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Valvular heart disease associated with fenfluramine-phentermine

July 8, 1997
Web posted at: 2:58 p.m. EDT (1858 GMT)

    Heidi M. Connolly, M.D.
    Jack L. Crary, M.D.
    Michael D. McGoon, M.D.
    Donald D. Hensrud, M.D., M.P.H.
    Brooks S. Edwards, M.D.
    William D. Edwards, M.D.
    Hartzell V. Schaff, M.D.

From the Divisions of Cardiovascular Diseases and Internal Medicine (H.M.C., M.D.M., B.S.E.), Preventive and Occupational Medicine, Endocrinology and Internal Medicine (D.D.H.), Anatomic Pathology (W.D.E.), Thoracic and Cardiovascular Surgery (H.V.S.), Mayo Clinic and Mayo Foundation, Rochester, Minnesota, and the MeritCare Medical Center, Heart Services, Fargo, North Dakota (J.L.C.). Address reprint requests to Dr. Connolly at Mayo Clinic, 200 First Street SW, Rochester, MN 55905

NOTE: This is the manuscript of the study that has been submitted to The New England Journal of Medicine. The published version of the report may differ.

ABSTRACT

Background
Fenfluramine and phentermine are anorectic agents individually approved by the United States Food and Drug Administration. The drugs used in combination may yield equivalent efficacy in weight reductions at lower doses of each agent and with fewer reported side effects. In 1996, the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million.

Methods
Valvular heart disease was identified in 24 women treated with fenfluramine-phentermine who had no previous history of cardiac disease. Patients presented with symptoms or a murmur. A perceived association between the clinical features and the fenfluramine-phentermine therapy evolved by communication among authors.

Results
Twenty-four women (mean age 43.5 +/- 7.9 years) received fenfluramine-phentermine therapy for 12.2 +/- 6.8 months before presentation. Echocardiology demonstrated unusual valvular morphology and regurgitation in all patients. Eight women had newly documented pulmonary hypertension. Cardiac surgical intervention was required in five women to date. Valves were noticed to have a glistened white appearance. Histopathologic findings included plaque-like encasement of the leaflets and chordal structures with a "stuck-on" appearance and intact valve architecture. Valve features were identical to those seen in ergotamine toxicity or carcinoid disease.

Conclusions
These causes raise concern that fenfluramine-phentermine therapy has important implications regarding valvular heart disease. The mechanism of valve injury is uncertain but may be related to an alteration in circulating serotonin. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease.

Key Words: appetite; diet; drugs; heart valves; weight loss; treatment

Fenfluramine and phentermine are prescription medications individually approved by the United States Food and Drug Administration as appetite suppressants for the treatment of obesity. Fenfluramine and phentermine (fenfluramine-phentermine) used in combination may yield equivalent efficacy in weight reduction at lower doses of each agent, with fewer side effects and improved patient tolerance. In 1996, the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million monthly prescriptions.

Pulmonary hypertension has been reported to occur in association with fenfluramine or phentermine given alone. In addition, the d-isomer of fenfluramine, dexfenfluramine, increases the risk of pulmonary hypertension, particularly when patients receive high doses for more than three months. These drugs may cause pulmonary hypertension through the vasoconstrictor action of serotonin or by alteration of pulmonary vascular smooth muscle membrane depolarization.

Vascular disease has been reported with exposure to serotonin-like drugs such as ergotamine and methylsergide and with increased serotonin levels associated with carcinoid disease. Valvular heart disease in patients taking anoretic agents has not been reported. We report 24 cases of unusual valvular heart disease in patients receiving treatment with fenfluramine-phentermine.

PATIENT ACQUISITION

All patients were identified during the course of routine clinical evaluation for various clinical concerns. No attempt was made to discover cases by review of databases, cross-index searches of patient files, or solicitation of suspected cases from clinical practices. As increasing numbers of patients were identified with similar features, a perceived association between the clinical features and previous or current use of fenfluramine-phentermine evolved. The serendipitous connection between these individual cases occurred through fortuitous communication among several physicians (the authors), as follows:

May 1996: Mitral valve repair was performed (by H.V.S.) on Patient 1 for treatment of severe mitral regurgitation. Intraoperatively, the valve was noted to have a glistening white appearance suggesting ergotamine-induced valvular injury as observed in previous patients, but the patient had no history of ergotamine ingestion.

July 1996: Patient 1 developed severe symptomatic tricuspid regurgitation and was evaluated (by H.M.C.). Echocardiology confirmed severe tricuspid regurgitation and thickening of the valve leaflets. These findings were similar to those seen in patients with carcinoid or ergotamine-induced valve disease. A history was obtained of fenfluramine-phentermine use for 18 months until one month before mitral valve surgery. A 24-hour urinary 5-HIAA value was normal.

January 1997: A patient (Patient 7) with pulmonary hypertension was evaluated (ny B.S.E.), and echocardiography (reviewed by H.M.C.) demonstrated thickening aortic valve leaflets and aortic regurgitation. An echocardiogram obtained two years previously was normal. The patient had taken fenfluramine-phentermine for one year before the recent echocardiographic examination.

January 1997: A physician (J.L.C.) from MeritCare Medical Center contacted the Mayo Clinic (M.D.M.) and inquired whether there was a recognized association between diet medications and valvular heart disease. The inquiry was precipitated by the physician's awareness that his echocardiographic sonographers had identified a cohort of 12 patients (Patients 2,3,6,10-18) with valvular heart disease exhibiting a peculiar valvular morphology. After further review of the patient records, all 12 patients were found to have taken fenfluramine-phentermine therapy. Patient records and echocardiograms were sent to the Mayo Clinic. The echocardiograms disclosed valve lesions very similar to those noted in the first two cases. Excised valve tissue was obtained from two patients (Patients 2 and 3) and slides prepared with elastic-van Giesan Stain were reviewed by a cardiac pathologist (W.D.E.). Histopathologic examination revealed features identical to those of ergotamine and carcinoid valvular disease.

January-April 1997: Seven other patients (Patients 9,19-24) with similar clinical histories and echocardiographic findings were identified (by J.L.C.) during clinical evaluations.

March 1997: A surgeon (H.V.S.) was contacted by a patient (Patient 4) in whom he had performed mitral valve repair in 1996. The patient informed him that aortic regurgitation and pulmonary hypertension had developed. On reviewing the surgical records, a distinctly unusual valve not consistent with rheumatic heart disease had been described. Further inquiry revealed that the patient had taken fenfluramine-phentermine for 12 months before mitral valve surgery.

March 1997: Valve tissue from a cardiac surgical patient (Patient 5) operated on at another institution was received for a pathologic opinion (by W.D.E.). The explanted valve demonstrated morphologic features identical to those of valves from Patients 1 and 4 at the time of surgical inspection. Gross pathologic features included thickening of the leaflets and chordae and a glistening white appearance. The histopathologic features were identical to those in Patients 2 and 3. Patient 5 had been treated with fenfluramine-phentermine for 11 months.

April 1997: A patient (Patient 8) with a 6-month history of fenfluramine-phentermine use developed dyspnea and was evaluated by a Mayo Clinic cardiologist consulting in another city. Multivalvular heart disease and pulmonary hypertension were identified. The cardiologist, unaware of the previous cases, asked a colleague (M.D.M.) whether he knew of an association between fenfluramine-phentermine therapy and valvular heart disease. Echocardiography revealed valvular morphology similar to that noted in the other cases.

SELECTED CASES

Patient 1: A 41-year-old woman (body mass index, 39.6 kg/m2) was referred to the Mayo Clinic for mitral valve surgery 3 months after a systolic murmur was first noted. She had taken fenfluramine-phentermine (fenfluramine, 40 mg three times per day, and phentermine hydrochloride, 16 mg three times per day) for 18 months. Therapy had been discounted one month before cardiac surgery because of the reported potentially catastrophic catecholamine-depleting effect of fenfluramine. Echocardiography and cardiac catheterization confirmed severe mitral regurgitation.

During mitral valve repair, unusual morphologic features were noted: the posterior and anterior leaflets were tethered and the chordae was shortened. The valve was glistening white, lacked rheumatic calcification or yellowish discoloration, and resembled valves affected by ergot alkaloid derivatives. The patient had not used ergot preparations, Intraoperative transesophageal echocardiography demonstrated severe mitral regurgitation and mild tricuspid regurgitation.

After hospital dismissal, symptomatic tricuspid valve regurgitation developed. Echocargiography demonstrated that the mitral valve was intact without regurgitation. The tricuspid valve was thickened and failed to coapt; tricuspid regurgitation was severe. With medical management, symptoms of right heart failure improved despite persistent severe tricuspid regurgitation.

Patient 2: A 45-year-old woman (pretreatment body mass index, 34.2 kg/m2) was treated with fenfluramine-phentermine (fenfluramine, 20 mg three times daily, and phentermine, 30 mg per day) for one year before dyspnea and a heart murmur were noted. Echocardiography demonstrated thickened aortic, mitral and tricuspid valves with regurgitation. Because of progressive symptoms, mitral and aortic valve replacement and tricuspid valve repair were performed at MeritCare six months after cessation of fenfluramine-phentermine therapy. Histopathologic examination of the resected mitral valve demonstrated intact valve architecture, with a plaque-like process that extended along the leaflet surfaces and encased the tendinous cords. Lesions on aortic valve were similar but less extensive.

Patient 3: A 48-year-old woman (pretreatment body mass index, 34.7 kg/m2) without a history of cardiac disease was treated with fenfluramine-phentermine (fenfluramine, 20 mg three times daily, and phentermine. 30 mg per day) for nine months. Therapy was discontinued when a murmur was noted. and symptoms of edema and breathlessness were reported. The mitral valve was thickened at echocardiography and severely regurgitant. Three months later, she underwent mitral valve replacement at MeritCare for symptomatic mitral regurgitation. Histopathologic examination demonstrated intact valve architecture and plaque-like lesions of apparent myofibroblasts in an abundant extracellular matrix of glycosaminoglycans and collagen.

Patient 6: A 51-year-old woman (pretreatment body mass index, 32.8 kg/m2) with normal findings on cardiac examination was treated with fenfluramine-phentermine (fenfluramine, 20 mg three times daily, and phentermine, 30 mg per day in divided doses). Seven months after this treatment was initiated, dyspnea and edema developed and a new murmur was noted. Transthoracic and transesophageal echocardiography at MeritCare demonstrated thickened valves with severe mitral regurgitation and moderate aortic and tricuspid valve regurgitation. Fenfluramine-phentermine therapy was discontinued, and medical therapy for heart failure was instituted. Echocardiography performed three months later demonstrated minimal improvement in the valvular disease. The patient continues to be observed medically and has persistent symptoms of dyspnea.

Patient 7: A 45-year-old woman began receiving fenfluramine-phentermine for a pretreatment body mass index of 30.6 kg/m2. Two years before fenfluramine-phentermine therapy, echocardiography revealed normal valves. The initial dose was fenfluramine, 60 mg per day in divided doses and phentermine, 30 mg per day. Under medical direction, the doses were gradually increased to 220 mg of fenfluramine and 60 mg of phentermine per day.

Eleven months after the fenfluramine-phentermine treatment was initiated, dyspnea on exertion developed. Echocardiography demonstrated a thickened trileaflet aortic valve with moderate regurgitation. Pulmonary artery systolic pressure measured by right heart catheterization was 75 mm Hg. Treatment with fenfluramine-phentermine was discontinued.

ADDITIONAL PATIENT DATA

The Table summarizes the features of the selected patients (above) and of other patients with similar characteristics. Except for systemic hypertension, all patients were thought to be free of cardiovascular disease at the onset of weight reduction therapy. The authors had not prescribed the anorectic agents for their patients. Patients were evaluated 12.2 +/- 6.8 months after fenfluramine-phentermine initiation. Twenty patients presented with cardiovascular symptoms and 4 patients had only a new murmur.

All patients underwent comprehensive two-dimensional echocardiography, pulsed- and continuous-wave Doppler, and color flow examination using previously described techniques. Valve morphology was noted by two examiners to be atypical for rheumatic, congenital, or degenerative lesions. The mitral and aortic valves exhibited echocardiographic features similar to those seen in patients with chronic rheumatic involvement; however, there was no evidence of valve obstruction. Thickening and diastolic doming of the anterior mitral leaflet with preserved mobility, and thickening and immobility of the posterior leaflet were typical. Subvalvular involvement was characterized by thickening and shortening of the chordae tendineae, causing tethering of the posterior leaflet. The combination of abnormalities resulted in malcoaptation and central regurgitation. The aortic valve was characterized by thickening and mild reaction to the leaflets. With tricuspid valve involvement, the septal leaflet was thickened and variably fixed to the septum. The anterior leaflet appeared thickened and exhibited decreased mobility, diastolic doming, and loss of coaptation visible on two-dimensional imaging. Color flow imaging demonstrated variable degrees of regurgitation in all patients. The echocardiography appearance of the valves was similar in the medically treated and the surgically treated patients.

Eight patients had Doppler echocardiographic or catheter evidence of significant pulmonary hypertension (right ventrical systolic pressures of 52 to 93 mm Hg) that had not been documented previously. Tricuspid regurgitation of moderate or greater severity was present in five of the eight patients with pulmonary hypertension.

DISCUSSION

Fenfluramine is a sympathomimetic amine that has an anorectic action mediated through activation of serotonergic pathways in the brain. Fenfluramine promotes the rapid release of serotonin, inhibits its rouptake, and may have receptor agonist activity, thus making serotonin more susceptible to metabolism and breakdown. The d-isomer of fenfluramine, dexfenfluramine, appears to be relatively selective for the central serotonergic system. Phentermine is a noradrenergic agent. Commonly used dosages for these medications are 20 to 120 mg per day of fenfluramine and 15 to 30 mg per day of phentermine hydrochloride or 18.75 to 37.5 mg per day of phentermine resin.

Patients with malignant carcinoid syndrome have high levels of circulating serotonin. Associated cardiac disease is characterized by fibroplasia that involves primarily the valvular endocardium on the right side of the heart. The mechanism of valve injury in patients with carcinoid heart disease has not been established but is believed to be serotonin-mediated because patients with carcinoid heart disease have higher circulating levels of serotonin than do their counterparts without cardiac involvement. The predilection for right-sided valve disease in carcinoid sundrome is likely related to the hepatic venous, serotonin rich blood directly entering the right heart and the subsequent partial pulmonary degradation of serotonin.

The pathophysiologic mechanism in patients with ergot alkaloid-induced valve disease has not been established, but it is thought to be related to the similar chemical structure of serotonin, methylsergide, and ergotamine. Ergotamine-induced and carcinoid valve disease are microscopically identical, with fibrotic endocardial changes. The pathologic, surgical, and echocardiographic features of carcinoid and ergotamine-induced valve disease are indistinguishable from the features noted in our patients.

Fenfluramine alters serotonin metabolism in the brain. Phentermine interferes with the pulmonary clearance of serotonin which may explain its association with primary pulmonary hypertension. Although serotonin levels were not measured in our patients, we postulate the combination of fenfluramine and phentermine may potentiate the effect or concentration of circulating serotonin and result in valvular injury similar to that seen in patients with carcinoid syndrome or in those taking ergot preparations. However, the precise process by which this might occur is not known. No animal studies examining the effect of the combination of fenfluramine and phentermine have been reported. Five of the 24 patients included in this series were either on sertraline or fluoxetine while receiving fenfluramine-phentermine.

LIMITATIONS: This description of patients is limited by the absence of pathologic confirmation in the majority of cases. Many of the patients continue to be treated medically and have not undergone invasive or interventional procedures. Consequently, neither direct inspection nor histopathologic evaluation is available for most of the patients. Because no patient had symptomatic or clinical evidence of cardiovascular disease before the initiation of appetite suppressants, no routine pretreatment echocardiographic baseline studies were obtained. Only one patient had had an incidental echocardiographic study two years before treatment, and it was normal. In the aggregate, however, these patients and those who underwent operative intervention exhibited similar clinical and echocardiographic features with one another. Mean age at initiation of treatment, body mass index, and duration of treatment until the development of symptoms were similar in the medically and surgically treated groups.

In the absence of a control group or case-control study, definitive statements about a true association with fenfluramine-phentermine administration cannot be made. However, significant de novo left-sided regurgitant valvular heart disease in a population less than 50 years old is rare. Thus, the association of valvular regurgitation with fenfluramine-phentermine is not likely due to chance. Moreover, the unusual echocardiographic morphology of the lesions further diminishes the likelihood of a coincidental observation.

These cases should raise concern that this combination of appetite suppressants has important implications regarding valvular heart disease. Prospective studies of this association will be required to validate the possibility that this combination of medications may cause valvular heart disease. The mechanism of valve injury and the frequency of the association have yet to be determined. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease.

 
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