Fwd: Heart Valve Disorders and Appetite-Suppressant Drugs
jikeda at socrates.berkeley.edu
jikeda at socrates.berkeley.edu
Tue Apr 4 18:17:00 PDT 2000
> JAMA, April 5, 2000
>Vol 283, No. 13, pp 1647-1778
>Heart Valve Disorders and Appetite-Suppressant Drugs
>Hershel Jick, MD
>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implicated agents, fenfluramine and dexfenfluramine, were withdrawn from the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
>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 mild MR.
>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 fenfluramineheart 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.
>Author Affiliation: Department of Medicine, Boston University School of
>Medicine, Lexington, Mass.
>Corresponding Author and Reprints: Hershel Jick, MD, Department of Medicine,
>Boston University School of Medicine, 11 Muzzey St, Lexington, MA 02421.
>Editorials represent the opinions of the authors and THE JOURNAL and not
>those of the American Medical Association.
>Funding/Support: Neither this Editorial nor our study (reference 11) were
>directly funded. The Boston Collaborative Drug Surveillance Program is
>funded by the Food and Drug Administration and many pharmaceutical
>Nationwide class action settlement agreement with American Home Products
>Available at: http://www.settlementdietdrugs.com/. Accessed March 16, 2000.
>Connolly HM, Crary JL, McGoon M, et al.
>Valvular heart disease associated with fenfluramine-phentermine.
>N Engl J Med.
>Graham DJ, Green L.
>Further cases of valvular heart disease associated with
>N Engl J Med.
>Food and Drug Administration.
>FDA analysis of cardiac valvular dysfunction with the use of appetite
>Available at: http://www.fda.gov/cder/news/slides/sld001.htm. Accessed
>February 17, 1998.
>Khan M, Herzog C, St. Peter J, et al.
>The prevalence of cardiac valvular insufficiency assessed by transthoracic
>echocardiography in obese patients treated with appetite-suppressant drugs.
>N Engl J Med.
>Weissman N, Tighe J, Gottdiener J.
>An assessment of heart valve abnormalities in obese patients taking
>dexfenfluramine, sustained release dexfenfluramine or placebo.
>N Engl J Med.
>Griffen L, Anchors M.
>Asymptomatic mitral and aortic valve disease is seen in half of the patients
>Arch Intern Med.
>Griffen L, Anchors M.
>The "phen-pro" diet drug combination is not associated with valvular heart
>Arch Intern Med.
>Shively BK, Roldan CA, Gill EA, et al.
>Prevalence and determinants of valvulopathy in patients treated with
>Burger AJ, Sherman HB, Charlamb MJ, et al.
>Low prevalence of valvular heart disease in 226 phentermine-fenfluramine
>protocol subjects prospectively followed for up to 30 months.
>J Am Coll Cardiol.
>Jick H, Vasilakis C, Weinrauch LA, et al.
>A population-based study of appetite-suppressant drugs and the risk of
>N Engl J Med.
>Gardin JM, Schumacher D, Constantine G, Davis KD, Leung C, Reid CL.
>Valvular abnormalities and cardiovascular status following exposure to
>dexfenfluramine or phentermine/fenfluramine.
>ABSTRACT | FULL TEXT | PDF
>Hensrud DD, Connolly HM, Grogan M, et al.
>Echocardiographic improvement over time after cessation of use of
>fenfluramine and phentermine.
>Mayo Clin Proc.
>The Fen-Phen controversy.
>Mayo Clin Proc.
>Li R, Serdula MK, Williamson DF, et al.
>Dose-effect of fenfluramine use on the severity of valvular heart disease
>among fen-phen patients with valvulopathy.
>Int J Obes Relat Metab Disord.
>© 2000 American Medical Association. All rights reserved.
Joanne P. Ikeda,MA,RD
Center on Weight and Health
Cooperative Extension Nutrition Education Specialist
Department of Nutritional Sciences
University of California, Berkeley, CA 94720-3104
E-Mail: jikeda at socrates.berkeley.edu
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