In July, 1997, the FDA issued a health advisory concerning the potential
of fen-phen for causing valvular heart disease (see article summarized
A case series of 24 patients was described in the NEJM (summarized here)
in August, 1997 and the three drugs were subsequently withdrawn from the
market. Since the morphology of some of the valvular lesions that were
seen at surgery resembled valve damage seen with the carcinoid syndrome,
which is postulated to be due to high serotonin levels, it has been speculated
that the appetite suppressants may cause heart valve damage through a serotonin-related
mechanism. The risk for valvular lesions associated with these drugs has
been estimated to be as high as 20 to 30 percent, but many feel that this
greatly overestimates the risk, particularly for short-term users.
The three important studies summarized here were undertaken to shed
light on the actual risk of valvular heart disease associated with exposure
to fenfluramine, dexfenfluramine and phentermine.
The prevalence of cardiac valvular insufficiency assessed by transthoracic
echocardiography in obese patients treated with appetite-suppressant drugs
||Khan M, Herzog C, St Peter J, Hartley G, Madlon-Kay R, Dick
C, Asinger R, Vessey J.
||New England Journal of Medicine. 339:713-8. September
||Multi-institutional in Minneapolis, Minnessota, USA.
||National Institutes of Health; Centers for Disease Control
This study was an echocardiographic study of patients who had previously
taken appetite suppressants and matched controls.
Patients had all previously participated in one of three studies of
appetite suppressant medications. These studies utilized fen-phen (fenfluramine
60-120 mg daily plus phentermine 30 mg daily), or dexfenfluramine (30 mg
daily) or dexfenfluramine (30 mg) with optional phentermine (30 mg). Patients
were at least 30% above ideal body weight and were without overt cardiovascular
Controls were recruited by advertisement and were matched for age, sex,
height and body-mass-index.
Echocardiograms were interpreted by at least two observers. Valvular
regurgitation was graded -- aortic regurgitation was judged significant
if it was at least mild, mitral regurgitation if it was at least moderate.
Of the 295 patients enrolled in the three original
studies, 257 agreed to participate in this study. 6 were excluded because
of protocol violations and another 18 could not be matched to controls,
leaving 233 matched pairs of patients and controls.
Patients (and controls) were predominantly women
(87%), with a mean age of 45, mean weight of 247 lbs and mean BMI of 40.5.
Significant valvular regurgitation (as defined
above) was present in 1.3% of controls and in 22.7% of patients. Among
patients, regurgitation was present in 12.8% of the 39 patients who had
been treated with dexfenfluramine alone for a mean of 4.9 months, in 22.6%
of the 31 who had been treated with dexfenfluramine-phentermine for 9 months
and in 25.2% of the 163 who had been treated with fenfluramine-phentermine
for a mean of 26.5 months.
A population-based study of appetite-suppressant drugs and the risk of
||Jick H, Vasilakis C, Weinrauch L, Meier C, Jick S, Derby
||New England Journal of Medicine. 339:719-24. September
||Boston University Medical Center; Harvard Medical School.
||Food and Drug Administration; indirect support by multiple
This was a case-control study, utilizing a computerized system from the
UK, the General Practice Research Database, which contains clinical information
on over 4 million patients in private practices.
Subjects were identified from the database who were under 70 years of
age, without overt cardiovascular disease and who had been given at least
one prescription for an appetite suppressant (fenfluramine, dexfenfluramine,
phentermine) after January 1, 1988. Controls were selected from the
same database and matched for sex, age, weight and medical practice.
The incidence of new valvular heart disease, occurring after the date
of the first appetite suppressant prescription (or the same date for matched
controls), was compared between patients and controls. Valvular heart
disease was identified by diagnostic codes for valve disease entered in
the database and by reviewing any available echocardiograms.
9765 patients were identified who had been prescribed appetite suppressants.
Of these, 1001 had taken more than one agent but were assigned to one of
the three drugs for the purpose of analysis (based on quantity prescribed
or, if the quantities were equal, which one had been taken last).
In this fashion, 6532 were classified as dexfenfluramine users, 2371 as
fenfluramine users and 862 as phentermine users. A total of 9281 matched
control subjects were identified from the database.
Among the 19,046 patients and controls, 22 patients with apparently
incident cardiac valve abnormality were found. After record review, 11
of these were excluded because they had evidence of prior valvulopathy,
leaving 11 with newly incident valve abnormalities.
These 11 had been referred for cardiac evaluation because of symptoms
(8) or a murmur (3). The valvulopathy was confirmed by echocardiography
in 8 out of the 11 patients. Two of the eleven had only mitral regurgitation,
the remainder had only aortic regurgitation (6) or combined aortic and
mitral regurgitation (3).
The cumulative incidence of valvular disease was 7.1 per 10,000 subjects
among those who had taken dexfenfluramine or fenfluramine for one to three
months and 35 per 10,000 subjects among those who had taken dexfenfluramine
or fenfluramine for four or more months.
5 of the cases were from the 6532 dexfenfluramine users. 2 of these were
from 5086 who had used the drug for 1-3 months; 3 from 1446 who had used
it for more than 4 months.
6 were from the 2371 fenfluramine users. 2 of these were from 1831 who
had used the drug for 1-3 months; 4 from 540 who had used it for more than
none were from either the 862 phentermine users or the 9281 controls.
An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine,
sustained-release dexfenfluramine, or placebo
||Weissman N, Tighe J, Gottdeiner J, Gwynne J, for the Sustained-Release
Dexfenfluramine Study Group.
||New England Journal of Medicine. 339:725-32. September
||Georgetown University Medical Center; Wyeth-Ayerst Research.
This study was initially designed as a randomized, double-blind trial comparing
a sustained-release formulation of dexfenfluramine (30 mg daily), conventional
dexfenfluramine (15 mg twice daily) and placebo. The drugs were to be administered
for 16 weeks, but the trial was discontinued early when dexfenfluramine
was withdrawn from the market. The protocol was then modified to include
ehocardiographic evaluation of all subjects.
Echocardiograms were performed and evaluated for valvular morphology
and regurgitation. When these were judged to be abnormal, they were re-evaluated
by a second echocardiographer.
1212 patients were randomized, and 1072 underwent echocardiography, a median
of 33-34 days after drug discontinuation. Patients were predominantly white
women, with an average age of 45 and an average body mass index of 38.
The average duration of treatment was 71-72 days.
Using the FDA criteria for significant valvular regurgitation (at least
mild aortic regurgitation and at least moderate mitral regurgitation),
and combining the two treatment groups (sustained release and regular dexfenfluramine),
the prevalence of significant aortic regurgitation was 5.4% in dexfenfluramine-treated
patients vs. 3.6% in those who had received placebo (p=0.27, NS). Similarly,
the prevalence of significant mitral regurgitation was 1.8% vs. 1.2% (p=0.60)
and of significant mitral or aortic regurgitation was 6.9% vs. 4.5%
When all degrees of valvular regurgitation were considered, including
trace aortic regurgitation and physiologic or mild mitral regurgitation,
the differences did reach statistical significance. Aortic regurgitation
was present in 17% of the treatment group vs. 11.8% of the placebo group
(p=0.03). Mitral regurgitation of any severity was present in 61.4% of
the treatment group vs. 54.4% of the placebo group (p=0.01). Tricuspid
regurgitation was not correlated with dexfenfluramine use.
There was no significant difference between the groups in aortic or
mitral valve thickening, or in aortic leaflet mobility. The posterior mitral
leaflet demonstrated less mobility in the combined dexfenfluramine groups
than in the placebo group.
Although all three of the studies found some increase in valvular regurgitation
among patients who had been treated with appetite suppressants, the degree
of risk varied greatly. This variation is attributable to differences in
the design of the studies and in the length of exposure to the drugs.
The greatest incidence of valvular regurgitation attributable to appetite
suppressant use (about 20%) was found in the first study by Khan et al..
This study examined patients who had had a relatively long exposure to
the drugs (about 20 months on average). Patients all had echocardiograms,
and mild aortic regurgitation was considered significant. Thus, the high
incidence of valvular abnormalities caused by the drugs is in part attributable
to the long duration of exposure and to the fact that some lesions which
may not be clinically significant were included.
In the study by Jick et al., based on a review of a clinical database
from the U.K., the incidence of attributable valvulopathy was only 0.35%
among those who had used the drugs for over 4 months. However, these patients
came to be diagnosed because of symptoms or the appearance of a new murmur,
and thus represent clinically more significant disease. Furthermore, the
average duration of drug use in this study was substantially less than
In the study by Weissman et al., all patients underwent echocardiography.
The increase in detectable valvular regurgitation did not reach statistical
significance unless even the mildest degrees of leakage were included.
However, these patients only took the drugs for less than 3 months, on
In an accompanying editorial, Dr. Richard Devereux points out that these
three studies are important because they confirm the association between
the drugs and valvular heart disease and exclude obesity as a confounding
explanation. He also notes that the studies are reassuring for those patients
who have taken these drugs for only a few months, since the incidence of
valvulopathy was quite low in this group.
Unfortunately, the three studies do not help tease out the contribution
of phentermine to the development of valvular lesions. Although phentermine
does not act by a serotoninergic mechanism and was not associated with
any valvulopathies in the second study (Jick et al), the number of phentermine
users in this study was too small to draw any clear conclusions. Since
much of the published data on valvular damage is from fen-phen users, phentermine
is likely to remain "guilty by association", at least until data to the
November 15, 1998
related to this article from the NLM's PubMed
February 22, 1999
to the editor about these articles, from the NEJM.
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