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Author Affiliation: Department of Medicine, Boston University School of Medicine, Lexington, Mass.
An association between appetite-suppressant medications and cardiac
valve disorders is now generally believed to have been established, but remains
an important scientific and clinical issue. Even though the 2 most commonly
implicated agents, fenfluramine and dexfenfluramine, were withdrawn from the
US market in 1997 and despite the recent multibillion dollar class action
settlement by the manufacturer of these drugs,1
ongoing research continues to attempt to more accurately and more completely
characterize the pathophysiology and natural history of anorexigen-associated
valvular heart disorders. However, the totality of the evidence to date favoring
a causal connection between fenfluramines and cardiac valve disorders is persuasive,
if somewhat complex.
In the initial 1997 report of cardiac valvular abnormalities associated
with appetite-suppressant drugs, Connolly et al2
described 24 patients who had developed symptomatic heart valve disorders
in the absence of preexisting conditions after receiving phentermine and fenfluramine.
The patients had moderate to severe symptomatic aortic regurgitation (AR),
mitral regurgitation (MR), or both, and had taken both drugs for at least
4 months. Five of the patients required valve replacement. The valves had
an unusual morphologic appearance consisting of glistening white leaflets
and chordae with diffuse thickening and were considered "identical" to those
seen in carcinoid or ergotamine-induced valve disease. Carcinoid and ergotamines
are associated with elevated levels of serotonin, and because fenfluramines
stimulate the secretion of serotonin, it was suggested that the mechanism
by which fenfluramines may cause heart valve disorders could be related to
elevated levels of serotonin.
At the same time, the Food and Drug Administration described the case
histories of 36 recipients of fenfluramines with similar heart valve disorders.3 Six of the patients had received fenfluramine or dexfenfluramine
alone. Subsequently, the Food and Drug Administration reported the result
of echocardiographic studies on 271 patients that found that on average 32%
had valve abnormalities after receiving fenfluramines.4
As a result of these observations, fenfluramines were voluntarily withdrawn
from the market.
These reports prompted 2 types of studies on the relation of fenfluramines
and heart valve disorders. The first involved echocardiographic examination
of asymptomatic obese patients who had received fenfluramines. The second
type was a formal long-term, population-based follow-up study of a large number
of fenfluramine users designed to identify patients who had developed clinically
diagnosed symptomatic heart valve disorders.
In a study of 496 otherwise healthy obese subjects, Khan et al5 reported a prevalence of heart valve abnormalities
of 22.7% in recipients of fenfluramines compared with 1.3% in comparable nonrecipients.
The primary valve abnormality noted was AR, most often considered to be trace
to mild. The duration of use of fenfluramines varied, but no details were
provided. Weissman et al6 reported the results
of a placebo-controlled randomized study of dexfenfluramine and found a modestly
elevated prevalence of AR (5.8%) in 718 dexfenfluramine recipients compared
with 3.6% in 354 control subjects. Of importance, the average duration of
treatment was only 71 to 72 days. Griffen and Anchors7
obtained echocardiograms (ECHOs) on 22 patients who had taken phentermine/fenfluramine
for more than 3 months and reported that 10 (46%) had "significant" asymptomatic
AR. By contrast, Griffen and Anchors8 also
obtained ECHOs on 60 patients who had received a combination of phentermine
and fluoxetine for weight control and found that only 1 patient had mild AR.8
More recently, Shively and colleagues9
described the risk of valve disorders diagnosed by ECHO in 412 subjects, among
whom 223 had taken dexfenfluramine for a mean duration of 6.9 months, and
189 subjects matched on age, sex, and body mass index who were unexposed.
Valvular regurgitation, most often AR, was observed in 7.6% of subjects in
the dexfenfluramine-exposed group compared with 2.1% in the nonexposed group
(P=.01). In a study by Burger et al,10
18 (8%) of 226 phentermine/fenfluramine users were found to have mild to moderate
AR by ECHO, but no comparison group of nonobese users was reported.
Taken together, echocardiographic studies of asymptomatic obese patients
have consistently found an increased prevalence of valve disorders, particularly
AR, in users of fenfluramines compared with nonusers.5-8
The prevalence of valve disorders in nonexposed subjects has varied from 1%
to 4%, whereas the prevalence of such disorders in fenfluramine users has
been reported to be as high as 32%.
Jick and colleagues11 conducted a population-based,
long-term follow-up study of more than 17,000 obese patients using a database
that provides virtually complete information over 8 years about drugs prescribed,
clinical diagnoses, and records on referrals and hospitalizations of more
than 3 million patients in the United Kingdom. The study, which included more
than 8000 recipients of fenfluramines alone and a comparable group of obese
nonrecipients, identified 22 symptomatic patients referred or hospitalized
with a first-time computer-recorded clinical diagnosis of a valve disorder
including 11 patients with newly diagnosed valve disorders in the absence
of predisposing conditions (ie, idiopathic) and 11 with predisposing conditions
such as congenital or rheumatic heart disease. Among the 11 patients considered
to have idiopathic valve disorders, all were recipients of fenfluramines,
9 had received the drug for more than 3 months, and a similar proportion had
aortic insufficiency. No such cases of valvulopathy were found in nonrecipients.
By contrast, among the 11 patients with predisposing conditions, use of fenfluramines
was similar to that in the base population. This study provided evidence that
heart valve disorders associated with fenfluramines can lead to clinically
diagnosed symptomatic illness and also indicated that the prevalence of clinically
symptomatic heart valve disorders associated with fenfluramines was low (approximately
1 per 1000 recipients) and occurred primarily in patients with aortic insufficiency
who had taken fenfluramines for more than 3 months. The results suggest that
the vast majority of the echocardiographic-described valve disorders in asymptomatic
patients associated with fenfluramines5-10
remain asymptomatic for many years and perhaps indefinitely.
In this issue of THE JOURNAL, Gardin and colleagues12
report the results of their study of 1473 patients from 25 clinical centers
in the United States. The results again demonstrate a significantly higher
prevalence of asymptomatic AR, primarily mild, in 479 recipients of dexfenfluramine
(8.9%) and 455 recipients of phentermine/fenfluramine (13.7%), compared with
539 (4.1%) matched controls. In a secondary analysis in which patients with
echocardiographic evidence of heart valve abnormalities characteristic of
other valvular pathology (eg, mitral valve prolapse) and those who had an
ECHO prior to anorexigen use were excluded, the prevalence of AR also was
significantly increased among anorexigen-treated patients (6.3% for dexfenfluramine,
13.9% for phentermine/fenfluramine, and 3.4% for controls). Moreover, although
the authors report no significant difference in the prevalence of MR of at
least moderate severity among the 3 groups, there was a significant increase
in the prevalence of MR in both anorexigen-treated groups when all grades
of regurgitation were evaluated, primarily due to an increase in cases of
This study also is the first to provide considerable data on the relation
of duration of use. The prevalence of AR in the subjects who had used fenfluramines
for 3 months or less (n=48 for phentermine/fenfluramine; n=92 for dexfenfluramine)
was 1.4%, whereas the prevalence was 13% in the 781 subjects who had used
fenfluramines for more than 3 months. Furthermore, the prevalence of AR increased
with increasing duration of exposure, reaching 21.2% in subjects who had received
fenfluramines for more than 18 months.
However, the findings of Gardin et al should be interpreted with care.
The mean time from the last dose of the anorectic agent to performance of
the ECHO was 5.3 months for patients in the dexfenfluramine group and 6.8
months in the phentermine/fenfluramine group. In a recently published small
prospective study in which patients who had received anorectic agents as part
of a clinical trial and had ECHOs obtained at the termination of the trial
and then at 6 months, Hensrud et al13 reported
that the findings of anorexigen-linked valvulopathy noted at the time of the
first ECHO did not progress after cessation of use of anorexigens, and in
some patients appeared to improve over time. As pointed out by Asinger,14 ECHO screening several months after cessation of
anorexigen treatment may result in a lower incidence of valvular abnormalities
than screening performed while patients were taking the drug or shortly thereafter.
Accordingly, the data reported by Gardin et al may underestimate the actual
prevalence of heart valve abnormalities related to the use of these drugs.
Several factors apparent from the body of evidence linking fenfluramines
and valve disorders appear to favor a causal connection. The majority of echocardiographic
studies comparing asymptomatic fenfluramine recipients with comparable nonrecipients
show a substantially increased prevalence of valve disorders in the fenfluramine-treated
patients. The most common abnormality is AR, which is most often minor and
benign (ie, associated with no cardiac symptoms). Clinically important valvular
disease attributable to fenfluramines appears to be uncommon.
Moreover, and of critical importance to a causal inference, there is
now persuasive evidence of a large duration effect.12
In the United Kingdom follow-up study,11 92%
of patients with symptomatic valve disorders, primarily AR, had used fenfluramines
for more than 3 months, whereas only 23% of subjects in the base population
received fenfluramines for more than 3 months. In the series reported by Connolly
et al,2 22 of 24 cases occurred in fenfluramine
recipients who used the drug for more than 3 months, despite the fact that
only 20% to 30% of fenfluramine users in the United States are estimated to
have taken the drug for that long. The study by Gardin et al demonstrates
a clear duration effect of the fenfluramine–heart valve disorder association.
In addition, a recent study by Li et al15 suggests
that the severity of valvulopathy is associated with use of higher doses of
Millions of patients were prescribed fenfluramines prior to 1997. For
the substantial majority who took the drug for less than 3 months, the risk
of heart valve disorders appears to be minimal. In those who took the drug
longer than 3 months, many will have developed echocardiographic evidence
of cardiac valve disorders, particularly mild AR. In the majority of instances,
these abnormalities most likely are benign and are unlikely to lead to clinical
disease. However, a small proportion of patients have substantially increased
risk for clinically important valvulopathy and cardiovascular consequences
as a result of taking anorexigens. However, because fenfluramines have been
unavailable since 1997, judgments about the overall consequences of fenfluramine
use are likely to be limited to the results of those studies already completed.
Jick H. Heart Valve Disorders and Appetite-Suppressant Drugs. JAMA. 2000;283(13):1738–1740. doi:10.1001/jama.283.13.1738
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