NIA statement data published on safety review of anti-inflammatory drugs in ADAPT Alzheimer's disease clinical trial
On Dec. 17, 2004, the Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT) Steering Committee suspended treatments with two non-steroidal anti-inflammatory drugs (NSAIDs) in a large, three-arm, national Alzheimer’s disease prevention trial. ADAPT, sponsored by the NIH’s National Institute on Aging (NIA), was designed to test the potential benefit of long-term use of naproxen sodium (220 mg twice a day) and celecoxib (200 mg twice a day) in decreasing risk of Alzheimer’s disease and cognitive decline in non-symptomatic people 70 and older who were at elevated risk because of family history of the disease.
The ADAPT Steering Committee halted the Alzheimer’s trial medications following a report earlier in the day linking use of celecoxib to increased risk of cardiovascular disease in an unrelated clinical trial for cancer prevention [APC: Adenoma Prevention with Celecoxib] and after a preliminary review of data from ADAPT signaled a possible increased risk for heart disease and stroke among participants taking naproxen. While the naproxen data were not considered sufficient in themselves to warrant interruption of treatment, they raised substantial concerns about the practicality or wisdom of continuing ADAPT as a two-arm trial comparing naproxen and placebo. The ADAPT data did not suggest a similarly increased risk of cardiovascular disease related to celecoxib.
At the time the ADAPT medications were halted, the investigators and the NIH promised to notify the public and health professionals as soon as their data became available in a peer-reviewed publication. Those data appear in the Nov. 17, 2006, issue of PLoS Clinical Trials, a journal of the Public Library of Science, reported by the ADAPT Research Group, with Barbara K. Martin, Ph.D., of the Johns Hopkins Bloomberg School of Public Health as corresponding author.
According to the journal report, “For celecoxib, the ADAPT data do not show the same level of risk as those of the APC trial. The data for naproxen, although not definitive, are suggestive of increased cardiovascular and cerebrovascular risk.” The researchers emphasize that the results are not definitive because of the relatively small numbers of heart attacks and strokes during the trial. The risk analysis is also limited because the study was intended to measure cognitive symptoms and dementia, not heart disease and stroke, as the primary outcomes of drug treatment.
“The ADAPT researchers and the NIH felt it important to follow up with a thorough review of the safety data and to then make that review available to the scientific community and the broader public,” says Richard J. Hodes, M.D., director of NIA. “Though the results of the review did not produce definitive answers on the risks and benefits of NSAIDs in patients at risk of Alzheimer’s disease, they add to the body of information on the safety of these anti-inflammatory drugs.”
Several recent reports have summarized available data from multiple studies related to the safety of specific NSAID agents and provide a broad perspective on this important and complex issue, Hodes noted. These include recent systematic reviews and meta-analyses of cyclooxygenase 2 (COX-2) inhibitors and an editorial on NSAIDs in the October 4, 2006, Journal of the American Medical Association.
The ADAPT trial began in 2001 and was conducted in six U.S. cities: Tampa, Fla.; Rochester, N.Y.; Baltimore, Md.; Sun City, Ariz.; Seattle, Wash.; and, Boston, Mass. Approximately 2,500 people were enrolled in ADAPT when the medications were suspended. About 1,100 enrollees were assigned to a control group, while about 700 received celecoxib and another 700 received naproxen. In their safety analysis, researchers counted participants who experienced death due to heart disease or stroke, non-fatal heart attack or stroke, congestive heart failure and transient ischemic attack (brief stroke), or who started high blood pressure treatment during the trial.
Investigators are continuing to follow volunteers in the trial for cardiovascular and cognitive symptoms, and dementia.
NIA leads the federal effort supporting and conducting research on aging and the medical, social and behavioral issues of older people, including Alzheimer’s disease and age-related cognitive decline. For information on dementia and aging, please visit the NIA’s Alzheimer’s Disease Education and Referral (ADEAR) Center at www.nia.nih.gov/alzheimers, or call 1-800-438-4380. For more general information on research and aging, go to www.nia.nih.gov.
The National Institutes of Health (NIH) — the Nation's Medical Research Agency — includes 27 institutes and centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.