New Studies Support Connection Between Fenfluramine or Dexfenfluramine and Valvular Heart Disease

Newly published research lends considerable credence to the suspected link between the diet drugs fenfluramine or dexfenfluramine and valvular heart disease.

In September 1997, the popular appetite suppressants were voluntarily withdrawn from the market by their manufacturer in the wake of reports that patients who took the drugs--whether alone or in combination with phentermine, a combination commonly called "fen-phen"--developed potentially dangerous heart-valve abnormalities.

Questions remained, however, about the prevalence and severity of the problems, and more information was urgently needed. Three studies published in the September 10, 1998, issue of the New England Journal of Medicine (NEJM) shed new light on the heart-valve problems associated with these drugs.

The journal's cover article described a study performed by endocrinologist Mehmood A. Khan, M.D., and others, supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the Centers for Disease Control and Prevention, in association with the Minnesota Obesity/Nutrition Research Center. In this study, patients who had taken fenfluramine or dexfenfluramine (alone or in combination with phentermine) for various time periods had a significantly higher incidence of cardiac-valve abnormalities than those who had not. Of those who had taken these drugs, 22.7 percent had heart-valve abnormalities, compared to only 1.3 percent of a control group. Most of the abnormalities were mild. The control group was made up of people who were matched to the study subjects by sex, age, height, and body mass index, but had not taken appetite-suppressant drugs.

The NEJM also reported a study of the effects of phentermine, fenfluramine, and dexfenfluramine, headed by Hershel Jick, M.D., and supported in part by the Food and Drug Administration (FDA); and a study focusing on dexfenfluramine alone, led by Neil J. Weissman, M.D., and supported by Wyeth Laboratories.

The researchers defined a heart-valve abnormality as at least mild aortic regurgitation or at least moderate mitral-valve insufficiency, because this was the definition used by the FDA in calling for the drugs' withdrawal. The Weissman and Khan studies used echocardiographs to determine the degree of valvular abnormality. The Weissman study, which compared patients exposed to dexfenfluramine for an average of 2 1/2 months to those on placebo, found no statistically significant difference between groups in the prevalence of valvular regurgitation meeting FDA criteria. However, even this short-term study found an increase in mitral and aortic regurgitation in those exposed to the drug, though the levels were primarily trace or mild.

The Jick study was a population-based study that evaluated the prevalence of clinically evident valvular heart disease among exposed and unexposed patients. One important finding of this study was that short-term exposure to an appetite suppressant (4 months or less) was less likely to cause clinically evident heart-valve abnormalities.

The implications for the public remain the same. Patients who took fenfluramine or dexfenfluramine should be examined by a physician, who should perform a stethoscopic examination of the heart. An echocardiograph is recommended if the patient has any signs or symptoms of heart disease (including a murmur). In addition, the Department of Health and Human Services' interim guidelines recommend echocardiographic examination of the heart for all patients exposed to fenfluramine or dexfenfluramine before these patients undergo any dental or medical procedures for which antibiotic prophylaxis is recommended by the American Heart Association.

The recently released American College of Cardiology/American Heart Association Practice Guidelines for Management of Patients with Valvular Heart Disease make similar recommendations, except that they do not advocate universal echocardiographic screening for asymptomatic exposed patients before procedures for which antibiotic prophylaxis is indicated. However, these guidelines do recommend echocardiography for asymptomatic exposed patients in whom cardiac auscultation (examination with a stethoscope) cannot be performed adequately (due to obesity, for example). They also recommend that asymptomatic patients without murmurs should undergo repeat physical examination in 6 to 8 months. Because of the rare association between certain appetite-suppressant drugs and the development of primary pulmonary hypertension, patients exposed to fenfluramine or dexfenfluramine should also alert their health care provider if they develop a decrease in exercise tolerance or shortness of breath.

Timeline

1959 FDA approves phentermine.

1973 FDA approves fenfluramine (Pondimin).

1992 Reports of the effectiveness of fen-phen appear in Clinical Pharmacology and Therapeutics, and widespread "off-label" use of the combination begins.

1996 FDA approves dexfenfluramine (Redux), a close chemical relative of fenfluramine. New England Journal of Medicine article notes possible link between appetite-suppressant drugs and pulmonary hypertension.

1997 Fourteen million prescriptions for fenfluramine or dexfenfluramine written to date. July 8: Mayo Clinic researcher Heidi M. Connolly, M.D., and others report that 24 fen-phen patients have developed heart-valve abnormalities. FDA releases a public health advisory. August 28: The Connolly et al. findings are published in the New England Journal of Medicine along with a letter to the editor from FDA reporting nine additional cases of heart-valve abnormalities. September 15: FDA announces the voluntary withdrawal of fenfluramine and dexfenfluramine by their manufacturers, Wyeth-Ayerst Laboratories and Interneuron Pharmaceuticals (respectively). November 13: FDA, Centers for Disease Control and Prevention (CDC), and National Institutes of Health jointly release interim treatment recommendations. These recommendations appear in CDC's Morbidity and Mortality Weekly Report.

1998 New England Journal of Medicine publishes three studies further supporting the link between fenfluramine or dexfenfluramine and heart-valve abnormalities, validating the FDA's decision to recall the drugs and reiterating recommendations for evaluation.