Early release of NEJM studies highlights cardiovascular risks of cough/cold remedies and weight-loss products

Shelley Wood

November 08, 2000

Wed, 08 Nov 2000 17:07:55

Boston, MA - The New England Journal of Medicine has authorized the early release of two separate studies due to "the potential clinical and public health implications" of the research, originally slated for publication on December 21, 2000. Coincidentally, both studies deal with the potential cardiovascular (CV) risks of desiring a thinner, fitter physique - and taking specific agents to attain it. Both studies appeared on the Journal's website on November 6, 2000.



Media reaction to early release of data

Boston, MA - The early release of data from two New England Journal of Medicine articles on the dangers of phenylpropanolamine (PPA) and ephedra in over-the-counter (OTC) drugs sent shivers through manufacturers of cough medicines and diet pills containing these ingredients, according to the media on November 7, 2000.

The FDA issued a health warning against PPA, found in many name-brand cold remedies and weight-loss drugs, calling the ingredient "unsafe," according to CBS News. "Representatives of the over-the-counter drug market are not surprised about the FDA's action, since PPA has been under scrutiny for a long time," reports CBS News medical correspondent Elizabeth Kaledin. She quotes Mara Goldstein (CIBC World Markets): "It's safe to say that companies have been moving away from PPA use as a primary active ingredient for nasal decongestants." Some companies have said they would recall their products, and several national drugstore chains began taking PPA products off their shelves. "The manufacturers of several PPA-containing cold remedies, including Contac 12-hour Cold Capsules and Comtrex Flu Therapy and Fever Relief, told retailers yesterday to remove their products from store shelves. Bristol-Myers Squibb (BMS) said most of its Comtrex products do not contain PPA.

Bayer Consumer Care Division, maker of Alka-Seltzer Plus cold products, said that although hemorrhagic stroke may be associated with PPA from appetite suppressants, "there is no research clearly connecting the strokes with PPA in cold medicines," reports the Washington Post. Walgreens said it would pull about 75 PPA-containing products from its 3200 stores, and CVS/pharmacy also said it had begun removing PPA products from its 4100 stores, the Pos t reports. Yet USA Today reports that analysts claim the FDA's move "will have little effect on most of the large drug companies, because the remedies are only a small percentage of total sales."

Other manufacturers say they will reformulate their products. "Makers of the diet drug Dexatrim recently developed 'Dexatrim Natural,'" states CBS, noting that the new product contains PPA's chemical cousin, ephedra. But the Wall Street Journal reports that Dexatrim manufacturer Chattem Inc "predicts a significant reduction in its per-share earnings for 2001 due to the FDA decision." "This is going to be a real problem" for Chattem because it dominates the market, drug analyst Hemant Shah tells the Journal. What's more, as the Journal reports, "FDA officials are considering tougher restrictions on supplements that contain ephedra because of health concerns, and plan to make a decision by the end of the year."

The Associated Press (AP) notes that the report of side effects to ephedra is the first to appear in a medical journal. AP reports that Dr Joseph Levitt (Director, Food Safety Center, FDA) says four research groups had similar findings, "although in some cases they did not agree on whether ephedra was to blame." But ephedra supporters claim the supplement is safe when taken as directed, reports CNN. "There really is no correlation between the serious effects - I'm talking about death and stroke - that can be attributed solely to the ephedra-containing dietary supplement," says Norbert Page (Ephedra Education Council), a Washington-based industry organization. Consumer advocates, however, feel vindicated by the early release of the ephedra data. The study "confirms that ephedra as sold in dietary supplement form is a public health threat," Bruce Silverglade (Legal Affairs Director, Center for Science in the Public Interest) told the Post. "The evidence is now in. This study should provide a basis for the FDA to move ahead with regulatory limits on its sale."

The Post reports that Dr Gregory Curfman (Executive Editor, New England Journal of Medicine) says articles are released early "three or four times a year," and only when public health concerns are raised. Curfman says the New England Journal of Medicine was not trying to "make a political statement" about ephedra: "We look at the data, and treat each and every manuscript on its own merits." However, prepublication of the information "could change the debate," acknowledges Michael McGuffin (President, American Herbal Products Association), an industry group: "If the New England Journal of Medicine thinks ephedra has public health implications, it is important."

- Mark L Fuerst


One of the two studies, led by Dr Walter N Kernan (Yale University School of Medicine), examined the link between phenylpropanolamine (PPA) and hemorrhagic stroke. PPA is a synthetic sympathomimetic amine commonly found in appetite suppressants and cough/cold remedies. Reports dating back as far as 1969 have documented incidents of spontaneous hemorrhagic stroke potentially linked to medications containing PPA, and an FDA advisory committee has recently recommended that the ingredient be removed from over-the-counter diet drugs and cold remedies, as previously reported in heart wire .

High stroke rates in women taking appetite suppressants

Kernan and colleagues, in collaboration with the FDA and manufacturers of PPA (including Novartis, Thompson Medical Company, and Chattem), identified 702 patients between the ages of 18 and 49 from 43 US hospitals, who were admitted with a subarachnoid or intracerebral hemorrhage. All patients were then matched with two control subjects and all participants completed a questionnaire detailing demographic, clinical, behavioral, and pharmaceutical information.

The authors found that, astonishingly, the odds ratio for hemorrhagic stroke in women taking appetite suppressants containing PPA was 16.58, and 3.3 for women using any product containing PPA for the first time, which, in all cases was a cough/cold remedy. None of the men - who made up almost half of the cohort - were taking appetite suppressants, and the data showed no increased risk of hemorrhagic stroke in men alone. When men and women were combined, the risk of hemorrhagic stroke was again substantial in association with appetite suppressants, and considerably less so in association with all products containing the amine, or with cough and cold drugs.

 

One woman may have a stroke due to phenylpropanolamine for every 107 000 to 3 268 000 who use products containing phenylpropanolamine as an appetite suppressant

 

The authors conclude that their dramatic findings have huge implications for women, although the risks to men could not be determined, since no men were taking appetite suppressants. Calculating the "number needed to harm," Kernan and colleagues estimated that "One woman may have a stroke due to phenylpropanolamine for every 107000 to 3268000 who use products containing phenylpropanolamine as an appetite suppressant within a 3-day window." While the risks may, on the surface, seem low, the authors conclude that, "for both persons considering the use of phenylpropanolamine and for policy makers, our study provides important data for a contemporary assessment of risk associated with the use of this common medication."



FDA issues Public Health Advisory on Phenylpropanolamine

Washington, DC - The FDA has issued a Public Health Advisory warning consumers about the risks of phenylpropanolamine and urging them "to discuss alternative over-the-counter and prescription products with their health care providers or pharmacists." The agency also announced that it is "taking steps to remove phenylpropanolamine from all drug products and has requested that all drug companies discontinue marketing products containing phenylpropanolamine." At this time, the FDA's request to companies constitutes a voluntary discontinuation of phenylpropanolamine products, although the products themselves may be reformulated such that phenylpropanolamine is not included.

The FDA sent letters to any pharmaceutical company involved in the manufacturing, re-packing, re-labeling, or distribution of products containing phenylpropanolamine on November 3, 2000. In the letter, the FDA claims that it "intends to initiate rule-making to classify phenylpropanolamine as nonmonograph (not generally recognized as safe and effective)." A copy of the letter, along with additional information on phenylpropanolamine and the full report of the Hemorrhagic Stroke Project have been posted on the net by the FDA on a Phenylpropanolamine (PPA) Information Page.

-SW


Big muscles make for big heartache

In the second of the two studies, Drs Christine Haller and Neal Benowitz (UCSF and California Poison Control System, San Francisco, CA) report that millions of people may be putting themselves at risk of a cardiovascular event, by taking dietary supplements that contain ephedra alkaloids. The supplements, write the authors, are also known as "ma huang" and "are widely promoted in the United Sates as a means of losing weight and increasing energy." In 1999, approximately 12 million people taking doses of about 60 mg per day used the unregulated substance, the authors estimate.

These numbers are alarming, the authors point out, in light of their study, which reviewed 140 reports of adverse cardiovascular events potentially associated with ephedra alkaloids. Initiated at the request of the FDA, their in-depth review of events that occurred between June 1, 1997, and March 31, 1999, determined that 31% of cases were "definitely or probably related" to the use of supplements containing ephedra alkaloids. An additional 31% were deemed "possibly related." The most common adverse event was hypertension (listed in 17 reports), followed by palpitations, tachycardia, stroke and seizures. More disturbing, 10 deaths and 13 cases of permanent disability due to a cardiovascular event were linked to ephedra alkaloid use.

 

Our findings arouse concern about the risks of these products, given that they have no scientifically established benefits

 

The authors list several weight-loss or muscle-bulking products that contain the ephedra alkaloids, including Shape-Fast Plus (a meal-replacement for dieters), Ripped Fuel (capsules promising increased lean muscle mass), and Ripped Force and Ultimate Orange (both sports drinks). They note that in many cases, the amounts of ephedra alkaloids listed on the label proved to be incorrect or inconsistent on testing. Many products also contained caffeine, which in combination with ephedrine "could increase the risk of adverse events."

Haller and Benowitz conclude that dietary supplements containing ephedra alkaloids "pose a serious health risk to some users." They add, "Our findings arouse concern about the risks of these products, given that they have no scientifically established benefits." The authors advocate stricter labeling regulations, appropriate dosage analyses, and further investigation into determinants of individual susceptibility.



Related links

1.

2. Bethesda, MD: November 6, 2000.

3. mediapulse / Oct 25, 2000 /

4. mediapulse / Jul 21, 2000 /


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