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Archives of cardiovascular diseases
Volume 108, n° 3
pages 172-180 (mars 2015)
Doi : 10.1016/j.acvd.2014.10.006
Received : 9 November 2013 ;  accepted : 31 October 2014
Clinical and echographic characteristics of patients exposed to fenfluramin or its derivatives: Results of a prospective, single-centre, observational study
Caractéristiques cliniques et échocardiographiques des patients exposés aux fenfluramines : étude épidémiologique et prospective
 

David Cambon , Florence Leclercq
 Department of Cardiology, University Hospital Montpellier, Montpellier, France 

Corresponding author. Department of Cardiology, CHRU Arnaud-de-Villeneuve, 371, avenue Doyen-Gaston-Giraud, 34295 Montpellier cedex 5, France.
Summary
Background

Fenfluramine and its derivatives have been associated with significant risk of developing valvular heart disease but its exact prevalence and severity are still debated.

Aim

To evaluate the clinical and echocardiographic characteristics of patients hospitalized in a cardiology centre and who had past exposure to these drugs.

Methods

Between July 2011 and February 2012, patients admitted to the hospitalization and intensive care units at the University Centre of Montpellier, France were questioned about past exposure to fenfluramine or its derivatives. In patients who reported exposure, a questionnaire assessing prescribing patterns and medical history was proposed and echocardiography performed. All of the usual echocardiographic variables were analysed. We applied criteria from a French multicentre registry for diagnosis of drug-induced valvulopathy: leaflets and subvalvular apparatus thickening and retraction, leaflets loss of coaptation, no calcification, and no stenosis.

Results

Ninety-five patients exposed to these drugs were included. The majority were female (n =62, 65.3%), 53.2% (n =50) had diabetes and 90.5% (n =86) were exposed to benfluorex. Mean treatment duration was 52.3months (95% confidence interval [CI] 39.0–65.6). Valvular regurgitations were observed in 64.0% of patients (n =57) while 19.8% (n =17) had pulmonary hypertension. Highly probable fenfluramine-induced regurgitations were present in 18.6% (n =16) of patients, possibly fenfluramine-induced regurgitations in 38.2% (n =34) of patients, and unlikely fenfluramine-induced regurgitations in 25.8% (n =23) of patients. Highly probable fenfluramine-induced regurgitations were mild to moderate in severity in all except three patients.

Conclusion

Considering the frequency of probable or possible fenfluramine-induced regurgitations and in the absence of definite knowledge about the evolution of drug-induced valvular disease, systematic questioning about fenfluramine use may be advisable in hospitalized cardiac patients.

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Résumé
Contexte

La consommation de dérivés fenfluraminiques a été associée à un sur-risque de survenue de lésions valvulaires mais la prévalence et la sévérité de ces valvulopathies est encore discutée.

Objectif

Évaluer les caractéristiques cliniques et échocardiographiques des patients hospitalisés en cardiologie et qui ont été exposés aux dérivés fenfluraminiques.

Méthodes

Entre juillet 2011 et février 2012, les patients hospitalisés en cardiologie au centre universitaire de Montpellier (France) ont été interrogés quant à une exposition à un dérivé fenfluraminique. Un questionnaire était remis aux patients exposés afin de préciser les modalités de prescription et les antécédents médicaux. Une échocardiographie était réalisée et nous avons utilisé les critères du Registre multicentrique français pour le diagnostic de lésions valvulaires d’origine toxique liées à l’exposition aux dérivés fenfluraminiques : épaississement et rétraction de la valve et de l’appareil sous-valvulaire, défaut de coaptation, absence de calcification, et absence de sténose.

Résultats

Quatre-vingt-quinze patients exposés aux dérivés fenfluraminiques ont été inclus. La majorité d’entre eux étaient des femmes (n =62, 65,3 %) ; 53,2 % (n =50) avaient un diabète sucré et 90,5 % (n =86) avaient été exposés au benfluorex. La durée moyenne de traitement était de 52,3mois (IC 95 % 39,0–65,6). Des fuites valvulaires ont été observées chez 64 % des patients (n =57), tandis que 19,8 % (n =17) avaient une hypertension artérielle pulmonaire. Les fuites valvulaires probablement imputables aux dérivés fenfluraminiques concernaient 18,6 % (n =16) des patients, les fuites valvulaires possiblement imputables 38,2 % (n =34) et les fuites valvulaires non imputables 25,8 % (n =23). Les fuites valvulaires probablement imputables étaient toutes de sévérité légère à modérée exceptée pour 3 cas.

Conclusions

Étant donné la fréquence des fuites valvulaires probablement ou possiblement imputables aux dérivés fenfluraminiques et en l’absence de certitude quant au potentiel évotutif des lésions valvulaires d’origine toxique, la recherche systématique d’une exposition aux dérivés fenfluraminiques pourrait être envisagée en pratique quotidienne pour les patients hospitalisés en cardiologie.

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Keywords : Benfluorex, Appetite-suppressants, Valve disease, Echocardiography

Mots clés : Benfluorex, Anorexigènes, Maladie valvulaire, Échocardiographie

Abbreviations : CI, EROA, LVEF, PAH, VHD


Background

Fenfluramine and its derivatives are sympathomimetic amines with an anorectic action mediated through the activation of serotoninergic pathways in the brain. These drugs have been suspected to cause valvular heart disease (VHD) [1, 2, 3] and pulmonary artery hypertension (PAH) [4]. Fenfluramine was introduced first in France in 1963 under the brand name Ponderal®; then as the dextrorotatory isomer dexfenfluramine in 1985 under the name Isomeride®; and as benfluorex in 1976 under the name Mediator®. Ponderal® and Isomeride® were withdrawn from the market in 1997, followed by Mediator® in 2009, after the publication of case reports reporting cardiovascular adverse drug reactions.

In 2010 Frachon et al. [1] established an association between benfluorex and unexplained mitral regurgitation. Exposure to benfluorex was found in 70% of patients with mitral insufficiency of undetermined cause (cases) and in 5.6% of the control group. Benfluorex was associated with a high-risk of mitral regurgitation (odds ratio [OR] 17.1, 95% confidence interval [CI] 3.5–83, P <0.01). In the REGULATE trial [5, 6], Derumeaux et al. reported that minimal valvular abnormalities were detected in 51% of patients before any exposure to benfluorex. In the Health Insurance Fund for Salaried Workers (CNAMTS) survey [7], the adjusted relative risk of hospitalization for valvular regurgitation was 3.1 times greater (95% CI 2.4–4.1) in patients exposed to benfluorex and the risk of hospitalization for heart valve replacement was multiplied by 3.9 (95% CI 2.6–6.1). The risk of developing mitral and aortic regurgitations was also higher with benfluorex exposure (adjusted relative risk 2.5, 95% CI 1.9–3.7 and 4.4, 95% CI 3.0–6.6, respectively). According to Hill et al. [8], benfluorex was responsible for 465 deaths after a follow-up of 5.5years, and for 3500 hospitalizations for valvular insufficiency and 1750 cardiac surgeries after 4years of follow-up. Valvular heart disease related to benfluorex mainly affects the mitral and/or aortic valves, but can simultaneously alter the four valves [3].

The aim of this single-centre prospective study was to report the clinical characteristics and echocardiographic features of patients admitted to our cardiology department and who had a history of treatment with fenfluramine or its derivatives.

Methods
Subjects

Between July 2011 and February 2012, all patients admitted to the hospitalization unit and the intensive care unit of the University Hospital of Montpellier were questioned about past exposure to fenfluramine or its derivatives, dexfenfluramine and benfluorex.

Clinical data

Patients who reported previous exposure to fenfluramine or its derivatives were invited to complete a questionnaire that assessed prescribing patterns, medical history and symptoms. Patients with advanced dementia were excluded from the study. The data from questionnaires were validated against any medical reports available on the hospital medical database, to correct any error or approximation.

Ischaemic heart disease was defined as history of acute coronary syndromes and/or the presence of significant coronary lesions. History of heart failure was defined as previous hospitalization for acute pulmonary oedema or right heart failure or significant exertional dyspnoea (New York Heart Association class II). Chronic respiratory disease was defined as chronic restrictive or obstructive pulmonary disease. We searched for evidence of a primary or secondary cause of VHD, including valvular prolapse, active or previous infectious endocarditis, rheumatic heart disease or history of rheumatic fever, radiation-induced VHD, congenital disease, associated connective disease and/or vasculitis, ischaemic or ventricular dilatation-associated regurgitation. We identified patients with a history of valve surgery and gathered the type of surgery performed and the pattern of valvular lesions.

Doppler echographic data

Echocardiography was performed for each patient who reported exposure to fenfluramine or its derivatives. All of the usual echocardiographic parameters were analysed, with special attention to valve aspects and pulmonary pressure evaluation. We applied the criteria for the diagnosis of drug-induced VHD identified in a French multicentre registry [3, 9], which included: leaflets and subvalvular apparatus thickening and retraction, leaflets loss of coaptation, no calcification and no stenosis. Before the diagnosis of highly probable drug-induced valvulopathy could be made, other causes of restrictive VHD were excluded, in particular remodelling of the left ventricle and rheumatic heart disease. We retained the following criteria as indicating highly probable drug-induced valvulopathy: pure regurgitation, no calcification, leaflets retraction without significant left ventricular dysfunction in the case of mitral regurgitation, no dilatation of the ascending aorta in the case of aortic regurgitation. We thought that thickening and reduced mobility of leaflets, and thickening of subvalvular apparatus were more difficult to establish. We retained the following criteria as indicating unlikely drug-induced valvulopathy: stenosis, calcifications, and commissural fusions in the case of mitral regurgitation. Mitral and aortic regurgitations, which did not match with criteria for either highly probable or unlikely drug-induced valvulopathy, were considered as possible drug-induced valvulopathies. PAH was considered significant when>40 mmHg. Patients who had history of valve surgery were included only if the valvulopathy was discovered3months after the start of the drug.

Several options were considered for obtaining echocardiographic data. For patients admitted to the intensive care unit, transthoracic echocardiography images taken on admission were recovered. Patients admitted to the hospitalization unit were referred for echocardiographic examination at the echocardiography laboratory. If an echocardiogram could not be performed, we gathered the echocardiographic data available on the hospital internal network. In the absence of any such information, we contacted the out-of-hospital cardiologist to obtain any echocardiographic data, as accurately as possible in the case of valvular lesions. The echocardiography equipment used included: Aloka, Philips iE33, General Electric VIVID7 and General Electric VIVID9.

All of the available echocardiographic information was analysed, irrespective of when the scans were performed. Transesophageal echocardiography images, when available, were preferred for the analysis of valves. In patients with a history of valve surgery, we sought to investigate the type of VHD at the time of surgery. Echocardiographic evaluation criteria were those established by the American Society of Echocardiography [10].

Statistical analysis

Clinical and echocardiographic characteristics were expressed as mean and 95% CI for continuous variables and as counts and percentages for non-continuous variables.

Results
Study population and clinical data

The study involved 95 patients who completed the questionnaires (Table 1). There was predominance of women (65.3%) and the mean age was 66.8 (95% CI 64.2–69.3) years. Most patients were overweight, with a mean body mass index (BMI) of 29.5 (95% CI 28.3–30.7) kg/m2. The most common comorbidities were hypertension (72.3%), dyslipidemia (68.1%), diabetes mellitus (53.2%) and coronary artery disease (49.5%). Hospitalization was linked to the management of coronary artery disease in 47.3% of patients, heart failure in 18.7% and VHD in 8.8%.

Thirty-two patients (34.0%) had known VHD; 5 patients (5.3%) had heart disease officially linked to fenfluramine or a derivative (PAH in 4 patients and aortic regurgitation in 1 patient). Sixty-eight patients (71.6%) reported dyspnoea, 58.9% chest pain and 37.9% palpitations. Seventeen patients (18.7%) reported surgical or percutaneous valve interventions that had already been completed or were scheduled; the distribution of different types of surgery is summarized in Table 1. The most common intervention was surgical aortic valve replacement and the most common heart valve disease was aortic stenosis. Two of the three cases of aortic regurgitation were caused by infective endocarditis. Excluding infective endocarditis, surgical or percutaneous valve interventions for mitral or aortic regurgitations were reported in 3 of 95 (3.2%) patients.

Treatment

Of the 95 patients, 90.5% had been treated with benfluorex, 35.8% with dexfenfluramine and 1.1% with fenfluramine (Table 2). Twenty-five patients (26.3%) had been exposed to both benfluorex and dexfenfluramine. The primary indication for treatment was overweight, followed by diabetes mellitus; misuse of benfluorex was reported in a large proportion of the population (47.7%). Treatment was initiated after 1997 (date of withdrawal of dexfenfluramine) in 36.0% of patients. The mean duration of treatment was 52.3 (95% CI 39.0–65.6) months, and 90.5% had been exposed for3months and 31.6% for5years.

Treatment was most commonly prescribed by a general practitioner (75.8% of patients), followed by an endocrinologist (15.8% of patients), and by a cardiologist in only 3.2% of patients (Table 2). The drug was taken without a prescription in 3.2% of patients. Cardiologists were the most likely to discontinue medication (10.5%), followed by endocrinologists (8.4%), whereas general practitioners were least likely to discontinue it (0.4%); 34.7% of patients discontinued the treatment without medical advice. The main reasons given for treatment discontinuation were intolerance and inefficiency.

Echocardiographic data

Doppler echocardiogram images were available for 75 patients. In 18 of the 20 patients without echocardiogram images, echocardiographic reports were retrieved from the hospital medical database (11 patients, 61.1%) or the patient's cardiologist (7 patients, 38.9%). Six patients had no echocardiographic data available (images or reports) (Table 3).

Mitral valve abnormalities were found in 54 (61.4%) patients, aortic valve abnormalities in 47 (54.0%) patients, and both abnormalities in 41.4% (Table 4). Both mild mitral regurgitation and mild aortic regurgitation were found in 22 patients (25.9%). No patient had both moderate to severe mitral regurgitation and mild aortic regurgitation. Both mild mitral regurgitation and moderate to severe aortic regurgitation were found in 4 patients (4.8%). One patient (1.2%) had both moderate to severe mitral and aortic regurgitation. Calcifications of the valvular tissue were common. Twenty-three patients were free of left VHD (26.4%). Left ventricular ejection fraction (LVEF) was>45% in most patients (n =76, 85.4%).

Mitral regurgitation was identified in 47 (52.8%) patients, and was moderate to severe in 3.4% (Table 4). Restrictive mitral regurgitation with LVEF45% and without stenosis or calcification of the leaflet tissue was seen in 8 (10.0%) patients. Mitral regurgitation in this subgroup was considered as highly probable drug-induced VHD, and was moderate to severe in 1 patient. The transthoracic echocardiogram from this patient had shown left ventricular dilatation (end-diastolic diameter 59mm) with normal walls and hyperkinesis (LVEF 69%), dilatation of the left atrium (surface area 32cm2), severe mitral regurgitation (effective regurgitant orifice area [EROA] 31mm2 and regurgitant volume 56mL) with reduced mobility of leaflets, severe aortic regurgitation without leaflets retraction, PAH (systolic pulmonary artery pressure 52mmHg), and a dilated inferior vena cava. The male patient was born in 1941, had undergone mechanical valve replacement of both the mitral and the aortic valve in 2007, had type 2 diabetes and had been exposed to benfluorex for 12months.

Aortic regurgitation was identified in 38 (43.6%) patients, and was moderate to severe in 8.0% (Table 4). Restrictive aortic regurgitation with neither dilatation of ascending aorta nor stenosis of calcification of the cusp tissue was described in 11 (13.3%) patients. Aortic regurgitation in this subgroup was considered as highly probable drug-induced aortic VHD, and was moderate to severe in 2 patients. For the first patient, transthoracic and transesophageal echocardiograms had shown a normal left ventricle, dilatation of the left atrium, mild mitral regurgitation with leaflets retraction, moderate aortic regurgitation (vena contracta 4.5mm, proximal isovelocity surface area 4.8mm) with thickened leaflets and central loss of coaptation, and no PAH. This female patient was born in 1960, had type 2 diabetes, coronary heart disease and end-stage kidney disease with a history of renal transplantation. She had been exposed to benfluorex for 6years. For the second patient, transthoracic and transesophageal echocardiograms had shown left ventricular dilatation (end-diastolic diameter 54mm) with normal walls and normal LVEF (62%), dilatation of the left atrium (surface area 23cm2), mild mitral regurgitation (EROA 11mm2 and regurgitant volume 15mL) with normal leaflets, moderate aortic regurgitation (vena contracta 5.4mm, EROA 13mm2 and regurgitant volume 17mL) with central loss of coaptation, and no pulmonary arterial hypertension. This female patient was born in 1934, had arterial hypertension and atrial fibrillation. She had been exposed to benfluorex for 13years. Right heart findings are summarized in Table 4.

Mild tricuspid regurgitation was found in 49 (60.5%) patients, and moderate to severe tricuspid regurgitation in 10 (11.9%) patients (Table 4). PAH with LVEF45% was present in 12 (14.0%) patients. A highly probable drug-induced VHD was associated with PAH in 2 (2.4%) patients, both of whom had highly probable drug-induced mild aortic regurgitation.

In total, mitral regurgitation and/or aortic regurgitation was found 57 (64.0%) patients. Highly probable drug-induced mitral and/or aortic valve disease was described in 16 (18.6%) patients (Table 5). An unlikely drug-induced mitral and/or aortic valve disease was identified in 23 (25.8%) patients. A possible drug-induced mitral and/or aortic valve disease was found in 34 (38.2%) patients. Simultaneous involvement of highly probable drug-induced mitral and aortic VHD was uncommon, and was present in 3 of 77 (3.9%) patients. No left heart valvular abnormality was identified in 23 of 87 (26.4%) patients. One patient with a history of valve surgery (combined mitral and aortic valve replacement) had a highly probable drug-induced VHD.

Discussion

The profile of patients exposed to fenfluramine or its derivatives was similar to that in the published literature [1, 2, 3]. Consumers of fenfluramine or its derivatives were mainly middle-aged overweight women. Benfluorex was used off-label, for treatment of overweight, in 47.7% of patients. This frequency was estimated at 20% by the investigation report of the General Inspectorate of Social Affairs. More than 90% of patients had been exposed to fenfluramine or its derivatives for3months, which was the minimum time during which valvular abnormalities appeared in the CNAM study [7]. The most frequent prescribers of fenfluramine or its derivatives were general practioners, whereas cardiologists were the least likely to initiate them and the most likely to discontinue them. Treatment was initiated after the withdrawal from the market of dexfenfluramine in a sizeable proportion of patients, in spite of the fact that the cardiotoxicity of fenfluramine or its derivatives had already been established. Moreover, only 10.8% of discontinuations were driven by the knowledge of their cardiotoxicity. These statements highlight the lack of reactivity of French drug-control agencies to stop prescription of these drugs. Consumption without medical prescription was very rare (3.2%), as suggested by the wide off-label use (for overweight) of benfluorex.

Most patients were highly symptomatic, which likely reflects their high prevalence of comorbidities. The study group comprised patients at high cardiovascular risk who were clearly at greater risk of atherosclerosis than those in the CNAM study [7] (diabetes mellitus 53.2% vs 33% in CNAM, hypertension 72.3% vs 15.5%, coronary artery disease 49.5% vs 15.5%). The Framingham study [11] reported a higher risk of developing mitral insufficiency in individuals with hypertension (hazard ratio 1.6, 95% CI 1.2–2.0). Thanassoulis et al. [12] showed an association between a higher Framingham score and the prevalence and severity of aortic valve calcium. Anvari et al. [13] reported that valvular atherosclerotic changes were strongly analogous with coronary atherosclerosis and generalized atherosclerotic processes. Anvari et al. [13] found that BMI, smoking habit, diabetes and aortic stenosis were risk factors for valvular atherosclerosis. The aspect of valvular abnormalities associated with atherosclerosis is still quite different from that associated with drug-induced valvulopathies, because of the presence of valvular calcifications.

Mitral and aortic valve abnormalities were frequent in the present study, affecting nearly three-quarters of our population with past exposure to fenfluramine or its derivatives. The frequency of valve abnormalities was high in the REGULATE study [5], even before exposure to benfluorex, with at least one morphological valvular abnormality in 51% of patients and at least one functional valvular abnormality in 84% of patients. The rates of mitral and aortic regurgitations observed in our study are higher than those reported in the Framingham study [11], respectively, 53.9% versus 38.1% and 43.7% versus 21.5%. Calcifications were common and were found in>20% of cases for both mitral and aortic valves in this relatively old population, who were as a consequence more prone to degenerative VHD. This finding highlights the problem of toxic valvulopathies that would have degenerated, with the possible development of stenotic calcifications, making it impossible to recognize the pattern of drug-induced VHD. It is also conceivable that drug-induced valvular lesions could promote valve degeneration. While>90% of the patients were exposed to benfluorex for3months, greater than one-quarter did not have a left heart valvular abnormality, which corroborates the hypothesis of individual susceptibility to developing the lesion [6]. However, some studies have found no association between VHD and fenfluramines. Hepp et al. [14] and Davidoff et al. [15] performed echocardiographic comparative studies that showed no difference between patients exposed or not. A randomized double-blind study by Weissman et al. [16] showed only a slight increase in non-significant mitral and aortic regurgitations, similar to “physiological” leaks. These abnormalities were no longer present 3–5months after stopping treatment [17].

Tricuspid valve involvement is rare in the literature on drug-induced VHD [18]. In our population, moderate to severe tricuspid regurgitations were not associated with significant morphological abnormalities. In the French multicentre registry [3], moderate to severe tricuspid regurgitations were mostly secondary to PAH and annulus dilatation; PAH was identified in 50% of patients suffering from unexplained restrictive valvular disease with a previous exposure to benfluorex. In contrast, PAH was uncommon in our study and was associated with a highly probable drug-induced VHD in only 2.4% of patients. According to the International Primary PAH Study [19], the relative risk of PAH associated with the use of at least one anorectic was 3.8. The annual incidence of PAH in the general population is approximately 1–2 cases per 1 million persons and the risk of developing PAH is multiplied by 30 during an exposure of3months to anorexigens. In our study, the cases of PAH without significant left ventricular dysfunction (14.0% of patients) could not be attributed to fenfluramine or its derivatives because patients had not undergone a right heart catheterization. The pulmonary valve is rarely considered in the literature on drug-induced VHD. This also applies to our study.

In total, a highly probable drug-induced mitral and/or aortic valve disease was described in 18.6% of patients. These regurgitations were mild in over four-fifths of the patients and one patient had a history of valve surgery. This patient stated that no one had suggested a link between past exposure to fenfluramine or its derivatives and his VHD. This case illustrates the potential severity of drug-induced VHD, highlighted by the French multicentre registry [3]. Burger et al. [20] reported that phentermine–fenfluramine therapy was associated with a low prevalence of significant valvular regurgitation, similar to the normal offspring in the Framingham Heart Study [11]. Obviously, the number of significant regurgitations in our population does not explain the frequency of history of heart failure, found in 26.3% of patients. It is certainly difficult to quantify the risk of severe VHD attributable to benfluorex and leading to heart failure and/or surgery and/or death of the patient. This was the aim of the statistical survey conducted by CNAM [7], based on two national medicoadministrative databases that used ICD-10 diagnostic codes, whose labels were insufficient to describe drug-induced valvular regurgitations. They only determine the location of the damaged valve and the type of lesion, whether rheumatic or non-rheumatic.

We could not determine the ratio between the number of patients with highly probable drug-induced valve disease and the total number of patients hospitalized during the period of study because the questionnaire could not be given to all patients. It is awkward to compare the frequency of VHD observed in our study with that reported in the literature, as the study design is very different. Frachon et al. [1] and Tribouilloy et al. [2] conducted two case-control studies in order to assess the rates of exposure to benfluorex in patients with restrictive mitral regurgitations of unclear aetiology compared with matched controls. The CNAM survey [7] sought to estimate the risk of hospitalization for assessment of VHD and the risk of valve replacement in patients treated with benfluorex and identified by linking two databases: the information system of the Health Insurance Fund for Salaried Workers (SNIIRAM) and the French hospital discharge database (PMSI). The echocardiographic features of these valvulopathies were not considered. The French multicentre registry [3] retrospectively identified patients with unexplained and moderate to severe VHD with a previous exposure to benfluorex. Conversely, the design of our study is quite similar to that used in the latest prospective multicentre study by Tribouilloy et al. [21], which included 835 subjects previously exposed to benfluorex. Drug-induced VHD was less frequent in this population referred by primary care physicians and 6.8% of patients were classified as “drug-induced VHD (+)” versus 18.6% in our study. Mitral and aortic drug-induced VHD were reported in 5.1% and 3.6% of patients, respectively, versus 10.0% and 13.3% in our study.

A history of surgical or percutaneous valve interventions was reported in 18.7% of patients; and almost half had aortic stenosis. Surgical or percutaneous valve interventions for mitral or aortic regurgitations were uncommon (3.2%). In our cohort, fenfluramine or its derivatives could not be held responsible most of the valve interventions. The CNAMTS survey [7] reported a rate of hospitalization for valvular complications and/or PAH not exceeding 1 per 1000/year in patients exposed to benfluorex. The size of our population might not be sufficient to demonstrate an association.

Echocardiograms were performed in the University Hospital of Montpellier in only 78.9% of patients. This is partly explained by the absence of slot allocation reserved for this study at the echocardiography laboratory. The accuracy of the analysis of valves was variable depending on the available data. After examination of information retrieved from both hospital medical database and echocardiogram reports from the usual cardiologists, only 6 patients (6.3%) had no echocardiographic data available. The absence of a double-blind review of the echocardiograms is a limitation of our study, even though analysis of the images was very thorough. Moreover, variables that were not properly assessable were reported as such. Excluding the determination of commissural fusion and bicuspid aortic valve (which was possible in only half of the patients), echocardiographic parameters could be evaluated in>80% of the 95 patients included. Finally, our study is descriptive only and cannot prove a direct relationship between drug consumption and presence or severity of drug-induced VHD.

Conclusion

Valvulopathies were frequent among patients admitted to our hospitalization and intensive care units and who had past exposure to fenfluramine or its derivatives. Highly probable drug-induced valvulopathies affected 18.6% of patients but in most cases regurgitation was mild. Causation is difficult to prove, however, given the non-specific echocardiographic aspects of drug-induced VHD. No score for diagnosis has yet been established. Degenerative VHD in this high-risk population is therefore not excluded and explained most cases of surgical and percutaneous valve interventions. Considering the frequency and in the absence of definite knowledge about the evolution of these valve diseases, systematic questioning concerning fenfluramine or derivative use should be considered in hospitalized cardiac patients.

Disclosure of interest

D.C. Conferences: invitations as auditor (travelling and accommodation expenses paid for by the company) for Servier.

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