[Biosimilar medicines: Regulatory issues and medico-economic impacts]. / Médicaments biosimilaires : enjeux réglementaires et impacts médicoéconomiques.

The concept of biosimilar medicine was launched by 2001 and 2004 European Directives. First European marketing authorizations were delivered in 2006. They are "copies" of biologically manufactured medicines, mostly proteins. Taking into account the intrinsic variability related to the biological manufacture process, some variation of the chemical structure of the finished compound may be observed. They impact especially the glycosylation residues but not the amino-acid sequence (for proteins). For this reason, the marketing authorization application dossier has to involve, as opposed to the generic medicine procedure, the demonstration of the therapeutic equivalence in at least one clinical indication of the princeps medicine. Introduction of biosimilar medicines of monoclonal antibodies has represented a remarkable event in the domain of rheumatology, gastroenterology and dermatology with infliximab, etanercept and adalimumab biosimilars and in cancerology domains with rituximab, trastuzumab and bevacizumab biosimilars. Biosimilar medicines availability reduces the risk of drug supply rupture of princeps but their main impact is the economic one allowing cost reduction of costly princeps biological medicines. With the acquired clinical experience, the initial fears concerning switch form princeps to a biosimilar for a given patient has progressively disappeared.

Amoxicillin-clavulanic acid prescriptions at the Greater Paris University Hospitals (AP-HP).

OBJECTIVE: We aimed to document amoxicillin-clavulanic acid prescription to improve the proper use of antibiotics in hospital settings. We used three criteria: quality of medical charts, adequacy of indications, and adequacy of treatment duration. METHOD: This study was designed as a one-day point prevalence survey carried out by antibiotic lead specialists. RESULTS: We included 387 prescriptions from 32 hospitals. Immunodeficiency was recorded as a risk factor in 30% of patients. Computerized prescriptions were observed in 79% of cases. The indication was mentioned in 73% of cases and a 48/78-hour re-assessment of the antibiotic therapy was performed in 54% of cases. The antibiotic indication was primarily for pneumonia and was deemed appropriate in 75% of patients. Adult mean treatment duration was 11.1 days. Use of dual combination therapy and/or treatment duration exceeding two weeks accounted for the main reasons for an inappropriate use of antibiotics. Prescriptions recorded as having been made by senior physicians were of the shortest treatment duration (P=0.0163). CONCLUSION: Medical charts should be better filled in. Reinforcing the role of senior physicians in supervising antibiotic prescriptions is likely to result in a better control of treatment duration and ultimately in a reduced antibiotic consumption. By reinforcing the collaboration between pharmacists and antibiotic lead specialists, the improvement of computerized prescriptions at hospital level should help better detect the "at risk" prescriptions, namely those exceeding seven days or those combining antibiotics.

[Introduction of Health technology assessment at hospital]. / Mise en place de l'évaluation des technologies de santé en milieu hospitalier.

INTRODUCTION: The Medical Devices Committee (CODIMS) of the Assistance publique-Hôpitaux de Paris (AP-HP) is responsible for deciding whether innovative and costly sterile medical devices (SMD) should be adopted for the AP-HP network and for issuing recommendations on their proper use. The aim of this study was to qualify retrospectively the level of evidence of clinical studies used for the device evaluations by the CODIMS in 2012 and 2013 and to analyze the relationship between levels of evidence and decisions. MATERIAL AND METHOD: Executive summaries written in 2012 and 2013 about studied SMD was analyzed and the level of evidence of clinical studies used was qualified in high/low levels of evidence according to the scale of Sackett et al. Then, levels of evidence were correlated to decisions published by the CODIMS. RESULTS: Sixty-one files of SMD (72.1% of implantable MD) have been evaluated (225 clinical studies). Among them, only 28% of clinical studies had a high level of evidence (and 28.6% of MD at-risk) and 18% did not have any clinical studies. The CODIMS delivered an unfavourable opinion for 16 SMD: only 28 clinicals studies were available for evaluation. Among these, only 6 studies had a high level of evidence. DISCUSSION ET CONCLUSION: The amount and level of evidence of clinical studies is naturally correlated to admittance of SMD. These findings suggest that the clinical evidence used to demonstrate safety and efficacy for high-risk medical devices is based on clinical studies with poor quality data, making more difficult the evaluation of SMD in hospital. The development of a multi-criteria tool to help decision-making would improve the process of SMD evaluation by the CODIMS.

Impact of ABCC2 polymorphisms on high-dose methotrexate pharmacokinetics in patients with lymphoid malignancy.

Human multidrug resistance-related protein 2 (MRP2, encoded by ABCC2) is involved in the transport of anionic drugs such as methotrexate (MTX). We prospectively investigated the influence of four common ABCC2 genetic variants (rs717620, rs2273697, rs8187694 and rs8187710) on MTX pharmacokinetics parameters. MTX concentrations were monitored in 50 patients with lymphoid malignancy (27 males; mean age: 53±17 years) receiving high-dose MTX (5.13±1.88 g m(-)(2) in a 4-h perfusion). The population pharmacokinetics modelling showed that ABCC2 -24T allele (rs717620) had a combined influence on both MTX elimination and distribution. The MTX clearance and distribution volume were significantly higher in carriers of at least one copy of the -24T allele as compared with noncarriers: 8.6±2.2 vs 6.7± 2.5 l h(-1), P<0.01 and 30.7±7.7 vs 22.1±8.8 l, P<0.001, respectively. Consequently, -24T allele carriers were more prone to reach MTX nontoxic levels, 48 h after administration.

Changes in enoxaparin pharmacokinetics during pregnancy and implications for antithrombotic therapeutic strategy.

Enoxaparin is frequently prescribed for pregnant women who are at high risk for thromboembolic complications. We conducted a population pharmacokinetics study with 75 pregnant women and 38 nonpregnant women as controls to evaluate enoxaparin pharmacokinetics during pregnancy and the postpartum period. Clearance of the drug was higher in the pregnant women throughout pregnancy when compared with nonpregnant women (0.78 +/- 0.03 l/h vs. 0.52 +/- 0.03 l/h, respectively P < 0.001) with the stage of the pregnancy having no influence. The volume of distribution was influenced by stage of the pregnancy, characterized by a two-step increase, with an initial rise paralleling the woman's increase in body weight during the first two trimesters, followed by an additional increase of 41% during the last 2 months of pregnancy, independent of changes in weight. Using enoxaparin pharmacokinetic parameters to simulate anti-Xa time profiles, we observed that the maintenance of the same doses throughout pregnancy resulted in a progressive reduction in mean and peak anti-Xa activities. We recommend the administration of doses normalized for body weight changes so as to counteract enoxaparin pharmacokinetic changes that accompany various stages of pregnancy.

[New insights and perspectives in the management of dyslipidemia]. / Avancées récentes et perspectives dans le traitement des dyslipidémies athérogènes.

PURPOSE: Recent end point trials of lipid-lowering drugs have shown that patients at very high-risk for coronary disease benefit from treatments that lowers low density lipoprotein cholesterol (LDL cholesterol) plasma levels< or =70 mg/dl and that patients with at least 2 risk factors benefit from LDL cholesterol levels< or =100 mg/dl. Epidemiologic studies have shown that the concentration of high density lipoprotein cholesterol (HDL cholesterol) is a strong, independent, inverse predictor of coronary disease risk. Innovative pharmacological approaches to raise low HDL cholesterol levels are currently of considerable interest, especially for patients with type 2 diabetes or metabolic syndrome. RESULTS: Rosuvastatin has shown superior efficacy in lowering LDL cholesterol, although evidence of clinical benefit is actually lacking. Ezetimibe is a lipid-lowering drug that inhibits absorption of dietary and biliary cholesterol. Its co-administration with statin has given very interesting results. Niacin is the most effective of currently available options for raising HDL cholesterol, although tolerability can be an issue, with serious side effects such as loss of glucose control and liver toxicity. Flushing may occur in 80% of treated patients. Two CETP inhibitors have shown therapeutical efficacy to raise HDL cholesterol, but clinical benefit remains uncertain.

Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases.

OBJECTIVE: The antimalarial agents chloroquine (CQ) and hydroxychloroquine (HCQ) are used in long-term treatment of connective tissue diseases (CTDs). A high incidence of heart conduction disorders, including bundle-branch block and incomplete or complete atrioventricular block, has been observed among patients treated with CQ. Since no data were available for HCQ, we studied electrocardiograms (ECGs) in 85 unselected patients with CTD treated with HCQ as the sole antimalarial. METHODS: Eighty-five unselected out-patients treated with HCQ for a minimum of 1 yr, and without established cardiac diseases had standard 12-lead ECGs. RESULTS: Two incomplete right bundle-branch blocks and one left bundle-branch block were observed. No atrioventricular block was observed. The mean PR interval was 137 +/- 20 ms (range 99-188). The mean QTc interval was 410 ms (range 349-464). The mean heart rate was 73 beats/min (range 53-102). CONCLUSION: PR interval, QTc interval and heart rate were not different from normal values. The rate of heart conduction disorders was similar to what is expected in the general population, and contrasted with prior results in CQ-treated patients. Our results add further evidence on the safety of HCQ compared with CQ.

[Prevention of major ischemic events in lower limb arterial disease: does aspirin play a role?]. / Prévention des évènements ischémiques majeurs au cours de l'artériopathie oblitérante des membres inférieurs: l'aspirine a-t-elle un rôle?

OBJECTIVE: To determine the effect of aspirin among patients with lower limb occlusive arterial disease. DESIGN: Meta-analysis of trials issuing from a collaborative meta-analysis of randomized trials of anti-platelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Five trials were identified as comparing aspirin (with or without dipyridamole) to placebo, in 1 029 patients with lower limb occlusive arterial disease. There was no new publication found comparing aspirin and placebo in lower limb occlusive arterial disease. MAIN OUTCOME MEASURE: As in the main meta-analysis, "serious vascular event": non fatal myocardial infarction, non fatal stroke or vascular death. RESULTS: Among these 1 029 patients, allocation to aspirin did not reduce the outcome of serious vascular event, nor of any of the individual events. This result, as opposed to the enhancement of 23% +/- 8% announced in the main meta-analysis, clearly demonstrate that the beneficial effect cannot be attributable to aspirin. DISCUSSION: In the collaborative meta-analysis, aspirin was the most widely used product (75% of the trials) and it showed its beneficial effect when administered at doses ranging from 75 to 150 mg/day, as compared to placebo. Among the other anti-platelet treatments analyzed, clopidogrel was the only product for which large scale randomized evidence versus aspirin was available. Various national health institutions, in the United States as well as in Europe, show a major concern regarding the use of anti-platelet treatments, in peripheral arterial occlusive disease as well as in other manifestations of cardiovascular disease. Their guidelines take of course the patient's health into account but the economical aspect of this prevention is increasingly hard to circumvent. Based on the results of the collaborative meta-analysis, these guidelines all recommend a lifetime use of low doses of aspirin, reserving clopidogrel for patients intolerant to aspirin, mainly because they do not consider the additional benefit recognized with clopidogrel as important enough to counterbalance the cost of the treatment. While aspirin as a first choice antiplatelet therapy cannot be discussed in coronary disease, after a myocardial infarction, or in cerebrovascular disease, its use in lower limb occlusive arterial disease does not enable a reduction in morbi-mortality. From an economical point of view, the use of a cheap but inefficient preventive treatment could also lead to an increased cost for curing the complications expected with an uncontrolled widely spread disease as chronic lower limb ischemia.

Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies.

Cardiovascular events (CVEs) are the leading cause of death in chronic hemodialysis patients. Results of trials in non-end-stage renal disease (ESRD) patients cannot be extrapolated to patients with ESRD. It is critical to test cardiovascular therapies in these high-risk patients who are usually excluded from major cardiovascular trials. The study objective was to evaluate the effect of fosinopril on CVEs in patients with ESRD. Eligible patients were randomized to fosinopril 5 mg titrated to 20 mg daily (n=196) or placebo (n=201) plus conventional therapy for 24 months. The primary end point was combined fatal and nonfatal first major CVEs (cardiovascular death, resuscitated death, nonfatal stroke, heart failure, myocardial infarction, or revascularization). No significant benefit for fosinopril was observed in the intent to treat analysis (n=397) after adjusting for independent predictors of CVEs (RR=0.93, 95% confidence interval (CI) 0.68-1.26, P=0.35). The per protocol secondary supportive analysis (n=380) found a trend towards benefit for fosinopril (adjusted RR=0.79 (95% CI 0.59-1.1, P=0.099)). In the patients who were hypertensive at baseline, systolic and diastolic blood pressures were significantly decreased in the fosinopril as compared to the placebo group. After adjustment for risk factors, trends were observed suggesting fosinopril may be associated with a lower risk of CVEs. These trends may have become statistically significant had the sample size been larger, and these findings warrant further study.

Drug eluting stents: an updated meta-analysis of randomised controlled trials.

OBJECTIVE: To confirm the overall benefit of drug eluting stents (DES), to evaluate the effect of different DES, and to assess the global safety of DES compared with bare stents through a meta-analysis of randomised controlled trials. METHODS: Randomised controlled trials comparing sirolimus and derivates or paclitaxel and derivates eluting stents versus bare stents. Binary restenosis and major adverse cardiac events (MACE) were chosen as primary end points. Death, Q wave myocardial infarction (MI), and stent thrombosis up to 12 months' follow up were also analysed. RESULTS: MACE overall occurrence was highly reduced with DES from 19.9% to 10.1% (odds ratio (OR) 0.46, 95% confidence interval (CI) 0.41 to 0.52, p < 0.001). A significant heterogeneity (p < 0.001) was found between subgroups according to the drug: MACE OR was 0.28 (95% CI 0.22 to 0.35) in the sirolimus subgroup and 0.62 (95% CI 0.53 to 0.73) in the paclitaxel subgroup. Restenosis was also highly reduced from 31.7% with bare stents to 10.5% with DES (OR 0.25, 95% CI 0.22 to 0.29, p < 0.001) with a similar heterogeneity between subgroups. Mortality, Q wave MI, and stent thrombosis were not significantly different between DES and control group, whereas Q wave MI and stent thrombosis tended to be more frequent with paclitaxel. CONCLUSION: This meta-analysis confirms the overall benefit of DES on restenosis and MACE with significant heterogeneity between drugs, suggesting higher efficacy of sirolimus eluting stents. Additional data with longer follow up and in high risk populations are needed to clarify issues on stent thrombosis.

Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice.

BACKGROUND: Serotonin (5-hydroxytryptamine; 5-HT) overproduction is responsible for cardiac valvular disease in patients with carcinoid tumors. Reduced 5-HT inactivation is one proposed mechanism of the valvulopathy observed in individuals treated with the appetite suppressants fenfluramine and phentermine. One key protein limiting systemic availability of 5-HT is the 5-HT transporter (5-HTT) expressed by platelets and pulmonary vascular cells; 5-HTT is responsible for 5-HT uptake and subsequent inactivation of the amine passing through the lung. Here we investigated whether 5-HTT-deficient (5-HTT-KO) mice developed structural and/or functional cardiac abnormalities and valvulopathy. METHODS AND RESULTS: Cardiac endothelial cells expressed large amounts of 5-HTT in wild-type mice. 5-HTT deficiency appeared to be associated with marked interstitial, perivascular, and valvular fibrosis as evidenced by staining of cardiac collagen in 5-HTT-KO mice. Histological analysis provided evidence for valvulopathy characterized by valvular hyperplasia and prominent fibrosis at the attachment site and base of the leaflets. Echocardiography revealed an increase in left ventricular lumen diameter and a decrease in left ventricular diameter fractional shortening. Although 5-HT1B receptors mediated the 5-HT-induced collagen secretion by human cardiac myofibroblasts, the contribution of this receptor type to valvulopathy was ruled out because double-KO mice deficient in both 5-HTT and 5-HT1B receptors showed the same cardiac alterations as 5-HTT-KO mice. CONCLUSIONS: The present results establish a link between 5-HTT and the development of cardiac fibrosis and valvulopathy in vivo. 5-HTT-KO mice represent an especially relevant model for studying the mechanisms by which 5-HT induces valvulopathy.

Revascularization strategies in acute myocardial infarction: a meta-analysis.

OBJECTIVE: Many treatments and procedures have been tested to reduce complications after myocardial infarction. Our objective was to assess in this clinical situation the best evidence-based medicine revascularization strategy including the most recently developed interventions such as thrombolysis, angioplasty, stent implantation and glycoprotein IIb/IIIa (GpIIb/IIIa) antagonists. MATERIAL AND METHODS: We performed the meta-analyses of randomized controlled trials by testing the addition of a stent to primary angioplasty, the addition of GpIIb/IIIa antagonists to primary angioplasty, the addition of GpIIb/IIa antagonists to primary angioplasty + stent and finally addition of GpIIb/IIIa antagonists to thrombolytics. The primary outcome was the combined endpoint of death or myocardial infarction or urgent revascularization at 1 month. RESULTS: The combined endpoint was significantly reduced by 31% (95% CI: 11% - 47%) at 30 days when stent was added to primary angioplasty. GpIIb/IIIa blockers provided an additional benefit by reducing the combined criteria by 50% (95% CI: 27% - 66%) in patients who underwent primary angioplasty, and by 42% (95% CI: 16% - 60%) when associated with angioplasty and stent implantation. Administration of GpIIb/IIIa in addition to thrombolytics, aspirin and heparin was associated with a significant reduction in the combined criteria by 17% (95% CI: 10% - 23%) and a significant excess of major bleeding by 69% (95% CI: 38% - 109%). However, the risk/benefit ratio indicates that patients with this association should be treated with the corresponding doses used in these trials. CONCLUSION: In acute myocardial infarction, stent implantation provides therapeutic benefit when added to primary angioplasty. The addition of GpIIb/IIIa blockers appears to provide further benefit if bleeding complications are minimized.

[Anticoagulant treatment in atrial fibrillation]. / Traitement anticoagulant dans la fibrillation auriculaire.

Atrial fibrillation is the most frequent arrhythmia in the general population, and it increases with age. The prevention of thromboembolic events, the most important complication of the disease, is a major problem. Antivitamin K is to date the most efficient therapeutic class for the prevention of these events. Although they allow a decrease in stroke by at least 50%, they are associated with an increased haemorrhagic risk (annual incidence ranging from 7% to 22%). This risk makes oral anticoagulant treatment underused in high risk patients, particularly in the elderly populations. Optimisation of the management of patients with atrial fibrillation should be based on an individual evaluation of the thromboembolic and haemorrhagic risks. Several stratifications have been performed to identify the risk predictors of thromboembolic and haemorrhagic events in patients with atrial fibrillation, allowing an evaluation of the benefit/risk ratio of antithrombotic treatments and using indices such as NNT (number of patients needed to treat to avoid an event) and NNH (number of patients needed to harm with haemorrhagic event). The available data do not allow, however, to evaluate precisely the individual level of haemorrhagic risk.

Transfer for primary angioplasty versus immediate thrombolysis in acute myocardial infarction: a meta-analysis.

BACKGROUND: The benefit of primary percutaneous coronary intervention (PCI) over thrombolysis has been clearly demonstrated in acute myocardial infarction (AMI). However, the best therapeutic strategy for a patient with AMI presenting to acute care services without catheterization facilities remains under debate. Our objective was to gather all available information from clinical trials comparing transfer of patients experiencing AMI for angioplasty versus immediate thrombolysis. METHODS AND RESULTS: We performed a meta-analysis of all data available from published randomized trials and from presentations in scientific sessions of major cardiology congresses comparing the 2 strategies. The primary end point was the combined criteria (CC) of death/reinfarction/stroke as defined in each trial. Relative risk (RR) evaluated the treatment effect. We identified 6 clinical trials including 3750 patients. Transfer time was always <3 hours. The CC was significantly reduced by 42% (95% confidence interval [CI] 29% to 53%, P<0.001) in the group transferred for primary PCI compared with the group receiving on-site thrombolysis. When CC parameters were considered separately, reinfarction was significantly reduced by 68% (95% CI, 34% to 84%; P<0.001) and stroke by 56% (95% CI, -15% to 77%; P=0.015). There was a trend toward reduction in all-cause mortality of 19% (95% CI, -3% to 36%; P=0.08) with transfer for PCI. CONCLUSIONS: Even when transfer to an angioplasty center is necessary, primary PCI remains superior to immediate thrombolysis. Organization of ambulance systems, prehospital management, and adequate PCI capacity appear now to be the key issues in providing reperfusion therapy for AMI.

Sensitive determination of tenofovir in human plasma samples using reversed-phase liquid chromatography.

A new high-performance liquid chromatography assay was developed for the determination of tenofovir, a nucleotide analogue, in plasma. A solid-liquid extraction procedure was coupled with a reversed-phase HPLC system. The system requires a mobile phase containing Na(2)HPO(4) buffer, tetrabutylammonium hydrogen sulfate and acetonitrile for different elution through a C(18) column with UV detection. The method proved to be accurate, precise and linear between 10 and 4000 ng/ml. The method was applied to determine trough levels of tenofovir in 11 HIV-infected patients with virologic failure under multiple antiretroviral therapy. This method was also successfully applied to a pharmacokinetic study in an HIV infected patient with renal failure.

Pharmacodynamics and pharmacokinetics of single nasal (5 mg and 10 mg) and oral (50 mg) doses of ephedrine in healthy subjects.

OBJECTIVE: To determine the cardiovascular, subjective effects and potential of abuse liability of single dose (-) ephedrine (E) administered orally (50 mg) or intranasally (10 mg and 5 mg). METHODS: Sixteen healthy Caucasian men with no history of drug/alcohol/nicotine abuse or dependence received intranasal single doses of E 5 mg, 10 mg and oral doses of 50 mg and placebo in a double-blind, double-dummy, crossover study. Dependent measures included assessment of subjective feelings by Addiction Research Centre Inventory (ARCI). Profile of Mood States (POMS). visual analogue scales (VAS); "drug liking", "any drug effect", subjective quality of sleep and blood pressure and heart rate. Plasma E concentrations were also determined. RESULTS: (-) E increased supine systolic, diastolic blood pressure (P < 0.01). Changes in supine systolic blood pressure (areas under the 8 h of the experimental sessions) were -59 +/- 47 mmHgh with placebo, -59 +/- 57 mmHg-h with E5 mg by the nasal route, -18 +/- 48 mmHg x h with E 10 mg by the nasal route and 13 +/- 58 mmHgh with E 50 mg by the oral route (P<0.001). (-) E-induced orthostatic hypotension (P < 0.01) (maximal systolic blood pressure drop: E 50 mg 14 +/- 10 mmHg, P < 0.03; E 10 mg 11 +/- 6 mmHg, P = 0.08 compared with placebo) and resulted in decreased tiredness (placebo -2 +/- 39 mm x h, E 5 mg -17 +/- 39 mm x h, E 10 mg -30 +/- 42 mm x h, E 50 mg -24 +/- 35 mm x h; P < 0.03). E did not modify ARCI subscales--in particular the "amphetamine" subscale--but showed a tendency for drug liking (P= 0.09). On the "any drug effect" questionnaire, subjects could identify drug effect (P=0.007). Maximal plasma E concentration (Cmax) and areas under the curves for up to 8 h were proportional to the doses. Elimination half-life was approximately 6 h. A clockwise hysteresis was observed for systolic blood pressure in all but one subject with E 50 mg by the oral route. CONCLUSION: E even at low doses and by the nasal route can decrease tiredness in healthy persons; this is accompanied by a substantial increase in blood pressure and orthostatic hypotension exposing individuals in case of intensive physical exercise to cardiovascular risks. No clear evidence of abuse liability in healthy drug naive subjects was observed.

Anticoagulant (fluindione)-aspirin combination in patients with high-risk atrial fibrillation. A randomized trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontané; FFAACS).

BACKGROUND: A combination of low-dose aspirin with anticoagulants may provide better protection against thromboembolic events compared to anticoagulants alone in high-risk patients with atrial fibrillation. OBJECTIVE: Evaluation of the preventive efficacy against nonfatal thromboembolic events and vascular deaths of the combination of the oral anticoagulant fluindione and aspirin (100 mg) in patients with high-risk atrial fibrillation. METHODS: A multicenter, placebo-controlled, double-blind, randomized trial was conducted at 49 investigating centers in France. Atrial fibrillation patients with a previous thromboembolic event or older than 65 years and with either a history of hypertension, a recent episode of heart failure or decreased left ventricular function were included in the study. Patients were treated with fluindione plus placebo (i.e. anticoagulant alone) or fluindione plus aspirin (i.e. combination therapy), with an international normalized ratio target of between 2 and 2.6. The combined primary endpoint was stroke (ischemic or hemorrhagic), myocardial infarction, systemic arterial emboli or vascular death. The secondary endpoint was the incidence of hemorrhagic complications. RESULTS: The 157 participants (average age 74 years; 52% women; 42% with paroxysmal atrial fibrillation) were followed for an average of 0.84 years. Three nonfatal thromboembolic events were observed (1 in the anticoagulation group, 2 in the combination group) and 6 patients died (3 in the anticoagulation group, 3 in the combination group), none of them from a thromboembolic complication. However, 3 deaths were secondary to severe hemorrhagic complications (1 in the anticoagulation group, 2 in the combination group). Nonfatal hemorrhagic complications occurred more often in the combination group (n = 10, 13.1%) compared to the anticoagulation group (n = 1, 1.2%) (p = 0.003). CONCLUSION: The combination of aspirin with anticoagulant is associated with increased bleeding in elderly atrial fibrillation patients. The effect on thromboembolism and the overall balance of benefit to risk could not be accurately assessed in this study due to the limited number of ischemic events.

[Bisprolol in heart failure: efficacy and costs in a French setting according to CIBIS II]. / Bisoprolol dans l'insuffisance cardiaque: efficacité et coûts dans le cadre français selon CIBIS II.

After a significant mortality benefit with bisoprolol in heart failure was demonstrated in CIBIS-II, an economic evaluation has been performed in cost-effectiveness terms. Average direct costs per patient were based on clinical data from 231 French patients, and measured in the perspective of the French National Health Insurance, effectiveness being expressed in terms of life days gained per patient. The extra cost of bisoprolol treatment and follow-up (averaging FF 1300 per 1.3 years) is outweighed by the reduction in hospitalization costs (representing a saving of FF 10,500 per patient) and other medication costs. Finally, bisoprolol therapy induces benefits in terms of both cost and survival: on average FF 9500 and 11 life days per patient. Sensitivity analyses confirm these results.