**4. Different regimens for Bevacizumab and Ranibizumab**

#### **4.1. Ranibizumab: As-needed regimen**

Numerous studies evaluated the effect of PRN intravitreal ranibizumab for the treatment of nvAMD.

ously treated). Cohort 1 subjects were retreated on the basis of OCT or BCVA criteria. Co‐ hort 2 subjects (n = 1922) received an initial single intravitreal dose of 0.5 mg ranibizumab and were retreated at physician discretion. Safety was evaluated at all visits. It concluded that Intravitreal ranibizumab was safe and well tolerated in a large population of subjects with neovascular AMD. Ranibizumab had a beneficial effect on VA but quarterly visits were insufficient to monitor and capture disease progression [36] If a fixed regimen of monthly injections is not applied, than monthly visits are recommended and injectios performed as

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The HORIZON study was an open-label multicenter extension study that included 853 pa‐ tients (600 had been previously treated with ranibizumab initially, 184 had crossed over to treatment with ranibizumab, and 69 had not been treated with ranibizumab) who had com‐ pleted one of the three 2-year, randomized, controlled trials of monthly intravitreal ranibi‐ zumab treatment (MARINA, ANCHOR or FOCUS trial). Of the 853 patients, two-year VA data were available for 384 [37]. These patients could receive 0.5 mg ranibizumab at 30-day or longer intervals as needed. Of the patients who received initial treatment with ranibizu‐ mab during the ANCHOR, MARINA, and FOCUS trials, there was a mean 10.2-letter in‐ crease in VA during the first 2 years of the studies Patients that did not receive anti-VEGF therapy in those trials had worse outcomes. During the first year of the HORIZON study and the third year of the original trials, there was a 5.1-letter loss The initial VA gain de‐ creased by a mean of 8 letters with less frequent dosing in years 3 and 4. During the as need‐ ed dosing phase, the mean number of injections in the group initially treated with ranibizumab was 3.6. compared to 4.2 injections for patients that were treated with sham in

The results of the HORIZON trial demonstrate that a delay in the initiation of treatment is associated with poorer visual outcomes and continued but less frequent dosing in years 3

PRN regimen of ranibizumab guided by monthly BCVA and other ophthalmic examina‐ tions, as detailed before, appears effective in sustaining the BCVA gained with 12 monthly injections with a significant lower number of injections during the extension phase [38].

Each one of these studies evaluated PRN regimens and had its own retreatment criteria, most of them retreated patients with a 100 μm increase in CRT from the thinnest measure‐ ment, and/or a Decreased VA >5 letters compared with VA score from the previous sched‐ uled study visit, but each study had its particular criteria, and follow up regimen. All those studies mentioned previously have used the Time Domain OCT which is less accurate than the Spectral Domain OCT (SD-OCT) – therefore re-treatment criteria usually used the 100 microns increase in thickness. Nowadays by using the SD OCT, residual or recurrent fluid which is less than 100 microns in height can be detected, so patients are re-treated earlier – which may account for a better visual outcome using the PRN regimen. Strengths of PRON‐ TO and SUSTAIN include monthly follow-up, but the PRONTO trialconsists of only a small cohort of patients. The SAILOR trial is the largest, but mandated only quarterly follow up visits. Overall, these studies support frequent follow up and individualized retreatment to achieve the best visual acuity gains with the as-needed treatment regimen as an alternative

needed usually guided by visual acuity and OCT findings.

and 4 was associated as well with visual decline [37].

the original trials.

The Prospective OCT Imaging of Patients with nvAMD Treated with Intraocular Ranibizu‐ mab (PrONTO) study was the first open-label, prospective, uncontrolled study to investi‐ gate a variable-dosing of intravitreal ranibizumab over two years [34]. Thirty-seven patients received 3 consecutive monthly injections of 0.5 mg ranibizumab and were then followed monthly and re-treated if there was an increase in OCT central retinal thickness (CRT) of at least 100 microns or a loss of BCVA of 5 letters or more. During the second year, the retreat‐ ment criteria were amended to include re-treatment if any qualitative increase in the amount of fluid was detectedon OCT. At 24 months (end of 2 years study), mean VA improved by 11letters with an average of 9.9 injections In the PrONTO study therefore we can conclude that VA outcomes were nearly comparable with those reported in the MARINA and AN‐ CHOR, but these results were achieved with less than half number of intravitreal injections given in the MARINA and ANCHOR[34].

The SUSTAIN trial was a phase III multicenter open-label single arm study that assessed the safety and efficacy of ranibizumab in patients with sub foveal CNV secondary to AMD us‐ ing a dosing regimen individualized to patient characteristics. 513 patients who were either ranibizumab treatment –naïve (69 patients) or had completed treatment with ranibizumab or verteporfin PDT in the ANCHOR trial participated in this study [35].

Patients received three consecutive monthly injections of ranibizumab 0.3mg (or 0.5mg for the ANCHOR patients) (the "loading phase"), followed by monthly monitoring visits. Fur‐ ther treatment was administered if VA decreased by *>*5 letters or if CRT increased by *>*100 *μ*m. Compared with baseline, mean VA at month 12 increased by approximately 7 letters. VA reached a maximum level after the first 3 monthly injections, decreased slightly when shifting to PRN during the next 2 to 3 months and was then sustained throughout the treat‐ ment period. Over 12 months, the mean standard deviation (SD) number of ranibizumab in‐ jections received by the 69 ranibizumab naıve patients was 5.3 (±2.2), including the three "loading" injections. This study demonstrated that flexible, guided dosing with fewer injec‐ tions and monthly monitoring can be efficient and result in good visual outcome in at least some patients [35].

The SAILOR (Safety Assessment of IntravitrealLucentis for age-related macular degenera‐ tion) study, a Phase IIIb study of Lucentis for patients with all subtypes of new or recurrent active sub fovealCNV due to AMD, was a twelve-month randomized (cohort 1) or open-la‐ bel (cohort 2) multicenter clinical trial [36]. 4300 subjects were recruited. Cohort 1 subjects were randomized 1:1 to receive 0.3 mg (n = 1169) or 0.5 mg (n = 1209) intravitreal ranibizu‐ mab for 3 monthly loading doses, followed by monthly visits. Cohort 2 subjects received 1 single open-label 0.5 mg intravitreal ranibizumab, and than continue the monthly follow up visits. Those groups were stratified by AMD treatment history (treatment-naïve vs. previ‐ ously treated). Cohort 1 subjects were retreated on the basis of OCT or BCVA criteria. Co‐ hort 2 subjects (n = 1922) received an initial single intravitreal dose of 0.5 mg ranibizumab and were retreated at physician discretion. Safety was evaluated at all visits. It concluded that Intravitreal ranibizumab was safe and well tolerated in a large population of subjects with neovascular AMD. Ranibizumab had a beneficial effect on VA but quarterly visits were insufficient to monitor and capture disease progression [36] If a fixed regimen of monthly injections is not applied, than monthly visits are recommended and injectios performed as needed usually guided by visual acuity and OCT findings.

**4. Different regimens for Bevacizumab and Ranibizumab**

170 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

Numerous studies evaluated the effect of PRN intravitreal ranibizumab for the treatment of

The Prospective OCT Imaging of Patients with nvAMD Treated with Intraocular Ranibizu‐ mab (PrONTO) study was the first open-label, prospective, uncontrolled study to investi‐ gate a variable-dosing of intravitreal ranibizumab over two years [34]. Thirty-seven patients received 3 consecutive monthly injections of 0.5 mg ranibizumab and were then followed monthly and re-treated if there was an increase in OCT central retinal thickness (CRT) of at least 100 microns or a loss of BCVA of 5 letters or more. During the second year, the retreat‐ ment criteria were amended to include re-treatment if any qualitative increase in the amount of fluid was detectedon OCT. At 24 months (end of 2 years study), mean VA improved by 11letters with an average of 9.9 injections In the PrONTO study therefore we can conclude that VA outcomes were nearly comparable with those reported in the MARINA and AN‐ CHOR, but these results were achieved with less than half number of intravitreal injections

The SUSTAIN trial was a phase III multicenter open-label single arm study that assessed the safety and efficacy of ranibizumab in patients with sub foveal CNV secondary to AMD us‐ ing a dosing regimen individualized to patient characteristics. 513 patients who were either ranibizumab treatment –naïve (69 patients) or had completed treatment with ranibizumab

Patients received three consecutive monthly injections of ranibizumab 0.3mg (or 0.5mg for the ANCHOR patients) (the "loading phase"), followed by monthly monitoring visits. Fur‐ ther treatment was administered if VA decreased by *>*5 letters or if CRT increased by *>*100 *μ*m. Compared with baseline, mean VA at month 12 increased by approximately 7 letters. VA reached a maximum level after the first 3 monthly injections, decreased slightly when shifting to PRN during the next 2 to 3 months and was then sustained throughout the treat‐ ment period. Over 12 months, the mean standard deviation (SD) number of ranibizumab in‐ jections received by the 69 ranibizumab naıve patients was 5.3 (±2.2), including the three "loading" injections. This study demonstrated that flexible, guided dosing with fewer injec‐ tions and monthly monitoring can be efficient and result in good visual outcome in at least

The SAILOR (Safety Assessment of IntravitrealLucentis for age-related macular degenera‐ tion) study, a Phase IIIb study of Lucentis for patients with all subtypes of new or recurrent active sub fovealCNV due to AMD, was a twelve-month randomized (cohort 1) or open-la‐ bel (cohort 2) multicenter clinical trial [36]. 4300 subjects were recruited. Cohort 1 subjects were randomized 1:1 to receive 0.3 mg (n = 1169) or 0.5 mg (n = 1209) intravitreal ranibizu‐ mab for 3 monthly loading doses, followed by monthly visits. Cohort 2 subjects received 1 single open-label 0.5 mg intravitreal ranibizumab, and than continue the monthly follow up visits. Those groups were stratified by AMD treatment history (treatment-naïve vs. previ‐

or verteporfin PDT in the ANCHOR trial participated in this study [35].

**4.1. Ranibizumab: As-needed regimen**

given in the MARINA and ANCHOR[34].

some patients [35].

nvAMD.

The HORIZON study was an open-label multicenter extension study that included 853 pa‐ tients (600 had been previously treated with ranibizumab initially, 184 had crossed over to treatment with ranibizumab, and 69 had not been treated with ranibizumab) who had com‐ pleted one of the three 2-year, randomized, controlled trials of monthly intravitreal ranibi‐ zumab treatment (MARINA, ANCHOR or FOCUS trial). Of the 853 patients, two-year VA data were available for 384 [37]. These patients could receive 0.5 mg ranibizumab at 30-day or longer intervals as needed. Of the patients who received initial treatment with ranibizu‐ mab during the ANCHOR, MARINA, and FOCUS trials, there was a mean 10.2-letter in‐ crease in VA during the first 2 years of the studies Patients that did not receive anti-VEGF therapy in those trials had worse outcomes. During the first year of the HORIZON study and the third year of the original trials, there was a 5.1-letter loss The initial VA gain de‐ creased by a mean of 8 letters with less frequent dosing in years 3 and 4. During the as need‐ ed dosing phase, the mean number of injections in the group initially treated with ranibizumab was 3.6. compared to 4.2 injections for patients that were treated with sham in the original trials.

The results of the HORIZON trial demonstrate that a delay in the initiation of treatment is associated with poorer visual outcomes and continued but less frequent dosing in years 3 and 4 was associated as well with visual decline [37].

PRN regimen of ranibizumab guided by monthly BCVA and other ophthalmic examina‐ tions, as detailed before, appears effective in sustaining the BCVA gained with 12 monthly injections with a significant lower number of injections during the extension phase [38].

Each one of these studies evaluated PRN regimens and had its own retreatment criteria, most of them retreated patients with a 100 μm increase in CRT from the thinnest measure‐ ment, and/or a Decreased VA >5 letters compared with VA score from the previous sched‐ uled study visit, but each study had its particular criteria, and follow up regimen. All those studies mentioned previously have used the Time Domain OCT which is less accurate than the Spectral Domain OCT (SD-OCT) – therefore re-treatment criteria usually used the 100 microns increase in thickness. Nowadays by using the SD OCT, residual or recurrent fluid which is less than 100 microns in height can be detected, so patients are re-treated earlier – which may account for a better visual outcome using the PRN regimen. Strengths of PRON‐ TO and SUSTAIN include monthly follow-up, but the PRONTO trialconsists of only a small cohort of patients. The SAILOR trial is the largest, but mandated only quarterly follow up visits. Overall, these studies support frequent follow up and individualized retreatment to achieve the best visual acuity gains with the as-needed treatment regimen as an alternative to the traditional monthly treatments used in the ANCHOR and MARINA trials. Further‐ more, the CATT study (detailed later) showed that ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab ad‐ ministered monthly.

Several retrospective studies demonstrated stabilization or improvement in VA following PRN treatment regimen with bevacizumab without a loading phase [45, 46]. One prospec‐ tive, open-label, nonrandomized clinical study reported a mean VA gain of 8.6 letters in 51 eyes after their second year of PRN bevacizumab treatment with a mean of only 1.5injec‐

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Gupta et al. retrospectively reviewed 74 eyes of 73 patients with treatment-naive nvAMD. The patients were treated monthly with intravitreal bevacizumab until no intraretinal or subretinal fluid was observed on OCT. The treatment intervals then were lengthened se‐ quentially by 2 weeks until signs of exudation recurred and then was reduced accordingly to maintain an exudation-free macula. Main outcomes measured included mean change from baseline visual acuity, proportion of eyes losing fewer than 3 and gaining 3 or more Snellen visual acuity lines at 1 year of follow-up, annual mean number of injections, OCT (Zeiss stratus) mean central retinal thickness change from baseline, mean maximum period of extension, adverse events, and mean direct annual medical cost. The mean follow-up pe‐ riod was 1.41 years. Mean Snellen VA improved from 20/230 at baseline to 20/109 at 12 months (P <.001) and 20/106 at 24 months (P <.001). The mean number of injections over the first year was 7.94. The mean OCT central retinal thickness decreased from 316 to 239 μm at

12 months (P <.001). The mean direct medical cost over the first year was \$3493.85.

**5. Comparison of AMD treatment trials (CATT and IVAN trials)**

The treat and-extend regimen in their study, was associated with significant visual improve‐ ments with fewer patient visits and injections along with lower costs when compared to the

Several retrospective studies have tried to evaluate the efficacy of ranibizumab as compared to bevacizumab, however they were not powered enough to show the differences in efficacy or safety between the 2 drugs. The CATT and the IVAN trials are two prospective large scale randomized controlled trials that compared the two drugs in different regimens of treatment. The CATT trial is a multicenter, single-blind, non-inferiority trial that collectively enrolled 1208 patients with nvAMD [49]. Patients were randomized to 4 treatment groups: monthly bevacizumab, monthly ranibizumab, as-needed bevacizumab and as needed rani‐ bizumab. In the as needed groups, retreatment was performed if at least one of the follow‐ ing criteria was met: fluid present on Time Domain OCT, decreased VA as compared to previous exam, new or persistent hemorrhage detected on clinical exam, or dye leakage or increased lesion size visible on fluorescein angiography. The primary outcome measure was mean change in VA at one year. The results at 12 months showed that Bevacizumab admin‐ istered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 let‐ ters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as need‐

tions given during year 2 [47].

**4.4. Bevacizumab: Treat-and-extend regimen**

MARINA, ANCHOR, and PrONTO protocols [48].

#### **4.2. Ranibizumab: Treat-and-extend regimen**

Treat-and-extend dosing regimen was first described by Freund et al. for the treatment of retinal angiomatous proliferation with an anti-VEGF agent. It involved increasing intervals between intravitreal injections up to 10 weeks as long as no fluid is present on OCT. If fluid is present, the interval between treatments is shortened[39].The treat-and-extend regimen is quite variable in terms of treatment criteria, which can include vision loss and/or macular hemorrhage [39], and the time between treatment, which can extend up to 12 weeks [40, 41]. Unfortunately, there are no large, randomized, prospective trials that investigated the effica‐ cy of this regimen compared to the PRN protocol.

Oubraham et al. compared two ranibizumab retreatment strategies; as-needed (PRN) and treat-and-extend, in a retrospective review of 90 patients, 52 in the PRN group, and 38 in the treat-and-extend group. Their treatment regimen included 3 loading doses monthly for the first three months in both groups, and the decision to re-treat was based only on the exis‐ tence of fluid on OCT They found that at one year, mean gain in VA was greater in the treatand-extend group than in the PRN (+10.8 versus +2.3 letters, resp.). Eyes in the treat-andextend group received significantly more injections (7.8 versus 5.2). Patients in the PRN group were followed every 4-5 weeks and the number of follow-up visits was similar in both groups (8.5 versus 8.8) [40].

Gupta et al. published a retrospective case series of 92 eyes treated with the treat-and-extend ranibizumab regimen. After 2 years, 32% had gained at least3 lines of vision and received 8.36 and 7.45 injections during the first and second years, respectively. In his study, this reg‐ imen was associated with fewer patient visits, injections, and direct annual medical costs compared with monthly injections [41].

#### **4.3. Bevacizumab: As-needed regimen**

The ABC trial is a prospective, double-masked, multicenter, randomized-controlled trial that included 131 patients randomized to 3 loading doses of bevacizumab at 6-week intervals fol‐ lowed by as-needed treatment at six week intervals or an alternate treatment atthe start of the trial (PDT, pegaptanib, or sham). Thirty-two percent of patients in the bevacizumab group gained at least15 letters with a mean VA increase of 7 letters vs a mean decrease of 9.4 letters in the alternate group. The median number of injections during the 12 months was 7 injections [42].

Other smaller, retrospective studies note a substantial improvement in VA using a protocol of three loading doses of bvacizumab followed by a PRN regimen, based mostly on OCT findings [43, 44].

Several retrospective studies demonstrated stabilization or improvement in VA following PRN treatment regimen with bevacizumab without a loading phase [45, 46]. One prospec‐ tive, open-label, nonrandomized clinical study reported a mean VA gain of 8.6 letters in 51 eyes after their second year of PRN bevacizumab treatment with a mean of only 1.5injec‐ tions given during year 2 [47].

#### **4.4. Bevacizumab: Treat-and-extend regimen**

to the traditional monthly treatments used in the ANCHOR and MARINA trials. Further‐ more, the CATT study (detailed later) showed that ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab ad‐

172 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

Treat-and-extend dosing regimen was first described by Freund et al. for the treatment of retinal angiomatous proliferation with an anti-VEGF agent. It involved increasing intervals between intravitreal injections up to 10 weeks as long as no fluid is present on OCT. If fluid is present, the interval between treatments is shortened[39].The treat-and-extend regimen is quite variable in terms of treatment criteria, which can include vision loss and/or macular hemorrhage [39], and the time between treatment, which can extend up to 12 weeks [40, 41]. Unfortunately, there are no large, randomized, prospective trials that investigated the effica‐

Oubraham et al. compared two ranibizumab retreatment strategies; as-needed (PRN) and treat-and-extend, in a retrospective review of 90 patients, 52 in the PRN group, and 38 in the treat-and-extend group. Their treatment regimen included 3 loading doses monthly for the first three months in both groups, and the decision to re-treat was based only on the exis‐ tence of fluid on OCT They found that at one year, mean gain in VA was greater in the treatand-extend group than in the PRN (+10.8 versus +2.3 letters, resp.). Eyes in the treat-andextend group received significantly more injections (7.8 versus 5.2). Patients in the PRN group were followed every 4-5 weeks and the number of follow-up visits was similar in

Gupta et al. published a retrospective case series of 92 eyes treated with the treat-and-extend ranibizumab regimen. After 2 years, 32% had gained at least3 lines of vision and received 8.36 and 7.45 injections during the first and second years, respectively. In his study, this reg‐ imen was associated with fewer patient visits, injections, and direct annual medical costs

The ABC trial is a prospective, double-masked, multicenter, randomized-controlled trial that included 131 patients randomized to 3 loading doses of bevacizumab at 6-week intervals fol‐ lowed by as-needed treatment at six week intervals or an alternate treatment atthe start of the trial (PDT, pegaptanib, or sham). Thirty-two percent of patients in the bevacizumab group gained at least15 letters with a mean VA increase of 7 letters vs a mean decrease of 9.4 letters in the alternate group. The median number of injections during the 12 months was 7

Other smaller, retrospective studies note a substantial improvement in VA using a protocol of three loading doses of bvacizumab followed by a PRN regimen, based mostly on OCT

ministered monthly.

**4.2. Ranibizumab: Treat-and-extend regimen**

cy of this regimen compared to the PRN protocol.

both groups (8.5 versus 8.8) [40].

compared with monthly injections [41].

**4.3. Bevacizumab: As-needed regimen**

injections [42].

findings [43, 44].

Gupta et al. retrospectively reviewed 74 eyes of 73 patients with treatment-naive nvAMD. The patients were treated monthly with intravitreal bevacizumab until no intraretinal or subretinal fluid was observed on OCT. The treatment intervals then were lengthened se‐ quentially by 2 weeks until signs of exudation recurred and then was reduced accordingly to maintain an exudation-free macula. Main outcomes measured included mean change from baseline visual acuity, proportion of eyes losing fewer than 3 and gaining 3 or more Snellen visual acuity lines at 1 year of follow-up, annual mean number of injections, OCT (Zeiss stratus) mean central retinal thickness change from baseline, mean maximum period of extension, adverse events, and mean direct annual medical cost. The mean follow-up pe‐ riod was 1.41 years. Mean Snellen VA improved from 20/230 at baseline to 20/109 at 12 months (P <.001) and 20/106 at 24 months (P <.001). The mean number of injections over the first year was 7.94. The mean OCT central retinal thickness decreased from 316 to 239 μm at 12 months (P <.001). The mean direct medical cost over the first year was \$3493.85.

The treat and-extend regimen in their study, was associated with significant visual improve‐ ments with fewer patient visits and injections along with lower costs when compared to the MARINA, ANCHOR, and PrONTO protocols [48].

### **5. Comparison of AMD treatment trials (CATT and IVAN trials)**

Several retrospective studies have tried to evaluate the efficacy of ranibizumab as compared to bevacizumab, however they were not powered enough to show the differences in efficacy or safety between the 2 drugs. The CATT and the IVAN trials are two prospective large scale randomized controlled trials that compared the two drugs in different regimens of treatment. The CATT trial is a multicenter, single-blind, non-inferiority trial that collectively enrolled 1208 patients with nvAMD [49]. Patients were randomized to 4 treatment groups: monthly bevacizumab, monthly ranibizumab, as-needed bevacizumab and as needed rani‐ bizumab. In the as needed groups, retreatment was performed if at least one of the follow‐ ing criteria was met: fluid present on Time Domain OCT, decreased VA as compared to previous exam, new or persistent hemorrhage detected on clinical exam, or dye leakage or increased lesion size visible on fluorescein angiography. The primary outcome measure was mean change in VA at one year. The results at 12 months showed that Bevacizumab admin‐ istered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 let‐ ters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as need‐ ed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. Ranibizumab as-needed was found to be equivalent to monthly ranibizumab, but the comparison between bevacizumab asneeded and monthly ranibizumab was inconclusive [49]. This could be due to the less dura‐ ble treatment effect of bevacizumab in a subgroup of patients [50]. Ranibizumab given as needed was equivalent to bevacizumab given monthly. The comparison between bevacizu‐ mab given as needed and ranibizumab given monthly was also inconclusive.

ters in favor of the Ranibizumab, 95% confidence interval [CI], -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (-0.35 letters; 95% CI, -2.40 to 1.70). Mena foveal total thickness did not differ by drug, but was 9% less using the continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants re‐ ceiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion of subjects experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF levels were found to be significantly lower in subjects treated with beva‐ cizuamb compared to ranibizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P<0.0001) and higher with discontinuous treatment compared to continuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42; P = 0.004). These results clearly indicate the higher systemic exposure to bevacizumab compared with ranibizumab. Researchers concluded that the comparison of VA at 1 year be‐ tween bevacizumab and ranibizumab was inconclusive. Visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs and

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The results of the second year of the IVAN trial and others like the VIBERA (Germany), EQUAL (Netherlands) and MANTA (Austria) studies [53-55] are about to be published in

As many as 10% of patients demonstrate a significant loss of vision in spite of 2 years of monthly anti-VEGF therapy [9, 20]. Within this group of individuals exist those who progress to disciform scar, RPE tear, massive subretinal hemorrhage, geographic atrophy, and in addition eyes that demonstrate persistent macular fluid/blood and leakage on OCT and fluorescein angiography associated with vision loss. This subgroup of patients is referred to as anti-VEGF non-responders. This variability in anti-VEGF treatment re‐ sponse can be attributed to more aggressive forms of nvAMD, including retinal angioma‐ tous proliferation (RAP), tachyphylaxis to anti-VEGF drugs, mimics of wet AMD [56],

The therapeutic approach in these patients include alternating bevacizumab and ranibizu‐ mab, switching to a newer anti VEGF drug- Eylea, combination therapy which is further dis‐ cussed in the next section, or other treatment options such as brachytherapy and

Since the development and progression of nvAMD involve pro-angiogenic factors, vascular permeability molecules, and inflammatory proteins, targeting only one component of this process may be insufficient and temporary, as shown by the data presented above. Anti VEGF agents are very effective in halting vascular leakage, but it has shown to be a tempo‐ rizing treatment, and there is an increased need for a treatment with longer efficacy dura‐

treatment regimens having similar efficacy and safety.

**6. Management of nonresponders**

and genetic differences among patients [57, 58].

transpupillary thermotherapy.

**6.1. Combination therapy**

the coming future.

The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance) Although not powered sufficiently to compare adverse event rates associated with the two drugs, the rates of death, arteriothrombotic events, and venous thrombotic events were similar for patients receiving bevacizumab or ranibizumab. The rate of serious sys‐ temic adverse events, primarily hospitalizations, was higher among the patients who had received bevacizumab, but rates of adverse events did not increase with increased expo‐ sure to the drug [49].

At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment[51] The 2 year results demonstrate that among patients receiving monthly injections for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). However mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion of patients without fluid on OCT ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment in the sec‐ ond year resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arterio‐ thrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizu‐ mab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009), even thoughmost of the excess events have not been associated previously with systemic ther‐ apy targeting vascular endothelial growth factor (VEGF) [51].

The first year results from an NIHR Health Technology Assessment (HTA) programmed funded trial, IVAN (Inhibit VEGF in Age related choroidal Neovascularization) were recent‐ ly published [52]. The trial compared the efficacy of ranibizumab vs bevacizumab in 610 subjects with nvAMD from 23 hospitals and academic institutions in the UK. In addition blood samples were repeatedly evaluated for the VEGF concentration in the plasma. Pa‐ tients received injections of the drug into the affected eye every month for the first three months. Groups were then subdivided to receive either injections at every visit thereafter namely the continuous group or only if the specialist decided there was persistent disease – namely the discontinuous group. Whenever re-treatment was performed the patient re‐ ceived a series of 3 monthly consecutive injections as opposed to 1 injection given in the CATT. After 12 months the comparison between the two drugs was inconclusive (-1.99 let‐ ters in favor of the Ranibizumab, 95% confidence interval [CI], -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (-0.35 letters; 95% CI, -2.40 to 1.70). Mena foveal total thickness did not differ by drug, but was 9% less using the continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants re‐ ceiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion of subjects experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF levels were found to be significantly lower in subjects treated with beva‐ cizuamb compared to ranibizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P<0.0001) and higher with discontinuous treatment compared to continuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42; P = 0.004). These results clearly indicate the higher systemic exposure to bevacizumab compared with ranibizumab. Researchers concluded that the comparison of VA at 1 year be‐ tween bevacizumab and ranibizumab was inconclusive. Visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs and treatment regimens having similar efficacy and safety.

The results of the second year of the IVAN trial and others like the VIBERA (Germany), EQUAL (Netherlands) and MANTA (Austria) studies [53-55] are about to be published in the coming future.
