M. Samama

Extended-Duration Venous Thromboembolism Prophylaxis in Acutely Ill Medical Patients With Recently Reduced Mobility: A Randomized Trial

BACKGROUND Extended-duration low-molecular-weight heparin has been shown to prevent venous thromboembolism (VTE) in high-risk surgical patients. OBJECTIVE To evaluate the efficacy and safety of extended-duration enoxaparin thromboprophylaxis in acutely ill medical patients. DESIGN Randomized, parallel, placebo-controlled trial. Randomization was computer-generated. Allocation was centralized. Patients, caregivers, and outcome assessors were blinded to group assignment. (ClinicalTrials.gov registration number: NCT00077753) SETTING: 370 sites in 20 countries across North and South America, Europe, and Asia. PATIENTS Acutely ill medical patients 40 years or older with recently reduced mobility (bed rest or sedentary without [level 1] or with [level 2] bathroom privileges). Eligibility criteria for patients with level 2 immobility were amended to include only those who had additional VTE risk factors (age >75 years, history of VTE, or active or previous cancer) after interim analyses suggested lower-than-expected VTE rates. INTERVENTION Enoxaparin, 40 mg/d subcutaneously (2975 patients), or placebo (2988 patients), for 28 +/- 4 days after receiving open-label enoxaparin for an initial 10 +/- 4 days. MEASUREMENTS Incidence of VTE up to day 28 and of major bleeding events up to 48 hours after the last study treatment dose. RESULTS Extended-duration enoxaparin reduced VTE incidence compared with placebo (2.5% vs. 4%; absolute risk difference favoring enoxaparin, -1.53% [95.8% CI, -2.54% to -0.52%]). Enoxaparin increased major bleeding events (0.8% vs. 0.3%; absolute risk difference favoring placebo, 0.51% [95% CI, 0.12% to 0.89%]). The benefits of extended-duration enoxaparin seemed to be restricted to women, patients older than 75 years, and those with level 1 immobility. LIMITATION Estimates of efficacy and safety for the overall trial population are difficult to interpret because of the change in eligibility criteria during the trial. CONCLUSION Use of extended-duration enoxaparin reduces VTE more than it increases major bleeding events in acutely ill medical patients with level 1 immobility, those older than 75 years, and women. PRIMARY FUNDING SOURCE Sanofi-aventis.

An international multicenter randomized study of computer‐assisted oral anticoagulant dosage vs. medical staff dosage

Summary.  Background: Increased demand for oral anticoagulants is overwhelming facilities worldwide, resulting in increasing use of computer assistance. A multicenter clinical endpoint study has been performed to compare the safety and effectiveness of computer‐assisted dosage with dosage by experienced medical staff at the same centers. Methods: A randomized study of dosage of two commercial computer‐assisted dosage programs (PARMA 5 and DAWN AC) vs. manual dosage at 32 centers with an established interest in oral anticoagulation in 13 countries. The aim was to recruit a minimum of 16 000 patient‐years randomized to medical staff or computer‐assisted dosage. In total, 13 219 patients participated, 6503 patients being randomized to medical staff and 6716 to computer‐assisted dosage. The safety and effectiveness of computer‐assisted dosage were compared with those of medical staff dosage. Results: In total, 13 052 patients were recruited (18 617 patient‐years). International Normalized Ratio (INR) tests numbered 193 890 with manual dosage and 193 424 with computer‐assisted dosage. The number of clinical events with computer‐assisted dosage was lower (P = 0.1), but in the 3209 patients with deep vein thrombosis/pulmonary embolism, they were reduced by 37 (24%, P = 0.001). Time in target INR range was significantly improved by computer assistance as compared with medical staff dosage at the majority of centers (P < 0.001). Conclusions: The safety and effectiveness of computer‐assisted dosage has been demonstrated using two different marketed programs in comparison with experienced medical staff dosage at the centers with established interest in anticoagulation. Significant prevention of clinical events in patients with deep vein thrombosis/pulmonary embolism and the achievement of target INR in all clinical groups has been observed. The reliability and safety of other marketed computer‐assisted dosage programs need to be established.

Effect of the anti‐factor Xa and anti‐factor IIa activities of low‐molecular‐weight heparins upon the phases of thrombin generation

Summary.  Background: Low‐molecular‐weight heparins (LMWHs), derived from unfractionated heparin (UFH) by different depolymerization procedures, vary in both their relative abilities to enhance the inhibition of FXa (anti‐FXa) and thrombin (anti‐FIIa), and in their physicochemical properties. Objective: We aimed to profile the inhibition of thrombin generation induced by bemiparin, enoxaparin, nadroparin, dalteparin and tinzaparin in platelet‐rich plasma (PRP), and to compare them with UFH and fondaparinux (a synthetic pentasaccharide that specifically enhances FXa inhibition). Methods: Different LMWHs, UFH or fondaparinux were added to normal PRP. Thereafter, tissue factor‐triggered thrombin generation was assessed using the Thrombogram–Thrombinoscope® assay. Results: At equivalent anti‐FIIa activity concentrations, LMWHs and UFH exhibited similar inhibitory effects upon thrombin generation. However, when used at equivalent anti‐FXa activity concentrations, tinzaparin was significantly more active than the other LMWHs at inhibiting thrombin generation, and had similar activity to that of UFH. Enoxaparin, nadroparin and dalteparin all showed similar inhibitory activities. In these experiments, bemiparin exhibited the lowest inhibitory effect on thrombin generation of all the LMWHs. At 0.1 μg mL–1 (0.093 anti‐FXa IU mL–1), fondaparinux inhibited the rate of thrombin generation by 50%. A 7‐fold higher concentration of fondaparinux was required to inhibit the endogenous thrombin potential by 50%. Conclusions: LMWHs have a variable inhibitory effect on thrombin generation in vitro when compared by anti‐FXa activity, but are similar when compared by their anti‐FIIa activities. The rate of thrombin generation during the propagation phase, rather than the endogenous thrombin potential, is more sensitive to the anticoagulant activity of fondaparinux and the polysaccharide chains of LMWHs possessing only anti‐FXa activity.

Extended-duration thromboprophylaxis in acutely ill medical patients with recent reduced mobility: methodology for the EXCLAIM study.

AbstractBackground: Venous thromboembolism (VTE) is a significant cause of mortality and morbidity in medical patients. Although thromboprophylaxis with enoxaparin reduces the risk of VTE in these patients, the optimal duration of therapy is not currently known. The EXCLAIM (EXtended CLinical prophylaxis in Acutely Ill Medical patients) study is designed to compare the efficacy and safety of extended-duration thromboprophylaxis using enoxaparin with the standard regimen of enoxaparin in acutely ill medical patients with recent reduced mobility. Methods: All enrolled acutely ill medical patients receive enoxaparin 40 mg subcutaneously once daily for 10 ± 4 days. Eligible patients are then randomized in a blinded manner to receive either extended-duration thromboprophylaxis with enoxaparin 40 mg subcutaneously once daily or placebo subcutaneously once daily for an additional 28 ± 4 days. The primary efficacy endpoint is the incidence of VTE during the 28 ± 4 days after randomization. This study utilizes a standardized bilateral compression ultrasonography examination protocol that consists of an intensive interrogation of the deep veins of the lower extremities for proximal deep-vein thrombosis. The secondary efficacy endpoints are the rate of symptomatic VTE during the 3 months after randomization and mortality at 3 and 6 months after enrollment. The primary safety endpoint is the incidence of major hemorrhagic complications during the 28 ± 4 days after randomization. Results: To date, 3,983 patients, with a broad range of medical conditions, have been included in the study. Almost one third of the enrolled patients with reduced mobility are acutely ill due to respiratory insufficiency and one third have infectious diseases. Conclusions: The EXCLAIM study is designed to show the efficacy and safety of extended-duration thromboprophylaxis using enoxaparin in acutely ill medical patients with recent reduced mobility, which may potentially lead to a reduction in the incidence of late VTE events in these patients.Abbreviated abstractThe EXCLAIM (EXtended CLinical prophylaxis in Acutely Ill Medical patients) study, involving 4,726 acutely ill medical patients with recent reduced mobility, is designed to compare the efficacy and safety of extended-duration thromboprophylaxis using 40 mg once daily enoxaparin (38 ± 4 days) with the standard regimen for enoxaparin (40 mg once daily for 10 ± 4 days). The objective of this study is to demonstrate that the extended-duration enoxaparin regimen is an effective and safe thromboprophylaxis regimen out of hospital.

The inhibition of the generation of thrombin and the antithrombotic effect of a pentasaccharide with sole anti-factor Xa activity

A chemically synthesized heparin pentasaccharide (Institut Choay, Paris, France) has been shown to exhibit an antithrombotic action in a rabbit stasis induced thrombosis model, in an IV dose range of 25 to 200 micrograms/kg (0.5 to 3.5 micrograms/ml plasma circulating concentrations). Ex vivo plasma analysis from treated animals revealed expected anti-factor Xa activity but no direct inhibitory effect against thrombin. Global anticoagulant activities were not found by PT and APTT methods. Platelet activation remained unaffected at the antithrombotic dosages of pentasaccharide. To more specifically elucidate the anti-factor Xa mediated antithrombotic mechanism of action of this pentasaccharide, it was studied in several thrombin generation assays. Pentasaccharide added to human and rabbit plasmas in vitro from 0 to 5.0 micrograms/ml produced a concentration dependent effect up to a 35 to 50% inhibition of generated thrombin. In ex vivo studies similar concentration dependent inhibition of thrombin generation was observed. Analysis of plasma obtained from animals in which a complete antithrombotic effect was observed in vivo demonstrated an approximate 45 to 55% inhibition of thrombin generation. These results indicate that a relationship exists between the pentasaccharide induced inhibition of experimental venous stasis thrombosis and the inhibition of thrombin generation.

Clinical studies with anticoagulants to improve survival in cancer patients.

Cancer is linked with hypercoagulability and risk of thrombosis and this close association was recognized by Armand Trousseau in 1865. The relation between cancer and blood coagulation is reciprocal: cancer induces a hypercoagulable state and predisposes to thrombosis and activation of platelets, blood coagulation and fibrinolysis interfere with tumor cell biology, tumor growth, angiogenesis and metastatic process. In the present article, we analyze the clinical trials which assessed the influence of anticoagulant treatment on the survival of patients with cancer. The available data show that low-molecular-weight heparins (LMWHs) tend to be more effective and safer than vitamin K antagonists (VKA) in improving survival in patients with cancer. The beneficial effect of anticoagulation with either LMWHs or VKA is not universal for all patients with cancer. There are some histological types of cancers which, at early stages, appear to be more sensitive than others to the effect of anticoagulant treatment. The available clinical trials, although limited, are encouraging for the beneficial effect of anticoagulant treatment on the survival of cancer patients. More clinical trials are needed, targeting groups of patients homogenous regarding the type of cancer, the stage of the disease and life expectancy. The forthcoming clinical trials have to address some issues regarding the optimal dose, the timing and the duration of treatment with LMWH in relation to chemotherapy or other anticancer therapies.

Red blood cell aggregability in patients with a history of leg vein thrombosis: influence of post-thrombotic treatment

Summary. Reversible aggregation or red blood cells (RBC) plays an important role in determining blood flow properties, and it is this aggregation which increases blood viscositgy at low shear rates. The structure and sites of venous thrombi, as well as the fact that stasis is a major predisposing factor in venous thrombosis, suggest a strong association between vein thrombosis, slow blood flow and increased blood viscosity. RBC aggregation and disaggregation were measured (SEFAM erythroaggregameter, France) in 54 patients with a history of unexplained leg vein thrombosis. Results were compared to those of controls classified according to age. Increased RBC aggregability was observed in 41% of the patients, and the mean values indicated a significant elevation of RBC aggregability in patients when compared with controls (P < 0.05). Subgroups were compared to study the influence of thrombus recurrence and thrombosis type (deep versus superficial vein thrombosis) on the aggregation parameters. No significant difference was found between these subgroups. The use of compression stockings and veinotropic drugs tended to reduce the abnormalities in RBC aggregability (P < 0.05). An increase in RBC aggregability and in the shear resistance of RBC aggregates, by predisposing ro circulatory stasis, is likely to contribute to the evolution and complications of leg vein thrombosis.

Pregnancy-associated venous thromboembolism (VTE) in combined heterozygous factor V Leiden (FVL) and prothrombin (FII) 20210 A mutation and in heterozygous FII single gene mutation alone.

Summary. The risk of venous thromboembolism (VTE) in the absence of prophylaxis was evaluated in a retrospective study of 47 women (84 pregnancies) with combined thrombophilia [heterozygous factor V Leiden (FVL) plus prothrombin (FII) 20210A mutation (group I)] and in 82 women (193 pregnancies) with the FII alone (group II). VTE was more frequent in group I than in group II [17·8% versus 6·2%, P = 0·003, relative risk (RR) 2·9, 95% confidence interval (CI) 1·4–5·9], ante partum (7·1% and 2·1%) and post partum (11·5% and 4·2%). The risk was higher in index cases than in family members (RR 2·5, 95% CI 1·2–5·2 and RR 2·1, 95% CI 0·2–22·3 respectively) Even women who had no history of VTE before pregnancy had an increased risk (RR 2·2, 95% CI 1·0–4·8). Our results suggest that, during ante partum, prophylaxis is indicated in women with combined thrombophilia and with a VTE before pregnancy. In those without VTE before pregnancy, prophylaxis might be decided for each individual case, taking into consideration all risk factors. In women with the FII mutation alone, the low risk may not justify prophylaxis in the absence of previous VTE. In post partum, prophylaxis is indicated in all cases.

Importance of a 3-0-sulfate group in a heparin pentasaccharide for antithrombotic activity

Previous theoretical and experimental evidence led to the formulation of a specific pentasaccharide structure which represents the site in heparin for binding to antithrombin III. This pentasaccharide was subsequently synthesized. A pentasaccharide of the same structure but lacking only the sulfate group on the hydroxyl group of the middle glucosamine (position C-3) was also synthesized to test the structure - activity relationships. Previous biochemical studies showed the 3-O-desulfated pentasaccharide to have a low affinity binding to AT III and to be devoid of the high anti-factor Xa activity characteristic of the pentasaccharide. Our in vivo studies, in a venous stasis thrombosis model proved the 3-O-desulfated pentasaccharide, at equigravimetric dosages, to be devoid of the antithrombotic activity previously reported for the pentasaccharide. These studies confirm the fact that inhibition of factor Xa at a high level of activity produces an antithrombotic effect.

Diagnosis And Clinical Characteristics Of Inherited Activated Protein C Resistance

The diagnostic strategies and clinical characteristics of thrombophilia associated with heterozygous or homozygous factor V Leiden mutation have been determined according to the literature and to a personal study in 51 families. Factor V mutation was present in the 51 propositi and in 84 out of 125 family members (81 heterozygous, 3 homozygous). Venous thrombosis was observed in all the propositi, in 17 of the 84 family members with the mutation and in 6 of the 41 with a normal APC resistance test and no mutation. An associated protein C or protein S deficiency was present in 5 families (10%). The most frequent clinical manifestations were superficial or deep vein thrombosis and/or pulmonary embolism, but also thrombosis at an unusual site (cerebral, mesenteric or central retinal vein). A causal relationship is frequently difficult to demonstrate. A precipitating factor was observed in 84% of cases and a recurrent thrombotic episode occurred in 50% of propositi. The risk of thrombosis associated with pregnancy was high in the post-partum period, especially in homozygous women. In the 28 homozygous subjects, markers of coagulation activation were frequently elevated in untreated patients. Finally, the efficacy of anticoagulant treatment is suggested but the long period often observed between treatment interruption and a recurrence does not militate in favour of long term treatment.