Closing the barn door after the horse is out: Cleveland Clinic To Lead Large Study on Safety, Efficacy of COX-2 Inhibitors, OTC Painkillers…a summary of links to stories around the country

      Researchers at the Cleveland Clinic will lead the first large-scale study to compare the cardiovascular risks of COX-2 inhibitors and older pain medications in patients with risk factors, clinic officials announced on Tuesday, the New York Times reports. Pfizer, which manufactures the COX-2 inhibitor Celebrex, will fund the study. According to Steven Nissen, a cardiologist at the Cleveland Clinic who will lead the study, the study will include 20,000 arthritis patients who have previously experienced a heart attack, stroke or angina; underwent coronary bypass surgery or a stent procedure; or have diabetes. Concerns about the cardiovascular risks of COX-2 inhibitors have increased recently, but researchers have not conducted a large-scale study on high-risk patients to examine the issue, Nissen said (Saul, New York Times, 12/14). Merck withdrew the COX-2 inhibitor Vioxx from the market in September 2004 over concerns that the medication could increase risk for cardiovascular events, and Pfizer in April removed the COX-2 inhibitor Bextra from the market over similar concerns. Celebrex is the only COX-2 inhibitor that remains on the market in the U.S., and the label warns that the medication could increase risk for cardiovascular events. In addition, FDA earlier this year warned that other non-steroidal anti-inflammatory drugs, such as the over-the-counter pain medications Advil and Aleve, also could increase risk for cardiovascular problems.

Study Details
The double-blind study will include arthritis patients in the U.S., Canada, Latin America, Europe and Australia (Sternberg, USA Today, 12/14). Researchers will randomly assign study participants to take a daily dose of one of three pain medications -- 200 milligrams of Celebrex; 2,400 milligrams of ibuprofen, sold under the brand-name Motrin; or 1,000 milligrams of naproxen, sold under the brand-name Aleve -- for 24 months (Henderson, Boston Globe, 12/14). Study participants also will take low doses of aspirin and other medications, such as statins, recommended for individuals with heart diseases. In addition, study participants will take Prilosec to help prevent stomach bleeding and ulcers, which are possible side effects of NSAIDs. Researchers will begin an 18-month enrollment period for the study in 2006 and will track participants for an average of two years. Researchers will collect and store study data at Cleveland Clinic and will provide a copy of the data to NIH, with results expected after four years (Winslow, Wall Street Journal, 12/14). Thomas Fleming, chair of the Department of Biostatistics at the University of Washington, will lead a committee that will monitor the study with the authority to end the study if safety concerns develop (USA Today, 12/14). Members of the committee will not accept compensation from companies that manufacture medications used in the study.

Nissen Comments
Nissen said that Pfizer initiated the study, which could cost as much as $100 million to conduct. He added that Pfizer has agreed to provide researchers with "an extraordinary degree of independence." He added, "The public and the medical community are confused. The relative safety of these three drugs is simply not known. We're going to answer the question: are they the same or are they not" (Wall Street Journal, 12/14). Nissen said, "All the other trials that I'm aware of are really in quite low-risk patients, and so they just aren't comparable" (New York Times, 12/14). He added, "The idea here is if you know what happens in the highest-risk individuals, you will know how to use the drugs in people at lower risk. We will have 10 times the statistical power of any trial ever done of these drugs" (Marchione, AP/Detroit News, 12/14).

Additional Comments
Pfizer spokesperson Mariann Caprino said that the company could not comment on the cost of the study. She added, "We're certainly very pleased that the Cleveland Clinic is heading the study, and it is about to get under way, because clearly this is an important question and a very important patient population that the study is going to look at" (New York Times, 12/14). Jason Napodano, an analyst at Zacks, said that the study would have only a small impact on Celebrex sales until the release of results (Boston Globe, 12/14). Celebrex sales have decreased by 45% since last year to $1.26 billion in the first nine months of this year (New York Times, 12/14). "Vioxx took 18 months to see a real statistical difference between Vioxx and naproxen, and we know that Vioxx clearly is not as safe. But Celebrex, I don't know," Napodano said, adding, "I think Celebrex is safer than Vioxx, but how it will compare to naproxen?" (Boston Globe, 12/14). Alastair Wood, a professor of medicine and pharmacology at Vanderbilt University and chair of a former FDA advisory committee on the safety of pain medications, said, "It may be that at the end of this, one or the other drug will be superior. That's exactly what we need to know" (New York Times, 12/14).