When seven Belgian patients unexpectedly developed leaky heart valves, a cardiologist named Mariane Ewalenko asked them what medications they were taking. In each case, the answer was the same: diet pills.
The Belgian doctor says she informed the French company that made the drugs. She also gave a talk on the subject to several dozen obesity specialists at a conference in Brussels. "This is very suspicious," she told the doctors. "Listen carefully to your patients for heart murmurs."
That was in February 1994. It was, in other words, more than 3 1/2 years before the same two drugs were pulled from the U.S. market amid suddenly surging fears about pills that had become hugely popular among overweight Americans.
In all, various Belgian doctors reported at least 30 cases of heart-valve problems in diet-pill users between 1994 and 1996, according to the doctors themselves and to records at the United Nations' World Health Organization. Some reports were made to Belgian drug regulators and some to the European supplier, Laboratoires Servier SA. WHO keeps a database that is available to national health agencies.
The Belgian cases raise new questions about the regulation of prescription diet pills that were taken by about 70 million people world-wide, including six million Americans, and that now are a cause of concern for former users. Leaky valves can lead to an enlarged heart and be a serious matter. To date, 27 Americans have had surgery to correct diet-drug-related valve problems, according to the Centers for Disease Control and Prevention. Three have died from surgical complications.
The Food and Drug Administration has said the recall of the drugs in September shows that the U.S. drug-safety system works: As soon as new evidence of serious side effects emerged -- in a July Mayo Clinic study, confirmed by an FDA survey of doctors -- the U.S. distributor pulled the pills from the market.
The little-noticed Belgian cases paint a quite different picture.
Adverse Reactions
U.S. pharmaceutical companies are required to notify the FDA quickly of any "serious and unexpected" adverse effects in users of drugs they market-whether the effects occur here or abroad, and whether or not they appear to be related to the drug. The U.S. companies are supposed to make sure that any foreign affiliates, such as companies that license drugs to them, tell them of any bad reactions.
The U.S. distributor of the diet pills was American Home Products Corp. of Madison, N.J. It licensed one drug, fenfluramine, from the same company that supplied diet pills in Belgium, France's Servier. Fenfluramine, part of the popular "fen-phen" combination, was sold for many years under the name Pondimin.
More recently, Servier licensed the chemically similar dexfenfluramine to a U.S. company, Interneuron Pharmaceuticals Inc., which joined with American Home to market it as Redux. This drug didn't win U.S. marketing approval until 1996, although Servier began selling it earlier in Belgium and elsewhere.
Servier says it heard of some Belgian heart-valve cases. In each instance, a spokesman says, it informed U.S. associates "in a timely fashion." When the Mayo Clinic found heart-valve problems in two dozen patients last summer, American Home gave no indication it was familiar with the problem. An American Home physician, referring to the serious abnormalities found by Mayo, was quoted as saying that "we'd never seen anything like this."
Reporting to the FDA
But when asked recently if it knew of any heart-valve cases before the Mayo study, American Home said it did know of 25 Belgian cases and six others elsewhere in Europe, having learned of them from Servier. American Home says it passed 10 of the reports on to the FDA. The FDA confirms having been told of eight.
Why didn't American Home report all of the cases to the FDA? "We reported everything that we thought was "serious and unexpected," " says Joseph Pittelli, executive vice president of research at the company's Wyeth-Ayerst Laboratories. Interneuron, without elaborating, says it, too, has met all reporting requirements. It notes that it was involved with only one of the drugs, Redux.
FDA regulations define "serious" effects as those that are life threatening or permanently disabling. It defines "unexpected" side effects as ones not already listed on the warning label.
American Home's reason for not telling the FDA about the six European cases outside Belgium is that those pill takers' main problem was a lung disorder already known to be a possible side effect. As for the 15 Belgian cases it didn't report, the company declines to explain why it didn't judge them to be serious and unexpected. FDA officials say it is possible that some didn't meet the seriousness test because the valve problems weren't affecting health.
Some authorities, though, consider all valve leaks serious. Michael Rawlins, a British pharmacologist who heads a drug-monitoring effort of 10 European nations, says, "Heart-valve problems are serious by anyone's standards, even if they are asymptomatic. Common sense would dictate that."
Sources of Information
The FDA could have learned about more of the earlier heart-valve cases from other agencies that catalog side effects. Belgium's health authorities had received 43 reports of valvular heart disease in diet-drug users before the U.S. recall, they say in a letter to the editor in today's New England Journal of Medicine, adding that 31 were confirmed by ultrasound tests called echocardiograms. Records show that Belgium shared 13 of the reports with the World Health Organization. The FDA says it doesn't usually keep up with side effects reported to its counterparts abroad. It says it doesn't usually check WHO's database because the FDA itself is the source of much of the data in it.
In 1995, an FDA advisory panel considered Interneuron's application to sell Redux in the U.S. Panel members say they knew nothing of the Belgian problems. James Bilstad, director of the FDA drug-evaluation office that dealt with Redux, says the agency had received no reports of heart-valve problems associated with its main ingredient, dexfenfluramine.
Most of the Belgian heart-valve reports didn't involve this particular diet drug. However, at least seven did. Four of the obesity patients took it alone, and three took it along with the other diet drug, which is a chemical cousin. All seven cases were reported either to Servier or to the Belgian agency before the eventual Redux approval.
Dr. Bilstad says it is possible that Interneuron included some of the Belgian cases in a summary of "nonserious" cardiac side effects, without identifying them as heart-valve problems. Interneuron, of Lexington, Mass., says it gave the FDA a detailed report on at least one Belgian case involving Redux's ingredient in an amendment to its drug application.
Easier in Hindsight
Although it isn't known whether the heart-valve problems were due to the diet pills, Dr. Bilstad says knowledge of the Belgian cases might have triggered a more thorough review of Redux at the FDA. "It's much easier to look in hindsight with what we know now and say, "Gee that's obvious," " he notes. "But when you're in a situation with all the noise around, it's not so easy to pick out the truth."
Leo Lutwak, an FDA staffer who reviewed the Redux application and opposed approval because of other side effects, says that had he known about all of the Belgian cases, "I would have tried to use it as another argument against approval."
In November 1995, after two contentious hearings that focused on other possible side effects, including a rare but often-fatal lung disorder, the advisory panel voted to approve Redux by the slimmest of margins, 6-5. The FDA gave it final approval five months later.
Roger Illingworth, a panel member who supported the drug, says he probably would have voted no had he known of the Belgian cases. They wouldn't have been conclusive, he says, but could have been a "red flag" that sparked further inquiry, including clinical testing for heart-valve problems.
Pill Binge
Ignorant of Belgium's experience, the U.S. went on a diet-pill binge in 1995, adding Redux to the pharmacopeia when it became available. Physician entrepreneurs set up pill-dispensing clinics across the nation. Redux and Pondimin brought $305 million in revenue to American Home in 1996. At the peak of the craze last February, 200,000 prescriptions were being filled each week.
Nicole Jackson, a 32-year-old waitress from Bemidji, Minn., took the fen-phen combination for more than a year and lost 70 pounds. But she also developed a leaky heart valve. She was one of the two dozen pill takers in whom the Mayo Clinic and its collaborators found problems. Told that a possible link between the pills and valve problems had surfaced earlier in Belgium, Ms. Jackson said, "It's really sad that this didn't come out earlier. If I had known these drugs had anything to do with heart problems, I would never have taken them."
American Home and Interneuron are the targets of litigation by diet-pill users, accusing them, among other things, of failing to warn users of health risks they knew about. The Belgian cases are sure to figure in the litigation. "It's going to look like there was a coverup," says George J. Annas, an expert in health law who teaches at Boston University School of Law. "And that's basically the worst thing that you can be accused of from a jury's perspective -- that you have information that's important to the safety of the public and you're keeping it to yourself or tried to explain it away."
Chinese Herbs
The defendants say they covered up nothing -- that they reported everything they were supposed to report. And American Home raises a complicating factor that it says made the reports hard to interpret: Some of the Belgian patients were also taking Chinese herbs to lose weight -- herbs suspected of leading to another dangerous condition, kidney disease.
American Home believed the herbs were also responsible for the heart-valve problems, says Louis L. Hoynes, the company's general counsel. As a result, the Belgian cases "were not seen as a signal of any problem that required further investigation," he says. "Obviously, we have a lot more questions now than we would have had then."
As it happened, it was a scare over the Chinese herbs that eventually led some doctors in Belgium to make a link between diet pills and heart-valve problems.
In the early 1990s, some Belgian doctors grew alarmed when a crippling and potentially fatal kidney disease arose in women who had taken a weight-loss formula containing Chinese herbs and fenfluramine. In October 1992, Belgium banned sale of the herbs, Stephania tetranda and Magnolia officinalis.
Researchers began to notice that some of the patients also had leaky heart valves. But little thought was given to the notion that fenfluramine might be the culprit until Dr. Ewalenko discovered the valve leaks among patients who hadn't taken any herbs.
Heart Murmur
Word of her findings reached Jean Malak, a physician who was at the center of the herb scandal. Dr. Malak, of Binche, Belgium, was the majority owner of an herb-import company that is being sued by herb takers. He believes the herbs are safe and is intent on proving they were unfairly blamed.
After hearing about Dr. Ewalenko's February 1994 Brussels talk about diet drugs and heart valves, Dr. Malak examined his own patients' hearts. The following month, he says, he found a serious heart murmur, suggesting a valve leak, in an otherwise healthy patient who had taken fenfluramine -- but no herbs.
"I felt ice cubes down my spine when I heard it," he says. Dr. Malak says he confirmed the leak with an echocardiogram and reported the case to Servier and to Belgian health authorities. He says he followed up between 1994 and 1996 by reporting at least a dozen leaky-valve cases to Belgian authorities, all in patients who hadn't taken any herbs.
But many in Belgium were skeptical because Dr. Malak appeared to have an ax to grind. "Nobody believed him because of the herbs," Dr. Ewalenko says.
"It is true that my interest in this began because I wanted to defend the herbs," Dr. Malak says. "But I have conducted a serious inquiry to get to the truth."
Letter to Lancet
Dr. Malak says that in 1995, he wrote a letter to the British medical journal Lancet outlining his suspicions that diet pills were causing heart-valve leaks. Lancet rejected it, citing the many letters it receives.
Dr. Ewalenko says she, too, wanted to publish her data. Short of time, she forwarded her case studies to Jean-Louis Vanherweghem, president of the Free University of Brussels, seeking a collaborator on an article.
Dr. Vanherweghem, one of Belgium's leading authorities on the Chinese-herb scare, says he, too, had seen some leaky valves in patients who took both herbs and diet drugs. Indeed, he briefly mentioned this in a 1995 journal article about the herbs and kidney disease. But after speaking with Servier, he says, he concluded that the valve problems were probably due to the herbs, not to the drugs. "At this time, [Servier] told us no other cases were reported in the world," he says.
Dr. Vanherweghem decided against pursuing an article with Dr. Ewalenko on her cases. But now he believes that the diet drugs, not the herbs, were "probably the cause of the valvular heart disease that we observed." He recently sent a letter to Lancet stating his new conclusion.
Scant Attention
Belgian physicians remain puzzled that so little attention was paid to their early efforts to link diet pills to heart-valve problems. Belgian health authorities confirm in their New England Journal of Medicine letter that a majority of the heart-valve problems they learned of were in patients who hadn't taken any Chinese herbs. The agency says it didn't routinely pass such reports along to the drugs' manufacturers until mid-1996, when new European Union rules required it to do so.
However, four Belgian doctors say they were in touch with Servier officials by phone, letter or in person about at least nine of the cases well before the U.S. recall. Dr. Ewalenko says that when she spoke with Magda Opsomer, a Servier representative, in 1994, Dr. Opsomer was initially "very concerned" but later said Servier hadn't found any corroborating reports in other countries.
Belgian physician Jean-Francois Adam says he spoke with Dr. Opsomer in 1995 and told her of a patient who developed a leaky valve after taking dexfenfluramine. "She listened to what I had to say, but I don't think she took me seriously," Dr. Adam says. "She said she knew of no other cases like it but would do some checking and get back to me. She never called back."
Dr. Opsomer declines to comment. But a spokesman for Servier says it believes that adequate scientific testing will show that its diet drugs don't cause damage to heart valves. The spokesman says Servier hopes eventually to get them back on the market "for appropriate prescription to those who benefit from these products."
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