Three clinical trials with 3 COX-2 inhibitors, each showing an increased cardiovascular risk, have been published in full online February 15, 2005 in the New England Journal of Medicine. The papers will appear in print in the March 17, 2005 issue, the journal says; they were released early because of “the possible health implications.”
The 3 papers give details of the CV risk shown for:- Rofecoxib (Vioxx, Merck & Co) in the Adenomatous Polyp Prevention on Vioxx (APPROVE) trial the placebo-controlled data that led to the drug’s withdrawal. – Celecoxib (Celebrex, Pfizer) in the Colorectal Adenoma Prevention (APC) trial the first and so far only signal of an increased CV risk for celecoxib compared with placebo. APC was stopped as a result of this finding, but a second similar trial has shown no increase in CV risk. – The combination of the injectable parecoxib (Dynastat, Pfizer) followed by oral valdecoxib (Bextra, Pfizer) in patients undergoing coronary artery bypass graft (CABG) surgery this is the second trial showing an increased CV risk in this patient population; the other was published earlier. An accompanying editorial, written by Journal editor Dr Jeffrey Drazen, says the 3 trials confirm the cardiovascular toxicity of COX-2 inhibitors which was first suggested 5 years ago and comments that as 3 different drugs were involved, it appears that this is a class effect. “Because there are well-established options for the treatment of all the approved indications for these drugs, it is reasonable to ask whether the use of these drugs can now be justified,” Drazen says. “We must not forget that our first job is to do no harm.”A similar point but a different sentiment is expressed in a second editorial, from Dr Bruce Psaty (Washington University, Seattle) and Dr Curt Furberg (Wake Forest University, Winston-Salem, NC). “In clinical trials, NSAIDs, aspirin, and acetaminophen (paracetamol) are just as effective in relieving pain as the COX-2 inhibitors,” they point out. If a COX-2 inhibitor is necessary, patients should be informed of the potential risks, and the lowest dose should be used for the shortest possible time, they say.Rheumatologist Dr Andrew Laster (in private practice in Charlotte, NC) says these publications are “the final nail in the coffin for the COX-2 inhibitors.” He says he makes these comments reluctantly, as he has defended the use of these drugs in his practice for several months now, but he has changed his mind after having read through these 3 papers and both editorials. [Laster acts as an editorial consultant to jointandbone.org and was approached by rheumawire for comment.] The main findings have already been announced, he said, but “having now had a chance to read through the data in detail, I think the case is even worse that it had appeared.” He finds particularly worrisome the fact that many of the patients in these trials were on aspirin (19% to 20% in APPROVE, 29% to 30% in APC, and 100% in the CABG trials), but it appeared to offer no protection against the increased cardiovascular risk of the coxibs. The cardiovascular signal was seen in both subgroups, Laster points out: in both those taking aspirin who were presumably at higher CV risk, and in whom aspirin would be expected to offer blanket protection but didn’t and also in those who weren’t on aspirin, which is declaring that the drugs are causing heart problems in people who are not at high risk to begin with. “These new data on aspirin make the issue even more worrisome,” he says.”Although individual practitioners who know their patients well can identify select individuals with low cardiovascular risk and could prescribe this class of drug to them with relative confidence, a larger number of people exist with significantly increased cardiovascular risk or whose risk profile is unknown,” Laster tells rheumawire. “As these drugs have been heavily marketed and widely prescribed, the greater public good will dictate that they now be withdrawn from the market.” Reports that pharmaceutical companies failed to publish earlier incriminating data (as in the celecoxib Alzheimer’s trial for which Pfizer has only recently released data) or that they tried to “neutralize” physician thought leaders with financial backing (in Merck’s marketing of rofecoxib, see sidebar) “will only hasten the burial of this class of drugs,” Laster says. First evidence of CV signal with celecoxib The APC data are particularly interesting as they show for the first time a CV signal with celecoxib. This finding led to the trial’s early discontinuation. APC was a placebo-controlled trial in 2035 patients with a history of colorectal neoplasia; follow-up was between 2.8 and 3.1 years, except for those patients who died. A composite cardiovascular end point of death from cardiovascular causes, myocardial infarction, stroke, or heart failure was reached by:- Seven of 679 patients (1%) in the placebo group; this includes 1 death from CV causes. – Sixteen of 685 patients (2.3%) on celecoxib 400 mg (taken as 200 mg twice daily), hazard ratio 2.3 (95% CI 0.9-5.5); this includes 3 deaths from CV causes. – Twenty-three of 671 patients (3.4%) on celecoxib 800 mg (taken as 400 mg twice daily), hazard ratio 3.4; (95% CI 1.4-7.8); this includes 6 deaths from CV causes.This published report contains 3 events that were not included in the preliminary analysis that was released in December 2004, when the announcement about the trial being stopped was made; however, they do not change the overall conclusions reached then and repeated now, the authors comment. Dr Scott Solomon (Brigham and Women’s Hospital, Boston, MA) and the other APC trialists conclude that celecoxib was associated with a dose-related increase in the composite CV end point, and these results are consistent among the individual components of the composite end point. In addition, the point estimate of the number of venous thromboembolic events was also increased (although not significantly) in patients taking the drug 4 events in the celecoxib 800-mg group and 3 on celecoxib 400 mg, in contrast with only 1 in the placebo group (hazard ratio for both doses combined 3.5 [95% CI 0.4-28.5]).”Our results heighten concern that this class of drug may be associated with cardiovascular risk,” they comment. However, they also point out that a trial very similar to APC, the Prevention of Spontaneous Adenomatous Polyps (PRESAP) trial comparing celecoxib 400 mg daily with placebo, has shown no apparent increase in cardiovascular risk in a preliminary analysis. One important difference between these 2 trials is that celecoxib was taken twice daily in APC and only once daily in PRESAP, and this supports the hypothesis that sustained inhibition of prostacyclin may contribute to the increase in CV risk, they comment.APC findings “are consistent” with those from APPROVESolomon et al comment that the CV findings for celecoxib in the APC trial “are consistent” with those found for rofecoxib in the APPROVE study, which led to that drug’s withdrawal.The APPROVE study was also conducted in patients with a history of colorectal adenomas, but Dr Robert Bresalier (University of Texas, Houston) and colleagues qualify cardiovascular risk in a slightly different way. They report in terms of a “confirmed thrombotic event” (which includes cardiac events such as myocardial infarction, cerebrovascular events, and peripheral vascular events including pulmonary edema). Such an event was found in:- Forty-six of 1287 patients on rofecoxib 25 mg daily 1.5 events per 100 patient years. – Twenty-six of 1299 patients on placebo 0.78 events per 100 patient years.The corresponding relative risk was 1.92 (95% CI 1.19-3.11, p=0.008). The increased risk became apparent after 18 months of treatment; before that the events rates were similar in the 2 groups. Bresalier et al comment that the events primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. There was an earlier separation (at approximately 5 months) between the groups in the incidence of nonadjudicated investigator reports of congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio 4.61; 95% CI 1.5-18.83). Overall mortality and cardiovascular deaths were similar in both groups. Bresalier et al note that patients on rofecoxib had increases in systemic arterial pressure during the trial; these changes were reported early in the study, along with investigator-reported edema and congestive heart failure. However, the mean arterial pressure did not appear to have a significant association with confirmed thrombotic events, and “it is unlikely that changes in blood pressure were the explanation for the excess cardiovascular risk in our study,” they comment. So far, no efficacy data have been released from any of these colorectal chemoprevention studies, so it is still unclear whether selective COX-2 inhibitors have a benefit in this condition. Both sets of investigators comment that the cardiovascular effects that they report will have to be taken into account in any assessment of these agents and their potential in preventing cancer in the intestine and other organs. Parecoxib and valdecoxib in CABG The third trial reported is in a different high-risk population patients undergoing CABG surgery. The COX inhibitors were given for pain relief as an addition to opioids, with intravenous parecoxib given for at least 3 days followed by oral valdecoxib for 10 days. Previous studies in other surgical settings (eg, gynecologic, orthopedic) have shown that the use of these drugs reduces the need for opioid medication; however, use in CABG patients is not an approved indication for either product. In this trial, cardiovascular adverse events (Including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism) were seen more frequently in patients given parecoxib and valdecoxib than those on placebo: 0.5% vs 0.2%, risk ratio 3.7 (95% CI 1.0-13.5), p=0.03. These results arouse “serious concern about the use of these drugs in such circumstances,” the authors comment. They conclude, “Short-term COX-2 inhibition is associated with a significant risk of thromboembolic events in patients at high risk for such events.” Dr Nancy Nussmeier (Texas Heart Institute, Saint Luke’s Episcopal Hospital, Houston) and colleagues note that a previous trial in CABG patients had given a hint of this adverse effect, but that trial involved only 311 patients in the parecoxib/valdecoxib group and 151 patients in the control group. Their own study was much larger (1671 patients in total), and the difference they found between the groups was significant. They conclude that “selective COX-2 inhibitors should be avoided in patients undergoing CABG” and add that this caution should probably be extended to patients undergoing vascular procedures for atherosclerotic disease, although this population has not been studied. In their editorial, Psaty and Fitzgerald comment that together, these 3 papers have now more clearly documented the cardiovascular risks of COX-2 inhibitors. However, they point out that these drugs have still not been adequately evaluated in long-term studies in low-risk or high-risk populations. “The absence of evidence here is not evidence of safety.”Merck’s marketing of Vioxx has been exposed yet again in a newspaper article in the February 11, 2005 issue of the New York Times. It describes how the company tried to “neutralize” doctors who were supporting the competitor product Celebrex. Among those targeted were rheumatologists Dr Roy Altman (now at the University of California, Los Angeles), Dr Max Hamburger (In private practice in Melville, NY), and Dr Robert Ettlinger (in private practice in Tacoma, WA), who says the marketing battle between the 2 products was “like a Coke-Pepsi war.”Merck says that its program consisted of providing information to doctors who had “misinformation” or a “lack of information” to “bring them back to a balanced or neutral position.” But the newspaper asserts that internal documents “offer a rare, behind-the-scenes look into the extremes of this process one that may have blurred the line between legitimate promotion and offering inducements to doctors to prescribe a drug.” Solomon SD, McMurray JJV, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med; published online before print February 15, 2005. Available at: http://www.nejm.org.  Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med; published online before print February 15, 2005. Available at: http://www.nejm.org. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med; published online before print February 15, 2005. Available at: http://www.nejm.org.