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The Fen-Phen Controversy: Is Regression Another Piece of the Puzzle?

  • Richard W. Asinger
    Correspondence
    Address reprint requests and correspondence to Richard W. Asinger, MD, Cardiology Division, Department of Medicine, Hennepin County Medical Center, 701 Park Ave S, Minneapolis, MN 55415
    Affiliations
    Cardiology Division, Department of Medicine, Hennepin County Medical Center, Minneapolis, Minn
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      The recently described cardiac valvulopathy attributed to the appetite-suppressant drugs fenfluramine and phentermine (fen-phen)
      • Connolly HM
      • Crary JL
      • McGoon MD
      • et al.
      Valvular heart disease associated with fenfluramine-phentermine [published correction appears in N Engl J Med. 1997,337:1783].
      took the medical community and the public by surprise. In the months since the original report by Connolly et al,
      • Connolly HM
      • Crary JL
      • McGoon MD
      • et al.
      Valvular heart disease associated with fenfluramine-phentermine [published correction appears in N Engl J Med. 1997,337:1783].
      there has been controversy over the very existence, etiology, and clinical importance of this valvulopathy. Identified in the era of sophisticated and sensitive noninvasive imaging, the anatomy, pathophysiology, and natural history of this anomaly are still incompletely understood. In this month's Proceedings, Hensrud et al
      • Hensrud DD
      • Connolly HM
      • Grogan M
      • Miller FA
      • Bailey KR
      • Jensen MD
      Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine.
      describe a potentially important piece to this complex puzzle. After patients were removed from fen-phen treatment, their existing valvulopathy did not progress over a 6-month period of observation off medication; instead, it may have actually regressed.
      The initial report of valvulopathy associated with appetite-suppressant drugs was based on clinical observations of 24 patients exposed to the fen-phen combination for approximately 1 year.
      • Connolly HM
      • Crary JL
      • McGoon MD
      • et al.
      Valvular heart disease associated with fenfluramine-phentermine [published correction appears in N Engl J Med. 1997,337:1783].
      Clinical symptoms were related to valvular insufficiency, and 5 patients required valve replacement or repair (4 had mitral valve surgery; 1 had combined aortic, mitral, and tricuspid valve surgery). Based on the report by Connolly et al
      • Connolly HM
      • Crary JL
      • McGoon MD
      • et al.
      Valvular heart disease associated with fenfluramine-phentermine [published correction appears in N Engl J Med. 1997,337:1783].
      and solicited reports from other institutions,
      Cardiac valvulopathy associated with exposure to fenfluramine or dexfcnfluramine: US Department of Health and Human Services interim public health recommendations, November 1997.
      the US Food and Drug Administration issued a health advisory,
      • Food and Drug Administration
      Health advisory on fenflur-amine/phentermine for obesity [press release, No. P97-20, July 8, 1997].
      and fenfluramine and dexfenfluramine were voluntarily withdrawn from the market on September 15, 1997. Subsequent studies of echocardiographic findings in patients exposed to these appetite-suppressant drugs for various periods have reported left-sided valvulopathy, more commonly aortic than mitral.
      • Graham DJ
      • Green L
      Further cases of valvular heart disease associated with fenfluramine-phentermine [letter].
      • Rasmussen S
      • Corya BC
      • Classman RD
      Valvular heart discase associated with fenfluramine-phentermine [Letter].
      • Wadden TA
      • Berkowitz Rl
      • Silvestry F
      • et al.
      The fen-phen finale: a study of weight loss and valvular heart disease.
      • Bowen RL
      • Foreyt JP
      • Poston II, WSC
      • et al.
      Echocardiographic assessment of patients receiving long-term treatment with ano-rexiant medications.
      • Kurz X
      • Van Ermcn A
      Valvular heart disease associated with fenfluramine-phentermine [letter].
      • Burger AJ
      • Sherman HB
      • Charlamb MJ
      • et al.
      Low prevalence of valvular heart disease in 226 phentermine-fenfluramine protocol subjects prospectivcly followed for up to 30 months.
      In case-control studies, the prevalence of valvulopathy was higher in those treated with fenfluramine or its d-isomer dexfenfluramine than in controls.
      • Khan MA
      • Herzog CA
      • St Peter JV
      • et al.
      The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs.
      • Weissman NJ
      • Tighe Jr, JF
      • Gottdiener JS
      • Gwynne JT
      • Sustained-Release Dexfenfluramine Study Group
      An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine. sustained-release dexfenfluramine, or placebo.
      • Jick H
      • Vasilakis C
      • Weinrauch LA
      • Meier CR
      • Jick SS
      • Derby IE
      A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation.
      Independent clinical features associated with this valvulopathy include age at onset and treatment duration.
      • Bowen RL
      • Foreyt JP
      • Poston II, WSC
      • et al.
      Echocardiographic assessment of patients receiving long-term treatment with ano-rexiant medications.
      • Khan MA
      • Herzog CA
      • St Peter JV
      • et al.
      The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs.
      A population-based incidence study (conducted before widespread echocardiographic screening for valvular lesions) documented an increased risk of clinically evident valvulopathy (primarily aortic and not requiring surgery), especially in those exposed to these agents for more than 4 months.
      • Ryan DH
      • Bray GA
      • Helmcke F
      • et al.
      Serial echocardiographic and clinical evaluation of valvular regurgitation before, during, and after treatment with fenfluramine or dexfenfluramine and mazindol or phentermine.
      Echocardiography performed before, during, and after treatment to determine the incidence of valvulopathy verifies a causative role of these agents.
      • Li R
      • Serdula MK
      • Williamson DF
      • Bowman BA
      • Graham DJ
      • Green L
      Dose-effect of fenfluramine use on the severity of valvular heart disease among fen-phen patients with valvulopathy.
      Finally, echocardiographic findings support a dose-effect relationship between fenfluramine and severity of valvulopathy.
      • Li R
      • Serdula MK
      • Williamson DF
      • Bowman BA
      • Graham DJ
      • Green L
      Dose-effect of fenfluramine use on the severity of valvular heart disease among fen-phen patients with valvulopathy.
      Collectively, these data provide indisputable evidence that exposure to these agents for several months is associated with valvulopathy. The valvulopathy is primarily left sided, particularly involving the aortic valve, and causes insufficiency detected more commonly by echocardiography than by clinical examination. Given the preponderance of evidence for aortic valvulopathy, it is curious that although 75% of those in the original series reported by Connolly et al
      • Connolly HM
      • Crary JL
      • McGoon MD
      • et al.
      Valvular heart disease associated with fenfluramine-phentermine [published correction appears in N Engl J Med. 1997,337:1783].
      had aortic insufficiency, all 5 requiring surgery had mitral repair or replacement, and only 1 had aortic valve replacement.
      Surgically removed valves from patients in the initial series described by Connolly et al
      • Connolly HM
      • Crary JL
      • McGoon MD
      • et al.
      Valvular heart disease associated with fenfluramine-phentermine [published correction appears in N Engl J Med. 1997,337:1783].
      showed a remarkable similarity to ergot-induced and carcinoid valvulopathy.
      • Redfield MM
      • Nicholson WJ
      • Edwards WD
      • Tajik AJ
      Valve disease associated with ergot alkaloid use: echocardiographic and pathologic correlations.
      • Pellikka PA
      • Tajik AJ
      • Khandheria BK
      • et al.
      Carcinoid heart disease: clinical and echocardiographic spectrum in 74 patients.
      “Carcinoid valvulopathy is secondary to alterations in serotonin levels. Since fenfluramine and dexfenfluramine alter serotonin activity,
      • Wellman PJ
      • Maher TJ
      Synergistic interactions between fenfluramine and phentermine.
      it has been assumed, but by no means confirmed, that similar mechanisms link carcinoid and appetite-suppressant–related valvulopathies. An unproved hypothesis is that the combination of fenfluramine or dexfenfluramine plus phentermine is synergistic not only in appetite suppression but also in induction of cardiac valvulopathy.
      • Wurtman RJ
      • Maher TJ
      • Ulus I
      Valvulopathy or primary pulmonary hypertension as possible consequences of administering a serotonin uptake blocker with a monoamine oxidasc inhibitor (“phen-fen”) [editorial).
      The natural history of this valvulopathy is still being defined. In general, cardiac valvulopathy is considered a progressive process, which may result in the need for medical or surgical treatment. The observations of Hensrud et al
      • Hensrud DD
      • Connolly HM
      • Grogan M
      • Miller FA
      • Bailey KR
      • Jensen MD
      Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine.
      challenge this traditional notion and suggest that valvulopathy may regress. Documentation of a change in valvulopathy depends on the reproducibility of the detection technique and physiologic response to the lesion. Reproducibility of the interpretation of aortic and mitral valvular insufficiency has been high in reported series and their controls.
      • Khan MA
      • Herzog CA
      • St Peter JV
      • et al.
      The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs.
      • Weissman NJ
      • Tighe Jr, JF
      • Gottdiener JS
      • Gwynne JT
      • Sustained-Release Dexfenfluramine Study Group
      An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine. sustained-release dexfenfluramine, or placebo.
      The reproducibility of valvular thickening is less clear.
      Valvular insufficiency may also vary with hemodynamic loading conditions. It is entirely possible that the hemodynamic response to aortic or mitral insufficiency is reduced impedance, which may result in less insufficiency for the same structural lesion. The time course for such pathophysiologic change is unknown, but this remains an alternative explanation of the observations in the study by Hensrud et al.
      • Hensrud DD
      • Connolly HM
      • Grogan M
      • Miller FA
      • Bailey KR
      • Jensen MD
      Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine.
      Similarly, pharmacologic intervention aimed at reducing peripheral resistance could decrease the extent of aortic insufficiency without an accompanying change in valvular pathology.
      • Bonow RO
      • Lakatos E
      • Maron BJ
      • Epstein SE
      Serial long-term assessment of the natural history of asymptomatic patients with chronic aortic regurgitation and normal left ventricular systolic function.
      The article by Hensrud et al
      • Hensrud DD
      • Connolly HM
      • Grogan M
      • Miller FA
      • Bailey KR
      • Jensen MD
      Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine.
      is the first peer-reviewed report of a series of patients with cardiac valvulopathy secondary to appetite-suppressant use that suggests regression of valvular pathology and insufficiency. Regression of valvular insufficiency after withdrawal of these agents has been reported in a patient treated with vasodilator therapy.
      • Cannistra LB
      • Cannistra AJ
      Regression of multivalvular regurgitation after the cessation of fenfluramine and phentermine treatment [letter].
      In contrast, the cases reported by Hensrud et al
      • Hensrud DD
      • Connolly HM
      • Grogan M
      • Miller FA
      • Bailey KR
      • Jensen MD
      Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine.
      had neither decreased systemic blood pressure nor treatment with vasodilators to alter hemodynamics. Several preliminary serial echocardiographic studies of patients with appetite-suppressant–related valvulopathy suggest that regression of valvular dysfunction occurs.
      • Ryan DH
      • Bray GA
      • Greenway F
      • Helmckc F
      Does valvulopathy in patients treated with appetite suppressants regress over time? [abstract].
      • Mancini MC
      • Leite CC
      • Grinberg M
      • Halpern A
      Regression of heart-valve abnormalities after discontinuation of dexfenfluramine treatment [abstract].
      The series reported by Hensrud et al
      • Hensrud DD
      • Connolly HM
      • Grogan M
      • Miller FA
      • Bailey KR
      • Jensen MD
      Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine.
      is small but consecutive and well defined, and changes in both anatomy and physiology (insufficiency) followed the same direction, ie, improvement after withdrawal of these fenfluramine derivatives. The data did not reach statistical significance, as the authors clearly report, but nevertheless, the valvulopathy did not progress over a 6-month period of observation after appetite suppressants were stopped. In fact, the valvulopathy tended to regress.
      The variability in echocardiographic evidence of valvulopathy, which has troubled some investigators,
      • Schiller NB
      Fen/phen and valvular heart disease: if it sounds too bad to be true, perhaps it isn't [editorial].
      may be explained in part by the observations of Hensrud et al
      • Hensrud DD
      • Connolly HM
      • Grogan M
      • Miller FA
      • Bailey KR
      • Jensen MD
      Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine.
      indicating regression and the reported dose-effect relationship with these agents.
      • Li R
      • Serdula MK
      • Williamson DF
      • Bowman BA
      • Graham DJ
      • Green L
      Dose-effect of fenfluramine use on the severity of valvular heart disease among fen-phen patients with valvulopathy.
      Screening for valvulopathy several months after stopping these agents may result in a lower incidence than that performed during or shortly after treatment. Also differences in prevalence may be secondary to dosage or cumulative exposure. These explanations seem more likely to account for the variability in the reported prevalence of valvulopathy than technical, geographic, or environmental factors.
      • Schiller NB
      Fen/phen and valvular heart disease: if it sounds too bad to be true, perhaps it isn't [editorial].
      Definitive evidence of regression of this valvulopathy awaits further evaluation of larger series of patients. A continuing challenge to all who have prospectively studied patients exposed to these agents will be evaluation for longer periods. Patients exposed to these appetite-suppression agents are unique, and these case series will not be repeated. It is critical, in my judgment, to determine the natural history of this valvulopathy now for the benefit of those exposed and for our understanding of the pathophysiology of this acquired valvulopathy. Even if regression occurs in the short term, there is no guarantee that it will not recur or progress later. The prevalence of aortic insufficiency increases with age,
      • Klein AL
      • Burstow DJ
      • Tajik AJ
      • et al.
      Age-related prevalence of valvular regurgitation in normal subjects: a comprehensive color flow examination of 118 volunteers.
      and whether individuals exposed to these agents are at increased risk with time is unknown but deserves study since so many were exposed. Combined multicenter experience may be necessary to establish the natural history. Such analyses should take into consideration known or suspected clinical associations with this unique valvulopathy, specifically the age at onset of treatment, specific treatment, including dosage and its duration, changes in blood pressure, treatment with vasodilators, and, as suggested by Hensrud et al,
      • Hensrud DD
      • Connolly HM
      • Grogan M
      • Miller FA
      • Bailey KR
      • Jensen MD
      Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine.
      the timing of the echocardiographic evaluation following treatment, since regression may occur. Finally, if regression of this cardiac valvulopathy occurs after withdrawal of the offending agents, it would raise hope that other types of valvulopathy are also dynamic and may regress with appropriate intervention. The traditional notion that valvulopathy is progressive and cannot regress is being challenged by observations of the natural course of this unique valvulopathy.

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        Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine.
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