Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine

Context Fenfluramine and dexfenfluramine were voluntarily withdrawn from th e market in September 1997 because of reports of an association with heart valve abnormalities. Studies have been limited by lack of comparison with u ntreated controls. Objective To evaluate cardiovascular status and the prevalence of valvular abnormalities, as assessed by clinical cardiovascular parameters and echoca rdiography, in patients treated for obesity with dexfenfluramine or phenter mine/fenfluramine. Design Reader-blinded controlled study completed in February 1998. Setting and Participants Twenty-five clinical centers in the United States. Of 1640 enrolled subjects, 1473 were eligible (479 and 455 had taken dexfe nfluramine and phentermine/fenfluramine, respectively, continuously for 30 days or more in the previous 14 months, and 539 were untreated matched cont rols) and provided clinical and echocardiographic data. Mean (SD) age was 4 7.4 (11.4) years, mean body mass index was 35.0 (7.4) kg/m(2), and 74% were women. Mean (SD) duration of therapy was 6.0 (3.3) months (range, 1 - 18.4 months) in the dexfenfluramine group, and 11.9 (10.4) months (range, 1.4-6 3 months) in the phentermine/fenfluramine group, while the untreated group had no anorexigen use during the previous 5 years. Main Outcome Measures Cardiovascular signs and symptoms; echocardiographic evidence of aortic (AR) or mitral (MR) regurgitation according to US Food a nd Drug Administration (FDA) criteria (AR greater than or equal to mild or MR greater than or equal to moderate) and by grade; tricuspid and pulmonic valve regurgitation; and aortic, mitral, and tricuspid valve leaflet mobili ty and thickness, for treated vs untreated subjects. Results Cardiovascular signs and symptoms were similar among anorexigen-tre ated and untreated subjects. Prevalence rates and relative risk (RR) of AR were significantly increased in anorexigen-treated patients and were 8.9% i n the dexfenfluramine group (RR, 2.18; 95% confidence interval [CI], 1.32-3 .59), 13.7% in the phentermine/fenfluramine group (RR, 3.34; 95% CI, 2.09-5 .35), and 4.1% in the untreated group (P<.001). No statistically significan t differences in prevalence were observed for MR, thickening or decreased m obility of any valve leaflet, calculated pulmonary artery systolic pressure , or left ventricular ejection fraction. Serious cardiac events (including myocardial infarction, congestive heart failure, or ventricular arrhythmia) occurring at any time were not statistically different in treated and untr eated subjects (dexfenfluramine, 9.0%; phentermine/fenfluramine, 4.0%; and untreated, 8.4%); and following anorexigen treatment were uncommon (dexfenf luramine, 2.3%; phentermine/fenfluramine, 2.4%,and untreated, 3.3%, when ad justed for the median start date of anorexigen use). Conclusions Our data indicate that use of dexfenfluramine and phentermine/ fenfluramine is associated with an increase in the prevalence of AR using F DA echocardiographic criteria, but was not associated with an increase in t he prevalence of MR using FDA criteria or with serious cardiac events.