Neurological outcomes in patients with ischemic stroke receiving enoxaparin or heparin for venous thromboembolism prophylaxis: subanalysis of the Prevention of VTE after Acute Ischemic Stroke with LMWH (PREVAIL) study.

BACKGROUND AND PURPOSE: The Prevention of VTE after Acute Ischemic Stroke with LMWH (PREVAIL) study demonstrated that enoxaparin was superior to unfractionated heparin (UFH) in preventing venous thromboembolism in patients with ischemic stroke and was associated with a small but statistically significant increase in extracranial hemorrhage rates. In this PREVAIL subanalysis, we evaluate the long-term neurological outcomes associated with the use of enoxaparin compared with UFH. We also determine predictors of stroke progression. METHODS: Acute ischemic stroke patients aged >or=18 years, who could not walk unassisted, were randomized to receive enoxaparin (40 mg once daily) or UFH (5000 U every 12 hours) for 10 days. Patients were stratified according to baseline stroke severity using the National Institutes of Health Stroke Scale score. End points for this analysis included stroke progression (>or=4-point increase in National Institutes of Health Stroke Scale score), neurological outcomes up to 3 months postrandomization (assessed using National Institutes of Health Stroke Scale score and modified Rankin Scale score), and incidence of intracranial hemorrhage. RESULTS: Stroke progression occurred in 45 of 877 (5.1%) patients in the enoxaparin group and 42 of 872 (4.8%) of those receiving UFH. Similar improvements in National Institutes of Health Stroke Scale and modified Rankin Scale scores were observed in both groups over the 90-day follow-up period. Incidence of intracranial hemorrhage was comparable between groups (20 of 877 [2.3%] and 22 of 872 [2.5%] in enoxaparin and UFH groups, respectively). Baseline National Institutes of Health Stroke Scale score, hyperlipidemia, and Hispanic ethnicity were independent predictors of stroke progression. CONCLUSIONS: The clinical benefits associated with use of enoxaparin for venous thromboembolism prophylaxis in patients with acute ischemic stroke are not associated with poorer long-term neurological outcomes or increased rates of symptomatic intracranial hemorrhage compared with UFH.

The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison.

BACKGROUND: Venous thromboembolism prophylaxis with low molecular weight heparin or unfractionated heparin is recommended in acute ischaemic stroke, but which regimen provides optimum treatment is uncertain. We aimed to compare the efficacy and safety of enoxaparin with that of unfractionated heparin for patients with stroke. METHODS: 1762 patients with acute ischaemic stroke who were unable to walk unassisted were randomly assigned within 48 h of symptoms to receive either enoxaparin 40 mg subcutaneously once daily or unfractionated heparin 5000 U subcutaneously every 12 h for 10 days (range 6-14). Patients were stratified by National Institutes of Health Stroke Scale (NIHSS) score (severe stroke > or =14, less severe stroke <14). The primary efficacy endpoint was the composite of symptomatic or asymptomatic deep vein thrombosis, symptomatic pulmonary embolism, or fatal pulmonary embolism. Primary safety endpoints were symptomatic intracranial haemorrhage, major extracranial haemorrhage, and all-cause mortality. This study is registered with ClinicalTrials.gov, number NCT00077805. FINDINGS: In the efficacy population (ie, one or more dose received, presence of deep vein thrombosis or pulmonary embolism, or assessment for venous thromboembolism), enoxaparin (n=666) and unfractionated heparin (669) were given for 10.5 days (SD 3.2). Enoxaparin reduced the risk of venous thromboembolism by 43% compared with unfractionated heparin (68 [10%] vs 121 [18%]; relative risk 0.57, 95% CI 0.44-0.76, p=0.0001; difference -7.9%, -11.6 to -4.2); this reduction was consistent for patients with an NIHSS score of 14 or more (26 [16%] vs 52 [30%]; p=0.0036) or less than 14 (42 [8%] vs 69 [14%]; p=0.0044). The occurrence of any bleeding was similar with enoxaparin (69 [8%]) or unfractionated heparin (71 [8%]; p=0.83). The frequency of the composite of symptomatic intracranial and major extracranial haemorrhage was small and closely similar between groups (enoxaparin 11 [1%] vs unfractionated heparin 6 [1%]; p=0.23). We noted no difference for symptomatic intracranial haemorrhage between groups (4 [1%] vs 6 [1%], respectively; p=0.55); the rate of major extracranial bleeding was higher with enoxaparin than with unfractionated heparin (7 [1%] vs 0; p=0.015). INTERPRETATION: Our results suggest that for patients with acute ischaemic stroke, enoxaparin is preferable to unfractionated heparin for venous thromboembolism prophylaxis in view of its better clinical benefits to risk ratio and convenience of once daily administration.

Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

This article discusses the prevention of venous thromboembolism (VTE) and is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggestions imply that individual patient values may lead to different choices (for a full discussion of the grading, see the "Grades of Recommendation" chapter by Guyatt et al). Among the key recommendations in this chapter are the following: we recommend that every hospital develop a formal strategy that addresses the prevention of VTE (Grade 1A). We recommend against the use of aspirin alone as thromboprophylaxis for any patient group (Grade 1A), and we recommend that mechanical methods of thromboprophylaxis be used primarily for patients at high bleeding risk (Grade 1A) or possibly as an adjunct to anticoagulant thromboprophylaxis (Grade 2A). For patients undergoing major general surgery, we recommend thromboprophylaxis with a low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH), or fondaparinux (each Grade 1A). We recommend routine thromboprophylaxis for all patients undergoing major gynecologic surgery or major, open urologic procedures (Grade 1A for both groups), with LMWH, LDUH, fondaparinux, or intermittent pneumatic compression (IPC). For patients undergoing elective hip or knee arthroplasty, we recommend one of the following three anticoagulant agents: LMWH, fondaparinux, or a vitamin K antagonist (VKA); international normalized ratio (INR) target, 2.5; range, 2.0 to 3.0 (each Grade 1A). For patients undergoing hip fracture surgery (HFS), we recommend the routine use of fondaparinux (Grade 1A), LMWH (Grade 1B), a VKA (target INR, 2.5; range, 2.0 to 3.0) [Grade 1B], or LDUH (Grade 1B). We recommend that patients undergoing hip or knee arthroplasty or HFS receive thromboprophylaxis for a minimum of 10 days (Grade 1A); for hip arthroplasty and HFS, we recommend continuing thromboprophylaxis > 10 days and up to 35 days (Grade 1A). We recommend that all major trauma and all spinal cord injury (SCI) patients receive thromboprophylaxis (Grade 1A). In patients admitted to hospital with an acute medical illness, we recommend thromboprophylaxis with LMWH, LDUH, or fondaparinux (each Grade 1A). We recommend that, on admission to the ICU, all patients be assessed for their risk of VTE, and that most receive thromboprophylaxis (Grade 1A).

Prevention of venous thromboembolism after ischemic stroke.

PURPOSE OF REVIEW: Venous thromboembolism is an important cause of morbidity and mortality after stroke. Its potential for prevention is substantial with the use of antithrombotic agents, but there is no agreement on the relative advantages and disadvantages of various available prophylactic drugs. There have been recent publications that clarify some of these issues. RECENT FINDINGS: Data from recently published controlled clinical trials have added to our understanding of the risk-benefit ratio of the two most commonly used antithrombotics: unfractionated heparin and low-molecular-weight heparins. These data suggest that the low-molecular-weight heparin enoxaparin has a superior clinical profile in comparison with unfractionated heparin. SUMMARY: Antithrombotic agents are the mainstay in the prevention of venous thromboembolism after stroke. The highly effective unfractionated heparin and low-molecular-weight heparins may have a different clinical profile that could have a substantial impact in clinical practice.

Multicenter evaluation of the use of venous thromboembolism prophylaxis in acutely ill medical patients in Canada.

BACKGROUND: Venous thromboembolism (VTE) prophylaxis in acutely ill medical patients has been shown to be safe and effective. Underutilization of this patient safety practice may result in avoidable mortality and morbidity. OBJECTIVES: We aimed to determine the proportion of hospitalized, acutely ill medical patients across Canada who were eligible to receive thromboprophylaxis and to evaluate the frequency, determinants and appropriateness of its use. PATIENTS/METHODS: CURVE is a national, multicenter chart audit of 29 Canadian hospitals. Data were collected on consecutive patients admitted to hospital for an acute medical illness during a defined 3-week study period. Information on demographic and clinical characteristics, risk factors for VTE and bleeding and use of VTE prophylaxis were recorded. The indications for and appropriateness of VTE prophylaxis were assessed using pre-specified criteria based on international consensus guidelines. Multivariable analyses were performed to identify determinants of prophylaxis use. RESULTS: Of the 4124 medical admissions screened over the study period, 1894 patients (46%) were eligible for study inclusion. The most common specified admitting diagnoses were severe infection (28%), COPD exacerbation or respiratory failure (12%), malignancy (9%) and congestive heart failure (8%). Thromboprophylaxis was indicated in 1702 (90%) study patients. Overall, some form of prophylaxis was administered to 23% of all patients. However, only 16% received appropriate thromboprophylaxis. Factors independently associated with greater use of prophylaxis included internist (vs. other specialty) as attending physician (OR 1.33, 95% confidence interval (CI) [1.03, 1.71]), university-associated (vs. community) hospital (OR 1.46, 95% CI [1.03, 2.07]), immobilization (per day) (OR 1.60, 95% CI [1.45, 1.77]), presence of >or=1 VTE risk factors (OR=1.78, 95% CI [1.35, 2.34]) and duration of hospitalization (per day of stay) (OR 1.05, 95% CI [1.03, 1.07]), however, use of prophylaxis was unacceptably low in all groups. Patients with cancer had a significantly reduced likelihood of receiving prophylaxis (OR=0.40, 95% CI [0.24, 0.68]). Presence of risk factors for bleeding did not influence the use or choice of prophylaxis. CONCLUSION: Most patients hospitalized for medical illness had indications for thromboprophylaxis, yet only 16% received appropriate prophylaxis. Efforts should be made to elucidate the reasons that underlie the very low rate of thromboprophylaxis in medical patients and to develop and test strategies to improve implementation of this patient safety practice.

Vitamin K antagonists and direct thrombin inhibitors: present and future.

Warfarin and related compounds are efficacious and safe in a variety of clinical thrombotic disorders; however, these drugs have a narrow therapeutic window, whereby inadequate therapy is associated with an increased thrombotic risk and overanticoagulation is associated with bleeding. Therefore, attempts have been made to develop alternatives to warfarin. Ximelagatran, an oral direct thrombin inhibitor, has been shown to be as efficacious and safe as warfarin for the prevention and treatment of different thrombotic disorders. This article reviews the pharmacology of the coumarins, the most commonly used vitamin K antagonists, and the practical aspects regarding their use in the management of thrombotic disorders. The future role of the oral direct thrombin inhibitor ximelagatran also is reviewed.

Low-molecular-weight heparin for the treatment of venous thromboembolism in the elderly.

Venous thromboembolism (deep vein thrombosis and/or pulmonary embolism) is a common problem in the elderly population. Indeed, increasing age is a significant risk factor for venous thromboembolism. The treatment of venous thromboembolism in the elderly population presents certain unique problems related to aging, such as decreasing body weight, increasing renal insufficiency and numerous comorbid conditions, which complicate therapy. Treatment of venous thromboembolism in the elderly has been complicated by an increased incidence of bleeding, particularly with the use of warfarin. The risk of bleeding may be substantially reduced by carefully adjusting the warfarin dose to maintain a therapeutic INR and for this purpose anticoagulant management clinics have been shown to be useful. The low-molecular-weight heparins have been shown to be efficacious and safe for the treatment of venous thromboembolism in several clinical trials, including many patients in the older age brackets. Furthermore, these agents can safely be used in the out-of-hospital setting. Long-term use of low-molecular-weight heparin is an alternative to the use of oral anticoagulant therapy, particularly in patients with cancer or recurrent venous thromboembolism.

Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

This article discusses the prevention of venous thromboembolism (VTE) and is part of the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following. We recommend against the use of aspirin alone as thromboprophylaxis for any patient group (Grade 1A). For moderate-risk general surgery patients, we recommend prophylaxis with low-dose unfractionated heparin (LDUH) (5,000 U bid) or low-molecular-weight heparin (LMWH) [< or = 3,400 U once daily] (both Grade 1A). For higher risk general surgery patients, we recommend thromboprophylaxis with LDUH (5,000 U tid) or LMWH (> 3,400 U daily) [both Grade 1A]. For high-risk general surgery patients with multiple risk factors, we recommend combining pharmacologic methods (LDUH three times daily or LMWH, > 3,400 U daily) with the use of graduated compression stockings and/or intermittent pneumatic compression devices (Grade 1C+). We recommend that thromboprophylaxis be used in all patients undergoing major gynecologic surgery (Grade 1A) or major, open urologic procedures, and we recommend prophylaxis with LDUH two times or three times daily (Grade 1A). For patients undergoing elective total hip or knee arthroplasty, we recommend one of the following three anticoagulant agents: LMWH, fondaparinux, or adjusted-dose vitamin K antagonist (VKA) [international normalized ratio (INR) target, 2.5; range, 2.0 to 3.0] (all Grade 1A). For patients undergoing hip fracture surgery (HFS), we recommend the routine use of fondaparinux (Grade 1A), LMWH (Grade 1C+), VKA (target INR, 2.5; range, 2.0 to 3.0) [Grade 2B], or LDUH (Grade 1B). We recommend that patients undergoing hip or knee arthroplasty, or HFS receive thromboprophylaxis for at least 10 days (Grade 1A). We recommend that all trauma patients with at least one risk factor for VTE receive thromboprophylaxis (Grade 1A). In acutely ill medical patients who have been admitted to the hospital with congestive heart failure or severe respiratory disease, or who are confined to bed and have one or more additional risk factors, we recommend prophylaxis with LDUH (Grade 1A) or LMWH (Grade 1A). We recommend, on admission to the intensive care unit, all patients be assessed for their risk of VTE. Accordingly, most patients should receive thromboprophylaxis (Grade 1A).

Tinzaparin in the treatment of venous thromboembolism.

Low molecular weight heparin (LMWH) has been widely used for the initial treatment of patients presenting with venous thromboembolism. The LMWH, tinzaparin, has been shown in randomised clinical trials to be as effective and safe as unfractionated heparin for the initial treatment of venous thromboembolism and in clinical trials, it has been used in place of warfarin for the long-term treatment of deep vein thrombosis. Tinzaparin can safely be given to patients with significant renal impairment (creatinine clearance of > or = 20 ml/min) and the dose of tinzaparin does not need to be altered in patients with a body mass index of > 25.

Dalteparin: pharmacological properties and clinical efficacy in the prophylaxis and treatment of thromboembolic diseases.

Dalteparin is a low molecular weight heparin (LMWH) with a mean molecular weight of approximately 5,000. As with the other low molecular weight heparins, dalteparin has certain advantages over unfractionated heparin (UFH) most important of which are improved bio-availability by subcutaneous injection, a prolonged antithrombotic activity which is highly correlated with body weight permitting the once daily administration of the drug. Other possible advantages of LMWH including dalteparin include a lower incidence of heparin induced thrombocytopenia and thrombosis and decreased tendency to produce osteopenia on prolonged administration. Dalteparin has been subjected to a large number of well designed randomised clinical trials for the prevention and treatment of venous thromboembolism. Based on data from the randomised clinical trials, dalteparin has been approved internationally for a wide spectrum of clinical indications.

The economic impact of enoxaparin versus unfractionated heparin for prevention of venous thromboembolism in acute ischemic stroke patients.

Venous thromboembolism (VTE) is a common complication after acute ischemic stroke that can be prevented by the use of anticoagulants. Current guidelines from the American College of Chest Physicians recommend that patients with acute ischemic stroke and restricted mobility receive prophylactic low-dose unfractionated heparin or a low-molecular-weight heparin. Results from clinical studies, most recently from PREVAIL (PREvention of Venous Thromboembolism After Acute Ischemic Stroke with LMWH and unfractionated heparin), suggest that the low-molecular-weight heparin, enoxaparin, is preferable to unfractionated heparin for VTE prophylaxis in patients with acute ischemic stroke and restricted mobility. This is due to a better clinical benefit-to-risk ratio, with the added convenience of once-daily administration. In line with findings from modeling studies and real-world data in acutely ill medical patients, recent economic data indicate that the higher drug cost of enoxaparin is offset by the reduction in clinical events as compared with the use of unfractionated heparin for the prevention of VTE after acute ischemic stroke, particularly in patients with severe stroke. With national performance measures highlighting the need for hospitals to examine their VTE practices, the relative costs of different regimens are of particular importance to health care decision-makers. The data reviewed here suggest that preferential use of enoxaparin over unfractionated heparin for the prevention of VTE after acute ischemic stroke may lead to reduced VTE rates and concomitant cost savings in clinical practice.

Iliac vein compression syndrome in an active and healthy young female.

Iliac vein compression syndrome is a condition involving external compression of the left common iliac vein by the right iliac artery, which was first described in the 1850s. It predominates in females typically between the third and fourth decade of life and has been associated with thrombophilias. Importantly, the syndrome is amenable to endovascular treatment. Here, we describe a case of a young athletic female with an incidental finding of a left iliac vein thrombosis while taking oral contraceptives, who was identified as having iliac vein compression syndrome on follow-up MR venography with positive testing for Factor V Leiden mutation.