Implementation studies of ranibizumab for neovascular age‐related macular degeneration

Age-related macular degeneration (AMD) has for decades been the most common cause of irreversible blindness in the elderly population in Denmark and in other developed countries (Vinding 1995; Bressler 2004; Buch et al. 2004). The vast majority of vision loss resulting from the disease occurs in individuals with the neovascular form of AMD, primarily during the first 2 years after onset of choroidal neovascularization (CNV; Klein et al. 1995; Vinding 1995; Attebo et al. 1996; Bressler et al. 1988; Macular Photocoagulation Study Group 1991a; Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group 1999; Wong et al. 2008). In advanced neovascular AMD, vision impairment is caused by severe morphological damage to the retina following growth and involution of subfoveal CNV (Chandra et al. 1974; Green & Enger 1993). The introduction of ranibizumab, a selective inhibitor of all isoforms of VEGF-A, markedly improves the visual prognosis in neovascular AMD, if given repetitively at fixed 4-week intervals, compared with the natural history of the disease and other known categories of pharmacotherapy (Macular Photocoagulation Study Group 1991a; TAP Study Group 1999; Gragoudas et al. 2004; Brown et al. 2006; Rosenfeld et al. 2006). Treatment with ranibizumab for neovascular AMD was introduced on a national scale in Denmark in 2006. A fixed monthly treatment regimen with ranibizumab for neovascular AMD has only rarely been used in clinical practice, where various approaches have been taken to reduce the need for retreatment guided by a variety of retreatment criteria (Fung et al. 2007; Lalwani et al. 2009; Rothenbuehler et al. 2009; Gupta et al. 2010, 2011; Kaiser et al. 2012; Larsen et al. 2012). Part of the rationale for a reduced injection frequency is that in preclinical experiments, VEGF has been shown to have the characteristics of a neuroprotector. Thus, iatrogenic suppression of VEGF in the eye is thought to promote neurodegeneration (Rosenfeld et al. 2011). In Denmark, ranibizumab therapy for neovascular AMD was implemented under guidelines describing an individualized regimen after monthly was guided by CNV of the in was to in a clinical under The of and of ranibizumab from clinical with to 2 years of and by a of that is injection et al. 2009; et al. 2006; Rosenfeld et al. 2006; et al. years and in of an the of is Thus, for of for the of by in and therapy and from a is a to the need for retreatment reduced in an if characteristics at after of treatment of in the a to treatment in The natural history is for neovascular AMD to an by subfoveal and of the retina and (Chandra et al. 1974; Green & Enger 1993). the in from monthly treatment with in the with the and of with neovascular AMD to vision (Rosenfeld et al. 2011). known to to vision treatment et al. is therapy that reduce the of the visual of VEGF inhibitor in the that is used to is by of visual in the Thus, is a to the for and of that in by to characteristics that the of subfoveal that treatment Treatment with ranibizumab for neovascular AMD has been implemented in Denmark under a and in a treatment categories of pharmacotherapy used in to neovascular AMD, therapy introduced in Denmark in and VEGF first introduced in Denmark in Study Group 1999; Brown et al. 2006; Rosenfeld et al. 2006). a of and and to reduce the of AMD has to in with AMD Study Group for neovascular AMD the of the most in the for years and in AMD of a of visual the to blindness in an of The of was to treatment of a ranibizumab regimen for neovascular AMD with to of visual and morphological The in is the in the of the of the the of the is the with a the of that vision et al. et al. The is of and from the choroidal of the with from the and the et al. & The retina is of from the and the and with the of the and the and of the In to and with the is the et al. The have of of the of and A & The is to a the the and the The choroidal has a to the of the retina and that the of most other in the et al. has been that the choroidal a in the et al. the of the retina and the of the of and the by and of from and is in a of et al. 2011). The of the the the a the retina et al. The of the retina to in The and reduced in the where is only from the The reduced is for in an with et al. macular was first a clinical in A was by AMD is a disease primarily in the The of AMD is the of in to clinical is of that AMD is AMD AMD at in and advanced AMD et al. The advanced of AMD a with a of the and a neovascular by the of from the that the et al. neovascularization from the In advanced AMD, the have visual the of the in is with the of In the of the of AMD, for of with severe vision loss et al. Bressler et al. neovascular AMD in is with of of the and et al. The of AMD is to that the of AMD is by and the primarily of history of AMD, and (Vinding 1995; et al. et al. et al. Klein et al. et al. et al. et al. for with the of AMD have been with the most the in et al. Klein et al. and in the to have a with AMD compared with in the et al. 2009; et al. 2012). the an AMD has been of an 2 and et al. et al. 2006; et al. 2006; et al. with and to the of AMD et al. 2006; et al. 2006). A the retina with and a in the retina and The is in a by and with from and & 2012). damage of the is and and and The and in the retina and of a variety of the damage of the the and the 2012; & 2012). of a that is a of and a of occurs the of reduce and cause and et al. 1995; et al. & et al. is that to the in to a and to the of and et al. 2008). from the to the at in et al. 2007; et al. The of in most by of with and reduce the to et al. et al. in with and of in the and of the to a in of from the to et al. to of the and and AMD in the retina with and to AMD is on and in the of In AMD, and of the and a that the of 2004). the of is is the is the and the and the the of Green & Enger 2004). The of to et al. in the of in and with the of the and cause of of the the of to of the and The of the of is with the macular of and et al. in with with of the and the a with of and the and to of the and the 2004). In to the a on to promote is that is neovascular AMD 2004; et al. the of to the choroidal of the and with the et al. growth is in retina and of from with the of The to the of the VEGF that CNV and with various in the and VEGF and other in with has been that the of VEGF and to promote a of VEGF et al. et al. 2006; et al. & 2011). of of is for the of in the retina and VEGF in and in neovascular AMD, and other that common in disease and The of in AMD to the of in with of that and 2011). is that AMD is to and et al. 2009; et al. 2011; et al. The and of AMD in Denmark (Vinding 1995; Buch et al. to have been in in the et al. et al. and et al. et al. A from that the of AMD in individuals years and was that of advanced AMD was et al. The of advanced AMD in at eye in Denmark in years and is to to & The of AMD is to to a elderly population et al. 2009; & a from that the of AMD in the the decades et al. 2011). in and and Age-related macular degeneration is the most common cause of blindness in years of and in Denmark et al. 2004). The and of blindness from AMD in Denmark most in after the introduction of and of VEGF et al. with onset of neovascular AMD have a of and In advanced with severe visual visual The onset of from to to the of neovascular AMD, of clinical visual is to the of vision In clinical practice, visual is by the of a at is and a for is to the in all of and is to of visual in AMD et al. Kaiser the of on an at a of 2 has the of in in individuals with The of the retina with in an eye with of the in first by et al. is on the selective of from the In a of the retina and to et al. the CNV in the the the of the of and on the & Green 2004; et al. 2012). of the retina have been for the of disease in neovascular AMD, in the visual is is a in the morphological to treatment & 2007; & et al. in neovascular AMD is most on by an in of is a to the and of the neovascular clinical practice, a is used to that by In most clinical of the is the of and of the of the et al. Macular Photocoagulation Study Group et al. Brown et al. 2006; Rosenfeld et al. 2006). injection of the a is taken to the injection of taken during the from to the and and the and after The the and the CNV the the and in the neovascular of the CNV by the CNV in the of the CNV is by a of in the of the with of in the CNV in and to CNV has The first a CNV and with is with of the and is with in the and of the In the the the of in the and is an of the retina to The of CNV has of in the of the The CNV is by the from the where CNV first The is the of the CNV and the of of the and to the of the of the of an is of CNV only et al. Macular Photocoagulation Study Group et al. the is the of The is that CNV is by CNV that the and the with a under the 2 growth CNV is the and growth & et al. & Green 2004; Group 2006). The that CNV to a growth that a in the the and the the Group 2006). is an in the of in of the and et al. In the of is by to that in the of neovascular to form a of of and growth growth and growth other and that and in the & 2007; et al. under the with the of the the with et al. The that CNV and & is at the first in 2 CNV on is in the form of of that the and Bressler et al. In to and has a with and an that is that by In the of the is used to the is a of and a of the retina and the on by on the of the et al. Macular Photocoagulation Study Group et al. The on a with a loss of the et al. 2012). vision loss is a of in AMD the the after of growth under the in with has been in with VEGF inhibitor treatment of neovascular AMD in to visual loss et al. to visual following VEGF inhibitor treatment in CNV to AMD has in been with of by that in the a and in the of the by a of (Rosenfeld et al. 2011). to and in advanced AMD is et al. decades therapy was the only treatment for neovascular for CNV in AMD was on a scale in of in the Macular Photocoagulation the frequency of with for treatment was and of treatment was Photocoagulation for Macular Degeneration for neovascularization was first given in Denmark on Study Group is for that and was to Treatment with was at individuals with and vision loss after compared with the natural of the visual in the with neovascular AMD Bressler et al. The in that of and reduced the of from severe AMD in at eye advanced AMD in eye vision loss to AMD in to advanced AMD with years Group The of in with AMD has been common in Denmark The first injection of a VEGF inhibitor in Denmark was given on ranibizumab therapy was the treatment of for neovascular AMD in the in Denmark of after treatment with ranibizumab given at a fixed 4-week to an in visual after of treatment in the of in the is natural history (Rosenfeld et al. 2006; Brown et al. was used therapy for neovascular AMD in Denmark was for the treatment of neovascular AMD in Denmark at the the treatment is was used on a scale the and introduction of ranibizumab et al. 2004). in the VEGF in the VEGF was by the for treatment of neovascular AMD in et al. 2012). growth is a of and has been in the of neovascular AMD et al. et al. 1996; et al. et al. The that a in the to neovascular AMD has a of of for clinical ranibizumab and and the and is in clinical and ranibizumab that all isoforms and of VEGF-A, of to and ranibizumab is for was developed for The of ranibizumab in the eye is to is a that has a for VEGF-A, for compared with The of after injection in the eye is et al. 2012). by other growth VEGF-A, and that in growth to to and in neovascular AMD and other & 2007; et al. growth in neovascular AMD the visual prognosis in AMD et al. et al. 1995; et al. 2006; & 2012; criteria in Denmark for ranibizumab treatment subfoveal CNV to caused by to with treatment and of and a CNV on to of involution and an of on and is of disease by vision an in the of if is on et al. 2006; Rosenfeld et al. 2006). The treatment with ranibizumab for neovascular AMD ranibizumab at of by a clinical after the the first injection and ranibizumab injection is given in a regimen on monthly disease the history of of and at the ranibizumab only is if the of CNV in a is after of CNV is a is on and to of CNV an in under the compared with an in macular of and in the ranibizumab and growth of the CNV (Fung et al. of on a the most is a of CNV that in a for guidelines and clinical from the retreatment criteria for of treatment and for of the of the and subfoveal the of a for visual criteria for of ranibizumab of treatment was during the first in treatment and treatment with ranibizumab was introduced in Denmark under a A treatment with a common of guidelines was at of and Treatment with ranibizumab for neovascular AMD was and under a in by the of to and to treatment in Denmark the of the clinical was A for was developed for the to treatment and in with neovascular The of was by and a The in of from and clinical characteristics of and ranibizumab during and from to first injection with ranibizumab, visual in and at and of the population from the The was to The first in a from and from all with ranibizumab during was developed and implemented at the in from the the In the has been at the the national and used in the of the and a was to an and of blindness on the of of the of the a national in that and for and of Denmark and the blindness of in the vision to of have to the of the the population was from the of the national of Denmark 2011). and and and and and a of used to the and of the neovascular from the Macular Photocoagulation Study and an of the et al. Klein et al. Macular Photocoagulation Study Group of Group The CNV was by the on to In CNV for and and 2 CNV for & et al. & Green 2004). was on and under the was in to and Group was a and 2 of was on the of and a et al. A was that on has the of a the retina and with the that if by and that if is in a CNV et al. 2007; et al. 2012). was with with and with of the retina The of and visual and of visual in with ranibizumab for neovascular and The in with CNV in AMD the et al. 2006; Rosenfeld et al. criteria and with ranibizumab in a clinical with at 4-week by a regimen for the and morphological characteristics at and after of ranibizumab for was used to in from to and with was used to for visual at from to and at was from A after during the by in after A is that on to vision visual loss after of The of of in the first was in the after by and a of in after was from in all of the by the in visual in the first a in the with a in during the first in with compared with in the The of of in the first of treatment was in the compared with in the on in the first to to first injection a on the in from to and of in after of treatment with ranibizumab primarily to at and Thus, with of at a of of at the of the at with of at a of of after with of at at a of a visual of at In to the at and at and compared with a of of after and characteristics of CNV in AMD in to the of subfoveal and The in of with CNV in AMD subfoveal at first with ranibizumab in a at the of A was used to the and subfoveal after of ranibizumab A of was used to for subfoveal on treatment and In the of was years In the majority of subfoveal developed during the first after of treatment The for subfoveal of 2 years was in with 2 CNV and to that in and The for in with a of was compared with at A CNV was with a of 2 years compared with a CNV of the of and CNV and treatment of was to a of compared to an of The for was in with 2 to other a on the of with in in with developed and after was in of the the of blindness and blindness from other in Denmark from years to in years and and A of of blindness in the of the from a population of years and in and in of blindness from to The of blindness in the elderly population from in to in 2010, to a of for the of the after 2006. The of blindness from other AMD by most of the and The the in given to the and of the to clinical and with neovascular AMD ranibizumab treatment in the regimen for CNV in a clinical that visual was to visual in the compared with AMD with and the natural of the compared with the visual in clinical (Macular Photocoagulation Study Group 1991a; TAP Study Group 1999; Bressler et al. Brown et al. 2006; Rosenfeld et al. 2006; et al. 2007; Wong et al. Larsen et al. 2012). A in the and clinical characteristics of the population to the clinical characteristics of the in the and that the criteria of the and and with severe from the of the of treatment with to with treatment and and from the if a disease was to if that developed severe during the treatment from the if the of the that with of the in population during the of have a of have to a in with neovascular of characteristics was in was the of visual in clinical practice, by The of visual was implemented the of an and clinical et al. 2008). population on visual with visual at to at to and at The is that is a of that after after that the shown in in and that the by and that loss in with the and in the with of population on an after of ranibizumab is to a fixed monthly of ranibizumab (Rosenfeld et al. 2011). of treatment in of and in to is treatment in to the natural of the was by the population in by in all after compared with in in the first most a in the with vision at that to the retreatment of the with the The of of in the first of treatment was to the of in clinical treatment (Fung et al. 2007; Rothenbuehler et al. 2009; Larsen et al. 2012). In the with ranibizumab in a regimen after the to the with a fixed monthly regimen et al. 2006; Rosenfeld et al. 2006; Larsen et al. 2012). The in the compared with the after with the of in clinical was the of monthly and the of disease and is of a have clinical to injection on the the of neovascular AMD is at first and at to was by the The that all a of at and in the eye after of ranibizumab a that with visual during the first of fixed ranibizumab treatment a of visual after is an clinical the of on the of ranibizumab a to treatment on given the of to a of 2 years and given that treatment is of neurodegeneration et al. 2009; et al. 2006; Rosenfeld et al. 2011; et al. In clinical practice, the to an for treatment that and visual after the first with that the in from to and with the of neovascular AMD and the of the first injection of of was that visual at the of the first injection with to a of the from to first injection on visual et al. et al. 2007; Kaiser et al. Rosenfeld et al. 2011). The clinical a criteria of for ranibizumab treatment in to the criteria for treatment in Denmark of Brown et al. 2006; Rosenfeld et al. 2006). in to that the of treatment with ranibizumab, from with 2 CNV with ranibizumab developed subfoveal compared with CNV that developed subfoveal and a and and on an compared with that subfoveal subfoveal the first in a majority of of visual and for have been of is an in AMD et al. Macular Photocoagulation Study Group Group was on a an of subfoveal after that the subfoveal the of by et al. have a with on to of the was neovascularization with in the where was rarely the been that is in neovascular AMD of have the of of the the is of reduced the has characteristics that of have been a have an a to a of in the of the retina and The on in in clinical first by and by the from the A was if at the of in the the of the by the all in a The and in of and In the and only by the a of compared with CNV the et al. a in and the of in to the to the of the neovascular In the with a in visual in with Rosenfeld et al. 2011). A is by in and is a with the in that with subfoveal was to visual after ranibizumab given that of the of to a retreatment to a of compared with a fixed monthly regimen et al. The neovascular to degeneration of the and from the the cause and degeneration by the retina with an and the and the the to the is by the In the of subfoveal on an to in the of the of the The that of the CNV has an on to is in with of other where has been shown to et al. The that of in 2 CNV et al. et al. et al. 2006; & 2012; In of the that the of blindness in Denmark in years and was reduced by from to The after with the national introduction of ranibizumab treatment of neovascular The a in a population where a treatment for neovascular AMD been The was by the of a national for visual impairment and of blindness is and has been in to the et al. for to the of for the and to with the of the is thought that for the visual is The have to the and for the of The criteria and of the have been for the and for to the have a of a of in a treatment the that of blindness is a in with neovascular AMD with The only an of the in the have to from the other treatment in A that of the et al. that a of by the other in to by from the for and of years and with of at eye caused by AMD in the by an from that a in the of blindness from to et al. 2012). The that of the have that the and of AMD have the decades et al. Klein et al. 2011). 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