Three Pivotal Trials of COX-2 Inhibitors Released Early by NEJM

Laurie Barclay, MD

February 15, 2005

Feb. 15, 2005 — As the cyclooxygenase-2 (COX-2) inhibitor debate continues, the New England Journal of Medicine has released early three pivotal studies, posted online Feb. 15 and published in the March 15 print issue. Results of the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial led to the withdrawal of rofecoxib from the market, and the results of the Adenoma Prevention with Celecoxib (APC) study led to modified warnings and use of Celebrex. The third study shows similar cardiovascular harm associated with valdecoxib and parecoxib. The editorialists review the history of these agents, the issues associated with their study, approval, and marketing, and recommends that if these drugs are used, it should be at the lowest effective dose and shortest interval.

"Selective inhibition of cyclooxygenase-2 (COX-2) may be associated with an increased risk of thrombotic events, but only limited long-term data have been available for analysis," write Robert S. Bresalier, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues from the APPROVe Trial Investigators. This study was designed to test the effect of rofecoxib on the risk of recurrent neoplastic polyps of the large bowel.

In this long-term, multicenter, double-blind trial, 2,586 patients with a history of colorectal adenomas were randomized to receive 25 mg rofecoxib daily (n = 1,287) or placebo (n = 1,299) for three years. An external committee evaluated in a blinded fashion all investigator-reported serious adverse events that represented potential thrombotic cardiovascular events.

During 3,059 patient-years of follow-up, 46 patients in the rofecoxib group had a confirmed thrombotic event (1.50 events per 100 patient-years) compared with 26 patients in the placebo group during 3,327 patient-years of follow-up (0.78 event per 100 patient-years). This yielded a relative risk of 1.92 (95% confidence interval [CI], 1.19 - 3.11; P = .008).

During the first 18 months, the event rates were similar in both groups, but the increased relative risk became apparent after 18 months of treatment, primarily because of a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. At approximately five months, there was separation between groups in the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio [HR], 4.61; 95% CI, 1.50 - 18.83). Both groups had similar overall and cardiovascular mortality.

"Among patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk," the authors write. "It is unclear whether the results seen with rofecoxib represent a general effect of COX-2 inhibitors or a specific effect of rofecoxib.... The possibility that conventional [nonsteroidal anti-inflammatory drugs (NSAIDs)] may have similar effects also has to be considered."

Merck, the maker of rofecoxib, funded this study, employs five of its authors, and paid consulting fees to seven other authors, one of whom also served as an unpaid consultant to Bayer.

"Selective COX-2 inhibitors have come under scrutiny because of reports suggesting an increased cardiovascular risk associated with their use," write Scott D. Solomon, MD, from Brigham and Women's Hospital, Harvard Medical School, in Boston, Massachusetts, and colleagues from the Adenoma Prevention with Celecoxib (APC) Study Investigators.

"Experimental research suggesting that these drugs may contribute to a prothrombotic state provides support for this concern."

The investigators reviewed all potentially serious cardiovascular events among 2,035 patients with a history of colorectal neoplasia who were enrolled in a trial comparing two doses of celecoxib (200 mg or 400 mg twice daily) with placebo for colorectal adenoma prevention. All surviving patients had 2.8 to 3.1 years of follow-up.

A composite end point of cardiovascular death, myocardial infarction, stroke, or heart failure occurred in 7 (1.0%) of 679 patients in the placebo group, in 16 (2.3%) of 685 patients receiving 200 mg celecoxib twice daily (HR, 2.3; 95% CI, 0.9 - 5.5), and in 23 (3.4%) of 671 patients receiving 400 mg of celecoxib twice daily (HR, 3.4; 95% CI, 1.4 - 7.8). There were similar trends for other composite end points, leading the data and safety monitoring board to recommend early discontinuation of the study drug.

The authors note that the observed increase in cardiovascular risk was based on a small number of events in a trial that was not designed or statistically powered to evaluate this risk. They recommend interpreting the results with caution because some adverse cardiovascular events may have remained unreported.

"Celecoxib use was associated with a dose-related increase in the composite end point of death from cardiovascular causes, myocardial infarction, stroke, or heart failure," the authors conclude. "In light of recent reports of cardiovascular harm associated with treatment with other agents in this class, these data provide further evidence that the use of COX-2 inhibitors may increase the risk of serious cardiovascular events.... These risks will need to be weighed against any potential benefits of celecoxib in preventing colorectal neoplasia and in relieving pain."

The National Cancer Institute and Pfizer, the maker of celecoxib, sponsored the APC. This cardiovascular review was funded solely by the National Cancer Institute. Four authors report having received consulting fees from Pfizer, and one from Merck.

The third study, by Nancy A. Nussmeier, MD, from the Texas Heart Institute at St. Luke's Episcopal Hospital in Houston, Texas, and colleagues, was a randomized trial to assess the safety of valdecoxib and its intravenous prodrug parecoxib in the treatment of postoperative pain after coronary artery bypass graft (CABG) surgery.

In this double-blind study, 1,671 patients were randomized to receive intravenous parecoxib for at least three days, followed by oral valdecoxib through day 10; intravenous placebo followed by oral valdecoxib; or placebo for 10 days. All patients had access to standard opioid medications. The primary end point was the frequency of predefined adverse events, including cardiovascular events, renal failure or dysfunction, gastroduodenal ulceration, and wound-healing complications, occurring within 30 days of follow-up.

Compared with the group receiving only placebo, both the group receiving parecoxib and valdecoxib and the group receiving placebo and valdecoxib had more patients with at least one confirmed adverse event (7.4% in each of the active drug groups vs 4.0% in the placebo group; risk ratio [RR], 1.9; 95% CI, 1.1 - 3.2; P = .02). Cardiovascular events, including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism, occurred in 2.0% of patients given parecoxib and valdecoxib compared with 0.5% of patients given only placebo (RR, 3.7; 95% CI, 1.0 - 13.5; P = .03).

"The use of parecoxib and valdecoxib after CABG was associated with an increased incidence of cardiovascular events, arousing serious concern about the use of these drugs in such circumstances," the authors conclude. "In view of all these findings, this study, and other current data, selective COX-2 inhibitors should be avoided in patients undergoing CABG. This caution should probably be extended to patients undergoing vascular procedures for atherosclerotic disease, although this population has not been studied."

Pharmacia and Pfizer, the makers of valdecoxib and parecoxib, helped support this study, and Pfizer employs two of the authors. Some of the other authors report various financial arrangements with Pfizer, Novartis, TAP Pharmaceuticals,GlaxoSmithKline, and Eyetech Pharmaceuticals.

In an accompanying editorial, Jeffrey M. Drazen, MD, reviews the history of COX-2 inhibitors and the clinical, research, and public health implications of these studies.

"Taken together, these three large, randomized, controlled trials designed to test the efficacy of different COX-2 inhibitors for a variety of indications confirmed the cardiovascular toxicity that had been suggested five years earlier, " Dr. Drazen writes. "Since three different COX-2 inhibitors were all found to be associated with cardiovascular complications, it appears that this is a class effect. Because there are well-established options for treatment of all the approved indications for these drugs, it is reasonable to ask whether the use of the drugs can now be justified."

Spontaneous reporting systems allow detection of an increased incidence of rare events associated with a new drug, but Dr. Drazen notes that the detection of an increased incidence of a common event, such as heart attack or stroke, is much more difficult. Unfortunately, the latter has a much greater effect on public health than the former.

"It is a sobering thought that although the number of deaths and cardiovascular events attributable to COX-2 inhibitors remains in dispute, had trials designed to test the question of cardiovascular toxicity directly been launched in 1999 and executed with urgency, substantial morbidity and perhaps a substantial number of deaths could have been prevented," Dr. Drazen concludes. "As we apply new science to develop new medicines, we must not forget that our first job is to do no harm."

A second editorial by Bruce M. Psaty, MD, PhD, from the University of Washington in Seattle, and Curt D. Furberg, MD, PhD, from Wake Forest University School of Medicine in Winston-Salem, North Carolina, points out that we still lack adequate information about the exact levels of risk for each drug, the time course of the risk during therapy, and the populations of patients, if any, in whom the benefits might exceed the known risks.

Drs. Psaty and Furberg recommend that medicines designed for widespread use for long periods be evaluated in large, long-term clinical trials that begin as early as possible in the drug-approval process, and that all randomized clinical trials be registered and their results made public in a timely fashion.

"We believe that to protect the health of the public, Congress needs to provide the FDA with the necessary authority and also to create an independent Center for Drug Safety with new authority and funding," the editorialists write. "In clinical trials, NSAIDs, aspirin, and acetaminophen are just as effective in relieving pain as the COX-2 inhibitors. If a COX-2 inhibitor were necessary, patients would have to be informed of the potential risks, and the lowest possible dose should be used for the shortest possible time."

N Engl J Med. Published online Feb. 15, 2005.

Reviewed by Gary D. Vogin, MD

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