**6. Management of nonresponders**

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‐

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‐

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‐

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‐

mab given as needed and ranibizumab given monthly was also inconclusive.

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

apy targeting vascular endothelial growth factor (VEGF) [51].

sure to the drug [49].

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], and genetic differences among patients [57, 58].

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 transpupillary thermotherapy.

#### **6.1. Combination therapy**

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‐ tion..The ideal combination therapy regimen would provide a longer-lasting treatment effect in addition to potentially being more or equally efficacious to monotherapy alone.

cases of PCV, because this combined treatment yields the best VA results and highest

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Augustin et al. described a combination therapy involving standard fluence PDT with re‐ duced light duration (70 seconds instead of 83 seconds),with total light dose of 42J/ cm2. Six‐ teen hours after PDT administration patients were taken to the operating room, and underwent limited vitrectomy followed by intravitreal dexamethasone (800 mcg) and intra‐ vitreal bevacizumab (1.5 mg) injections [62]. Most patients treated with this triple therapy hadlong-lasting improvement in VA with only one treatment at final follow-up (The mean follow-up period was 40 weeks (range, 22-60 weeks). Less than one-fourth of the patients treated with this regimen required additional treatment either with repeat triple therapy or

Bakri et al. retrospectively reviewed the treatment benefit in patients receiving a same-day combination of reduced fluence PDT, intravitreal dexamethasone (200mcg), and intravitreal bevacizumab (1.25 mg). Patients were either treatment naïve or previously treated. At final follow-up, patients treated with this regimen showed stable VA and decreased macular

An average of less than one additional treatment with either repeat triple therapy or anti-VEGF was required in the treatment of naive group while almost four additional treatments were required in previously treated patients [63]. No steroid-related complications were not‐ ed in either study [62, 63]. A prospective interventional case series of 17 patients treated with a same-day regimen of standard fluence PDT, intravitreal bevacizumab(1.25 mg), and intravitreal triamcinolone (IVTA) (2 mg), was recently published. Patients treated with this regimen also showed an improvement in VA and reduced central macular thickness [64].

The Reduced Fluence Visudyne Anti-VEGF Dexamethasone in Combination for AMD Lesions (RADICAL) trial is a prospective, multicenter, randomized trial of combination therapy for the treatment of wet AMD that began in 2008. Patients are randomized in‐ to four treatment arms including anti-VEGF monotherapy with ranibizumab, half-flu‐ ence PDT with ranibizumab, half-fluence PDT with ranibizumab and dexamethasone, or quarter-fluence PDT with ranibizumab and dexamethasone. The dose of ranibizu‐ mab used was 0.5 mg and dexamethasone 500 mcg. Patients enrolled in the trial were followed for a total of 24 months. For the first 12 months, patients were followed monthly with decision for retreatment made at each visit. After 12 months, patients were reassessed every 3 months or sooner at physician's discretion. Patients in the an‐ ti-VEGF monotherapy arm received mandatory first 3 monthly consecutive injections followed by retreatment as needed thereafter. Retreatment with combination therapy was not administered prior to 8 weeks interval. Twelve-month data released by the sponsor [65], QLT incorporated, showed significantly fewer re-treatments in all combi‐ nation therapy arms compared with the groups of patients treated with anti-VEGF

rate of anatomic closure of the polyps.

anti-VEGF alone during the follow-up period [62].

*6.1.2. Triple therapy*

thickness [63].

monotherapy [65].

The main combination therapies are further discussed.

#### *6.1.1. PDT+ anti VEGF*

SUMMIT is a clinical trial program that includes three similarly designed, controlled studies to further examine the safety, efficacy, and treatment burden of combination therapy with PDT and ranibizumab compared with ranibizumab alone: DENALI in the USA, and Cana‐ da, examining verteporfin PDT in combination at both standard- and reduced-fluence light doses; MONT BLANC in Europe, examining verteporfin PDT in combination at standardfluence light dose only, and an Asian study (EVEREST) which is designed to compare stand‐ ard fluence PDT combined with ranibizumab and ranibizumab monotherapy in the treatment of polypoidal choroidal vasculopathy (PCV). Twelve-month results of the MON‐ TBLANC study showed that combining standard-fluence PDT with ranibizumab 0.5mg re‐ sults in VA improvement that is noninferior to a ranibizumab monotherapy regimen with three ranibizumab-loading doses followed by injections on a monthly PRN basis (non-inferi‐ ority margin of 7 letters There was no significant difference between the two treatment arms with regard to proportion of patients with a treatment-free interval of at least three months duration after month 2. Adverse event incidence was similar between treatment groups [59].As monotherapy is not inferior to the combination; they concluded that monotherapy should be the preferred treatment.

Twelve-month results of the DENALI study showed that combining PDT with ranibizumab in a regimen that consists three ranibizumab loading doses followed by additional injections on a monthly PRN basis and PRN PDT every 3 months can improve VA at month 12 in pa‐ tients with sub foveal CNV secondary to nvAMD [60]. However the combination treatment was found inferior to the monotherapy with ranibizumab alone. At month 12, patients in the standard fluence combination group and the reduced fluence combination group gained on average 5.3 and 4.4 letters from baseline, compared to a more significant gain of 8.1 letters in the ranibizumab monthly monotherapy group. DENALI did not demonstrate non-inferior visual acuity gain for PDT combination therapy compared with ranibizumab monthly mon‐ otherapy, meaning the monotherapy with monthly ranibizumab was found superior to the combination therapy.

Six months results of the EVEREST trial were recently published [61]. At Month 6, verte‐ porfin PDT combined with ranibizumab or verteporfin PDT alone was superior to ranibi‐ zumab monotherapy in achieving complete polyp regression (77.8% and 71.4% vs. 28.6%; P < 0.01); mean change ± standard deviation in best-corrected visual acuity (letters) was the highest in the combination group although not statistically better than the ranibizu‐ mab monotherapy. There was a mean improvement of 10.9 ± 10.9 letters in the vertepor‐ fin PDT + ranibizumab, 7.5 ± 10.6 letters in the verteporfin PDT alone, and 9.2 ± 12.4 letters in the ranibizumab monotherapy. There were no new safety findings with either drug used alone or in combination. Based on the results of the EVERST we can conclude that combination therapy of reduced fluence PDT with ranibizumab should be applied in cases of PCV, because this combined treatment yields the best VA results and highest rate of anatomic closure of the polyps.

#### *6.1.2. Triple therapy*

tion..The ideal combination therapy regimen would provide a longer-lasting treatment effect in addition to potentially being more or equally efficacious to monotherapy alone.

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

SUMMIT is a clinical trial program that includes three similarly designed, controlled studies to further examine the safety, efficacy, and treatment burden of combination therapy with PDT and ranibizumab compared with ranibizumab alone: DENALI in the USA, and Cana‐ da, examining verteporfin PDT in combination at both standard- and reduced-fluence light doses; MONT BLANC in Europe, examining verteporfin PDT in combination at standardfluence light dose only, and an Asian study (EVEREST) which is designed to compare stand‐ ard fluence PDT combined with ranibizumab and ranibizumab monotherapy in the treatment of polypoidal choroidal vasculopathy (PCV). Twelve-month results of the MON‐ TBLANC study showed that combining standard-fluence PDT with ranibizumab 0.5mg re‐ sults in VA improvement that is noninferior to a ranibizumab monotherapy regimen with three ranibizumab-loading doses followed by injections on a monthly PRN basis (non-inferi‐ ority margin of 7 letters There was no significant difference between the two treatment arms with regard to proportion of patients with a treatment-free interval of at least three months duration after month 2. Adverse event incidence was similar between treatment groups [59].As monotherapy is not inferior to the combination; they concluded that monotherapy

Twelve-month results of the DENALI study showed that combining PDT with ranibizumab in a regimen that consists three ranibizumab loading doses followed by additional injections on a monthly PRN basis and PRN PDT every 3 months can improve VA at month 12 in pa‐ tients with sub foveal CNV secondary to nvAMD [60]. However the combination treatment was found inferior to the monotherapy with ranibizumab alone. At month 12, patients in the standard fluence combination group and the reduced fluence combination group gained on average 5.3 and 4.4 letters from baseline, compared to a more significant gain of 8.1 letters in the ranibizumab monthly monotherapy group. DENALI did not demonstrate non-inferior visual acuity gain for PDT combination therapy compared with ranibizumab monthly mon‐ otherapy, meaning the monotherapy with monthly ranibizumab was found superior to the

Six months results of the EVEREST trial were recently published [61]. At Month 6, verte‐ porfin PDT combined with ranibizumab or verteporfin PDT alone was superior to ranibi‐ zumab monotherapy in achieving complete polyp regression (77.8% and 71.4% vs. 28.6%; P < 0.01); mean change ± standard deviation in best-corrected visual acuity (letters) was the highest in the combination group although not statistically better than the ranibizu‐ mab monotherapy. There was a mean improvement of 10.9 ± 10.9 letters in the vertepor‐ fin PDT + ranibizumab, 7.5 ± 10.6 letters in the verteporfin PDT alone, and 9.2 ± 12.4 letters in the ranibizumab monotherapy. There were no new safety findings with either drug used alone or in combination. Based on the results of the EVERST we can conclude that combination therapy of reduced fluence PDT with ranibizumab should be applied in

The main combination therapies are further discussed.

*6.1.1. PDT+ anti VEGF*

should be the preferred treatment.

combination therapy.

Augustin et al. described a combination therapy involving standard fluence PDT with re‐ duced light duration (70 seconds instead of 83 seconds),with total light dose of 42J/ cm2. Six‐ teen hours after PDT administration patients were taken to the operating room, and underwent limited vitrectomy followed by intravitreal dexamethasone (800 mcg) and intra‐ vitreal bevacizumab (1.5 mg) injections [62]. Most patients treated with this triple therapy hadlong-lasting improvement in VA with only one treatment at final follow-up (The mean follow-up period was 40 weeks (range, 22-60 weeks). Less than one-fourth of the patients treated with this regimen required additional treatment either with repeat triple therapy or anti-VEGF alone during the follow-up period [62].

Bakri et al. retrospectively reviewed the treatment benefit in patients receiving a same-day combination of reduced fluence PDT, intravitreal dexamethasone (200mcg), and intravitreal bevacizumab (1.25 mg). Patients were either treatment naïve or previously treated. At final follow-up, patients treated with this regimen showed stable VA and decreased macular thickness [63].

An average of less than one additional treatment with either repeat triple therapy or anti-VEGF was required in the treatment of naive group while almost four additional treatments were required in previously treated patients [63]. No steroid-related complications were not‐ ed in either study [62, 63]. A prospective interventional case series of 17 patients treated with a same-day regimen of standard fluence PDT, intravitreal bevacizumab(1.25 mg), and intravitreal triamcinolone (IVTA) (2 mg), was recently published. Patients treated with this regimen also showed an improvement in VA and reduced central macular thickness [64].

The Reduced Fluence Visudyne Anti-VEGF Dexamethasone in Combination for AMD Lesions (RADICAL) trial is a prospective, multicenter, randomized trial of combination therapy for the treatment of wet AMD that began in 2008. Patients are randomized in‐ to four treatment arms including anti-VEGF monotherapy with ranibizumab, half-flu‐ ence PDT with ranibizumab, half-fluence PDT with ranibizumab and dexamethasone, or quarter-fluence PDT with ranibizumab and dexamethasone. The dose of ranibizu‐ mab used was 0.5 mg and dexamethasone 500 mcg. Patients enrolled in the trial were followed for a total of 24 months. For the first 12 months, patients were followed monthly with decision for retreatment made at each visit. After 12 months, patients were reassessed every 3 months or sooner at physician's discretion. Patients in the an‐ ti-VEGF monotherapy arm received mandatory first 3 monthly consecutive injections followed by retreatment as needed thereafter. Retreatment with combination therapy was not administered prior to 8 weeks interval. Twelve-month data released by the sponsor [65], QLT incorporated, showed significantly fewer re-treatments in all combi‐ nation therapy arms compared with the groups of patients treated with anti-VEGF monotherapy [65].

VA appears to equally improve among all groups, but confidence intervals varied. Of the three combination therapy arms, the triple therapy half-fluence PDT group shared similar mean visual improvement compared with monotherapy and had the fewest retreatments. After 12 months, three retreatments of triple therapy with half-fluence PDT were required compared to 5.1 re-treatments of monotherapy (p<0.001). Adverse event incidence was similar amongst all treatment groups. The final results of the 24-months trial were not published yet.

Systemic AEs are a concern, since inhibitors of VEGF injected intravitreally, can penetrate the general circulation and compromise functions that rely on VEGF outside of the eye, such as wound healing and the formation of new blood vessels around the heart or brain in cases of ischemia [68, 69]. Patients with AMD already are at higher risk of cardiovascular disease than the general population because of their age and the association of AMDwith systemic hypertension [70], consequently, participants in clinical trialsof VEGF inhibitors were care‐ fully monitored for possible increases in blood pressure, occurrence of myocardial infarc‐

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Among participants in the MARINA trial, approximately16% in both the ranibizumab 0.5 mg and sham injectiongroups developed hypertension [8] and in the ANCHOR treatment related hypertension was higher in the PDT group (8.4%) than in the ranibizumab group

In the CATT trial there was no evidence that ranibizumab0.5 mg was associated with in‐

Nonocular hemorrhages include events such as cerebral or gastrointestinal bleeding. In the ANCHOR trial, non ocular hemorrhage was more frequent in the 0.5-mg ranibizumab group (6.4%) than in the PDT group (2.1%) [20]. In the MARINA trial, the cumulative fre‐ quency of nonocular hemorrhage by month 24 was 5.5% in the sham injection group com‐

Among participants in the MARINA trial, approximately 16% in both the ranibizumab 0.5

In the CATT trial Gastrointestinal disorders (e.g., hemorrhage, hernia, nausea, and vomit‐ ing), occurred in 11 (1.8%) ranibizumab-treated and in 28 (4.8%) bevacizumab-treated pa‐

With respect to cardiovascular or cerebrovascular events, during the ANCHOR trial, 1 sub‐ ject in the PDT group (0.7%) and 3 subjects in the ranibizumab 0.5-mg group (2.1%) devel‐ oped nonfatal myocardial infarctions, although the events did not occurshortly after treatment. [20]. The frequency of stroke (1 in each group) and cerebral infarction (0 in each

At 24 months, the overall frequency of cardiovascular systemic events in the MARINA trial was similar in the0.5-mg ranibizumab and sham injection groups [8]. Therewere only small differences in the frequency of thromboembolic events between the sham injection group (3.8%) and the ranibizumab 0.5-mg group (4.6%) [8]. The frequency of death (2.5%) was the same in the ranibizumab 0.5-mgand sham injection groups [8]. Two individuals in each

There was no significant difference in the frequency of myocardial infarction between the 2

In the CATT trial at 2 years, 5.3% assigned to ranibizumab and 6.1% assigned to Bevacizu‐ mab had died (*P* = 0.62). The proportion of patients with arteriothrombotic events was simi‐

group) in the ANCHOR trial were too low to draw meaningful conclusion [20].

tion/stroke, and nonocular hemorrhages [8, 20].

creases in either diastolic or systolic blood pressure [49, 50].

pared with 8.8% in the 0.5-mgranibizumab group [8].

mg and sham injection groups developed hypertension [3].

(6.4%) [20].

tients (*P* = 0.005) [51].

group died of stroke.

treatment groups in the SAILOR trial [36].
