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Maker Withdraws Vioxx

Sports Medicine Perspectives

Acute and chronic pain characterize most conditions that sports medicine physicians treat. In the last 4 years, cyclooxygenase-2 (COX-2) inhibitors have expanded pain management options in the nonsteroidal anti-inflammatory drug (NSAID) class. However, the voluntary withdrawal of rofecoxib, one of three COX-2 inhibitors on the US market, is causing some physicians to change the way they manage pain and has touched off calls from worried patients.

The New Era of COX-2s

Though COX-2 inhibitors are no more effective for the treatment of pain and inflammation than other NSAIDs, their gastroprotective effects have made them an attractive option for patients who are at risk for gastrointestinal (GI) bleeding, particularly those who are on long-term pain medication for conditions such as osteoarthritis and rheumatoid arthritis. Other NSAIDs inhibit cyclooxygenase 1 (COX-1), which has been dubbed a "housekeeper" enzyme because it synthesizes prostaglandins that regulate mucus production in the GI tract, the ability of platelets to control bleeding, and renal blood flow and sodium excretion.1 The inhibition of COX-1 is thought to be an undesirable effect of nonselective NSAIDs. COX-2 is produced in response to inflammation and other physiologic and hormonal stresses.1

The US Food and Drug Administration (FDA) approved the first COX-2 inhibitor (celecoxib) in 1998, followed by rofecoxib and valdecoxib. A recent press release from the American College of Rheumatology details how dramatically the COX-2 inhibitors changed NSAID prescribing patterns. Overall NSAID prescriptions between 1998 and 2003 increased 67%, largely because of the availability of the COX-2 inhibitors. The percentage of NSAID prescriptions written for COX-2 inhibitors peaked in 2001, despite the introduction of valdecoxib, the third drug in its class. COX-2 inhibitors are now thought to represent about 44% of the total NSAID market.

Heavily marketed in direct-to-consumer advertising, COX-2 inhibitors are estimated to account for $10 billion in annual sales.2

Cardiovascular Concerns

The decision by Merck & Co, Inc to voluntarily withdraw rofecoxib from the market was based on 3-year data from a prospective, randomized, placebo-controlled trial to evaluate the efficacy of rofecoxib in preventing recurrence of colorectal polyps in patients who have a history of colorectal adenomas. (Celecoxib is already indicated for the reduction of such polyps in patients who have familial adenomatous polyposis.) The polyp study, known as the APPROVe trial, was originally set to determine the effect of 3 years of treatment with a daily 25-mg dose of rofecoxib on polyp recurrence. The multicenter trial enrolled 2,600 patients.

According to a Merck press release, an increased risk of cardiovascular events was found in patients who had been taking rofecoxib, as compared with those taking placebo, after 18 months of treatment. The company noted that data from the first 18 months of the study was consistent with two earlier placebo-controlled studies on rofecoxib that did not detect any cardiovascular risks.

In withdrawing its product from the market, Merck was notifying healthcare practitioners and advising patients currently taking rofecoxib to contact their healthcare providers to discuss discontinuing the drug and selecting alternative treatments. Merck pointed out that the significance of the APPROVe trial for long-term use of other COX-2 inhibitors is unknown, and they stated that they will continue collecting additional longer-term data on their newest COX-2 inhibitor (etoricoxib), which has already been approved in 47 countries and is under FDA review in the United States.

Questions About a Mechanism

In a recent New England Journal of Medicine report,2 Garret A. FitzGerald, MD, chair of the department of pharmacology at the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania in Philadelphia, shared his perspectives on the cardiovascular events and suggested a mechanism. He and his colleagues had previously reported that rofecoxib and celecoxib suppress the formation of prostaglandin I2, an endothelial product that inhibits platelet aggregation, causes vasodilation, and prevents proliferation of vascular smooth-muscle cells in vitro.

In examining whether clinical experience with the two COX-2 inhibitors supports such a mechanism, he pointed to studies that were done after approval that demonstrated that the GI benefits for both drugs appeared to outweigh evidence of cardiovascular risk. A study comparing rofecoxib to naproxen showed a small but significant increase in myocardial infarction, and researchers argued that the small number of events could reflect chance or that naproxen has cardioprotective effects. FitzGerald pointed out, though, that epidemiologic studies on the cardioprotective effects of naproxen have been inconclusive. A post hoc study on data that compared celecoxib with ibuprofen or diclofenac showed that while there were GI benefits in patients on celecoxib who didn't take aspirin, there were also signs of increased cardiovascular risk.

FitzGerald said that the FDA responded with labeling changes for the two COX-2 inhibitors that reflected the results. "However, the APPROVe study has shifted the burden of proof. We now have clear evidence of an increase in cardiovascular risk that revealed itself in a manner consistent with a mechanistic explanation that extends to all the coxibs," he wrote.

Medical Establishment Reaction

In his article on a possible cardiovascular mechanism, FitzGerald calls on the FDA to go beyond watchful waiting and adjust its guidance to physicians and patients.

In a commentary in the same issue of the New England Journal of Medicine,3 Eric J. Topol, MD, chief academic officer of the Cleveland Clinic and provost of the Cleveland Clinic Lerner College of Medicine, at Case Western Reserve University, faults the drug company and the FDA for not pushing for trials to specifically assess cardiovascular risk. Given the anti-inflammatory action of the COX-2 inhibitors, such studies may have also been useful for pointing out possible cardiovascular benefits, he added. Topol asserts that cardiovascular concerns surrounding rofecoxib, a drug that 80 million patients have taken, is enormous, and that the findings warrant Congressional review.

In a press release from the FDA, acting commissioner Lester M. Crawford, MD, said that the FDA would monitor other COX-2 inhibitors for cardiovascular side effects, and he pointed out that all NSAIDs have risks when taken chronically, "Especially of gastrointestinal bleeding, but also liver and kidney toxicity. They should only be used continuously under the supervision of a physician." A spokesperson for the FDA said that when Merck notified the agency that it was removing rofecoxib from the market, the FDA was reviewing further studies on the drug to determine if further labeling changes were needed.

Changes Alter Medical Practice

FitzGerald wrote that COX-2 inhibitors remain a rational choice for patients at low cardiovascular risk who have had serious GI events, particularly while taking traditional NSAIDs.2 "It would also seem prudent to avoid coxibs in patients who have cardiovascular disease or who are at risk for it," he added.

Nicholas DiNubile, MD, an orthopedic surgeon in private practice in Havertown, Pennsylvania, says his office staff was deluged with calls from patients after the rofecoxib recall. He says switching patients to another medication requires individualization. "Patients have individualized responses, and no one NSAID outshines the other," he says.

The withdrawal emphasizes the importance of safe and simple efforts for addressing arthritis, DiNubile says. "Patients have control over adjuncts such as exercise and weight loss, and there are 'non-pill' options as well, including joint supplements and viscosupplementation that decrease the need for NSAIDS," he says.

DiNubile says the rofecoxib recall should send a message to patients as well. "This is a wake-up call for patients demanding new drugs. Physicians are often backed into a corner," he says.

Aaron Rubin, MD, director of the Kaiser Permanente Sports Medicine Fellowship in Fontana, California, says the impact of the rofecoxib recall has not had a big impact on his practice because of Kaiser's restrictions and guidelines on its use. "Since its only advantage was preventing ulcers in NSAID users, and since we had alternatives and could carefully screen individuals, it was not prescribed very often," says Rubin, a former pharmacist. "Its benefit in ulcer prevention was lost if patients took an aspirin a day, which many of my older patients were taking."

In Rubin's view, the recall raises warnings about the hype surrounding some drugs and the danger of large numbers of patients taking a new drug. "It takes time and numbers of patients taking it to find problems." he says

Jack E. Taunton, MD, a professor in the department of family medicine and School of Human Kinetics at the University of British Columbia, Vancouver, Canada, says rofecoxib has been useful for many of his patients who have arthritis and that his clinic has had to switch a number of them to other alternatives. Patients who are on rofecoxib and have no sulfa allergy are usually switched to valdecoxib because they most likely failed on celecoxib. "We place these patients on an enteric-coated aspirin per day to protect platelet potential as a risk factor for myocardial infarction and stroke," Taunton says. He also monitors these patients for any fluid retention and blood pressure increase. "For those with sulfa allergy and hypertension, we are back to diclofenac and stomach protection," Taunton says.

In reviewing long-term data on celecoxib, Taunton says the cardiovascular risk doesn't appear to be a class effect, and that changes with rofecoxib could be specific to that drug. "Celebrex [celecoxib] has longer follow-up to this point as compared to Bextra [valdecoxib], so we will need to watch the literature carefully," he says.

Lisa Schnirring


  1. Schnirring L: Will COX-2 inhibitors change pain management? Phys Sportsmed 1999;27(2)34-35
  2. FitzGerald GA: Coxibs and cardiovascular disease. N Engl J Med 2004;351(17):1709-1711
  3. Topol EJ: Failing the public health—rofecoxib, Merck, and the FDA. N Engl J Med 2004;351(17):1707-1709

Field Notes

Boston Marathon Patriarch Dies

John A. (Johnny) Kelley, who completed a record 58 Boston Marathons, died on October 6 at age 97. The cause of death was not reported.

According to a press release from the Boston Athletic Association, Kelley won the marathon twice (1935 and 1945), finished second a record seven times, and had 18 top-10 finishes. He also finished 18th at the 1936 Olympic Games in Berlin.

In 1992, at age 84, he started his 61st and final Boston Marathon. Even after his racing days ended, he remained a popular figure at the Boston Marathon, often serving as grand marshal and participating in prerace activities. One of his signatures during his racing days and after he retired from the sport was the Frank Sinatra song "Young at Heart," which Kelley often sang at races and speaking engagements.

Paul D. Thompson, MD, director of preventive cardiology at the Hartford Hospital in Hartford, Connecticut, finished 16th in the Boston Marathon in 1976, competed in Olympic marathon trials, and knew Kelley from their mutual connections with the Boston Marathon and other competitions throughout New England. Thompson says his first encounter with Kelley was in 1965 when Thompson, an 18-year-old high school senior, competed against Kelley in a 30-K championship. Kelley was 52 at the time. "He beat me, and I was pretty darn good," Thompson says.

Another memory that Thompson has of Kelley is from 1971, when both ran a 10-mile race in Portland, Maine. The date stands out in Thompson's mind because it was his first wedding anniversary. "And my wife Camilla and I spent it with Johnny Kelley," he says.

As a cardiologist, Thompson has long had a keen interest in studying athlete's heart, particularly medical reports on the autopsy studies that were done on Clarence DeMar, who competed in the Boston Marathon in the early 1900s and won the event a record seven times. (DeMar's coronary arteries were found to be unusually large.) In 1992, Thompson says he wrote to Kelley, asking if he would consider allowing Thompson to examine his heart upon Kelley's death. In response, Kelley's attorney declined the request and asked Thompson not to recontact Kelley about the matter. Despite the rejection, Thompson reflects warmly on the encounter. "He never thought he was going to die, and never thought of being ill or sick," he says.