New Study Revisits Heart Valve Abnormalities Associated With Diet Drugs

The Food and Drug Administration (FDA) withdrew the appetite suppressants fenfluramine and dexfenfluramine from the market in 1997 because of their association with heart valve abnormalities. Since this time, several studies have looked further into the causal nature of this connection. Most recent is an investigation led by Julius M. Gardin, M.D., of the Division of Cardiology, University of California, Irvine, and funded by Wyeth Laboratories. The investigators concluded that these anti-obesity agents are associated with an increase in the prevalence of some—but not all—valvular abnormalities, and that the drugs are not related to serious cardiac events like heart attack, congestive heart failure, or ventricular arrhythmia.

The study compared three groups of roughly 500 patients each. One group had been treated with dexfenfluramine alone, another group with phentermine/fenfluramine (also known as phen/fen), and a control group was untreated. In all three groups, the majority of participants were white obese females in their 40s. There were no statistically significant differences between the three groups in terms of cardiovascular symptoms (such as chest pain or shortness of breath upon exertion), but echocardiographic (ECHO) comparisons showed a greater prevalence of aortic regurgitation (AR) among those who took the drugs for longer than 3 months. In these patients, blood leaving the heart through the aortic valve backwashes into the left ventricle due to heart valve insufficiency or incompetence. Prevalence rates of AR were 8.9 percent in the dexfenfluramine group, 13.7 percent in the phen/fen group, and 4.1 percent in the untreated group. The vast majority of cases were considered mild by FDA criteria.

The researchers noted that among patients who took the drugs for less than 3 months, there was no statistically significant difference in the prevalence of AR between treated and untreated patients. With increasing duration of exposure, however, prevalence rates increased, reaching 21.2 percent among those taking phen/fen for longer than 18 months.

In an accompanying editorial, Hershel Jick, M.D., of the Boston University School of Medicine finds this duration effect to be critical evidence of the causal relationship between the drugs and heart valve abnormalities. Jick also cautions that the prevalence rates reported in the Gardin study may be underestimates. ECHOs were performed on these patients roughly 6 months after their last dose of the drugs, enough time for improvement of valvular abnormalities in some patients, as demonstrated in other studies. Jick agrees with Gardin and colleagues that most drug-related cardiac abnormalities are minor and unlikely to lead to clinical disease.

The full report and editorial appear in the April 5, 2000, issue of the Journal of the American Medical Association, and can be accessed at http://jama.ama-assn.org. s