Valvular Heart Disease and Exposure to Dexfenfluramine or Phenteramine/fenfluramine

ABSTRACT & COMMENTARY

Synopsis: There were no statistical differences in prevalence of serious cardiac events in treated and untreated patients.

Source: Gardin JG, et al. JAMA 2000;283:485-491.

Gardin et al report a reader-blinded controlled study of 1473 obese patients evaluated by history, physical examination, and echocardiogram for the presence of valvular heart disease associated with the use of anorexigenic medication. The study population consisted of obese subjects, 74% women, mean age 47, and mean BMI 35.0 kg/m2 with 479 treated with dexfenfluramine, 455 treated with phenteramine/fenfluramine, and 539 untreated by anorexigenic medication. Patients treated with anorexigenic medication were excluded if exposure had ended more than 14 months prior to the study or if they had taken over-the-counter anorexigens or serotonergic migraine headache medications in the five years prior to the study. This study was designed to look at a general population of patients who had taken anorexigenic medication; therefore, patients with a prior cardiac history were not excluded. Echocardiograms were performed by sonographers and interpreted at a central cardiology laboratory by cardiologists specializing in echocardiography using standard methods for grading of valvular regurgitation. Both sonographers and cardiologists were blinded to all patient historical information.

Results of the study included the prevalence of valvular disorders, duration of treatment, and median maximum daily doses. The duration of treatment for dexfenfluramine-treated patients was 6.0 months and 11.9 months for phenteramine/fenfluramine. The median maximum daily doses were within recommended dosage guidelines, but some patients had been treated with doses two or three times the usual recommended daily dose. The prevalence of aortic regurgitation (AR) was 8.9% in the dexfenfluramine group (RR, 2.18; 95% confidence interval [CI], 1.32-3.59), 13.7% in the phenteramine/fenfluramine treated group (RR, 3.34; 95% CI, 2.09-5.35), and 4.1% in the untreated group (P < 0.001). When all grades of mitral regurgitation (MR) were included, there was a statistically significant increase in the anorexigen-treated group compared to the untreated group (P = 0.2). There were no statistical differences in AR prevalence in untreated patients and those patients who had been treated with anorexigens for less than three months, although this group of patients was very small, limiting the power to detect a difference to less than 50%. There were no statistical differences in prevalence of serious cardiac events in treated and untreated patients.

Comment by Ellen l. Sakornbut, MD

When the FDA initially reported valvular abnormalities in fenfluramine-treated patients, the prevalence of valvular disorders was alarming—up to 32% of treated patients. The valve disorders described consisted of diffuse thickening consistent with carcinoid and ergotamine-induced valve disease. The proposed mechanism of damage common to these conditions is an elevation in serotonin levels. Dexfenfluramine, phenteramine/fenfluramine, sibutramine, ergotamine, sumatriptan, and numerous other medications all affect serotonin receptors, transport proteins, or serotonin release by platelets.

The study by Gardin et al provides no information on long term consequences of these medications. However, a long-term follow-up study in the United Kingdom covering eight years included information on more than 8000 fenfluramine-treated patients. Of these patients, a small number demonstrated symptomatic idiopathic valvular disease (approximately 1 in 1000), and 9 of 11 of these patients had been treated for longer than three months. These findings suggest that valvular changes do not frequently progress to clinically symptomatic disease. Additionally, a newer medication, sibutramine, was not associated with an increase in valvular abnormalities in a 12-month study . It is not known at this time whether the risk of primary pulmonary hypertension is increased with this medication.

The clinician is left with the following concerns: which patients should be screened for valvular heart disease following anorexigen exposure? Can other anorexigenic medications be safely prescribed and with what precautions? The following guidelines are suggested:

1. Patients with less than three months exposure to phenteramine/fenfluramine or dexfenfluramine and without cardiac history or physical findings are at low risk and need not be evaluated by echocardiogram. Patients with murmurs, cardiac symptoms, or longer exposures should be screened for valvular defects.

2. Sibutramine should not be prescribed for patients with hypertension or borderline blood pressure elevation, undiagnosed heart murmurs or a history of valvular heart disease, patients treated with ergots or "triptan" medications for migraine, or in combination with SSRI’s. Other contraindicated medications include ketoconazole, erythromycin, pseudoephedrine, phenylpropanolamine, and MAO inhibitors. Patients should be compliant and should be followed closely on this medication, looking for elevated blood pressures, cardiac symptoms, and findings related to the cardiopulmonary system. Its safety has not been demonstrated for periods of use greater than one year. The manufacturer recommends that its use be reconsidered if the patient does not lose at least 1 lb/wk in the first four weeks of therapy.

3. Some questions about the safety of anorexigenic medication remain unanswered (such as the link to primary pulmonary hypertension). A number of medications have been removed from the market, but phenteramine remains available. There seems to be no rationale for prescription of this class of drug for obesity unless risk for valvular heart disease has been proven to be low. Given that many obese patients are not candidates for sibutramine, many physicians will prefer to avoid the use of anorexigenic medication per se. "First, do no harm."

Author’s note: Terminology varies with these medications. An alternative term used in some publications is "appetite suppressant."

References

1. 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.

2. Jick H, et al. N Engl J Med 1998;339:719-724.

3. Bach DS, et al. Obes Res 1999;7:363-369.

Contraindications for the use of sibutramine include:

a. A family history of hypertension, diabietes, or cprpnary artery disease.

b. A history of migraine headaches treated with intermittent analgesics.

c. Concomitant treatment for major depression with fluoxetine.

d. Concomitant treatment with ranitidine for gastroesophageal reflux.