In contrast to the experience with dofetilide, in which an adverse drug effect was identified during product development, the consequences of appetite suppressants were detected serendipitously.
APPETITE SUPPRESSANTS
In
contrast to the experience with dofetilide, in which an adverse drug effect was
identified during product development, the consequences of appetite
suppressants were detected serendipitously. Phentermine was approved by the
FDA for appetite suppression in 1959, fenfluramine in 1973, and dexfenfluramine
in 1996. The former two were approved for short-term use, and all three drugs
were approved for use as single agents. In the 1990s, prescription of
fenfluramine in combi-nation with phentermine and for periods longer than a few
weeks was widespread. From 1995 to 1997, 14 million prescriptions were written
for fenfluramine or dexfenfluramine, exposing an estimated 1.2–4.7 million
persons to these agents (MMWR, 1997).
In
July 1997, physicians in Minnesota reported 24 women with valvular heart
disease who had taken fenfluramine–phentermine for 2–28 months (Connolly et al., 1997). The women were identified
during evaluation of conditions such as congestive heart failure, heart
murmurs, or arrhythmias. Echocar-diographic features of the dysfunctional valves
resem-bled those seen in carcinoid heart disease; in five, valvular
incompetence was severe enough to require cardiac surgery. Because of the
morphologic simi-larity to carcinoid valvular disease, which has been
attributed to high circulating levels of serotonin, the authors hypothesized
that the valvular damage seen with fenfluramine might be due to its promotion
of serotonin release and inhibition of serotonin reuptake. Phentermine is a
nonadrenergic agent which impedes pulmonary clearance of serotonin, and which
might potentiate the effect or concentration of circulating serotonin.
The
Minnesota report, in conjunction with an FDA public health advisory, rapidly
spawned additional case reports (Cannistra, Davis and Bauman, 1997; Graham and
Green et al., 1997; Kurz and Van
Ermen, 1997). A trio of larger clinical studies, each of differ-ent design, was
published in September 1998 in the New
England Journal of Medicine.
In
the first study, echocardiograms were performed on 257 of 295 participants in
prior appetite suppres-sant studies at Hennepin County Medical Center and in
gender, age and body mass index-matched controls (Khan et al., 1998). Study participants had taken fenfluramine 60–120 mg + phentermine 30 mg daily,
dexfenfluramine 30 mg daily alone, or in combi-nation with phentermine 30 mg
daily. Mean dura-tion of treatment was 20 5 ± 12 months. Echocardio-graphic
aortic and mitral insufficiency was scored (none, trace, mild, moderate or
severe) by two blinded readers; if they disagreed, the study was reviewed by a
third reader. FDA criteria for valvular abnormal-ity were applied, that is,
aortic valvular disease of mild or greater severity and mitral valvular disease
of moderate or greater severity ( = 0 79 for corre-lation between
readers). Valvular insufficiency was identified in 3/233 control subjects
(1.3%) and 53/233 appetite suppressant consumers (22.7%). In multivari-ate
analysis which included age, gender, body mass index, blood pressure, and
diabetes as covariates, and control subjects as the reference group, the odds
ratios (95% confidence intervals) for valvular abnor-mality were 12.7
(2.9–56.4), 24.5 (5.9–102.2), and 26.3 (7.9–87.1) for dexfenfluramine,
dexfenfluramine + phentermine, and fenfluramine + phentermine use, respectively.
The second study
compared patients who
had been prescribed dexfenfluramine= 6532 , fenfluramine (n = 2371) , or phentermine (n = 862) with age, gender, and
weight-matched controls in the UK General Practice Research Database (Jick et al., 1998). During follow-up of about
4 years, the database identified 22 new diagnoses of valvular abnormality.
Eleven patients were excluded when other causes of valvular disease, such as
rheumatic heart disease or mitral valve prolapse, were identified by medical
record review. The remaining 11 subjects had been referred to cardiologists for
recent symptom onset or new heart murmur. In eight patients, valvular
insuf-ficiency was confirmed by echocardiography and in three by clinical
examination. All 11 patients had been prescribed dexfenfluramine or
fenfluramine, a cumu-lative incidence of 14.2 per 10 000 (95% confidence
interval 7.8–26.2). No valvular abnormalities were identified in untreated
subjects or those prescribed phentermine.
The
third study performed echocardiograms on participants in a randomized,
double-blind trial comparing dexfenfluramine (15 mg bd), sustained-release
dexfenfluramine (30 mg daily) and placebo, which was ongoing at the time
dexfenfluramine was withdrawn from the US market (Weissman et al., 1998). Echocardiograms were performed on 1072 of 1212
randomized participants and interpreted by blinded readers; mean exposure was
72 days. Using FDA criteria for valvular abnormality (aortic insuffi-ciency of
mild or greater severity and mitral insuf-ficiency of moderate or greater
severity), valvular disease was not significantly more prevalent in the
combined dexfenfluramine groups compared with placebo. When any degree of
valvular insufficiency was compared between the treatment groups, aortic = 0 03 and mitral insufficiency = 0 01 were more frequent in the combined
dexfenfluramine groups compared with placebo.
In
November 1998, the American College of Cardi-ology and American Heart
Association (ACC/AHA) recommended evaluation of appetite suppressant users,
including history and physical examination, with echocardiography in those with
signs or symp-toms of valvular disease (Bonow et al., 1998). Subse-quent meta-analyses have tempered initial
estimates of the frequency of valvular insufficiency associ-ated with appetite-suppressant
use, supporting the ACC/AHA statement that routine echocardiography was not
recommended for all of the millions of indi-viduals exposed.
Pooled
data from six controlled cohort studies yielded a relative risk ratio of 2.32
for aortic insuf-ficiency (95% confidence interval 1.79–3.01) and 1.55 for
mitral insufficiency (95% confidence interval 1.06–2.25) (Loke, Derry and
Pritchart-Copley, 2002). A second analysis which included ten studies found a
prevalence odds ratio of 2.2 (95% confidence interval 1.7–2.7) for aortic
insufficiency meeting FDA crite-ria among individuals treated for at least 90
days with fenfluramine derivatives (Sachdev et
al., 2002). The odds ratio for mitral insufficiency of moderate or greater
severity was 1.6 (95% confidence interval 1.05–2.3).
The
experience with appetite suppressants illustrates the role of fortuitous
observation in identifying adverse drug effects and the potential for
inaccuracy of early risk estimates due to methodologic weak-nesses.
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