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Aetna Aetna
Clinical Policy Bulletin:
Vascular Endothelial Growth Factor Inhibitors for Ocular Indications
Number: 0701


Policy

Aetna considers pegaptanib sodium injection (Macugen) medically necessary for the treatment of individuals with neovascular (wet) age-related macular degeneration (AMD) and diabetic macular edema.

Aetna considers pegaptanib sodium injection experimental and investigational for the treatment of the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

  • Cystoid macular degeneration,
  • Ocular von Hippel Lindau disease lesions

Aetna considers intravitreal ranibizumab (Lucentis) or bevacizumab (Avastin) injections medically necessary for the treatment of the following indications:

  • Diabetic macular edema
  • Macular edema following retinal vein occlusion (RVO)
  • Neovascular (wet) AMD
  • Neovascular glaucoma
  • Pseudoxanthoma elasticum
  • Rare causes of choroidal neovascularization (angioid streaks, choroiditis [including choroiditis secondary to ocular histoplasmosis], idiopathic degenerative myopia, retinal dystrophies, rubeosis iridis, and trauma)
  • Retinopathy of prematurity (stage 3 to 5; bevacizumab only)

Aetna considers intravitreal ranibizumab and bevacizumab injections experimental and investigational for treatment of the following indications (not an all-inclusive list) because their effectiveness for these indications has not been established.

  • Amblyopia
  • Central serous retinopathy
  • Choroidal hemorrhage not related to a medically necessary indication
  • Choroidal melanoma
  • Cystoid macular edema
  • Diabetic retinopathy without macular edema (including pre-treatment of vitrectomy for proliferative diabetic retinopathy)
  • Primary pterygium (including as adjunctive therapy for primary pterygium surgery)
  • Radiation retinopathy
  • Retinal angioma
  • Vitreous hemorrhage not related to a medically necessary indication

Aetna considers topical administration, subconjunctival or intrastromal injections of ranibizumab or bevacizumab for the treatment of corneal neovascularization experimental and investigational because their effectiveness for this indication has not been established.

Aetna considers intravitreal aflibercept (Eylea) injections medically necessary for the treatment of neovascular (wet) AMD, diabetic macular edema, and macular edema following retinal vein occlusion (RVO) (including central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO)). 

Aetna considers aflibercept experimental and investigational for the treatment of colorectal, ovarian, and prostate cancers, and all other indications because its effectiveness for these indications has not been established.

VEGF inhibitors for ocular indications are contraindicated and considered not medically necessary for persons with endophthalmitis or with ocular or periocular infections.

See also CPB 0594 - Visudyne (Verteporfin) Photodynamic TherapyCPB 0685 - Bevacizumab (Avastin)CPB 0706 - Anecortave Acetate (Retaane), and CPB 0842 - Ziv-Aflibercept (Zaltrap).



Background

Age-related macular degeneration (AMD), characterized as a progressive degenerative disease of the macula, is the leading cause of blindness in developed countries afflicting approximately 15 million people in the United States. 

There are 2 forms of AMD: (i) neovascular and (ii) non-neovascular.  The non-neovascular form of AMD is more common and leads to a slow deterioration of the macula with a gradual loss of vision over a period of years.  The neovascular (wet) form of the disease is responsible for the majority of cases of severe vision loss and is due to proliferation of abnormal blood vessels behind the retina.  These blood vessels leak blood and fluid into the retina, resulting in visual abnormalities.  The development of these abnormal blood vessels is due in part to the activity of vascular endothelial growth factor (VEGF), which induces angiogenesis, and increases vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular (wet) form of AMD. 

Macugen (pegaptanib sodium injection) is an intravitreal injection developed for the treatment of neovascular (wet) AMD.  Pegaptanib binds to VEGF and inhibits its binding to cellular receptors.  Macugen’s anti-VEGF activity is expected to inhibit abnormal blood vessel proliferation and therefore decrease the vision loss associated with the proliferation of abnormal blood vessels.

Gragoudas et al (2004) reported the results of 2 concurrent, prospective, randomized, double-blind, multi-center, dose-ranging, controlled clinical trials (n = 1,186) on the use of pegaptanib in the treatment of neovascular AMD.  Intravitreous injection into 1 eye per patient of pegaptanib (at a dose of 0.3 mg, 1.0 mg, or 3.0 mg) or sham injections were administered every 6 weeks over a period of 48 weeks, for a total of 9 treatments.  The primary end point was the proportion of patients who had lost fewer than 15 letters of visual acuity at 54 weeks. 

In the combined analysis of the primary end point, efficacy was demonstrated, without a dose-response relationship, for all 3 doses of pegaptanib (p < 0.001 for the comparison of 0.3 mg with sham injection; p < 0.001 for the comparison of 1.0 mg with sham injection; and p = 0.03 for the comparison of 3.0 mg with sham injection).  Verteporfin photodynamic therapy (PDT) usage was permitted at the discretion of the investigators in patients with predominantly classic lesions.  Concomitant use of PDT overall was low.  More sham treated patients (25 %) received PDT than Macugen 0.3 mg treated patients (20 %).  In the group given pegaptanib at 0.3 mg, 70 % of patients lost fewer than 15 letters of visual acuity, as compared with 55 % among the controls (p < 0.001).  The risk of severe loss of visual acuity (loss of 30 letters or more) was reduced from 22 % in the sham-injection group to 10 % in the group receiving 0.3 mg of pegaptanib (p < 0.001).  More patients receiving pegaptanib (0.3 mg), as compared with sham injection, maintained their visual acuity or gained acuity (33 % versus 23 %; p = 0.003).  As early as 6 weeks after beginning therapy with the study drug, and at all subsequent points, the mean visual acuity among patients receiving 0.3 mg of pegaptanib was better than in those receiving sham injections (p < 0.002).  Dose levels above 0.3 mg did not demonstrate any additional benefit.  On average, Macugen (0.3) mg treated patients and sham treated patients continued to experience vision loss.  However, the rate of vision decline in the Macugen treated group was slower than the rate in the patients who received sham treatment.  Among the adverse events that occurred, endophthalmitis (1.3 % of patients), traumatic injury to the lens (0.7 %), and retinal detachment (0.6 %) were the most serious and required vigilance.  These events were associated with a severe loss of visual acuity in 0.1 % of patients.  The authors concluded that pegaptanib appears to be an effective therapy for neovascular AMD; however, its long-term safety is not known.

Prescribing information available on the Eyetech Pharmaceuticals, Inc. and Pfizer, Inc. website reports that at the end of the first year (week 54), approximately 1,050 patients were re-randomized to either continue the same treatment or to discontinue treatment through week 102.  Macugen was shown to be less effective during the second year of the study than during the first year. 

Macugen 0.3 mg should be administered once every 6 weeks by intravitreous injection into the eye to be treated.  The safety and efficacy of Macugen therapy administered to both eyes concurrently have not been studied.

In a short-term phase II clinical trial, Cunningham et al (2005) assessed the safety and effectiveness of pegaptanib sodium injection (pegaptanib) in the treatment of diabetic macular edema (DME).  Subjects were individuals with a best-corrected visual acuity (VA) between 20/50 and 20/320 in the study eye and DME involving the center of the macula for whom the investigator judged photocoagulation could be safely withheld for 16 weeks.  Intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections were administered at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks.  Final assessments were conducted at week 36.  Main outcome measures include best-corrected VA, central retinal thickness at the center point of the central subfield as assessed by optical coherence tomography measurement, and additional therapy with photocoagulation between weeks 12 and 36.  A total of 172 patients appeared balanced for baseline demographic and ocular characteristics.  Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (p = 0.04).  A larger proportion of those receiving 0.3 mg gained VAs of greater than or equal to 10 letters (approximately 2 lines) (34 % versus 10 %, p = 0.003) and greater than or equal to 5 letters (18 % versus 7 %, p = 0.12). Mean central retinal thickness decreased by 68 micron with 0.3 mg, versus an increase of 4 micron with sham (p = 0.02).  Larger proportions of those receiving 0.3 mg had an absolute decrease of both greater than or equal to 100 micron (42 % versus 16 %, p = 0.02) and greater than or equal to 75 micron (49 % versus 19 %, p = 0.008).  Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg versus sham, 25 % versus 48 %; p = 0.04).  All pegaptanib doses were well-tolerated.  Endophthalmitis occurred in 1 of 652 injections (0.15 %/injection; i.e., 1/130 [0.8 %] pegaptanib subjects) and was not associated with severe visual loss.  Subjects assigned to pegaptanib had better VA outcomes, were more likely to show reduction in central retinal thickness, and were deemed less likely to need additional therapy with photocoagulation at follow-up.  These investigators noted that confirmation of these preliminary results across a broad spectrum of patients with DME in sufficiently powered prospective clinical trials is being planned.

A 2-year phase III study demonstrated that pegaptanib sodium improved vision in persons with diabetic macular edema (Pfizer, 2010).  The study included 260 subjects who received 0.3 mg pegaptanib sodium or a sham procedure consisting of anesthesia and a simulated injection in the eye every 6 weeks for a total of 9 injections in year 1.  In year 2, subjects received injections as often as every 6 weeks based on pre-specified criteria.  Up to 3 focal or grid laser treatments per year were permitted beginning at week 18, at the investigator’s discretion.  The primary outcome measure of the study was the proportion of subjects who, after 1 year, experienced an improvement in vision from baseline of 2 lines, or 10 letters, on the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart.  The investigators reported that 37 % of subjects treated with pegaptanib sodium gained 2 lines, or 10 letters, of vision on the ETDRS eye chart at 54 weeks, versus 20 % of subjects who received the sham procedure (p = 0.0047).  On average, subjects treated with pegaptanib sodium gained 5.2 letters of vision at year 1 compared to 1.2 letters for subjects receiving sham (p < 0.05).  At the end of year 2, subjects receiving pegaptanib sodium had gained on average 6.1 letters of vision compared to 1.3 letters for subjects in the sham arm of the study (p < 0.01).  The investigators reported that adverse events were consistent with those observed in clinical trials of pegaptanib sodium in persons with neovascular age-related macular degeneration and similar to clinical experience with pegaptanib sodium. 

In a pilot study, Dahr et al (2007) examined the safety and effectiveness of pegaptanib for patients with juxtapapillary or large peripheral angiomas secondary to von Hippel-Lindau (VHL) disease.  A total of 5 patients with severe ocular VHL lesions received intravitreal injections of pegaptanib (3 mg/100 microL), given every 6 weeks for minimum of 6 injections.  The primary outcome of this study was a change of greater than or equal to 15 letters (3 lines) in best-corrected VA by 1 year.  Secondary outcomes included changes in macular thickness, as determined by optical coherence tomography, and changes in fluorescein leakage.  Two of 5 patients completed the course of treatment and 1 year of follow-up.  These 2 patients had progressive decrease in retinal hard exudate and reduction in central retinal thickness measured by optical coherence tomography.  One of these 2 patients had improvement in VA of 3 lines.  No significant change in fluorescein leakage or tumor size was detected in either patient.  Lesions in the other 3 patients continued to progress despite treatment, and these patients did not complete the entire treatment course.  One patient developed a tractional retinal detachment.  Additional serious adverse events included transient post-injection hypotony in 2 eyes.  The authors concluded that intravitreal injections of pegaptanib may decrease retinal thickening minimally and reduce retinal hard exudates in some patients with advanced VHL angiomas.  This finding may be related to a reduction in vasopermeability, because there was no apparent effect of treatment on the size of the primary retinal angiomas in this small pilot study.

On June 30, 2006, the United States Food and Drug Administration (FDA) approved Lucentis (ranibizumab injection, Genentech Inc., South San Francisco, CA) for the treatment of patients with neovascular AMD.  Lucentis is designed to block new blood vessel growth and leakiness, and is the first treatment which, when given monthly, can maintain the vision of more than 90 % of patients with this type of AMD.  In contrast to pegaptanib (Macugen), ranibizumab is a recombinant humanized monoclonal antibody fragment with specificity for all isoforms of human VEGF.  Ranibizumab exhibits high affinity for human VEGF and exerts its neutralizing effects by inhibiting the VEGF-receptor interaction.  Unlike the larger whole antibody, ranibizumab can penetrate the internal limiting membrane and reach the sub-retinal space following intravitreal injection (van Wijngaarden et al, 2005).

The FDA approval of Lucentis is based on data from 2 phase III clinical studies (MARINA and ANCHOR).  In these studies, nearly all patients (about 95 %) treated with Lucentis (0.5 mg) maintained (defined as the loss of less than 15 letters in VA) and up to 40 % improved (defined as the gain of 15 letters or more in VA) vision at 1-year, as measured on the Early Treatment of Diabetic Retinopathy eye chart.  On average, patients treated with Lucentis in the MARINA study experienced an improvement from baseline of 6.6 letters at 2-year compared to a loss of 14.9 letters in the sham group.  In the ANCHOR study, patients treated with Lucentis, on average, experienced an 11.3 letter gain from baseline at 1-year compared to a loss of 9.5 letters in the Visudyne photodynamic therapy control group.  Up to 40 % of patients treated with Lucentis achieved vision of 20/40 or better.

In addition to data from the 2 phase III clinical trials, data from phase I/II studies were also included in the FDA review.  In an open-label, 2-center, uncontrolled, randomized, phase I clinical trial, Rosenfeld and colleagues (2006) examined if multiple intravitreal doses of up to 2 mg of ranibizumab can be tolerated and are biologically active when injected using a dose-escalating strategy in eyes of patients with neovascular AMD.  A total of 32 patients with primary or recurrent sub-foveal choroidal neovascularization secondary to AMD were enrolled.  Baseline best-corrected VA in the study eye was from 20/40 to 20/640 (Snellen equivalent).  Treatment regimens consisted of 5, 7, or 9 intravitreal injections of ranibizumab at 2- or 4-week intervals for 16 weeks, with escalating doses ranging from 0.3 to 2.0 mg.  Patients were evaluated through day 140, 4 weeks after their last injection.  Safety was assessed based on ocular and non-ocular adverse events, changes in VA, changes in intraocular pressure (IOP), slit-lamp ocular examination, changes in lesion characteristics based on fluorescein angiography and color fundus photography, and the presence of anti-ranibizumab antibodies.  A total of 29 patients received an injection at baseline, and 27 patients completed the study through day 140.  Results were similar across the 3 treatment groups.  All patients experienced ocular adverse events, most of which were mild.  The most common ocular adverse events were iridocyclitis (83 %), and injection-site reactions (72 %).  Inflammation did not increase with repeated injections, despite the increasing ranibizumab doses.  Transient mild IOP elevations were common after ranibizumab injection.  No serum anti-ranibizumab antibodies were detected.  In general, median and mean VAs in the study eyes improved by day 140 in all 3 groups.  Only 3 of the 27 patients lost significant vision.  There was no significant lesion growth, and a decrease in area of leakage from choroidal neovascularization was detected through day 140.  The authors concluded that multiple intravitreal injections of ranibizumab at escalating doses ranging from 0.3 to 2.0 mg were well-tolerated and biologically active in eyes with neovascular AMD through 20 weeks.  Mild transient ocular inflammation was the most common post-injection adverse event.

In a multi-center, controlled, open-label, phase I/II clinical study, Heier and associates (2006) evaluated the safety of repeated intravitreal injections of ranibizumab in treating neovascular AMD, and assessed changes in VA and AMD lesion characteristics.  A total of 64 patients with sub-foveal predominantly or minimally classic AMD-related choroidal neovascularization were enrolled.  In part 1, patients were randomized to monthly intravitreal ranibizumab for 3 months (4 injections of 0.3 mg or 1 injection of 0.3 mg followed by 3 injections of 0.5 mg; n = 53) or usual care (UC; n = 11).  In part 2, patients could continue their regimen for 3 additional months or cross over to the alternative treatment.  Main outcome measures were adverse events, IOP, VA, and lesion characteristics assessed by fluorescein angiography and fundus photography.  Of the 64 randomized subjects, 62 completed the 6-month study.  Twenty of 25 subjects (80 %) randomized to 0.3 mg, and 22 of 28 subjects (79 %) randomized to 0.5-mg ranibizumab in part 1 continued on that treatment in part 2; 9 of 11 (82 %) subjects randomized to UC in part 1 crossed over to ranibizumab treatment in part 2.  The most common side effects with ranibizumab were reversible inflammation and minor injection-site hemorrhages.  Serious side effects were iridocyclitis, endophthalmitis, and central retinal vein occlusion (1 subject each).  Post-injection, IOP increased transiently in 22.6 % of ranibizumab-treated eyes in parts 1 and 2.  After 4 ranibizumab injections (day 98), mean (+/- standard deviation) VA increased 9.4 +/- 13.3 and 9.1 +/- 17.2 letters in the 0.3- and 0.5-mg groups, respectively, but decreased 5.1 +/- 9.6 letters with UC.  In part 2 (day 210), VA increased from baseline 12.8 +/- 14.7 and 15.0 +/- 14.2 letters in subjects continuing on 0.3 and 0.5 mg, respectively.  Visual acuity improved from baseline greater than or equal to 15 letters in 26 % (day 98) and 45 % (day 210) of subjects initially randomized to and continuing on ranibizumab, respectively, and areas of leakage and sub-retinal fluid decreased.  No UC subject had a greater than or equal to 15-letter improvement at day 98.  These investigators concluded that repeated intravitreal injections of ranibizumab had a good safety profile and were associated with improved VA and decreased leakage from choroidal neovascularization in subjects with neovascular AMD.

In clinical trials, the most common side effects among patients treated with Lucentis (reported in at least 6 % more patients than in the control groups in at least one study) included conjunctival hemorrhage, eye pain, vitreous floaters, increased IOP and intraocular inflammation.  Although there was a low rate (less than 4 %) of arterial thromboembolic events observed in the Lucentis clinical studies that was not statistically different between the Lucentis and control groups, there is a theoretical risk of arterial thromboembolic events following intravitreal use of inhibitors of VEGF.  Serious side effects related to the injection procedure occurred in less than 0.1 % of intravitreal injections, including endophthalmitis (severe inflammation of the interior of the eye), retinal tear, retinal detachment, and traumatic cataract.  Lucentis is contraindicated in patients with hypersensitivity and ocular or periocular infections.

The FDA-approved labeling of Lucentis recommends 0.5 mg of Lucentis administered by intravitreal injection once a month.  Although less effective, treatment may be reduced to 1 injection every 3 months after the first 4 injections if monthly injections are not feasible.  Compared to continued monthly dosing, dosing every 3 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average, over the following 9 months.  Genentech said the average patient will receive only 5 to 7 injections in their 1st year because of the risk of eye pain, inflammation, and increased IOP.

In June 2010, the FDA approved Lucentis (ranibizumab injection) for the treatment of macular edema following retinal vein occlusion (RVO).  The FDA approval was based upon 2 randomized controlled clinical studies -- the BRAVO study, which assessed the safety and efficacy profile of ranibizumab in a total of 397 patients with macular edema following branch-RVO, and the CRUISE study, which assessed the safety and efficacy profile of ranibizumab in a total of 392 patients with macular edema following central-RVO.  During the first 6-month period, participants in both trials received monthly injections of either 0.3 mg or 0.5 mg of ranibizumab (n = 527) or monthly sham injections (n = 262).  The primary endpoint of both studies was mean change from baseline in best-corrected visual acuity (BCVA) at 6 months compared with patients receiving sham injections.  In the BRAVO study, the percentage of patients in the ranibizumab 0.5 mg study arm who gained 15 or more letters in BCVA from baseline at month 6 was 61 % (compared with 29 % in the sham injection arm).  In the CRUISE study, the percentage of patients in the ranibizumab 0.5 mg study arm who gained 15 or more letters in BCVA from baseline at month 6 was 48 % (compared with 17 % in the sham injection arm).  At month 6, patients in BRAVO who received 0.5 mg of ranibizumab had a mean gain of 18.3 letters (compared to 7.3 letters in patients receiving sham injections).  In the CRUISE study, at month 6, patients who received 0.5 mg of ranibizumab had a mean gain of 14.9 letters (compared to 0.8 letters for patients receiving sham injections).

Available evidence indicates that anti-VEGF therapy with either ranibizumab or bevacizumab plays an important role in the management of diabetic macular edema.  An NIH-sponsored, multi-center, randomized clinical trial demonstrated that ranibizumab in combination with macular laser photocoagulation is superior to macular laser photocoagulation alone at 12 months of follow-up (Diabetic Retinopathy Clinical Research Network, 2010).  The need for re-treatment was determined by retinal thickness as measured by optical coherence tomography (OCT) and visual acuity.  The 1-year mean change in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9, p < 0.001) and ranibizumab + deferred laser group (+9, p < 0.001) but not in the triamcinolone + prompt laser group (+4, p = 0.31) compared with the sham + prompt laser group (+3).  Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula.

A second single-center, randomized clinical trial also demonstrated that intravitreal injection of bevacizumab every 6 weeks based on clinical response determined by OCT and visual acuity is superior to macular photocoagulation every 4 months (Michaelides et al, 2010).  The authors reported the odds of gaining greater than or equal to 10 ETDRS letters over 12 months were 5.1 times greater in the bevacizumab group than in the laser group (adjusted odds ratio, 5.1; 95 % confidence interval [CI]: 1.3 to 19.7; p = 0.019).

Ciulla and Rosenfeld (2009) stated that anti-VEGF treatments that arrest choroidal angiogenesis and reduce vascular permeability have revolutionized clinical practices for neovascular eye diseases.  These researchers reviewed anti-VEGF therapies that are being evaluated in ocular diseases, other than neovascular AMD, in which neovascularization plays a critical role in pathogenesis.  Early studies of the anti-VEGF agents, pegaptanib sodium, ranibizumab, bevacizumab, VEGF trap, and bevasiranib in the treatment of various neovascular diseases (e.g., diabetic macular edema, retinal vein occlusion, choroidal neovascularization) have shown promising results.  The efficacy and safety of these agents, either alone or combined with standard treatments (e.g., laser photocoagulation), anti-inflammatory agents, or other non-VEGF-based anti-angiogenic therapies, was actively investigated.  Non-VEGF-driven pathways and growth factors other than VEGF may play important roles in pathogenesis and are included in certain combination therapies with VEGF inhibitors.  The authors concluded that the discovery of VEGF-A's role in the pathogenesis of neovascular ocular disease provided a strong rationale for the development of anti-VEGF-based therapies.  There is now ample evidence that anti-VEGF therapies are viable treatment options for these diseases.  Nevertheless, large, randomized controlled trials are still needed to confirm early safety and efficacy findings from small, open-label prospective studies.

Rodriguez-Fontal et al (2009) stated that ranibizumab is a Fab-Antibody with high affinity for VEGF, and is being designed to bind to all VEGF isoforms.  This quality makes it a powerful drug for VEGF inhibition.  Diseases of retinal and choroidal blood vessels are the most prevalent causes of moderate and severe vision loss in developed countries.  Vascular endothelial growth factor plays a critical role in the pathogenesis of many of these diseases.  Results of the pilot studies showed that intra-ocular injections of ranibizumab decrease the mean retinal thickness and improve the best corrected visual acuity in all the subjects.  Proliferative diabetic retinopathy, currently treated with destructive laser photocoagulation, represents another potential target for anti-VEGF therapy.  The early experience in animal models with proliferative retinopathy and neovascular glaucoma shows that posterior and anterior neovascularizations are very sensitive to anti-VEGF therapy. The outcome of 2 phase III clinical trials will increase the knowledge of the role of ranibizumab in the treatment of diabetic macular edema.

In a phase IIIb, multi-center, 12-month, randomized core study and 24-month open-label extension study, Schmidt-Erfurth et al (2014) evaluated long-term efficacy and safety profiles during 3 years of individualized ranibizumab treatment in patients with visual impairment due to DME.  Of the 303 patients who completed the randomized RESTORE 12-month core study, 240 entered the extension study.  In the extension study, patients were eligible to receive individualized ranibizumab treatment as of month 12 guided by BCVA and disease progression criteria at the investigators' discretion.  Concomitant laser treatment was allowed according to the ETDRS guidelines.  Based on the treatments received in the core study, the extension study groups were referred to as prior ranibizumab, prior ranibizumab + laser, and laser.  Main outcome measures were change in BCVA and incidence of ocular and non-ocular AEs over 3 years.  Overall, 208 patients (86.7 %) completed the extension study.  In patients treated with ranibizumab during the core study, consecutive individualized ranibizumab treatment during the extension study led to an overall maintenance of BCVA and central retinal subfield thickness (CRST) observed at month 12 over the 2-year extension study (+8.0 letters, -142.1 μm [prior ranibizumab] and +6.7 letters, -145.9 μm [prior ranibizumab + laser] from baseline at month 36) with a median of 6.0 injections (mean, 6.8 injections; prior ranibizumab) and 4.0 (mean, 6.0 injections; prior ranibizumab + laser).  In the prior laser group, a progressive BCVA improvement (+6.0 letters) and CRST reduction (-142.7 μm) at month 36 were observed after allowing ranibizumab during the extension study, with a median of 4.0 injections (mean, 6.5 injections) from months 12 to 35.  Patients in all 3 treatment groups received a mean of less than 3 injections in the final year.  No cases of endophthalmitis, retinal tear, or retinal detachment were reported.  The most frequently reported ocular and non-ocular AEs over 3 years were cataract (16.3 %) and nasopharyngitis (23.3 %); 8 deaths were reported during the extension study, but none was suspected to be related to the study drug/procedure.  The authors concluded that ranibizumab was effective in improving and maintaining BCVA and CRST outcomes with a progressively declining number of injections over 3 years of individualized dosing.  Ranibizumab was generally well-tolerated with no new safety concerns over 3 years.

The main drawbacks of this study included (i) patients with stroke and transient ischemic attack were excluded from this study in contrast to the real-life setting where there is a possibility that a more diverse patient population with multiple co-morbid conditions would receive ranibizumab therapy.  Thus, the safety results of this study should be interpreted relative to this exclusion; and (ii) this extension study was not powered to evaluate the occurrence of infrequent but important severe AEs, including systemic events (e.g., stroke).  Furthermore, the authors stated that long-term studies such as LUMINOUS conducted in a broad patient population will help to further describe the long-term safety profile, effectiveness, and treatment patterns of ranibizumab in a real-life setting.

Neovascular glaucoma is a severe, blinding consequence of ocular ischemia.  Rubeosis (neovascularization of the iris) develops followed by the onset of neovascular glaucoma once the angle structures are involved.  The natural history of the disease is progressive, and may ultimately result in blindness.  All cases of rubeosis and neovascular glaucoma require treatment of the underlying condition which caused the retinal ischemia, most often with panretinal photocoagulation (Sivak-Callcott et al, 2001).  The onset of the beneficial effect of panretinal photocoagulation takes approximately 3 weeks after treatment to be evident.  In patients with fulminant neovascular glaucoma where sight-threatening elevated intraocular pressure is present, treatment involves providing panretinal photocoagulation, or panretinal cryotherapy when the retina is not visible, followed by glaucoma filtration surgery, preferably waiting several weeks for the neovascularization to regress before the filter surgery (Allen et al, 1982).  Florid neovascularization that is visible at presentation will slowly regress after panretinal photocoagulation, eventually positively influencing the outcome and reducing the complication rate of filtration surgery.  However, during the several weeks waiting for an effect, the patient is at great risk for losing further vision due to glaucoma.  For those eyes that have rubeosis with only minimal involvement of the anterior chamber angle withe neovascularization, intravitreal bevacizumab may be able to prevent further progression by hastening the regression of neovascularization.  Case series have demonstrated that intravitreal bevacizumab will cause the intraocular pressure to drop rapidly.  In order to preserve the effect, panretinal photocoagulation must still be performed, but the rapidity with which intravitreal bevacizumab acts in days may save substantial visual function.  There is currently substantial published literature documenting the positive effect of bevacizumab-induced regression of anterior segment neovascularization and positive influences on the outcome of glaucoma surgery when it is necessary.  This adjuvant use of intravitreal bevacizumab is not a repeated, long-term therapy to treat neovascular glaucoma; rather, it is used as a bridge to create a more favorable intraocular environment for further treatment of the neovascular glaucoma with other modalities like panretinal photocoagulation and filtration surgery.  Concerns about intraocular pressure spikes and resulting secondary ischemia from intravitreal bevacizumab are outweighed by the need for prompt treatment of progressive ischemia from neovascular glaucoma.

Intravitreal bevacizumab is one form of treatment for rare causes of choroidal neovascularization such as degenerative myopia, idiopathic, angioid streaks, trauma, choroiditis and retinal dystrophies.  Because these are rare conditions, it is not possible to perform definitive clinical trials.  These diseases are characterized by a subretinal neovascular process which is similar to that seen in neovascular age-related macular degeneration.  Therefore, there is strong biologic plausibility that intravitreal bevacizumab may be effective in these conditions.  For these conditions, intravitreal bevacizumab would be indicated in persons with visual loss due to the presence of active choroidal neovascular as seen on fluorescein angiography or ocular coherence tomography.

In a pilot study, Lo Giudice et al (2009) evaluated the efficacy of single-session PDT combined with intra-vitreal bevacizumab (IVB) in the treatment of retinal angiomatous proliferation (RAP) in age-related macular degeneration.  A total of 8 patients with RAP underwent indocyanine green angiography (ICGA)-guided single-session verteporfin PDT followed by IVB (1.25 mg) within a 0-day +/- 1-day interval.  All patients were naïve to treatment.  Best-corrected visual acuity, fluorescein angiography, ICGA, and OCT were performed at baseline and at each follow-up visit.  All patients received 3 consecutive monthly IVB injections; thereafter, retreatment with bevacizumab was performed in the case of worsening BCVA or a deterioration of angiographic or OCT findings.  All patients had 9 months of follow-up.  Complete resolution of angiographical leakage was achieved in all eyes at 9 months.  A significant improvement in the mean BCVA was observed at 1 month, 3 months, 6 months, and 9 months after combined treatment (p = 0.004).  Visual acuity improved in 62.5 % and was stable in 37.5 % of cases.  No patients had a decrease in BCVA of 3 or more lines during follow-up.  Mean central macular thickness was significantly reduced in all patients (p < 0.0001) as controlled at 1-month, 3-month, 6-month, and 9-month intervals from initial treatment.  The mean number of injections for the 9 months were 3.2 +/- 0.4.  No ocular complications or systemic events developed.  The authors concluded that sequenced combined treatment with single-session PDT and IVB injections may be useful in treating RAP, reducing or eliminating retinal edema, and improving or stabilizing visual acuity.  They stated that further investigations are warranted to outline the appropriate treatment paradigm for combination therapy.

Mennel et al (2010) reported a case of retinal juxtapapillary capillary hemangioma causing consecutive leakage with macular involvement.  The tumor was treated with a combination of anti-VEGF and PDT and was followed for 1 year.  A 44-year-old woman with retinal juxtapapillary capillary hemangioma in the right eye experienced a decrease of visual acuity from 20/20 to 20/60 because of a severe leakage from the tumor involving the macula with lipid depositions.  Two sessions of PDT (sparing the part of the hemangioma located within the optic disc) and 5 injections of bevacizumab were applied in a period of 5 months.  Visual acuity, visual field testing, retinal thickness measurements, fundus photography and fluorescein angiography were performed to evaluate the treatment effect.  One year after the last injection, visual acuity increased to 20/40.  All lipid exudates at the posterior pole resolved.  Retinal thickness decreased from 490 to 150 microm with the restoration of normal central macular architecture.  Leakage in fluorescence angiography reduced significantly, but hyper-fluorescence of the tumor was still evident.  Visual field testing and angiography did not show any treatment-related vaso-occlusive side-effects.  The authors concluded that in this single case, the combination of anti-VEGF and PDT appeared to be an effective strategy for the treatment of retinal juxtapapillary capillary hemangioma without side-effects.  The authors stated that further studies with a greater number of eyes and adequate follow-up are necessary to support these first clinical results.

Nicholson and Schachat (2010) stated that diabetic retinopathy (DR) is a leading cause of vision loss in the working-age population worldwide.  Many observational and pre-clinical studies have implicated VEGF in the pathogenesis of DR, and recent successes with anti-VEGF therapy for AMD have prompted research into the application of anti-VEGF drugs to DR.  These researchers reviewed the early studies that suggested a potential role for anti-VEGF agents in the management of DR.  The authors concluded that for DME, phase II trials of intra-vitreal pegaptanib and intra-vitreal ranibizumab have shown short-term benefit in visual acuity.  Intra-vitreal bevacizumab also has been shown to have beneficial short-term effects on both VA and retinal thickness.  For proliferative diabetic retinopathy (PDR), early studies suggest that intra-vitreal bevacizumab temporarily decreases leakage from diabetic neovascular lesions, but this treatment may be associated with tractional retinal detachment (TRD).  Furthermore, several studies indicated that bevacizumab is likely to prove a helpful adjunct to diabetic pars plana vitrectomy (PPV) for TRD.  Finally, 3 small series suggested a potential beneficial effect of a single dose of bevacizumab to prevent worsening of DME after cataract surgery.  Use of anti-VEGF medications for any of these indications is off-label.  These investigators stated that despite promising early reports on the safety of these medications, they eagerly await the results of large, controlled trials to substantiate the safety and efficacy of anti-VEGF drugs for DR.

Boscia (2010) noted that DR is a major cause of blindness in Europe and North America, and the incidence is expected to increase in parallel with the rising incidence of diabetes mellitus.  Boscia reviewed the current state of knowledge of the epidemiology, clinical presentation and pathophysiology of DR and its principal associated complications, DME and neovascularization, and then proceeded to the primary focus of clinical management.  A series of major randomized controlled trials conducted over the past few decades has confirmed that tight glycemic regulation is the most effective measure to reduce the risk of developing DR and to minimize the likelihood of its progression, and that control of blood pressure is also an important feature of preventive management.  Laser-based therapies remain the cornerstone of treatment, with pan-retinal photocoagulation indicated for PDR and severe non-PDR and focal photocoagulation indicated for treatment of DME.  For patients who do not benefit from these approaches, vitrectomy may provide therapeutic benefits.  Medical therapies include 2 broad classes of agents: anti-inflammatory drugs and agents with molecular targets.  The utility of oral anti-inflammatory drugs remains to be established, as dose-finding studies have yet to provide definitive conclusions.  Intra-vitreal corticosteroids may be of value in specific circumstances, although adverse effects include cataract progression and elevated IOP.  However, these complications appear to have been limited with new extended-release technologies.  With respect to molecular targets, evidence has been adduced for the roles of VEGF, tumor necrosis factor (TNF)-alpha and protein kinase C (PKC)-beta2 in the pathogenesis of DR, and agents targeting these factors are under intense investigation.  Preliminary efficacy of pegaptanib and ranibizumab in the treatment of DME is being confirmed in additional clinical trials with these agents and with the off-label use of bevacizumab, another monoclonal antibody related to ranibizumab.  Moreover, other agents targeting VEGF, as well as drugs directed against TNF-alpha and PKC-beta2, are under study.  Evaluation of the ultimate utility of these approaches will await the safety and effectiveness results of properly designed phase III trials.

In a review on diabetic retinopathy, Cheung and colleagues (2010) stated that although anti-VEGF therapy has promising clinical applications for management of DR, its long-term safety in patients with diabetes has not yet been established.  Moreover, Elman and associates (2011) stated that further investigation is needed to ascertain the role of anti-VEGF drugs in the prevention or treatment of PDR.

Waisbourd et al (2011) summarized the latest developments in the treatment of DR with anti-VEGF drugs.  These researchers reviewed recent studies that evaluated the role of the anti-VEGF agents bevacizumab, ranibizumab and pegaptanib in the treatment of DR.  There was only 1 large randomized controlled trial that evaluated the role of ranibizumab in DME.  Other prospective and retrospective studies provided important insight into the role of anti-VEGF drugs in DR, but most of them were not conducted in large scales.  The growing evidence indicates that anti-VEGF drugs are beneficial in DR, especially in DME.  The authors concluded that further studies are needed to fully evaluate the role of these agents, especially in PDR and in DR candidates for vitrectomy surgery.

Ishikawa et al (2009) evaluated the safety and effectiveness of IVB as a pretreatment of vitrectomy for severe proliferative diabetic retinopathy (PDR).  A total of 8 eyes of 6 patients (33 to 64 years old, all male subjects) with severe PDR were investigated.  An intra-vitreal injection of 1.25 mg bevacizumab was carried out 3 to 30 days before planned vitrectomy.  All cases showed minimum bleeding during surgical dissection of fibro-vascular membrane.  Two cases receiving bevacizumab 7 days before the surgery showed strong fibrosis and adhesion of fibro-vascular membrane, resulted in some surgical complications.  The cases having IVB for shorter time did not show extensive fibrosis.  The authors concluded that pre-treatment of bevacizumab is likely effective in the vitrectomy for severe PDR.  The appropriate timing of vitrectomy after bevacizumab injection should be further evaluated.

In a prospective, comparative case series, El-Sabagh and colleagues (2011) evaluated the effects of intervals between pre-operative IVB and surgery on the components of removed diabetic fibro-vascular proliferative membranes.  A total of 52 eyes of 49 patients with active diabetic fibro-vascular proliferation with complications necessitating vitrectomy were included in this study.  Participant eyes that had IVB were divided into 8 groups in which vitreo-retinal surgery was performed at days 1, 3, 5, 7, 10, 15, 20, and 30 post-injection.  A group of eyes with the same diagnosis and surgical intervention without IVB injection was used for comparison.  In all eyes, proliferative membrane specimens obtained during vitrectomy were sent for histopathologic examination using hematoxylin-eosin stain, immunohistochemistry (CD34 and smooth muscle actin), and Masson's trichrome stain.  Main outcome measure was comparative analysis of different components of the fibro-vascular proliferation (CD34, smooth muscle actin, and collagen) among the study groups.  Pan-endothelial marker CD34 expression levels starting from day 5 post-injection were significantly less than in the control group (p < 0.001), with minimum expression (1+) in all specimens removed at or after day 30 post-injection.  Positive staining for smooth muscle actin was barely detected in the control eyes at day 1, and consistently intense at day 15 and beyond (p < 0.001).  The expression level of trichrome staining was significantly high at day 10, compared with control eyes (p < 0.001), and continued to increase at subsequent surgical time points.  The author concluded that a pro-fibrotic switch was observed in diabetic fibro-vascular proliferation after IVB, and these findings suggest that at approximately 10 days post-IVB the vascular component of proliferation is markedly reduced, whereas the contractile components (smooth muscle actin and collagen) are not yet abundant.  Moreover, the authors noted that their histologic findings are in agreement with many published clinical findings and might be predictive of an optimal time interval for the pre-operative use of adjunctive IVB, which makes surgery more successful with less intra-operative bleeding and complications; thus resulting in better visual outcomes.  However, such favorable outcomes need validation from large-scale clinical studies.

In a comparative, retrospective case series, Fong et al (2010) compared VA outcomes after bevacizumab or ranibizumab treatment for AMD.  These researchers followed 452 patients in a retrospective study of exudative AMD treated with anti-VEGF drugs; 324 patients were treated with bevacizumab and 128 patients with ranibizumab.  All treatment-naive patients who received either bevacizumab or ranibizumab were followed for 1 year.  Baseline characteristics and VA were recorded using standard descriptive statistics.  Main outcome measure was VA.  At 12 months, the distribution of VA improved in both groups with 22.9 % of bevacizumab and 25.0 % of ranibizumab attaining greate than or equal to 20/40.  Improvement in vision was observed in 27.3 % of the bevacizumab group and 20.2 % of the ranibizumab group.  The mean number of injections at 12 months was 4.4 for bevacizumab and 6.2 for ranibizumab.  There were 8 (2 %) deaths in the bevacizumab group and 4 (3 %) in the ranibizumab group.  Two patients developed endophthalmitis in the bevacizumab group and the ranibizumab group.  The bevacizumab group had slightly worse acuity at baseline, but both groups showed improvement and stability of vision over time.  The authors concluded that both treatments seem to be effective in stabilizing VA loss.  There was no difference in VA outcome between the 2 treatment groups.  Because the study is a non-randomized comparison, selection bias could mask a true treatment difference.  Results from the Comparison of the Age-related Macular Degeneration Treatment Trials (CATT) will provide more definitive information about the comparative effectiveness of these drugs.

In a multi-center, single-blind, non-inferiority trial, Martin and colleagues/the CATT Research Group (2011) randomly assigned 1,208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation.  The primary outcome was the mean change in VA at 1 year, with a non-inferiority limit of 5 letters on the eye chart.  Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively.  Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively.  Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive.  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).  Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (p > 0.20).  The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1 % versus 19.0 %; risk ratio, 1.29; 95 % confidence interval [CI]: 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.  The authors concluded that at 1 year, bevacizumab and ranibizumab had equivalent effects on VA when administered according to the same schedule.  Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly.  Differences in rates of serious adverse events require further study.

In an editorial that accompanied the afore-mentioned study, Rosenfeld (2011) stated that "The CATT results, together with the totality of global experience, support the use of either bevacizumab or ranibizumab for the treatment of neovascular AMD ... The CATT data support the continued global use of intravitreal bevacizumab as an effective, low-cost alternative to ranibizumab".

Schmucker and associates (2011) performed a systematic review to compare adverse effects (AE) and the reporting of harm in randomized controlled trials (RCTs) and non-RCTs evaluating intravitreal ranibizumab and bevacizumab in AMD.  Medline, Embase and the Cochrane Library were searched with no limitations of language and year of publication.  Studies which compared bevacizumab or ranibizumab as monotherapy with any other control group were included.  Case series were included if they met pre-defined quality standards. The results of phase III trials evaluating ranibizumab showed that the rates of serious ocular AE were low (less than or equal to 2.1 %) but indicated major safety concerns (RR 3.13, 95 % CI: 1.10 to 8.92).  A possible signal with regard to thrombo-embolic events (RR 1.35, 95 % CI: 0.66 to 2.77) and a significant increase in non-ocular hemorrhage (RR 1.62, 95 % CI: 1.03 to 2.55) were also noted.  In contrast to ranibizumab trials, the RCTs evaluating bevacizumab were of limited value.  The main shortcomings are small sample sizes and an apparent lack of rigorous monitoring for AE.  A critical assessment of the large number of published case series evaluating bevacizumab also showed that no reliable conclusions on safety can be drawn using this study design.  Therefore, any perception that intravitreal bevacizumab injections are not associated with major ocular or systemic AE are not supported by reliable data.  The authors concluded that bevacizumab studies showed too many methodological limitations to rule out any major safety concerns.  Higher evidence from ranibizumab trials suggested signals for an increased ocular and systemic vascular and hemorrhagic risk that warrants further investigation.

Mintz-Hittner et al (2011) stated that retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide.  Peripheral retinal ablation with conventional (confluent) laser therapy is destructive, causes complications, and does not prevent all vision loss, especially in cases of retinopathy of prematurity affecting zone I of the eye.  Case series in which patients were treated with VEGF inhibitors suggested that these agents may be useful in treating ROP.  These researchers conducted a prospective, controlled, randomized, stratified, multi-center trial to assess IVB monotherapy for zone I or zone II posterior stage 3+ (i.e., stage 3 with plus disease) ROP.  Infants were randomly assigned to receive IVB (0.625 mg in 0.025 ml of solution) or conventional laser therapy, bilaterally.  The primary ocular outcome was recurrence of ROP in 1 or both eyes requiring re-treatment before 54 weeks' post-menstrual age.  These investigators enrolled 150 infants (total sample of 300 eyes); 143 infants survived to 54 weeks' post-menstrual age, and the 7 infants who died were not included in the primary-outcome analyses.  Retinopathy of prematurity recurred in 4 infants in the IVB group (6 of 140 eyes [4 %]) and 19 infants in the laser-therapy group (32 of 146 eyes [22 %], p = 0.002).  A significant treatment effect was found for zone I ROP (p = 0.003) but not for zone II disease (p = 0.27).  The authors concluded that IVB monotherapy, as compared with conventional laser therapy, in infants with stage 3+ ROP showed a significant benefit for zone I but not zone II disease.  Development of peripheral retinal vessels continued after treatment with IVB, but conventional laser therapy led to permanent destruction of the peripheral retina.

Dani et al (2012) reported the preliminary findings in 7 premature infants with complicated ROP or aggressive posterior ROP (APROP) who were treated with IVB as first line monotherapy or rescue therapy combined with laser treatment.  These researchers studied retrospectively 7 preterm infants, who were affected by APROP (n = 4) or pre-threshold ROP (n = 3).  Infants were treated with IVB (0.625 mg; Avastin) monotherapy (n = 2) when they were too sick to undergo lengthy laser treatment.  Monotherapy IVB (n = 3 eyes) and IVB combined with laser therapy (n = 3 eyes) of APROP cases were followed by regression of the ROP and complete peripheral vascularization.  The combined therapy with IVB and laser therapy of pre-threshold ROP (5 eyes) produced a regression of neovascularization and good retinal anatomical outcome.  The authors concluded that in this series, IVB was successful in treating ROP in a small cohort of extremely preterm infants with APROP or pre-threshold ROP, both as monotherapy or rescue treatment after laser therapy, without the development of ocular and systemic short- and long-term adverse effects.

Choovuthayakorn and Ubonrat (2012) reported the effectiveness of IVB injection for advanced ROP patients.  A retrospective chart review was performed for 19 advanced ROP patients (34 eyes), who had IVB injection between January 1, 2007 and July 31, 2009.  The baseline characteristics including gestational age, post-menstrual age of first injection, anterior and posterior segment changes, and complications between treatments to 1-year followed-up were analyzed.  The patients were divided into 2 groups according to the indications for treatment.  Group 1 -- 2 patients (4 eyes), received initial IVB injection followed by laser photocoagulation due to APROP.  Group 2 -- 17 patients (30 eyes), received IVB injection due to persistence of the vascular activity after laser treatment.  There were statistical significant difference between the 2 groups in terms of a mean gestation age, a mean birth weight, and a mean time for first intra-vitreal injection (p = 0.002, 0.008, and 0.007 respectively).  However, there was no statistical significant difference between the 2 groups in terms of timing for resolution of vascular activity and retinal vasculogenesis across the laser scar (p = 0.172).  One patient with APROP progressed to stage 4A ROP with successful anatomical attachment by pars plana vitrectomy.  At 1-year follow-up, no other ocular or systemic side effects were observed.  There was no statistical significant difference of a mean spherical equivalent between the 2 groups (p = 0.280).  The authors concluded that IVB injection is an effective procedure either as an adjuvant or initial treatment in advanced ROP cases.

Autrata et al (2012) evaluated the safety and effectiveness of intravitreal injection of pegaptanib or bevacizumab and laser photocoagulation for treatment of threshold stage 3+ ROP affecting zone I and posterior zone II, and compared the results in terms of regression, development of peripheral retinal vessels with conventional laser photocoagulation or combined with cryotherapy.  In this prospective comparative study, a total of 174 eyes of 87 premature babies, from January 2008 to December 2011, were included.  All infants were diagnosed with stage 3+ ROP for zone I or posterior II.  Patients were randomly assigned to receive intravitreal pegaptanib (0.3 mg) or bevacizumab (0.625 mg/0.025 ml of solution) with conventional diode laser photocoagulation (Group A, 92 eyes of 46 infants) or laser therapy combined with cryotherapy (Group 8, 82 eyes of 41 infants), bilaterally.  The main evaluated outcomes include time of regression and decrease of plus signs and development of peripheral retinal vessels after treatment, final structural-anatomic outcomes compared in the both groups of patients.  Risk factors and other characteristics of infants include birth weight, gestational age, Apgar score, duration of intubation and hospitalizations, post-menstrual age at treatment, sepsis, surgery for necrotizing enterocolitis, intra-ventricular hemorrhage.  Primary outcome of treatment success was defined as absence of recurrence of stage 3+ ROP in 1 or both eyes (recurrence rate = 0) by 55 weeks' post-menstrual age.  Treatment failure was defined as the recurrence of neovascularization (recurrence rate = 1 or 2) in 1 or both eyes requiring re-treatment.  The mean follow-up after treatment was 23.5 months (range of 4 to 45 months) in the Group A, and 25.2 months in the Group B (range of 3 to 48 months).  Final favorable anatomic outcome and stable regression of ROP at last control examination have 90.2 % of eyes after adjuvant intravitreal pagaptanbib or bevacizumab in the Group A, and 62 % of eyes after only conventional treatment in the Group B (p = 0.0214).  Regression of plus disease and peripheral retinal vessels development appeared significantly more rapidly in Group A patients who received intravitreal VEGF inhibitors and laser.  An absence of recurrence of neovascularization (stage 3+ ROP) was identified at 87 % of patients in the Group A, and 53 % of patients in the Group B.  This difference between the both groups was statistically significant (p = 0.0183).  Retinopathy of prematurity recurred in 7 from 92 eyes (7.6 %) in the Group A, and 23 from 82 eyes (28 %) in the group B (p = 0.0276).  Significantly better treatment effect was found for adjuvant intravitreal pagaptanib or bevacizumab with laser compared with conventional therapy of ROP 3+ in zone I and posterior zone II.  Peri-operative retinal hemorrhages after laser photocoagulation occurred in 8 % of eyes in the Group A, and 11 % of eyes in the group B (p = 0.358), in all eyes with spontaneous resorption.  No systemic or significant ocular complications of intravitreal anti-VEGF injections, such as endophthalmitis or retinal detachment were found during follow-up period after operation.  The authors concluded that a combination of intravitreal pegaptanib or bevacizumab injection and laser photocoagulation showed to be a safe, well-tolerated and effective therapy in patients with stage 3+ ROP in zone I and posterior zone II.  Adjuvant intravitreal anti-VEGF injection, as compared with conventional laser or cryotherapy, showed significant benefit in terms of better final anatomic outcome, induction of prompt regression, rapid development of peripheral retinal vascularization and decrease of recurrence rate of neovascularization.  The authors concluded that results of this study supported the administration of pegaptanib and bevacizumab as an alternative useful therapy in the management of stage 3+ ROP.

Jalali et al (2013) reported serious adverse events and long-term outcomes of initial experience with intra-ocular bevacizumab in ROP.  Consecutive vascularly active ROP cases treated with bevacizumab, in addition to laser and surgery, were analyzed retrospectively from a prospective computerized ROP database.  Primary efficacy outcome was regression of new vessels.  Secondary outcomes included the anatomic and visual status.  Serious systemic and ocular adverse events were documented.  A total of 24 ROP eyes in 13 babies, received single intra-ocular bevacizumab for severe stage 3 plus after failed laser (7 eyes), stage 4A plus (8 eyes), and stage 4B/5 plus (9 eyes).  Drug was injected intravitreally in 23 eyes and intracamerally in 1 eye.  New vessels regressed in all eyes.  Vision salvage in 14 of 24 eyes and no serious neurodevelopmental abnormalities were noted up to 60 months (mean of 30.7 months) follow-up.  Complications included macular hole and retinal breaks causing rhegmatogenous retinal detachment (1 eye); bilateral, progressive vascular attenuation, perivascular exudation and optic atrophy in 1 baby, and progression of detachment bilaterally to stage 5 in 1 baby with missed follow-up.  One baby who received intra-cameral injection developed hepatic dysfunction.  One eye of this baby also showed a large choroidal rupture.  The authors concluded that although intra-ocular bevacizumab, along with laser and surgery salvaged vision in many otherwise progressive cases of ROP, vigilance and reporting of serious adverse events is essential for future rationalized use of the drug.  These researchers reported 1 systemic and 4 ocular adverse events that require consideration in future use of the drug.

In a prospective, interventional, non-comparative case-study, Martinez-Castellanos et al (2013) evaluated ocular function and systemic development in premature infants treated with IVB injections for ROP over a period of 5 years.  The primary outcome measure was VA.  The secondary outcomes were structural assessment, other ocular functional measurements, and developmental state.  A total of 18 eyes of 13 consecutive patients were divided into 3 groups: Group 1, stage 4 unresponsive to previous conventional treatment (n = 4); Group 2, in which conventional treatment was difficult or impossible because of inadequate visualization of the retina (n = 5); and Group 3, newly diagnosed high-risk pre-threshold or threshold ROP (n = 9).  All patients showed initial regression of neovascularization.  One patient was diagnosed with recurrence of neovascularization and was treated with IVB.  Visual acuity was preserved, and median vision was 20/25 (excluding 2 operated eyes).  Twelve eyes developed mainly low myopia over the years, with an overall mean value of 3.2 diopters.  Electroretinography was normal in 4 eyes that had no previous detachment.  One patient showed delay in growth and neurodevelopment, whereas all the others were within the normal range.  The authors concluded that 5 years of follow-up in a small series suggested that IVB for ROP results in apparently preserved ocular function and systemic development.

In a multi-center, retrospective case series, Wu and colleagues (2013) examined the effectiveness and complications associated with the use of bevacizumab, an anti-vascular endothelial growth factor agent, in the treatment of pre-threshold ROP.  Data from patients who had received IVB injections for the treatment of ROP were collected from 4 medical centers in Taiwan.  The main outcome measures were the regression of ROP and the complications that were associated with the IVB injections.  A total of 162 eyes from 85 patients were included in the study.  After receiving IVB injections, 143 eyes (88 %) exhibited ROP regression.  Fourteen eyes (9 %) required additional laser treatment for ROP regression after the absence of a positive response to the IVB injections.  Three eyes (2 %) progressed to stage 4 ROP and required vitrectomies to re-attach the retinas.  Two eyes (1 %) received 1 additional IVB injection to decrease persistent plus disease.  All of the eyes (100 %) had attached retinas after the various treatments that they received.  The major ocular complications that were associated with IVB injections included vitreous or pre-retinal hemorrhage in 2 eyes (1 %); cataract in 1 eye (1 %); and exotropia in 1 eye (1 %).  No notable systemic complications related to the IVB injections were observed.  The authors concluded that IVB injection seems to be an effective and well-tolerated method of treating pre-threshold ROP. Laser therapy may still be required as a backup treatment for patients who do not respond to an IVB injection or for those in whom ROP worsens after an IVB injection.

In a retrospective, non-randomized, interventional comparative study, Harder et al (2013) evaluated refractive error in infants who underwent IVB injection for treatment of threshold ROP.  The study group included all infants who consecutively received a single IVB (0.375 mg or 0.625 mg) injection for therapy of threshold ROP in fundus zone I or zone II.  The control group included infants who had previously undergone retinal argon laser therapy of ROP.  The follow-up examination included refractometry under cycloplegic conditions.  The study group included 12 children (23 eyes; mean birth weight of 622 ± 153 g; gestational age of 25.2 ± 1.6 weeks) and the control group included 13 children (26 eyes; birth weight of 717 ± 197 g; gestational age of 25.3 ± 1.8 weeks).  Both groups did not differ significantly in birth age and weight and follow-up.  At the end of follow-up at 11.4 ± 2.3 months after birth, refractive error was less myopic in the study group than in the control group (-1.04 ± 4.24 diopters [median of 0 diopters] versus -4.41 ± 5.50 diopters [median of -5.50 diopters]; p = 0.02).  Prevalence of moderate myopia (17 % ± 8 % versus 54 % ± 10 %; p = 0.02; OR: 0.18 [95 % CI: 0.05, 0.68]) and high myopia (9 % ± 6 % versus 42 % ± 10 %; p = 0.01; OR: 0.13 [95 % CI: 0.03, 0.67]) was significantly lower in the bevacizumab group.  Refractive astigmatism was significantly lower in the study group (-1.0 ± 1.04 diopters versus 1.82 ± 1.41 diopters; p = 0.03).  In multi-variate analysis, myopic refractive error and astigmatism were significantly associated with laser therapy versus bevacizumab therapy (p = 0.04 and p = 0.02, respectively).  The authors concluded that in a 1-year follow-up, a single IVB injection as compared to conventional retinal laser coagulation was helpful for therapy of ROP and led to less myopization and less astigmatism.

Sahin et al (2013) evaluated the treatment outcomes of IVB injections, used as a monotherapy in type 1 ROP.  A retrospective chart review was performed for 17 type 1 ROP patients (34 eyes), who had IVB injection between July 2011 and June 2012.  Birth weight, gestational age at birth, the stage and the location of ROP, IVB injection time, the time of complete retinal vascularization, and additional treatments if needed, were noted.  Bevacizumab (0.625 mg in 0.025 ml) was injected intravitreally.  A total of 30 eyes of 17 patients with type 1 ROP were treated with IVB injection enrolled in the study.  Of them 7 had APROP, 6 had stage 2 ROP, and 4 had stage 3 ROP.  The mean gestational age was 28.44 weeks (range of 26 to 31 weeks); and the mean birth weight was 1,151.88 g (range of 600 to 1,600 g).  The mean age for IVB injection was 35.47 weeks.  The mean full retinal vascularization time was 136.6 ± 26.6 days.  The mean follow-up time was 285.3 ± 70 days.  Retinopathy of prematurity was regressed and retinal vascularization was completed in all cases except 1 eye which had threshold disease.  The authors concluded that IVB injection, used as a monotherapy, is an effective treatment approach in patients with type 1 ROP.  These investigators suggested that timely treatment of stage 2 and early stage 3 ROP cases in which disease progression was observed prevents vitreo-retinal membrane formation in posterior disease.

Kim et al (2014) examined the anatomical outcome of combined IVB injection and zone I sparing laser ablation in patients with type 1 ROP in zone I.  The medical records of consecutive 18 eyes of 10 infants, who underwent combined IVB (0.25 mg) injection and zone I sparing laser ablation for the treatment of type 1 ROP in zone I, were retrospectively reviewed.  Laser photocoagulation was performed on the avascular retina anterior to the margin of zone I extending to the ora serrata.  Anatomical outcomes including progression to stage 4/5, macular changes, and vitreous organization were reviewed.  The mean gestational age at birth and the birth weight of included patients were 24.0 weeks and 628 g, respectively.  The timing of IVB injection ranged from post-menstrual age 33 to 35 weeks (mean of 34.3 weeks).  Post-menstrual age at last follow-up ranged from 74 to 107 weeks (mean of 83.6 weeks).  All 18 eyes demonstrated prompt regression of neovascular pathology and plus disease without recurrence.  Previously avascular zone I retina was vascularized in all eyes after the treatment.  All eyes showed excellent anatomical outcome with intact macula, but 1 eye showed mild vitreous organization above the vascular/avascular junction.  The authors concluded that combined IVB injection and zone I sparing laser ablation for type 1 ROP in zone I seem to be effective treatment options.  Possible advantages include lower dose of anti-VEGF, less recurrence than monotherapy, and preservation of central visual field.

Also, an UpToDate review on “Retinopathy of prematurity” (Paysse, 2013) states that “Treatment consists of ablation of the peripheral avascular retina, usually by laser photocoagulation.  Bevacizumab is effective in treating some forms of severe ROP, but long-term systemic and ocular outcomes are unknown”.

Orozco-Gomez et al (2011) evaluated the effectiveness of combined laser-ranibizumab therapy for ROP with threshold-prethreshold and "plus disease" and studied development of the newborn.  This was a prospective, experimental, longitudinal and open study including newborns of either less than 32 weeks of gestation or with a birth weight less than 1,500 g, with threshold-prethreshold retinopathy or "plus disease".  The effect of treatment was analyzed and development of the newborn was determined.  These investigators studied 34 eyes of 17 patients.  Age at birth was 29.9 ± 2.6 weeks.  Birth weight was 1,120 ± 253 g.  The statistics demonstrated an important relationship between severity of retinopathy and early birth age, along with a high probability of threshold-prethreshold disease at 29.4 weeks of age or 1,204 g birth weight.  The Bayley scale reported normal development in 23.5 % of cases, global retardation in 23.5 %, psychomotor retardation but normal mental behavior in 29.4 %, and mental retardation but normal psychomotor development in 23.5 %.  These researchers demonstrated regression of retinopathy in all cases.  Persistence of vascular tortuosity was present in 17.6 % of cases without vascular dilatation, and vitreous membrane development was demonstrated in 11.7 % of patients.  The authors concluded that laser-ranibizumab treatment has allowed a better control of retinopathy for threshold-prethreshold and "plus disease" in this group of patients.

Lin et al (2012) reported the effects of intravitreal ranibizumab as salvage therapy in an extremely low-birth-weight (ELBW) infant with rush type ROP. This case was a girl of 23 weeks gestational age weighing 480 g at birth.  At a post-conceptual age of 33 weeks, she presented with zone 1, stage 3 ROP with plus disease.  Despite intravitreal bevacizumab and laser photocoagulation, extra-retinal fibro-vascular proliferation persisted.  Intravitreal 0.25 mg (0.025 ml) ranibizumab was injected OU.  After treatment, extra-retinal fibro-vascular proliferation disappeared.  Fundus examination showed flat retinas and normal vasculature in both eyes.  She has been followed-up for 2 years.  Intravitreal ranibizumab injection seems effective and well-tolerated as salvage therapy in an ELBW infant with rush type ROP.  No short-term ocular or systemic side effects were identified.  The authors concluded that more cases and longer follow-up are mandatory.

Mota et al (2012) reported on 2 cases of APROP) treated with intravitreal ranibizumab and laser photocoagulation.  Two premature females, born at 25 and 26 weeks' gestation with a birth weight of 530 and 550 g, respectively, with AP ROP received combined treatment with laser photocoagulation and intravitreal ranibizumab (0.3 mg [30 µl]) to each eye.  Structural outcomes were evaluated by indirect ophthalmoscopy and documented by retinography.  An intravitreal injection was made at 34 weeks of post-menstrual age in the first case, followed by laser photocoagulation 1 week later.  There was a partial regression of ROP with treatment.  Five weeks later, neovascularization regrowth with bleeding in both eyes (intraretinal and subhyaloid) occurred and re-treatment with combined therapy was performed.  In the second case, single therapy with laser photocoagulation was made at 34 weeks of post-menstrual age.  In spite of the confluent photocoagulation in the avascular area, progression to 4A ROP stage occurred 1 week later.  Both eyes were re-treated 1 week later with intravitreal ranibizumab and laser photocoagulation.  Treatment resulted in ROP regression in both cases.  There were no signs of systemic or ocular adverse side effects.  The authors concluded that these 2 cases showed that combination therapy of indirect laser photocoagulation and intravitreal ranibizumab can be effective in the management of AP ROP.  They stated that further investigation on anti-VEGF safety in premature infants is necessary.

In an interventional case-series study, Castellanos et al (2013) evaluated ocular outcome in premature infants treated with intravitreal ranibizumab injections for ROP over a period of 3 years.  Premature infants with high-risk prethreshold or threshold ROP with plus disease received an off-label monotherapy with intravitreal injections of ranibizumab.  The primary outcome was treatment success defined as regression of neovascularization (NV) and absence of recurrence.  The secondary outcomes were ocular and systemic adverse events and VA.  A total of 6 eyes were included in the study and treated with intravitreal injections of ranibizumab.  All showed complete resolution of NV after a single injection.  The anti-angiogenic intravitreal injections allowed for continued normal vessel growth into the peripheral retina, without any signs of disease recurrence or progression during the follow-up period.  No ocular or systemic adverse effects were observed.  The authors concluded that 3 years of follow-up in a small series suggested that intravitreal ranibizumab injections for ROP result in apparently preserved ocular outcome.  Moreover, they stated that further large scale studies are needed to address the long-term safety and effectiveness.

Aflibercept, also known as VEGF Trap-Eye, is a highly potent blocker of VEGF and placental growth factor.  It is a fully human fusion protein consisting of portions of VEGF receptors 1 and 2, which binds all forms of VEGF-A, along with the related placental growth factor, which the drug blocks.

In a multi-center, randomized, double-masked study, Heier et al (2011) evaluated anatomic outcomes and vision, injection frequency, and safety during the as-needed (PRN) treatment phase of a study evaluating a 12-week fixed dosing period followed by PRN dosing to week 52 with VEGF Trap-Eye for neovascular (wet) AMD.  A total of 159 patients with subfoveal choroidal neovascularization (CNV) secondary to wet AMD were included in this study.  Patients were randomly assigned to 1 of 5 intra-vitreal VEGF Trap-Eye treatment groups: 0.5 mg or 2 mg every 4 weeks or 0.5, 2, or 4 mg every 12 weeks during the fixed-dosing period (weeks 1 to 12).  From weeks 16 to 52, patients were evaluated monthly and were retreated PRN with their assigned dose (0.5, 2, or 4 mg).  Main outcome measures included change in central retinal/lesion thickness (CR/LT), change in total lesion and CNV size, mean change in BCVA, proportion of patients with 15-letter loss or gain, time to first PRN injection, re-injection frequency, and safety at week 52.  The decrease in CR/LT at week 12 versus baseline remained significant at weeks 12 to 52 (-130 μm from baseline at week 52) and CNV size regressed from baseline by 2.21 mm(2) at 48 weeks.  After achieving a significant improvement in BCVA during the 12-week, fixed-dosing phase for all groups combined, PRN dosing for 40 weeks maintained improvements in BCVA to 52 weeks (5.3-letter gain; p < 0.0001).  The most robust improvements and consistent maintenance of VA generally occurred in patients initially dosed with 2 mg every 4 weeks for 12 weeks, demonstrating a gain of 9 letters at 52 weeks.  Overall, a mean of 2 injections was administered after the 12-week fixed-dosing phase, and the mean time to first re-injection was 129 days; 19 % of patients received no injections and 45 % received 1 or 2 injections.  Treatment with VEGF Trap-Eye was generally safe and well-tolerated, with few ocular or systemic AEs.  The authors concluded that PRN dosing with VEGF Trap-Eye at weeks 16 to 52 maintained the significant anatomic and vision improvements established during the 12-week fixed-dosing phase with a low frequency of re-injections.  Repeated dosing with VEGF Trap-Eye was well-tolerated over 52 weeks of treatment.

On November 18, 2011, the FDA approved aflibercept ophthalmic solution (Eylea, Regeneron Pharmaceuticals Inc.) for the treatment of neovascular (wet) AMD.  The FDA's approval of Eylea was based on positive results from the 2 phase III VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) trials.  Both found the drug non-inferior to ranibizumab, which is currently the most potent FDA-approved treatment option for wet AMD.  In VIEW 1 (n = 1,217), conducted in the United States, and VIEW 2 (n = 1,240), conducted in Europe, all regimens of the drug, including 2 mg dosed every 2 months (after 3 loading doses), successfully met the primary endpoint of statistical non-inferiority compared with ranibizumab.  The proportions of patients who maintained or improved vision over the course of 52 weeks in VIEW 1 were 96 %, 95 %, and 95 % of patients receiving aflibercept 0.5 mg monthly, 2.0 mg monthly, and 2.0 mg every 2 months, respectively.  This compared with 94 % of patients receiving the standard 0.5-mg monthly dose of ranibizumab.  For the secondary endpoint, visual acuity, the new drug was better.  Patients receiving 2 mg monthly had a greater mean improvement in visual acuity at week 52, with a gain of 10.9 letters compared with 8.1 letters with ranibizumab (p < 0.01).  All other dose groups were not significantly different from ranibizumab with respect to this secondary endpoint.  In VIEW 2, vision was maintained in 96 % of all aflibercept dose groups and in 94 % of the ranibizumab group.  All doses were statistically non-inferior to ranibizumab, and no differences were noted between the drugs in visual acuity gain.

The most commonly reported AEs in patients receiving aflibercept included eye pain, conjunctival hemorrhage, vitreous floaters, cataract, and an increase in eye pressure.  Aflibercept should not be used in those who have an active eye infection or active ocular inflammation.  It has not been studied in pregnant women, so the treatment should be used only in pregnant women if the potential benefits of the treatment outweigh any potential risks.  Age-related macular degeneration does not occur in children and aflibercept has not been studied in children.  The recommended dose is 2 mg every 4 weeks (monthly) for the first 12 weeks, followed by 2 mg every 8 weeks (2 months).

In September of 2012 the FDA approved aflibercept injection (Eylea) for use in macular edema following central retinal vein occlusion (CRVO).  Boyer et al (2012) conducted a multi-center, randomized, prospective, controlled trial to assess the efficacy and safety of intravitreal VEGF Trap-Eye in eyes with macular edema secondary to CRV. A total of 189 eyes with macular edema secondary to CRVO were included in this study.  Eyes were randomized 3:2 to receive VEGF Trap-Eye 2 mg or sham injection monthly for 6 months.  At week 24, 56.1 % of VEGF Trap-Eye treated eyes gained 15 letters or more from baseline versus 12.3 % of sham-treated eyes (p < 0.001).  The VEGF Trap-Eye treated eyes gained a mean of 17.3 letters versus sham-treated eyes, which lost 4.0 letters (p < 0.001).  Central retinal thickness decreased by 457.2 µm in eyes treated with VEGF Trap-Eye versus 144.8 µm in sham-treated eyes (p < 0.001), and progression to any neovascularization occurred in 0 and 5 (6.8 %) of eyes treated with VEGF Trap-Eye and sham-treated eyes, respectively (p = 0.006).  Serious ocular AEs were reported by 3.5 % of VEGF Trap-Eye patients and 13.5 % of sham patients while incidences of non-ocular serious AEs generally were well-balanced between both groups.  Conjunctival hemorrhage, reduced VA, and eye pain were the most common AEs.  The investigators concluded that at 24 weeks, monthly intra-vitreal injection of VEGF Trap-Eye 2 mg in eyes with macular edema resulting from CRVO improved VA and CRT, eliminated progression resulting from neovascularization, and was associated with a low rate of ocular AEs related to treatment.

In October 2014, the FDA approved aflibercept injection for the treatment of macular edema following retinal vein occlusion (RVO), which includes macular edema following branch retinal vein occlusion (BRVO) in addition to the previously-approved indication of macular edema following central retinal vein occlusion (CRVO) (Regeneron, 2014).  The recommended dosage of afilbercept in patients with macular edema following RVO is 2 milligrams (mg) every month (4 weeks). 

The expanded indication was based on the previously-approved indication for macular edema following CRVO and the positive results from the double-masked, randomized, controlled Phase 3 VIBRANT study of 181 patients with macular edema following BRVO (Regeneron, 2014).  The VIBRANT study compared afilbercept 2 mg once every 4 weeks with macular laser photocoagulation (control). The study continued for 52 weeks. At 24 weeks, significantly more patients treated with afilbercept gained at least 15 letters in vision (three lines on an eye chart) from baseline as measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, the primary endpoint of the study, compared with patients who received control (53 percent vs. 27 percent; P less than 0.01).  Patients treated with afilbercept achieved a 17.0 letter mean improvement over baseline in best-corrected visual acuity (BCVA) compared to a 6.9 letter mean improvement in patients who received control (P less than 0.01), a key secondary endpoint. 

The incidence of non-ocular serious adverse events (SAE) was 8.8 percent in the afilbercept group and 9.8 percent in the control group (Regeneron, 2014). One death and one Anti-Platelet Trialists' Collaboration (APTC)-defined arterial thromboembolic event (non-fatal stroke) occurred during the trial, both in patients in the control group.  The most common ocular adverse events in patients treated with afilbercept included conjunctival hemorrhage and cataract.  There were no cases of intraocular inflammation in either group.  There was one ocular SAE in a patient in the afilbercept group, which was traumatic cataract.

In June 2014, the U.S. Food and Drug Administration (FDA) approved aflibercept (Eylea) injection for the treatment of diabetic macular edema (DME) (Regeneron, 2014).  The FDA approval of afilbercept in DME was based on the one-year data from the Phase 3 VISTA-DME and VIVID-DME studies of 862 patients, which compared afilbercept 2 mg given monthly, afilbercept 2 mg given every two months (after five initial monthly injections), or macular laser photocoagulation (at baseline and then as needed).  In the DME studies, after one year, the mean changes in best corrected visual acuity (BCVA), as measured by the ETDRS chart for the monthly and every two month afilbercept groups, were statistically significantly improved compared to the control group and were similar to each other.  Across both trials, patients in both afilbercept dosing groups gained, on average, the ability to read approximately two additional lines on an eye chart compared with almost no change in the control group. The VISTA-DME and VIVID-DME studies will continue as planned for a total of three years.  

In the Phase 3 VISTA-DME and VIVID-DME trials, aflibercept injection 2 mg dosed monthly and afilbercept 2 mg dosed every two months after 5 initial monthly doses achieved statistically significant improvements in the primary endpoint of mean change in BCVA at one year and the secondary endpoint of proportion of patients who gained at least 15 letters in BCVA versus baseline compared to control (Regeneron, 2014). 

In the VISTA-DME trial, patients receiving afilbercept 2 mg monthly had a mean change from baseline in BCVA of 12.5 letters (p less than 0.01 compared to control), patients receiving afilbercept 2 mg every two months (after 5 initial monthly injections) had a mean change from baseline in BCVA of 10.7 letters (p less than 0.01 compared to control), and patients receiving control treatment had a mean change from baseline in BCVA of 0.2 letters (Regeneron, 2014).  In the VISTA-DME trial, the percentage of patients who gained at least 15 letters in BCVA from baseline, or three lines of vision, was 41.6 percent in the afilbercept 2 mg every month group (p less than 0.01 compared to control), 31.1 percent in the afilbercept 2 mg every 2 months group (after 5 initial monthly injections) (p less than 0.01 compared to control), and 7.8 percent in the control group. 

In the VIVID-DME trial, patients receiving afilbercept 2 mg monthly had a mean change from baseline in BCVA of 10.5 letters (p less than 0.01 compared to control), patients receiving afilbercept 2 mg every two months (after 5 initial monthly injections) had a mean change from baseline in BCVA of 10.7 letters (p less than 0.01 compared to control), and patients receiving control had a mean change from baseline in BCVA of 1.2 letters (Regeneron, 2014).  In the VIVID-DME trial, the percentage of patients who gained at least 15 letters in BCVA from baseline, or three lines of vision, was 32.4 percent in the afilbercept 2 mg every month group (p less than 0.01 compared to control), 33.3 percent in the afilbercept 2 mg every 2 months group (after 5 initial monthly injections) (P less than 0.01 compared to control), and 9.1 percent in the control group. 

In these trials, afilbercept had a similar overall incidence of adverse events (AEs), ocular serious AEs, and non-ocular serious AEs across treatment groups and the control group (Regeneron, 2014).  Arterial thromboembolic events as defined by the Anti-Platelet Trialists' Collaboration (non-fatal stroke, non-fatal myocardial infarction, and vascular death) also occurred at similar rates across treatment groups and the control group.  The most frequent ocular treatment emergent AEs (TEAEs) observed in the VISTA-DME and VIVID-DME trials included conjunctival hemorrhage, eye pain, cataract, and vitreous floaters.  The most common non-ocular TEAEs included hypertension and nasopharyngitis, which occurred with similar frequency in the treatment groups and the control group. 

The recommended dose for afilbercept is 2 mg administered by injection in the eye every 2 months (8 weeks) following 5 initial monthly (4 weeks) injections.  Afilbercept may be dosed once per month, but additional benefit was not seen with this dosing plan (Regeneron, 2014).

In a multi-center, randomized, double-masked, phase II clinical trial, Do and colleagues (2011) compared different doses and dosing regimens of vascular endothelial growth factor (VEGF) Trap-Eye with laser photocoagulation in eyes with diabetic macular edema (DME).  Diabetic patients (n = 221) with center-involved DME were included in this study.  Participants were assigned randomly to 1 of 5 treatment regimens: VEGF Trap-Eye 0.5 mg every 4 weeks (0.5q4); 2 mg every 4 weeks (2q4); 2 mg every 8 weeks after 3 initial monthly doses (2q8); or 2 mg dosing as needed after 3 initial monthly doses (2PRN), or macular laser photocoagulation.  Main outcome measures included the change in best-corrected visual acuity (BCVA) at 24 weeks (the primary end point) and at 52 weeks, proportion of eyes that gained 15 letters or more in ETDRS BCVA, and mean changes in central retinal thickness (CRT) from baseline.  As previously reported, mean improvements in BCVA in the VEGF Trap-Eye groups at week 24 were 8.6, 11.4, 8.5, and 10.3 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus 2.5 letters for the laser group (p ≤ 0.0085 versus laser).  Mean improvements in BCVA in the VEGF Trap-Eye groups at week 52 were 11.0, 13.1, 9.7, and 12.0 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus -1.3 letters for the laser group (p ≤ 0.0001 versus laser).  Proportions of eyes with gains in BCVA of 15 or more ETDRS letters at week 52 in the VEGF Trap-Eye groups were 40.9 %, 45.5 %, 23.8 %, and 42.2 % versus 11.4 % for laser (p = 0.0031, p = 0.0007, p = 0.1608, and p = 0.0016, respectively, versus laser).  Mean reductions in CRT in the VEGF Trap-Eye groups at week 52 were -165.4 μm, -227.4 μm, -187.8 μm, and -180.3 μm versus -58.4 μm for laser (p < 0.0001 versus laser).  Vascular endothelial growth factor Trap-Eye generally was well-tolerated.  The most frequent ocular adverse events with VEGF Trap-Eye were conjunctival hemorrhage, eye pain, ocular hyperemia, and increased intraocular pressure, whereas common systemic adverse events included hypertension, nausea, and congestive heart failure.  The authors concluded that significant gains in BCVA from baseline achieved at week 24 were maintained or improved at week 52 in all VEGF Trap-Eye groups.  Moreover, they stated that VEGF Trap-Eye warrants further investigation for the treatment of DME.

Bandello et al (2012) stated that DME is the most important cause of vision loss in patients with diabetes mellitus.  Diabetic retinopathy has a remarkable impact on public health and on the quality of life of diabetic patients and thus requires special consideration.  The first line of treatment remains the management of systemic risk factors but is often insufficient in controlling DME and currently, laser retinal photocoagulation is considered the standard of care.  However, laser treatment reduces the risk of moderate visual loss by approximately 50 % without guaranteeing remarkable effects on visual improvement.  For these reasons, new strategies in the treatment of DME have been studied, in particular the use of anti-VEGF drugs.  VEGF is a pluripotent growth factor that acts as a vaso-permeability factor and an endothelial cell mitogen.  For this reason, it represents an interesting candidate as a therapeutic target for the treatment of DME. 

Lang (2012) noted that diabetic retinopathy is one of the major complications of diabetes mellitus and a leading cause of visual loss.  Diabetic macular edema is an ocular manifestation of the disease causing visual deterioration.  The prevalence of visual impairment due to DME is estimated to be 5.4 % in Europe.  Vascular endothelial growth factor is over-expressed in diabetic eyes and plays a key role in the development of DME.  VEGF levels were proven to be elevated in the vitreous and retina in patients with diabetic retinopathy.  VEGF causes a breakdown of the blood-retinal barrier by influencing the tight junctions of retinal endothelial cells and leading to accumulation of fluid in the macula.  Therefore, intravitreal VEGF inhibitors are ideal candidates to treat DME by counteracting VEGF overexpression.  The author summarized the results of the most recent prospective, controlled studies on DME with promising novel VEGF inhibitors.  It focuses on the efficacy and safety aspects of anti-VEGF treatment of DME.

Zechmeister-Koss et al (2012) addressed the question of whether anti-VEGF lead to better clinical outcomes than current treatments in patients with clinically manifest DME, which is the leading cause of vision loss in the working age population in developed countries.  The authors performed a systematic literature search in common databases and compiled the evidence according to the GRADE methodology.  The authors analyzed clinically relevant improvement of visual acuity, vision-related quality of life and local or systemic adverse events.  In a proportion of patients (on average 25 %), VEGF inhibitors result in better VA (≥ 15 ETDRS letters or equivalent) than in patients treated with laser photocoagulation or sham injection.  The number of injections required for long-term improvement as well as the general long-term efficacy is unknown.  The evidence is not sufficient to confirm safety of the products in patients with DME and does not suggest superiority of a single product.  The authors concluded that for some patients with DME, VEGF inhibitors seem to be more effective as a short-term treatment option than alternative therapies.  The evidence is not of sufficient quality to confirm safety. 

In a review on “Anti-vascular endothelial growth factor drug treatment of diabetic macular edema”, Stewart (2012) noted that diabetic mellitus is the leading cause of blindness in working aged patients in developing nations.  Due to the buildup of abnormal metabolites from several overactive biochemical pathways, chronic hyperglycemia causes oxidative stress in the retina, which up-regulates VEGF.  Together with other growth factors and metabolites, VEGF causes endothelial cell proliferation, vasodilation, recruitment of inflammatory cells, and increased vascular permeability, leading to breakdown of the blood-retinal barrier.  This allows trans-cellular exudation into the interstitial space resulting in DME.  For over 3 decades the standard treatment for DME has been laser photocoagulation.  Though laser reduces the incidence of vision loss by 50 %, few eyes with diffuse edema experience improved vision.  This has led physicians to use the VEGF-binding drugs pegaptanib, ranibizumab, and aflibercept, each of which has been approved for the treatment of exudative macular degeneration, and bevacizumab that is commonly used off-label for a variety of chorio-retinal disorders.  Intravitreal administration of each drug frequently causes rapid improvement of DME with sustained improvement in vision through 2 years.  Though these drugs significantly out-perform laser photocoagulation over treatment periods of 1 year of less, the advantages appear to lessen when trials approach 2 years.  The author concluded that further studies to better determine relative efficacies of anti-VEGF drugs and laser photocoagulation are continuing.

In a Cochrane review, Virgili et al (2012) evaluated the safety, effectiveness, and cost-effectiveness of anti-VEGF therapy for preserving or improving vision in people with DME.  These investigators searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 6), MEDLINE (January 1946 to June 2012), EMBASE (January 1980 to June 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en).  They did not use any date or language restrictions in the electronic searches for trials.  They last searched the electronic databases on June 13, 2012.  These researchers included randomized controlled trials (RCTs) comparing any anti-angiogenic drugs with an anti-VEGF mechanism of action versus another treatment, sham treatment, or no treatment in patients with DME.  They also included economic evaluations to assess cost-effectiveness.  Two review authors independently extracted the data.  The risk ratio (RR) of visual loss and visual gain of 3 or more lines was estimated at least 6 months after treatment.  Each economic analysis was described narratively using a structured format.  A total of 11 studies provided data on 3 comparisons of interest in this review.  These investigators based their conclusions on the RR of gain or loss of 3 or more lines of vision at about 1 year, which was more consistently reported as follow-up.  Compared with sham treatment, there was evidence of moderate quality in 3 studies (497 participants, follow-up 8 to 12 months) that anti-angiogenic therapy (pegaptanib: 2 studies, 246 participants; ranibizumab: 1 study, 151 participants) doubled and, respectively, halved, the chance of gaining or losing 3 or more lines of vision (RR: 2.19, 95 % confidence interval (CI): 1.36 to 3.53; RR: 0.28, 95 % CI: 0.13 to 0.59).  In meta-analyses, the benefit was larger for ranibizumab compared to pegaptanib, but no significant subgroup difference could be demonstrated regarding our primary outcome.  Compared with grid laser photocoagulation, there was evidence of moderate quality that anti-angiogenic therapy (bevacizumab: 2 studies, 167 participants; ranibizumab: 2 studies, 300 participants; aflibercept: 1 study, 221 participants, 89 used for data extraction) more than doubled and, respectively, reduced by at least 2/3, the chance of gaining or losing 3 or more lines of vision (RR: 3.20, 95 % CI: 2.07 to 4.95 and RR: 0.13, 95 % CI: 0.05 to 0.34, respectively).  In meta-analyses, no significant subgroup difference could be demonstrated between bevacizumab, ranibizumab and aflibercept regarding our primary outcome, but, again, there was little power to detect a difference.  Compared with grid laser photocoagulation alone, there was high quality evidence that ranibizumab plus photocoagulation (3 studies, 783 participants) doubled and, respectively, at least halved, the chance of gaining or losing 3 or more lines of vision (RR: 2.11, 95 % CI 1.67 to 2.67; RR: 0.29, 95 % CI: 0.15 to 0.55).  Systemic and ocular adverse events were rare in the included studies.  Meta-analyses conducted for all anti-angiogenic drugs compared with either sham or photocoagulation (9 studies, 104 events in 2,159 participants) did not show a significant difference regarding arterial thromboembolic events (RR: 0.85 (0.56 to 1.28).  Similarly, no difference was suggested regarding overall mortality (53 events, RR: 0.95 (0.52 to 1.74), but clinically significant differences could not be ruled out.  The authors concluded that there is moderate quality evidence that anti-angiogenic drugs provide a definite, but small, benefit compared to current therapeutic options for DME, i.e., grid laser photocoagulation, or no treatment when laser is not an option.  The quality and quantity of the evidence was larger for ranibizumab, but there was little power to investigate drug differences.  Most data were obtained at 1 year, and a long-term confirmation is needed, since DME is a chronic condition.  Safety of both drug and the intravitreal injection procedure were good in the trials, but further long-term data are needed to exclude small, but clinically important differences regarding systemic adverse events.

In a meta-analysis, Hu and colleagues (2014) evaluated the safety and effectiveness of bevacizumab in the treatment of pterygium and explored its effects on recurrence rate and complications.  These investigators searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register from the inception to July 2013 for relevant RCTs that examined bevacizumab therapy for pterygium.  Data concerning study design, patient characteristics, treatment, and outcomes were extracted.  The methodological quality of the studies included was assessed using the Jadad score.  Relative risk (RR) was calculated for recurrence rate and complications.  A total of 474 patients with 482 eyes in 9 RCTs were analyzed.  The pooled estimate showed that bevacizumab had no statistically significant effect on preventing pterygium recurrence [RR 0.90, 95 % CI: 0.77 to 1.07, p = 0.23].  None of the subgroup analyses yielded significant results in favor of bevacizumab (surgery group: RR 0.77, 95 % CI: 0.50 to 1.18, p = 0.23; non-surgery group: RR 0.98, 95 % CI: 0.86 to 1.11, p = 0.76; primary pterygium group: RR 0.82, 95 % CI: 0.53 to 1.26, p = 0.36; recurrent pterygium group: RR 0.95, 95 % CI: 0.82 to 1.09, p = 0.44).  There were no statistically significant differences in the complications between the 2 groups (RR 1.00, 95 % CI: 0.73 to 1.37, p = 1.00).  However, the bevacizumab group was associated with a higher risk of developing subconjunctival hemorrhage (RR 3.34, 95 % CI: 1.07 to 10.43, p = 0.04).  The authors concluded that topical or subconjunctival bevacizumab was relatively safe and well-tolerated, but it had no statistically significant effect on preventing pterygium recurrence.  They stated that a large-scale trial with a suitable dosage and a longer follow-up would be needed to rule out the possibility of any treatment benefit.

Moradi et al (2013) stated that diabetic retinopathy (DR) is the most common cause of visual loss among working age individuals.  Diabetic macular edema (DME) is an important complication of DR that affects around 1/3 of the patients with DR.  Several treatments have been approved for DME ranging from blood pressure and glycemic control to photocoagulation and more recently the use of vascular endothelial growth factor (VEGF) antagonists.  These investigators discussed aflibercept (EYLEA®-Regeneron Pharmaceuticals, Inc., Tarrytown, New York, NY, and Bayer Healthcare Pharmaceuticals, Berlin, Germany) in the context of other VEGF antagonists currently available for the treatment of DME.  They performed a systematic search of literature on PubMed, Scopus, and Google Scholar with no limitation on language or year of publication.  Pre-clinical studies of aflibercept have shown a higher affinity of this molecule for VEGF-A along with a longer duration of action as compared to other VEGF antagonists.  Recent clinical trials have shown visual outcome results for aflibercept to be similarly favorable as compared to other available agents with the added benefit of fewer required injections and less frequent monitoring.   The authors concluded that aflibercept presents a potential exciting new addition to the armamentarium of current VEGF antagonists available for the treatment of DME and other retinal vascular diseases.  However, they stated that further studies are needed to confirm the role, safety, and efficacy of aflibercept for DME.

In a cost-effectiveness analysis of treatment of DME, Pershing et al (2014) reported that VEGF inhibitor monotherapy was sometimes preferred over laser treatment plus a VEGF inhibitor, depending on the reduction in quality of life with loss of visual acuity.  When the VEGF inhibitor bevacizumab was as effective as ranibizumab, it was preferable because of its lower cost.  This study did not include aflibercept in the analysis.

On behalf of the Diabetic Macular Edema Treatment Guideline Working Group, Mitchell and Wong (2014) provided evidence-based recommendations for DME management based on updated information from publications on DME treatment modalities.  A literature search for "diabetic macular edema" or "diabetic maculopathy" was performed using the PubMed, Cochrane Library, and ClinicalTrials.gov databases to identify studies from January 1, 1985 to July 31, 2013.  Meta-analyses, systematic reviews, and randomized controlled trials with at least 1 year of follow-up published in the past 5 years were preferred sources.  Although laser photocoagulation has been the standard treatment for DME for nearly 3 decades, there is increasing evidence that superior outcomes can be achieved with anti-VEGF therapy.  Data providing the most robust evidence from large phase II and phase III clinical trials for ranibizumab demonstrated visual improvement and favorable safety profile for up to 3 years.  Average best-corrected visual acuity (BCVA) change from baseline ranged from 6.1 to 10.6 ETDRS letters for ranibizumab, compared to 1.4-5.9 ETDRS letters with laser.  The proportion of patients gaining greater than or equal to 10 or greater than or equal to 15 letters with ranibizumab was at least 2 times higher than that of patients treated with laser.  Patients were also more likely to experience visual loss with laser than with ranibizumab treatment.  Ranibizumab was generally well-tolerated in all studies.  Studies for bevacizumab, aflibercept, and pegaptanib in DME were limited but also in favor of anti-VEGF therapy over laser.  The authors concluded that anti-VEGF therapy is superior to laser photocoagulation for treatment of moderate to severe visual impairment caused by DME.

Also, an UpToDate review on “Diabetic retinopathy: Prevention and treatment” (Fraser and D’Amico, 2014) notes that “VEGF inhibitors for ME -- VEGF inhibitors (pegaptanib, bevacizumab, ranibizumab) have been widely studied as a treatment for diabetic ME, and this therapy represents a major treatment advance.  In 2012, the US Food and Drug Administration (FDA) approved a 0.3 mg intravitreal dose of ranibizumab for treatment of diabetic ME.  Consequently, for many patients and clinicians, intravitreal pharmacotherapy with ranibizumab will be the initial treatment of choice, but the precise interrelation between this treatment and other modalities is not yet conclusively defined”.  This review does not include aflibercept as a therapeutic option of DME.

The National Institute for Health and Care Excellence clinical practice guideline on “Aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that has progressed following prior oxaliplatin-based chemotherapy” (NICE, 20140 states that “Aflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended within its marketing authorization for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen.  People currently receiving aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen should be able to continue treatment until they and their clinician consider it appropriate to stop”.

Aravantinos et al (2014) conducted a systematic literature review to identify available safety and effectiveness data for bevacizumab in ovarian cancer as well as for newer anti-angiogenic agents in development.  These researchers analyzed published data from randomized, controlled phase II/III clinical trials enrolling women with ovarian cancer to receive treatment with bevacizumab.  They also reviewed available data for emerging anti-angiogenic agents currently in phase II/III development, including trebananib, aflibercept, nintedanib, cediranib, imatinib, pazopanib, sorafenib and sunitinib.  Significant efficacy gains were achieved with the addition of bevacizumab to standard chemotherapy in 4 randomized, double-blind, phase III trials, both as front-line treatment (GOG-0218 and ICON7) and in patients with recurrent disease (OCEANS and AURELIA).  The type and frequency of bevacizumab-related adverse events was as expected in these studies based on published data.  Promising efficacy data have been published for a number of emerging anti-angiogenic agents in phase III development for advanced ovarian cancer.  The authors concluded that further research is needed to identify predictive or prognostic markers of response to bevacizumab in order to optimize patient selection and treatment benefit; data from phase III trials of newer anti-angiogenic agents in ovarian cancer are awaited.

Agarwal and colleagues (2014) stated that the therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years.  Immunotherapy in the form of sipuleucel-T, androgen axis inhibitors, including abiraterone acetate and enzalutamide, a chemotherapeutic agent, cabazitaxel, and a radiopharmaceutical, radium-223, have all yielded incremental extensions of survival and have been recently approved.  A number of other agents appear promising in early studies, suggesting that the armamentarium against castrate-resistant prostate cancer is likely to continue to expand.  Emerging androgen pathway inhibitors include androgen synthesis inhibitors (TAK700), androgen receptor inhibitors (ARN-509, ODM-201), AR DNA binding domain inhibitors (EPI-001), selective AR down-regulators or SARDs (AZD-3514), and agents that inhibit both androgen synthesis and receptor binding (TOK-001/galeterone).  Promising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab).  Biologic agents targeting the molecular drivers of disease are also being investigated as single agents, including cabozantinib (Met and VEGFR2 inhibitor) and tasquinimod (angiogenesis and immune modulatory agent).  Despite the disappointing results seen from studies evaluating docetaxel in combination with other agents, including GVAX, anti-angiogenic agents (bevacizumab, aflibercept, lenalinomide), a SRC kinase inhibitor (dasatinib), endothelin receptor antagonists (atrasentan, zibotentan), and high-dose calcitriol (DN-101), the results from the trial evaluating docetaxel in combination with the clusterin antagonist, custirsen, are eagerly awaited.  New therapeutic hurdles consist of discovering new targets, understanding resistance mechanisms, the optimal sequencing and combinations of available agents, as well as biomarkers predictive for benefit.  Novel agents targeting bone metastases are being developed following the success of zoledronic acid and denosumab.  The authors concluded that all of these modalities do not appear curative, suggesting that clinical trial enrollment and a better understanding of biology remain of paramount importance.

Kim and colleagues (2013) compared the short-term effects of bevacizumab and ranibizumab injections on the regression of corneal neovascularization (NV).  A total of 16 eyes of 16 patients with corneal NV were randomly assigned for an injection with 2.5 mg of bevacizumab (group 1, n = 8) or 1 mg of ranibizumab (group 2, n = 8) through subconjunctival and intrastromal routes.  The patients were prospectively followed-up for 1 month after the injections.  Corneal NV areas, as shown on corneal slit-lamp photographs stored in JPEG format, were calculated using Image J software before the injection, 1 week after the injection, and 1 month after the injection.  The corneal NV areas were compared before and after the injections.  A total of 7 women and 9 men, with an average age of 51 years, presented with corneal NV secondary to herpetic keratitis (7 cases), graft rejection (6), chemical burn (1), pemphigoid (1), and recurrent ulcer (1).  In group I, the pre-operative corneal NV area (8.75 ± 4.33 %) was significantly decreased to 5.62 ± 3.86 % 1 week after the injection and to 6.35 ± 3.02 % 1 month after the injection (p = 0.012, 0.012, respectively).  The corneal NV area in group 2 also exhibited a significant change, from 7.37 ± 4.33 % to 6.72 ± 4.16 % 1 week after the injection (p = 0.012).  However, no significant change was observed 1 month after the injection.  The mean decrease in corneal NV area 1 month after injection in group 1 (28.4 ± 9.01 %) was significantly higher than in group 2 (4.51 ± 11.64 %, p = 0.001).  The authors concluded that bevacizumab injection resulted in a more effective and stable regression of corneal NV compared to the ranibizumab injection.  Moreover, they stated that the potency and dose of these 2 drugs for the regression of corneal NV require further investigation.

Ahn et al (2014) reported on the case of a 32-year old female diagnosed with herpetic kerato-conjunctivitis with refractory corneal NV despite 2 previous subconjunctival and intrastromal bevacizumab injections, received 2 subconjunctival and intrastromal ranibizumab injections.  Six months post-operatively, there was significant regression of the neovascular area and vessel caliber.  The authors reported a case of improvement in corneal NV with subconjunctival and intrastromal ranibizumab injections, which was previously refractory to bevacizumab injection.  They stated that these findings may suggest a new prospect in treating corneal NV.

Turkcu et al (2014) compared the effectiveness of the topical and subconjunctival (SC) ranibizumab treatment in experimental corneal NV model in rats.  A model of NV was generated by cauterizing right corneas of 30 Sprague-Dawley rats with silver nitrate.  The animals were separated into 5 groups randomly: first group (control group) received topical artificial tear drops 2 times daily while second and third groups received topical ranibizumab 4 times daily at concentrations of 5 mg/ml and 10 mg/ml, respectively; fourth and fifth groups were given 0.5 mg/0.05 ml and 1 mg/0.1 ml of SC ranibizumab in the 1st, 3rd and 7th days.  The measurements (percentage of NV area and number of vessels) from digital photographs of the corneas were determined and analyzed using analysis software (ImageJ, v1.38).  The animals were sacrificed on the 10th day and their corneas were subjected to hemotoxylin-eosin histopathological staining and antisera against CD34 and von-Willebrand factor to evaluate microvascular structures immunohistochemically.  The percentage of the corneal NV area and number of vessels in all treatment groups was found to be significantly lower than the control group.  There was no significant difference in relation to the percentage of NV area and number of vessels in the treatment groups.  Score of the corneal edema was determined to be significantly less in the groups that undertook treatment.  Number of vessels and inflammatory cells were significantly lower in the histological and immunohistochemical sections in the treated groups than in the control group.  In all treatment groups, fibroblast intensity was significantly lower than the control group (p = 0.005).  The authors concluded that topical or SC administration of ranibizumab seems to be a promising and effective medication in the treatment of corneal NV.  Moreover, they stated that further research is recommended to assess the potential side effects and effective dose.

In a meta-analysis, Papathanassiou et al (2013) evaluated the therapeutic effect of bevacizumab on corneal NV.  A systematic review and meta-analysis of the literature was performed.  A total of 7 eligible clinical human studies and 18 eligible experimental animal studies examining the effectiveness of bevacizumab treatment on corneal NV were included in the meta-analysis.  Pertinent publications were identified through a systematic search of PubMed.  All references of relevant reviews and eligible articles were also screened, and data were extracted from each eligible study.  The random-effects model (of DerSimonian and Laird) was used to combine the results from the selected studies.  Heterogeneity was explored using available data.  Publication bias was also assessed.  A significant reduction of corneal neovascularized area was seen in clinical human studies, with a pooled reduction of 36 % [95 % CI: 18 % to 54 %] overall, of 32 % (95 % CI: 10 % to 54 %) for subconjunctival anti-VEGF injections, and 48 % (95 % CI: 32 % to 65 %) for topical treatment.  Pooled mean change in BCVA showed an improvement in BCVA by 0.04.  The summary standardized mean difference in animal studies indicated a statistically significant reduction in the area of corneal NV when treated with bevacizumab compared with the control group by -1.71 (95 % CI: -2.12 to -1.30).  The subtotal pooled standardized mean differences were -1.83 (95 % CI: -2.38 to -1.28) for subconjunctival anti-VEGF injections and -1.50 (95 % CI: -1.88 to -1.12) for topical treatment.  The authors concluded that these findings suggested that both topical and subconjunctival bevacizumab achieve significant reduction in the area of corneal NV.  This meta-analysis provided an evidential basis for the new therapeutic concept of treating corneal NV with anti-angiogenic therapy.  Moreover, the clinical significance of an improvement in BCVA by 0.04 is unclear.

In a pilot study, Petsoglou et al (2013) evaluated the off-label use of subconjunctival bevacizumab for corneal NV (CoNV).  A total of 30 patients with recent-onset CoNV from various causes were randomly assigned into a double-masked, placebo-controlled trial.  Each received three 0.1-ml injections containing either 2.5 mg bevacizumab or 0.9 % saline at monthly intervals.  Dexamethasone 0.1 % drops were used 4 times a day for the 1st month, when the dose was modified if clinically indicated.  The primary outcome was change in area of corneal involvement by CoNV from baseline to 3 months measured using specialized imaging technology.  The mean area of CoNV reduced by -36 % (range of -92 % to +40 %) in the 15 eyes that received bevacizumab compared with an increase of 90 % (range of -58 % to +1,394 %) in eyes that received saline placebo (analysis of covariance (ANCOVA); p = 0.007).  One outlier in the placebo arm developed corneal graft rejection with aggressive neovascularization (+1,384 %), but even when this patient was excluded the mean reduction in CoNV in the placebo group (-3 %, range of -58 % to +40 %) was still significantly different from the treatment arm (ANCOVA; p = 0.016).  Changes in BCVA, central corneal thickness, IOP and endothelial cell counts were similar between groups.  The intervention was well-tolerated with no major safety concerns.  The authors concluded that 3 subconjunctival injections of 2.5-mg bevacizumab are more effective than placebo at inducing the regression of recent onset CoNV.  Moreover, they stated that further studies are needed to confirm this effect and these findings suggested that a sample size of 40 patients per treatment group is needed.

Krizova and colleagues (2014) evaluated anti-angiogenic effect of local use of bevacizumab in patients with corneal NV.   Patients were divided into 2 groups.  All patients suffered from some form of corneal NV.  Patients in group A received 0.2 to 0.5 ml of bevacizumab solution subconjunctivally (concentration 25 mg/ml) in a single dose.  Group A included 28 eyes from 27 patients.  Patients in group B applied bevacizumab eye drops twice-daily (concentration 2.5 mg/ml) for 2 weeks.  Group B included 38 eyes from 35 patients.  These investigators evaluated the number of corneal segments affected by NV, CDVA, and the incidence of complications and subjective complaints related to the treatment.  The minimum follow-up period was 6 months.  By the 6-month follow-up, in group A the percentage reduction of the affected peripheral segments was 21.6 % and of the central segments was 9.6 %; in group B the percentage reduction of the central segments was 22.7 % and of the central segments was 38.04 %.  In both groups these researchers noticed a statistically significant reduction in the extent of NV.  The authors concluded that the use of bevacizumab seems to be an effective and safe method in the treatment of corneal NV, either in the subconjunctival or topical application form.  It is unclear whether the statistically significant reduction in the extent of NV is of clinical significance; the findings of this study need to be validated in well-designed studies.

Furthermore, an UpToDate review on “Overview of angiogenesis inhibitors” (Kuo, 2014) does not mention corneal neovascularization as an indication of bevacizumab or ranibizumab.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
67028
Pegaptanib sodium injection (Macugen):
HCPCS codes covered if selection criteria are met:
J2503 Injection, pegaptanib sodium, 0.3 mg
ICD-9 codes covered if selection criteria are met:
362.07 Diabetic macular edema
362.52 Exudative senile macular degeneration
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
017.30 - 017.36 Tuberculosis of eye
053.20 - 053.29 Herpes zoster with ophthalmic complications
076.0 - 076.9 Trachoma
077.1 Epidemic keratoconjunctivitis
077.3 Other adenoviral conjunctivitis
077.4 Epidemic hemorrhagic conjunctivitis
077.8 Other viral conjunctivitis
078.5 Cytomegalovirus disease (retinitis)
091.51 Syphilitic chorioretinitis (secondary)
115.02 Infection by Histoplasma capsulatum, retinitis
115.12 Infection by Histoplasma duboisii, retinitis
115.92 Histoplasmosis, unspecified, retinitis
130.2 Chorioretinitis due to toxoplasmosis
190.5 - 190.6 Malignant neoplasm of retina and choroid
277.87 Disorders of mitochondrial metabolism [NARP syndrome]
360.00 - 362.43 Disorders of globe, retinal detachments and defects, diabetic retinopathy other background retinopathy and vascular changes, other proliferative retinopathy, retinal vascular occlusion, and separation of retinal layers
362.01 - 362.06 Diabetic retinopathy
362.50 - 362.52
362.53 - 363.9
Degeneration of macula and posterior pole other than exudative senile macular degeneration, peripheral retinal degenerations, hereditary retinal dystrophies, other retinal disorders, chorioretinal inflammations, scars, and other disorders of choroid
370.00 - 370.9 Keratitis
372.00 - 372.06 Acute conjunctivitis
372.10 - 372.15 Chronic conjunctivitis
372.20 - 372.39 Blepharoconjunctivtis and other and unspecified conjunctivitis
373.00 - 373.02 Blepharitis
373.11 - 373.13 Hordeolum and other deep inflammation of eyelid
375.00 - 375.03 Dacryoadenitis
375.30 - 375.33 Acute and unspecified inflammation of lacrimal passages
375.41 - 375.43 Chronic inflammation of lacrimal passages
376.01 Orbital cellulitis
379.00 - 379.09 Scleritis and episcleritis
759.6 Other hamatoses, NEC [von Hippel-Lindau]
Ranibizumab (Lucentis) or Bevacizumab (Avastin):
CPT codes not covered for indications listed in the CPB:
66030
68200
HCPCS codes covered if selection criteria are met:
C9257 Injection, bevacizumab, 0.25mg [Avastin] [intraocular dose]
J2778 Injection, ranibizumab, 0.1 mg
J9035 Injection, bevacizumab, 10 mg [Avastin] [chemotherapy dose]
ICD-9 codes covered if selection criteria are met:
115.02 Infection by Histoplasma capsulatum, retinitis
115.12 Infection by Histoplasma duboisii, retinitis
115.92 Histoplasmosis, unspecified, retinitis
360.21 Progressive high (degenerative) myopia
362.07 Diabetic macular edema
362.13 Retinal vascular changes; changes in vascular appearance
362.14 Retinal microaneurysms NOS
362.16 Retinal neovascularization NOS
362.17 Other intraretinal microvascular abnormalities
362.18 Retinal vasculitis
362.20 - 362.29 Retinopathy of prematurity
362.35 Central retinal vein occlusion
362.36 Venous tributary (branch) occlusion
362.52 Exudative senile macular degeneration
362.70 - 362.77 Hereditary retinal dystrophies
363.00 - 363.08 Focal chorioretinitis and focal retinochoroiditis
363.10 - 363.15 Disseminated chorioretinitis and disseminated retinochoroiditis
363.20 Chorioretinitis, unspecified
363.43 Angioid streaks of choroid
363.50 - 363.57 Hereditary choroidal dystrophies
364.42 Rubeosis iridis
365.63 Glaucoma associated with vascular disorders
757.39 Other specified anomalies of skin [pseudoxanthoma elasticum]
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
017.30 - 017.36 Tuberculosis of eye
053.20 - 053.29 Herpes zoster with ophthalmic complications
076.0 - 076.9 Trachoma
077.1 Epidemic keratoconjunctivitis
077.3 Other adenoviral conjunctivitis
077.4 Epidemic hemorrhagic conjunctivitis
077.8 Other viral conjunctivitis
078.5 Cytomegalovirus disease (retinitis)
091.51 Syphilitic chorioretinitis (secondary)
130.2 Chorioretinitis due to toxoplasmosis
190.5 - 190.6 Malignant neoplasm of retina and choroid
228.03 Hemangioma of retina
277.87 Disorders of mitochondrial metabolism [NARP syndrome]
360.00 - 360.20 Disorders of globe
360.23 - 360.9 Other disorders of globe
361.00 - 361.9 Retinal detachments and defects
362.01 - 362.06 Diabetic retinopathy [except with macular edema]
362.11 - 362.12 Hypertensive and exudative retinopathy
362.15 Retinal telangiectasia
362.30 - 362.34 Retinal vascular occlusion, central retinal artery occlusion, arterial branch occlusion, partial arterial occlusion, and transient arterial occlusion
362.37 - 362.43 Venous engorgement and separation of retinal layers
362.50 - 362.51
362.53 - 362.66
Degeneration of macula and posterior pole other than exudative senile macular degeneration and peripheral retinal degenerations
362.81 - 362.9 Other retinal disorders
363.21 - 363.42 Pars planitis, Harada's disease, chorioretinal scars and degenerations except angioid streaks
363.61 - 363.9 Choroidal hemorrhage, detachment, and other disorders
365.00 - 365.62
365.64 - 365.9
Glaucoma except when associated with vascular disorders
368.00 - 368.03 Amblyopia ex anopsia
370.00 - 370.9 Keratitis
372.00 - 372.06 Acute conjunctivitis
372.10 - 372.15 Chronic conjunctivitis
372.20 - 372.39 Blepharoconjunctivitis and other and unspecified conjunctivitis
372.40 - 372.45 Pterygium
373.00 - 373.02 Blepharitis
373.11 - 373.13 Hordeolum and other deep inflammation of eyelid
375.00 - 375.03 Dacryoadenitis
375.30 - 375.33 Acute and unspecified inflammation of lacrimal passages
375.41 - 375.43 Chronic inflammation of lacrimal passages
376.01 Orbital cellulitis
379.00 - 379.09 Scleritis and episcleritis
759.6 Other hamatoses, NEC [von Hippel-Lindau]
Intravitrial aflibercept (Eylea):
HCPCS codes covered if selection criteria are met:
J0178 Injection, aflibercept, 1 mg
ICD-9 codes covered if selection criteria are met:
362.07 Diabetic macular edema
362.35 Central vein occlusion of retina
362.36 Venous tributary (branch) occlusion
362.52 Exudative senile macular degeneration
362.83 Retinal edema
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
053.20 - 053.29 Herpes zoster with ophthalmic complications
076.0 - 076.9 Trachoma
077.1 Epidemic keratoconjunctivitis
077.3 Other adenoviral conjunctivitis
077.4 Epidemic hemorrhagic conjunctivitis
077.8 Other viral conjunctivitis
154.0 Malignant neoplasm of rectosigmoid junction
183.0 Malignant neoplasm of ovary
185 Malignant neoplasm of prostate
360.00 - 360.19 Endophthalmitis
370.00 - 370.9 Keratitis
372.00 - 372.06 Acute conjunctivitis
372.10 - 372.15 Chronic conjunctivitis
372.20 - 372.39 Blepharoconjunctivtis and other and unspecified conjunctivitis
373.00 - 373.02 Blepharitis
373.11 - 373.13 Hordeolum and other deep inflammation of eyelid
375.00 - 375.03 Dacryoadenitis
375.30 - 375.33 Acute and unspecified inflammation of lacrimal passages
375.41 - 375.43 Chronic inflammation of lacrimal passages
376.01 Orbital cellulitis
379.00 - 379.09 Scleritis and episcleritis


The above policy is based on the following references:

Macugen (pegaptanib):

  1. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351(27):2805-2816.
  2. Ferris FL 3rd. A new treatment for ocular neovascularization. N Engl J Med. 2004;351(27):2863-2865.
  3. Eyetech Pharmaceuticals, Inc. and Pfizer, Inc. Macugen (pegaptanib sodium injection).  Prescribing Information. LAB-0293-1.0. New York, NY: Pfizer; December 2004. Available at: http://www.macugen.com. Accessed February 2, 2005.
  4. Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO. Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res. 2003;22:1-29.
  5. National Horizon Scanning Centre (NHSC). Pegaptanib for age-related macular degeneration - horizon scanning review. Birmingham, UK: NHSC; 2002.
  6. U.S. Food and Drug Administration (FDA). FDA approves new drug treatment for age-related macular degeneration. FDA News. P04-110. Rockville, MD: FDA; December 10, 2004. Available at: http://www.fda.gov/bbs/topics/news/2004/new01146.html. Accessed February 3, 2005.
  7. U.S. Food and Drug Administration (FDA), Division of Anti-inflammatory, Analgesic and Ophthalmic Drug Products. Advisory committee meeting briefing package for macugen (pegaptanib sodium injection) for the treatment of neovascular age-related macular degeneration. Rockville, MD: FDA; August 19, 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4053B1_02_FDA-Backgrounder.doc. Accessed February 3, 2005.
  8. Vedula SS, Krzystolik M. Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2008,(2):CD005139.
  9. Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112(10):1747-1757.
  10. Maberley D. Pegaptanib for neovascular age-related macular degeneration. Issues in Emerging Health Technologies Issue 76. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 2005.
  11. Fraunfelder FW. Pegaptanib for wet macular degeneration. Drugs Today (Barc). 2005;41(11):703-709.
  12. BlueCross BlueShield Association (BCBSA), Technology Evaluation Center (TEC). Special report: Current and evolving strategies in the treatment of age-related macular degeneration. TEC Assessment Program. Chicago, IL: BCBSA; January 2006:20(11). Available at: http://www.bcbs.com/tec/vol20/20_11.html. Accessed July 31, 2006.
  13. Dahr SS, Cusick M, Rodriguez-Coleman H, et al. Intravitreal anti-vascular endothelial growth factor therapy with pegaptanib for advanced von Hippel-Lindau disease of the retina. Retina. 2007;27(2):150-158.
  14. Augustovski F, Colantonio L, Pichon Riviere A. Vascular endothelial growth factor inhibitors (pegaptanib, ranibizumab and bevacizumab) in age-related macular degeneration treatment [summary]. Report ITB No. 33. Buenos Aires, Argentina: Institute for Clinical Effectiveness and Health Policy (IECS); 2007.
  15. Fraser-Bell S, Kaines A, Hykin PG. Update on treatments for diabetic macular edema. Curr Opin Ophthalmol. 2008;19(3):185-189.
  16. Calvo-González C, Reche-Frutos J, Donate-López J, et al. Combined Pegaptanib sodium (Macugen) and photodynamic therapy in predominantly classic juxtafoveal choroidal neovascularisation in age related macular degeneration. Br J Ophthalmol. 2008;92(1):74-75.
  17. Colquitt JL, Jones J, Tan SC, et al. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration: A systematic review and economic evaluation. Health Technol Assess. 2008;12(16):1-201.
  18. Brown A, Hodge W, Cruess A, et al. Management of neovascular age-related macular degeneration: Systematic drug class review and economic evaluation. Technology Report No. 110. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); April 2008.
  19. Pfizer. Phase 3 study showed Macugen improved vision over standard of care in patients with diabetic macular edema. Patients on Macugen maintained and expanded vision gains over two years. Press Release. New York, NY: Pfizer; June 5, 2010.

Lucentis (ranibizumab):

  1. National Horizon Scanning Centre (NHSC). Ranibizumab for age-related macular degeneration - horizon scanning review. Birmingham, UK: NHSC; 2005.
  2. van Wijngaarden P, Coster DJ, Williams KA. Inhibitors of ocular neovascularization: Promises and potential problems. JAMA. 2005;293(12):1509-1513.
  3. Rosenfeld PJ, Schwartz SD, Blumenkranz MS, et al. Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration. Ophthalmology. 2005;112(6):1048-1053.
  4. Pauleikhoff D, Bornfeld N, Gabel VP, et al. The position of the Retinological Society, the German Ophthalmological Society and the Professional Association of Ophthalmologists -- comments on the current therapy for neovascular AMD. Klin Monatsbl Augenheilkd. 2005;222(5):381-388.
  5. Rosenfeld PJ, Heier JS, Hantsbarger G, Shams N. Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration. Ophthalmology. 2006;113(4):632.e1.
  6. Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: A phase I/II multicenter, controlled, multidose study. Ophthalmology. 2006;113(4):642.e1-e4.
  7. U.S. Food and Drug Administration (FDA). FDA approves new biologic treatment for wet age-related macular degeneration. FDA News. P06-94. Rockville, MD: FDA; June 30, 2006. Available at: http://www.fda.gov/bbs/topics/NEWS/2006/NEW01405.html. Accessed July 5, 2006.
  8. No authors listed. Comments on current therapeutic possibilities for neovascular age-related macula degeneration. Klin Monatsbl Augenheilkd. 2006;223(4):271-278.
  9. Genentech, Inc. LUCENTIS ranibizumab injection. Full Prescribing Information. South San Francisco, CA: Genentech; June 2006. Available at: http://www.gene.com/gene/products/information/tgr/lucentis/insert.jsp. Accessed July 31, 2006.
  10. Chakravarthy U, Soubrane G, Bandello F, et al. Evolving European guidance on the medical management of neovascular age related macular degeneration. Br J Ophthalmol. 2006;90(9):1188-1196.
  11. Augustovski F, Colantonio L, Pichon Riviere A. Vascular endothelial growth factor inhibitors (pegaptanib, ranibizumab and bevacizumab) in age-related macular degeneration treatment [summary]. Report ITB No. 33. Buenos Aires, Argentina: Institute for Clinical Effectiveness and Health Policy (IECS); 2007.
  12. Swedish Council on Technology Assessment in Health Care (SBU). Ranibizumab in treating age-related macular degeneration - Alert. Stockholm, Sweden: SBU; 2008.
  13. Vedula SS, Krzystolik M. Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2008,(2):CD005139.
  14. Antoszyk AN, Tuomi L, Chung CY, et al. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): Year 2 results. Am J Ophthalmol. 2008;145(5):862-874.
  15. Colquitt JL, Jones J, Tan SC, et al. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration: A systematic review and economic evaluation. Health Technol Assess. 2008;12(16):1-201.
  16. Lantry LE. Ranibizumab, a mAb against VEGF-A for the potential treatment of age-related macular degeneration and other ocular complications. Curr Opin Mol Ther. 2007;9(6):592-602.
  17. Ciulla TA, Rosenfeld PJ. Anti-vascular endothelial growth factor therapy for neovascular ocular diseases other than age-related macular degeneration. Curr Opin Ophthalmol. 2009;20(3):166-174.
  18. Rodriguez-Fontal M, Alfaro V, Kerrison JB, Jablon EP. Ranibizumab for diabetic retinopathy. Curr Diabetes Rev. 2009;5(1):47-51.
  19. Subramanian ML, Ness S, Abedi G, Ahmed, et al. Bevacizumab vs ranibizumab for age-related macular degeneration: Early results of a prospective double-masked, randomized clinical trial. Am J Ophthalmol. 2009;148(6):875-882.
  20. Stepien KE, Rosenfeld PJ, Puliafito CA, et al. Comparison of intravitreal bevacizumab followed by ranibizumab for the treatment of neovascular age-related macular degeneration. Retina. 2009;29(8):1067-1073.
  21. Gamulescu MA, Radeck V, Lustinger B, et al. Bevacizumab versus ranibizumab in the treatment of exudative age-related macular degeneration. Int Ophthalmol. 2010;30(3):261-266.
  22. Ishikawa K, Honda S, Tsukahara Y, Negi A. Preferable use of intravitreal bevacizumab as a pretreatment of vitrectomy for severe proliferative diabetic retinopathy. Eye (Lond). 2009;23(1):108-111.
  23. Lo Giudice G, Gismondi M, De Belvis V, et al. Single-session photodynamic therapy combined with intravitreal bevacizumab for retinal angiomatous proliferation. Retina. 2009;29(7):949-955.
  24. Mennel S, Meyer CH, Callizo J. Combined intravitreal anti-vascular endothelial growth factor (Avastin) and photodynamic therapy to treat retinal juxtapapillary capillary haemangioma. Acta Ophthalmol. 2010;88(5):610-613.
  25. Fong DS, Custis P, Howes J, Hsu JW. Intravitreal bevacizumab and ranibizumab for age-related macular degeneration a multicenter, retrospective study. Ophthalmology. 2010;117(2):298-302.
  26. Nicholson BP, Schachat AP. A review of clinical trials of anti-VEGF agents for diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2010;248(7):915-930.
  27. Boscia F. Current approaches to the management of diabetic retinopathy and diabetic macular oedema. Drugs. 2010;70(16):2171-2200.
  28. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010;376(9735):124-136.
  29. Elman MJ, Bressler NM, Qin H, et al; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118(4):609-614.
  30. Waisbourd M, Goldstein M, Loewenstein A. Treatment of diabetic retinopathy with anti-VEGF drugs. Acta Ophthalmol. 2011;89(3):203-2077.
  31. El-Sabagh HA, Abdelghaffar W, Labib AM, et al. Preoperative intravitreal bevacizumab use as an adjuvant to diabetic vitrectomy: Histopathologic findings and clinical implications. Ophthalmology. 2011;118(4):636-641.
  32. Mitchell P, Bandello F, Schmidt-Erfurth U, et al, Weichselberger A; RESTORE study group. The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):615-625.
  33. Giuliari GP, Sadaka A, Hinkle DM, Simpson ER. Current treatments for radiation retinopathy. Acta Oncol. 2011;50(1):6-13.
  34. CATT Research Group, Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908.
  35. Rosenfeld PJ. Bevacizumab versus ranibizumab for AMD. N Engl J Med. 2011;364(20):1966-1967.
  36. Schmucker C, Loke YK, Ehlken C, et al. Intravitreal bevacizumab (Avastin) versus ranibizumab (Lucentis) for the treatment of age-related macular degeneration: A safety review. Br J Ophthalmol. 2011;95(3):308-317.
  37. Orozco-Gomez LP, Hernandez-Salazar L, Moguel-Ancheita S, et al. Laser-ranibizumab treatment for retinopathy of prematurity in umbral-preumbral disease. Three years of experience. Cir Cir. 2011;79(3):207-214, 225-232.
  38. Lin CJ, Chen SN, Hwang JF. Intravitreal ranibizumab as salvage therapy in an extremely low-birth-weight infant with rush type retinopathy of prematurity. Oman J Ophthalmol. 2012;5(3):184-186.
  39. Mota A, Carneiro A, Breda J, et al. Combination of intravitreal ranibizumab and laser photocoagulation for aggressive posterior retinopathy of prematurity. Case Rep Ophthalmol. 2012;3(1):136-141.
  40. Castellanos MA, Schwartz S, Garcia-Aguirre G, Quiroz-Mercado H. Short-term outcome after intravitreal ranibizumab injections for the treatment of retinopathy of prematurity. Br J Ophthalmol. 2013;97(7):816-819.
  41. Ahn YJ, Hwang HB, Chung SK. Ranibizumab injection for corneal neovascularization refractory to bevacizumab treatment. Korean J Ophthalmol. 2014;28(2):177-180.
  42. Turkcu FM, Cinar Y, Turkcu G, et al. Topical and subconjunctival ranibizumab (lucentis) for corneal neovascularization in experimental rat model. Cutan Ocul Toxicol. 2014;33(2):138-144.
  43. Schmidt-Erfurth U, Lang GE, Holz FG, et al; RESTORE Extension Study Group. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: The RESTORE extension study. Ophthalmology. 2014;121(5):1045-1053.

Eylea (aflibercept):

  1. Heier JS, Boyer D, Nguyen QD, et al CLEAR-IT 2 Investigators. The 1-year results of CLEAR-IT 2, a phase 2 study of vascular endothelial growth factor trap-eye dosed as-needed after 12-week fixed dosing. Ophthalmology. 2011;118(6):1098-1106.
  2. Stewart MW. Aflibercept (VEGF-TRAP): The next anti-VEGF drug. Inflamm Allergy Drug Targets. 2011;10(6):497-508.
  3. Helwick C. FDA approves aflibercept for age-related macular degeneration. Medscape Pharmacists News. New York, NY: Medscape; November 18, 2011. Available at: http://www.medscape.com/viewarticle/753787. Accessed January 10, 2012.
  4. U.S. Food and Drug Administration (FDA). FDA approves Eylea for eye disorder in older people. FDA News. Silver Spring, MD: FDA; November 18, 2011. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280601.htm. Accessed January 10, 2012.
  5. Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: Six-month results of the phase 3 COPERNICUS study. Ophthalmology. 2012;119(5):1024-1032.
  6. Regeneron Pharmaceuticals, Inc. Regeneron announces FDA approval of EYLEA® (aflibercept) injection for macular edema following central retinal vein occlusion. Press Release. Tarrytown, NY: Regeneron; September 21, 2012. Available at:
    http://investor.regeneron.com/releasedetail.cfm?releaseid=708835. Accessed: October 1, 2012.
  7. Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the DA VINCI Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology. 2012;119(8):1658-1665.
  8. Bandello F, Berchicci L, La Spina C, et al. Evidence for anti-VEGF treatment of diabetic macular edema. Ophthalmic Res. 2012;48 Suppl 1:16-20.
  9. Lang GE. Diabetic macular edema. Ophthalmologica. 2012;227 Suppl 1:21-29.
  10. Zechmeister-Koss I, Huic M. Vascular endothelial growth factor inhibitors (anti-VEGF) in the management of diabetic macular oedema: A systematic review. Br J Ophthalmol. 2012;96(2):167-178.
  11. Stewart MW. Anti-vascular endothelial growth factor drug treatment of diabetic macular edema: The evolution continues. Curr Diabetes Rev. 2012;8(4):237-246.
  12. Virgili G, Parravano M, Menchini F, Brunetti M. Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for diabetic macular oedema. Cochrane Database Syst Rev. 2012;12:CD007419.
  13. Moradi A, Sepah YJ, Sadiq MA, et al. Vascular endothelial growth factor trap-eye (Aflibercept) for the management of diabetic macular edema. World J Diabetes. 2013;4(6):303-309.
  14. Pershing S, Enns EA, Matesic B, et al. Cost-effectiveness of treatment of diabetic macular edema. Ann Intern Med. 2014;160(1):18-29.
  15. Mitchell P, Wong TY; Diabetic Macular Edema Treatment Guideline Working Group. Management paradigms for diabetic macular edema. Am J Ophthalmol. 2014;157(3):505-513.
  16. National Institute for Health and Care Excellence (NICE). Aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that has progressed following prior oxaliplatin-based chemotherapy. London, UK: National Institute for Health and Care Excellence (NICE); March 2014.
  17. Fraser CE, D’Amico DJ. Diabetic retinopathy: Prevention and treatment. UpToDate [serial online]. Waltham, MA: UpToDate; reviewed June 2014. 
  18. Agarwal N, Di Lorenzo G, Sonpavde G, Bellmunt J. New agents for prostate cancer. Ann Oncol. 2014 Mar 20 [Epub ahead of print].
  19. Regeneron Pharmaceuticals, Inc. Eylea (aflibercept) injection receives FDA approval for the treatment of diabetic macular edema (DME). Press Release. Tarrytown, NY: Regeneron; July 29, 2014.
  20. Regeneron Pharmaceuticals, Inc. Eylea (aflibercept) injection receives FDA approval for macular edema following retinal vein occlusion (RVO). Press Release. Tarrytown, NY: Regeneron; October 6, 2014.

Bevacizumab (Avastin):

  1. Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603-615.
  2. Dani C, Frosini S, Fortunato P, et al. Intravitreal bevacizumab for retinopathy of prematurity as first line or rescue therapy with focal laser treatment. A case series. J Matern Fetal Neonatal Med. 2012;25(11):2194-2197.
  3. Choovuthayakorn J, Ubonrat K. Intravitreal bevacizumab injection in advanced retinopathy of prematurity. J Med Assoc Thai. 2012;95 Suppl 4:S70-S75.
  4. Autrata R, Senkova K, Holousova M, et al. Effects of intravitreal pegaptanib or bevacizumab and laser in treatment of threshold retinopathy of prematurity in zone I and posterior zone II -- four years results. Cesk Slov Oftalmol. 2012;68(1):29-36.
  5. Ho A, Scott I, Kim S, et al. Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: A report by the American Academy of Ophthalmology. Ophthalmology. 2012;119(10):2179-2188.
  6. Jalali S, Balakrishnan D, Zeynalova Z, et al. Serious adverse events and visual outcomes of rescue therapy using adjunct bevacizumab to laser and surgery for retinopathy of prematurity. The Indian Twin Cities Retinopathy of Prematurity Screening database Report number 5. Arch Dis Child Fetal Neonatal Ed. 2013;98(4):F327-F333.
  7. Martinez-Castellanos MA, Schwartz S, Hernandez-Rojas ML, et al. Long-term effect of antiangiogenic therapy for retinopathy of prematurity up to 5 years of follow-up. Retina. 2013;33(2):329-38.
  8. Wu WC, Kuo HK, Yeh PT, et al. An updated study of the use of bevacizumab in the treatment of patients with prethreshold retinopathy of prematurity in Taiwan. Am J Ophthalmol. 2013;155(1):150-158.
  9. Harder BC, Schlichtenbrede FC, von Baltz S, et al. Intravitreal bevacizumab for retinopathy of prematurity: Refractive error results. Am J Ophthalmol. 2013;155(6):1119-1124.
  10. Paysse EA. Retinopathy of prematurity. UpToDate [serial online]. Waltham, MA: UpToDate; reviewed June 2013.
  11. Sahin A, Sahin M, Cingu AK, et al. Intravitreal bevacizumab monotherapy in retinopathy of prematurity. Pediatr Int. 2013;55(5):599-603.
  12. Kim J, Kim SJ, Chang YS, Park WS. Combined intravitreal bevacizumab injection and zone 1 sparing laser photocoagulation in patients with zone 1 retinopathy of prematurity. Retina. 2014;34(1):77-82.
  13. Kim JH, Seo HW, Han HC, et al. The effect of bevacizumab versus ranibizumab in the treatment of corneal neovascularization: A preliminary study. Korean J Ophthalmol. 2013;27(4):235-242.
  14. Papathanassiou M, Theodoropoulou S, Analitis A, et al. Vascular endothelial growth factor inhibitors for treatment of corneal neovascularization: A meta-analysis. Cornea. 2013;32(4):435-444.
  15. Petsoglou C, Balaggan KS, Dart JK, et al. Subconjunctival bevacizumab induces regression of corneal neovascularisation: A pilot randomised placebo-controlled double-masked trial. Br J Ophthalmol. 2013;97(1):28-32.
  16. Krizova D, Vokrojova M, Liehneova K, Studeny P. Treatment of corneal neovascularization using anti-VEGF bevacizumab. J Ophthalmol. 2014;2014:178132.
  17. Kuo CJ. Overview of angiogenesis inhibitors. UpToDate [serial online]. Waltham, MA: UpToDate; reviewed July 2014.
  18. Hu Q, Qiao Y, Nie X, et al. Bevacizumab in the treatment of pterygium: A meta-analysis. Cornea. 2014;33(2):154-160.
  19. Aravantinos G, Pectasides D. Bevacizumab in combination with chemotherapy for the treatment of advanced ovarian cancer: A systematic review. J Ovarian Res. 2014;7:57.


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