Yesterday, the NEI released the results of the Comparison of AMD Treatments Trial (CATT). The results were published online in the New England Journal of Medicine. Ophthalmology has a rich history throughout all of medicine of leadership in clinical trials. In the early 1950s, Arnall Patz, MD, headed one of the very first (if not the first) large, major, randomized prospective clinical trials (dealing with retinopathy of prematurity) ever performed. The Diabetic Retinopathy Study and the Early Treatment Diabetic Retinopathy Study of the 1970s and 1980s are still considered benchmarks in trial design and conduct. They addressed major clinical questions of significant public health importance. The results of these trials still resonate in our treatment plans today.
The CATT stands with these monumental clinical investigations as a “first” in its own right and a landmark study in the emerging field of comparative effectiveness research. It was a head-to-head comparison of two highly effective anti-VEGF medications — ranibizumab (Lucentis) and bevacizumab (Avastin) — and of two different and widely used dosing regimens — monthly and an “as-needed regimen” — in the management of AMD. It addressed two key clinical questions — “which drug” and “how often” — that confront every ophthalmologist and patient facing treatment for neovascular AMD. And this means over 250,000 patients annually in the United States alone.
The top-line results are important. Analysis of one-year data reveals both drugs to be equally effective in terms of visual acuity in treating eligible patients. Evaluation of Medicare claims data suggests that currently about 60 percent of AMD patients undergoing anti-VEGF treatment receive bevacizumab and about 40 percent receive ranibizumab. The good news for ophthalmologists and patients both is that both drugs are very effective.
The data also demonstrate that an “as-needed” dosing regimen (determined by visual acuity and imaging studies) is also a very effective treatment option — using either drug. This has tremendous implications for patients, but it also places a big compliance burden on physician and patient alike. It must be emphasized that in the CATT “as-needed” arm, even though injections were given “as-needed,” patients were examined monthly and imaged monthly with OCT to determine whether treatment was indicated.
In addition to clinical efficacy, the CATT delivered some intriguing information regarding adverse events. Adverse events may or may not relate to the treatment under investigation, but the information is collected during the course of the study. In the CATT, the median patient age was over 80. A high rate of concurrent diseases, of hospitalizations and of death was expected. In the trial, the number of deaths, heart attacks and strokes were low and similar for both drugs. The cumulative rate of serious adverse events was 24 percent for patients receiving bevacizumab and 19 percent for ranibizumab. Whether this observation is pertinent to the study and whether it will hold up with the year two results is unclear. It is notable that both the half-life of ranibizumab is shorter than bevacizumab and that the dose of bevacizumab used for AMD is 500 times lower than the dose used for cancer treatment.
As with any study of this magnitude, the data set is bound to be phenomenally rich, and mining this data set will occupy the investigators for years to come. For example, we can anticipate forthcoming analysis of extensive retinal imaging data.
Whether the CATT will lead to substantive changes in treatment patterns remains to be seen. However, several things appear self-evident. First, we have scientific data from a fresh study carried out with a great degree of integrity and precision to guide our clinical judgments. Our decisions can now be made in the context of more scientific evidence. Second, we are fortunate to have available to us two pharmaceutical agents of significant efficacy. The choice of treatment plan should be made in concert by the treating ophthalmologist and the patient. The choice can be complex, involving issues of prior treatment, coincident systemic disease, cost, logistical factors and personal preference. Both drugs need to be available to patients to maximize choice, but the choice should be based on scientific evidence from carefully controlled trials such as CATT.
Much will be made of the economic and health policy implications of CATT, since we have two drugs of such widely varying cost and similar efficacy. It is important that these discussions take place, since the science of ophthalmology is enmeshed within health care policy, coverage decisions and systemic economic impact.
We should not underestimate the importance of CATT as a touchstone for future comparative effectiveness research. The CATT leaders literally had to establish coalitions to help with thorny issues of Medicare drug payment in clinical trials, co-payments, treatment masking and gaining approval from individuals and agencies not normally involved in more typical clinical trials. The work that they did, the policies that were changed, and the legislation passed benefited not only CATT, but many trials yet to come. The American Academy of Ophthalmology was proud to play a role in facilitating that work. The impact of this trial will go far beyond AMD, beyond retina and beyond ophthalmology. It will impact how future clinical trials research is conducted in all of medicine. As ophthalmologists, we should be proud to have blazed this new trail and continued the rich history of seminal clinical trials design begun by Dr. Patz and his co-workers.
Congratulations to Genentech for developing the drugs and getting them to market, congratulations to all in Washington and particularly at the NEI who allowed the trial to go forward, and congratulations to the trials leaders (particularly Dan Martin, MD) and the investigators for designing and conducting a benchmark piece of science. And, finally, thank you to the 1,200 patients whose commitment to the importance of answering critical clinical questions led them to participate in the trial.