The Finnish National Guideline for Diagnosis, Treatment and Follow&#X2010;Up of Patients with Wet Age Related Macular Degene

ACTA OPHTHALMOLOGICA 2017

ACTA OPHTHALMOLOGICA http://www.actaophthalmologica.com

The Finnish national guideline for diagnosis, treatment and follow-up of patients with wet age related macular degeneration

Raimo Tuuminen, Hannele Uusitalo-Järvinen, Vesa Aaltonen, Nina Hautala, Sulevi Kaipiainen, Nina Laitamäki, Marko Ollila, Jari Rantanen, Satu Välimäki, Raija Sipilä, Tanja Laukkala, Jorma Komulainen, Petri Tommila, Ilkka Immonen, Anja Tuulonen and Kai Kaarniranta

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Disclosures: Raimo Tuuminen: Advisory Board/Consultant (Allergan, Bayer); Grant/Research/Clinical Trial Support (Bayer, Laboratoires Thea); Honorarium (Alcon, Allergan) Hannele Uusitalo-Järvinen: Advisory Board/Consultant (Allergan, Bayer, Novartis); Speaker’s Bureau (Santen) Vesa Aaltonen: Honorarium (Allergan, Bayer, Novartis); Speaker’s Bureau (Santen) Nina Hautala: Advisory Board/Consultant (Allergan, Bayer, Novartis), Speaker’s Bureau (Allergan, Bayer, Santen) Sulevi Kaipiainen: Nothing to disclose Nina Laitamäki: Nothing to disclose Marko Ollila: Nothing to disclose Jari Rantanen: Nothing to disclose Satu Välimäki: Advisory Board/Consultant (Allergan, Novartis); Honorarium (Allergan); Speaker’s Bureau (MSD, Santen, Sanoﬁ Aventis, Novo Nordisc) Raija Sipilä: Nothing to disclose Tanja Laukkala: Nothing to disclose Jorma Komulainen: Nothing to disclose Petri Tommila: Nothing to disclose Ilkka Immonen: Grant/Research/Clinical Trial Support (Novartis, Ophtec); Honorarium (Alcon, Bayer, Novartis), Speaker’s Bureau (Alcon, Bayer, Novartis) Anja Tuulonen: Nothing to disclose Kai Kaarniranta: Nothing to disclose

Funding: This review was supported by grants from the Finnish Ophthalmological Society and the Departments of Ophthalmology of the University and Central Hospitals in Finland.

Correspondence: Kai Kaarniranta, MD PhD, Professor, Chief Physician, Department of Ophthalmology, Kuopio University Hospital, Finland. E-mail: kai.kaarniranta@kuh.ﬁ

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Table of Contents

Abstract 1 Process of compiling the guideline 1 Deﬁning the topic 2 Objective 2 Target groups 2 Occurrence 2 Risk factors 3 Symptoms 3 Diagnosis 3 Treatment 4 Follow-up 6 References 7

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The Finnish national guideline for diagnosis, treatment and follow-up of patients with wet age- related macular degeneration

Raimo Tuuminen,1,2,3 Hannele Uusitalo-Jarvinen,€ 4 Vesa Aaltonen,5 Nina Hautala,6,7 Sulevi Kaipiainen,8 Nina Laitamaki,€ 9 Marko Ollila,10 Jari Rantanen,11 Satu Valim€ aki,€ 12 Raija Sipila,€ 13 Tanja Laukkala,13 Jorma Komulainen,13 Petri Tommila,14 Ilkka Immonen,14 Anja Tuulonen4 and Kai Kaarniranta15,16

1Department of Ophthalmology, Kymenlaakso Central Hospital, Kotka, Finland 2Helsinki Retina Research Group, University of Helsinki, Helsinki, Finland 3Patient Insurance Centre, Helsinki, Finland 4Tays Eye Centre, Tampere University Hospital, Tampere, Finland 5Department of Ophthalmology, Turku University Hospital, Turku, Finland 6Department of Ophthalmology, Oulu University Hospital, Oulu, Finland 7Medical Research Center, University of Oulu, Oulu, Finland 8Department of Ophthalmology, North Karelian Central Hospital, Joensuu, Finland 9Department of Ophthalmology, Kanta-Hame€ Central Hospital, Hameenlinna,€ Finland 10Department of Ophthalmology, Lapland Central Hospital, Rovaniemi, Finland 11Department of Ophthalmology, Satakunta Central Hospital, Pori, Finland 12Department of Ophthalmology, Paij€ at-H€ ame€ Central Hospital, Lahti, Finland 13The Finnish Medical Society Duodecim, Helsinki, Finland 14Department of Ophthalmology, Helsinki University Hospital, Helsinki, Finland 15Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland 16Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland

ABSTRACT • The process is described in detail at Age-related macular degeneration (AMD) is the main cause of visual impairment http://www.terveysportti.fi/xmedia/ in developed countries. Several improvements in the visualization of posterior ccs/process/Suositus.html. segment of the eye together with the introduction of intravitreal anti-VEGF • In summary, the process consists of treatment have revolutionized the prognosis of the wet form of AMD (wAMD). (i) formulating clinically relevant key Increasing incidence of wAMD together with the limited resources of society and questions, (ii) trying to answer the of the healthcare system poses challenges for the provision and development of key questions by creating Evidence care. In context of these current aspects, we aimed to set evidence-based medical Summaries based on a systematic guidelines for diagnosis, treatment and follow-up of patients with wAMD. literature search and (iii) ﬁnally making practical evidence-based recommendations for everyday practice. Acta Ophthalmol. 2017: 0: 1–9 The evidence of key statements is ª 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd graded from A to D: doi: 10.1111/aos.13501 . Level A (expressed with the verb This review was supported by grants from the Finnish Ophthalmological Society and the Departments of is better/the same as, etc.) refers to Ophthalmology of the University and Central Hospitals in Finland. strong research-based evidence, for example homogenous results from high-quality systematic review(s), or departments of hospital districts in multiple, relevant, high-quality Process of Compiling the Finland. studies (e.g. two or more random- Guideline • The writing group consisted of three ized controlled trials). editors of Current Care Guidelines . Level B (expressed with the verb • The initiative for creating the and the ophthalmic Expert ‘seem’ to be better/the same as, etc.) guideline was born by the eye Panel from the hospital districts. refers to moderate evidence, for

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example one randomized controlled stakeholders responded.2 The stake- . When and with what criteria the trial, or multiple adequate studies. holders presented 48 suggestions for treatment should be discontinued? . Level C (expressed with the verb improvement; these were formally • Follow-up ‘may’ be better/the same as, etc.) reviewed by the Expert Panel. refers to limited research-based evi- According to the review, 17 reword- . What methods are required for dence, for example controlled ings but no major changes in the the follow-up of wAMD? prospective studies, or studies where recommendations were made in the . When and by what criteria may a there is considerable incongruity final version of the Guideline. patient be taken off control visits among outcomes; and switched to self-monitoring? . Level D (expressed as ‘no, or Defining the Topic • The recommendations do not cover unclear evidence’) refers to retro- the screening or prevention of spective studies, or the consensus • This guideline aimed to answer the wAMD or the rehabilitation after reached by the group in the absence following questions concerning the wAMD. of good-quality evidence. diagnosis, treatment and follow-up • The treatment discussed here focuses of wet age-related macular degener- • The Current Care consensus process mainly on intravitreal anti-VEGF ation (wAMD). is informal; the Expert Panel dis- injections. • Diagnosis cusses the evidence in the context of the Finnish healthcare system. When . What methods are required for Objective grading the evidence, the applicabil- the diagnosis of wAMD? ity of results of the study population • The objective of the recommenda- • Treatment is considered, especially when evi- tions was to standardize and improve dence in the Finnish population is . What are the indications for the diagnosis, treatment and follow- not available. treatment in wAMD? up of wAMD. • This review is an English translation . Which clinical findings may pre- of the Finnish Current Care Guide- dict poor treatment effect? Target Groups line for wet age-related macular . Do laser photocoagulation and degeneration (AMD). It is based photodynamic therapy (PDT) have • The primary targets of the recom- primarily on published systematic a place in treatment of wAMD in mendations are the ophthalmologists literature reviews searched up to some indications? and eye clinics that carry out diag- May 2015. This Current Care Guide- nosis, treatment and follow-up of • Treatment with anti-VEGF drugs line based on 18 Evidence Sum- wAMD. (bevacizumab, ranibizumab and maries (seven summaries with level • The recommendations may be useful aflibercept) B evidence, 10 summaries with level for all medical professionals dealing C evidence and one summary with . Are there differences in their with patients with wAMD. level D evidence). The evidence sum- effectiveness? maries, written in English, are found . Are there differences in their Occurrence in http://www.kaypahoito.fi/web/ adverse effects and safety? english/guidelines. . What are the contraindications • Wet AMD is the most common • The recommendations were circu- for anti-VEGF treatment? cause of impaired vision in the lated in 44 stakeholders in Finland . What kind of expertise is developed countries (Javitt et al. for comments.1 Altogether, 11 required for carrying out anti- 2003; Klein et al. 2004; Cruess VEGF treatment? et al. 2007; Jager et al. 2008). Of . the total number of AMD patients, 1These stakeholders included five university Should the treatment be initiated with a loading dose? 10–20% have the wet form of the hospital eye departments, fifteen central hos- . Should the medication be admin- disease. pital eye department, the Council of Choices istered regularly or as needed? • Forty-one percent of visual impair- for Health Care in Finland led by the Ministry . Is there a difference in the ment in the Finnish Register of of Social Affairs and Health (STM/PALKO), adverse effects between different Visual Impairment is due to AMD. the Social Insurance Institution (Kela), the treatment protocols? For people 65-years or older, AMD Finnish Medicines Agency (Fimea), the Fin- . Is there a difference in the cost- accounts for 59% of all cases of nish Office for Health Technology Assessment effectiveness between the different visual impairment (Annual report of (FinOHTA), and the National Supervisory treatment protocols? the Finnish Register of Visual Authority for Welfare and Health (Valvira), . What can be done when there is Impairment 2014 http://www.nkl.fi/ the Finnish Ophthalmological Society, the no response to treatment? index.php?__file_display_id=7892). Society for Visually Disabled Patients, the Approximately half of the visual Finnish Register of Visual Impairment, the impairment in this group of elderly Finnish Medical Society Duodecim, the Asso- patients with AMD is due to wAMD. ciation of Clinical Pharmacology, the Finnish 2Six responders represented university hospi- • One-third of patients with wAMD Association for General Practice, the Finnish tal eye departments, three represented the develop bilateral disease during 3– Nurses Association, the Association of Fin- central hospital eye departments and two 5 years (Macular Photocoagulation nish Ophthalmic Nurses. represented the Social Insurance Institution.

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Study Group 1993; Rasmussen et al. needed. Autofluorescence can be ination method in the diagnosis of 2013). camera or optical coherence tomog- wAMD (Castillo et al. 2014; Mowatt • Prior to availability of effective treat- raphy (OCT)-based. et al. 2014; Wilde et al. 2015). (C) ment, half of the patients with bilat- • Recommendation 1. The diagnosis o Comment: OCT is used to visu- eral wAMD became severely visually of wAMD should always be carried alize the thickening or swelling of impaired within 5 years (best-cor- out by or under the surveillance of a the retina. It should be especially rected visual acuity in the better eye physician specialized in its diagnosis noted that hemorrhages might not ≤0.1) (Macular Photocoagulation and treatment. be visible in an OCT picture. Study Group 2014 1993). o Comment: While OCT angiogra- • Wet AMD is associated with a signif- . The presence of other eye dis- phy is a new upcoming tool to icant loss in quality of life, particularly eases, risk factors for AMD, and diagnose retinal diseases, there is when the visual acuity of both eyes is systemic diseases should always be not enough evidence of its usability <0.5 (Sahel et al. 2007; Soubrane determined. in diagnosing wAMD so far. et al. 2007; Matamoros et al. 2015). . Clinical examination should always include bilateral visual acu- • Recommendation 3. In clinically ity testing, biomicroscopy, and obvious cases, wAMD can be diag- Risk Factors examination of the fundus. nosed and the treatment initiated using the satisfactory level of wAMD • Age (Mitchell et al. 2002; Javitt et al. • Interobserver interpretation of fluo- diagnosis as shown in Table 1 2003; Klein et al. 2004; Mukesh rescein angiography (FA) images in (BCVA, biomicroscopy, OCT). et al. 2004; Cruess et al. 2007; Jager the diagnosis of wAMD may be et al. 2008). variable (Friedman & Margo 2000; . There should also be the possi- • Smoking (Klein et al. 2008). Holz et al. 2003; Zayit-Soudry et al. bility to take a FA as needed. 2007; Muni et al. 2008). (C) . According to the Expert Panel, in . Increased risk of wAMD can last • clinically obvious cases the treat- up to 20 years after quitting smok- Recommendation 2. Whenever feasi- ment can be initiated based on the ing (Zerbib et al. 2014). ble, the diagnosis of wAMD should satisfactory level of diagnostics in . Nevertheless, quitting smoking be based at least on the good level of order to avoid delays in treatment. seems to reduce the risk of wAMD diagnostics as shown in Table 1 [best . The presence of sequential fun- (Klein et al. 2014). corrected visual acuity (BCVA), dus images may help the monitoring • biomicroscopy, OCT, fundus pho- Hereditary predisposition tography and when necessary FA] of treatment effect. . Heredity accounts for 60% of . There should be a possibility to • Recommendation 4. In diagnosti- cases of wAMD (Edwards et al. perform FA before the treatment is cally challenging cases, it is recom- 2005; Haines et al. 2005; Klein et al. initiated. mended to implement the excellent 2005; Kanda et al. 2007; Canter . Both eyes should be examined. level of diagnostics [Table 1: BCVA, et al. 2008; Fritsche et al. 2013). . Fluorescein angiography may be biomicroscopy, fundus photography, OCT and together with indocyanine • Cardiovascular diseases (Javitt et al. regarded as the gold standard in the green angiography (ICGA) as 2003; Klein et al. 2004; Cruess et al. diagnosis of wAMD compared to needed]. 2007; Jager et al. 2008). OCT when it is not contraindicated € (Sturzlinger et al. 2007; Mowatt . Indocyanine green angiography Symptoms et al. 2014; Schmidt-Erfurth et al. may be suitable as a complementary 2014a; Wilde et al. 2015). (C) method in the diagnostics of • Symptoms appear and progress o Comment: FA as an examination wAMD (Landa et al. 2007; Sulzba- rapidly. cher et al. 2011; Mowatt et al. 2014; • requires considerably more time and The typical symptoms referring to resources than OCT. Schmidt-Erfurth et al. 2014a). (C) wAMD are as follows: . Fluorescein angiography may be . Optical coherence tomography . Loss of both near and far vision regarded as the golden standard in may be sensitive but not accurate the diagnosis of wAMD (Sturzlinger€ occurring within days or weeks. enough to be used as the only exam- . Sudden visual distortion. et al. 2007; Mowatt et al. 2014; . Central scotoma (loss of central vision). . Changes in colour vision. Table 1. Recommendation for diagnostic tests of wAMD. Level of Visual Biomicroscopy OCT Fundus FA ICGA Diagnosis diagnosis acuity* image • The means to diagnose wAMD is Excellent X X X X X As shown in Table 1. needed • The fundus image may be taken to Good X X X X As aid the diagnosis and documenta- needed Satisfactory X X X tion. The pictures can be colour, red-free or autofluorescent as * Best-corrected visual acuity.

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Schmidt-Erfurth et al. 2014a; Wilde monthly injected ranibizumab of symptoms and initiation of treat- et al. 2015). (C) (0.5 mg) in maintaining visual acu- ment worsened the prognosis signif- ity (Heier et al. 2012; Schmidt- icantly. A delay over 21-week • Recommendation 5. If the diagnosis Erfurth et al. 2014b; Schmid et al. between the onset of symptoms of wAMD still remains uncertain – 2015; Yuzawa et al. 2015). (B) and treatment had worse impact in spite of implementing the good . There seem to be no clinically on visual acuity compared to level of diagnostics – trial with anti- significant short-term safety differ- patients with a delay of <7 weeks VEGF treatment may be justified. ences between ranibizumab and (OR) 2.62 (95% confidence interval . According to the Expert Panel, bevacizumab in the treatment of 1.20–5.68) (Lim et al. 2012). in diagnostically uncertain cases wAMD (CATT Research Group trial with anti-VEGF treatment 2012; Daniel et al. 2014; Moja et al. • Recommendation 8. In case of recent may be more beneficial than 2014; Chen et al. 2015; Schmid cardiovascular event (within monitoring the eye and delaying et al. 2015). (B) 3 months), anti-VEGF treatment the treatment when the patient’s . Monthly or less frequent intrav- can be considered after careful eval- vision is at risk (Rasmussen itreal injections of aflibercept (0.5– uation of the possible treatment- et al. 2015). 2 mg) may be as safe as monthly related benefits and adverse effects. injected ranibizumab (0.5 mg) in the . In a case-control study, no con- treatment of wAMD (Heier et al. nection was found between intravit- Treatment 2012; Schmidt-Erfurth et al. 2014b; real injections of bevacizumab or Schmid et al. 2015; Yuzawa et al. • Recommendation 6. Treatment with ranibizumab and increased risk of 2015). (C) intravitreal anti-VEGF injections ischemic stroke, heart attack, . Treatment of wAMD patients should be considered for every eye venous thrombosis or heart failure. with PDT combined with ranibizu- with wAMD. There was no difference between the mab does not seem to improve drugs in this respect (Campbell . There are no clinically significant visual acuity compared to treatment et al. 2012). differences in the efficacy and safety with ranibizumab alone (Si et al. . The percentage of adverse effects between the different anti-VEGF 2014; Hatz et al. 2015). (B) found in randomized controlled drug ingredients in the treatment o In the treatment of polypoidal studies are: of wAMD during the first few years choroidal vasculopathy, PDT may of follow-up. o 3.5% for thromboembolic event be as effective and as safe as intrav- . There are significant cost differ- with ranibizumab (Moja et al. 2014), itreally injected anti-VEGF drug in ences between the different anti- 3.2% with bevacizumab (Moja et al. maintaining visual acuity (Oishi VEGF drugs. 2014), 0.7–2.3% with aflibercept et al. 2014; Yong et al. 2015). When – o (Heier et al. 2012), and 3.6 3.8% Comment: Althoughbevacizumab combined, PDT reduces the need for with placebo injections (Heier et al. is not officially indicated in the treat- intravitreal anti-VEGF injections 2006; Rosenfeld et al. 2006). ment of wAMD, in December 2015, (Koh et al. 2012). o 1.4% for heart attack with rani- the Council of Choices for Health . High quality evidence of the bizumab (Moja et al. 2014), 1.2% Care in Finland (COHERE) treatment of peripapillary choroidal with bevacizumab (Moja et al. approved off-label use of beva- neovascularization is lacking. Based 2014), 1–2% with aflibercept (Heier cizumab for the treatment of AMD on the opinion of the Expert Panel, et al. 2012), and 1.7–3.6% with in Finland. COHERE Finland is peripapillary choroidal neovascular- placebo injections (Heier et al. interconnected to and led by the ization may be treated either by 2006; Rosenfeld et al. 2006). Ministry of Social Affairs and Health anti-VEGF drugs, PDT, laser pho- o 1.1% for stroke with ranibizu- http://stm.fi/neuvottelukunnat/terve tocoagulation treatments or their mab (Moja et al. 2014), 0.9% with ydenhuollon_palveluvalikoimaneu combination (Jutley et al. 2011). bevacizumab (Moja et al. 2014), vosto. COHERE stated that beva- • 0.5–0.8% with aflibercept (Heier cizumab is an effective therapy for Recommendation 7. According to et al. 2012), and 0.8% with placebo improving vision in AMD, equal in the opinion of the Expert Panel, the injections (Rosenfeld et al. 2006). efficacy and safety to intravitreal anti-VEGF treatment should be ini- o Comment: The data of placebo ranibizumab and aflibercept in the tiated without delay after the onset injections are based on two small treatment of wAMD. of symptoms in order to promote studies. There were no significant prognosis. . Bevacizumab and ranibizumab statistical differences in the above seem to have the same efficacy in . Initiating anti-VEGF treatment mentioned adverse effects between maintaining visual acuity in the immediately or within a few days the anti-VEGF and the placebo treatment of wAMD during 1– after the diagnosis versus after group. A network meta-analysis 2 years of follow-up (Solomon et al. about 2-week delay may lead to study found a slightly higher 2014; Chen et al. 2015; Schmid better improvement of vision during amount of adverse effects for anti- et al. 2015). (B) 3 month follow-up (Rasmussen VEGF treatment compared to the . Monthly or less frequent intrav- et al. 2015). (C) placebo group (relative difference itreal injections of aflibercept (0.5– . In a prospective series of approximately 2–6%) (Schmid et al. 2 mg) seem to be as effective as patients, a delay between the onset 2015).

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. Comment: The risks of anti- . Loading dose injections of beva- Research Group and Martin 2012; VEGF treatment in non-selected cizumab given three times 4– Stein et al. 2013; Dakin et al. 2014; patients may be different compared 6 weeks apart may lead to better Elshout et al. 2014). (B) to selected patients in randomized improvement of visual acuity in the . Ranibizumab monthly and controlled trials. short term than a PRN protocol to aflibercept bimonthly both seem to . Contraindications reported in begin with (Arias et al. 2008; improve the quality of life of the selling permits of the medica- Menon et al. 2013; Barikian et al. patients and show no differences in tions are listed in Table 2. 2015). (C) this respect (Yuzawa et al. 2015). (B) . If treatment is initiated from day . There is only one randomized • Recommendation 9. The benefits one with a PRN protocol without controlled trial on the effectiveness and risks should be taken into loading doses, OCT examinations of treat-and-extend treatment pro- account when considering the treat- should be done every 4–6 weeks to tocol compared to anti-VEGF injec- ment. These include the patient’s evaluate the need for injections. tions with regular intervals. prevalent visual acuity in both eyes, According to this study, TER pro- • Recommendation 11. The aim of systemic diseases and life expectancy tocol results in similar effects com- anti-VEGF treatment is to halt the as well as the expected treatment pared to fixed protocol with progression of the disease. The pro- effect on ability to function and ranibizumab during 1-year follow- gression of wAMD is monitored quality of life. up (Wykoff et al. 2015). with repeated measurements of . Also prospective and retrospec- . Based on the opinion and expe- visual acuity, biomicroscopy and tive studies refer to similar treat- rience of the Expert Panel, the OCT. ment effects with different protocols expected benefit of treatment, in . The recommendations of the (TER versus PRN and fixed proto- terms of ability to function and Expert Panel for different treatment cols) in improving and maintaining quality of life, is small for a patient protocols are presented in Table 4. visual acuity in the long-run. whose BCVA is <0.0625 in the . During short-term follow-up, . In spite of lacking high-quality treated eye. bevacizumab and ranibizumab evidence, a group of international . Most studies have excluded injected at fixed 4–6-week intervals experts regards the OCT-guided patients with visual acuity <0.0625. may not lead to clinically signifi- TER protocol as an alternative for • Recommendation 10. Anti-VEGF cantly better visual acuity than anti-VEGF treatment in wAMD treatment can be initiated with three drugs injected according to PRN (Freund et al. 2015). loading doses given approximately protocol (Schmidt-Erfurth et al. • Recommendation 12. If adequate 1 month apart, or given on an as- 2011; CATT Research Group et al. treatment is not gained with one needs basis (pro re nata, PRN). 2012; El-Mollayess et al. 2012; Bus- anti-VEGF drug, treatment with bee et al. 2013; Lushchyk et al. another anti-VEGF drug may be 2013; Ho et al. 2014; Jiang et al. justified. Table 2. Contraindications for intravitreal 2014). (C) injections reported in the selling permits of . Monthly injections of beva- . Within about 1-year, aflibercept the anti-VEGF drugs in Finland (for bevacizumab or ranibizumab may may improve visual acuity and cizumab regarding intravenous dosage). increase risk for geographic retinal decrease anatomical changes in Aflibercept • Hypersensitivity to afliber- atrophy compared to PRN proto- patients for whom other anti-VEGF cept or any pharmaceutical col. Otherwise no clinically signifi- drugs have not produced expected aid substance • Active or suspected infec- cant differences seem to appear in effect. However, high-quality evi- tion in the eye or eye region the risk of adverse effects between dence is still missing (Chang et al. • Active severe intraocular the treatment protocols (Schmidt- 2014; Ferrone et al. 2014; Singh inflammation Erfurth et al. 2011; Comparison of et al. 2014, 2015). (D) Bevacizumab • Hypersensitivity to beva- Age-related Macular Degeneration • Recommendation 13. Intravitreal cizumab or any pharma- Treatments Trials (CATT) Research ceutical aid substance anti-VEGF injection can be admin- Group and Martin 2012; Ueta et al. • Hypersensitivity to sub- istered in an appropriate setting by a 2014; Dakin et al. 2014; Schmidt- stances produced in Chinese well-trained ophthalmologist, resi- hamster (Cricetulus griseus) Erfurth et al. 2014b; Grunwald dent in ophthalmology, or a nurse ovary cell or to other et al. 2014; Daniel et al. 2014). (C) human (or humanized) acquainted in ophthalmologic nurs- . Bevacizumab injected for antibodies produced with ing. recombinant DNA technol- wAMD as needed seems to be a . • ogy more cost-effective treatment proto- Two meta-analyses reported a Pregnancy col than monthly injections as small 0.049–0.056% risk for endoph- Ranibizumab • Hypersensitivity to ranibi- increases in effects incur higher thalmitis after intravitreal anti- zumab or any pharmaceu- additional costs. (B) Bevacizumab VEFG injections, i.e. about five tical aid substance seems to be more cost-effective than infections per 10 000 injections • Ocular or periocular infection or suspected infection ranibizumab and aflibercept given (McCannel 2011; Fileta et al. 2014). • Severe intraocular inflam- as needed or monthly (Comparison . A retrospective cohort study mation of Age-related Macular Degenera- reported that bevacizumab and tion Treatments Trials (CATT) ranibizumab injections given in an

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operation theatre had a significantly residents and special-trained nurses . The Expert Panel suggests treat- smaller risk for endophthalmitis have a very small risk of local ment to be discontinued at the latest than office-based injections (Abell adverse effects, and the risk does when the visual acuity in the et al. 2012). not vary with the educational back- treated eye permanently drops below . A UK prospective cohort study ground of the person giving the 0.0625. found that ranibizumab injected by injection (Hasler et al. 2015). trained nurses in a properly equipped • Recommendation 14. Anti-VEGF Follow-up room, was neither associated with an treatment should be discontinued in increased risk of endophthalmitis Tables 3 and 4 present the summary of case of no benefit and no expecta- nor other local adverse effects (Sim- the treatment and follow-up protocols tions for improvement of the cock et al. 2014). for wAMD. patient’s ability to function or qual- . An Iranian retrospective cohort • ity of life, or if the adverse effects and The definition of adequate treatment study did not find an increased risk risks associated with treatment are response as referred to in Table 4: of endophthalmitis when beva- estimated to be greater than the . cizumab injections were given by No retinal swelling or subretinal expected benefits. ophthalmic residents (Falavarjani fluid is found in OCT (pigment et al. 2015). . The health and visual acuity of epithelial detachment is permitted). . A Danish retrospective cohort both eyes should be considered. o If minimial retinal swelling and/ study found that intravitreal ranibi- . The decision to discontinue treat- or subretinal fluid has remained zumab injections administered by ment should be made together with stable for a long time and the ophthalmologists, ophthalmology the patient. visual acuity is stable despite ongo-

Table 3. The recommendation of the expert panel for the follow-up of wet form of age-related macular degeneration.

Level of follow-up Visual acuity Biomicroscopy Optical coherence tomography Fundus image Fluorescein angiography

Excellent X X X As needed As needed Good X 1–2 times per year* X

* Clinical examination, including measurement of intraocular pressure.

Table 4. The recommendation of the expert panel for scheduling treatment and follow-up for wAMD in diﬀerent treatment protocols.

Protocol Time intervals between injections Follow-up examinations

Fixed (injections given according to • Aflibercept: First 3 injections at 4- to 6-week • After every three injections predetermined and regular time intervals, thereafter at 8-week intervals • Treatment is continued regardless of the activity • – intervals) Bevacizumab: 4 6 weeks of the disease until the criteria for discontinua- • Ranibizumab: 4–6 weeks tion of treatment are met PRN (pro re nata, injections given If treatment response is inadequate* • Within 4–6 weeks (bevacizumab and ranibizumab) or 4–8 weeks (aflibercept) of the last according to the status of the macula) • – Aflibercept: 4 8 weeks injection. • – Bevacizumab: 4 6 weeks • If no injection is given, follow-up examination • – Ranibizumab: 4 6 weeks after 4–6 weeks. • If treatment response is adequate* • • Note: A series of, for example, three injections No treatment in this follow-up visit can be preplanned so that the follow-up visits are carried out after the series of injections Treat-and-extend (injections given at Until adequate treatment response has been • Always before the planned injection gradually increasing intervals achieved* according to the status of the macula) • Aflibercept: 4–8 weeks • Bevacizumab: 4–6 weeks • Ranibizumab: 4–6 weeks After adequate treatment response has been achieved† • The interval between follow-up visits is lengthened by at most 2 weeks gradually up to 12-16- weeks • If inadequate treatment response is detected, return to the previous treatment time interval • In case of a severe recurrence†, the treatment is reverted back to monthly injections and then extended according to the treatment protocol

* Adequate treatment response is deﬁned in the recommendation text below. † Severe recurrence of intraretinal or subretinal ﬂuid associated with visual loss of ≥6 letters, subfoveal or large extrafoveal haemorrhage.

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ing injection treatment, the activity and an adequate treatment response A4917G is independently associated with of the disease can be evaluated has been maintained. age-related macular degeneration. PLoS with a FA or by pausing injection . In the TER, the maximum fol- ONE 3: e2091. treatment. Surveillance should low-up interval with anti-VEGF Castillo MM, Mowatt G & Lois N (2014): for the diagnosis of neovascular age-related follow the chosen treatment treatment has been reached and the macular degeneration: a systematic review. protocol. adequate treatment response has Eye (Lond) 28: 1399–1406. o In monitoring the activity of the been maintained, which after fol- Castillo MM, Mowatt G & Elders A (2015): disease, OCT may be rather sensi- lowed without anti-VEGF treat- Optical coherence tomography for the mon- tive compared to FA in discovering ment for the past 6–12 months itoring of neovascular age-related macular an active disease, but the specificity (with no signs of active wAMD). degeneration: a systematic review. Ophthal- of OCT may be acceptable at best . The Amsler grid can be used in mology 122: 399–406. (Castillo et al. 2015). self-monitoring (Yannuzzi 1982; Chang AA, Li H & Broadhead GK (2014): Intravitreal aflibercept for treatment-resis- Augustin et al. 2005; Keane et al. . Best-corrected visual acuity is tant neovascular age-related macular 2015) as well as patients monitoring stable. degeneration. Ophthalmology 121: 188– their symptom (e.g. changes in 192. o The treatment and follow-up time visual acuity, distorted vision or Chen G, Li W, Tzekov R, Jiang F, Mao S & interval in both the fixed and PRN increased difficulty in reading). Tong Y (2015): Bevacizumab versus ranibi- protocols is 4–6 weeks; with afliber- zumab for neovascular age-related macular o Comment: After 3 ranibizumab cept the interval is 4–8 weeks. With degeneration: a meta-analysis of randomized injections, wAMD re-activated – TER protocol, the time interval controlled trials. Retina 35: 187 193. within a 2-year follow-up period in Comparison of Age-related Macular Degener- between injections and follow-ups is 75% of patients in a Japanese ation Treatments Trials (CATT) Research gradually lengthened up to 12– cohort study (Kuroda et al. 2015). Group & Martin DF (2012): Ranibizumab 16 weeks. and bevacizumab for treatment of neovascular age-related macular degeneration: two- • Recommendation 15. The treatment year results. Ophthalmology 119: 1388– and surveillance in the majority of References 1398. cases should be based at least on the Cruess A, Zlateva G, Xu X & Rochon S good level of follow up protocol Abell RG, Kerr NM, Allen P & Vote BJ (2007): Burden of illness of neovascular age- (Table 3). (2012): Intravitreal injections: is there benefit related macular degeneration in Canada. for a theatre setting? Br J Ophthalmol 96: Can J Ophthalmol 42: 836–843. . Best-corrected visual acuity 1474–1478. Dakin HA, Wordsworth S & Rogers CA should be examined periodically to Annual report of the Finnish Register of (2014): Cost-effectiveness of ranibizumab make sure that any decline in vision Visual Impairment (2014). Available at: and bevacizumab for age-related macular is unrelated optical causes. http://www.nkl.fi/index.php?__file_display_ degeneration: 2-year findings from the . The treatment protocol determi- id=7892. (Accessed on 00 000 0000). IVAN randomised trial. BMJ Open 4: nes the frequency of the follow-up Arias L, Caminal JM & Casas L (2008): A e005094. study comparing two protocols of treatment examinations. Daniel E, Toth CA & Grunwald JE (2014): with intravitreal bevacizumab (Avastin) for Risk of scar in the comparison of age-related o If the treatment is initiated with neovascular age-related macular degenera- macular degeneration treatments trials. three loading doses, and then moved tion. Br J Ophthalmol 92: 1636–1641. Ophthalmology 121: 656–666. to PRN or the treat-and-extend Augustin AJ, Offermann I, Lutz J, Schmidt- Edwards AO, Ritter R 3rd, Abel KJ, Manning Erfurth U & Tornambe P (2005): Compar- A, Panhuysen C & Farrer LA (2005): protocol, a follow-up examination ison of the original Amsler grid with the – Complement factor H polymorphism and should be scheduled 4 6 weeks after modified Amsler grid: result for patients age-related macular degeneration. Science the last loading dose. During the with age-related macular degeneration. 308: 421–424. follow-up examination it will be Retina 25: 443–445. El-Mollayess GM, Mahfoud Z, Schakal AR, determined if new injections are Barikian A, Mahfoud Z, Abdulaal M, Safar A Salti HI, Jaafar D & Bashshur ZF (2012): needed (PRN). If TER protocol is & Bashshur ZF (2015): Induction with Fixed-interval versus OCT-guided variable followed an injection is given and intravitreal bevacizumab every two weeks dosing of intravitreal bevacizumab in the the date for the next injection is set. in the management of neovascular age- management of neovascular age-related related macular degeneration. Am J Oph- macular degeneration: a 12-month random- o If PRN is selected to begin with, thalmol 159: 131–137. ized prospective study. Am J Ophthalmol follow-up examinations should be Busbee BG, Ho AC & Brown DM (2013): 153: 481–489. scheduled from day one at intervals Twelve-month efficacy and safety of 0.5 mg Elshout M, van der Reis MI, Webers CA & of 4–6 weeks. or 2.0 mg ranibizumab in patients with Schouten JS (2014): The cost-utility of • subfoveal neovascular age-related macular aflibercept for the treatment of age-related According to the Expert Panel, tran- degeneration. Ophthalmology 120: 1046– macular degeneration compared to beva- sition to self-monitoring is possible, 1056. cizumab and ranibizumab and the influence when: Campbell RJ, Gill SS, Bronskill SE, Paterson of model parameters. Graefes Arch Clin Exp JM, Whitehead M & Bell CM (2012): Ophthalmol 252: 1911–1920. . The patient understands how the Adverse events with intravitreal injection of Falavarjani KG, Aghamirsalim M & Modar- self-monitoring is carried out and vascular endothelial growth factor inhibi- res M (2015): Endophthalmitis after resi- interpreted. tors: nested case-control study. BMJ 345: dent-performed intravitreal bevacizumab . In the fixed or the PRN proto- e4203. injection. Can J Ophthalmol 50:33–36. cols, 6–12 months have elapsed Canter JA, Olson LM & Spencer K (2008): Ferrone PJ, Anwar F & Naysan J (2014): Early after the last anti-VEGF injection Mitochondrial DNA polymorphism initial clinical experience with intravitreal

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aflibercept for wet age-related macular Javitt JC, Zhou Z, Maguire MG, Fine SL & degeneration. Am J Ophthalmol 153: 678– degeneration. Br J Ophthalmol 98(Suppl Willke RJ (2003): Incidence of exudative 686. 1): i17–i21. age-related macular degeneration among Lushchyk T, Amarakoon S, Martinez-Ciriano Fileta JB, Scott IU & Flynn HW Jr (2014): elderly Americans. Ophthalmology 110: JP, van den Born LI, Baarsma GS & Meta-analysis of infectious endophthalmitis 1534–1539. Missotten T (2013): Bevacizumab in age- after intravitreal injection of anti-vascular Jiang S, Park C & Barner JC (2014): Ranibi- related macular degeneration: a randomized endothelial growth factor agents. Oph- zumab for age-related macular degenera- controlled trial on the effect of injections thalmic Surg Lasers Imaging Retina 45: tion: a meta-analysis of dose effects and every 4 weeks, 6 weeks and 8 weeks. Acta 143–149. comparison with no anti-VEGF treatment Opthalmol 91: e456–e461. Freund KB, Korobelnik JF & Devenyi R and bevacizumab. J Clin Pharm Ther 39: Macular Photocoagulation Study Group 2014 (2015): Treat-and-extend regimens with anti- 234–239. (1993): Five year follow-up of patients with vegf agents in retinal diseases: a literature Jutley G, Jutley G, Tah V, Lindfield D & age-related macular degeneration and uni- review and consensus recommendations. Menon G (2011): Treating peripapillary lateral extrafoveal choroidal neovasculariza- Retina 35: 1489–1506. choroidal neovascular membranes: a review tion. Arch Ophthalmol 111:1189–1199. Friedman SM & Margo CE (2000): Choroidal of the evidence. Eye (Lond) 25: 675–681. Matamoros E, Maurel F & Leon N (2015): neovascular membranes: reproducibility of Kanda A, Chen W & Othman M (2007): A Quality of life in patients suffering from angiographic interpretation. Am J Ophthal- variant of mitochondrial protein active exudative age-related macular degen- mol 130: 839–841. LOC387715/ARMS2, not HTRA1, is eration: the EQUADE study. Ophthalmo- Fritsche LG, Chen W & Schu M (2013): Seven strongly associated with age-related macular logica 234: 151–159. new loci associated with age-related macular degeneration. Proc Natl Acad Sci USA 104: McCannel CA (2011): Meta-analysis of degeneration. Nat Genet 45: 433–439. 16227–16232. endophthalmitis after intravitreal injection Grunwald JE, Daniel E & Huang J (2014): Keane PA, de Salvo G, Sim DA, Goverdhan S, of anti-vascular endothelial growth factor Risk of geographic atrophy in the compar- Agrawal R & Tufail A (2015): Strategies for agents: causative organisms and possi- ison of age-related macular degeneration improving early detection and diagnosis of ble prevention strategies. Retina 31: 654– treatments trials. Ophthalmology 121: 150– neovascular age-related macular degenera- 661. 161. tion. Clin Ophthalmol 9: 353–366. Menon G, Chandran M, Sivaprasad S, Cha- Haines JL, Hauser MA & Schmidt S (2005): Klein R, Peto T, Bird A & Vannewkirk MR van R, Narendran N & Yang Y (2013): Is it Complement factor H variant increases the (2004): The epidemiology of age-related necessary to use three mandatory loading risk of age-related macular degeneration. macular degeneration. Am J Ophthalmol doses when commencing therapy for neo- Science 308: 419–421. 137: 486–495. vascular age-related macular degeneration Hasler PW, Bloch SB, Villumsen J, Fuchs J, Klein RJ, Zeiss C & Chew EY (2005): Com- using bevacizumab? (BeMOc Trial) Eye Lund-Andersen H & Larsen M (2015): plement factor H polymorphism in age- (Lond) 27: 959–963. Safety study of 38,503 intravitreal ranibizu- related macular degeneration. Science 308: Mitchell P, Wang JJ, Foran S & Smith W mab injections performed mainly by physi- 385–389. (2002): Five-year incidence of age-related cians in training and nurses in hospital Klein R, Knudtson MD, Cruickshanks KJ & maculopathy lesions: the Blue Mountains setting. Acta Ophthalmol 93: 122–125. Klein BE (2008): Further observations on Eye Study. Ophthalmology 109: 1092– Hatz K, Schneider U, Henrich PB, Braun B, the association between smoking and the 1097. Sacu S & Prunte€ C (2015): Ranibizumab long-term incidence and progression of age- Moja L, Lucenteforte E & Kwag KH (2014): plus verteporfin photodynamic therapy in related macular degeneration: the Beaver Systemic safety of bevacizumab versus neovascular age-related macular degenera- Dam Eye Study. Arch Ophthalmol 126: ranibizumab for neovascular age-related tion: 12 months of retreatment and vision 115–121. macular degeneration. Cochrane Database outcomes from a randomized study. Oph- Klein R, Lee KE, Gangnon RE & Klein BE Syst Rev 9: CD011230. thalmologica 233:66–73. (2014): Relation of smoking, drinking, and Mowatt G, Hernandez R & Castillo M (2014): Heier JS, Boyer DS & Ciulla TA (2006): physical activity to changes in vision over a Optical coherence tomography for the diag- Ranibizumab combined with verteporfin 20-year period: the Beaver Dam Eye Study. nosis, monitoring and guiding of treatment photodynamic therapy in neovascular age- Ophthalmology 121: 1220–1228. for neovascular age-related macular degen- related macular degeneration: year 1 results Koh A, Lee WK & Chen LJ (2012): EVER- eration: a systematic review and economic of the FOCUS Study. Arch Ophthalmol EST study: efficacy and safety of verteporfin evaluation. Health Technol Assess 18:1– 124: 1532–1542. photodynamic therapy in combination with 254. Heier JS, Brown DM & Chong V (2012): ranibizumab or alone versus ranibizumab Mukesh BN, Dimitrov PN & Leikin S (2004): Intravitreal aflibercept (VEGF trap-eye) in monotherapy in patients with symptomatic Five-year incidence of age-related macu- wet age-related macular degeneration. Oph- macular polypoidal choroidal vasculopathy. lopathy: the Visual Impairment Project. thalmology 119: 2537–2548. Retina 32: 1453–1464. Ophthalmology 111: 1176–1182. Ho AC, Busbee BG & Regillo CD (2014): Kuroda Y, Yamashiro K & Miyake M (2015): Muni RH, Altaweel M, Tennant M, Weaver B Twenty-four-month efficacy and safety of Factors associated with recurrence of age- & Kertes PJ (2008): Agreement among 0.5 mg or 2.0 mg ranibizumab in patients related macular degeneration after anti- Canadian retina specialists in the determi- with subfoveal neovascular age-related mac- vascular endothelial growth factor treat- nation of treatment eligibility for photody- ular degeneration. Ophthalmology 121: ment: a retrospective cohort study. Ophthal- namic therapy in age-related macular 2181–2192. mology 122: 2303–2310. degeneration. Retina 28: 1421–1426. Holz FG, Jorzik J, Schutt F, Flach U & Landa G, Springler A, Bukelman A & Pollack Oishi A, Miyamoto N & Mandai M (2014): Unnebrink K (2003): Agreement among A (2007): The diagnostic contribution of LAPTOP study: a 24-month trial of verte- ophthalmologists in evaluating fluorescein indocyanine green fluorescein angiography porfin versus ranibizumab for polypoidal angiograms in patients with neovascular in fellow drusen eyes of patients with wet choroidal vasculopathy. Ophthalmology age-related macular degeneration for photo- age-related macular degeneration. Eur J 121: 1151–1152. dynamic therapy eligibility (FLAP-study). Ophthalmol 17: 615–619. Rasmussen A, Bloch SB & Fuchs J (2013): A Ophthalmology 110: 400–405. Lim JH, Wickremasinghe SS & Xie J (2012): 4-year longitudinal study of 555 patients Jager RD, Mieler WF & Miller JW (2008): Delay to treatment and visual outcomes in treated with ranibizumab for neovascular Age-related macular degeneration. N Engl J patients treated with anti-vascular endothe- age-related macular degeneration. Ophthal- Med 358: 2606–2617. lial growth factor for age-related macular mology 120: 2630–2636.

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Rasmussen A, Brandi S & Fuchs J (2015): arm, investigator-initiated study of the effi- Wilde C, Patel M & Lakshmanan A (2015): Visual outcomes in relation to time to cacy, safety and tolerability on intravitreal The diagnostic accuracy of spectral-domain treatment in neovascular age-related macu- aflibercept injection in subjects with exuda- optical coherence tomography for neovas- lar degeneration. Acta Ophthalmol 93: 616– tive age-related macular degeneration, pre- cular age-related macular degeneration: a 620. viously treated with ranibizumab or comparison with fundus fluorescein angiog- Rosenfeld PJ, Brown DM & Heier JS (2006): bevacizumab: 6-month interim analysis. Br raphy. Eye (Lond) 29: 602–609. Ranibizumab for neovascular age-related J Ophthalmol 98(Suppl 1): i22–i27. Wykoff CC, Croft DE & Brown DM (2015): macular degeneration. N Engl J Med 355: Singh RP, Srivastava SK & Ehlers JP (2015): Prospective trial of treat-and-extend versus 1419–1431. A single-arm, investigator-initiated study of monthly dosing for neovascular age-related Sahel JA, Bandello F & Augustin A (2007): the efficacy, safety, and tolerability of macular degeneration: TREX-AMD 1-year Health-related quality of life and utility in intravitreal aflibercept injection in subjects results. Ophthalmology 122: 2514–2522. patients with age-related macular degenera- with exudative age-related macular degener- Yannuzzi LA (1982): A modified amsler grid. tion. Arch Ophthalmol 125: 945–951. ation previously treated with ranibizumab or A self-assessment test for patients with Schmid MK, Bachmann LM, Fas L, Kessels bevacizumab (ASSESS study): 12-month macular disease. Ophthalmology 89: 157– AG, Job OM & Thiel MA (2015): Efficacy analysis. Clin Ophthalmol 9: 1759–1766. 159. and adverse events of aflibercept, ranibizu- Solomon SD, Lindsley K & Vedula SS (2014): Yong M, Zhou M & Deng G (2015): Photo- mab and bevacizumab in age-related macu- Anti-vascular endothelial growth factor for dynamic therapy versus anti-vascular lar degeneration: a trade-off analysis. Br J neovascular age-related macular degenera- endothelial growth factor agents for poly- Ophthalmol 99: 141–146. tion. Cochrane Database Syst Rev 8: poidal choroidal vasculopathy: a meta-ana- Schmidt-Erfurth U, Eldem B & Guymer R CD005139. lysis. BMC Ophthalmol 15: 82. (2011): Efficacy and safety of monthly versus Soubrane G, Cruess A & Lotery A (2007): Yuzawa M, Fujita K & Wittrup-Jensen KU quarterly ranibizumab treatment in neovas- Burden and health care resource utilization (2015): Improvement in vision-related func- cular age-related macular degeneration: the in neovascular age-related macular degener- tion with intravitreal aflibercept: data from EXCITE study. Ophthalmology 118: 831– ation: findings of a multicountry study. Arch phase 3 studies in wet age-related macular 839. Ophthalmol 125: 1249–1254. degeneration. Ophthalmology 122: 571– Schmidt-Erfurth U, Chong V & Loewenstein Stein JD, Newman-Casey PA, Mrinalini T, 578. A (2014a): Guidelines for the management Lee PP & Hutton DW (2013): Cost-effec- Zayit-Soudry S, Alfasi M & Goldstein M of neovascular age-related macular degener- tiveness of bevacizumab and ranibizumab (2007): Variability among retina specialists ation by the European Society of Retina for newly diagnosed neovascular macular in evaluating fluorescein angiograms of Specialists (EURETINA). Br J Ophthalmol degeneration. Trans Am Ophthalmol Soc patients with neovascular age-related macu- 98: 1144–1167. 111:56–69. lar degeneration. Retina 27: 798–803. Schmidt-Erfurth U, Kaiser PK & Korobelnik Sturzlinger€ H, Genser D & Froschl€ B (2007): Zerbib J, Delcourt C & Puche N (2014): Risk JF (2014b): Intravitreal aflibercept injection Evaluation of optical coherence tomography factors for exudative age-related macular for neovascular age-related macular degen- in the diagnosis of age related macular degeneration in a large French case-control eration: ninety-six-week results of the degeneration compared with fluorescence study. Graefes Arch Clin Exp Ophthalmol VIEW studies. Ophthalmology 121: 193– angiography. GMS Health Technol Assess 252: 899–907. 201. 3: Doc02. Si JK, Tang K & Bi HS (2014): Combination Sulzbacher F, Kiss C, Munk M, Deak G, Sacu of ranibizumab with photodynamic therapy S & Schmidt-Erfurt U (2011): Diagnostic vs ranibizumab monotherapy in the treat- evaluation of type 2 (classic) choroidal Correspondence: ment of age-related macular degeneration: a neovascularization: optical coherence Kai Kaarniranta, MD PhD systematic review and meta-analysis of ran- tomography, indocyanine green angiogra- Department of Ophthalmology domized controlled trials. Int J Ophthalmol phy, and fluorescein angiography. Am J Kuopio University Hospital 7: 541–549. Ophthalmol 152: 3799–3806. Finland Simcock P, Kingett B, Mann N, Reddy V & Ueta T, Noda Y, Toyama T, Yamaguchi T & Tel: 358-17-172485 Park J (2014): A safety audit of the first 10 Amano S (2014): Systemic vascular safety of Fax: 358-17-172486 000 intravitreal ranibizumab injections per- ranibizumab for age-related macular degen- Email: kai.kaarniranta@kuh.fi formed by nurse practitioners. Eye (Lond) eration: systematic review and meta-analysis 28: 1161–1164. of randomized trials. Ophthalmology 121: Singh RP, Srivastava S, Ehlers JP, Bedi R, 2193–2203. Schachat AP & Kaiser PK (2014): A single-

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