CATT: Lucentis and Avastin equally effective for wet AMD Avastin and Lucentis had equivalent effects on visual acuity at 1 year, accirding to the much anticipated Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) research group.

Clinical trials have established the efficacy of Lucentis (ranibizumab) for the treatment of neovascular age-related macular degeneration (AMD). In addition, Avastin (bevacizumab) is used off-label to treat AMD, despite the absence of similar supporting data.

Avastin is the most commonly used drug in the United States for the treatment of neovascular AMD, despite the absence of large-scale clinical-trial data supporting its use. Also, an as-needed regimen has been widely adopted for Lucentis, a departure from the monthly regimen that was used in the pivotal trials of this drug. The Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) study set out to assess the relative efficacy and safety of Lucentis and Avastin and to determine whether an as-needed regimen would compromise long-term visual acuity, as compared with monthly dosing.

Methods and Results

In a multicenter, single-blind, noninferiority trial, 1208 patients with neovascular AMD were randomly assigned to receive intravitreal injections of Lucentis or Avastin on either a monthly schedule or as needed with monthly evaluation.

Eligibility criteria included an age of 50 years or more, the presence in the study eye (one eye per patient) of previously untreated active choroidal neovascularization due to AMD, and visual acuity between 20/25 and 20/320 on electronic visual-acuity testing.

Inclusion criteria were neovascularization, fluid, or hemorrhage under the fovea.

Patients were randomly assigned to one of four study groups. Study groups were defined according to the drug and the regimen of administration after the first mandatory intravitreal injection: ranibizumab every 28 days (ranibizumab monthly), bevacizumab every 28 days (bevacizumab monthly), ranibizumab only when signs of active neovascularization were present (ranibizumab as needed), and bevacizumab only when signs of active neovascularization were present (bevacizumab as needed).

Every 28 days, patients in the groups that received study drugs as needed underwent time-domain OCT and were evaluated for treatment. Time-domain OCT was performed with the use of macular thickness maps and fast macular thickness maps. Signs of active neovascularization were defined as fluid on OCT, new or persistent hemorrhage, decreased visual acuity as compared with the previous examination, or dye leakage or increased lesion size on fluorescein angiography.

The primary outcome was the mean change in visual acuity at 1 year, with a non-inferiority limit of 5 letters on the eye chart. Secondary outcomes included the proportion of patients with a change in visual acuity of 15 letters or more, the number of injections, the change in fluid and foveal thickness on OCT (as measured by the OCT Reading Center), the change in lesion size on fluorescein angiography (as measured by the Fundus Photograph Reading Center), the incidence of ocular and systemic adverse events, and annual drug cost (per-dose cost, approximately $2,000 for ranibizumab and $50 for bevacizumab).

At 1 year, Avastin administered monthly was equivalent to Lucentis administered monthly, with 8.0 and 8.5 letters gained, respectively. Avastin administered as needed was equivalent to Lucentis as needed, with 5.9 and 6.8 letters gained, respectively.

At 1 year, Lucentis as needed was equivalent to monthly Lucentis, although the comparison between Avastin as needed and monthly Avastin was inconclusive.

The mean decrease in central retinal thickness was greater in the Lucentis-monthly group (196 µm) than in the other groups (152 to 168 µm).

Rates of death, myocardial infarction, and stroke were similar for patients receiving either Avastin or Lucentis. The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with Avastin than with Lucentis (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.

Discussion and Conclusions

In each of the head-to-head comparisons of Lucentis with Avastin, the drugs had equivalent effects on visual acuity at all time points throughout the first year of follow-up. The mean number of letters gained, the proportion of patients in whom visual acuity was maintained (<15 letters lost), and the proportion of those who had a gain of at least 15 letters were nearly the same for each drug when the regimen was the same.

We also found that excellent results for visual acuity could be achieved with less-than-monthly regimens for both drugs. Lucentis given as needed was equivalent to Lucentis given monthly, with a mean difference of 1.7 letters. Avastin given as needed was equivalent to Avastin given monthly at all time points through 36 weeks (with mean differences all within 1.6 letters); at 52 weeks, the difference of 2.1 letters yielded an inconclusive comparison. The mean gains of 5.9 letters with Avastin given as needed and of 6.8 letters with Lucentis given as needed are the best outcomes observed with less-than-monthly regimens in any large, multicenter clinical trial of Lucentis. There are several possible explanations. Previous studies had retreatment guidelines that were set according to time or retinal thickness. The protocol for our study specified treatment whenever there was evidence of disease activity (e.g., fluid on OCT), with no minimum threshold for retinal thickness. This strategy allowed therapy to be more responsive to disease activity. During the first year, patients assigned to Lucentis as needed received a mean of seven injections, which was more than the mean number of injections received in previous studies.

Both Avastin and Lucentis substantially and immediately reduced the amount of fluid in or under the retina. The proportion of patients who had complete resolution of fluid was greater with Lucentis than with Avastin. This difference was evident after the first injection, with no fluid seen at 4 weeks in 27.5% of patients receiving Lucentis and 17.3% of those receiving Avastin, and the difference persisted throughout the first year. In the majority of patients, neither drug eliminated all fluid. Monthly injections of either drug resulted in no increase in the mean lesion area, whereas there was a small increase with injections given as needed.

One of the many factors that contribute to selection of a drug for a patient is cost. A single dose of Lucentis costs 40 times as much as a single dose of Avastin. This cost differential has important economic implications when extrapolated to the more than 250,000 patients who are treated for neovascular AMD annually in the United States.

Clinical trials of intravenous Avastin in patients with cancer have identified associations with arteriothrombotic events, venous thrombotic events, gastrointestinal perforation and hemorrhage, wound-healing complications, and hypertension. With a limited statistical power to detect important adverse events, we found no significant differences between the two drugs in rates of death, arteriothrombotic events, or venous thrombotic events, findings that are consistent with the results of a study of Medicare claims involving more than 145,000 treated patients. However, in our study, the rate of serious systemic adverse events, primarily hospitalizations, was higher among Avastin-treated patients than among Lucentis-treated patients (24.1% vs. 19.0%, P = 0.04). The difference in rates may be attributable to chance, imbalances in baseline health status that were not included in the medical history or multivariate models, or a true difference in risk. Resolving this issue will require many more patients than were available for this study.

In conclusion, Avastin and Lucentis had equivalent effects on visual acuity at 1 year when administered according to the same schedule.

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N Engl J Med. 2011 May 19; 364(20): 1897–1908.