Researchers today reported results from the first year of the Comparison of AMD Treatments Trials (CATT), the first head-to-head comparisons of ranibizumab (Lucentis) with bevacizumab (Avastin). The two drugs had equivalent effects on visual acuity at all time points throughout the first year of follow-up. In especially good news for patients, the results show equivalent visual-acuity outcomes with both monthly and as-needed regimens, and no safety issues were observed.
The National Eye Institute, part of the National Institutes of Health, sponsored the randomized trial involving 1,208 patients in 43 centers across the US. Patients were randomly assigned and treated with one of four regimens for a year. They received Lucentis monthly or PRN, or Avastin monthly or PRN. Enrollment criteria required that study participants had active disease.
Patients in the monthly dosing groups received an initial treatment and then had an injection every 28 days. Patients in the PRN groups received an initial treatment and were then examined every 28 days to determine medical need for additional treatment. PRN groups received subsequent treatment when there were signs of disease activity on optical coherence tomography (OCT). Patients in the PRN group received an average of four to five injections over the course of the year.
In a press conference, Daniel F. Martin, MD, study chair for CATT, and chairman of the Cole Eye Institute at the Cleveland Clinic, said that one-year visual acuity results were "virtually identical" between the two drugs.
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.
Patients treated with as-needed bevacizumab compared less favorably with monthly regimens for either bevacizumab or ranibizumab. But the difference was small. "There was a two-letter difference with PRN dosing compared with monthly injections, but the overall results were excellent," Dr. Martin said.
The OCT retinal thickness measurements did favor ranibizumab, but this difference is not reflected in any of the visual-acuity or angiographic outcomes. Whether this difference is associated with changes in vision should become clear during the second year of follow-up.
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 percent vs. 19.0 percent), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.
CATT results were scheduled to be presented for the first time this Sunday, May 1, at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Fort Lauderdale, Fla. But plans were changed after The New York Times published an article yesterday describing the study's findings.
However, another study on this subject will debut at ARVO this weekend. The drugs' maker, Genentech, has sponsored a study suggesting safety issues with bevacizumab.
The retrospective study looked at records of nearly 78,000 Medicare recipients with AMD and found that those who received bevacizumab had an 11 percent higher risk of dying and a 57 percent higher risk of hemorrhagic stroke than those getting ranibizumab, according to an abstract of the study.
Genentech arranged for the lead investigator of this study, Dr. Emily W. Gower of Johns Hopkins University, to brief Congressional staffers on the results on Tuesday.
At today's press conference, Dr. Martin stated emphatically that the CATT study detected no differences in the safety profile between the two drugs.
"There is absolutely no difference in rates of death, myocardial infarction or stroke," Dr. Martin said, noting that the Johns Hopkins/Genentech study is not peer reviewed. "It's a retrospective analysis of a subset of patients from an administrative database." The level of evidence offered simply doesn't compare with CATT, a randomized, controlled, multi-center trial.
Additionally, the higher rate of serious systemic adverse events among bevacizumab-treated patients represents events 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, given twice a month.
More importantly, Dr. Martin said, they saw higher rates of systemic adverse events among patients given less of the drug. He said 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. But resolving this issue will require a much larger study. The CATT trial was insufficiently powered to identify differences in drug-related adverse events.
In an editorial published with the study results, Philip J. Rosenfeld, MD, Ph.D., the physician who pioneered the use of bevacizumab in AMD patients, wrote:
"The CATT results, together with the totality of global experience, support the use of either bevacizumab or ranibizumab for the treatment of neovascular AMD. An as-needed regimen is an acceptable alternative to a monthly regimen, but strict compliance on the part of both the clinician and the patient is required. Health care providers and payers worldwide will now have to justify the cost of using ranibizumab. Regulators in certain countries will be forced to reconsider their policies that make it illegal to use drugs off-label, particularly when so many of their citizens cannot afford ranibizumab. The CATT data support the continued global use of intravitreal bevacizumab as an effective, low-cost alternative to ranibizumab."