Statement: Vioxx (Rofecoxib), Other Cox-2 Inhibitors Have Safety Problems
September 30, 2004
Sidney M. Wolfe, M.D., Director of Public Citizen’s Health Research Group
Today’s announcement by Merck is the latest evidence that this family of drugs, the Cox-2 inhibitors, once referred to as “super aspirins,” are turning out to be more like super disasters. As discussed below, there are safety problems with Celebrex as well as Bextra, the two other big-selling Cox-2 inhibitors that are the most-prescribed alternatives to Vioxx.
In trying to appear “a good citizen,” Merck ignores its checkered history with Vioxx. In today’s statement announcing the withdrawal of Vioxx from the market, Peter S. Kim, Ph.D., president of Merck Research Laboratories asserted that “Merck has always believed that prospective, randomized, controlled clinical trials are the best way to evaluate the safety of medicines.” Yet after an earlier randomized trial, the VIGOR study, published almost four years ago (November 2000), that found Vioxx caused a four- to five-fold increase in heart attacks, Merck received, on Sept. 17, 2001, a warning letter from the U.S. Food and Drug Administration (FDA) because the company’s ads for the drug failed to mention this increased risk of heart attacks. In the eight-page warning letter addressed to Merck President and CEO Raymond V. Gilmartin, the FDA stated:
You have engaged in a promotional campaign for Vioxx that minimizes the potentially serious cardiovascular findings that were observed in the Vioxx Gastrointestinal Outcomes Research (VIGOR) study, and thus, misrepresents the safety profile for Vioxx. Specifically, your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator nonsteroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen).
In Merck’s VIGOR study, comparing rofecoxib to naproxen, there was a highly statistically significant five-fold increase in heart attacks in the overall rofecoxib group (0.5 percent) compared to the naproxen group (0.1 percent). This amounted to 20 heart attacks with rofecoxib (out of 4,047 patients) compared with four with naproxen (out of 4,029 patients). This increased number of heart attacks was also accompanied by an increase in other thrombotic (blood clotting) adverse effects such as strokes and blood clots in the legs as well as problems with hypertension in the rofecoxib group compared with the naproxen group.
In an article published three and a half years ago in our monthly newsletter, Worst Pills, Best Pills News (now online at www.WorstPills.org), we warned readers that both Vioxx and Celebrex were Do Not Use drugs — our designation for drugs that are not safe and effective enough to use. Although Merck’s withdrawal of Vioxx “solves” the serious safety problems with this drug, the most-prescribed alternatives, Celebrex and Bextra, also have some concerns about their cardiac toxicity.
Cardiovascular Toxicity and Cox-2 Inhibitors
In a study published in the Aug. 29, 2000, Proceedings of the National Academy of Sciences, the ability of rabbits to withstand temporary experimental coronary artery occlusion (experimental heart attack) was significantly impaired by treatment with celecoxib (Celebrex), which completely blocked the cardioprotective effects of the COX-2 enzyme. The authors of that study concluded that COX-2 enzyme is a “cardioprotective protein.” Therefore, it is implied, drugs that block this cardioprotective enzyme, such as COX-2 inhibitors, may neutralize its protective effects.
Problems with Celebrex
Although a CLASS study involving Celebrex did not find a significantly elevated number of heart attacks in those using celecoxib compared to those using the older NSAIDs (ibuprofen or diclofenac), there was also cause for concern about heart toxicity with celecoxib. An expert from the FDA’s Division of Cardio-Renal Drug Products, Dr. Douglas Throckmorton, found that “the incidence of adverse events related to cardiac ischemia (decreased blood flow to the heart) was higher in the celecoxib [Celebrex] group ... and was most pronounced in the group of patients not taking ASA (aspirin)” as a cardiovascular protective drug. In these patients, the rate of heart attack was also highest in the celecoxib group (0.2 percent) compared with users of the other two drugs (0.1 percent). For all patients, on and off aspirin, there was a higher incidence of atrial fibrillation, a type of heart rhythm disturbance, in the celecoxib group compared to those taking ibuprofen or diclofenac. Again this was more pronounced in the group not taking aspirin. Dr. Throckmorton concluded by stating that “the data do not exclude a less apparent pro-thrombotic [blood clot-forming] effect of celecoxib, reflected in the relative rates of cardiac adverse events related to ischemia.”
Safety Problems with the New Cox-2 inhibitor, Valdecoxib (Bextra)
We have also warned readers of Worst Pills, Best Pills News not to use Bextra. Because the FDA and Bextra’s manufacturer, Pfizer, refused to give us unpublished data concerning the drug, we filed suit against the agency. The FDA had originally redacted all information in its reviews concerning valdecoxib and acute pain. In the course of our litigation, we received most of what we had requested in the lawsuit, including the unredacted FDA Medical Officer’s conclusions and recommendations about the use of the drug for acute pain.
In the unredacted review the Medical Officer recommended:
Nonapproval [for the treatment] of the acute pain, including opioid-sparing and prevention of operative pain. The only substantial multidose safety database is found in the Coronary Artery Bypass Graft (CABG) Surgery study 035. This study demonstrated an excess of serious adverse events including death in association with the use of paracoxib and valdecoxib 40 mg bid [twice daily] when added to ad lib [as needed] parenteral [injectable] narcotic analgesia. ... These finding[s] warrants further investigation before valdecoxib can be considered safe and effective for the treatment of pain, particularly multidose therapy in the perioperative setting.
In summarizing the safety of valdecoxib the FDA Medical Officer stated:
With two notable exceptions — edema [swelling] and hypertension — valdecoxib (Bextra) was comparable to the standard non-steroidal agents [ibuprofen, naproxen, diclofenac] used as active controls in the trials. ... The finding of a greater incidence of edema and hypertension at doses above 20 mg/day, almost uniformly in the databases and clearly when prospectively addressed in formal safety Trials 47 and 62, is of concern. ... The excess of serious cardiovascular thromboembolic [blood clots] in the valdecoxib arm of the CABG [Coronary Artery Bypass Graft] trial is of note as the entire study population received prophylactic low dose aspirin as part of the standard of care in this setting to minimize just such events. Given the emerging concern over a possible pro-thrombotic action of certain agents in the COX2 class, these data are of concern. (Emphasis added.)
In summary, we advise patients not to use any of these “super aspirin” Cox-2 inhibitors and, instead, to rely on the older drugs in the NSAID family such as ibuprofen and naproxen.