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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.).

Purpose: We investigated whether acetaminophen, given at 2 g/day and 3 g/day might potentiate the anticoagulant effect of warfarin., Methods: Forty-five patients on stable warfarin therapy, enrolled in this prospective, randomized, parallel (three arms), placebo-controlled study, received a 10-day regimen of acetaminophen (2 g/day or 3 g/day) or placebo., Results: The mean maximal INR increase was 0.70 ± 0.49 and 0.67 ± 0.62 in patients receiving acetaminophen at 2 g/day and 3 g/day, respectively (P=0.01 for the respective comparisons versus placebo). The INR increase became significant on day 3 and was independently and significantly predicted by a maximal decrease in factor II (R(2)=0.36, P<0.0001), factor VII (R (2)=0.46, P<0.0001) and a maximal increase in acetaminophen plasma concentrations (R(2)=0.563, P<0.0001)., Conclusion: Acetaminophen, at 2 g/day or 3 g/day, enhanced the anticoagulant effect of warfarin in stable patients, thus requiring close INR monitoring in the clinical setting.

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., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Objective: To determine the incidence of clinical venous thromboembolic events in home-care patients presenting an acute condition resulting in a significant and transitory reduction in mobility. To describe the measures implemented to prevent thromboembolic risks., Method: Prospective, multicenter, observational cohort study conducted among 2,895 general practitioners randomly drawn, who included the first 6 eligible patients: outpatients aged 40 years and over in which a reduction in mobility longer than 48 hours was expected due to acute medical condition. The primary endpoint was the incidence of deep venous thrombosis and symptomatic pulmonary embolism at 3 weeks., Results: 16,532 patients whose average age was 71 years were included between October 2002 and June 2003. The most common acute conditions resulting in a reduction in mobility were infections, acute rheumatologic diseases and falls without fracture. The incidences of deep venous thrombosis and symptomatic pulmonary embolism were respectively 1% (95% CI = 0.84-1.14) and 0.20% (95% CI = 0.13-0.27). Cancer and personal or family history of venous thromboembolic disease were independent risk factors for thromboembolic events. A thromboprophylaxis was initiated in 35% of patients. The main decisive factor for prescription was the personal history of venous thromboembolic disease., Discussion: The risk of symptomatic venous thromboembolic disease in outpatients whose mobility is reduced for medical reasons is close to that described in hospitalized patients.

Background: Information about the variation in the risk for venous thromboembolism (VTE) and in prophylaxis practices around the world is scarce. The ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study is a multinational cross-sectional survey designed to assess the prevalence of VTE risk in the acute hospital care setting, and to determine the proportion of at-risk patients who receive effective prophylaxis., Methods: All hospital inpatients aged 40 years or over admitted to a medical ward, or those aged 18 years or over admitted to a surgical ward, in 358 hospitals across 32 countries were assessed for risk of VTE on the basis of hospital chart review. The 2004 American College of Chest Physicians (ACCP) evidence-based consensus guidelines were used to assess VTE risk and to determine whether patients were receiving recommended prophylaxis., Findings: 68 183 patients were enrolled; 30 827 (45%) were categorised as surgical, and 37 356 (55%) as medical. On the basis of ACCP criteria, 35 329 (51.8%; 95% CI 51.4-52.2; between-country range 35.6-72.6) patients were judged to be at risk for VTE, including 19 842 (64.4%; 63.8-64.9; 44.1-80.2) surgical patients and 15 487 (41.5%; 41.0-42.0; 21.1-71.2) medical patients. Of the surgical patients at risk, 11 613 (58.5%; 57.8-59.2; 0.2-92.1) received ACCP-recommended VTE prophylaxis, compared with 6119 (39.5%; 38.7-40.3; 3.1-70.4) at-risk medical patients., Interpretation: A large proportion of hospitalised patients are at risk for VTE, but there is a low rate of appropriate prophylaxis. Our data reinforce the rationale for the use of hospital-wide strategies to assess patients' VTE risk and to implement measures that ensure that at-risk patients receive appropriate prophylaxis.

Background: The safety and optimal use of prophylactic treatment with low-molecular-weight heparins in elderly patients with impaired renal function remain undefined., Methods: The primary aim of this study was to analyse, in 'real life', the influence of renal function, as assessed by creatinine clearance (CL(CR)), on the level of anti-Xa activity in medical hospitalised elderly patients receiving prophylactic dosages of enoxaparin. Consecutive hospitalised acutely ill medical patients aged >or=75 years receiving daily dosages of enoxaparin 4000 IU 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., Results: One hundred and twenty-five patients (31 men, 94 women), mean age 87.5 +/- 6.3 years, mean bodyweight 56.4 +/- 11.9 kg and mean CL(CR) 39.8 +/- 16.1 mL/min, were enrolled in the study. The mean maximum anti-Xa activity (day 1 to day 10) [anti-Xa(max1-10)] was 0.64 +/- 0.23 IU/mL (range 0.24-1.50 IU/mL). Weak negative correlations were found between CL(CR) and anti-Xa(max) and between bodyweight and anti-Xa(max). Mean anti-Xa(max) was slightly but significantly higher in patients with CL(CR) of 20-30 mL/min compared with patients with CL(CR) 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 <50 kg compared with patients weighing 50-60 kg or >60 kg (0.74 vs 0.64 and 0.52 IU/mL, respectively). Serious bleeding occurred in five patients, but anti-Xa(max) values in these patients were not different to those in patients without bleeding (p = 0.77). Individual anti-Xa(max) 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-Xa(max) 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)., Conclusion: Only CL(CR) <30 mL/min and bodyweight <50 kg were associated with significantly higher anti-Xa(max) 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.

Objective: To assess the effectiveness of providing doctors with written thromboprophylaxis prescription aids based on current recommendations., Design: A prospective trial of specific anticoagulant prescription forms: a 1-day survey before and after the intervention in each centre., Setting: 30 Internal Medicine departments of Assistance Publique-Hôpitaux de Paris., Subjects: All inpatients were included, except those who were either admitted or discharged on the day of the survey, and those receiving curative anticoagulant treatment., Interventions: The study included three parts: (i) a 1-day baseline survey; (ii) over the following 3-month period, departments were randomized into two groups: all practitioners in wards allocated to the intervention group were required to systematically use specific anticoagulant prescription forms, whilst doctors in the control group continued prescribing according to their usual practices and (iii) a 1-day postintervention survey., Main Outcome Measure: The proportion of prescriptions in accordance with the recommendations., Results: 1,469 patients were included. The intervention produced a significant reduction in the frequency of over-prescriptions, from 25% to 14% of the patients who did not meet the guideline criteria (adjusted OR: 0.3; 95% CI: 0.1-0.8). Using specific forms did not improve under-prescription of anticoagulants. A little over 60% of the patients who met guideline criteria for thromboprophylaxis were prescribed anticoagulants in both intervention and control wards, either at baseline or after intervention., Conclusions: Multitargeted interventions using a variety of means and strategies should still be considered to improve prescriptions that may have a significant impact on health expenses and, most importantly, on patients outcomes.

Background: Hospitalised medical patients are at significant risk of venous thromboembolic disease through fatal pulmonary embolism; low-molecular-weight heparins have been proved efficient in preventing deep venous thrombosis in surgical and medical patients, but their effect on mortality in bedridden medical patients remains unknown., Methods: In a multi-centre, randomised, double-blind, placebo-controlled study, 2,474 consecutive patients aged over 40 years admitted to internal medicine departments in the last 24 h and unable to move alone were randomised to receive 0.3 ml nadroparin (7,500 anti-Xa units) or placebo for up to 21 days. The primary end-point was overall mortality at day 21., Results: There were no significant differences between the patients' characteristics. Overall mortality between the two groups was not statistically different [10.08% (124 of 1,230) versus 10.29% (128 of 1,244), respectively, in the nadroparin and in the placebo groups; relative risk reduction 0.02, CI (-0.27, +0.25), P=0.89]. An autopsy was performed in 123 of the 252 patients who died (49%). Pulmonary embolism was discovered at autopsy in 10 of 63 patients in the nadroparin group and in 17 of 60 in the placebo group [relative risk reduction 0.38, CI (-0.27, +0.70), P=0.13]., Conclusion: Nadroparin does not have a significant effect on mortality in bedridden medical patients, based on the study results. The study provides no data suggesting that low-molecular-weight heparins might reduce the incidence of thromboembolic in-patients hospitalised for an acute medical disease.

The risk of venous thromboembolism (VTE) in medical patients is generally underestimated. However, recent studies including two large double-blind placebo-controlled trials, the Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilised Patients trial (PREVENT) and prophylaxis in MEDical patients with ENOXaparin, study show that low-molecular-weight heparins (LMWHs) provide effective thromboprophylaxis for medical patients at risk from VTE without increasing the risk of bleeding. In PREVENT the significant 45%, reduction in VTE among patients receiving dalteparin 5000 IU once daily for 14 days was attributed entirely to a reduction in clinically relevant VTE. The recently published guidelines for the prevention and treatment of VTE, issued by the American College of Chest Physicians, recommend prophylaxis with LMWHs (or low-dose unfractionated heparin) in acutely ill medical patients with risk factors for VTE (grade 1A). Current evidence should encourage the more widespread adoption of thromboprophylaxis in at-risk medical patients, and thus reduce the number of preventable deaths and complications due to VTE.

Aim: To quantify the effect of paracetamol on the anticoagulant effect of warfarin under normal clinical conditions., Patients and Methods: In a prospective double-blind, cross-over, placebo-controlled study, 11 patients on stable warfarin therapy received in random order two 14-day regimens of paracetamol 4 g day(-1) or placebo, with a 14-day or more wash-out period in between, time necessary to fulfil the inclusion criteria., Results: In patients on paracetamol, the mean maximum increase in the International Normalized Ratio (INR) observed was 1.04 +/- 0.55 vs. 0.20 +/- 0.32 in those on placebo (P = 0.003). The mean maximum INR observed was significantly higher with paracetamol than with placebo (3.47 vs. 2.61, P = 0.01). In patients receiving paracetamol, the mean observed INR was significantly increased after 4 days (+ 0.6 +/- 0.6, P < 0.001)., Conclusion: Paracetamol at 4 g day(-1) induces a significant increase in INR in patients receiving a stable regimen of warfarin, increasing the risk of bleeding associated with warfarin.

Oral anticoagulant (OA) therapy is widely used in elderly patients because of the increase of indications with age (venous thromboembolism and atrial fibrillation). A particularity of France is to administer three different OAs (warfarin and more often fluindione or acenocoumarol). In an attempt to assess the particularities of managing all three OAs in elderly patients in clinical practice, we studied the modalities of anticoagulation of 187 consecutive OA therapy patients (mean age = 74.4 years) hospitalized in an Internal Medicine department (95 patients on OA at admission and 92 patients initiated on OA during hospitalization). Patients aged 75 years or older more often required a low dosage of OA than those aged younger than 75, irrespective of the OA (warfarin and more often fluindione or acenocoumarol). Ambulatory patients aged 75 years or older were more susceptible to receive acenocoumarol than were ambulatory patients younger than 75 years (respectively 30/67 vs 8/28, respectively), whereas fluindione was prescribed at the same frequency in ambulatory patients and hospitalized patients, regardless of age group (> or =75: 32/67; <75: 19/28). In hospitalized patients with OA induction, fluindione was prescribed as often in patients younger than 75 than in patients aged 75 years or older (40/47 vs 35/45, respectively). On admission, international normalized ratio was in the target range in 26 of the 95 patients (27.4%) and was >3 in 51 of the 95 patients (51.6%). OA therapy was stopped during hospitalization in 35 patients (36.8%). In conclusion, we have a picture of the practice of anticoagulation with three different OA therapies. Although it is usually recommended to prescribe long half-time OA therapy (2), it appears that short half-time therapy such as acenocoumarol still represents an important number of OA prescriptions in France, especially in ambulatory and elderly patients. International normalized ratio is not in the target range as often as expected in clinical practice, and elderly patients require specific modalities of OA therapy management, such as half dose initiation, use of long-half-life OA, and close monitoring.

Paracetamol (acetaminophen) is the analgesic and antipyretic therapy of choice for patients receiving oral anticoagulation. It is widely used by patients in both prescription and over-the-counter products, resulting in frequent co-prescription with oral anticoagulants, especially in elderly patients. Indeed, older patients are the most likely to receive this combination of drugs because indications for both oral anticoagulation and analgesic therapy increase with age. For many years reports have presented evidence both for and against the idea that paracetamol may potentiate the anticoagulant effect of oral anticoagulants, thus increasing haemorrhagic risk in patients receiving this combination of drugs. This issue has continued to be a matter of debate in recent publications. No clear practical conclusion can be drawn from the studies because of methodological bias and the lack of clinical relevance. No prospective, randomised study assessing the effect of paracetamol on the anticoagulant effect of oral anticoagulants as used in clinical practice (i.e. the types of patients and dosages used in clinical practice) are available in the literature. The implications are considerable since on the one hand, the ingestion of paracetamol may be a cause of altered anticoagulation in patients who regularly take oral anticoagulation and who may have a haemorrhagic risk factor; and on the other hand, paracetamol might be the analgesic drug of choice that can be used without the need for any restrictions in patients receiving oral anticoagulant drugs. A comprehensive search of Medline and EMBASE for studies and case reports from 1966-2002 was performed in order to review the available literature on the interaction between paracetamol and oral anticoagulant drugs. In conclusion, the potential interaction between oral anticoagulant drugs and paracetamol is an important unanswered question, due to the growing incidence of the concomitant use of these drugs and the possible bleeding implications. The association between paracetamol and the occurrence of excessive INR values remains controversial due to lack of prospective clinical studies assessing the effect of the prescription of paracetamol in patients receiving long-term oral anticoagulation in clinical conditions. Such a study is currently ongoing.

Unlabelled: FREQUENCY AND CONSEQUENCES: The incidence of atrial fibrillation (AF) increases regularly with age and affects nearly 10% of persons aged over 80. The risk of thromboembolism (notably stroke) associated is enhanced the older the patient and the more cardiovascular risk factors she/he exhibits. ADVANTAGES AND RISKS OF ANTICOAGULANTS: Treatment with anticoagulants is the only treatment that has demonstrated its efficacy in reducing the risks of thromboembolism, however there is a risk of haemorrhage., In Practice: A patient with AF exhibits both a risk of thromboembolism and a risk of haemorrhage. When confronted with such patients, the practitioner must choose an antithrombotic (anticoagulant or anti-arrhythmic agent) after careful objective and individual assessment of all the risks present in a given patient.

A multicenter, randomized double-blind study compared in two parallel groups the efficacy and safety of a low molecular weight heparin (LMWH) enoxaparin 20 mg once daily, with unfractionated heparin (UFH) 5000 IU twice daily, administered subcutaneously for 10 days, in the prevention of venous thrombosis disease in 442 hospitalized elderly patients bedridden for an acute medical illness. The main efficacy endpoint was defined as the occurrence of venous thrombosis, diagnosed by a daily fibrinogen uptake test, and/or documented clinical pulmonary embolism. Intention-to-treat analysis of efficacy showed that the incidence of venous thromboembolic events was low: 4.8% (10/207) in the LMWH group (9 episodes of isotopic venous thrombosis and one of scintigraphic pulmonary embolism), and 4.6% (10/216) in the UFH group (10 episodes of isotopic venous thrombosis). The two treatments were equivalent, where equivalence was defined as a maximum difference of 7% between the two groups (p = 0.0005). There were no significant differences in terms of safety between the 216 patients in the LMWH group and the 223 patients in the UFH group who received at least one injection of the randomized treatment. During the study period, 15 patients (3.4%) died (7 in the LMWH group and 8 in the UFH group): 2 sudden deaths, one in each group including one case in which pulmonary embolism could not be excluded since no autopsy was performed, and 13 others deaths unrelated to the study treatments. Six patients (1.4%) presented a bleeding complication: 2 (0.9%) in the enoxaparin group (one major and one minor hemorrhage), and 4 (1.8%) in the UFH group (2 major and 2 minor hemorrhages). These results indicate that subcutaneous enoxaparin 20 mg once daily for 10 days is as effective and well tolerated as subcutaneous UFH 5000 IU twice daily in the prevention of venous thromboembolic disease in bedridden elderly in-patients presenting an acute medical illness.