Benfluorex and Unexplained Valvular Heart Disease: A Case-Control Study

Abstract

BackgroundRecent case reports suggest that benfluorex, a fenfluramine derivative used in the management of overweight diabetic patients and dyslipidemia, is associated with cardiac valve regurgitation.MethodsWe conducted a case-control study. Eligible patients were those admitted in the cardiology or the cardiac surgery units of our hospital between January, 1st 2003 and June 30th 2009, with mitral insufficiency diagnostic codes (ICD-10 I340 and I051). Patients with either a primary cause (degenerative, known rheumatic heart disease, infectious endocarditis, congenital, radiation-induced valvular disease, associated connective and/or vasculitis disease, trauma, tumor) or a secondary (functional) cause were considered as having an “explained” mitral regurgitation. Other patients were considered as having an “unexplained” mitral regurgitation and were included as cases. For each case, two controls were matched for gender and for the closest date of birth, among a list of patients with an “explained” mitral regurgitation. Drug exposures were assessed blindly regarding the case or control status, through contacts with patients, their family and/or their physicians.ResultsOut of the 682 eligible patients, 27 cases and 54 matched controls were identified. The use of benfluorex was reported in 22 patients: 19 of the 27 cases, versus 3 of the 54 controls, odds-ratio 17.1 (3.5 to 83), adjusted for body mass index, diabetes and dexfenfluramine use.ConclusionThe use of benfluorex is associated with unexplained mitral regurgitation.

Increased Risk of Left Heart Valve Regurgitation Associated With Benfluorex Use in Patients With Diabetes Mellitus

“…7 The high frequency of combined aortic and mitral restrictive valve regurgitation associated with benfluorex exposure was also observed by Boudes et al 24 in a single-center study of hospitalized patients with restrictive valve disease. In a single-center case-control study, Frachon et al 8 reported high exposure to benfluorex among patients hospitalized for mitral regurgitation of unclear origin (70%) compared with patients with mitral regurgitation of known origin (5.6%) and concluded that benfluorex was associated with a high risk of mitral regurgitation. This finding was confirmed by another case-control study showing that among patients with mitral regurgitation of unclear origin, exposure to benfluorex was identified in 40.9% of cases compared with 4.5% in a matched group of patients with degenerative mitral regurgitation resulting from flail leaflets.…”

“…7 Moreover, 2 case-control studies have reported an important proportion of benfluorex use in patients admitted to hospital for severe organic mitral regurgitation of unclear origin. 8,9 In a retrospective cohort study of 2 French national databases including a large number of patients with diabetes mellitus, Weill et al 10 observed a 3-fold increase in the risk of hospitalization for valve regurgitation and a 4-fold increase in the risk of valve replacement surgery in patients exposed to benfluorex. According to recent estimations, exposure to benfluorex might have been responsible for up to 3100 admissions to hospital for valvular heart disease and up to 1300 deaths resulting from valve regurgitations in France.…”

Drug-induced pulmonary arterial hypertension: a recent outbreak

“…In 2009, a case series provided evidence of possible cardiotoxic effects of benfluorex [17]. In addition, a case-control study demonstrated that benfluorex is associated with valvular heart diseases, and premature deaths [18]. Recently, the French PAH Network reported 85 cases of PH associated with benfluorex exposure diagnosed between 1998 and 2011 and among them 70 patients with PAH [19].…”

Pulmonary hypertension associated with benfluorex exposure

“…However, benfluorex was not subjected to the same restrictions as the fenfluramine derivatives in 1997 in France, at least in part because it was approved as an agent for the treatment of diabetes and the metabolic syndrome and not an anorexigen. As a result, and in spite of case reports, benfluorex remained available in France until November 2009, until compelling data were brought from a case-control study by FRACHON et al [15] that highlighted the potential cardiotoxic effects, even though benfluorex had been withdrawn from commercial use in other European countries several years previously [15,16] We have previously reported a small series of patients with PAH that had prior exposure to benfluorex [17]. The aim of the current study was to establish the clinical and haemodynamic characteristics and outcomes of patients identified by the French Network of Pulmonary Hypertension with prior exposure to benfluorex and confirmed PH.…”