Cleveland, OH - A huge trial comparing three anti-inflammatories in patients with both heart disease and arthritis should answer once and for all questions about the relative cardiovascular risks of these agents, says lead investigator Dr Steven Nissen (Cleveland Clinic, OH). "There's no question that this will be the definitive trial," he tells heartwire. "It's large enough with 20 000 patients, and it's looking at the right drugs in the right patient population." In fact, he points out, no previous study has looked specifically at patients with heart disease, so "this is new territory."

The trial will compare the COX-2-selective agent celecoxib (Celebrex, Pfizer) with two traditional nonsteroidal anti-inflammatory drugs (NSAIDs), naproxen and ibuprofen. Until now, celecoxib has been considered to be less risky for the GI tract, and naproxen less risky for the cardiovascular system, with ibuprofen falling somewhere in between, Nissen says. "Now we will see how they compare in a real-life situation." All the trial participants will have both arthritis and heart disease (eg, prior myocardial infarction or stroke, angioplasty, peripheral vascular disease, and/or diabetes), so they are high-risk secondary-prevention patients. As a result, all of them will be taking low-dose aspirin for cardiovascular prophylaxis; in addition, all of the patients will also be taking a proton pump inhibitor (omeprazole) to protect the gastrointestinal tract and to ensure blinding across the three arms, Nissen explained. "This pitches the three drugs on a level playing field," he said. "Let the chips fall where they will."

The trial addresses an urgent clinical question. "At the moment, we just don't know what to advise patients," he says. "Almost every day I have patients coming into the clinic with heart disease and arthritis, and they are asking me what they should they take for pain relief. We haven't had a way to answer that question.

"I think that we will be able to sort out the cardiovascular safety, the gastrointestinal safety, and also the pain relief," Nissen tells heartwire in an interview. "And we'll have what I believe will be a really strong and powerful statistical analysis." Results will be available about four years from now, he says, but if there is a clear difference between the drugs, it may emerge earlier. The first patient will start in the new year, and enrollment is expected to take about 18 months, with follow-up planned for two years.

Known as the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION), the trial will be funded by Pfizer and has been estimated to cost in the region of $100 million. However, there will be a firewall between the company and the trial, Nissen says: the Cleveland Clinic will run the trial independently of the company, and all of the data will be housed at the clinic. He says, "We intend to share a copy of the data with the US National Heart, Lung, and Blood Institute."

Pfizer has been talking for some time now about carrying out a trial to establish the cardiovascular safety of celecoxib, but plans for a trial dubbed 4C, which had aimed to show benefits in heart-disease patients, were abandoned after data showing a CV risk with the drug emerged and a black-box warning was added in the US. Nissen says that Pfizer approached him about the current study in August, but it has taken months to plan, and he notes that the executive committee sought input from both the US FDA and the European agency EMEA on the design of the trial. "It's really a consensus from academia, industry, and government on what needs to be done," Nissen says, "and I can assure everyone that we are committed to doing this with the best scientific methods and a high degree of independence."

None of the investigators on the executive committee responsible for the trial are allowed to have any financial relationship with any manufacturer of analgesics or anti-inflammatories, either marketed or still in development, or with any hedge funds, financial institutions, or lawyers involved in Vioxx trials. "I absolutely insisted on that point," Nissen tells heartwire, emphasizing that there must be total transparency and distancing of the science from industry, especially in the current climate. "The withdrawal of Vioxx and the black-box warnings have seriously shaken public confidence in the safety of commonly used painkillers," he says. "We understand that to restore public confidence, there has to be complete transparency."