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Echocardiographic Examination of Women Previously Treated With Fenfluramine
Long-term Follow-up of a Randomized, Double-blind, Placebo-Controlled Trial
Ravin Davidoff, MB, BCh;
Anne McTiernan, MD, PhD;
Ginger Constantine, MD;
Kelly D. Davis, MD;
Gary J. Balady, MD;
Lisa A. Mendes, MD;
Rebecca E. Rudolph, MD, MPH;
Deborah J. Bowen, PhD
Arch Intern Med. 2001;161:1429-1436.
ABSTRACT
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Background Fenfluramine hydrochloride was withdrawn from the market in September
1997 after reports of heart valve abnormalities in patients who used it. The
prevalence of echocardiographic abnormalities and the clinical cardiovascular
status of patients who received fenfluramine monotherapy remains uncertain.
Methods A long-term, follow-up evaluation was undertaken in subjects who were
randomly assigned to receive either fenfluramine hydrochloride (60 mg daily)
or placebo as part of a double-blind smoking cessation therapy study. Cardiovascular
status was evaluated by echocardiography, medical history, and physical examination.
Results From the group of 720 smokers who had originally participated in the
smoking cessation therapy trial, 619 women were enrolled; data from 530 (276
in the fenfluramine group and 254 in the placebo group) were evaluable. No
statistically significant differences were identified in the prevalence of
aortic or mitral regurgitation by Food and Drug Administration criteria or
by grade, aortic or mitral valve leaflet mobility restriction or thickening,
elevated pulmonary artery systolic pressure, or abnormal left ventricular
ejection fraction. No significant differences were demonstrated in cardiovascular
status by physical examination, and no serious cardiac events were noted among
fenfluramine-treated subjects.
Conclusion There was no evidence of drug-related heart disease up to 4.9 years
after anorexigen therapy in subjects who were randomly assigned to receive
fenfluramine at the recommended dose for up to 3 months.
INTRODUCTION
THE ANTIOBESITY agent fenfluramine hydrochloride (D,L-fenfluramine)
was indicated as a short-term (a few weeks) adjunct as part of a regimen of
weight reduction based on restriction of energy intake.1
In preliminary smoking cessation studies, dexfenfluramine hydrochloride (D-fenfluramine)
decreased food cravings, carbohydrate consumption, and withdrawal effects.2-5 Therefore,
a prospective, randomized, double-blind, placebo-controlled, single-center
study (Seattle Smoking Cessation Therapy [SCT] Study) was initiated at Fred
Hutchinson Cancer Research Center, Seattle, Wash, in 1993 to evaluate the
role of fenfluramine in women attempting smoking cessation; the treatment
phase was completed in 1994.
Fenfluramine and dexfenfluramine were voluntarily withdrawn from the
market in September 1997 after observations of valvular abnormalities in patients
taking anorexigens.6 These reports lacked pretreatment
echocardiographic data and a control cohort, and predominantly involved patients
who used phentermine hydrochloride in combination with fenfluramine. More
recently, systematic and controlled clinical evaluations have been undertaken
to determine the clinical significance of the initial findings. Several recent
reports have indicated that short-term exposure to anorexigens (3 months or
less) is not associated with an increased risk of cardiac valvular abnormalities,7-10 with
one recent report showing no increased prevalence of aortic or mitral regurgitation
(AR and MR, respectively) as defined by the Food and Drug Administration (FDA)6 in patients who took the phentermine-fenfluramine
combination for 6 months or less when compared with an untreated control group.11 These and other echocardiographic studies have demonstrated
an increased prevalence of aortic valve regurgitation that is generally mild12 and not accompanied by serious cardiac events in
patients who used anorexigens for longer than 3 months.10
The prevalence of clinically overt valvular disease is reported to be lower
than in initial reports, even with more than 3 months of drug exposure 10 or 4 years of posttreatment follow-up.7
The present follow-up study is a single-center, retrospective cohort
study designed to evaluate the prevalence of cardiovascular abnormalities
in subjects who previously participated in the SCT study and had been randomized
to treatment with either fenfluramine alone or placebo. The SCT study treatment
phase was planned for a maximum of 3 months, and all treatments were completed
by the end of 1994. Therefore, this evaluation permits as much as 4.9 years
of posttreatment follow-up.
SUBJECTS AND METHODS
This study was conducted at Fred Hutchinson Cancer Research Center according
to a prospectively designed clinical protocol and was in full compliance with
all federal, state, and local regulations pertaining to human research and
with the Good Clinical Practice Guidelines from the Fred Hutchinson Cancer
Research Center. The study center had prior approval from the appropriate
institutional review board.
SUBJECTS
Female smokers enrolled in the SCT study between September 1, 1993,
and April 30, 1994, and all study treatments were completed by August 31,
1994. Women aged 18 to 65 years, of any race or ethnic background, who smoked
at least 10 cigarettes per day were randomly assigned to receive either fenfluramine
hydrochloride (60 mg daily) or matched placebo for up to 3 months, provided
they met the following criteria: their weight was between 85% and 150% of
ideal based on the Metropolitan Life Insurance Tables; they were not pregnant
or nursing at the time of study entry or anticipating pregnancy during the
study treatment phase; they had no history of cardiovascular disease, cancer,
or other significant disease; they had no previous or current long-term use
of medication known to interact with fenfluramine; and they had no history
of drug or alcohol abuse.
Eligibility for the current trial was limited to subjects who had participated
in the SCT study, had no history of carcinoid tumor, and had documented informed
consent for both studies. If, during the 5 years since the SCT study, a subject
had received treatment with serotoninergic migraine headache medications or
excluded anorexigens (dexfenfluramine, phentermine, phentermine and fenfluramine
in combination, mazindol, phendimetrazine tartrate, sibutramine hydrochloride,
herbal phen-fen, or liquid phen-fen), she was not eligible to participate.
STUDY PROTOCOL
Attempts were made to contact all SCT study subjects for possible enrollment
in this follow-up study. Introductory letters and screening telephone calls
were used to prequalify potential subjects, and clinic visits were scheduled
for subjects who were tentatively eligible and willing to participate. At
the clinic visit, each participant provided a detailed medical history and
received a complete physical examination with emphasis on the cardiovascular
system. The medical history collected in this study included dates of onset
for medical symptoms and diagnoses (particularly related to the cardiovascular
history and examination) and confirmed that obtained in the SCT. All SCT participants
were asked to participate; data from those who did not meet eligibility criteria
for the follow-up study were analyzed separately (ineligible population).
ECHOCARDIOGRAPHIC ASSESSMENT
Two-dimensional, M-mode, color-flow, pulsed, and continuous wave Doppler
echocardiograms were performed by trained sonographers who were blinded to
all aspects of subject history. Echocardiograms were obtained according to
a specified imaging protocol13 using standardized
echocardiographic equipment (Sonos 2000 Imaging Systems; Hewlett-Packard,
Andover, Mass) and recorded on videotape. The tapes were forwarded to an established
central core laboratory (Boston Medical Center, Boston, Mass) staffed by board-certified
cardiologists (R.D., G.J.B., and L.A.M.) specializing in echocardiography
who were blinded to subject group and medical history.
Measures of valvular function, including (1) AR, MR, tricuspid regurgitation
(TR), and pulmonic regurgitation and (2) aortic, mitral, and tricuspid valve
leaflet thickness and mobility, were evaluated. Aortic regurgitation was visually
graded on the basis of modified Perry et al criteria14
as follows: none, no regurgitant color flow; trace, regurgitant jet diameter in the parasternal (or
apical) long-axis view 5% or less of the outflow tract diameter; mild, jet diameter greater than 5% and less than 25% of the outflow
tract diameter; moderate, jet diameter 25% or more
and less than 47% of the outflow tract diameter; moderately
severe, jet diameter 47% or more and less than 65% of outflow tract
diameter; and severe, jet diameter 65% or more of
the outflow tract diameter, usually associated with diastolic flow reversal
in the abdominal aorta. Both MR and TR were graded on the basis of modified
Helmcke et al criteria15 as follows: none, no regurgitant color flow; physiologic, nonsustained jet within 1 cm behind the annular plane with a maximal
jet 5% or less of the atrial area; mild, sustained
color flow jet and maximal jet area greater than 5% and less than 20% of atrial
area; moderate, maximal jet area 20% or more and
40% or less of atrial area; and severe, maximal jet
area greater than 40% or jet reaches the back of the atrium. Eccentric jets
(mitral and tricuspid valves) were upgraded 1 grade if jet impingement on
a chamber wall precluded development of the full jet area. For all valves,
regurgitation was graded not evaluable if assignment
of a grade was considered impossible because of technical difficulty. The
AR and MR were considered present in accordance with FDA criteria,6, 16 that is, subjects were AR positive when mild or greater AR was present and MR positive when moderate or greater MR was present.
Valve leaflets were considered abnormally thickened if, on visual inspection,
mitral leaflets were greater than 4 mm during diastole, or if echodensities
were detected involving the tip, body, and/or base of aortic leaflets. Valve
leaflet mobility was considered abnormal if morphological changes resulted
in moderate or greater mobility impairment according to the following criteria
for the aortic valve: normal, full excursion of leaflets
to the margins of the aortic annulus; mildly impaired,
minimal restriction with maximal cusp separation greater than 1.5 cm; moderately impaired, restriction with cusp separation of
1.0 to 1.5 cm; and severely impaired, restriction
of all 3 leaflets with cusp separation less than 1.0 cm. Mitral valve mobility
was graded by means of the following criteria: normal, full excursion; mildly
impaired, slightly decreased mobility that does not impair excursion to the
posterior wall by more than 50%; moderately impaired, impaired motion by more
than 50% with some mobility of leaflet body maintained; and severely impaired,
complete immobility. Pulmonary artery systolic pressure (PAP) was calculated
by means of the modified Bernoulli equation: PAP = 4v2 + RAP, where v was the peak systolic velocity
of TR jet recorded by continuous wave Doppler and RAP (right atrial pressure)
was assumed to be 10 mm Hg.17 Left ventricular
and left atrial dimensions were measured according to American Society of
Echocardiography convention.18 Left ventricular
ejection fraction (LVEF) was visually estimated by integrating information
from all views and was considered normal if greater than 0.50.
The number of echocardiographic readings performed was equally distributed
among 3 cardiologists (R.D., G.J.B., and L.A.M.) at the core echocardiography
laboratory. A second, independent, blinded reading of an echocardiogram was
performed when AR or MR (FDA criteria), leaflet thickening, or restricted
leaflet mobility was detected on the initial reading. Disagreements between
readers were resolved by consensus readings.
STATISTICS
Study end points included echocardiographic variables, cardiovascular
signs on physical examination, and serious cardiovascular events. Primary
echocardiographic end points included AR and MR by FDA criteria (see the "Subjects
and Methods" section). Secondary echocardiographic end points included cardiac
valve regurgitation by grade, and aortic and mitral valve leaflet mobility
and thickness. A sample size of 250 subjects per group was anticipated, to
provide 90% power to detect a difference between the 2 study groups of at
least 7% ( = .05) with the use of a 2-tailed test of proportions, assuming
a control group prevalence of 2%. Means and SDs were calculated for numerically
continuous variables, and percentages were calculated for categorical and
ordinal data. Demographic variables for the fenfluramine and placebo groups
were compared with a 1-way analysis of variance for numerically continuous
variables and the Fisher exact or  2 tests for categorical
variables.
Prevalence of AR and MR (FDA criteria) were compared in the fenfluramine
and placebo groups by means of the Fisher exact test. Regurgitation grade
data were compared with the Kruskal-Wallis test. Valve leaflet mobility and
thickening data were also compared with the Fisher exact test, and calculated
data on pulmonary artery systolic pressure were compared with analysis of
variance. Unadjusted relative risks with 95% confidence intervals were calculated
for the prevalence of FDA-defined AR and MR, and abnormal thickening and mobility
of aortic and mitral leaflets for the fenfluramine group vs the control group.
A series of multivariate logistic regression analyses were performed
to identify predictors of valvular regurgitation by means of FDA criteria
for AR and MR. Independent variables tested in the models were selected because
of study hypotheses, clinical relevance with respect to cardiac valvular regurgitation,
or bivariate statistical association with regurgitation. Variables tested
were treatment group, compliance, age, body mass index (calculated as weight
in kilograms divided by the square of height in meters), hypertension, other
medical and cardiac history, previous echocardiogram, menopausal status, and
previous medication use. Two-way interaction terms were considered among variables.
The analyses were conducted first with both treatment groups and then for
the fenfluramine-treated patients only. A .05 level of significance was used
to determine both entry and removal of a term in the stepwise selection process.
The Hosmer-Lemeshow goodness-of-fit test was used to assess the models.
The Cohen  statistic and percentage exact agreement were calculated
as a measure of interreader variability with the use of second readings performed
to verify an abnormality and a 5% randomly selected sample of tapes.
Comparisons between treatment groups were considered statistically significant
for P values less than .05, and all statistical tests
were 2-tailed. All statistical analyses were performed with SAS statistical
software, version 6.09 (SAS Institute Inc, Cary, NC).
RESULTS
Of the 720 women who participated in the SCT trial, 619 were enrolled
in the present study. Of these 619, 89 were found to be ineligible, most because
they had taken serotoninergic migraine medications, other prescription anorexigens,
or herbal phen-fen that were prohibited by the study eligibility criteria
(including control subjects who had exposure to fenfluramine). Of the 101
women who were not enrolled, 65 were unavailable for follow-up and no further
information was obtainable for them, 31 declined participation, and 5 had
died. As a result, 530 women are included in the evaluable population of study
subjects. Study participant flow is described in Figure 1. Data presented herein describe the evaluable population
unless otherwise specified.
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Enrollment data, showing subject flow from smoking cessation therapy
(SCT) study participation through the present follow-up study. The evaluable
population includes all eligible subjects with echocardiograms.
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DEMOGRAPHICS
Study participants were generally white (92%), in their fifth decade
(48.8 ± 8.2 years of age), and overweight (mean body mass index, 26.5).
In both treatment groups, slightly more than one third of subjects were overweight,
defined as body mass index greater than 25 but less than 30, and an additional
one fifth were obese, defined as BMI of 30 or more.19
Most participants (about 75%) were current smokers; this was expected, because
they had all previously participated in the SCT study, which required that
they smoke an average of more than 1 pack per day at the time of enrollment
(D.J.B., unpublished data, 1994). Demographic data are presented in Table 1.
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Table 1. Study Population Characteristics*
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ANOREXIGEN EXPOSURE
More than 4 years (range, 4.1-4.9 years) elapsed from the start of the
original smoking cessation trial to echocardiographic assessment in the present
study (4.4 years, mean and median in both treatment groups). Because specific
fenfluramine dose and duration data were not available from the SCT, compliance
was estimated from returned pill counts at the 3-month visit or subject-reported
usage data if pill counts were unavailable. Compliance estimates were available
for 93% of study subjects with evaluable data; mean compliance was comparable
among the study groups (53.4% ± 36.6% in fenfluramine-treated subjects
and 56.6% ± 36.5% in placebo-treated subjects).
ECHOCARDIOGRAPHIC RESULTS
Overall, no statistically significant difference was demonstrated in
comparisons between fenfluramine-treated subjects and placebo-treated control
subjects (evaluable and ineligible populations) for any echocardiographic
variable measured. Echocardiogram quality was high; of the 617 echocardiograms
performed on enrolled subjects, 97% were considered by the readers to be of
fair quality or better and more than 97% of the 530 echocardiograms performed
on subjects in the evaluable population were of sufficient quality to assess
all echocardiographic end points.
VALVULAR REGURGITATION
At median posttreatment follow-up of 4.4 years, no statistically significant
difference was demonstrated between study groups in the prevalence of left-sided
cardiac valvular regurgitation assessed by FDA criteria (Table 2). Aortic regurgitation was present (ie, mild or greater
severity) in 6.2% of the treated group and 4.3% of the control group (relative
risk vs control, 1.42; 95% confidence interval, 0.68-2.98; P = .44), and mitral valve regurgitation was present (ie, moderate
or greater severity) in 5.1% of treated subjects and in 4.7% of control subjects
(relative risk vs control, 1.07; 95% confidence interval, 0.51-2.28; P>.99).
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Table 2. Prevalence of Aortic and Mitral Regurgitation*
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Similarly, there were no significant differences between study groups
when cardiac valvular regurgitation was compared by grade (Table 2). There was a trend toward increased prevalence of AR in
the fenfluramine group, but the difference vs the control group was not significant
(P = .26). The MR and TR prevalence rates were very
similar in the anorexigen-treated and placebo groups. One fenfluramine-treated
subject had severe MR associated with mitral annular calcification. Tricuspid
regurgitation of moderate or greater grade was present in 7.2% of fenfluramine-treated
subjects and 5.1% of control subjects (P = .37).
In addition, there was no statistically significant difference in the prevalence
of pulmonic regurgitation in the fenfluramine vs the placebo group (P = .51).
Comparisons of AR and MR prevalence among participants in the fenfluramine
group vs placebo by compliance category demonstrated no statistically significant
differences (for AR, P = .44; for MR, P>.99; Table 3). The AR
prevalence appeared to increase with increasing compliance (P = .04); however, there was a significant age-compliance interaction
(P = .03), where compliance increased with increasing
age. In a multivariate logistic regression analysis with compliance, age,
and the interaction of age and compliance, there was no statistically significant
association with age (P = .46) or compliance (P = .80; adjusted odds ratio, 1.25). No other factors entered
the model.
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Table 3. Prevalence of Aortic and Mitral Regurgitation (FDA Criteria)
by Compliance Tertile*
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VALVULAR MORPHOLOGICAL CHARACTERISTICS
Aortic and mitral valve leaflets were evaluated for thickening and mobility
restriction in a high proportion (97% or greater) of subjects with evaluable
data in both treatment groups; no significant differences between treatment
groups were identified (Table 4).
Aortic valve leaflets were thickened in approximately 8% of subjects in each
treatment group, and leaflet mobility was normal in all aortic valves evaluated.
Thickened mitral valve leaflets were observed in 5.8% of fenfluramine-treated
subjects and 2.8% of those who received placebo (P
= .09). Mitral leaflet mobility restriction (moderate or greater) was not
statistically significantly different when the groups were compared (0.7%
for fenfluramine, 0% for placebo; P = .50). When
all grades of mobility impairment were considered, the fenfluramine and placebo
groups were also not statistically different (P>.99).
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Table 4. Other Echocardiographic Measures*
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PULMONARY ARTERY PRESSURE
Pulmonary artery systolic pressure could be estimated in 358 subjects
(68%) with TR sufficient for measurement of peak jet velocity (see the "Subjects
and Methods" section; Table 4).
Mean estimated pulmonary artery systolic pressure was 30 mm Hg in both treatment
groups and was 40 mm Hg or higher in 7 placebo-treated subjects and 5 fenfluramine-treated
subjects.
LVEF AND CARDIAC DIMENSIONS
No subject in either treatment group had an abnormal LVEF, ie, an LVEF
less than 0.50, and comparisons of active treatment with placebo identified
no significant differences in left ventricular or left atrial dimensions (Table 4).
INTERPRETATION: INTERREADER AGREEMENT
Interreader agreement was evaluated by comparing valve regurgitation
and morphology ratings made on 182 echocardiograms with second readings performed
for abnormality verification and quality control purposes. The coefficients
(and percentage exact agreement) for interreader concordance (using FDA criteria
for AR and MR, and moderate or greater grade to define TR and pulmonic regurgitation)
were as follows: AR, 0.78 (93%); MR, 0.79 (95%); TR, 0.48 (93%); and pulmonic
regurgitation, 0.66 (99%). Interreader consistency was addressed by a consensus
adjudication process.
CARDIOVASCULAR EXAMINATION
No significant difference was demonstrated between treated and control
groups for any cardiovascular physical finding, including third and fourth
heart sounds, murmur, peripheral edema, jugular venous distention, rales,
rhonchi, and wheezing (Table 5).
Vital signs (systolic and diastolic blood pressures, pulse, and respiration
rate) were similar in the 2 treatment groups, with the exception of systolic
blood pressure, which was higher in the fenfluramine-treated subjects than
in the placebo group (P = .03).
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Table 5. Cardiovascular Examination*
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SUBJECT OUTCOMES
Serious cardiovascular events occurring after study treatment were rare
and not statistically different between the fenfluramine and placebo groups.
There were no reports of cardiac valve replacements among the study participants.
A single case of congestive heart failure was reported in a fenfluramine-treated
subject and a single case of endocarditis occurred in a subject who received
placebo. One fenfluramine-treated subject experienced cardiac arrest related
to pneumonia and adult respiratory distress syndrome. There were 5 known deaths
among the smokers who originally participated in the SCT trial, all of which
occurred from 1 to 3 years after their SCT study treatment was completed.
Four deaths occurred in women in the fenfluramine group who were aged 49 to
57 years at death; 3 of these were related to cancer, with 1 case each of
pancreatic carcinoma, acute myelogenous leukemia, and lung cancer. One non–cancer-related
death occurred in a 56-year-old woman with end-stage chronic obstructive pulmonary
disease. In addition, a 42-year-old placebo-treated subject died of disseminated
non-Hodgkin lymphoma.
INELIGIBLE POPULATION
As a group (n = 89), the ineligible subjects (fenfluramine group, n
= 35; placebo group, n = 54; Figure 1)
were slightly younger (fenfluramine group, 45.3 ± 7.7 years; placebo
group, 44.2 ± 6.9 years) and heavier (fenfluramine group, 74.9 ±
10.8 kg; placebo group, 76.6 ± 13.0 kg) than the women in the evaluable
population (Table 1), but were
otherwise similar. (Data for weight and age are given as mean ± SD.)
In the ineligible population, the prevalence of AR (FDA criteria) was 2.9%
in the fenfluramine group and 5.8% in the placebo group, and MR prevalence
(FDA criteria) was 2.9% in the fenfluramine group and 1.9% in the placebo
group. No statistically significant differences were noted between ineligible
study groups for any echocardiographic variable.
COMMENT
We examined subjects previously given fenfluramine or matched placebo
for up to 3 months to evaluate the prevalence of cardiac valvular abnormalities
at a median of 4.4 years after treatment and found no statistically significant
differences between the fenfluramine and placebo groups in any cardiac valvular
measure evaluated. Study participants were predominantly white and in their
40s, and more than half were overweight or obese. In this investigation, aortic
and mitral regurgitation according to FDA criteria were present among placebo-treated
subjects in 4.3% and 4.7%, respectively, and among fenfluramine-treated subjects
in 6.2% and 5.1%, respectively. No serious cardiac events, valve replacements,
or endocarditis were reported in fenfluramine-treated subjects followed up
for up to 4.9 years after drug exposure.
COMPARISON WITH PREVIOUS STUDIES
In this study we report a lower prevalence of valvular regurgitation
among those in the fenfluramine group than did initial reports.6, 20
Although we observed numeric increases in the prevalence of AR and MR among
the fenfluramine-treated subjects, in neither case did these differences approach
statistical significance. To put our study in perspective, the prevalence
of AR demonstrated in anorexigen-treated patients in published cohort studies
is shown in Table 6. By study
design, all of our subjects were treated for no more than 3 months, and this
is in contrast to the longer duration in most of the other studies. The age
ranges are similar. The prevalences of mild (4%), moderate (1.4%), and severe
(0.7%) AR are not different from those in our control group and are contrasted
in Table 6 with results of the
other reported studies.
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Table 6. Prevalence of Aortic Regurgitation (AR) in Anorexigen-Treated
Patients: Published Cohort Studies*
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Recent reports of clinical investigations have concluded that treatment
with fenfluramine-based anorexigens for 3 months or less is not associated
with an increase in the prevalence of echocardiographic cardiac valvular abnormalities.8, 10 Physical findings of cardiovascular
disease are rare among patients who used these drugs7
and not different from findings in untreated obese patients.10
However, unlike this study, the time elapsed between drug discontinuation
and follow-up echocardiogram has been relatively short in the other investigations
that reported echocardiographic data (median, 1-6.6 months).
The present clinical trial differs from previous investigations in several
meaningful ways, including (1) the substantial length of follow-up after anorexigen
discontinuation, (2) recruitment from a cohort of subjects who had previously
been prospectively randomized to treatment or matched placebo, and (3) the
examination of a population who took fenfluramine alone (rather than in combination
therapy with phentermine). While on the market, most fenfluramine was used
in combination with phentermine (Wyeth-Ayerst Research Division, Philadelphia,
Pa, unpublished data, May 1997) after reports by Weintraub and colleagues22-23 of comparable efficacy with an improved
side effect profile when the agents were combined.
LIMITATIONS OF THE STUDY
The present study enrolled subjects who had been treated in the context
of a previous randomized placebo-controlled trial; therefore, duration of
treatment was limited to 3 months or less and baseline echocardiographic data
were not available for the subjects. Also, possibly because of the nature
of the original trial (smoking cessation), study drug compliance was somewhat
lower than average. However, there was no statistically significant relationship
between drug compliance and the echocardiographic abnormalities observed.
CONCLUSIONS
It is now generally agreed that treatment with fenfluramine-based anorexigens
for 3 months or less does not increase the prevalence of valvular abnormalities.
However, concerns regarding long-term follow-up have not previously been addressed.
This study provides additional information regarding cardiovascular status
almost 5 years after drug discontinuation.
AUTHOR INFORMATION
Accepted for publication November 8, 2000.
This study was supported by a grant from the Wyeth-Ayerst Research Division
of Wyeth Laboratories, Philadelphia, Pa.
Presented at the Second Annual and Plenary Meeting of the Working Group
on Echocardiography of the European Society of Cardiology, Trieste, Italy,
December 10, 1998.
We acknowledge the contributions of the following people: Fred Hutchinson
Cancer Research Center: Margaret M. Hanrahan, MN (clinical
services and coordination), and Diane Powers, MA (clinical study management). Boston Medical Center (echocardiography core laboratory): Bruce Talbot Joziatis, RDCS, Quirino Orlandi, MD,
and Patricia Ray, RDCS (sonography). Wyeth-Ayerst Research: M. Linda Clarke, RN, Anita B. Hudak, Denise Mestichelli, and Karen P. Taylor
(trial management); Harvey Kushner, PhD (statistical support); Stacy L. Hankin
and Madelyn R. McGee (administrative assistance); and Laura L. Snyder (writing
assistance).
Corresponding author and reprints: Ravin Davidoff, MB, BCh, Section
of Cardiology C8, Boston University Medical Center, 88 E Newton St, Boston,
MA 02118-2393 (e-mail: ravin.davidoff{at}bmc.org).
From the Section of Cardiology, Evans Department of Medicine, Boston
University Medical Center, Boston, Mass (Drs Davidoff, Balady, and Mendes);
Cancer Prevention Research Program and Women's Health Initiative, Fred Hutchinson
Cancer Research Center, Seattle, Wash (Drs McTiernan, Rudolph, and Bowen);
and Wyeth-Ayerst Research, Philadelphia, Pa (Drs Constantine and Davis).
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