Risks of CVD for COX-2 inhibitors lower than previously reported

Feb 27 2008

In an article published in the March issue of the Journal of Cardiovascular Pharmacology and Therapeutics, researchers from Florida Atlantic University (FAU) assess the totality of evidence, including strengths and limitations of different types of evidence contributing to the debate about cardiovascular disease (CVD) risks of cyclooxygenase-2 (COX-2) inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs).

In the article, “Cyclooxygenese-2 Inhibitors and Most Traditional Non-steroidal Anti-Inflammatory Drugs Cause Similar Moderately Increased Risks of Cardiovascular Disease,” the researchers conclude that the risks of CVD for COX-2 inhibitors are no greater than most traditional NSAIDs, except naproxen, and are smaller than previously suggested. The research was coauthored by Charles H. Hennekens, M.D., the first Sir Richard Doll Research Professor in the Charles E. Schmidt College of Biomedical Science at FAU, and Steven Borzak, M.D., a clinical associate professor at FAU. Hennekens has elucidated numerous causal, therapeutic and preventive factors in the treatment and prevention of CVD, most notably low-dose aspirin.

Selective COX-2 inhibitors were believed to cause large CVD risks, including heart attacks, strokes and deaths. Of the originally marketed drugs, rofecoxib (Vioxx), lumaricoxib (Bextra) and celecoxib (Celebrex), only the latter remains on the U.S. market. Traditional NSAIDs are frequently used to treat inflammatory arthritis and are often the first line drug prescribed by health care providers or selected by patients to relieve pain and reduce inflammation. Drugs in this class include ibuprofen (e.g. Motrin, Advil), diclofenac (e.g. Voltarin) and naproxen (e.g. Aleve).

Some of the key findings of the research are that:

• In the observational studies suggesting large CVD hazards, the results were not consistent and the patients prescribed COX-2 inhibitors were systematically different from those prescribed other drugs. Because of uncontrolled as well as uncontrollable confounding by indication inherent in all observational studies, it was not possible to discern whether, and if so, how much of the observed high risks were real.
• Although randomized drug trials of sufficient size, dose and duration provide the most reliable design strategy to test the most plausible small to moderate benefits (or harm), randomized trials for COX-2 inhibitors were designed to demonstrate lower side effects than traditional NSAIDs on the gastrointestinal tract and were not specifically designed to evaluate risks of CVD.
• The COX-2 inhibitors and NSAIDs have not been adequately studied in large-scale randomized trials of sufficient size, dose and duration. Even the most reliable quantitation of the magnitude of the effects of COX-2 inhibitors and NSAIDs on the risk of vascular events is based on relatively small numbers of CVD endpoints. The most comprehensive world-wide meta-analysis includes data from 138 randomized trials.
• COX-2 inhibitors produce moderately increased risks of CVD, almost exclusively nonfatal heart attacks, which are similar to those caused by most traditional NSAIDs other than naproxen.
• Indirect comparisons showed similar increases for rofecoxib and celecoxib, the most widely studied of the COX-2 inhibitors.
• The totality of available data suggest that for relief of pain of inflammatory arthritis, naproxen may have the best benefit to risk ratio on CVD.
• The authors speculate that the findings on naproxen may be due to its long acting aspirin-like cardio-protective antiplatelet effects which may counterbalance any prothrombotic (predisposition to the formation of a blood clot) effects of these classes of drugs.

“At present, individual clinical judgments about COX-2 inhibitors and NSAIDs should not be limited to risks of CVD,” said Hennekens. “They should also include concerns about non-CVD risks such as gastrointestinal bleeding, and other benefits, including improved quality of life resulting from decreases in impairment from musculoskeletal pain syndromes.”

Florida Atlantic University opened its doors in 1964 as the fifth public university in Florida. Today, the University serves more than 26,000 undergraduate and graduate students on seven campuses strategically located along 150 miles of Florida's southeastern coastline. Building on its rich tradition as a teaching university, with a world-class faculty, FAU hosts ten colleges: College of Architecture, Urban & Public Affairs, Dorothy F. Schmidt College of Arts & Letters, the Charles E. Schmidt College of Biomedical Science, the Barry Kaye College of Business, the College of Education, the College of Engineering & Computer Science, the Harriet L. Wilkes Honors College, the Graduate College, the Christine E. Lynn College of Nursing and the Charles E. Schmidt College of Science.