Lifelines Online
Published: March, 2005; Vol. 1, Num. 10

Link between COX-2 Inhibitors and Heart Attack/Stroke:

Drug Safety Controversies Plague FDA

Acting to repair its tattered image on drug safety, the Federal Drug Administration (FDA) held a high-profile, three-day advisory conference last month to assess the safety risks of a class of arthritis pain drugs that, a decade ago, the agency had approved for prescription use.

In a decision likely to be adopted by the FDA, the conference concluded that the benefits of the popular painkillers outweigh the risks, so they should remain on the market. However, the committee recommended additional warnings for the packaging, possible limits on which patients can receive them and a possible ban on direct-to-consumer advertising.

"Though it remains unclear how the conference's outcome will ultimately affect FDA drug approval policy, the mounting controversy around how the agency makes its decisions invites LIUNA health and welfare funds to consider their own policies on the use of these and other new drugs," says Armand E. Sabitoni, LIUNA General Secretary-Treasurer and LHSFNA Labor Co-Chairman.

The drugs in question, known as COX-2 inhibitors, originally included Vioxx, Celebrex and Bextra, all well-known because they were promoted in direct-to-consumer advertising campaigns. Last fall, however, Merck & Co. removed Vioxx from the market after a study showed that, for long-term use (beyond 18 months), Vioxx doubled patients' risk of heart attack and stroke. Since then, sales of all COX-2 inhibitors have fallen.

Despite mounting concerns that Celebrex and Bextra might have long-term risks similar to Vioxx, Pfizer Inc., their manufacturer, kept the drugs on the market. However, in December, without any explanation, Pfizer suspended its advertising campaign. The reason became clear on February 11 when Pfizer revealed that the National Cancer Institute (NCI) had stopped the treatment phase of a trial of Celebrex that was designed to see if the drug protected against the recurrence of colon polyps. During the trial, participants who were given Celebrex were two and a half times more likely to suffer a stroke or heart attack than those given a placebo. Immediately after that announcement, the FDA decided to convene the special advisory conference on COX-2 inhibitors.

Some 27 million Americans have used Celebrex since its introduction in 1998. "Yet, Celebrex and the other COX-2 inhibitors were never intended to be the drug of first choice for arthritis suffers," says LHSFNA Health Promotion Director Mary Jane MacArthur. "They were to be used in more severe cases that were unresponsive to other medications such as aspirin, ibuprofen or naproxen." Ibuprofen is sold as Motrin or Advil, and naproxen is known as Aleve. All three are over-the-counter (OTC) drugs that do not require a doctor's prescription.

"What happened," MacArthur explains, "is that the COX-2 inhibitors were marketed direct-to-consumers, especially through television and magazine advertising, and patients then requested them by name when they visited their doctors. Many doctors were quick to pull out their Rx pad or reach for free samples, rather than recommend the trip to the pain relief aisle at the grocery or drug store.

"That was a problem," she continues, "because the new drugs, though proven effective in short-term clinical trials before their approval by the FDA, were never tested for long-term safety. Suddenly, they came into extremely wide use, but no one knew or had responsibility for monitoring patients' long-term experience."

Criticism of FDA procedures had increased throughout 2004, and the agency, no doubt, sensed that the February disclosure of the NIC decision to stop the Celebrex trial would provoke a new wave. Also, on February 11, Pfizer and the FDA announced a new warning for Bextra's label after two studies showed increased risk of stroke and heart attacks among bypass patients who took that drug.

While the conference brought out considerable evidence of risk for long-term and higher dosage users of the COX-2 inhibitors, it also brought testimony from many arthritis suffers whose adverse reactions to OTC painkillers leave them no other alternative. They would rather accept the higher risk of heart problems than endure the harsh pain of arthritis. The FDA advisors adopted the middle ground of continued, but more restricted access.

Next on the agenda may be Mobic, another arthritis painkiller, whose sales have tripled since Vioxx was withdrawn. Though not a COX-2 inhibitor, Mobic - made by the German pharmaceutical firm Boehringer Ingelheim GmbH - is a "bad actor" and potentially just as dangerous, according to David J. Graham, the FDA safety officer who first blew the whistle on unsafe drugs and who has been heavily criticized by some industry sources.

One of Graham's chief complaints is that the FDA, though aware of evidence that indicates some drugs are unsafe, keeps that knowledge to itself until further analysis is done and reported in peer-reviewed journals, a process that can take many months. At the hearing, he thanked the acting FDA administrator Lester Crawford for allowing him to comment on Mobic, despite the lack of published analysis. However, Graham testified on his own behalf, not as an FDA official.

The COX-2 controversies follow in the wake of several FDA drug approvals that have recently been called into question by subsequent patient experience. Perhaps best known is the FDA’s decision last fall - after more than a year of sharp criticism - to require warning labels on anti-depressant medications against their use with children. Many doctors and patients had reported increased incidence of suicidal thoughts or actions among young patients. Also, in February, Eli Lilly added a warning to its drug, Strattera - used to treat attention deficit/hyperactivity disorder (ADHD) - after its use by two million patients since approval in 2002 revealed potential danger for those with liver problems. In another February decision, AstraZeneca pulled Iressa, a lung cancer drug, from the market after a study showed the drug did not prolong survival for patients any better than placebos.

Then, following as if on cue, a new Canadian study, published in the British Medical Journal while the FDA conference was in progress, cited evidence that popular anti-depressants such as Prozac, Paxil and Zoloft - long approved without warning requirements by the FDA - are twice as likely to invoke attempted suicide among adult users as sugarpills.

"The pattern here is worrisome," says Sabitoni, who notes that the FDA, itself, is re-examining its practice.

U.S. Health and Human Services Secretary Mike Leavitt, whose department oversees the FDA, reacted to criticism last month by creating an independent board to monitor the safety of drugs already approved and on the market. He said the Drug Safety Oversight Board would separate officials who approve drugs from any significant role in assessing whether safety concerns that arise after approval warrant further regulatory action, including possible withdrawal of a drug from the approved list.

Critics were reluctant to concede that the new board would make much difference. Graham, the most prominent critic, told a Washington Post reporter, "It's an important admission at the highest levels that the FDA hasn't handled drug safety up to now, but it won't address the root causes of the problem. Until drug safety becomes as important as approving drugs quickly, the fundamental problem will remain and unsafe drugs will continue to be approved and will stay on the market."

A practical approach to prescribing and taking medicine is step therapy which was introduced by responsible pharmacy benefits managers to encourage the use of lower dose, less costly and, in many cases, just as effective treatment, rather than starting with the higher strength medications. The idea is to start with the least risky, lower cost options and step up only if they are not effective. LIUNA health and welfare fund administrators and trustees should evaluate their prescription drug benefit and consider including step therapy.



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