Circulation. 1999;100:e147
(Circulation. 1999;100:e147.)
© 1999 American Heart Association, Inc.
Circulation Electronic Pages |
Aminorex to Fen/Phen: An Epidemic Foretold
Charles Pollick, MB, ChB
Medical Director Department of Non-Invasive
Cardiology,
Good Samaritan Hospital,
Los Angeles, California
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Introduction
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To the Editor:
I read the article by Alfred P. Fishman1 with interest. He
refers to "an unexpected outbreak of valvular heart disease
related to the use of anorectic agents" and implicates the
combination of fenfluramine and phentermine as the cause of this
outbreak. He states that the fen/phen combination "enables high
levels of circulating serotonin to reach the left side of
the heart" and, in commenting on the similarity between the cardiac
valvular lesions in patients taking fen/phen and carcinoid
syndrome, he states that "in both instances, the lesions are
attributable to inordinately high concentrations of
serotonin in the blood." He explains the disparity
between the presence of left-sided lesions in fen/phen patients and
their absence in patients with carcinoid syndrome by a hypothetical
diagram suggesting that both fenfluramine and phentermine impair the
pulmonary clearance of serotonin and permit
"abnormally high concentrations of serotonin to reach the
left side of the heart."
Although there may have been an outbreak of uncontrolled research
papers and abstracts (at the last count, there were 21 such reports)
and legal symposia on the proposed association between anorectic drugs
and left-sided valve regurgitation, to my knowledge, as
a busy cardiologist and echocardiographer, I am not aware
of any outbreak of disease per se. My experience is borne out by the
only large-scale epidemiological study2 to date, in which
the number of patients with idiopathic cardiac valve disorders was 6 of
2371, 5 of 6532, and 0 of 862 for patients prescribed fenfluramine,
dexfenfluramine, and phentermine, respectively. Although fenfluramine
and dexfenfluramine have been shown in some (but not all) studies to be
associated with mostly hemodynamically nonsignificant
valvular regurgitation, phentermine, when taken
alone, has not been shown to cause valvular
regurgitation.2 Although the theory
regarding serotonin uptake seems very appealing, studies
have shown no increase in circulating serotonin in patients
taking fenfluramine alone or in combination with
phentermine.3
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References
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Fishman AF. Aminorex to fen/phen: an epidemic
foretold. Circulation.. 1999;99:156161.[Free Full Text]
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Jick H, Vasilakis C, Weinrauch LA, Meier CR, Jick SS,
Derby LE. A population-based study of appetite-suppressant drugs and
the risk of cardiac-valve regurgitation. N
Engl J Med. 1998;339:719724.[Abstract/Free Full Text]
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Redmon B, Raatz S, Bantle JP. Valvular heart
disease associated with fenfluramine-phentermine. N Engl
J Med. 1997;337:17731774.
Letter.
Response
Alfred P. Fishman, MD
University of Pennsylvania School of Medicine,
Philadelphia, Pa
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Introduction
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The main thrust of Dr Telliers letter seems to be that
my article
builds a house of pathophysiologic mechanisms without
a firm foundation
of epidemiologic evidence. His major misgivings
center around the
prospective International Primary Pulmonary
Hypertension Study
(IPPHS), which was conducted in 35 centers
in Europe.
1
Although some still challenge particular aspects
of the
study,
2 for those working in the field of primary
pulmonary
hypertension, the study has generally been heralded
as a landmark.
Moreover, the recent rebuttal by Abenhaim et
al
3 lends even
greater strength to the argument that
fenfluramines can cause
pulmonary hypertension in genetically
predisposed individuals.
In comparison with the IPPHS study, which dealt with pulmonary
hypertension, the evidence implicating fen/phen in the pathogenesis of
the left-sided cardiac lesions is on less solid footing.4
The cause-and-effect relationship between fen/phen and the cardiac
lesions is based on relatively small numbers of patients,
inconsistent protocols, and variable diagnostic
techniques. However, the similarity between carcinoid valvular
lesions on the right side of the heart and the fen/phenassociated
lesions on the valves of the left side supports the idea that impaired
pulmonary clearance of serotonin caused by
phentermine may enable inordinate concentrations of
serotonin to reach the left side of the
heart.5 However, as in the case of carcinoid lesions, it
may well be that high levels of serotonin are not the sole
mechanism. For example, direct effects of fenfluramines on receptors in
the valves and on the pulmonary vessels might also be
involved.
Dr Pollicks letter raises 3 issues. The first is a mater of
definition. In my view, the unexpected occurrence of valvular
heart disease in 24 healthy women qualifies as an "outbreak." The
second question minimizes the significance of a frequency of
1:1000;
but, in doing so, it does not take into account the fact that if
millions were to ingest fenfluramines, the prevalence of
valvular heart disease in a ratio of 1:1000 would soon rise
exponentially to epidemic proportions. The third question, ie, about
levels of circulating serotonin, can be debated. In
contrast to the letter by Redmon et al6 that is cited,
more extensive studies by Simonneau et al7 indicate that
dexfenfluramine does increase blood levels of
serotonin.
A major point of my article is that impaired clearance by the lungs
would allow inordinate concentrations of serotonin to reach
and damage the left side of the heart. Dr Pollick questions the levels
of serotonin that were achieved by fen/phen. More to the
point would be the demonstration of high levels of
serotonin in the blood of those who developed left-sided
cardiac lesions. Unfortunately, this information is not available. Also
unknown is whether phentermine allows high concentrations of
fenfluramine to reach, and act directly on, serotonin
receptors on the left side of the heart.
As the questions above indicate, taking full stock of the
pharmacological, metabolic, clearance, and biochemical
behaviors of each of the anorexigenics is a complicated affair. This
complexity underscores the need to reserve such agents for the morbidly
obese and to remind all concerned that the safest and most effective
way to lose weight is still by controlling diet and increasing physical
activity.
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References
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Abenhaim L, Moride Y, Brenot F, Rich S, Benichou
J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau
G, Begaud B. Appetite suppressant drugs and the risk of primary
pulmonary hypertension. N Engl J Med. 1996;335:609616.[Abstract/Free Full Text]
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Myers MD. Letter to the editor. N Engl
J Med. 1999;340:476477.[Free Full Text]
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Abenhaim L, Rich S, Benichou J, Begaud B. The authors
reply. N Engl J Med.. 1999;340:481482.
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Williamson DF, Yanoviski SZ. Letter to the editor.
N Engl J Med. 1999;340:476.
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Fishman AP. Aminorex to fen/phen: an epidemic
foretold. Circulation.. 1999;99:156161.
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Redmon B, Raatz S, Bantle JP. Letter to the Editor.
N Engl J Med. 1999;337:17721776.[Free Full Text]
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Simonneau G, Fartoukh M, Sitbon O, Humbert M, Jagot
J-L, Hervé P. Primary pulmonary hypertension associated
with the use of fenfluramine derivatives. Chest. 1998;114:19551995.