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Nutrition
& Obesity Publications
WIN
NIDDK
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Winter 1999
New Studies Support Connection Between Fenfluramine
or Dexfenfluramine and Valvular Heart Disease
Newly published research lends considerable credence to the suspected
link between the diet drugs fenfluramine or dexfenfluramine and valvular
heart disease.
In September 1997, the popular appetite suppressants were voluntarily
withdrawn from the market by their manufacturer in the wake of reports
that patients who took the drugs--whether
alone or in combination with phentermine, a combination commonly called
"fen-phen"--developed
potentially dangerous heart-valve abnormalities.
Questions remained, however, about the prevalence and severity of the
problems, and more information was urgently needed. Three studies published
in the September 10, 1998, issue of the New England Journal of Medicine
(NEJM) shed new light on the heart-valve problems associated with
these drugs.
The journal's cover article described a study performed by endocrinologist
Mehmood A. Khan, M.D., and others, supported by the National Institute
of Diabetes and Digestive and Kidney Diseases and the Centers for Disease
Control and Prevention, in association with the Minnesota Obesity/Nutrition
Research Center. In this study, patients who had taken fenfluramine or
dexfenfluramine (alone or in combination with phentermine) for various
time periods had a significantly higher incidence of cardiac-valve abnormalities
than those who had not. Of those who had taken these drugs, 22.7 percent
had heart-valve abnormalities, compared to only 1.3 percent of a control
group. Most of the abnormalities were mild. The control group was made
up of people who were matched to the study subjects by sex, age, height,
and body mass index, but had not taken appetite-suppressant drugs.
The NEJM also reported a study of the effects of phentermine,
fenfluramine, and dexfenfluramine, headed by Hershel Jick, M.D., and supported
in part by the Food and Drug Administration (FDA); and a study focusing
on dexfenfluramine alone, led by Neil J. Weissman, M.D., and supported
by Wyeth Laboratories.
The researchers defined a heart-valve abnormality as at least mild aortic
regurgitation or at least moderate mitral-valve insufficiency, because
this was the definition used by the FDA in calling for the drugs' withdrawal.
The Weissman and Khan studies used echocardiographs to determine the degree
of valvular abnormality. The Weissman study, which compared patients exposed
to dexfenfluramine for an average of 2 1/2 months to those on placebo,
found no statistically significant difference between groups in the prevalence
of valvular regurgitation meeting FDA criteria. However, even this short-term
study found an increase in mitral and aortic regurgitation in those exposed
to the drug, though the levels were primarily trace or mild.
The Jick study was a population-based study that evaluated the prevalence
of clinically evident valvular heart disease among exposed and unexposed
patients. One important finding of this study was that short-term exposure
to an appetite suppressant (4 months or less) was less likely to cause
clinically evident heart-valve abnormalities.
The implications for the public remain the same. Patients who took fenfluramine
or dexfenfluramine should be examined by a physician, who should perform
a stethoscopic examination of the heart. An echocardiograph is recommended
if the patient has any signs or symptoms of heart disease (including a
murmur). In addition, the Department of Health and Human Services' interim
guidelines recommend echocardiographic examination of the heart for all
patients exposed to fenfluramine or dexfenfluramine before these patients
undergo any dental or medical procedures for which antibiotic prophylaxis
is recommended by the American Heart Association.
The recently released American College of Cardiology/American Heart
Association Practice Guidelines for Management of Patients with Valvular
Heart Disease make similar recommendations, except that they do not
advocate universal echocardiographic screening for asymptomatic exposed
patients before procedures for which antibiotic prophylaxis is indicated.
However, these guidelines do recommend echocardiography for asymptomatic
exposed patients in whom cardiac auscultation (examination with a stethoscope)
cannot be performed adequately (due to obesity, for example). They also
recommend that asymptomatic patients without murmurs should undergo repeat
physical examination in 6 to 8 months. Because of the rare association
between certain appetite-suppressant drugs and the development of primary
pulmonary hypertension, patients exposed to fenfluramine or dexfenfluramine
should also alert their health care provider if they develop a decrease
in exercise tolerance or shortness of breath.
Timeline
1959 FDA approves phentermine.
1973 FDA approves fenfluramine (Pondimin).
1992 Reports of the effectiveness
of fen-phen appear in Clinical Pharmacology and Therapeutics,
and widespread "off-label" use of the combination begins.
1996 FDA approves dexfenfluramine
(Redux), a close chemical relative of fenfluramine. New England
Journal of Medicine article notes possible link between appetite-suppressant
drugs and pulmonary hypertension.
1997 Fourteen million prescriptions
for fenfluramine or dexfenfluramine written to date. July 8:
Mayo Clinic researcher Heidi M. Connolly, M.D., and others report
that 24 fen-phen patients have developed heart-valve abnormalities.
FDA releases a public health advisory. August 28: The Connolly
et al. findings are published in the New England Journal of Medicine
along with a letter to the editor from FDA reporting nine additional
cases of heart-valve abnormalities. September 15: FDA announces
the voluntary withdrawal of fenfluramine and dexfenfluramine by
their manufacturers, Wyeth-Ayerst Laboratories and Interneuron Pharmaceuticals
(respectively). November 13: FDA, Centers for Disease Control
and Prevention (CDC), and National Institutes of Health jointly
release interim treatment recommendations. These recommendations
appear in CDC's Morbidity and Mortality Weekly Report.
1998 New
England Journal of Medicine publishes three studies further
supporting the link between fenfluramine or dexfenfluramine and
heart-valve abnormalities, validating the FDA's decision to recall
the drugs and reiterating recommendations for evaluation.
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