From evidence-based medicine to personalized medicine, with particular emphasis on drug-safety monitoring.

Nowadays, guidelines are derived from the findings of randomized controlled therapeutic trials. However, an overall significant P value does not exclude that some patients may be harmed by or will not respond to the therapeutic agent being studied. Trials in patients with a low risk of events and/or a limited chance of providing significant differences in therapeutic effects require a large patient population to demonstrate a beneficial effect. Composite efficacy endpoints are often employed to obviate the need for a large patient population when low rates of events or limited therapeutic efficacy are anticipated. Results of randomized controlled therapeutic trials are commonly expressed in terms of relative risk reduction, whereas absolute risk reduction allows the calculation of the "number needed to treat" to prevent an adverse outcome. The number needed to treat is a far more clinically relevant variable than relative risk reduction. The clinician's mission is to match treatment to patient with the goal of achieving optimal therapeutic response. Drug-safety monitoring is also of major importance to avoid exposing patients to irreversible adverse effects. Unfortunately, drug-safety monitoring is often overlooked in routine clinical practice. Finally, the lack of long-term therapeutic data (>5-10 years) is an unsolved dilemma, as most trials are limited to a duration of a few months or years.

Adaptation and validation of an adverse drug reaction preventability score for bleeding due to vitamin K antagonists.

Although drug therapy is inherently associated with the risk of adverse drug reactions (ADRs), some of these events are preventable. The estimated proportion of preventable ADRs varies from one study or clinical context to another. Bleeding caused by antithrombotic agents (and particularly vitamin K antagonists, VKAs) constitutes one of the most frequent causes of ADR-related hospitalization.Hence, the objective of the present study was to adapt and validate an ADR preventability score for bleeding due to VKAs and evaluate the preventability of bleeding in 906 consecutive hospitalized, VKA-treated adult patients with a risk of major bleeding (defined as an international normalized ratio ≥5) over a 2-year period. A specific preventability scale for VKA-associated bleeding was developed by adapting a published tool.Overall, 241 of the 906 patients in the study experienced at least 1 VKA-associated bleeding event. The scale's reliability was tested by 2 different evaluators. The inter-rater reliability (evaluated by calculation of Cohen's kappa) ranged from "good" to "excellent." Lastly, the validated scale was used to assess the preventability of the VKA-associated bleeding. We estimated that bleeding was preventable or potentially preventable in 109 of the 241 affected patients (45.2%).We have developed a useful, reliable tool for evaluating the preventability of VKA-associated bleeding. Application of the scale in a prospective study revealed that a high proportion of VKA-associated bleeding events in hospitalized, at-risk adult patients were preventable or potentially preventable.

Risk Factors for Bleeding in Hospitalized at Risk Patients With an INR of 5 or More Treated With Vitamin K Antagonists.

Various predictive scores for vitamin K antagonist (VKA)-related bleeding have been developed and validated in outpatients and in patients treated for specific indications (when VKAs are used under optimal therapeutic conditions). However, there are few published data on the evaluation of bleeding risk factors in hospitalized, at-risk patients (with a high international normalized ratio [INR]) treated with VKAs. The objective of the present study was to identify the most relevant bleeding risk factors in 906 VKA-treated patients with an INR of 5 or more hospitalized in a French university medical center.Over a 2-year period, we screened all consecutive VKA-treated adults with a risk of major bleeding (defined as an INR ≥ 5 on admission). Demographic and clinical characteristics, medications, and bleeding characteristics were recorded prospectively.The overall incidence of bleeding was 26.6% (serious bleeding: 21.4%; fatal bleeding: 5.4%). An INR ≥ 8.5, a history of recent digestive tract lesions, trauma in the preceding 2 weeks, and known noncompliance were independent risk factors for bleeding and serious bleeding.Our present findings emphasize that VKAs should not be prescribed to patients with a high risk of bleeding (noncompliant patients and those with recent trauma or recent gastrointestinal lesions). It is essential to monitor the INR on a frequent basis and adjust oral anticoagulant treatment appropriately.

Sub-aortic obstruction of left ventricular outflow tract secondary to benfluorex-induced endocardial fibrosis.

Patients exposed to benfluorex have an increased risk of restrictive organic valvular heart disease. Aortic and mitral regurgitations caused by fibrotic valve disease are the most common features observed in exposure to fenfluramine derivatives in general and benfluorex in particular. We report here, for the first time to our knowledge, a well-documented case in which obstructive sub-aortic endocardium fibrosis within the left ventricular outflow tract is related with exposure to a drug that modifies the metabolism of serotonin. It now remains to be established whether extensive fibrosis of the myocardium in addition to well-documented valvular fibrosis may develop in patients exposed to amphetamine-derived drugs affecting the serotonin system.

Two cases of fatal encephalopathy related to Ifosfamide: an adverse role of aprepitant?

Ifosfamide is used in the treatment of sarcomas and other tumors. It sometimes provokes encephalopathy, which is a serious complication even if it is usually reversible within 48-72 h after drug cessation. Ifosfamide is required to be activated by hepatic cytochrome P450 (CYP), especially the 3A4 subtype, leading to 4-hydroxy-ifosfamide. Ifosfamide is also converted by CYP3A4 to inactive but neurotoxic metabolites. Aprepitant is a neurokinin-1 receptor antagonist that is a potent antiemetic used in combination with 5-HT3 antagonists and corticosteroids. Aprepitant has an inhibitory effect, as well as a possible inductive effect, on CYP3A4. Since ifosfamide and aprepitant are both substrates of CYP3A4, a pharmacokinetic interaction could result in secondary effects such as the potentialization of neurological side effects. In this report, we describe 2 cases of fatal encephalopathy in patients who have received both ifosfamide and aprepitant, and we discuss the mechanisms that could be involved. Our observations draw attention to the fact that aprepitant must be avoided, or at least used with caution, in patients who are receiving ifosfamide due to the risk of severe neurological side effects.

Valvular heart disease associated with long-term treatment by methysergide: a case report.

This case report concerns a woman treated continuously since at least 10 years by methysergide for cluster headache. The echocardiographic and histological features of the severe valve fibrosis presented by this patient are very similar to those described with 5 HT(2B) receptors agonistic drugs.

Ulceration of the oral mucosa following direct contact with ferrous sulfate in elderly patients: a case report and a review of the French National Pharmacovigilance Database.

OBJECTIVE: To report a series of cases of ulceration of the oral mucosa linked to direct contact with ferrous sulfate in elderly patients. CASE SUMMARY: The first case report concerns the occurrence of widespread oral ulceration in an 87-year-old woman with Alzheimer's disease. The ulceration extended from the side of the tongue to the floor of the mouth. No clear explanation was found and various local treatments were ineffective. Once it was realized that the ferrous sulfate tablets (given as an iron supplement) were crushed prior to administration (due to the patient's deglutition disorder), withdrawal of this treatment led to rapid resolution of the ulceration. Nine other cases of oral ulcerations associated with ferrous sulfate were identified in the French National Pharmacovigilance Database. All but one of the patients were over 80 years of age and the youngest patient (a 54-year-old) had dysphagia associated with facial paralysis. DISCUSSION: Only two other reports of oral ulceration due to ferrous sulfate have been published to date. Mucosal toxicity of ferrous sulfate (which is probably related to oxidative stress) has previously been reported for the hypopharynx, the esophageal lumen, and (after inhalation of a tablet) the tracheobronchial tree. CONCLUSION: The mucosal toxicity of ferrous sulfate must be taken into account when deglutition disorders are present (as in elderly patients) and appropriate pharmaceutical formulations (such as syrups) should be administered to at-risk patients. The use of iron salts other than ferrous sulfate could be considered.

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.

The end-of-treatment ribavirin concentration predicts hepatitis C virus relapse.

BACKGROUND: The optimization of combination therapy with ribavirin (RBV) and pegylated interferon alpha has substantially improved sustained virologic response (SVR) rates and lowered virologic relapse rates in patients infected with hepatitis C virus (HCV). In this study, we performed an analysis of the relationship between the end-of-treatment plasma RBV concentration and virologic relapse. METHODS: Thirty-four patients with HCV treated with pegylated interferon/RBV and with an end-of-treatment response were assayed for plasma RBV concentration using liquid chromatography assay coupled to tandem mass-spectrometric detection on the last day of the treatment. Clinical data and the concentration of RBV were compared between patients classified as either relapsers or nonrelapsers. RESULTS: Eleven patients (32.4%) relapsed and 23 patients (67.6%) achieved an SVR. The mean plasma RBV concentration on the last day of treatment was 1380 ± 312 ng/mL for relapsers and 2278 ± 569 ng/mL for SVR patients (P < 0.0001). A receiver operating characteristic analysis showed that a threshold of 1960 ng/mL was associated with the greatest sensitivity and specificity (100% and 83%, respectively, with an area under the curve of 0.94; P < 0.0001) for discriminating between patients who relapsed and those who did not. A univariate logistic regression analysis indicated that a plasma RBV concentration of <1960 ng/mL at the end of the treatment was strongly associated with relapse (odds ratio, 55; 95% confidence interval, 7.24-∞; P = 0.0001) independently of age, body weight, RBV dose, baseline viral load, the interleukin-28B genotype, and response to previous courses of treatment. CONCLUSIONS: Our study results highlight the relevance of measuring plasma RBV concentrations during and at the end of HCV treatment, with a view to avoiding virologic relapse.

Drug-induced valvular heart disease: an update.

Numerous reports have shown an unquestionable association between fibrotic valve disease and the following drugs: ergot alkaloids (such as methysergide and ergotamine), ergot-derived dopaminergic agonists (such as pergolide and cabergoline) and drugs metabolized into norfenfluramine (such as fenfluramine, dexfenfluramine and benfluorex). This review focuses on different aspects of drug-induced valvular heart disease: historical background; echocardiographic features; different drugs recognized as being responsible for valvular heart disease; and pathophysiology.

Extrapyramidal adverse drug reactions associated with trimetazidine: a series of 21 cases.

Over the last few years, a number of cases of extrapyramidal disorders associated with trimetazidine (TMZ) use has been reported. Here, we report on a series of 21 cases. All but one of the patients (mean age 74) had been taking TMZ for several years. The indication for prescription of TMZ could not be identified in seven cases. The TMZ-associated adverse drug reactions were typical parkinsonism (akinesia and/or rigidity and/or rest tremor) in 17 cases, gait disorders in three cases (one with orthostatic tremor), and restless leg syndrome in one case. Discontinuation of TMZ led to complete disappearance of the symptoms in 16 cases and a significant reduction in the five other patients. TMZ has the same piperazine core as the dopamine antagonists flunarizine and cinnarizine (both of which have been reported to induce extrapyramidal symptoms). Hence, striatal D2 receptor blockade could result in the onset or the worsening of extrapyramidal disorders. Even though this adverse drug reaction is now listed in TMZ's Summary of Product Characteristics (because of the initial reports), the risk remains poorly known by clinicians. There is a need to raise awareness of this phenomenon and to reassess TMZ 's risk-benefit ration, especially in the elderly.

[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).

[Sarcoïdosis and anti-TNF: a paradoxical class effect? Analysis of the French Pharmacovigilance system database and literature review]. / Sarcoïdose et anti-TNF : un effet paradoxal de classe? Analyse des cas de la base française de Pharmacovigilance et revue de la littérature.

OBJECTIVES: To identify and characterize the observations of sarcoidosis occurring during anti-TNF blockade collected in the French Pharmacovigilance system database and reported in the literature. RESULTS: Seven cases were reported in the French Pharmacovigilance system database and 39 cases (37 original) have been reported internationally. Monoclonal antibodies (infliximab and adalimumab) and fusion protein (etanercept) are equally involved. Sarcoidosis have been confirmed histologically and occurred predominantly in the rheumatoid arthritis (22) and spondylarthropathy (16). CONCLUSION: The lack of protopathic bias suggests that these paradoxical sarcoidosis occurring during treatment with anti-TNF are a class-effect, as with psoriasis, uveitis, and IBD reported under similar conditions. Their pathogenesis remains unclear.

High circulating levels of large splice variants of tenascin-C is associated with mortality and cardiovascular disease in chronic kidney disease patients.

OBJECTIVES: Tenascin-C (TN-C) is an adhesion-modulating extracellular matrix glycoprotein which is overexpressed in various organs under disease conditions (infection and inflammation). In patients with heart disease, plasma TN-C levels have been shown to be predictive of cardiac remodeling. Chronic kidney disease (CKD) is associated with a state of chronic inflammation and high cardiovascular morbidity and mortality. METHODS: In a prospective observational study, we examined the relationship between plasma concentration of large splice variants of TN-C (cTN-C) and cardiovascular outcomes, we studied a cohort of 94 prevalent CKD patients (mean±SD age: 68±13; 31% at CKD stages 2-3, 31% at stages 4-5, 38% at stage 5D). RESULTS: Plasma cTN-C levels were elevated in this population and tended to rise as CKD progressed, with the increase becoming statistically significant at CKD stage 4-5 and 5D. Multivariate linear regression analysis indicated that CKD stage (p=0.04), IL-6 (p=0.02) and albumin (p=0.02) were independently associated with plasma cTN-C levels. During follow-up (mean duration: 969±405 days), 32 patients died (19 from CV events, 7 from infectious diseases and 6 from other causes). In a crude analysis, higher plasma cTN-C levels predicted overall and CV mortality (p=0.007 and p=0.003, respectively) and were associated with higher occurrence of CV events. Cox analyses confirmed that elevated plasma cTN-C levels were independently associated with cardiovascular events, cardiovascular and overall mortality. CONCLUSION: Our findings suggest, for the first time, that plasma cTN-C levels are independently associated with cardiovascular outcomes in CKD patients. Further studies are needed in order to confirm the above observations and better understand TN-C's role in cardiovascular remodeling in CKD.