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ABSTRACT: In a meta-analysis of case-control studies, Zhang et al. (2011) found an increased risk of venous thromboembolic events (VTE) in patients exposed to antipsychotics (OR=2.39 [1.71-3.35]). Our updated meta-analysis including the 2 available cohort studies, recognized as a more relevant type of observational study, showed a weaker, but still strong association (OR=1.84 [1.39; 2.44]). In view of the lack of data on the confirmed risk factors for VTE in existing studies, prospective studies including adjustment for these risk factors are warranted to confirm this association and to assess the benefit/risk ratio of antipsychotics in high-risk patients.
Pharmacopsychiatry 07/2012; · 2.07 Impact Factor
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ABSTRACT: Despite the need for effective and safe thromboprophylactic drugs for patients with renal impairment, clinical trial data on anticoagulant agents are limited in this population. The study aim was to assess in the real-world setting the use of the once-daily 1.5 mg reduced dosage regimen of fondaparinux available for this context. In this prospective cohort study, patients with a creatinine clearance (CrCl) of 20-50 ml/minute, undergoing total hip (THR) or knee (TKR) replacement or hip fracture surgery (HFS) received fondaparinux thromboprophylaxis. Main clinical outcomes were bleeding (major/clinically relevant non-major), symptomatic venous thromboembolism (VTE) and death. Overall, 442 patients (353 women; median age: 82 years; 39.4% in ASA class ≥3; mean ± SD CrCl: 39.0 ± 8.0 ml/minute; 78% with additional risk factors for bleeding), undergoing THR (43.7%), TKR (27.6%), or HFS (28.7%) received fondaparinux 1.5 mg for a mean ± SD duration of 16.0 ± 12.5 days. At postoperative day 10, the rates (95% confidence interval) of major bleeding, clinically relevant bleeding and symptomatic VTE were 4.5% (2.8-6.9), 0.5% (0.1-1.6) and 0.5% (0.05-1.62), respectively; no fatal bleeding, bleeding into a critical organ, pulmonary embolism or proximal deep-vein thrombosis occurred. Corresponding rates at one month were 5.2%, 0.7% and 0.7%. One-month mortality was 2.3% (0.9-3.6). This large clinical prospective study provides for the first time, under conditions reflecting "real-world" routine clinical practice, data on the bleeding and VTE risks of thromboprophylaxis with fondaparinux 1.5 mg after major orthopaedic surgery in renally impaired patients. It shows that these patients constitute a very elderly and fragile population.
Thrombosis and Haemostasis 04/2012; 107(6):1151-60. · 5.04 Impact Factor
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ABSTRACT: The existence of poor biological response to clopidogrel has been shown in some patients. Despite the increasing number of studies, this phenomenon remains difficult to quantify. We performed a systematic review to estimate the prevalence of poor biological response to clopidogrel and investigate the factors known to modulate this. An exhaustive search was performed. Altogether 171 publications were identified, providing data for a total of 45,664 subjects. The estimated prevalence of poor biological response to clopidogrel ranged from 15.9% to 49.5% according to the platelet function assay employed. The assays most frequently used were light transmittance aggregometry (LTA), the vasodilator-stimulated phosphoprotein (VASP) assay and the Verifynow® assay. For all these assays, higher cut-off values were associated with a lower prevalence of poor biological response to clopidogrel. However, when choosing a fixed cut-off point for each assay, the prevalence of poor biological response to clopidogrel was highly variable suggesting that other factors could modulate poor biological response to clopidogrel. Finally, none of the studied factors could apparently explain the variability of poor biological response to clopidogrel. This meta-analysis shows that the prevalence of poor biological response depends on the assay employed, the cut-off value and on various unidentified additional factors.
Thrombosis and Haemostasis 03/2012; 107(3):494-506. · 5.04 Impact Factor
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Annales francaises d'anesthesie et de reanimation 11/2011; 30(12):947-51. · 0.77 Impact Factor
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ABSTRACT: Background: Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are both recommended for venous thromboembolism (VTE) prophylaxis in hospitalized medical patients. Objective: To perform an individual patient data meta-analysis to evaluate the relative efficacy and safety of the LMWH enoxaparin and UFH in preventing VTE in hospitalized medical patients. Methods: Randomized clinical trials comparing subcutaneous enoxaparin (4000 IU once-daily) and UFH (5000 IU subcutaneous two- or three-times daily) for VTE prevention were identified by a systematic search. Individual patient data were obtained from each eligible trial. Results: Overall, four trials were eligible, including 3600 patients randomized to receive enoxaparin (n = 1799) or UFH (n = 1801). Median patient age was 71 years, and 49.3% were female. Compared with UFH, enoxaparin was associated with risk reductions of 37% for total VTE [relative risk (RR) 0.63, 95% confidence interval (CI) 0.51–0.77] and 62% for symptomatic VTE (RR 0.38, 95% CI 0.17–0.85) at day 15. RR for total VTE in stroke and non-stroke patients was 0.59 (95% CI 0.47–0.74) and 0.87 (95% CI 0.51–1.50), respectively. Major bleeding rates were consistently low and similar between treatment groups at day 15 (RR 1.13, 95% CI 0.53–2.44). There was a trend towards reduced risk for mortality in patients receiving enoxaparin (RR 0.83, 95% CI 0.64–1.08), compared with UFH. Conclusions: Enoxaparin significantly reduces VTE in hospitalized medical patients, compared with UFH, without increasing the risk for major bleeding, and was associated with a trend towards reduced all-cause mortality.
Journal of Thrombosis and Haemostasis 02/2011; 9(3):464 - 472. · 5.73 Impact Factor
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Journal of Thrombosis and Haemostasis 10/2010; 8(10):2334-8. · 5.73 Impact Factor
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Journal of Thrombosis and Haemostasis 04/2010; 8(4):621-6. · 5.73 Impact Factor
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ABSTRACT: BSUMMARY BACKGROUND: Previous studies have shown an important risk of cardiovascular events in patients with clopidogrel biological non-response, and data have shown considerable, unexplored heterogeneity.
To evaluate the magnitude of cardiovascular risk associated with clopidogrel non-response and to explore heterogeneity.
This was a systematic review and meta-analysis of prospective studies of patients treated with clopidogrel for symptomatic atherothrombosis, evaluated by light transmission aggregometry with ADP and monitored prospectively for clinical ischemic events.
Fifteen studies were included, totaling 3960 patients, of whom 25% were considered to be clopidogrel non-responders. The global relative risk (RR) for recurrent ischemic events in clopidogrel non-responders was 3.5 [95% confidence interval (CI) 2.4-5.2, P < 0.0001]. The results of the different studies were heterogeneous (Cochran P = 0.01 and I(2) = 52%). The most recent studies yielded lower RRs [global RR = 2.9 (95% CI 2.3-3.8) after 2007, and global RR = 6.6 (95% CI 3.7-11.9) before 2007, P = 0.01]. Heterogeneity was present in the group of studies in which more than 10% of patients took glycoprotein (GP)IIb-IIIa inhibitors [Cochran P = 0.003 and I(2) = 70%; RR = 3.8 (95% CI 2.9-5.1)] and was absent in the other studies [Cochran P = 0.88 and I(2) = 0; RR = 2.5 (95% CI 1.7-3.6)]. The RR was significantly higher in studies using higher ADP maximal aggregation cut-offs (> 65%) for clopidogrel non-response than in studies using lower cut-offs [RR = 5.8 (95% CI 3.2-10.3) and RR = 2.9 (95% CI 2.2-3.7), respectively, P = 0.03].
The risk of ischemic events associated with clopidogrel non-response is now more precisely defined. The risk is heterogeneous across studies, possibly because of an interaction with GPIIb-IIIa inhibitors and the use of different cut-offs to identify non-responders.
Journal of Thrombosis and Haemostasis 02/2010; 8(5):923-33. · 5.73 Impact Factor
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P Mismetti,
J-M Baud,
F Becker,
F Belmahdi,
P Blanchard,
J Constans,
F Couturaud,
P Debourdeau,
L Drouet,
N Dumarcet, [......], S Laporte,
J-P Laroche,
A Leizorovicz,
F Liard,
I Mahé,
G Meyer,
E Oger,
F Parent,
I Quéré,
M Samama
Journal des Maladies Vasculaires 02/2010; 35(3):127-36. · 0.54 Impact Factor
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ABSTRACT: Dabigatran (Pradaxa) is a new oral, direct, selective and reversible inhibitor of the factor IIa of the coagulation cascade. The main pharmacokinetic characteristics of dabigatran are a bioavailability of approximately 7.5%, a maximum concentration obtained in 0.5 to 2 hours, a terminal half-life of elimination of 7 to 17 hours, a renal way of elimination, 80% as unchanged form and 20% as glucuronide conjugate. The main sources of variability are the renal function, the gastric motility, especially during the early post-operative period and a potential interaction with amiodarone. This compound can be orally administrated, once or twice daily, without any biological monitoring and without any need for dose adjustment. There is a contra-indication in case of severe renal or liver insufficiency. Two phases II with 2287 patients were carried out to for venous thromboembolic (VTE) prophylaxis after major orthopaedic surgery, showing that 150 mg and 220 mg once daily could be the optimal dose regimen to assess in phase III. One phase II with 502 patients vas carried out for the prevention of thromboembolic complications of atrial fibrillation (AF) showing that 110 mg or 150 mg twice daily could be the optimal dose regimen to evaluate in the following phases 3. From this study in AF patients, a dose regimen of 150 mg bid has been chosen to be evaluated for the treatment of VTE. No strong signal for a potential liver toxicity was shown during these studies.
Annales francaises d'anesthesie et de reanimation 09/2009; 28(9 Suppl):S8-14. · 0.77 Impact Factor
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ABSTRACT: A pharmacokinetic-pharmacodynamic (PK-PD) drug-drug interaction between acenocoumarol and amoxicillin + clavulanic acid antibiotic was assessed in eight healthy volunteers, using a population PK-PD) model. Each subject received at day 1 a single dose of 8 mg of acenocoumarol. Then 1 g of amoxicillin + 250 mg of clavulanic acid was given from days 3 to 9. On day 8, each subject received a single dose of 8 mg of acenocoumarol concomitantly with the antibiotic combination. Eleven blood samples were taken during 48 h following each acenocoumarol administration. Acenocoumarol plasma concentrations and prothrombin time were measured at each sampling time. We first identified the structural PK model by pooling data from this trial with individual data from other acenocoumarol PK trials. An indirect response model was used to fit PD data. Models were built using a non-linear mixed effect modelling approach with nonmem software. Covariates were tested on PK and PD parameters, including antibiotic treatment. Acenocoumarol PK data were fitted by a two-compartment, first-order input model with log normal inter-individual variability. Weight and antibiotic treatment were found to improve significantly the fit of PK data with a 15% decrease in acenocoumarol clearance with concomitant antibiotics (P < 0.05). An indirect response model was successfully applied to the PK-PD data of acenocoumarol. No covariate, including antibiotic treatment effect, significantly affected PT. Drug-drug interaction was demonstrated at the PK level, without any PD corollary.
Fundamental and Clinical Pharmacology 02/2009; 23(1):127-35. · 1.80 Impact Factor
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ABSTRACT: Rivaroxaban (Xarelto) is a new oral, direct and selective inhibitor of the factor Xa of the coagulation cascade. The main pharmacokinetic characteristics of rivaroxaban are a bioavailability of approximately 80-100%, a maximum concentration obtained in 2 to 4 hours, a terminal half-life of elimination of 7 to 11 hours, a renal elimination for 1/3 for the active hepatic metabolism from the cytochrome P450 (3A4) for the other 2/3. The main sources of variability are the renal and the liver function and potential interactions with some strong inhibitors or inducers of the CYP450 3A4. Phase II clinical studies have shown that this compound can be orally administrated, once or twice daily, without any biological monitoring and without any need for dose adjustment. There is a contra-indication in case of severe liver insufficiency and not recommended in case of severe renal impairment. Pharmacodynamically, Rivaroxaban is a direct and selective factor Xa inhibitor without any effect on the factor IIa and without any interaction on platelets. Four phases II with 2787 patients were carried out to for venous thromboembolic (VTE) prophylaxis after major orthopaedic surgery, showing that 10 mg once daily could be the optimal dose regimen to assess in phase III. Two phases II with 1446 patients were carried out for the treatment of VTE showing that 15 mg twice daily for 3 weeks and then 20 mg once daily could be the optimal dose regimen to evaluate in the following phases 3. No strong signal for a potential liver toxicity was shown during these 6 phases II.
Annales francaises d'anesthesie et de reanimation 01/2009; 27 Suppl 3:S16-21. · 0.77 Impact Factor
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Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 11/2008; 48(4):1063. · 3.52 Impact Factor
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ABSTRACT: Major bleeding complications with low-molecular-weight heparin (LMWH) treatment have been reported both in clinical studies and during postmarketing surveillance. Monitoring of antifactor Xa (anti-Xa) activities is therefore recommended in special populations often predisposed to renal impairment. The PROPHRE.75 study was conducted to estimate the distribution parameters of anti-Xa activity in the elderly.
PROPHRE.75 was a prospective study of a cohort of consecutive patients aged >75 years and treated with 4000 IU of enoxaparin once daily for venous thromboembolism prophylaxis. Dosing history and measurements of anti-Xa activity in sparse samples were recorded throughout treatment. The covariates included weight, gender, age, renal function, medical history and concomitant medication. Population parameters and interindividual variability were estimated using NONMEM V software.
Anti-Xa activity was studied in 189 patients (mean age 82 +/- 5 years, 22% weighing <50 kg, 50% presenting renal impairment according to the Cockcroft and Gault formula). A first-order input two-compartment model best fitted the data. Clearance was significantly related to body weight and creatinine clearance based on the simplified Modification of Diet in Renal Disease formula, central volume being related to body weight. According to individual Bayesian estimations, 4% of patients presented with a peak anti-Xa activity >1.0 IU ml(-1), but this group did not include the sole patient experiencing a major bleed (0.53%).
Systematic monitoring of anti-Xa activity in elderly patients treated with enoxaparin at prophylactic doses does not seem to be necessary to prevent the occurrence of major bleeding.
British Journal of Clinical Pharmacology 10/2007; 64(4):428-38. · 2.96 Impact Factor
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Annals of the New York Academy of Sciences 12/2006; 618(1):159 - 165. · 3.15 Impact Factor
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ABSTRACT: The optimal thromboprophylactic dosage regimen of low-molecular-weight heparins in high-risk general surgery remains debatable.
We performed a randomized, double-blind study to compare the efficacy and safety of nadroparin 2850 IU (0.3 mL) and enoxaparin 4000 IU (40 mg) in the prevention of venous thromboembolism (VTE) after colorectal surgery for cancer. Patients and methods: Patients undergoing resection of colorectal adenocarcinoma were randomized to receive once daily either 2850 IU nadroparin or 4000 IU enoxaparin s.c. for 9 +/- 2 days. The primary efficacy outcome was the composite of deep vein thrombosis (DVT) detected by bilateral venography or documented symptomatic DVT or pulmonary embolism up to day 12. The main safety outcome was major bleeding. A blinded independent committee adjudicated all outcomes.
Out of 1288 patients analyzed, efficacy was evaluable in 950 (73.8%) patients. The VTE rate was 15.9% (74/464) in nadroparin-treated patients and 12.6% (61/486) in enoxaparin-treated patients, a relative risk of 1.27 (95% confidence interval; CI: 0.93-1.74) that did not met the criterion for non-inferiority of nadroparin. The rate of proximal DVT was comparable in the two groups (3.2% vs. 2.9%, respectively), but that of symptomatic VTE was lower in nadroparin-treated patients (0.2% vs. 1.4%). There was significantly (P = 0.012) less major bleeding in nadroparin- than in enoxaparin-treated patients (7.3% vs. 11.5%, respectively).
Compared with those receiving enoxaparin 4000 IU, patients treated with nadroparin 2850 IU showed a higher incidence of asymptomatic distal DVT, but a lower incidence of symptomatic VTE. Nadroparin treatment was safer in terms of bleeding risk.
Journal of Thrombosis and Haemostasis 09/2006; 4(8):1693-700. · 5.73 Impact Factor
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ABSTRACT: The thromboembolic risk related to surgery may be considered as low for varicose vein surgery and non major digestive surgery. It could be defined as moderate in case of large dissection, long duration of procedures and emergency cases. The risk may be considered as high for major abdominal surgery involving cancer surgery or not and bariatric surgery. The absence of prophylaxis can be proposed for low risk surgery (grade B). However, elastic compression stocking are effective for all cases of digestive surgery and suggested to be used (grade A). There are no data concerning the moderate risk situation. Therefore, experts recommend the use of elastic compression stockings or low doses of LMWH (grade D). High-risk surgery requires the use of high doses of LMWH recommended for reasons of efficacy, tolerance, and easiness to use (grade A). Associated elastic stockings is efficious (grade B). The duration of prophylaxis lasts generally 7-10 days. Extension to 1 month is recommended for major abdominal cancer surgery (grade A).
Annales Françaises d Anesthésie et de Réanimation 09/2005; 24(8):890-901. · 0.84 Impact Factor
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Journal of Thrombosis and Haemostasis 06/2005; 3(5):1104-7. · 5.73 Impact Factor
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ABSTRACT: The benefit-to-risk ratio of vitamin K antagonists (VKA), relative to active comparators, especially low-molecular-weight heparins (LMWH), for preventing venous thromboembolism in patients undergoing major orthopedic surgery is debated.
We performed a meta-analysis of all randomized trials in orthopedic surgery comparing adjusted doses of VKA to control treatments.
An exhaustive literature search, both manual and computer-assisted, was performed. Studies were selected on the basis of randomization procedure (VKA vs. a control group). At least one of the following outcome measures was to be evaluated: deep vein thrombosis (DVT), pulmonary embolism (PE), death, major hemorrhage or wound hematoma. Four reviewers assessed each article to determine eligibility for inclusion and outcome measures.
VKAs were more effective than placebo or no treatment in reducing DVT [567 patients, relative risk (RR) = 0.56, 95% confidence interval (CI) 0.37, 0.84, P < 0.01] and clinical PE (651 patients, RR = 0.23, 95% CI 0.09, 0.59, P < 0.01). These results were obtained at the cost of a higher rate of wound hematoma (162 patients, RR = 2.91, 95% CI 1.09, 7.75, P = 0.03). VKAs were also more effective than intermittent pneumatic compression (534 patients, RR = 0.46, 95% CI 0.25, 0.82, P = 0.009) in preventing proximal DVT. In contrast, VKAs were less effective than LMWH in preventing total DVT and proximal DVT (9822 patients, RR = 1.51, 95% CI 1.27, 1.79, P < 0.001; and 6131 patients, RR = 1.51, 95% CI 1.04, 2.17, P = 0.028, respectively). The differences between VKA and LMWH in major hemorrhage and wound hematoma were not significant.
In patients undergoing major orthopedic surgery, VKAs are less effective than LMWH, without any significant difference in the bleeding risk.
Journal of Thrombosis and Haemostasis 07/2004; 2(7):1058-70. · 5.73 Impact Factor
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ABSTRACT: Tissue factor pathway inhibitor (TFPI) is of major importance in regulating the coagulation triggering effects of tissue factor. An association between TFPI deficiency and thrombosis has still not been clearly demonstrated. We evaluated the anticoagulant activity of exogenous TFPI added either to the plasma of patients with venous thrombosis (n = 118) or to the plasma of healthy controls similar in terms of mean age and sex ratio (n = 107). A poor anticoagulant response to TFPI, defined as TFPI resistance, was observed in 4.7% of controls and in 11.0% of patients. TFPI resistance was associated with an almost threefold increase in the risk of thrombosis and could therefore represent a novel hemostatic risk factor for venous thrombosis.
Journal of Thrombosis and Haemostasis 04/2003; 1(3):507-10. · 5.73 Impact Factor
