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

Ven, Florent Le; Tribouilloy, Christophe; Habib, Gilbert; Gueffet, Jean Pierre; Maréchaux, Sylvestre; Eicher, Jean‐Christophe; Blanchard-Lemoine, Bénédicte; Rousseau, J; Hénon, Philippe; Jobic, Yannick; Étienne, Yves

doi:10.1093/ejechocard/jeq172

Cited by 32 publications

(11 citation statements)

References 23 publications

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“…Drug exposure has been recognised as a cause of valvulopathy since the 1960s when methysergide and ergotamine were found to induce valve regurgitation [ 7 – 9 ]. Other drugs implicated later were fenfluramine and dexfenfluramine [ 10 – 12 ], pergolide and cabergoline [ 13 – 15 ] and most recently benfluorex [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Risk of cardiac valvulopathy with use of bisphosphonates: a population-based, multi-country case-control study

et al. 2015

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SummaryAnalyses of healthcare data from 30 million individuals in three countries showed that current use of bisphosphonates may be associated with a small increased risk of cardiac valvulopathy (vs. those not exposed within the previous year), although confounding cannot be entirely ruled out. The observed tendency for decreased valvulopathy risk with cumulative duration of bisphosphonate use >6 months may even indicate a protective effect with prolonged use. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy.IntroductionA signal of cardiac valve disorders with use of bisphosphonates was identified in the literature and EudraVigilance database, which contains reports of suspected adverse drug reactions from worldwide sources. The aim of this study was to evaluate the association using population-based healthcare data.MethodsThis was a case-control study among users of bisphosphonates and other drugs for osteoporosis in six healthcare databases covering over 30 million individuals in Italy, Netherlands and the UK from 1996 to 2012. Prescriptions/dispensations were used to assess drug exposure. Newly diagnosed cases of cardiac valvulopathy were identified via disease codes/free-text search. Controls were matched to each case by age, sex, database and index date. Adjusted odds ratios (ORs) were estimated using conditional logistic regression for the pooled data and meta-analysis of individual database risk estimates.ResultsA small but statistically significant association was found between exposure to bisphosphonates as a class and risk of valvulopathy. Overall risk was 18 % higher (95 % CI 12–23 %) in those currently exposed to any bisphosphonate (mainly alendronate and risedronate) vs. those not exposed within the previous year. Risk of valve regurgitation was 14 % higher (95 % CI 7–22 %). Decreased valvulopathy risk was observed with longer cumulative duration of bisphosphonate use, compared to use of less than 6 months. Meta-analyses of database-specific estimates confirmed results from pooled analyses.ConclusionsThe observed increased risks of cardiac valvulopathy with bisphosphonate use, although statistically significant, were quite small and unlikely to be clinically significant. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy and to investigate possible mechanisms for the association.Electronic supplementary materialThe online version of this article (doi:10.1007/s00198-015-3441-2) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Risk of cardiac valvulopathy with use of bisphosphonates: a population-based, multi-country case-control study

et al. 2015

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“…Data have been accumulated leading to the conclusion that benfluorex is associated with the development of VHD . Indeed, data in the recent literature, including clinical case reports, case series, case–control studies, a large‐scale cohort study and a randomised trial, established that benfluorex may cause valve lesions. Reported valve lesions consist of regurgitation, essentially affecting the mitral and/or aortic valves.…”

Section: Benfluorex and Valvular Heart Diseasementioning

confidence: 99%

“…Reported valve lesions consist of regurgitation, essentially affecting the mitral and/or aortic valves. Several valves can be affected simultaneously . A relationship has been demonstrated between the duration of treatment and the risk of VHD .…”

Section: Benfluorex and Valvular Heart Diseasementioning

confidence: 99%

“…Other case reports were subsequently published . A retrospective survey published in 2010 described 40 cases of VHD with initially unexplained aetiology in patients treated with benfluorex. The mean duration of treatment was 72 months, 87% of patients were women, and patients had a mean age of 57 years and a mean body mass index (BMI) of 30 kg/m 2 ; 37% of patients presented symptoms of severe heart failure; aortic and mitral valve regurgitations were diagnosed respectively in 87 and 82% of the patients and were severe in 72% of the cases.…”

Section: Benfluorex and Valvular Heart Diseasementioning

confidence: 99%

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Adverse effects of benfluorex on heart valves and pulmonary circulation

Szymanski

Andréjak

Peltier

et al. 2014

Pharmacoepidemiology and Drug

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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.

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“…Both drugs and a combination of fenfl uramine and phentermine (known as "fen-phen") were widely used as weight-loss drugs until 1997 when they were withdrawn from the market in the US, Europe and other countries after reports of valvular heart damage, apparently caused by a selective stimulation of 5-HT 2B receptors on human cardiac valves, and concerns on their possible association with pulmonary hypertension. 2,3,5,9 Rimonabant, an endocannabinoid receptor (subtype CB1) blocker, received marketing approval from the European Medicines Agency (EMA) in June 2006 for treatment of obese or overweight (BMI >27 kg/ m 2 ) patients with associated risk factors such as type 2 diabetes or dyslipidemia. In Brazil, where it was popularly known as "stomach fat pill," rimonabant was approved with similar indications in April 2007.…”

Section: Flaws Of Past Anti-obesity Drugsmentioning

confidence: 99%

Long-term health benefits of appetite suppressants remain unproven

Paumgartten¹

2011

Rev. Saúde Pública

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Because of the increasing prevalence of obesity, prevention and treatment of overweight has become a major public health concern. In addition to diet and exercise, drugs are needed for patients who failed to lose weight with behavioral treatment. The current article aimed to summarize recent concerns on the safety and effi cacy of appetite suppressants. Several appetite suppressants have been banned for safety reasons. In 2010, sibutramine was withdrawn from the market because a long-term study showed it increased the risks of cardiovascular events. So far no study with a suffi ciently large sample size has demonstrated that appetite suppressants can reduce morbidity and mortality associated with overweight. The withdrawal of sibutramine highlights that guidelines for the evaluation of weight control drugs must be more stringent, and studies on their long-term health benefi ts are needed prior to their marketing. RESUMOO aumento da prevalência da obesidade tornou a prevenção e tratamento do sobrepeso importante desafi o para a Saúde Pública. Além da dieta e exercício, os medicamentos são necessários para pacientes que não conseguem perder peso com as mudanças comportamentais. O objetivo do artigo foi sumarizar as preocupações atuais com a segurança e efetividade de medicamentos inibidores do apetite. Vários anorexígenos foram banidos por razões de segurança. Em 2010, a sibutramina foi retirada do mercado porque um estudo de longa duração mostrou que ela aumentava o risco de eventos cardiovasculares. Até agora nenhum estudo com número expressivo de pacientes demonstrou que anorexígenos reduzem a morbi-mortalidade associada ao sobrepeso. A retirada da sibutramina do mercado mostra que diretrizes para avaliação de medicamentos anorexígenos devem ser mais rigorosas, e que estudos de longa duração sobre os benefícios para a saúde devem ser realizados antes da comercialização. Rev Saúde Pública 2011;45(6):1192-6 During recent decades the prevalence of overweight (body mass index -BMI >25 kg/m 2 ) and obesity (BMI >30 kg/m 2 ) has steadily increased worldwide. It was recently reported that 33.8% of adults (≥20 years old) in the US, and 20% of adults in Europe are obese. DESCRITORES:1,a In Brazil, the prevalence of overweight and obesity have also soared, and a recent survey has estimated that nearly 50% of the population (all ages, males and females) are over the "ideal" weight and at least 13% are obese. Since overweight was shown to contribute to the development and aggravation of chronic conditions such as type 2 diabetes, hypertension, cardiovascular diseases, and several types of cancer, prevention and treatment of obesity is today a major public health concern.

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

Abstract: 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.

Cited by 32 publications

References 23 publications

Risk of cardiac valvulopathy with use of bisphosphonates: a population-based, multi-country case-control study

Risk of cardiac valvulopathy with use of bisphosphonates: a population-based, multi-country case-control study

Adverse effects of benfluorex on heart valves and pulmonary circulation

Long-term health benefits of appetite suppressants remain unproven

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