Major Painkiller Trial to Start

The Cleveland Clinic will direct a large-scale clinical trial to determine the cardiovascular safety of three painkillers commonly used by arthritis sufferers.

The trial will focus on three drugs -- ibuprofen (Advil/Motrin), naproxen (Naprosyn or Alleve) and celecoxib (Celebrex) -- all of which belong to the class of medications known as non-steroidal anti-inflammatory drugs (NSAIDs). Celebrex is a cox-2 inhibitor, a member of a newer class of NSAIDs that avoided the gastrointestinal problems of the older drugs. Two other cox-2 painkillers, Vioxx and Bextra, have been pulled off the market because of documented heart risks.

The Cleveland Clinic trial, which will enroll 20,000 at-risk heart patients, is an attempt to figure out whether the NSAIDS that remain on store shelves pose any cardiovascular risks.

"We've desperately needed this. The entire public confidence in terms of what is safe for pain has been eroded," said lead investigator Dr. Steven Nissen, who is the director of the clinic's Cardiovascular Coordinating Center.

"This is the trial that we've all been waiting for," added Dr. Mark Fendrick, an internal medicine professor at the University of Michigan. "It examines commonly used pain relievers at dosages frequently used in primary care, in patients at risk for cardiovascular events."

But the trial is also being funded by Pfizer Inc., which makes Celebrex, and experts worry that the integrity of the results could be called into question.

"I think the National Institutes of Health should take responsibility for conducting this type of clinical trial, where controversy and potential harm to the population are at stake," said Adil Shamoo, a professor of bioethics at the University of Maryland and co-founder of CIRCARE, a nonprofit dedicated to the protection of people used in research and medical treatment.

There is also the fact that the Cleveland Clinic itself was the subject of a lengthy expose published Monday by the Wall Street Journal. The article highlighted extensive ties between the institution and AtriCure, a company that makes equipment used in surgeries performed at the clinic.

According to the Journal article, a venture-capital partnership that the Cleveland Clinic helped found and invested in owns about 4.1 percent of AtriCure's stock. Patients were not told of these ties.

"In light of the problems they just had, I'm surprised they're doing this," Shamoo said. "What I would like to see are conflict-of-interest statements and complete financial disclosures for all involved, and the patients should be told that. This will affect what they're doing and the integrity of the research."

Nissen, who is also the president-elect of the American College of Cardiology, noted that special measures have been taken to guard the integrity of the trial's findings.

Pfizer will basically stay out of the trial, which has been dubbed the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen) trial, he stressed.

"We've done some very unusual things," Nissen added. "The executive committee to run the trial does not have a Pfizer person on it. It's all academic. I have asked the academic participants to all agree that they will accept no honoraria, speaking fees, etc. from any manufacturers of drugs in this class."

In addition, Nissen intends to place the trial's database into the public domain by giving it to the National Heart, Lung, and Blood Institute.

"We're going to make this trial so transparent that everybody will believe it," he said. "We're committed to doing this in a way that, for patients and physicians, answers the questions using the best scientific methods and integrity."

Nissen, along with Dr. Eric Topol (also of the Cleveland Clinic), was one of the first to reveal the potential risks associated with Vioxx. Since then, several studies have pointed out similar risks, and Vioxx manufacturer Merck & Co. is now immersed in litigation over whether the drug caused heart deaths.

The Vioxx saga took a new twist last week, when the editors of the prestigious New England Journal of Medicine published a rare "Statement of Concern." It charged that the authors of a major study called VIGOR, published in the journal in 2000 and subsequently used as a strong argument for the drug's safety, withheld information on three heart attacks and other cardiovascular events among participants taking Vioxx. Executives of Merck were among that study's authors.

The unusual accusation was released last Thursday afternoon, as jurors in Houston began deliberations in the first federal trial against Merck. On Monday, a mistrial was declared after the jury declared it could not reach a unanimous verdict.

Topol, who testified against Merck during the latest Vioxx trial, is not on the executive committee of the Cleveland Clinic study that is about to get underway. However, he is advising Nissen. "We didn't want to have more than one individual from any single center," Nissen said. "He has been very generous with advising us. I will keep him engaged."

The trial participants are expected to be enrolled over 18 months and will be followed for an average of two years. In addition, the researchers will be collecting information on pain relief and on gastrointestinal bleeding.

The study will end when 700 of the participants have died or suffered a heart attack or stroke, according to a New York Times report. That's a number consistent with what would be expected in such a group even without use of painkillers, the newspaper said.