Jean-François Bergmann

Low-molecular-weight heparin and mortality in acutely ill medical patients.

BACKGROUND Although thromboprophylaxis reduces the incidence of venous thromboembolism in acutely ill medical patients, an associated reduction in the rate of death from any cause has not been shown. METHODS We conducted a double-blind, placebo-controlled, randomized trial to assess the effect of subcutaneous enoxaparin (40 mg daily) as compared with placebo--both administered for 10±4 days in patients who were wearing elastic stockings with graduated compression--on the rate of death from any cause among hospitalized, acutely ill medical patients at participating sites in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia. Inclusion criteria were an age of at least 40 years and hospitalization for acute decompensated heart failure, severe systemic infection with at least one risk factor for venous thromboembolism, or active cancer. The primary efficacy outcome was the rate of death from any cause at 30 days after randomization. The primary safety outcome was the rate of major bleeding during and up to 48 hours after the treatment period. RESULTS A total of 8307 patients were randomly assigned to receive enoxaparin plus elastic stockings with graduated compression (4171 patients) or placebo plus elastic stockings with graduated compression (4136 patients) and were included in the intention-to-treat population. The rate of death from any cause at day 30 was 4.9% in the enoxaparin group as compared with 4.8% in the placebo group (risk ratio, 1.0; 95% confidence interval [CI], 0.8 to 1.2; P=0.83). The rate of major bleeding was 0.4% in the enoxaparin group and 0.3% in the placebo group (risk ratio, 1.4; 95% CI, 0.7 to 3.1; P=0.35). CONCLUSIONS The use of enoxaparin plus elastic stockings with graduated compression, as compared with elastic stockings with graduated compression alone, was not associated with a reduction in the rate of death from any cause among hospitalized, acutely ill medical patients. (Funded by Sanofi; LIFENOX ClinicalTrials.gov number, NCT00622648.).

Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function - A comparative pharmacokinetic study

Low-molecular-weight heparins (LMWHs) accumulate in patients with impaired renal function. As this accumulation depends on heparin chain length and subsequent reticulo-endothelial/renal elimination, LMWHs might have different pharmacodynamic profiles. The primary objective was to examine if any accumulation effect of two LMWHs, enoxaparin and tinzaparin, occurred after repeated administration of a prophylactic dose over eight days in elderly patients (age >75 years) with creatinine clearance between 20 and 50 ml/min and body weight <65Kg. Patients were openly randomized to two groups (enoxaparin 4,000 IU or tinzaparin 4,500 IU once daily). Anti-Xa was measured on day 1 and day 8. Blood samples were taken at 0, 2, 4, 5, 6, 9, 12, 16 and 24 hours. The primary end point was the accumulation factor calculated as a ratio between the maximal anti-Xa activity on day 1and day 8. Fifty-five patients were included (mean age 87.9 +/- 5.5). The creatinine clearance was 34.7 +/- 11.4 ml/min; the body weight was 52.3 +/- 8.6 kg. The accumulation factor defined was not significant for tinzaparin (1.05, p = 0.29) while it was significantly enhanced for enoxaparin (1.22, p < 0.0001). In this pharmacodynamic study performed in elderly patients with impaired renal function, a statistically significant accumulation effect was observed after eight days of prophylactic treatment with enoxaparin but not with tinzaparin, which are two LMWHs with different chain lengths. Trials based on clinical end points should be conducted to evaluate the clinical relevance of these observations.

Venous Thromboembolism Risk and Prophylaxis in the Acute Care Hospital Setting (ENDORSE Survey): Findings in Surgical Patients

Objective:To evaluate venous thromboembolism (VTE) risk in patients who underwent a major operation, including the use of, and factors influencing, American College of Chest Physicians-recommended types of VTE prophylaxis. Summary Background Data:The Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) survey, conducted in 358 hospitals in 32 countries, reported that globally, more than 40% of at-risk patients do not receive VTE prophylaxis. Limited data are available regarding VTE prophylaxis practices according to surgery type and patient characteristics. Methods:Patients aged ≥18 years undergoing major surgery were included in this prespecified subanalysis. VTE risk and use of prophylaxis were determined from hospital medical records according to the 2004 American College of Chest Physicians guidelines. Multivariable analyses were performed to identify factors associated with VTE prophylaxis use. Results:Of the 18,461 patients in ENDORSE who had undergone major surgery, 17,084 (92.5%) were at-risk for VTE and 10,638 (62.3%) received prophylaxis. Use of prophylaxis varied according to major surgery type from 86.0% for orthopedic surgery to 53.8% in urologic/gynecologic and 53.6% in other procedures. Major orthopedic surgery was most strongly associated with prophylaxis use (hip replacement: odds ratio 6.2, 95% confidence interval [CI] 5.0–7.6; knee replacement: odds ratio 5.9, 95% CI 4.6–7.8). Conclusions:The majority of surgical patients are at high-risk for VTE. Despite long-standing recognition of the high-risk for VTE in surgical patients, thromboprophylaxis remains underutilized.

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.

Amiodarone concentrations in plasma and fat tissue during chronic treatment and related toxicity

AIMS To determine if amiodarone, highly lipophilic, accumulates in excess with respect to dose in fat tissue during long-term administration, and study if plasma and fat tissue concentrations are correlated with adverse effects. METHODS Trough concentrations of amiodarone and N-desethyl-amiodarone were measured simultaneously in plasma and fat tissue, in 30 consecutive patients treated with amiodarone for 3 months to 12 years. Subcutaneous adipose tissue was obtained by needle aspiration from lumbar and abdominal areas. Concentrations were measured by liquid chromatography-tandem mass spectrometry. RESULTS Plasma levels of amiodarone and N-desethyl-amiodarone were significantly correlated with daily maintenance doses (R= 0.52, P= 0.003). Amiodarone concentrations in fat tissue were four to 226 times (mean 55) higher than in plasma, and well correlated with plasma levels (R= 0.68, P < 0.001). Concentrations of amiodarone and N-desethyl-amiodarone in adipose tissue did not significantly increase with higher total cumulated doses or longer treatment duration. Nine of 12 patients who had received amiodarone for > or =2 years developed clinically important adverse effects, predominantly hypothyroidism (n= 6), compared with two of 18 patients treated for less time (relative risk 6.75; 95% confidence interval 1.8, 26). The incidence of those adverse effects was not significantly associated with amiodarone concentrations, whether in plasma or in adipose tissue. CONCLUSIONS We found no evidence of excessive or unexpected accumulation of amiodarone in fat tissue on long-term administration. Late amiodarone adverse effects, particularly hypothyroidism, are associated with longer exposure times, but do not seem to be explained by higher concentrations in plasma or in fat tissue.

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.

Mini-series: I. Basic science. Uncertainty and inaccuracy of predicting CYP-mediated in vivo drug interactions in the ICU from in vitro models: focus on CYP3A4

Drug–drug interactions (DDIs) contribute significantly to the incidence of adverse drug reactions. Important advances in the knowledge of human drug-metabolizing enzymes have fueled the integration of in vitro drug metabolism and clinical DDIs studies for use in drug development programs and in the clinical setting. The activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein are critical determinant of drug clearance, interindividual variability in drug disposition and clinical efficacy, and appears to be involved in the mechanism of numerous clinically relevant DDIs. Cell-based in vitro models are being increasingly applied in elucidating the pharmacokinetic profile of drug candidates during the preclinical steps of drug development. Human liver, intestinal samples and recombinant human CYP3A4 are now readily available as in vitro screening tools to predict the potential for in vivo DDIs. Although it is easy to determine in vitro metabolic DDIs, the interpretation and extrapolation of in vitro interaction data to in vivo situations requires a good understanding of pharmacokinetic principles. Clinicians and pharmacokineticists should recognize that in vitro models may not be clinically relevant in all situations. In the current article, research will be presented on drug metabolism and DDIs along with examples illustrating the utility of specific in vitro or in vivo approaches. In addition, the impact and clinical relevance of complexities such as dosing-route dependent effects, multi-site kinetics of drug-metabolizing enzymes and non-CYP determinants of metabolic clearance will be addressed.

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).

Improving HIV Infection Management Using Antiretroviral Plasma Drug Levels Monitoring: A Clinicians Point of View

Due to genetic and environmental factors, there are wide inter-patient differences when measuring drug exposure to a standard dose. If there is a relationship between drug exposure and efficacy or toxicity, this inter-patient variability carries various risks to develop toxicity or failure. Therapeutic drug monitoring is an attempt to adjust the dose to obtain a level within a therapeutic range consisting in a minimum plasma concentration needed to be efficacious and a maximum plasma concentration not to exceed to avoid toxicity. Many studies have shown a relationship between various pharmacokinetic parameters and drug toxicity or efficacy for HIV protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Therapeutic drug monitoring (TDM) proves to be a useful tool to assess adherence, to investigate drug-drug interactions between antiretroviral (ARV) drugs or with co-medications, to prevent some ARV drug toxicities, to adjust the dosage in particular populations, and to increase ARV efficacy of some drugs in naive patients. The integration of virological and pharmacological parameters, using inhibitory quotients, looks promising to improve therapy in ARV-experienced patients. Effective and non-toxic target concentrations will be determined for all present and future antiretroviral drugs covering the extended spectrum of naive patients to multiple failures. In this article, we review the rationale of TDM for antiretroviral drugs, the retrospective and prospective studies assessing plasma drug concentrations in relation with antiretroviral toxicity or efficacy, and the actually recommended or proposed indications for TDM. We also highlight the benefits and limits of this tool as an adjunct in the care of HIV-infected patients.

Management of xerostomia in older patients : a randomised controlled trial evaluating the efficacy of a new oral lubricant solution.

BackgroundXerostomia is a subjective sensation of mouth dryness that may frequently occur in older patients.ObjectiveTo compare the clinical efficacy and acceptability of a new oxygenated glycerol triester (OGT) oral spray taken five times daily with that of a commercially available saliva substitute (Saliveze®) in the treatment of xerostomia.MethodsForty-one institutionalised patients (28 women, 13 men; mean age 84 ± 7 years) were randomly assigned to receive either OGT or Saliveze® in a 2-week, randomised, parallel-group study. Clinical assessment of xerostomia included evaluation of mouth dryness using a self-rated, 10cm long visual analogue scale (VAS), objective assessment of oral tissue condition using a four-point ordinal scale and subjective assessment of symptoms of xerostomia using dichotomous responses to a questionnaire. The primary endpoint was the day (D) 14 patient-based mouth dryness score measured on a self-rated VAS.ResultsAt D14, OGT resulted in significantly greater efficacy with respect to mouth dryness (mean between-treatment difference 2.1 ± 0.1, 95% CI 1.9, 2.3; p = 0.001), swallowing difficulty (1.8 ± 0.3, 95% CI 1.5, 2.1; p = 0.001), speech difficulty (1.1 ± 0.2, 95% CI 1.0, 2.4; p = 0.04) and overall sensation of symptom relief (2.7 ± 1.2, 95% CI 1.9, 3.8; p = 0.001). Objective assessment of oral tissues also showed significantly better improvement with OGT spray with respect to dryness (p = 0.01), stickiness (p = 0.005) and dullness (p = 0.001) of oral mucosa; severity of mucositis (p = 0.01); and thickening of the tongue (p = 0.03). A significant difference in taste acceptability was also noted in favour of OGT (1.4 ± 0.6, 95% CI 1.2, 1.9; p = 0.04).ConclusionOGT lubricant oral spray was superior to Saliveze® in improving xerostomia and oral tissue condition in older institutionalised patients.