A meta-analysis of randomized trials of ranibizumab for age-related macular degeneration (AMD) to elucidate systemic vascular risk included 11 trials comprising 6596 patients with AMD «Ueta T, Noda Y, Toyama T ym. Systemic vascular saf...»1. Comparisons between different intensities of ranibizumab regimens in terms of dose and retreatment frequency were performed. End points were incidence of cerebrovascular accidents (CVAs), myocardial infarctions, non-ocular hemorrhages, overall arterial thromboembolic events (ATEs), and all-cause mortality. A non-significant increase was observed in monthly vs. pro re nata risk for CVA (OR, 2.04; 95% CI, 0.94–4.45; p=0.07), nonocular hemorrhages (OR, 1.54; 95% CI, 0.98–2.42; p=0.06) and ATEs (OR, 1.58; 95% CI, 0.96–2.61; p=0.07).
Comment: A significant increase in the risk for CVA was demonstrated, when monthly dosing was compared with combined 0 mg/PRN group (OR, 1.89; 95% CI, 1.06-3.38; p=0.03).
In the CATT study «Comparison of Age-related Macular Degeneration Tre...»21185 patients with neovascular AMD were initially enrolled in the clinical trial, whereas 1107 of them were followed-up for 2 years. Patients were randomized in 4 groups: ranibizumab 0.5 mg or bevacizumab 1.25 mg and dosing regimen monthly or as needed. At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment. Primary end point was mean change in visual acuity. Secondary end points were: proportion of patients with a change in visual acuity of ≥15 letters, number of injections, drug costs, presence of fluid and change in foveal retinal thickness, change in lesion size on fluorescein angiography and incidence of systemic and ocular adverse events.
Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; p=0.046). After adjusting for baseline predictors of visual acuity in a multivariable longitudinal regression model, the estimated change in visual acuity, averaged over 2 years of follow-up, was 1.7 letters better for patients treated monthly (CI: [−0.1, 3.4]; p=0.07).
The mean (standard deviation) number of injections through year 2 in the as-needed groups, out of a maximum of 26, was 12.6 (6.6) for patients treated with ranibizumab and 14.1 (7.0) for those treated with bevacizumab (p=0.01). The estimated 2-year drug cost per patient varied from $705 in the bevacizumab-as-needed group to $44.800 in the ranibizumab-monthly group. At 2 years, mean retinal thickness was 29 µm less in patients treated monthly than in patients treated with an as-needed regimen (regimen p=0.005).
The proportion of patients without fluid on OCT ranged from 13.9%in the bevacizumab-as-needed group to 45.5%in the ranibizumab-monthly group (drug p=0.0003; regimen p<0.0001). Fluorescein dye leakage was absent in a higher percentage of patients treated monthly than in patients treated as needed (regimen p=0.002).
The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; p=0.009). Patients treated as needed had higher rates than patients treated monthly, but the difference was not statistically significant (risk ratio 1.20; CI: [0.98, 1.47]; p=0.08).
In the IVAN trial «Dakin HA, Wordsworth S, Rogers CA ym. Cost-effecti...»3 610 patients with untreated neovascular AMD were randomized in 4 groups: 0.5 mg ranibizumab given continuously (monthly) for 2 years; 0.5 mg ranibizumab given continuously (monthly) for 3 months, followed by further courses on 3 monthly injections if clinically indicated; 1.25 mg bevacizumab given continuously (monthly) for 2 years; 1.25 mg bevacizumab given continuously (monthly) for 3 months, followed by further courses on 3 monthly injections if clinically indicated. The primary end points were quality-adjusted life-years (QALYs) and their costs (costs incurred by patients and their families or employers were excluded).
The number of QALYs accrued over the 2-year trial period did not differ significantly between bevacizumab and ranibizumab, or between continuous and discontinuous treatments (p≥0.381). Ranibizumab was significantly more costly than bevacizumab for both continuous (+£14 989/patient [$23 468]; 95% CI £14 522 to £15 456; p<0.001). Using continuous rather than discontinuous treatment increased costs by £7090 ($11 102 [95% CI £6337 to £7844], p<0.001) for ranibizumab and £599 ($938 [95% CI £91 to £1107], p=0.021) for bevacizumab. The cost of medication changes, hospitalisations and ambulatory consultations associated with expected SAEs and expected AEs was relatively small (mean: £469 [$735] per patient), but varied substantially between patients (95th centile range: £0, £1401). There was no significant difference in such costs between drugs or between treatment regimens (p≥0.163).
Comment: Exclusion of costs incurred by patients, families and employers may underestimate the difference between continuous and discontinuous regimens.
In a cohort within a randomized clinical trial, the risk of development of geographical atrophy (GA) in patients with AMD was studied «Grunwald JE, Daniel E, Huang J ym. Risk of geograp...»4. Patients were those 1024 CATT patients with AMD and with no GA visible on color fundus photographs (CFPs) and/or fluorescein angiograms (FAs) at enrollment. The randomized treatment groups were ranibizumab monthly, ranibizumab pro re nata, bevacizumab monthly and bevacizumab pro re nata. During the 2 years follow-up, GA developed in 187 of 1024 patients (18.3%). Ranibizumab compared with bevacizumab had a higher risk (aHR, 1.43; 95% CI, 1.06–1.93), and monthly dosing had a higher risk (aHR, 1.59; 95% CI, 1.17–2.16) than PRN dosing.
A total of 353 patients with primary or recurrent subfoveal CNV secondary to AMD were randomized to receive 0.3 mg quarterly, 0.5 mg quarterly, or 0.3 mg monthly doses of ranibizumab. Treatment comprised of a loading phase (3 consecutive monthly injections) followed by a 9-month maintenance phase (either monthly or quarterly injection) «Schmidt-Erfurth U, Eldem B, Guymer R ym. Efficacy ...»5. Primary end point was mean change in best-corrected visual acuity (BCVA). Secondary end points were central retinal thickness (CRT) and incidence of adverse events (AEs). In the per-protocol population (293 patients), BCVA, measured by Early Treatment Diabetic Retinopathy Study-like charts, increased from baseline to month 12 by 4.9, 3.8, and 8.3 letters in the 0.3 mg quarterly (104 patients), 0.5 mg quarterly (88 patients), and 0.3 mg monthly (101 patients) dosing groups, respectively. Similar results were observed in the intent-to-treat (ITT) population (353 patients). Thus, the noninferiority of a quarterly regimen was not achieved with reference to 5.0 letters. The mean decrease in CRT from baseline to month 12 in the ITT population was -96.0 µm in 0.3 mg quarterly, -105.6 mum in 0.5 mg quarterly, and -105.3 mum in 0.3 mg monthly group. The most frequent ocular AEs were conjunctival hemorrhage (17.6%, pooled quarterly groups; 10.4%, monthly group) and eye pain (15.1%, pooled quarterly groups; 20.9%, monthly group).
A prospective cohort study within a randomized clinical trial assessed risk factors for scar in eyes treated with ranibizumab or bevacizumab for neovascular AMD «Daniel E, Toth CA, Grunwald JE ym. Risk of scar in...»6. Included were patients with no scar on color fundus photography (CFP) or fluorescein angiography (FA) at enrollment in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Eyes were assigned to ranibizumab or bevacizumab treatment and to 1 of 3 dosing regimens for 2 years. Scar developed in 480 of 1059 eyes (45.3%) by 2 years. Drug and dosing regimen had no statistically significant association with scarring.
The purpose of the study «Schmidt-Erfurth U, Kaiser PK, Korobelnik JF ym. In...»7 was to determine efficacy and safety of intravitreal aflibercept in patients with AMD during a second year of variable dosing after a first-year fixed-dosing period. At baseline 2457 patients were randomised to receive 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), 2 mg aflibercept every 4 weeks (2q4), 0.5 mg aflibercept every 4 weeks (0.5q4), or 2 mg aflibercept every 8 weeks (2q8) after 3 monthly injections. A total of 2235 patients entered the follow-up study and 2063 (91.0%) completed it. During weeks 52 through 96, patients received their original dosing assignment using an as-needed regimen with defined retreatment criteria and mandatory dosing at least every 12 weeks. There were no significant drug or dosing regimen associated differences in adverse events. Most common ocular adverse events were conjunctival hemorrhage (range 23.7-29.9%), retinal hemorrhage (13.6-16.2%), reduced visual acuity (11.3-13.0%), eye pain (8.9-12.1%), vitreous detachment (7.7-10.0%), and increased intraocular pressure (6.2-10.8%) from baseline to week 96. Intraocular inflammation was reported for 1.5%, 1.1%, 0.8%, and 0.5% for Rq4, 2q4, 0.5q4 and 2q8 groups. Serious ocular adverse events occurred for 4.4%, 3.6%, 3.2%, and 3.9%, respectively. The figures for serious non-ocular adverse events were 24.5%, 21.4%, 25.3%, and 25.2%. These events included atrial fibrillation, myocardial infarction, pneumonia, fall, congestive heart failure, coronary artery disease, TIA, cerebrovascular accident, COPD and osteoarthritis. Percentage of specific arterial thromboembolic end points as set forth by the Anti-Platelet Trialists' Collaboration was 3.2% for Rq4 group and 2.4% for 2q4, 3.8% for 0.5q4, and 3.6% for 2q8. The percentage of nonfatal myocardial infarction ranged from 1.0 to 2.0%and nonfatal stroke from 0.5% to 0.8%. The percentage of deaths was 2.7%, 2.1%, 3.2%, and 3.3% for the groups.