Cumulative incidence of cardiac surgery associated with exposure to benfluorex: A retrospective analysis based on compensation claims data.

Data on retrospective compensation claims for injuries caused by pharmaceutical drugs are prone to selection and reporting biases. Nevertheless, this case study of the antidiabetic drug benfluorex shows that such data can be used to estimate the cumulative incidence of drug-related injury, and to provide insights into its epidemiology. To this end, we develop a modelling framework for under-reporting of retrospective claims for compensation arising from drug damage. The model involves a longitudinal component related to attrition of cases over time, and a cross-sectional component related to incomplete reporting. We apply this model to cardiac valve surgery necessitated by exposure to benfluorex. Benfluorex was marketed in France between 1976 and 2009, when it was withdrawn because it caused valvular heart disease. A scandal erupted in 2010 over the scale of the damage caused by the drug. Since then, no further estimates of cumulative incidence have been published, though thousands of claims for compensation have been processed. The analysis combines compensation claims data and sociological survey data on benfluorex users, together with data on benfluorex sales and duration of treatment. We find a threshold of toxicity at about 6 months' exposure, and that at least 1690 individuals (95% CI 1290 to 2320) needed heart surgery to replace or repair valves damaged by exposure to benfluorex in France: a cumulative incidence of 3.68 per 10,000 (95% CI 2.68 to 5.34) benfluorex users or 3.22 per 10,000 (95% CI 2.48 to 4.39) person-years at risk above the exposure threshold. While these findings are tentative, they are consistent with those obtained previously using very different methods.

Fatal postoperative systemic pulmonary hypertension in benfluorex-induced valvular heart disease surgery: A case report.

RATIONALE: Drug-induced valvular heart disease (DI-VHD) remains an under-recognized entity. PATIENT CONCERNS: This report describes a heart valve replacement which was complicated by intractable systemic pulmonary arterial hypertension in a 61-year-old female with severe restrictive mitral and aortic disease. The diagnosis of valvular disease was preceded by a history of unexplained respiratory distress. The patient had been exposed to benfluorex for 6.5 years. DIAGNOSES: The diagnostic procedure documented specific drug-induced valvular fibrosis. INTERVENTIONS: Surgical mitral and aortic valve replacement was performed. OUTCOMES: Heart valve replacement was postoperatively complicated by unanticipated disproportionate pulmonary hypertension. This issue was fatal despite intensive care including prolonged extracorporeal life support. LESSONS: Benfluorex is a fenfluramine derivative which has been marketed between 1976 and 2009. Although norfenfluramine is the common active and toxic metabolite of all fenfluramine derivatives, the valvular and pulmonary arterial toxicity of benfluorex was much less known than that of fenfluramine and dexfenfluramine. The vast majority of benfluorex-induced valvular heart disease remains misdiagnosed as hypothetical rheumatic fever due to similarities between both etiologies. Better recognition of DI-VHD is likely to improve patient outcome.

Drug-induced aortic valve stenosis: An under recognized entity.

BACKGROUND: We have been intrigued by the observation that aortic stenosis (AS) may be associated with characteristic features of mitral drug-induced valvular heart disease (DI-VHD) in patients exposed to valvulopathic drugs, thus suggesting that beyond restrictive heart valve regurgitation, valvulopathic drugs may be involved in the pathogenesis of AS. METHODS: Herein are reported echocardiographic features, and pathological findings encountered in a series of patients suffering from both AS (mean gradient >15mmHg) and mitral DI-VHD after valvulopathic drugs exposure. History of rheumatic fever, chest radiation therapy, systemic disease or bicuspid aortic valve disease were exclusion criteria. RESULTS: Twenty-five (19 females, mean age 62years) patients having both AS and typical features of mitral DI-VHD were identified. Mean transaortic pressure gradient was 32+/-13mmHg. Aortic regurgitation was ≥ mild in 24 (96%) but trivial in one. Known history of aortic valve regurgitation following drug initiation prior the development of AS was previously diagnosed in 17 patients (68%). Six patients underwent aortic valve replacement and 3 both aortic and mitral valve replacement. In the 9 patients with pathology analysis, aortic valvular endocardium was markedly thickened by dense non-inflammatory fibrosis, a characteristic feature of DI-VHD. CONCLUSION: The association between AS and typical mitral DI-VHD after valvulopathic drug exposure may not be fortuitous. Aortic regurgitation was usually associated to AS and preceded AS in most cases but may be lacking. Pathology demonstrated the potential role of valvulopathic drugs in the development of AS.

Calcifications in benfluorex-induced valve heart disease: a misknown association.

Benfluorex, an anorexigenic agent, is recognized to induce noncalcified restrictive valvular regurgitation. We report a well-documented case of a 73-year-old patient who developed heart failure with aortic and mitral regurgitation following benfluorex intake. Echocardiography and peroperative analysis found large mitral annular calcifications and aortic subvalvular calcifications. Pathology confirmed drug-induced valve heart disease (DIVHD). The presence of valvular apparatus calcification should not lead to diagnosis of degenerative valvular disease and a priori preclude the diagnosis of DIVHD.

Adverse effects of benfluorex on heart valves and pulmonary circulation.

Benfluorex is responsible for the development of restrictive valvular regurgitation due to one of its metabolites, norfenfluramine. The 5-HT2B receptor, expressed on heart valves, acts as culprit receptor for drug-induced valvular heart disease (VHD). Stimulation of this receptor leads to the upregulation of target genes involved in the proliferation and stimulation of valvular interstitial cells through different intracellular pathways. Valve lesions essentially involve the mitral and/or aortic valves. The randomised prospective REGULATE trial shows a threefold increase in the incidence of valvular regurgitation in patients exposed to benfluorex. A cross-sectional trial shows that about 7% of patients without a history of VHD previously exposed to benfluorex present echocardiographic features of drug-induced VHD. The excess risks of hospitalisation for cardiac valvular insufficiency and of valvular replacement surgery were respectively estimated to 0.5 per 1000 and 0.2 per 1000 exposed patients per year. Recent data strongly suggest an aetiological link between benfluorex exposure and pulmonary arterial hypertension (PAH). The PAH development may be explained by serotonin, which creates a pulmonary vasoconstriction through potassium-channel blockade. Further studies should be conducted to determine the subsequent course of benfluorex-induced VHD and PAH, and to identify genetic, biological and clinical factors that determine individual susceptibility to developing such adverse effects.

Frequency of drug-induced valvular heart disease in patients previously exposd to benfluorex: a multicentre prospective study.

AIMS: The epidemiologic link between benfluorex use and an increased global frequency of left heart valve regurgitation has been well documented. However, no data linking previous drug exposure to the frequency of diagnosis of drug-induced valvular heart disease (DI-VHD) are available. The present study was conducted to address this issue. METHODS AND RESULTS: This echocardiography reader-blinded, controlled study conducted in 10 centres between February 2010 and February 2012 prospectively included 835 subjects previously exposed to benfluorex referred by primary care physicians for echocardiography. Based on blinded off-line analysis, echocardiography findings were classified as: (i) DI-VHD⁺ for patients with an echocardiographic diagnosis of DI-VHD, (ii) inconclusive, and (iii) DI-VHD⁻ for patients without signs of DI-VHD. Fifty-seven (6.8%) patients exposed to benfluorex were classified as DI-VHD⁺, 733 (87.8%) patients were classified as DI-VHD⁻, and 45 (5.4%) were classified as inconclusive. Mitral and aortic DI-VHD were reported in 43 patients (5.1%) and 30 (3.6%) patients, respectively. Longer duration of exposure, female gender, smoking, and lower BMI were independently associated with a diagnosis of DI-VHD. Good inter-observer reproducibility was observed for the echocardiography classification (Kappa = 0.83, P < 0.00001). CONCLUSIONS: About 7% of patients without a history of heart valve disease previously exposed to benfluorex present echocardiography features of DI-VHD. Further studies are needed to study the natural history of DI-VHD and to identify risk factors for the development of drug-induced valve lesions.

Increased risk of left heart valve regurgitation associated with benfluorex use in patients with diabetes mellitus: a multicenter study.

BACKGROUND: Benfluorex was withdrawn from European markets in June 2010 after reports of an association with heart valve lesions. The link between benfluorex and valve regurgitations was based on small observational studies and retrospective estimations. We therefore designed an echocardiography-based multicenter study to compare the frequency of left heart valve regurgitations in diabetic patients exposed to benfluorex for at least 3 months and in diabetic control subjects never exposed to the drug. METHODS AND RESULTS: This reader-blinded, controlled study conducted in 10 centers in France between February 2010 and September 2011 prospectively included 376 diabetic subjects previously exposed to benfluorex who were referred by primary care physicians for echocardiography and 376 diabetic control subjects. Through the use of propensity scores, 293 patients and 293 control subjects were matched for age, sex, body mass index, smoking, dyslipidemia, hypertension, and coronary artery disease. The main outcome measure was the frequency of mild or greater left heart valve regurgitations. In the matched sample, the frequency and relative risk (odds ratio) of mild or greater left heart valve regurgitations were significantly increased in benfluorex patients compared with control subjects: 31.0% versus 12.9% (odds ratio, 3.55; 95% confidence interval, 2.03-6.21) for aortic and/or mitral regurgitation, 19.8% versus 4.7% (odds ratio, 5.29; 95% confidence interval, 2.46-11.4) for aortic regurgitation, and 19.4% versus 9.6% (odds ratio, 2.38; 95% confidence interval, 1.27-4.45) for mitral regurgitation. CONCLUSIONS: Our results indicate that the use of benfluorex is associated with a significant increase in the frequency of left heart valve regurgitations in diabetic patients. The natural history of benfluorex-induced valve abnormalities needs further research.

Valvular heart disease with the use of fenfluramine-phentermine.

Exposure to the anorectic drug fenfluramine, alone or in combination with phentermine, a noradrenergic central nervous system stimulant, has been associated with unusual cardiac valvular morphology and resultant regurgitation of the left- and right-sided heart valves. The prevalence of significant valvular disease associated with the use of these anorectic drugs is reported to be as high as 23%. Herein, we report the occurrence of multivalvular disease and pulmonary hypertension associated with fenfluramine-phentermine use, discovered in an obese 59-year-old woman before expected gastric bypass surgery.

Valvular heart disease associated with benfluorex therapy: results from the French multicentre registry.

AIMS: The aim of this paper is to report clinical characteristics, consequences, echocardiographic features, and pathological findings encountered in patients suffering from valvular disease associated with benfluorex exposure in a multicentre French registry. METHODS AND RESULTS: Forty patients suffering from unexplained restrictive valvular disease with a previous exposition to benfluorex, a fenfluramine derivative, were identified from eight French university hospitals. Patients were mostly women (87.5%) with a mean age of 57 ± 9 years and high body mass index of 30 ± 7 kg/m²; 37.5% of them presented with severe heart failure symptoms (NYHA class III and IV). Benfluorex mean daily dose was 415 ± 131 mg with total therapy duration of 72 ± 53 months. Resulting cumulative dose was 910 ± 675 g. Common echocardiographic findings were leaflets and sub-valvular apparatus thickening and retraction. Aortic and mitral valve regurgitations resulting from leaflets loss of coaptation were the most frequent findings (87.5 and 82.5%) and were severe in 29 patients (72.5%). Multiple valve involvements were present in 31 cases (77.5%). Pulmonary arterial hypertension was identified in 20 cases (50%). Histopathological examination demonstrated abundant extra cellular matrix encasing the leaflets without modification of valve architecture. Fifteen patients (37.5%) underwent valvular surgery. CONCLUSION: Benfluorex-related valvulopathy shares numerous characteristics with other drug-induced valvular disease. Clinical consequences may be serious with severe heart failure symptoms that may lead to surgical treatment.

Benfluorex and valvular heart disease: a cohort study of a million people with diabetes mellitus.

PURPOSE: To evaluate and quantify in diabetic patients treated with benfluorex in France, a fenfluramine-derivated product, a possible increase in risk of valvular heart disease, previously suggested by several published case reports. METHODS: This was a French comparative cohort study using data from two large national linked databases, health insurance system (SNIIRAM) and hospitalization (PMSI). Patients aged 40-69 years with reimbursement for oral antidiabetic and/or insulin in 2006 were eligible. Exposed patients were defined as patients with at least one benfluorex reimbursement in 2006. Selected admission diagnoses of interest in 2007 and 2008 PMSI databases were valvular insufficiency for any cause, mitral insufficiency, aortic insufficiency, and valvular replacement surgery with cardiopulmonary bypass. Relative risks (RR) were adjusted on gender, age, and history of chronic cardiovascular disease. RESULTS: A total of 1,048173 diabetic patients were included, with 43,044 (4.1%) exposed to benfluorex. The risk of hospitalization in 2007 and 2008 for any cardiac valvular insufficiency was higher in the benfluorex group: crude RR=2.9 [95% confidence interval 2.2-3.7] and adjusted RR=3.1 [2.4-4.0], with a lower risk for patients with lower cumulative dose of benfluorex. Adjusted RR for mitral insufficiency and aortic insufficiency admissions were 2.5 [1.9-3.7] and 4.4 [3.0-6.6], respectively. Adjusted RR for valvular replacement surgery was 3.9 [2.6-6.1]. CONCLUSIONS: Benfluorex in diabetic patients was significantly associated with hospitalization for valvular heart disease in the 2 years following benfluorex exposure. Linkage between SNIIRAM and PMSI databases is in France a valuable tool to quantify the risk of serious adverse drug reactions.

[Diagnosis and classification of pulmonary hypertension]. / Diagnostic et classification de l'hypertension pulmonaire.

Pulmonary hypertension (PH) has been defined as an increase in mean pulmonary arterial pressure (mPAP) > or = 25 mmHg at rest as assessed by right heart catheterisation (RHC). Precapillary pulmonary hypertension is defined by an increase in mPAP > or =25 mmHg and a pulmonary capillary wedge pressure (PCWP)< or =15 mmHg associated with a normal or reduced cardiac output. No definition for PH on exercise as assessed by RHC can be provided at the present time. In group 1 pulmonary arterial hypertension (PAH), the term "familial PAH" has been replaced by "heritable PAH". Heritable forms of PAH include clinically sporadic idiopathic PAH with germline mutations and clinical familial cases with or without identified germline mutations. Schistosomiasis and chronic haemolytic anaemia have been included among the group of associated PAH. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis have been individualized and designated as clinical group 1'.

Benfluorex and unexplained valvular heart disease: a case-control study.

BACKGROUND: Recent case reports suggest that benfluorex, a fenfluramine derivative used in the management of overweight diabetic patients and dyslipidemia, is associated with cardiac valve regurgitation. METHODS: We conducted a case-control study. Eligible patients were those admitted in the cardiology or the cardiac surgery units of our hospital between January, 1(st) 2003 and June 30(th) 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. RESULTS: Out 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. CONCLUSION: The use of benfluorex is associated with unexplained mitral regurgitation.

Pharmacologic therapies for obesity.

This article examines the transitions in pharmacological therapy for obesity. It reviews the current options approved by the Food and Drug Administration and several drugs approved for other indications that can be used to treat obesity as well. Because weight regulation is complex and redundant systems protect against perceived starvation, optimal treatment of obesity in individual patients will likely require different combinations of behavioral, nutritional, pharmacologic, endoscopic, and surgical therapies.

Restrictive organic mitral regurgitation associated with benfluorex therapy.

AIMS: To investigate the association between benfluorex use and organic restrictive mitral regurgitation (MR) in patients admitted to hospital for diagnostic work-up of MR of unclear aetiology. METHODS AND RESULTS: Among patients referred between 2003 and 2008 to our tertiary centre for diagnostic work-up of MR, we retrospectively identified 22 consecutive patients (65 +/- 12 years, 64% women) with restrictive organic MR of unclear aetiology. Using propensity scores, 22 out of 156 patients who underwent surgery for dystrophic MR due to flail leaflets during the same time period were matched for age, sex, height, body weight, and diabetes with the study population. Eight of the 22 patients with restrictive organic MR of unclear aetiology (36.4%) had a history of benfluorex use, and in one patient (4.5%) we identified previous exposure to both benfluorex and fenfluramine. The frequency of benfluorex treatment in patients with restrictive organic MR of unclear aetiology was significantly higher compared with that observed in the dystrophic MR group (36.4 vs. 4.5%; P-value 0.039). Patients with restrictive MR treated with benfluorex (body mass index 31 +/- 6 kg/m(2)) were all dyslipidaemic and 67% had diabetes. Echocardiography identified moderate or severe restrictive organic MR in all cases. Median total duration of benfluorex therapy was 63(12-175) months, at a daily dose of 450 (300-450) mg, leading to a cumulative dose of 850 (108-2363) g. CONCLUSION: Although it cannot affirm a definitive causal relationship, the present study strongly suggests that patients treated with benfluorex might incur a risk of restrictive organic valvular heart disease. Therefore, echocardiography should be performed in patients exposed to benfluorex in case of occurrence of symptoms or signs of valvular disease. Further data are needed to confirm these findings.

Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals.

BACKGROUND: Use of fenfluramines for weight loss has been associated with the development of characteristic plaques on cardiac valves causing regurgitation. However, previously published studies of exposure to fenfluramines have been limited by relatively small sample size, short duration of follow-up, and the lack of any estimate of the frequency of subsequent valvular surgery. We performed an observational study of 5743 users of fenfluramines examined by echocardiography between July 1997 and February 2004 in a single large cardiology clinic. RESULTS: The prevalence of at least mild aortic regurgitation (AR) or moderate mitral regurgitation (MR) was 19.6% in women and 11.8% in men (p < 0.0001 for gender difference). Duration of use was strongly predictive of mild or greater AR (p < 0.0001 for trend), MR (p = 0.002), and tricuspid regurgitation (TR) (p < 0.0001), as was earlier scan date (p < 0.0001 for those scanned prior to 1 January 2000 versus later). Increasing age was also independently associated with increased risk of AR and MR (both p < 0.0001). With mean follow-up of 30.3 months, AR worsened in 15.2%, remained the same in 63.1%, and improved in 21.7%. Corresponding values for MR were 24.8%, 47.4% and 27.9%. Pulmonary hypertension was strongly associated with MR but not AR. Valve surgery was performed on 38 patients (0.66% of 5743), 25 (0.44%) with clear evidence of fenfluramine-related etiology. CONCLUSION: Regurgitant valvulopathy was common in individuals exposed to fenfluramines, more frequent in females, and associated with duration of use in all valves assessed. Valve surgery was performed as frequently for aortic as mitral valves and some tricuspid valve surgeries were also performed. The incidence of surgery appeared to be substantially increased compared with limited general population data.

Valvular heart disease associated with fenfluramine detected 7 years after discontinuation of treatment.

We report the case of a patient referred to us for mitral and aortic valvular disease with a rheumatic appearance. The unusual macroscopic appearance on valve resection was not compatible with a rheumatic cause. A detailed review of this patient's clinical history (ie, a history of treatment with fenfluramine) suggested an iatrogenic cause, which was confirmed by histology. For the first time, a case of valvular heart disease that deteriorated was discovered 7 years after treatment with fenfluramine, whereas this iatrogenic disease classically resolves after discontinuation of treatment. This case illustrates the need for continuing heart valve surveillance of patients who have used these anorectics.

When cure is care: diagnosis and management of pulmonary arterial hypertension.

PURPOSE: The purpose of this article is to provide nurse practitioners with an understanding of the pathophysiology of pulmonary arterial hypertension (PAH) disease, clinical manifestations, diagnostic evaluation, drug therapy, strategies for health promotion, and relevant care issues for patients and families. DATA SOURCES: Selected clinical and research articles, as well as current government guidelines. CONCLUSIONS: Symptoms expressed are more apparent as PAH disease progresses, leaving fewer treatment options in advanced disease stages. New drugs are currently being tested for the treatment of PAH; however, the costs of many of the currently approved treatments may be prohibitive. IMPLICATIONS FOR PRACTICE: Earlier recognition of disease symptoms leads to prompt initiation of diagnostic evaluation and referral to specializing medical centers. Upon referral, specialty centers may begin appropriate treatment regimens earlier in the disease process, which could improve clinical outcomes and quality of life.