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Naproxen & Celebrex join Vioxx as a killer; more on FDA's blindness

NIH Stops Study of Celebrex, Naproxen

Health-AP from

By PAUL RECER, AP Science Writer                                    12/20/4

Naproxen has been over the counter since 1976, and is the principle ingredient in Aleve, is found to be unsafe in NIH (National Institute of Health) study, which was stopped early.  Naproxen increased heart attacks and strokes 50% in long-term study.  Commonly used long-term for management of arthritic pain and inflammation,, the current FDA recommendation is “not take naproxen for longer than 10 days, unless a physician directs otherwise.”--jk

WASHINGTON - A study testing whether Celebrex or naproxen would reduce the risk of Alzheimer's disease (news - web sites) was halted Monday after researchers noted an increase in heart attack and stroke among participants who were taking naproxen, an over-the-counter pain reliever on the market for nearly 30 years. Officials at the National Institutes of Health (news - web sites) said the study was stopped after three years when it was noticed that patients taking naproxen, sold under the brand name Aleve, had a 50 percent greater incidence of cardiovascular events — heart attack or stroke — than patients taking placebo. Another factor, officials said, was the announcement last week that advertising for Celebrex was being halted after a study found that high doses of the drug was associated with an increase in heart attack risk. Data from the Alzheimer's study, however, did not indicate an increased risk for heart attack or stroke.

Celebrex and naproxen are both pain relievers commonly used to treat arthritis. Naproxen has been approved for sale, first as a prescription and then as an over-the-counter drug, since 1976.

Efforts to obtain reaction Monday night produced no answers at phone numbers for Bayer Healthcare, the maker of Aleve, a popular version of naproxen.  Dr. Sandra Kweder of the Food and Drug Administration (news - web sites) said the NIH study is the first to show that naproxen might increase the risk of heart attack or stroke.   "We agree that this is confusing," she said. The FDA (news - web sites) will closely evaluate the findings from the NIH study, said Kweder, but that no new regulatory action with naproxen is expected within the next few days.  She said patients who routinely take naproxen should follow the drug directions carefully, including the instruction not to take it for more than 10 days, and to consult a doctor if there continues to be pain.  The Alzheimer's disease study was being conducted by the National Institute on Aging, an arm of the NIH. It called for 2,500 patients, aged 70 or older and who had a family history of Alzheimer's, to take either Celebrex, naproxen or placebo.

The group was divided and each division, or arm, was assigned to receive one of the drugs or placebo. The drugs were blinded, which means the patients did not know which medication they were taking.   The goal was to determine if the pain-relieving drugs lowered the risk of developing Alzheimer's disease. The study started three years ago and was to continue for a few more years. Officials said the patients in the study will be monitored for developing Alzheimer's, but will not be given the test drugs.  Dr. Elias A. Zerhouni, the director of the National Institutes of Health, said the study linking heart attack to Celebrex last week was a major factor in deciding to suspend the Alzheimer's study.  He said there was a question whether patients in the study would continue to take their medicine since they knew they might be taking Celebrex.

Suspending the study, Zerhouni said, "is the prudent thing to do."   John Breitner of the Veterans Affairs medical facility in Seattle and the University of Washington, an investigator in the trial, said only preliminary data is available. But he said it suggests that about 70 patients of the 2,500 suffered stroke or heart attack, including 23 deaths, and that there were about 50 percent more such events in the naproxen arm of the study than in the placebo division.




Avoiding Another Vioxx


EMBATTLED: Merck CEO Raymond Gilmartin, whose company made the painkiller Vioxx, looks on as David J. Graham, associate directorfor science at the PDA's Office of Drug Safety, spells out the oversight errors culminating in the drug's withdrawal in a Senate hearing last November.


Too cozy" is how Senator Charles Grassley of Iowa referred to the re­lationship between the U.S. Food and Drug Administration and pharmaceuti­cal companies in the aftermath of the Vioxx debacle. Although the PDA admits no sub­stantive lapse in vigilance, congressional pressure and consumer outrage are forcing officials to rethink the agency's role and per­haps even the drug approval process itself. The furor began last September, when Merck, Vioxx's manufacturer, withdrew the popular anti-inflammatory drug after a study revealed that long-term use doubled the risk of heart attack and stroke. In a con­gressional hearing last November, David J. Graham, a drug safety reviewer at the agen­cy, estimated that as many as 55,000 Amer­icans may have died as a result of taking the painkiller, a member of the COX-2 inhibitor class of drugs.


Worse, early studies had shown elevated cardiovascular risks for patients taking Vioxx, but the PDA took no action against the drug other than adding a "precaution" to its label in 2002. Such a response led Gra­ham to testify that "the PDA, as currently configured, is incapable of protecting Amer­ica against another Vioxx."  PDA officials have defended themselves by claiming that they lacked enough infor­mation to order a recall of Vioxx. Sandra Kweder, deputy director of the PDA's office of new drugs, says the agency and its advi­sory committee were "stumped" by the con­flicting results of studies done before and after Vioxx was approved in 1999.  {The conflicting evidence is that Vioxx elevates cholesterol level, and thus takes years before its effect is statistically significant, thus the studies short-term studies showed little increased mortality.--jk} 


Medical experts point out, however, that this confusion arises from the systemic problems surrounding unreliable pre-approval trials and an inadequate system for monitoring new drugs after they come on the market. Because many adverse drug ef­fects are rare or hard to detect, researchers often cannot grasp the full extent of the dangers until hundreds of thousands of pa­tients are taking the medication. (The clini­cal trials required for PDA approval typically involve no more than a. few thousand subjects and can, as in the case of Vioxx, be too short-lived to indicate long-term trends.) The PDA orders drug companies to conduct post-marketing research as a condition of approval, but fewer than half of such studies are actually completed. And the PDA's Med-Watch program, which gathers reports of adverse effects voluntarily submitted by doctors[i], has garnered criticism from prom­inent medical journals and epidemiologists for its underreporting and unreliability. The current problems appear to stem in part from the 1992 Prescription Drug User Fee Act, which sought to speed the introduc­tion of new drugs by allowing the PDA to ac­cept user fees from pharmaceutical compa­nies, which were then siphoned into hiring additional drug reviewers. {However, Congress cut funding to the FDA at the same time; thereby, net reducing its overall budget.  This change in law was made with the approval of the pharmaceutical industry—jk.}  By focusing the agency's resources on the approval process, the law left less money for post-approval mon­itoring. Drummond Rennie, a deputy editor of the Journal of the American Medical As­sociation, says the financial contributions of the drug companies have also made the PDA less likely to confront them. "The PDA has lost its will and courage," he asserts.


To remedy the situation, Senator Grassley has proposed an independent body for oversight. "It doesn't make sense from an accountability standpoint to have the office that reviews the safety of drugs already on the market to be under the thumb of the of­fice that puts drugs on the market in the first place," he contends. Other policymakers have urged the PDA to be more aggressive about adding warnings to drug labels or to establish a public database containing the results of all major drug studies so that con­sumers can make more informed decisions. Under scrutiny, the PDA has hired the Na­tional Academy of Sciences's Institute of Medicine to study possible changes to the drug safety system.


The Vioxx withdrawal may also mark a turning point for the industry. Instead of seeking blockbuster drugs aimed at large numbers of consumers, companies may fo­cus on niche medications designed for par­ticular groups of ailing people. Garret A. FitzGerald of the University of Pennsylvania School of Medicine, an expert on COX-2 inhibitors," notes that Vioxx might have been able to stay on the market if its use had been restricted to people who have a low risk of cardiovascular disease but a history of gastrointestinal problems. (Vioxx is less likely to irritate the digestive tract than non-prescription painkillers.) "Here are drugs that are very useful in a segmented market," he says, "and their usefulness is being put at risk by the pursuit of a blockbuster strategy. I think, inevitably, the trend is going to be toward more segmented indications."




Like Vioxx, Celebrexand Bextra work by inhibiting the function of cyclooxygenase-2 (COX-2), an •nzyme that produces the prostaglandins that cause inflammation. One of these molecules, prostaglandin l2, appears to prevent damage to artery walls and the clumping of blood platelets; because all the COX-2 inhibitors curtail its production, researchers feared that Celebrex and Bextra  may also raise cardiovascular risks.  That fear has come true: last December, Pfizer announced that In one trial moderate doses of Celebrex produced cardiovascular risks comparable to those of Vioxx,  doubling the rate of heart attack and stroke. The company also warned doctors in late 2004 about Bextra's adverse effects on cardiac surgery patients. The PDA plans to review studies of the COX-2 inhibitors at an advisory committee meeting this month. 


[i]   The principle problems with such reporting is that normally a doctor will not notice a side effect unless the drug (1) causes a rare condition repeatedly (such as kidney failure through destruction of tissue as one of the statins does, (2) produces the side effect several times greater than expected, (3) there is a sufficiently number of patients on that drug, (4) and the doctor is tracking side-effect.  However, must side effects are sufficiently rare so that even the doubling of its incidents say from 4 to 8% of patients would go unnoticed; moreover, most doctors do not keep a log of side effects; and finally, most patients are on multiple medications so as to make it uncertain what is the cause of the side effect, one of the drugs, drug interaction, or so undiagnosed additional illness.   This strategy design by the drug industry and approved by Congress clearly is not in the public’s interest.   

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