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Painkiller Safety Study Announced

December 31, 2005

A major new study of three commonly used painkillers- Celebrex (celecoxib), Motrin (ibuprofen) and Aleve (naproxen)- will be conducted at the Cleveland Clinic starting in early 2006. The study was reported by MedPage Today on 14 December 2005.

The study is sponsored by Pfizer, who make Celebrex, which is the last COX-2 inhibitor remaining on the US market. Vioxx (rofecoxib), another COX-2 inhibitor, was withdrawn from the market by Merck, after studies linked it with increased cardiac risk.

The randomized trial will run for four years and will include 20,000 people with arthritis. The trial's cost is estimated at $100 million, according to MedPage Today.

The trial will be called "Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen" ("PRECISION").

Lead investigator Steven Nissen, MD, a Cleveland Clinic cardiologist and president-elect of the American College of Cardiology, was an early and outspoken critic of Vioxx. Vioxx was withdrawn from the market after a study showed that long-term daily use was linked with an increased risk of non-fatal heart attacks.

Dr Nissen said the global study will start to enroll participants at the beginning of 2006, and results are expected in 2009.

Because Pfizer is funding the study, there is some concern that people may perceive a conflict of interest. However, according to MedPage Today, Dr Nissen stated that the Cardiovascular Coordinating Center, of which he is medical director, will independently lead and conduct the trial. Moreover, the trial will be overseen by an executive committee including leaders in cardiovascular medicine, rheumatology and gastroenterology, including a staff member from the National Heart, Lung, and Blood Institute of the National Institutes of Health.

Cardiovascular Safety

Because cardiovascular safety is a main concern, the trial will include people with coronary disease or multiple risk-factors for heart disease, as well as osteoarthritis. The trial will also enroll a few people with rheumatoid arthritis, Dr Nissen reportedly said.

Trial participants will be randomized to receive Celebrex, Motrin or Aleve.

"Since so many arthritis patients are at risk for heart disease, it is critically important to understand the cardiovascular safety of these drugs," Dr Nissen said, according to MedPage Today.

"Currently available information is insufficient to determine whether typical dosages of celecoxib and other popular pain relievers are linked to an increased risk of heart disease."

The FDA said in April that cardiovascular safety is an issue for all NSAIDs except aspirin.

Two other COX-2 inhibitors are no longer on the US market. Merck voluntarily withdrew Vioxx from the market in September 2004, when preliminary results of a colon cancer chemoprevention trial linked long-term daily use of Vioxx with an increased risk of non-fatal heart attacks. Since VIoxx has been withdrawn, thousands of lawsuits have been filed.

Subsequently, the FDA requested that Pfizer withdraw Bextra (valdecoxib), another potent COX-2 inhibitor, from the market based on reports that it increased the risk of thrombotic events. Pfizer complied, and consequently Celebrex (celecoxib) is the last COX-2 inhibitor still available in the US.

The New Study

The events surrounding Celebrex and Vioxx prompted Dr Nissen's new study, according to MedPage Today.

Dr Nissen has a long-standing policy of refusing honoraria or compensation from drug companies. He said the PRECISION study extends the same policy to all participating investigators.

"We recognize the importance of conducting this trial according to the highest standards of integrity," Dr Nissen said, according to MedPage Today.

Dr Nissen, and Eric Topol, MD, chairman of cardiovascular medicine at the Cleveland Clinic, were among the first health professionals to speak out about potential risks associated with Vioxx. Dr Topol is not participating in the PRECISION study and testified for the plaintiff in the latest Vioxx trial, which recently ended in a mistrial.

The new study is already generating some controversy. While many cardiologists reportedly welcome the new study, Garret FitzGerald, MD, of the University of Pennsylvania - a frequent critic of COX-2 drugs - reportedly said that giving Celebrex to people with known heart disease was "ethically questionable." He also suggested that the trials' timing may benefit Pfizer by allowing them more time to profit from sales of Celebrex.

However, Dr Nissen reportedly said that all study participants will be maintained on both aspirin, for cardiovascular protection, and Prilosec (omeprazole), to reduce the risk of gastrointestinal complications.

Posted: December 2005