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Canadian preference and trends survey results for anti-VEGF treatment of macular edema

      The treatment of macular fluid from neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), and vein occlusion is evolving as new treatment modalities develop and research outcome results become available. Intravitreal injection of anti–vascular endothelial growth factor (anti-VEGF) agents has become one of the most common procedures performed by the retina specialist in the treatment of AMD, retinal vein occlusion (RVO), and DME. In 2009 and 2013, Health Canada estimated the number of prescriptions dispensed by pharmacies for bevacizumab and ranibizumab to be 24 504 and 338 889, respectively.

      Health Canada. Canada: drug and health products: summary and safety review—Avastin and Lucentis; 2014. 〈www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/bevacizumab_ranibizumab-eng.php#fnb1〉. Accessed August 12, 2015.

      Despite the increased use of these agents, there is no Canadian consensus regarding optimal technique, specific indications, agent of choice, second-line agents, treatment interval, and follow-up protocols. There is emerging evidence supporting the use of aflibercept (Eylea; Regeneron Pharmaceuticals) for AMD,
      • Homer N.
      • Grewal D.S.
      • Mirza R.G.
      • Lyon A.T.
      • Gill M.K.
      Transitioning to intravitreal aflibercept following a previous treat-and-extend dosing regimen in neovascular age-related macular degeneration: 24-month results.
      • Chang A.A.
      • Li H.
      • Broadhead G.K.
      • et al.
      Intravtireal aflibercept for treatment-resistant neovascular age-related macular degeneration.
      • Heier J.S.
      • Brown D.M.
      • Chong V.
      • et al.
      Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration.
      • Schmidt-Erfurth U.
      • Kaiser P.K.
      • Korobelnik J.F.
      • et al.
      Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies.
      RVO,
      • Heier J.S.
      • Clark W.L.
      • Boyer D.S.
      • et al.
      Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two year results from the COPERNICUS study.
      • Campochiaro P.A.
      • Clark W.L.
      • Boyer D.S.
      • et al.
      Intravitreal aflibercept for macular edema following branch retinal vein occlusion: the 24-week results of the VIBRANT study.
      • Ogura Y.
      • Roider J.
      • Korobelnik J.F.
      • et al.
      Intravitreal aflibercept for macular edema secondary to central retinal vein occlusion: 18 month results of the phase 3 GALILEO study.
      and DME.
      • Wells J.A.
      • Glassman A.R.
      • Ayala A.R.
      • et al.
      The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.
      • Korobelnik J.F.
      • Do D.V.
      • Schmidt-Erfurth U.
      • et al.
      Intravitreal aflibercept for diabetic macular edema.
      However, the role of aflibercept as a first-line treatment or second line for recalcitrant cases compared to ranibizumab (Lucentis; Genentech) and bevacizumab (Avastin; Genentech) remains unclear. Although the existing literature has explored practice patterns of anti-VEGF use,
      • Campbell R.J.
      • Bronskill S.E.
      • Bell C.M.
      • Paterson J.M.
      • Whitehead M.
      • Gill S.S.
      Rapid expansion of intravitreal drug injection procedures, 2000 to 2008: a population-based analysis.
      • Green-Simms A.E.
      • Ekdawi N.S.
      • Bakri S.J.
      Survey of intravitreal injection techniques among retinal specialists in the United States.
      • Waisbourd M.
      • Goldstein M.
      • Loewenstein A.
      National survey of the ophthalmic use of anti-vascular endothelial growth factor drugs in Israel.
      • Lad E.M.
      • Hammill B.G.
      • Qualls L.G.
      • Wang F.
      • Cousins S.W.
      • Curtis L.H.
      Anti-VEGF treatment patterns for neovascular age-related macular degeneration among medicare beneficiaries.
      • Xing L.
      • Dorrepaal S.J.
      • Gale J.
      Survey of intravitreal injection techniques and treatment protocols among retinal specialists in Canada.
      there are no clear guidelines in Canada. This is particularly true with rapidly expanding treatment indications and treatment options. To date, only 2 Canadian studies have examined anti-VEGF techniques, but this report predates the introduction of aflibercept into the market.
      • Campbell R.J.
      • Bronskill S.E.
      • Bell C.M.
      • Paterson J.M.
      • Whitehead M.
      • Gill S.S.
      Rapid expansion of intravitreal drug injection procedures, 2000 to 2008: a population-based analysis.
      • Xing L.
      • Dorrepaal S.J.
      • Gale J.
      Survey of intravitreal injection techniques and treatment protocols among retinal specialists in Canada.
      Our report describes the 2015 practice patterns relating to anti-VEGF usage in the treatment of macular edema secondary to neovascular AMD, DME, and RVO by Canadian retina specialists. The patterns of anti-VEGF usage reflect clinical evidence, provincial funding models and individual clinical preferences.

      Methods

      The executive committee of the Canadian Retina Society sent a national questionnaire, known as the Canadian Preference and Trends (CAN-PAT) Survey, via email to all members of the Canadian Retina Society. This 65-question survey focused on the surgical and medical treatment of retinal disease and was developed without industry funding or input. The online survey was voluntary and anonymous. Reminder emails were sent to maximize participation. The survey was completed and closed in February 2015. This article provides a summary of the intravitreal injection-related responses for AMD, DME, and RVO.

      Results

      Survey participants

      Of 118 Canadian retina specialists, 76 completed the survey with participation by individuals in all provinces. The majority of respondents had been in practice for at least 8 years (60.5%).

      Intravitreal injection procedure

      Topical anaesthesia was the most common (77.6%) form of anaesthesia for intravitreal injections, while bilateral injections were often performed on the same day (75.0%). Many Canadian retina specialists (43.4%) would examine anti-VEGF patients at the slit lamp before each injection, whereas 31.6% do so every 3 months.

      Age-related macular degeneration

      Retina specialists rely primarily (98.7%) on clinical examination and optical coherence tomography (OCT) to identify wet AMD (wAMD). Many retina specialists no longer perform fluorescein angiography as part of the initial diagnostic evaluation for patients with neovascular AMD (40.8%). The majority of retina specialists (85.5%) presently do not order genetic testing for patients with wet macular degeneration.
      Ranibizumab was the most common first-line agent in the treatment of wAMD (73.7%), followed by bevacizumab (23.7%) and aflibercept (2.6%). Most retina specialists (61.8%) believed that aflibercept covered the broadest range of neovascular AMD types, whereas 47.4% of respondents reported that, of the 3 available anti-VEGF agents, all were equally effective at decreasing subretinal and intraretinal fluid. In cases of persistent wAMD after 8 monthly injections (and vision 20/50), the majority of specialists (73.7%) would attempt a trial of an alternate anti-VEGF agent. Of the respondents, 52.6% believed that aflibercept provided the longest treatment interval in eyes with neovascular AMD. Aflibercept was also felt to be relatively good in the treatment of serous PEDs, with 34.2% of retinal specialists believing that it could successfully flatten a serous PED that had failed ranibizumab/bevacizumab.

      Diabetic retinopathy

      On average, most respondents (68.4%) stated that they would inject an anti-VEGF agent approximately 7 to 9 times in the first year of treatment for DME. When asked about first-line treatment for a new phakic diabetic patient with 20/50 vision and DME, 63.2% of retinal specialists would inject ranibizumab and 32.9% would inject bevacizumab. In cases of refractory DME, where patients have received focal laser and at least 6 prior ranibizumab injections, 46.1% of respondents would employ intravitreal triamcinolone acetonide, 19.7% would try aflibercept, and 14.5% would try the dexamethasone implant. In phakic patients with clinically significant DME (CSME), but with good vision (20/25) and central fluid on OCT, 57.9% physicians would inject an intravitreal anti-VEGF agent, whereas 27.6% would observe and a small subset (6.6%) would try micropulse laser. In contrast, in a phakic patient with central DME and 20/50 vision, 98.7% of respondents would use anti-VEGF. Ranibizumab (63.9%) was the agent most commonly utilized, followed by bevacizumab (32.9%) and aflibercept (2.6%).

      Retinal vein occlusions

      The CAN-PAT survey revealed that most retinal specialists would treat a central RVO (CRVO) with vision-affecting macular edema with ranibizumab (61.8%), bevacizumab (35.5%), or aflibercept (2.6%). Similar results for branch RVO (BRVO) with macular edema (ranibizumab 51.3%, bevacizumab 43.4%, and aflibercept 1.3%) were observed. None of the respondents listed grid laser as first-line therapy for BRVO. However, 53.9% would use it after stabilizing macular edema with an anti-VEGF or steroid agent, or use it in combination with an anti-VEGF injection (15.8%), whereas 26.3% do not use it at all.
      When dealing with macular edema from BRVOs that are unresponsive to bevacizumab, 46.1% of respondents would treat with ranibizumab, 27.6% would utilize intravitreal triamcinolone acetonide, 7.9% would try intravitreal dexamethasone implant (Ozurdex; Allergan), and 5.3% would choose aflibercept. In eyes with persistent macular edema after 6 monthly anti-VEGF injections and peripheral ischemia on fluorescein angiography, 64.5% of respondents would add sector panretinal photocoagulation with anti-VEGF, whereas 14.5% would try intravitreal triamcinolone acetonide only. When asked which treatment allows the longest interval between repeat injections, 50% of retinal specialists believe that the dexamethasone implant is the best, followed by aflibercept (13.2%) and intravitreal triamcinolone acetonide (11.8%).

      Discussion

      At the time of the CAN-PAT survey, ranibizumab was covered by all 10 provincial drug benefit plans for wAMD, whereas only 8 of 10 for DME, 6 of 10 for BRVO, and 7 of 10 for CRVO. Bevacizumab was covered by 1 of 10 provinces and Aflibercept was not covered by any provincial drug benefit program at the time of the conclusion of the survey.

      Alberta Blue Cross. Lucentis vial injection coverage criteria. Alberta, Canada. 〈https://idbl.ab.bluecross.ca/idbl/lookupCoverageCriteria.do?productID=0000036577&priceListID=0003〉. Accessed September 4, 2015.

      Government of British Columbia. Patients to benefit from new vision treatments. Victoria, Canada: Ministry of Health Services; 2009 〈www2.news.gov.bc.ca/news_releases_2005-2009/2009hserv0040-000789.htm〉. Accessed September 4, 2015.

      Government of Saskatchewan. Exception drug status program. Saskatchewan, Canada: Ministry of Health. 〈http://formulary.drugplan.health.gov.sk.ca/PDFs/APPENDIXA.pdf〉. Accessed September 4, 2015.

      Government of Manitoba. Lucentis is now available to Manitobans at no cost. Manitoba, Canada: Government of Manitoba; 2010. 〈http://news.gov.mb.ca/news/?archive=&item=8800〉. Accessed September 4, 2015.

      Government of Ontario. Limited used notes: ranibizumab. Ontario, Canada: Ministry of Health of Ontario; 2011. 〈www.healthinfo.moh.gov.on.ca/formulary/SearchServlet?searchType=luNoteQuery&phrase=exact&keywords=523600114〉. Accessed September 4, 2015.

      Government of Quebec. List of medications. Quebec, Canada: Government of Quebec; 2015. 〈www.prod.ramq.gouv.qc.ca/DPI/PO/Commun/PDF/Liste_Med/Liste_Med/liste_med_2015_07_24_en.pdf〉. Accessed September 4, 2015.

      Government of New Brunswick. New Brunswick drug plans formulary. New Brunswick, Canada: Government of New Brunswick; 2015. 〈www.gnb.ca/0212/pdf/NBPDP_Formulary-e.pdf〉. Accessed September 4, 2015.

      Government of Nova Scotia. Province to fund lucentis treatment. Nova Scotia, Canada: Department of Health; 2010. 〈http://novascotia.ca/news/release/?id=20101020006〉. Accessed September 4, 2015.

      Government of Prince Edward Island. Prince Edward Island Pharmacare Formulary. Prince Edward Island, Canada: Ministry of Health; 2015. 〈www.gov.pe.ca/photos/original/hpei_formulary.pdf〉. Accessed September 4, 2015.

      Government of Newfoundland and Labrador. Ranibizumab. Newfoundland and Labrador, Canada: Health and Community Services; 2013. 〈www.health.gov.nl.ca/health/prescription/criteria/Ranibizumab_Lucentis.pdf〉. Accessed September 4, 2015.

      Health Canada. First Nations and Inuit Health: updates to the drug benefit list. Canada: Health Canada; 2013. 〈www.hc-sc.gc.ca/fniah-spnia/pubs/nihb-ssna/_drug-med/2013-summer-ete/index-eng.php〉. Accessed September 4, 2015.

      Government of British Columbia. Eye program expanded in British Columbia. British Columbia, Canada: Ministry of Health; 2013. 〈https://news.gov.bc.ca/stories/eye-program-expanded-in-british-columbia〉. Accessed September 4, 2015.

      Government of Quebec. Lucentis–toutes indications. Quebec, Canada: Government of Quebec; 2015. 〈www.inesss.qc.ca/fileadmin/doc/INESSS/Inscription_medicaments/Avis_au_ministre/Fevrier_2015/Lucentis_2015_02_CAV.pdf〉. Accessed September 4, 2015.

      Government of Nova Scotia. More patients have access to retina disease treatment. Nova Scotia, Canada: Health and Wellness Ministry; 2014. 〈http://novascotia.ca/news/release/?id=20131108003〉. Accessed September 4, 2015.

      Government of Ontario. Ontario drug benefit formulary/comparative drug index. Ontario, Canada: Ministry of Health and Long-Term Care; 2015. 〈/www.health.gov.on.ca/en/pro/programs/drugs/formulary42/summary_edition42_20150720.pdf〉. Accessed September 4, 2015.

      Age-related macular degeneration

      Anti-VEGF therapy is the current mainstay for the treatment of wAMD. The anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial and the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) showed that continuous monthly intravitreous injections of ranibizumab for 2 years resulted in significant gains in visual acuity.
      • Rosenfeld P.J.
      • Brown D.M.
      • Heier J.S.
      • et al.
      Ranibizumab for neovascular age-related macular degeneration.
      • Brown D.M.
      • Kaiser P.K.
      • Michels M.
      • et al.
      Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
      • Brown D.M.
      • Michels M.
      • Kaiser P.K.
      • Heier J.S.
      • Sy J.P.
      • Ianchulev T.
      Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study.
      In the Comparison of AMD Treatment Trials, bevacizumab and ranibizumab in both continuous monthly and as-needed treatment regimens resulted in equivalent vision outcomes over a 2-year period.
      • Martin D.F.
      • Maguire M.G.
      • Fine S.L.
      • et al.
      Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results.
      The large parallel VIEW 1 and VIEW 2 studies investigating aflibercept for subfoveal neovascular AMD also found it to be noninferior to ranibizumab.
      • Heier J.S.
      • Brown D.M.
      • Chong V.
      • et al.
      Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration.
      • Schmidt-Erfurth U.
      • Kaiser P.K.
      • Korobelnik J.F.
      • et al.
      Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies.
      According to our CAN-PAT survey, the most common first-line anti-VEGF agent for wet AMD was ranibizumab (73.7%) followed by bevacizumab (23.7%) and aflibercept (2.6%). These usage patterns reflect current provincial funding for anti-VEGF agents. As the majority of respondents felt that aflibercept treated the widest range of wAMD subtypes and provided the longest effect, it is likely that its use will increase significantly once provincial coverage becomes available.

      Diabetic macular edema

      Canadian retina specialists utilize anti-VEGF injections as first-line therapy to treat DME in keeping with current evidence.
      • Ho A.C.
      • Scott I.U.
      • Kim S.J.
      • et al.
      Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema; a report by the American Academy of Ophthalmology.
      • Mitchell P.
      • Wong T.Y.
      Diabetic Macular Edema Treatment Guideline Working Group
      Management paradigms for diabetic macular edema.
      • Virgili G.
      • Parravano M.
      • Menchini F.
      • Brunetti M.
      Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for diabetic macular edema.
      A recent study from the Diabetic Retinopathy Clinical Research Network suggests that all 3 anti-VEGF agents are effective and equivalent for mild vision loss (≥20/50); however, aflibercept may be superior in eyes with worse vision (<20/50).
      • Wells J.A.
      • Glassman A.R.
      • Ayala A.R.
      • et al.
      The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.
      Despite these data, ranibizumab remains the most frequently used agent. Furthermore, although in an American model bevacizumab may be superior in terms of cost effectiveness and patient willingness to pay,
      • Stein J.D.
      • Newman-Casey P.A.
      • Kim D.D.
      • Nwanyanwu K.H.
      • Johnson M.W.
      • Hutton D.W.
      Cost-effectiveness of various interventions for newly diagnosed diabetic macular edema.
      ranibizumab remains more frequently used in Canada. The Canadian results were consistent with provincial funding for anti-VEGF medication at the time of the survey. It is likely that the use of anti-VEGF agents will change significantly as funding becomes available for aflibercept and bevacizumab across Canada.
      Although there is evidence to support the use of intravitreal steroids
      • Lazic R.
      • Lukic M.
      • Boras I.
      • et al.
      Treatment of anti-vascular endothelial growth factor-resistant diabetic macular edema with dexamethasone intravitreal implant.
      • Jeon S.
      • Lee W.K.
      Effect of intravitreal triamcinolone in diabetic macular edema unresponsive to intravitreal bevacizumab.
      and aflibercept
      • Korobelnik J.F.
      • Do D.V.
      • Schmidt-Erfurth U.
      • et al.
      Intravitreal aflibercept for diabetic macular edema.
      in DME, there is no clear consensus in the existing literature as to their use as first-line therapy or for recalcitrant cases. Interestingly, in patients refractory to ranibizumab, intravitreal triamcinolone acetonide (46.1%) was preferred to aflibercept (19.7%).

      Retinal vein occlusion

      The Central Retinal Vein Occlusion (CRUISE) and Branch Retinal Vein Occlusion (BRAVO) studies demonstrated efficacy of ranibizumab for macular edema related to RVO.
      • Brown D.M.
      • Campochiaro P.A.
      • Singh R.P.
      • et al.
      Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a Phase III study.
      • Campochiaro P.A.
      • Heier J.S.
      • Feiner L.
      • et al.
      Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study.
      Consistent with recent Canadian expert consensus guidelines,
      • Berger A.R.
      • Cruess A.F.
      • Altomare F.
      • et al.
      Optimal treatment of retinal vein occlusion: Canadian expert consensus.
      this survey demonstrated that anti-VEGF is now the favoured first-line treatment. A similar survey performed by the American Society of Retina Specialists (ASRS) for global trends in anti-VEGF use in 2015 found comparable results. In this survey, as-needed treatment with anti-VEGF injections were the mainstay of treatment for visually significant macular edema secondary to RVO.
      Rezaei KA, Stone TW, eds. 2014 Global Trends in Retina Survey. Chicago, Ill.: American Society of Retina Specialists; 2014.
      Ranibizumab was the preferred anti-VEGF agent for both CRVO and BRVO; however, the dexamethasone implant for RVO was felt to have the longest treatment interval. A minority of retinal specialists in this survey used aflibercept as first-line therapy. A recent review comparing ranibizumab and aflibercept in the treatment of macular edema secondary to RVO found that both groups had a similar interval between injections and received a similar number of injections.
      • Lotery A.J.
      • Regnier S.
      Patterns of ranibizumab and aflibercept treatment of central retinal vein occlusion in routine clinical practice in the USA.

      Conclusions

      The results of this survey regarding practice patterns pertaining to anti-VEGF usage are consistent with published randomized clinical trials and reflect the realities of the Canadian health-care system, where provincial funding may influence treatment patterns. It is likely that the use of aflibercept, bevacizumab, and dexamethasone implants may change with provincial funding for these and other newer agents.

      Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this article.

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      6. Government of Ontario. Limited used notes: ranibizumab. Ontario, Canada: Ministry of Health of Ontario; 2011. 〈www.healthinfo.moh.gov.on.ca/formulary/SearchServlet?searchType=luNoteQuery&phrase=exact&keywords=523600114〉. Accessed September 4, 2015.

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