Food and Drug Administration criteria for the diagnosis of drug-induced valvular heart disease in patients previously exposed to benfluorex: a prospective multicentre study.

AIMS: The Food and Drug Administration (FDA) criteria for diagnosis of drug-induced valvular heart disease (DIVHD) are only based on the observation of aortic regurgitation ≥ mild and/or mitral regurgitation ≥ moderate. We sought to evaluate the diagnostic value of FDA criteria in a cohort of control patients and in a cohort of patients exposed to a drug (benfluorex) known to induce VHD. METHODS AND RESULTS: This prospective, multicentre study included 376 diabetic control patients not exposed to valvulopathic drugs and 1000 subjects previously exposed to benfluorex. Diagnosis of mitral or aortic DIVHD was based on a combined functional and morphological echocardiographic analysis of cardiac valves. Patients were classified according to the FDA criteria [mitral or aortic-FDA(+) and mitral or aortic-FDA(-)]. Among the 376 control patients, 2 were wrongly classified as mitral-FDA(+) and 17 as aortic-FDA(+) (0.53 and 4.5% of false positives, respectively). Of those exposed to benfluorex, 48 of 58 with a diagnosis of mitral DIVHD (83%) were classified as mitral-FDA(-), and 901 of the 910 patients (99%) without a diagnosis of the mitral DIVHD group were classified as mitral-FDA(-). All 40 patients with a diagnosis of aortic DIVHD were classified as aortic-FDA(+), and 105 of the 910 patients without a diagnosis of aortic DIVHD (12%) were classified aortic-FDA(+). Older age and lower BMI were independent predictors of disagreement between FDA criteria and the diagnosis of DIVHD in patients exposed to benfluorex (both P ≤ 0.001). CONCLUSIONS: FDA criteria solely based on the Doppler detection of cardiac valve regurgitation underestimate for the mitral valve and overestimate for the aortic valve the frequency of DIVHD. Therefore, the diagnosis of DIVHD must be based on a combined echocardiographic and Doppler morphological and functional analysis of cardiac valves.

The value of cardiopulmonary exercise testing in individuals with apparently asymptomatic severe aortic stenosis: a pilot study.

BACKGROUND: Risk stratification in asymptomatic patients with severe aortic stenosis (AS) is based on exercise test results. However, differentiating between pathological and physiological breathlessness during exercise is sometimes challenging. Cardiopulmonary exercise testing (CPET) may improve quantification of cardiopulmonary exercise capacity in patients with valve diseases. AIMS: To assess the ability of CPET to detect abnormal responses to exercise and a clinical endpoint (occurrence of European Society of Cardiology guidelines surgical class I triggers). METHODS: Forty-three consecutive patients (mean age 69±13 years; 31 men) with no reported symptoms and severe AS (aortic valve surface area<1 cm2 or indexed aortic valve surface area ≤0.6 cm2/m2) prospectively underwent symptom-limited CPET. RESULTS: Twelve (28%) patients had an abnormal exercise test (AET) with symptoms (abnormal dyspnoea n=11; angina n=1). Both VE/VCO2 slope>34 (hazard ratio [HR]=5.76, 95% confidence interval [CI] 1.086-30.587; P=0.04) and peak VO2≤14 mL/kg/min (HR 6.01, 95% CI 1.153-31.275; P=0.03) were independently associated with an AET. Furthermore, VE/VCO2 slope>34 (HR 3.681, 95% CI 1.318-10.286; P=0.013) and peak VO2≤14 mL/kg/min (HR 3.058, 95% CI 1.074-8.713; P=0.036) were independent predictors of reaching the clinical endpoint. CONCLUSIONS: Cardiopulmonary exercise testing is a useful tool for characterizing breathlessness during an exercise test in apparently asymptomatic patients with AS. Peak VO2≤14 mL/kg/min and VE/VCO2 slope>34 were associated with an AET and the occurrence of European Society of Cardiology guideline surgical class I triggers.

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.

Impact of selective serotonin reuptake inhibitor therapy on heart valves in patients exposed to benfluorex: a multicentre study.

BACKGROUND: Given the association between valvular heart disease and drugs that alter serotonin metabolism, concerns have been raised about the possibility of an association between selective serotonin reuptake inhibitor (SSRI) use and drug-induced valvular disease. In France, SSRI use has been suggested to be an important confounding factor in the development of heart valve lesions in patients exposed to benfluorex in the context of the 'Médiator scandal'. AIMS: To address the relationship between SSRI use and valve regurgitation and morphology in a large cohort of patients exposed to benfluorex. METHODS: Overall, 832 consecutive patients exposed to benfluorex prospectively referred to 10 centres underwent complete echocardiography examinations according to a standardized protocol. Echocardiograms were independently and blindly read off-line by two experts. RESULTS: Ninety patients had been exposed to SSRIs for 3 months or more. The proportions of patients with no or trivial, mild, moderate or severe mitral regurgitation (MR) or aortic regurgitation (AR) were not different between SSRI patients and non-SSRI patients (P=0.63 and 0.58, respectively). The frequencies of AR ≥ mild (20 [22.2%] vs 145 [19.5%]; P=0.55) and MR ≥ mild (14 [15.6%] vs 118 [15.9%]; P=0.93) were similar in SSRI patients and non-SSRI patients. The frequencies of aortic and mitral valve abnormalities suggestive of drug-induced toxicity were also similar in the two patient groups. Multivariable logistic regression analysis confirmed the absence of any identifiable relationship between AR or MR and morphological abnormalities and SSRI use in the present cohort. CONCLUSION: Exposure to SSRIs was not associated with an increased risk of heart valve regurgitation or morphological abnormalities suggestive of drug-induced toxicity in this large cohort of patients exposed to benfluorex.

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.

Echocardiographic prediction of postoperative atrial fibrillation after aortic valve replacement for aortic stenosis: a two-dimensional speckle tracking left ventricular longitudinal strain multicentre pilot study.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery, with increased risk of embolic events, haemodynamic instability, haemorrhagic complications and prolonged hospital stay. AIMS: We sought to assess the value of preoperative left ventricular global longitudinal strain (GLS) for the prediction of POAF in a series of patients with severe symptomatic aortic stenosis who underwent aortic valve replacement (AVR). METHODS: Fifty-eight consecutive patients (52% men) aged 73±9 years, with severe symptomatic aortic stenosis (aortic valve area<1cm(2) or<0.5cm(2)/m(2)), in sinus rhythm, who underwent AVR were prospectively included in three centres between 2009 and 2010. Complete preoperative echocardiography was performed in all patients, including global and segmental longitudinal strain using two-dimensional speckle tracking. RESULTS: The POAF incidence was 28/58 (48%). On univariate analysis, aortic valve area (P=0.04), preoperative E/e' ratio (P=0.04) and GLS (P=0.005) were associated with the occurrence of POAF. Chronic obstructive pulmonary disease (P=0.05), preoperative statin treatment (P=0.09), age≥80 years (P=0.09), left ventricular ejection fraction (P=0.09) and systolic pulmonary artery pressure (P=0.06) tended to increase the risk of POAF. The best GLS cut-off value for the prediction of POAF was -15% (82% sensitivity, 53% specificity, area under the curve 0.72). On multivariable analysis, GLS>-15% was the only independent predictor of POAF (odds ratio 7.74, 95% confidence interval [1.15-52.03]; P=0.035). CONCLUSIONS: Incidence of POAF is high after AVR for severe aortic stenosis. Our results suggest an additive value of the study of left ventricular myocardial deformation to classical clinical and echocardiographic variables for the prediction of POAF in this setting.

[Benfluorex and valvular heart disease]. / Benfluorex (Mediator®) et atteintes valvulaires.

Benfluorex is responsible of restrictive organic valvular regurgitations via one of its metabolites, the norfenfluramine. It has been withdrawn from the european market in June 2010. In France, about five millions of people have been exposed to benfluorex since its market launch in 1976. At the time of its market withdrawn, over 300,000 patients in France were taking the drug. Aortic and mitral valves are the most frequent involved. The prevalence of this type of valve damage is not yet known with accuracy. Severe regurgitations appear to be rare (less than one case per thousand exposed patients-year).

Heart failure in left-sided native valve infective endocarditis: characteristics, prognosis, and results of surgical treatment.

AIMS: Although congestive heart failure (CHF) represents the most common cause of death in native valve infective endocarditis (IE), recent data on the outcome of IE complicated by CHF are lacking. We aimed to analyse the characteristics and prognosis of patients with left-sided native valve IE complicated by CHF and to evaluate the impact of early surgery on 1 year outcome. METHODS AND RESULTS: Two hundred and fifty-nine consecutive patients with definite left-sided native valve IE according to the Duke criteria were included in this analysis. When compared with patients without CHF (n = 151), new heart murmur, high comorbidity index, aortic valve IE, and severe valve regurgitation were more frequently observed in CHF patients (n = 108, 41.6%). Mitral valve IE, embolic events and neurological events were less frequent in CHF patients. Congestive heart failure was independently predictive of in-hospital [OR 3.8 (1.7-9.0); P = 0.0013] and 1 year mortality [HR 1.8 (1.1-3.0); P = 0.007]. Early surgery was performed in 46% of CHF patients with a peri-operative mortality of 10%. In the CHF group, comorbidity index, Staphylococcus aureus IE, uncontrolled infection, and major neurological events were univariate predictors of 1 year mortality. Early surgery was independently associated with improved 1 year survival [HR 0.45 (0.22-0.93); P = 0.03]. CONCLUSION: Left-sided native valve IE complicated by CHF is more frequent in aortic IE and is associated with severe regurgitation. Congestive heart failure is an independent predictor of in-hospital and 1 year mortality. In CHF patients, early surgery is independently associated with reduced mortality and should be widely considered to improve outcome.