Oral Fluoroquinolones and Risk of Mitral and Aortic Regurgitation.

BACKGROUND: Recent studies have linked fluoroquinolones (FQs) to cardiac adverse events, including aortic dissection and aneurysm. To date, whether FQs can increase the risk of aortic or mitral regurgitation has not been studied. OBJECTIVES: This disproportionality analysis and case-control study examined whether FQs increase the risk of aortic and mitral regurgitation. METHODS: Data from the U.S. Food and Drug Administration's adverse reporting system database was used to undertake a disproportionality analysis, and a random sample of 9,053,240 patients from the U.S. PharMetrics Plus database (IQVIA) was used for the matched nested case-control study. Current FQ exposure implied an active prescription at the index date or 30 days prior to the event date. Recent FQ exposure was defined as FQ use within days 31 to 60 and past within days 61 to 365 prior to the event date. Rate ratios (RRs) were compared to users of amoxicillin and azithromycin. Conditional logistic regression was used to compute RRs adjusting for confounders. RESULTS: The reported odds ratio for the disproportionality analysis was 1.45 (95% confidence interval [CI]: 1.20 to 1.77). A total of 12,505 cases and 125,020 control subjects were identified in the case-control study. The adjusted RRs for current users of FQ compared with amoxicillin and azithromycin users were 2.40 (95% CI: 1.82 to 3.16) and 1.75 (95% CI: 1.34 to 2.29), respectively. The adjusted RRs for recent and past FQ users when compared with amoxicillin were 1.47 (95% CI: 1.03 to 2.09) and 1.06 (95% CI: 0.91 to 1.21), respectively. CONCLUSIONS: These results show that the risk of aortic and mitral regurgitation is highest with current use followed by recent use. No risk was observed with past use of FQs. Future studies are necessary to confirm or refute these associations.

Benefits of combining change-point analysis with disproportionality analysis in pharmacovigilance signal detection.

BACKGROUND: Change-point analysis (CPA) is a powerful method to analyse pharmacovigilance data but it has never been used on the disproportionality metric. OBJECTIVES: To optimize signal detection investigating the interest of time-series analysis in pharmacovigilance and the benefits of combining CPA with the proportional reporting ratio (PRR). METHODS: We investigated the couple benfluorex and aortic valve incompetence (AVI) using the French National Pharmacovigilance and EudraVigilance databases: CPA was applied on monthly counts of reports and the lower bound of monthly computed PRR (PRR-). We stated a CPA hypothesis that the substance-event combination is more likely to be a signal when the 2 following criteria are fulfilled: PRR- is greater than 1 with at least 5 cases, and CPA method detects at least 2 successive change points of PRR- which made consecutively increasing segments. We tested this hypothesis by 95 test cases identified from a drug safety reference set and 2 validated signals from EudraVigilance database: CPA was applied on PRR-. RESULTS: For benfluorex and AVI, change points detected by CPA on PRR- were more meaningful compared with monthly counts of reports: More change points detected and detected earlier. In the reference set, 14 positive controls satisfied CPA hypothesis, 6 positive controls only met first requirements, 3 negative controls only met first requirement, and 2 validated signals satisfied CPA hypothesis. CONCLUSIONS: The combination of CPA and PRR represents a significant advantage in detecting earlier signals and reducing false-positive signals. This approach should be confirmed in further studies.

Cardiovascular Safety of Lorcaserin in Overweight or Obese Patients.

BACKGROUND: Lorcaserin, a selective serotonin 2C receptor agonist that modulates appetite, has proven efficacy for weight management in overweight or obese patients. The cardiovascular safety and efficacy of lorcaserin are undefined. METHODS: We randomly assigned 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors to receive either lorcaserin (10 mg twice daily) or placebo. The primary safety outcome of major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke) was assessed at an interim analysis to exclude a noninferiority boundary of 1.4. If noninferiority was met, the primary cardiovascular efficacy outcome (a composite of major cardiovascular events, heart failure, hospitalization for unstable angina, or coronary revascularization [extended major cardiovascular events]) was assessed for superiority at the end of the trial. RESULTS: At 1 year, weight loss of at least 5% had occurred in 1986 of 5135 patients (38.7%) in the lorcaserin group and in 883 of 5083 (17.4%) in the placebo group (odds ratio, 3.01; 95% confidence interval [CI], 2.74 to 3.30; P<0.001). Patients in the lorcaserin group had slightly better values with respect to cardiac risk factors (including blood pressure, heart rate, glycemic control, and lipids) than those in the placebo group. During a median follow-up of 3.3 years, the rate of the primary safety outcome was 2.0% per year in the lorcaserin group and 2.1% per year in the placebo group (hazard ratio, 0.99; 95% CI, 0.85 to 1.14; P<0.001 for noninferiority); the rate of extended major cardiovascular events was 4.1% per year and 4.2% per year, respectively (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P=0.55). Adverse events of special interest were uncommon, and the rates were generally similar in the two groups, except for a higher number of patients with serious hypoglycemia in the lorcaserin group (13 vs. 4, P=0.04). CONCLUSIONS: In a high-risk population of overweight or obese patients, lorcaserin facilitated sustained weight loss without a higher rate of major cardiovascular events than that with placebo. (Funded by Eisai; CAMELLIA-TIMI 61 ClinicalTrials.gov number, NCT02019264 .).

Bivalirudin and transcatheter aortic valve replacement: a cautionary tale.

Bivalirudin is an accepted alternative to heparin for anticoagulation during select cardiac procedures. Its use has not been well described during transcatheter aortic valve replacement. Herein is the report of a transcatheter valve replacement case that was complicated by catastrophe and need for emergent cardiopulmonary bypass. A successful outcome was achieved. However, the inability to rapidly reverse the anticoagulation effect of bivalirudin proved troublesome, and that provides for a cautionary tale about its use during transcatheter valve replacement.

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.

[About the settlement of litigations concerning the harm caused by benfluorex (Mediator®)]. / À propos de l'expertise des dossiers benfluorex (Mediator® et génériques).

Since September 1st 2011, the National Bureau for Compensation of Medical Accidents represents a unique portal for out-of-court settlement of litigations concerning the harm caused by benfluorex. In December 2012, its official record is as follows: 7627 patients files have been received, 1378 have been studied, 797 led to a recommendation, and compensation by the drug company Servier has been recommended for 46 cases. The large number of rejections raises a problem which needs to be examined in the light of the available evidence on benfluorex associated heart valve disease. This evidence concerns both the morphological characteristics of the disease and the epidemiology of its association with benfluorex. More than 90% of emergent double valve disease (aortic and mitral regurgitation), of emergent aortic valve regurgitation, and of prevalent grade 2 aortic valve regurgitation are attributable to benfluorex. The proportion of benfluorex-attributable disease is larger than 75% for prevalent double valve disease, or for prevalent aortic valve regurgitation of any grade. This probabilistic information, derived from the available epidemiological studies, needs to be considered as part of the evidence to establish or refute a causal link between benfluorex and valvular disease for a given patient, particularly if the patient has a low grade valvular insufficiency or no morphological anomaly.

Cardiac surgery for ergotamine-induced multivalvular heart disease.

Ergotamine is used to abort or prevent vascular headache. Valvular heart disease as an adverse effect of long-term ergotamine therapy has been rarely reported in the English literature, with only a few cases published. It is hypothesized that ergot-derived agents stimulate serotonergic receptors (5-HT2B), causing proliferation of myofibroblasts, with subsequent thickening of valve leaflets and chords. This case presentation aims at increasing clinicians' awareness of this potential complication.

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.

No evidence of a detrimental effect of cabergoline therapy on cardiac valves in patients with acromegaly.

CONTEXT: The effects of cabergoline on cardiac valves have been extensively studied in Parkinson's disease and hyperprolactinemia but not in acromegaly, a condition at risk of cardiac valve abnormalities. OBJECTIVE: We examined the prevalence and incidence of heart valve disease and regurgitation in a series of patients with acromegaly treated with cabergoline, by comparison with matched patients who had never received this drug. DESIGN AND SETTING: We conducted a cross-sectional and longitudinal study in a single referral center. PATIENTS AND METHODS: Forty-two patients who had received cabergoline at a median cumulative dose of 203 mg for a median of 35 months were compared to 46 patients with acromegaly who had never received cabergoline and who were matched for age, sex, and disease duration. A subgroup of patients receiving cabergoline (n = 26) was evaluated longitudinally before and during cabergoline treatment and compared to a group not receiving cabergoline and followed during the same period (n = 26). Two-dimensional and Doppler echocardiographic findings were reviewed by two cardiologists blinded to treatment. RESULTS: Demographic and clinical features were not significantly different between the groups. Compared to acromegalic controls, patients receiving cabergoline did not have a higher prevalence or incidence of valve abnormalities. A slightly higher prevalence of aortic valve regurgitation and remodeling was found in the controls relative to the cabergoline-treated patients (P < 0.02 and P < 0.03, respectively), but this was related to the presence of aortic dilatation. CONCLUSION: Cabergoline therapy is not associated with an increased risk of cardiac valve regurgitation or remodeling in acromegalic patients at the doses used in this study.

Reversible mitral and aortic regurgitation due to pioglitazone.

OBJECTIVE: To report the occurrence of pioglitazone-induced reversible valvular regurgitant lesions. METHODS: Clinical, laboratory, and imaging data are reported on a patient with known type 2 diabetes mellitus, who was prescribed pioglitazone to achieve better glycemic control. RESULTS: We present a case report of a 50-year-old woman, in whom diabetes had been diagnosed 5 years previously, who developed severe mitral and aortic regurgitation during 5 months of treatment with pioglitazone along with clinical and laboratory indications of fluid retention. Echocardiography 5 months after discontinued use of pioglitazone showed regression of regurgitant lesions and normalization of pertinent laboratory variables. CONCLUSION: Five months of treatment with pioglitazone could potentially induce major cardiac valvular dysfunction, which was reversible in our patient. This report emphasizes the importance of carefully monitoring patients during treatment with thiazolidinediones.

[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).

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.