Fwd: Heart Valve Disorders and Appetite-Suppressant Drugs

[jikeda at socrates.berkeley.edu]

>

>  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implicated agents, fenfluramine and dexfenfluramine, were withdrawn from the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

>reported.

>

>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

>fenfluramines.

>

>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/Article Information

>

>

>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

>companies.

>

>

>

>

>

>REFERENCES

>

>

>

>1.

>Nationwide class action settlement agreement with American Home Products

>Corporation.

>Available at: http://www.settlementdietdrugs.com/. Accessed March 16, 2000.

>

>

>

>2.

>Connolly HM, Crary JL, McGoon M, et al.

>Valvular heart disease associated with fenfluramine-phentermine.

>N Engl J Med.

>1997;337:581-588.

>MEDLINE

>

>

>3.

>Graham DJ, Green L.

>Further cases of valvular heart disease associated with

>fenfluramine-phentermine.

>N Engl J Med.

>1997;337:635.

>MEDLINE

>

>

>4.

>Food and Drug Administration.

>FDA analysis of cardiac valvular dysfunction with the use of appetite

>suppressants.

>Available at: http://www.fda.gov/cder/news/slides/sld001.htm. Accessed

>February 17, 1998.

>

>

>

>5.

>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.

>1998;339:713-718.

>MEDLINE

>

>

>6.

>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.

>1998;339:725-732.

>MEDLINE

>

>

>7.

>Griffen L, Anchors M.

>Asymptomatic mitral and aortic valve disease is seen in half of the patients

>taking "phen-fen."

>Arch Intern Med.

>1998;158:102.

>MEDLINE

>

>

>8.

>Griffen L, Anchors M.

>The "phen-pro" diet drug combination is not associated with valvular heart

>disease.

>Arch Intern Med.

>1998;158:1278-1279.

>MEDLINE

>

>

>9.

>Shively BK, Roldan CA, Gill EA, et al.

>Prevalence and determinants of valvulopathy in patients treated with

>dexfenfluramine.

>Circulation.

>1999;100:2161-2167.

>MEDLINE

>

>

>10.

>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.

>1999;34:1153-1158.

>MEDLINE

>

>

>11.

>Jick H, Vasilakis C, Weinrauch LA, et al.

>A population-based study of appetite-suppressant drugs and the risk of

>cardiac-valve regurgitation.

>N Engl J Med.

>1998;339:719-724.

>MEDLINE

>

>

>12.

>Gardin JM, Schumacher D, Constantine G, Davis KD, Leung C, Reid CL.

>Valvular abnormalities and cardiovascular status following exposure to

>dexfenfluramine or phentermine/fenfluramine.

>JAMA.

>2000;283:1703-1709.

>ABSTRACT  |  FULL TEXT  |  PDF

>

>

>13.

>Hensrud DD, Connolly HM, Grogan M, et al.

>Echocardiographic improvement over time after cessation of use of

>fenfluramine and phentermine.

>Mayo Clin Proc.

>1999;74:1191-1197.

>MEDLINE

>

>

>14.

>Asinger RW.

>The Fen-Phen controversy.

>Mayo Clin Proc.

>1999;74:1302-1304.

>MEDLINE

>

>

>15.

>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.

>1999;23:926-928.

>MEDLINE

>

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>© 2000 American Medical Association. All rights reserved.

>

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Joanne P. Ikeda,MA,RD
Co Director
Center on Weight and Health

Cooperative Extension Nutrition Education Specialist
Department of Nutritional Sciences
University of California, Berkeley, CA 94720-3104

Phone (510)642-2790
FAX (510)642-0535
E-Mail: jikeda at socrates.berkeley.edu