The results of two review studies published earlier this week in the web-based Early Release edition of the Journal ofthe American Medical Association (JAMA) have questioned the safety of a widely-prescribed class of arthritis
pain medications known as cyclooxygenase-2 (COX-2) inhibitors and, in some cases, suggesting that the use of COX-2 agents may actually double the patients risk of a significant cardiovascular event. A third study, which appeared in the journal Circulation, specifically studied the drug celecoxib (Celebrex(TM)).
COX-2 inhibitors have been widely touted as being more selective in their actions and thus decreasing the severity of abdominal pain, gastrointestinal bleeding, or other side effects that had been reported with other anti-inflammatory pain medications (all drugs in this class, which includes aspirin, are generally known as Non-Steroidal Anti-Inflammatory Drugs or NSAIDS). In the , COX-2 inhibitors are available by prescription only.In the Circulation report, Scott Solomon and colleagues from the Brigham & Women’s Hospital in Boston conducted a meta review (retrospective review of data accumulated by other researchers) and found that celecoxib was associated with an increased risk (reported as Hazard Ratio [HR] with 1.0 being considered as “baseline”) of cardiovascular events in what appeared to be a dose-related manner (400mg once daily = 1.3 HR; 200mg twice daily = 2.6 HR; 400mg twice daily = 3.4 HR).
In the first JAMA report Jingjing Zhang (Harvard School of Public Health in Boston, Massachusetts) and colleagues, focused on only possible renal function and heart rhythm abnormalities that may be associated with COX-2 inhibitors by retrospectively reviewing the results of data from 114 clinical trials involving 116,094 patients. The results of this review indicated that rofecoxib was associated with increased risk for fluid retention, hypertension, and decreased kidney function at both low and high doses. Risk for abnormal heart rhythm was also increased with rofecoxib (Vioxx was withdrawn from the market by its maker, Merck, in 2004) but neither renal effects nor arrhythmias were seen with other COX-2 inhibitors.
The second JAMA report, by Patricia McGettigan and David Henry (both from the University of Newcastle in New South Wales, ), was a systematic review of observational studies focusing on the cardiovascular risk of COX-2 selective and nonselective NSAIDs. Their results indicated that cardiovascular risk was also increased with diclofenac (Cataflam(TM), Voltaren(TM), Voltaren-XR(TM)), indomethacin (Advil(TM), Medipren(TM)) and meloxicam (Mobix(TM)) as well as with rofecoxib (Vioxx). Naproxen (Naprosin(TM), Aleve(TM)) was not cardioprotective, as has been previously suggested, but appeared to have a neutral risk, and results with ibuprofen (Advil(TM), Motrin(TM), Nuprin(TM), Medipren(TM)) were inconclusive.
Writing in the Discussion section of their report, the authors conclude that their “… review confirms the findings from randomized trials regarding the risk of cardiovascular events with rofecoxib and suggests that celecoxib in commonly used doses may not increase the risk, contradicts claims of a protective effect of naproxen, and raises serious questions about the safety of diclofenac…”
Discussion in summary, the above reports identify a potentially dangerous side-effect of a class of medications that are in widespread use in the and Abroad. While not specifically identifying the role of concurrent risk factors in subsequent cardiovascular events among COX-2 users, intuition would indicate a substantially higher risk in these patients. Those that are at risk for cardiac disease and currently taking COX-2 inhibitors should discuss their concerns with their health care provider.
The above-mentioned articles demonstrate the need for continuing oversight and evaluation of medications after they pass the FDA’s final approval and are released to the market. Also note that the 3 reports were produced by institutions and agencies outside the FDA. While there is no evidence that any drug manufacturer was less than thorough in the clinical trials prior to the release of these medications, the fact that private sector institutions and agencies were the first to report on the potential cardiac side effects of COX-2 inhibitors is disquieting. This writer is not the only observer to note the apparent shortcomings of post-release surveillance of new medications.In
In an editorial comment accompanying the JAMA reports David Graham, MD delivered a blistering condemnation of thFDA’s’s review and approval process. Despite being a senior official at the FDA, Graham is also one of its harshest critics. I urge those that are concerned about the possible bias toward manufacturers by the FDA to read Dr. Graham’opinions.ReferencesGraham
Graham, David. COX-2 InNSAIDsrs, Other NSAIDs, and Cardiovascular Risk. JAMA 2Jingjing.
et alnal and Arrhythmia EvCyclo-oxygenaseysis of Randomized Trials. JAMA 2006; 296.
McGettigan, Patricia and Henry, David. Cardiovascular Risk and Inhibition of Cyclo-oxygenase: A Systematic Review of the ObservationCyclo-oxygenaseelective and Nonselective Inhibitors of Cyclo-oxygenase-2. JAMA2006;Nonselective
n, Scott et alCyclo-oxygenaseecoxib on Cardiovascular Events anetBalod Pressure Celecoxibials for the Prevention of Colorectal Adenomas (Circulation 2006; 114:1028-1035).
ColorectalTAdenomasmation presented in this article anDisclaimerThed links is of an informational nature only and is not intended as a recommendation of any changes in the reader’s health care program. Before making any changes in diet, medications, or other treatments the reader is strongly advised to consult with their health care provider.