Clermont-Ferrand, France
Clermont-Ferrand, France

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Gould M.K.,University of Southern California | Garcia D.A.,University of New Mexico | Wren S.M.,Stanford University | Karanicolas P.J.,The Surgical Center | And 3 more authors.
Chest | Year: 2012

Background: VTE is a common cause of preventable death in surgical patients. Methods:We developed recommendations for thromboprophylaxis in nonorthopedic surgical patients by using systematic methods as described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. Results: We describe several alternatives for stratifying the risk of VTE in general and abdominalpelvic surgical patients. When the risk for VTE is very low (< 0.5%), we recommend that no specific pharmacologic (Grade 1B) or mechanical (Grade 2C) prophylaxis be used other than early ambulation. For patients at low risk for VTE (∼1.5%), we suggest mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC), over no prophylaxis (Grade 2C). For patients at moderate risk for VTE (∼3%) who are not at high risk for major bleeding complications, we suggest low-molecular-weight heparin (LMWH) (Grade 2B), low-dose unfractionated heparin (Grade 2B), or mechanical prophylaxis with IPC (Grade 2C) over no prophylaxis. For patients at high risk for VTE (∼6%) who are not at high risk for major bleeding complications, we recommend pharmacologic prophylaxis with LMWH (Grade 1B) or low-dose unfractionated heparin (Grade 1B) over no prophylaxis. In these patients, we suggest adding mechanical prophylaxis with elastic stockings or IPC to pharmacologic prophylaxis (Grade 2C). For patients at high risk for VTE undergoing abdominal or pelvic surgery for cancer, we recommend extended-duration, postoperative, pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B). For patients at moderate to high risk for VTE who are at high risk for major bleeding complications or those in whom the consequences of bleeding are believed to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2C). For patients in all risk groups, we suggest that an inferior vena cava filter not be used for primary VTE prevention (Grade 2C) and that surveillance with venous compression ultrasonography should not be performed (Grade 2C). We developed similar recommendations for other nonorthopedic surgical populations. Conclusions: Optimal thromboprophylaxis in nonorthopedic surgical patients will consider the risks of VTE and bleeding complications as well as the values and preferences of individual patients. ©2012 American College of Chest Physicians.


Samama M.M.,Hotel Dieu University Hospital | Samama M.M.,Biomnis Laboratory | Samama M.M.,British Petroleum | Guinet C.,Biomnis Laboratory
Clinical Chemistry and Laboratory Medicine | Year: 2011

With the introduction of new anticoagulant agents, there is a need for information on which coagulation tests are most suitable. These agents react differently to assays used to monitor older anticoagulant agents because they have alternative modes of action. Therefore, other tests, or modifications of existing tests which are more appropriate for newer agents, are needed. The prothrombin time test (with conversion to the international normalized ratio) is usually used to monitor warfarin. However, conversion to the international normalized ratio is not appropriate for measuring the effects of fondaparinux, dabigatran, rivaroxaban or apixaban. Instead, chromogenic assays, one-step prothrombinase-induced clotting time test and the HepTest with reduced incubation time, are among the different or modified tests that appear to give the most reproducible and accurate results. The tests show variations in response to anticoagulants-some of which have clinical relevance. Thus, it is important to be aware of the observed variations in order to prevent the misinterpretation of test results. © 2011 by Walter de Gruyter Berlin New York.


Samama M.M.,Hotel Dieu University Hospital | Samama M.M.,Biomnis Laboratory | Martinoli J.-L.,Stago | LeFlem L.,Biomnis Laboratory | And 4 more authors.
Thrombosis and Haemostasis | Year: 2010

Although there is no need for routine coagulation monitoring with rivaroxaban - an oral, direct factor Xa inhibitor - a haemostasis assay might be valuable to measure its pharmacodynamic effects. This study aimed to find assays, among those commercially available, to measure rivaroxaban pharmacodynamics. Several global conventional clotting tests, as well as clotting or chromogenic assays to measure anti-factor Xa activity, were studied. A thrombin generation test using calibrated automated thrombogram was also done. Tests were performed with the indirect factor Xa inhibitor fondaparinux for comparison. A concentration-dependent prolongation of prothrombin time (PT), dilute PT, and activated partial thromboplastin time was observed with rivaroxaban. The results varied depending on the reagents. This variability cannot be standardised with the international normalised ratio system commonly used for vitamin K antagonists. Using a standard calibration curve, PT test results can be expressed in plasma concentrations of rivaroxaban rather than PT seconds or ratio. Standard methods for HepTest and two-step prothrombinase- induced clotting time (PiCT) resulted in a paradoxical response, with low concentrations of rivaroxaban reducing clotting times. This was not observed with shorter incubation times, or when antithrombin-deficient (immunodepleted) plasma was used. The chromogenic tests found a dose-dependent relationship between anti-factor Xa activity and rivaroxaban concentration. Modified specific factor Xa chromogenic assays are being further investigated. One-step PiCT and HepTest with shortened incubation times, as well as the widely available PT assay (using a rivaroxaban calibrator) could be useful to monitor the pharmacodynamic effects of rivaroxaban accurately. Finally, all clotting and chromogenic assays showed a concentration-dependent effect induced by rivaroxaban. © Schattauer 2010.


Samama M.M.,Hotel Dieu University Hospital | Samama M.M.,Biomnis Laboratories R and D | Contant G.,Diagnostica Stago SA | Spiro T.E.,Bayer AG | And 6 more authors.
Thrombosis and Haemostasis | Year: 2012

Rivaroxaban is an oral, direct factor Xa inhibitor. Routine coagulation monitoring is not required, but a quantitative determination of rivaroxaban concentrations might be useful in some clinical circumstances. This multicentre study assessed the suitability of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations (ng/ml) using rivaroxaban calibrators and controls, and the inter-laboratory precision of the measurement. Twenty-four centres in Europe and North America were provided with sets of rivaroxaban calibrators (0, 41, 209 and 422 ng/ml) and a set of rivaroxaban pooled human plasma controls (20, 199 and 662 ng/ml; the concentrations were unknown to the participating laboratories). The evaluation was carried out over 10 days by each laboratory using local anti-factor Xa reagents as well as the centrally provided reagent, a modified STA ® Rotachrom ® assay. A calibration curve was produced each day, and the day-to-day precision was evaluated by testing three human plasma controls. When using the local anti-factor Xa reagents, the mean rivaroxaban concentrations (measured/actual values) were: 17/20, 205/199 and 668/662 ng/ml, and the coefficient of variance (CV) was 37.0%, 13.7% and 14.1%, respectively. When the modified STA Rotachrom method was used, the measured/actual values were: 18/20, 199/199 and 656/662 ng/ml, and the CV was 19.1%, 10.9% and 10.0%, respectively. The results suggest that, by using rivaroxaban calibrators and controls, the anti-factor Xa chromogenic method is suitable for measuring a wide range of rivaroxaban plasma concentrations (20-660 ng/ml), which covers the expected rivaroxaban plasma levels after therapeutic doses. © Schattauer 2012.


Samama M.M.,Hotel Dieu University Hospital | Samama M.M.,Biomnis Laboratories R and D
Thrombosis Research | Year: 2011

Although results of some phase III clinical trials of new oral anticoagulants are now known, it is important to understand the mechanisms of their actions. These new agents exert their anticoagulant effect via direct inhibition of a single Factor within the coagulation cascade (such as Factor Xa or thrombin). Rivaroxaban - the first oral, direct Factor Xa inhibitor - is a small-molecule oxazolidinone derivative that binds directly and reversibly to Factor Xa via the S1 and S4 pockets. Rivaroxaban competitively inhibits Factor Xa and is more than 10,000-fold more selective for Factor Xa than other related serine proteases, and it does not require cofactors (such as antithrombin) to exert its anticoagulant effect. Unlike indirect Factor Xa inhibitors, rivaroxaban inhibits both free and clot-bound Factor Xa, as well as prothrombinase activity, thereby prolonging clotting times. Dabigatran etexilate is a direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin. Although the mechanism of action differs between the direct Factor Xa and direct thrombin inhibitors, phase III studies of these new agents confirmed that both Factor Xa and thrombin are viable anticoagulation targets. © 2010 Elsevier Ltd. All rights reserved.


Levy J.H.,Duke University | Faraoni D.,Queen Fabiola Childrens University Hospital | Spring J.L.,Emory University | Douketis J.D.,McMaster University | Samama C.M.,Hotel Dieu University Hospital
Anesthesiology | Year: 2013

Managing patients in the perioperative setting receiving novel oral anticoagulation agents for thromboprophylaxis or stroke prevention with atrial fibrillation is an important consideration for clinicians. The novel oral anticoagulation agents include direct Factor Xa inhibitors rivaroxaban and apixaban, and the direct thrombin inhibitor dabigatran. In elective surgery, discontinuing their use is important, but renal function must also be considered because elimination is highly dependent on renal elimination. If bleeding occurs in patients who have received these agents, common principles of bleeding management as with any anticoagulant (including the known principles for warfarin) should be considered. This review summarizes the available data regarding the management of bleeding with novel oral anticoagulation agents. Hemodialysis is a therapeutic option for dabigatran-related bleeding, while in vitro studies showed that prothrombin complex concentrates are reported to be useful for rivaroxaban-related bleeding. Additional clinical studies are needed to determine the best method for reversal of the novel oral anticoagulation agents when bleeding occurs. .Copyright © 2013, the American Society of Anesthesiologists, Inc.


Weitz J.I.,McMaster University | Eikelboom J.W.,McMaster University | Samama M.M.,Hotel Dieu University Hospital
Chest | Year: 2012

This article focuses on new antithrombotic drugs that are in or are entering phase 3 clinical testing. Development of these new agents was prompted by the limitations of existing antiplatelet, anticoagulant, or fibrinolytic drugs. Addressing these unmet needs, this article (1) outlines the rationale for development of new antithrombotic agents; (2) describes the new antiplatelet, anticoagulant, and fibrinolytic drugs; and (3) provides clinical perspectives on the opportunities and challenges faced by these novel agents. © 2012 American College of Chest Physicians.


Kwaan H.C.,Northwestern University | Samama M.M.,Hotel Dieu University Hospital
Seminars in Thrombosis and Hemostasis | Year: 2010

The endothelium is recognized today as a functional and dynamic component of the body that plays an important part in health and disease. This article briefly reviews the role of endothelium in thrombosis and hemostasis. There is a paradigm shift from one that regards the endothelium as one single entity to the concept that the endothelium is heterogeneous. Thrombotic complications in many disorders show a predilection to specific locations, despite the fact that a hypercoagulable state affects the entire body. Likewise, bleeding is more commonly encountered in certain anatomical locations than in others. Recent observations of the heterogeneous distribution of coagulation and fibrinolytic factors in the endothelium and the adaptation of the endothelium to various stimuli may provide an explanation for the diverse phenotypes. Recognition of this changing paradigm is helpful to for the diagnosis and management of bleeding and thrombotic complications. It also helps in the understanding of the pathogenesis of many bleeding and thrombotic disorders, and in the development of new drug designs for site-specific therapy. Copyright © 2010 by Thieme Medical Publishers, Inc.


Amin A.N.,University of California at Irvine | Girard F.,Sanofi S.A. | Samama M.M.,Hotel Dieu University Hospital
Thrombosis and Haemostasis | Year: 2010

In the US, ambulatory status is often a criterion for stopping prophylaxis for venous thromboembolism (VTE). In an analysis of the prophylaxis in MEDical patients with ENOXaparin (MEDENOX) trial, ambulatory status was assessed as outcome and patients grouped accordingly for further analysis. Rates of VTE and bleeding were evaluated. Using multivariate logistic regression, the relationships between thromboprophylaxis, VTE risk, and ambulatory status were assessed. Ambulatory status was reached in 607/1,084 patients, in a mean time of 4.4 days. Thromboprophylaxis was provided for 7.3 and 7.7 days in the ambulatory and non-ambulatory groups. Although VTE rates were lower in ambulatory patients, enoxaparin 40 mg once daily significantly reduced the risk of VTE vs. placebo in ambulatory (3.3% vs. 10.6%; relative risk [RR] = 0.31; 95% confidence interval [CI], 0.13-0.78; p=0.008) and non-ambulatory patients (9.0% vs. 19.7%; RR = 0.46; 95% CI, 0.23-0.91; p=0.02). Major bleeding was not significantly different between enoxaparin and placebo in either group. By multivariate regression analysis, VTE risk in ambulatory patients was lower with enoxaparin vs. placebo (odds ratio [OR] = 0.28; 95% CI, 0.11-0.74; p=0.01), but higher in patients with a history of VTE (OR = 3.74; 95% CI, 1.59-8.84; p=0.003) or cancer (OR = 2.12; 95% CI, 1.00-4.48; p=0.049). Despite timely mobilisation, patients who become ambulatory are at VTE risk and experience a significant risk reduction with enoxaparin 40 mg. Therefore, it is essential that ambulatory patients receive recommended thromboprophylaxis. © Schattauer 2010.


Fournel L.,Hotel Dieu University Hospital
European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery | Year: 2013

Large cell neuroendocrine carcinoma (LCNEC) represents a relatively rare and poorly studied entity whose management is not clearly established. The aim of this study was to assess clinico-pathological characteristics, treatment modalities and outcomes of LCNEC. A retrospective study of patients operated on for LCNEC between 2000 and 2010 was carried out. Sixty-three patients (49 men, median age 64 years) with pathologically confirmed LCNEC of the lung were operated on between 2000 and 2010. Neoadjuvant chemotherapy was administered in 16 cases. Standard lobectomy, sleeve lobectomy, bilobectomy and pneumonectomy were performed in 63.5%, 9.5%, 1.6% and 15.8% of cases. There were two cases of extended resection. Sublobar resections were performed in four patients. Postoperative mortality was 1.6%. Postoperative staging was IA, IB, IIA, IIB, IIIA, IIIB and IV in 15.9%, 19%, 20.6%, 4.8%, 34.9%, 4.8% and 0% of cases, respectively. Adjuvant treatments were administered in 70% of cases. Overall 5-, and 8- year survival rates were 49.2% (37-61.6%) and 42% (28.8-56.4%), respectively. Multivariate analysis, including age >64 years, cumulative tobacco consumption, size of tumour, pT and pN parameters showed that only age (P = 0.05, RR 2.1 [0.99-4.43]) and pT parameter (P = 0.0078, RR 2.93[1.33-6.46]) were independent predictors of survival. Surgery may achieve satisfactory results in terms of survival, in spite of the similarities of LCNEC with small cell lung cancer. Multimodality management seems necessary.

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