In each of the head-to-head comparisons of ranibizumab with bevacizumab, 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 ( and ).
We also found that excellent results for visual acuity could be achieved with less-than-monthly regimens for both drugs. Ranibizumab given as needed was equivalent to ranibizumab given monthly, with a mean difference of 1.7 letters. Bevacizumab given as needed was equivalent to bevacizumab 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 bevacizumab given as needed and of 6.8 letters with ranibizumab given as needed are the best outcomes observed with less-than-monthly regimens in any large, multicenter clinical trial of ranibizumab.17–19
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 ranibizumab as needed received a mean of seven injections, which was more than the mean number of injections received in previous studies.17–19
We primarily assessed disease activity by means of time-domain OCT. In the second year of this ongoing study, we are investigating whether the use of high-resolution spectral-domain OCT results in increased detection of fluid and subsequent treatment.
Both bevacizumab and ranibizumab 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 ranibizumab than with bevacizumab. This difference was evident after the first injection, with no fluid seen at 4 weeks in 27.5% of patients receiving ranibizumab and 17.3% of those receiving bevacizumab, and the difference persisted throughout the first year. The absolute between-drug difference in the amount of residual fluid was small (), and in the majority of patients, neither drug eliminated all fluid. The greater prevalence of fluid in the group given bevacizumab as needed led to an average of 0.8 more injections during the first year than in the group given ranibizumab as needed. 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 (). On the basis of data from the 2-year analysis, we will evaluate the cumulative effect of the presence of fluid and change in lesion size on visual acuity.
One of the many factors that contribute to selection of a drug for a patient is cost. A single dose of ranibizumab costs 40 times as much as a single dose of bevacizumab. 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 bevacizumab in patients with cancer have identified associations with arteriothrombotic events, venous thrombotic events, gastrointestinal perforation and hemorrhage, wound-healing complications, and hypertension.20,21
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.22
However, in our study, the rate of serious systemic adverse events, primarily hospitalizations, was higher among bevacizumab-treated patients than among ranibizumab-treated patients (24.1% vs. 19.0%, P = 0.04). The excess numbers of these events were distributed over many different types of conditions, most of which were not identified in cancer trials involving patients who were receiving intravenous doses of bevacizumab that were 500 times those used in intravitreal injections. We also did not observe increased rates of adverse events with increased exposure to the study drugs; rates were higher for the two drugs when given as needed than when given monthly. 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. Results from the second year of this study and from other comparative trials will provide more information regarding the relative risks of serious adverse events.