Guy Simoneau

Elderly Medical Patients Treated with Prophylactic Dosages of Enoxaparin Influence of Renal Function on Anti-Xa Activity Level

BackgroundThe safety and optimal use of prophylactic treatment with low-molecular-weight heparins in elderly patients with impaired renal function remain undefined.MethodsThe primary aim of this study was to analyse, in ‘real life’, the influence of renal function, as assessed by Creatinine clearance (CLcr), on the level of anti-Xa activity in medical hospitalised elderly patients receiving prophylactic dosages of enoxaparin. Consecutive hospitalised acutely ill medical patients aged ≥75 years receiving daily dosages of enoxaparin 4000IU for up to 10 days were prospectively enrolled in two centres. Peak anti-Xa activity was measured at the beginning and during the course of therapy.ResultsOne hundred and twenty-five patients (31 men, 94 women), mean age 87.5 ± 6.3 years, mean bodyweight 56.4±11.9kg and mean CLcr 39.8 ± 16.1 mL/min, were enrolled in the study. The mean maximum anti-Xa activity (day 1 to day 10) [anti-Xamaxl–l0] was 0.64 ± 0.23 IU/mL (range 0.24–1.50 IU/mL). Weak negative correlations were found between CLcr and anti-Xamax and between bodyweight and anti-Xamax. Mean anti-Xamax was slightly but significantly higher in patients with CLcr of 20–30 mL/min compared with patients with CLcr of 31–40,41–50 or 51–80 mL/min (0.72 versus 0.61, 0.61 and 0.60 IU/ mL, respectively), and in patients weighing <50kg compared with patients weighing 50–60kg or >60kg (0.74 vs 0.64 and 0.52 IU/mL, respectively). Serious bleeding occurred in five patients, but anti-Xamax values in these patients were not different to those in patients without bleeding (p = 0.77). Individual anti-Xamax at the beginning or during the course of treatment was measured in the subgroup of 58 patients in whom anti-Xa activity was measured at least once during the study. The mean anti-Xamax value was slightly but significantly higher during the course of the therapy than at the beginning of the study (0.63 ± 0.26 IU/mL vs 0.56±0.23 IU/mL, p = 0.012).ConclusionOnly CLcr <30 mL/min and bodyweight <50kg were associated with significantly higher anti-Xamax values. The clinical relevance of these increases remains questionable. No conclusions about the safety of enoxaparin in elderly medical patients can be drawn from these findings.

Effect of the Thromboxane Prostaglandin Receptor Antagonist Terutroban on Arterial Thrombogenesis after Repeated Administration in Patients Treated for the Prevention of Ischemic Stroke

Background: The antithrombotic, antiplatelet and endothelial activity of terutroban, a specific thromboxane prostaglandin receptor antagonist, was assessed in patients previously treated with aspirin for the prevention of ischemic stroke. Methods: This double-blind, parallel-group, 10-day study included 48 patients (age = 70.5 ± 9.5 years) with cerebral ischemic event and/or carotid stenosis in 4 groups: terutroban 10 mg/day (n = 13), aspirin 300 mg/day (n = 12), terutroban 10 mg/day + aspirin 300 mg/day (n = 11) or clopidogrel 75 mg/day + aspirin 300 mg/day (n = 12). The measurements included parameters from an ex vivo model of thrombosis, platelet aggregation in platelet-rich plasma and plasma biomarkers of endothelial/platelet activation. Results: Between days 0 and 10, the mean cross-sectional surface of dense thrombus significantly decreased with terutroban (58%, p = 0.001), terutroban + aspirin (63%, p = 0.005) and clopidogrel + aspirin (61%, p < 0.05). On day 10, the value for terutroban was significantly lower than that for aspirin (p < 0.01) and was comparable to the dual therapy terutroban + aspirin or clopidogrel + aspirin. Similar results were found for total thrombus surface and platelet adhesion. Platelet aggregation induced by the specific thromboxane prostaglandin receptor agonist U46619 was almost completely inhibited on day 10 in both terutroban groups but not in the others. As regards markers of endothelial/platelet activation or lesions, thrombomodulin significantly increased and plasma soluble P selectin significantly decreased by day 10 in both terutroban groups, whereas the von Willebrand factor did not change significantly. Terutroban was found to be safe and well tolerated. Conclusions: Terutroban has demonstrated an antithrombotic activity that is superior to aspirin and similar to clopidogrel + aspirin; it induces a significant in vivo reduction in endothelial/platelet activation.

Aspirin alters arterial function in patients with chronic heart failure treated with ACE inhibitors: a dose-mediated deleterious effect.

By inhibiting prostaglandin synthesis, aspirin can interfere with both arterial functional and angiotensin‐converting enzyme inhibitor (ACEI) properties and be deleterious in chronic heart failure (CHF).

D-dimer: a characteristic of the coagulation state of each patient with chronic atrial fibrillation

BACKGROUND AND OBJECTIVE It is accepted that patients with atrial fibrillation (AF) are characterised by increased levels of plasmatic D-dimers, with a wide inter-individual variability depending on the patients and therapeutic characteristics, but it has not been established if this level was predictive of the risk of arterial thromboembolic event. In order to answer such a question, it has to be established if the D-dimer level in a given patient is characteristic of such a patient (stable over time) if also fluctuating with time (and useless to characterise the patient). METHODS AND RESULTS One hundred thirty clinically stable patients with chronic AF were recruited (anticoagulant: group 1, antiaggregant aspirin: group 2, no antithrombotic: group 3). During the follow-up of patients without clinical events (n=63), it is notable that in patients with D-dimer levels <500 ng/ml, these remained <1000 ng/ml, in patients with levels between 500 and 1000 ng/ml, these did not reach 1590 ng/ml, and in those with D-dimers >1000 ng/ml, the levels remained relatively stable. Mean age and D-dimer levels were lower in group 1 (74.4 years and 509.1 ng/ml, respectively) than in group 2 (82.4 years, p=0.0003 and 1015.7 ng/ml, p<0.0001, respectively) and in group 3 (79.3 years and 1289.3 ng/ml, p<0.0001, respectively). The effect of the antithrombotic therapy was independent of the age of patients (p=0.017). CONCLUSION D-dimer levels in patients with chronic AF remain in the same range over time. They are lower on anticoagulant therapy than on antiaggregant or no antithrombotic therapy, irrespective of age. Thus, D-dimers appear to be a useful parameter for assessing the degree of hypercoagulability of patients whatever their age.

Methadone dose in heroin‐dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity

AIMS Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients. METHODS Eighty-one stable patients (60 men and 21 women, 43.7 ± 8.1 years old, 63.1 ± 50.9 mg day(-1) methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes. RESULTS Methadone maintenance dose was correlated to the highest dose ever used (r(2) = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27-18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01-2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day(-1) in never-addict patients, P = 0.005) and ethnicity (Asian > Caucasian > African, P = 0.04) were independently associated with high-dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (Spearman rank correlation coefficient [rs ] = 0.21, P = 0.06) but not with highest dose ever used (rs = 0.15, P = 0.18) or dose-normalized R,S-methadone trough concentrations (rs = -0.05, P = 0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose. CONCLUSIONS Methadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients.

Protection against aspirin-induced gastric lesions by lansoprazole: Simultaneous evaluation of functional and morphologic responses

The protective effect of lansoprazole, a new proton pump inhibitor, against aspirin‐induced gastric lesions was studied in a double‐blind crossover trial with a simultaneous measure of the functional capacities of the mucosal barrier (by a recording of the gastric potential difference) and of the morphologic changes in the mucosa (by gastric endoscopy). After 1 week of treatment with lansoprazole (30 mg per day) or placebo, each healthy volunteer received 1 gm aspirin by mouth. Recording of the gastric potential difference lasted for 3 hours and was followed by gastric endoscopy. Morphologic lesions induced by aspirin were effectively prevented by lansoprazole: Lanza score was 0.67 ± 0.98 (mean ± SD) versus 2.25 ± 1.1 with placebo (p < 0.005, ANOVA). Conversely, the decrease in the gastric potential difference was similar. The inhibition of acid secretion induced by lansoprazole was therefore sufficient to prevent aspirin‐induced mucosal lesions without reinforcing the defense capacities of the mucosa. This simple pharmacologie model makes it possible to simultaneously evaluate the functional and morphologic effects of aspirin intake on the gastric mucosa.

Amoxicillin/clavulanic acid‐warfarin drug interaction: a randomized controlled trial

AIMS To investigate whether an interaction exists between amoxicillin/clavulanic acid (amoxiclav) and warfarin in patients treated with stable oral anticoagulant therapy. METHODS In a double-blind, cross-over, placebo-controlled study, 12 patients on stable warfarin therapy, received a 7 day amoxiclav regimen or placebo. RESULTS The mean maximum increase in INR observed was 0.22 ± 0.3 with amoxiclav vs. 0.24 ± 0.6 with placebo (P=0.94). The day 7-day 1 factor II, R(-) and S(-) warfarin plasma concentrations were similar during the amoxiclav and placebo study periods (P=0.81, P=0.45, P=0.75, respectively). CONCLUSION Amoxiclav did not modify anticoagulation in patients treated with stable warfarin therapy and without infection.

A multicentric prospective study in usual care: D-dimer and cardiovascular events in patients with atrial fibrillation☆ , ☆☆

AIM Atrial fibrillation (AF), the most frequent arrhythmia, is a major independent cardiovascular (CV) risk factor, especially in elderly patients. The interest of Ddimer (DD) measurement for predicting CV risk has been suggested in some subgroups of patients with AF but little is known about the negative prognostic value of DD measurement. The primary aim was to assess whether DD measurement and monitoring could predict the occurrence of subsequent CV events, defined as MI, stroke or transient ischemic attack and arterial embolic events. METHODS AND RESULTS It was a prospective observational study including patients with AF. Overall 425 patients (mean age 77years) were included and followed-up every 4months for a 16-months-mean duration. During this period, 26 patients experienced an endpoint of combined CV events. Patients with DD lower than 334ng/ml had a very low risk of suffering of CV events (1.7%). Patients who will suffer from a CV event had a higher DD value, just before the occurrence of the CV event, while patients without CV event kept stable levels. CONCLUSION We identified a DD threshold defining at any time patients at low risk of CV event. In addition, patients with higher DD levels are at higher risk of CV events, even if they are receiving oral anticoagulants. Otherwise, DD measurement is relevant in elderly patients. DD measurement and monitoring are useful to assess the risk of CV events in usual care. The implications of DD measurement on the choice and the intensity of the antithrombotic treatment remain to be determined.

Effects of aspirin and clopidogrel on plasma brain natriuretic peptide in patients with heart failure receiving ACE inhibitors

By inhibiting prostaglandins, aspirin may be deleterious in heart failure (HF) and/or may counteract angiotensin‐converting enzyme (ACE) inhibitor efficacy. Conversely, clopidogrel has no effect on prostaglandin metabolism.

Etiologies and Management of Aseptic Meningitis in Patients Admitted to an Internal Medicine Department

AbstractSeveral studies have focused on the clinical and biological characteristics of meningitis in order to distinguish between bacterial and viral meningitis in the emergency setting. However, little is known about the etiologies and outcomes of aseptic meningitis in patients admitted to Internal Medicine.The aim of the study is to describe the etiologies, characteristics, and outcomes of aseptic meningitis with or without encephalitis in adults admitted to an Internal Medicine Department.A retrospective cohort study was conducted in the Internal Medicine Department of the Lariboisière Hospital in Paris, France, from January 2009 to December 2011. Clinical and biological characteristics of aseptic meningitis were recorded. These included cerebrospinal fluid analysis, results of polymerase chain reaction testing, final diagnoses, and therapeutic management.The cohort included 180 patients fulfilling the criteria for aseptic meningitis with (n = 56) or without (n = 124) encephalitis. A definitive etiological diagnosis was established in 83 of the 180 cases. Of the cases with a definitive diagnosis, 73 were due to infectious agents, mainly enteroviruses, Herpes Simplex Virus 2, and Varicella Zoster Virus (43.4%, 16.8%, and 14.5% respectively). Inflammatory diseases were diagnosed in 7 cases. Among the 97 cases without definitive diagnoses, 26 (26.8%) remained free of treatment throughout their management whereas antiviral or antibiotic therapy was initiated in the emergency department for the remaining 71 patients. The treatment was discontinued in only 10 patients deemed to have viral meningitis upon admission to Internal Medicine.The prevalence of inflammatory diseases among patients admitted to internal medicine for aseptic meningitis is not rare (4% of overall aseptic meningitis). The PCR upon admission to the emergency department is obviously of major importance for the prompt optimization of therapy and management. However, meningitis due to viral agents or inflammatory diseases could also be distinguished according to several clinical and biological characteristics highlighted in this retrospective study. As recommendations are now available concerning the prescriptions of antiviral agents in viral meningitis, better therapeutic management is expected in the future.