avoid vision loss recurring. Standardised biomarkers need
`to be determined.
`Conclusion: Evidence-based guidelines will help to
`optimise treatment outcomes with ranibizumab in
`neovascular AMD.
`
`Neovascular age-related macular degeneration
`(AMD) causes severe and irreversible vision loss,
`and frequently results in legal blindness, with
`resulting considerable economic burden.
`Pharmacotherapies against vascular endothelial
`growth factor-A (VEGF-A), a key factor in the
`pathogenesis of choroidal neovascularisation
`(CNV), have been introduced to treat neovascular
`AMD.^'“ Pegaptanib sodium (Macugen, EyeTech,
`New York), a selective antagonist of the 165
`isoform of VEGF-A," was approved by the Food
`and Drug Administration (FDA) in December 2004.
`Ranibizumab (Lucentis, Novartis Pharma AG,
`Basel, Switzerland and Genentech, South San
`Francisco, California), a recombinant, humanised,
`monoclonal antibody Fab fragment that inhibits all
`biologically active VEGF-A isoforms, was approved
`by the FDA in June 2006 (monthly 0.5 mg
`intravitreal injection)."“" Bevacizumab (Avastin,
`Genentech), a full-length monoclonal antibody
`against all VEGF-A isoforms, was approved by
`the FDA for colorectal cancer in 2004 and later used
`intravitreally off-label in neovascular AMD.*® *'*
`
`Head-to-head ranibizumab and bevacizumab trials
`are under way but are not scheduled to report until
`2010 (GATT (NCT00593450), VIBERA
`(NCT00559715), IVAN and GEFAL trials).
`Although preliminary guidelines for anti-VEGF
`therapies exist,’®“^** more comprehensive clinical
`practice guidelines on applying ranibizumab are
`needed to optimise patient outcomes.
`Ranibizumab Phase III clinical trials in neovascular
`AMD have studied different treatment schedules,
`doses and populations, and this review applies the
`trial evidence to ranibizumab use in clinical
`practice. We evaluated the licensed 0.5 mg of
`ranibizumab dose, shown to be more effective
`than 0.3 mg in pivotal trials,*^ *® and focused
`solely on ranibizumab because: pegaptanib showed
`less visual-acuity (VA) decline than sham injection,
`although on average treated patients continued to
`experience vision loss;“ bevacizumab use in neo­
`vascular AMD currently remains off-label with
`relatively few reported clinical trial data and, to
`date, no completed large, prospective, randomised
`clinical trials."*
`
`RANKING AND SOURCES OF EVIDENCE
`Level I indicates strong evidence (eg, well-designed,
`randomised, controlled clinical trials that address
`the issue in question); level II indicates substantial
`evidence that lacks some qualities (eg, derived from
`randomised clinical trials but with flaws, such as
`absent control group or sufficiently long follow­
`up); level III indicates relatively weak evidence (eg,
`derived from non-comparative studies without
`controls, descriptive studies, panel consensus or
`expert opinion).
`A PubMed literature search on 31 October 2008
`(restricted to English literature; no date restriction)
`using the MeSH term macular degeneration
`(multi) and the words vascular endothelial growth
`factor, ranibizumab or Lucentis yielded 187 papers.
`The Cochrane Register of Controlled Trials and the
`Cochrane Database of Systematic Reviews were
`also searched, yielding 16 and four references,
`respectively. A total of 129 relevant articles were
`selected, from which 74 were selected for detailed
`assessment. Additional data from abstracts con­
`sidered relevant to this manuscript were included
`in the analysis. From this detailed literature search,
`the primary sources of data were all level I
`evidence: the Phase III trials MARINA*® and
`ANCHOR,*® **“ including quality-of-life and sub­
`group analyses,*** **** and the Phase Illb trials PIER,®®
`SAILOR Cohort 1,®’ SUSTAIN (assigned level II
`evidence as only interim data currently available),®'’
`and EXCITE®*. A small, open-label study
`
`2
`
`Br J Ophthalmol 2010:94:2-13. doi:10.1136/bjo.2009.159160
`
`

`

`Table 1 Recommendations for treatment indication with ranibizumab
`Evidence
`Parameters for recommended indication
`
`Level of evidence
`
`Review
`
`Predominantly classic, minimally classic and occult (with no
`classic component) CNV*
`
`Subfoveal (including juxtafoveal) lesions
`
`Active disease
`
`Abnormal retinal thickness with evidence of intraretinal or
`subretinal fluid by OCT
`Intraretinal or subretinal haemorrhage
`Enlargement of CNV size on FA unless solely due to dry,
`fibrotic staining
`New/persistent leakage on FA
`Any baseline VA
`
`Efficacy was seen over the whole VA range studied in
`trials, so it is expected that benefit would occur
`independently of VA whenever progressive vision loss is
`expected due to an active lesion
`Serous PED, RAP or PCV can be considered for ranibizumab
`treatment but might not respond as well as expected from
`average trial outcomes
`
`All CNV types included in PIER, EXCITE, SUSTAIN, SAILOR
`and PrONTO; predominantly classic CNV in ANCHOR and
`minimally classic and occult (with no classic component)
`CNV in MARINA
`Subfoveal CNV (defined as including the foveal centre within
`the boundaries of the CNV) was an inclusion criteria in all
`studies
`Active disease was an inclusion criteria in the MARINA and
`PIER studies!
`
`Level I evidence (MARINA, ANCHOR, PIER, EXCITE
`and SAILOR), supported by level II (SUSTAIN) and III
`evidence (PrONTO)
`
`Level I evidence (MARINA, ANCHOR, PIER, EXCITE
`and SAILOR), supported by level II (SUSTAIN) and III
`evidence (PrONTO)
`Level I evidence (MARINA and PIER) and level III
`evidence
`
`Baseline VA 20/40 to 20/320 was an inclusion criterion in all
`studies!
`Baseline VA better than 20/40 or worse than 20/320: no
`clinical data available, expert opinion based on extrapolation
`of clinical evidence
`
`Level I evidence (MARINA, ANCHOR, PIER and
`SAILOR), supported by level II evidence (SUSTAIN)
`Level III evidence
`
`No detailed clinical trial evidence currently available
`
`Level III evidence
`
`*ln the MARINA and PIER studies, evidence of recent disease progression was required for eyes with minimally classic or occult (with no classic) CNV.
`tActive disease was defined as meeting any of the following criteria: (1) >10% increase in lesion size by comparing a fluorescein angiogram performed within 1 month preceding
`day 0, inclusive, compared with a fluorescein angiogram performed within 6 months preceding day 0, inclusive; (2) resulting in VA loss of >1 Snellen line (or equivalent) and
`occurring at any time within the prior 6 months; (3) subretinal haemorrhage associated with CNV within 1 month preceding day 0; or (4) (not included in MARINA criteria) classic
`CNV comprised >50% of the CNV lesion area.
`JSnellen equivalent assessed by Early Treatment Diabetic Retinopathy Study charts; the PrONTO study included patients with baseline VA from 20/40 to 20/400.
`CNV, choroidal neovascularisation; FA, fluorescein angiography; OCT, optical coherence tomography; PCV, polypoidal choroidal vasculopathy;
`PED, pigment epithelial detachment; RAP, retinal angiomatous proliferation; VA, visual acuity.
`
`(PrONTO; level III evidence) also provided relevant informa­
`tion,and appropriate abstracts covering recent Phase III trial
`findings (unpublished) were included.
`
`NATURAL HISTORY AND ASSESSMENT OF NEOVASCULAR AMD
`What is the natural history or prognosis of untreated neovascular
`AMD?
`A systematic review covering the period 1980 to 2005 assessed
`studies reporting disease progression outcomes for untreated
`patients with neovascular age-related macular degeneration
`(AMD), by using random effects meta-analyses.'' Of 53 studies
`included, there were 28 randomised clinical trials (RCTs),
`totalling 4362 patients with untreated neovascular AMD. The
`most recent RCTs of antivascular endothelial growth factor
`therapy (VISION," MARINA
`’’ and PIER*'*
`’) were not included.
`*
`The systematic review found that, on average, one logarithm of
`the maximum angle of resolution (logMAR) line of visual acuity
`(VA) was lost by 3 months, three lines by 1 year and four lines
`by 2 years. This prognosis is relatively similar to that in
`MARINA, in which sham-treated eyes lost an average of two
`lines by 1 year and three lines by 2 years and in PIER, in which
`sham-treated eyes lost an average of three lines by 1 year. In this
`review, a doubling of the visual angle was found in the first
`year. At baseline, 20% of eyes already had a VA <20/200, but
`this proportion rose to 76% by 3 years."
`*
`
`How should neovascular AMD be diagnosed?
`Accurate diagnosis and classification of neovascular AMD using
`recommended criteria is critical. Assessment should include:
`history (duration and characteristics of visual symptoms); VA;
`stereoscopic biomicroscopic slit-lamp fundus examination (78 D
`
`or similar lens); fluorescein angiography (FA); and, where
`possible, optical coherence tomography (OCT).
`Logarithm of the minimum angle of resolution (logMAR) VA
`is preferable to Snellen VA due to its greater sensitivity, ordered
`progression of letter size (five equally readable letters per line),
`reproducibility and ability to compare with published trial
`data.’’ The Snellen chart has several limitations such as visual
`crowding and variable legibility of the letters. Non-geometric
`letter size progression and a variable number of letters per line
`also prevent Snellen outcomes from being easily equated to
`letters or lines of VA change.’^ ”
`For initial diagnosis, FA is deemed mandatory to detect CNV,
`exclude non-AMD causes (eg, neovascularisation due to
`myopia, pseudo-xanthoma elasticum, birdshot choroidopathy,
`etc, which could respond differently to AMD neovascularisa­
`tion) and determine CNV extent, type, size, location, degree of
`leakage and proportion of various lesion components.
`’ OCT
`*
`is also strongly recommended initially to define the extent of
`retinal thickening and both the localisation and qualitative
`pattern of extracellular fluid accumulation.” ” Indocyanine
`Green (ICG) angiography may also be useful in selected cases,
`eg, when polypoidal choroidal vasculopathy (PCV)“ ” ““ or
`retinal angiomatous proliferation (RAP)“*^ ’ is suspected, or the
`extent of CNV in occult lesions is unclear.
`
`RANIBIZUMAB THERAPY FOR NEOVASCULAR AMD:
`INDICATIONS AND CONTRAINDICATIONS
`Which neovascular AMD lesions should be considered for
`ranibizumab treatment?
`All three major CNV subtypes (predominantly classic, occult
`(with no classic component) and minimally classic) respond to
`ranibizumab" ’’ (table 1). Ranibizumab is primarily indicated
`
`Br J Ophthalmol 2010:94:2-13. doi:10.1136/bjo.2009.159160
`
`3
`
`

`

`Review
`
`for subfoveal (which could also be defined to include juxtafo-
`veal") lesions with “active disease.”
`The concept of active neovascular AMD is central to these
`guidelines (level III evidence). A similar concept was proposed in
`developing guidelines for verteporfin photodynamic therapy
`(PDT) for AMD and retreatment using specific clinical
`parameters.'''^Anti-VEGF therapy specifically targets angio­
`genesis and vascular permeability,'®" and the active disease
`concept has evolved to encompass the hallmarks of neovascular
`disease such as persistent or recurrent extracellular fluid.
`The following “starting criteria” (level III evidence) to define
`active disease may assist in identifying suitable patients for
`ranibizumab treatment:
`► abnormal retinal thickness, particularly with evidence of
`intraretinal, subretinal or subpigment epithelial fluid accu­
`mulation, optimally confirmed by OCT;
`► presence (or recurrence) of intraretinal or subretinal
`haemorrhage;
`► new or persistent leakage shown on FA;
`► CNV enlargement on FA unless solely due to dry, fibrotic
`staining;
`► VA deterioration, considered likely to represent CNV
`activity.
`In retrospective analyses of 24-month MARINA study data,
`ranibizumab was superior to sham across all subgroups based on
`patient age, gender, CNV lesion type, lesion size, baseline VA
`and AMD duration.^'® VA outcomes were predicted by baseline
`VA, then CNV lesion size and age (level I evidence).
`Importantly, for CNV lesion size, smaller lesions had a better
`prognosis than larger lesions. A subgroup analysis of 12-month
`ANCHOR study data showed similar results.®"®
`Although clinical data are only available for baseline VA levels
`of 20/40 (6/12) to 20/320 (6/48), the initial baseline VA was not
`a limiting factor for response to ranibizumab: all baseline VA
`subgroups gained with treatment.®®'® For example, cases with
`active subfoveal/juxtafoveal CNV and VA better than 20/40
`should always be considered for treatment, as these have the
`potential to retain the best possible vision outcomes, particu­
`larly for tasks such as reading and driving.
`/¿though the trials did not include cases with the following
`criteria, no evidence suggests that ranibizumab should be
`withheld in these populations (level III evidence):'®'
`► haemorrhage or serous pigment epithelial detachment (PED)
`involving an area >50% of the entire CNV lesion,
`particularly if any CNV can be documented before treat­
`ment (eg, using ICC);
`► glaucoma or elevated intraocular pressure;
`► advanced cataract—cataract surgery should generally follow
`ranibizumab therapy.
`Lesion characteristics such as isolated serous PED without
`documented CNV,"” RAP or PCV have not been investigated
`sufficiently in ranibizumab trials. These cases may be con­
`sidered for ranibizumab therapy, but they might not respond as
`well, or may respond more slowly,™ than would be expected
`from the average trial outcomes of other occult lesions. Current
`trials are investigating some of these subtypes (eg, ranibizumab
`Phase IV EVEREST PCV trial; clinical trials' identifier
`NCT00674323).
`
`What characteristics suggest that ranihizumab would likely be
`futile?
`Based on expert opinion (level III evidence),'^ and some
`clinical trial evidence, patients with active disease, but for
`
`whom treatment is not generally recommended, were defined
`by the following criteria:
`► Structural foveal damage: advanced subretinal fibrosis or
`significant geographic atrophy involving the foveal centre
`(both particularly important if longstanding, as any func­
`tional benefit from treatment would be unlikely).
`► Confounding severe ocular disease: vitreous or preretinal
`haemorrhage obscuring the central macula, or presence of
`rhegmatogenous retinal detachment (other forms of
`immediate therapy, eg, vitrectomy, may be indicated before
`reconsidering ranibizumab).
`Retinal pigment epithelial (RPE) tears with subfoveal
`involvement have been reported to occur occasionally following
`intravitreal ranibizumab,'*’ and may therefore be a relative
`contraindication. However, to date, no data indicate that
`continuing ranibizumab in such cases would be deleterious
`(level III evidence).
`
`COMMENCING AND CONTINUING RANIBIZUMAB THERAPY
`FOR NEOVASCULAR AMD
`What are appropriate intervals for the initiation of ranibizumab
`treatment?
`Evidence
`Ranibizumab initiation with three consecutive monthly injec­
`tions appears optimal as this is when the majority of patients
`experienced most VA gain in all studies (fig lA-F, tables 2, 3).
`Improvements occurred rapidly, and the largest VA gain
`occurred after the first injection. Several studies indicate that
`untreated subfoveal CNV may grow quickly, on average around
`10 pm per day.™ Furthermore, after the first month in the PIER
`trial, VA deteriorated in the untreated control group by a mean
`of five letters (one line).^® A recent study reported that delayed
`initiation of treatment in patients with newly diagnosed AMD
`was associated with substantial VA loss.’®
`MARINA, ANCHOR'®'®’®'* and the EXCITE ranibizumab
`active control arm®" were the only Phase III studies with
`monthly injections throughout the whole treatment period.
`Most VA improvement was seen during the initial 3-month
`phase with subsequent injections appearing to maintain the
`achieved benefit (fig 2). Prospective clinical trials would be
`valuable for investigating fewer injections in the initiation
`phase.
`
`Clinical recommendation (level I evidence)
`► 0.5 mg of ranibizumab should be initiated with at least
`three consecutive monthly intravitreal injections, using an
`aseptic procedure.™
`► Treatment should be commenced as soon as possible after
`diagnosis. As an indication of this time interval, the
`screening periods permitted before treatment initiation in
`the clinical studies were <14 or <28 days. Clearly,
`treatment as early as possible, and at a maximum of within
`2 weeks of diagnosis, is ideal. Durations longer than
`1 month risk increasing visual loss.®® ™
`► Before administering ranibizumab at months 1 and 2,
`follow-up examination is recommended: history, VA assess­
`ment and slit-lamp fundus examination to identify any
`ocular side effects or major criteria for treatment failure or
`discontinuation.
`- FA is generally recommended only for patients with
`significant or unexplained vision loss, at the ophthalmol­
`ogist’s discretion.
`OCT detects, localises, classifies and quantifies intraretinal,
`subretinal and sub-RPE fluid, and is therefore recommended to
`
`4
`
`Br J Ophthalmol 2010;94:2-13. doi:10.1136/bjo.2009.159160
`
`

`

`b) ANCHOR: Monthly regimen; 96.9% PC. 2.8% MC, 0.2% ONC
`
`Review
`
`15 -I
`
`-15 -
`
`I > > I I I I
`15
`21
`18
`
`“1
`24
`
`-A- Ranibizumab 0.3 mg
`—Ranibizumab 0.5 mg
`—Verteporfin PDT
`~ I 1 I 1 I I—I I I I
`6
`9
`0
`3
`
`T1
`
`2
`Time (months)
`
`d) EXCITE; Monthly vs quarterly maintenance; 20.7% PC, 40.2% MC, 39.1% ONC
`
`15 -,
`
`e) PrONTO; Individualised maintenance with monthly visits;
`17.5% PC, 57.5% MC, 25.0% ONC
`
`Ranibizumab
`Time (months)
`I I I
`I I
`injections
`(quarterly)
`f) SUSTAIN; Individualised maintenance with monthly visits
`
`Ranibizumab
`injections
`
`Time (months)
`Individualised dosing with monthly visits
`
`Ranibizumab 0.3 mg
`
`-25 q------------------------------------- ,-------,-------------- .-------,-------
`0
`3
`9
`6
`r, -L.- i_
`Time (months)
`Ranibizumab * a a
`individualised dosing with monthly visits
`injections
`
`The LOCF method was used to impute missing data.
`Vertical bars are ±1 standard error of the mean.
`LOCFsIast observation carried forward; PC=predominantly classic; PDT=photodynamtc therapy; MC»minimaHy classic; ONC=occutt (with no classic)
`
`Figure 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 Ophthalmology 2009, 116, Brown et al,
`Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: 2-year results of ANCHOR Study, 57-65,
`Copyright 2009, with permission from Elsevier; (C) reprinted from Regillo et al, Ranibizumab (Lucentis) in treatment of neovascular age-related macular
`degeneration (AMD): 2-year results of PIER study, poster P0459 presented at the AAO 2007; (E) reprinted from Am J Ophthalmol 2007,143, Fung ef al.
`An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular
`degeneration, 566-83, Copyright 2007, with permission from Elsevier).
`
`Br J Ophthalmol 2010:94:2-13. doi:10.1136/bjo.2009.159160
`
`5
`
`

`

`Review
`
`Table 2 Summary table of controlled (multicentre, randomised) ranibizumab clinical trials and key efficacy outcomes
`Study design
`MARINA (N = 716)”
`ANCHOR (N = 423)” ”
`PIER (N = 184)” "’
`EXCITE (N = 353)”
`
`Study masking
`Study duration
`Lesion typef
`(percentage of patients
`with PC/MC/ONC)
`Visit regimen in
`maintenance phase
`Ranibizumab regimen in
`maintenance phase
`No of ranibizumab injections
`in maintenance phase (over
`first 12-month period)
`
`Double
`24 months
`Minimally classic and occult
`(with no classic) CNV
`(0.1/36.9/63.0)
`Monthly
`
`Monthly
`
`9
`
`Double
`24 months
`Predominantly classic CNV
`(96.9/2.8/0.2)
`
`Double
`24 months
`All CNV types
`(18.0/38.6/43.0)
`
`Single
`12 months
`All CNV types (20.7/40.2/39.1)
`
`Monthly
`
`Monthly
`
`9
`
`Quarterly
`
`Quarterly
`
`3
`
`Monthly for control arm
`Quarterly for study arms
`Monthly for control arm
`Quarterly for study arms
`9 for control arm
`3 for study arms
`
`Key baseline and
`efficacy results
`
`Ranibizumab
`0.5 mgj:
`(n = 240)
`
`Sham
`control
`(n = 238)
`
`Ranibizumab
`0.5 mgt
`(n = 139)
`
`Verteporfin
`control
`(n = 143)
`
`Ranibizumab
`0.5 mg}:
`(n = 61)
`
`Sham
`control
`(n = 63)
`
`Ranibizumab
`0.3 mg control
`(n = 101)
`
`Ranibizumab
`0.3 mg
`In = 104)
`
`Ranibizumab
`0.5 mg
`(n = 88)
`
`4.3 (2.5)
`
`53.7 (12.8)
`
`90.0*
`
`33.3*
`
`Mean (SD) size of CNV at
`baseline (optic-disc area)
`Mean (SD) VA at baseline
`(letters)
`Stabilisation of VA§
`(percentage of patients)
`Improvement in VAT
`(percentage of patients)
`Mean VA change from
`baseline (letters)
`After three initial doses -F5.9*
`At 12 months
`4-7.2*
`At 24 months
`4-6.6*
`
`4.3 (2.4)
`
`1.3 (1.2)
`
`1.5 (1.3)
`
`3.3 (2.3)
`
`3.6 (3.2) NA
`
`NA
`
`NA
`
`53.6 (14.1)
`
`47.1 (13.2)
`
`45.5 (13.1)
`
`53.7 (15.5)
`
`55.1 (13.9) 56.5 (12.2)
`
`55.8 (11.8)
`
`57.7 (13.1)
`
`52.9
`
`3.8
`
`89.9**
`
`41.0**
`
`65.7
`
`6.3
`
`82.0**
`
`8.2
`
`41.3
`
`4.8
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`-3.7
`4-10.0*
`-2.5
`4-4.3
`-8.7
`4-7.1
`4-6.2
`-10.4
`4-11.3*
`-9.5
`-0.2**
`-16.3
`4-8.0
`4-4.0
`-14.9
`4-10.7*
`-9.8
`-2.2**
`-21.4
`NAP
`NAP
`*p<0.001; **p<0.0001; data are for the intent-to-treat population; the last observation carried forward method was used to calculate missing data-
`tAdditional inclusion criteria for all studies: CNV compris