Graham F. Pineo

Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial

BACKGROUND Low-molecular-weight heparins such as enoxaparin are preferred for prevention of venous thromboembolism after major joint replacement. Apixaban, an orally active factor Xa inhibitor, might be as effective, have lower bleeding risk, and be easier to use than is enoxaparin. We assessed efficacy and safety of these drugs after elective total knee replacement. METHODS In ADVANCE-2, a multicentre, randomised, double-blind phase 3 study, patients undergoing elective unilateral or bilateral total knee replacement were randomly allocated through an interactive central telephone system to receive oral apixaban 2.5 mg twice daily (n=1528) or subcutaneous enoxaparin 40 mg once daily (1529). The randomisation schedule was generated by the Bristol-Myers Squibb randomisation centre and stratified by study site and by unilateral or bilateral surgery with a block size of four. Investigators, patients, statisticians, adjudicators, and steering committee were masked to allocation. Apixaban was started 12-24 h after wound closure and enoxaparin 12 h before surgery; both drugs were continued for 10-14 days, when bilateral ascending venography was scheduled. Primary outcome was the composite of asymptomatic and symptomatic deep vein thrombosis, non-fatal pulmonary embolism, and all-cause death during treatment. The statistical plan required non-inferiority of apixaban before testing for superiority; analysis was by intention to treat for non-inferiority testing. The study is registered at ClinicalTrials.gov, number NCT00452530. FINDINGS 1973 of 3057 patients allocated to treatment (1528 apixaban, 1529 enoxaparin) were eligible for primary efficacy analysis. The primary outcome was reported in 147 (15%) of 976 apixaban patients and 243 (24%) of 997 enoxaparin patients (relative risk 0.62 [95% CI 0.51-0.74]; p<0.0001; absolute risk reduction 9.3% [5.8-12.7]). Major or clinically relevant non-major bleeding occurred in 53 (4%) of 1501 patients receiving apixaban and 72 (5%) of 1508 treated with enoxaparin (p=0.09). INTERPRETATION Apixaban 2.5 mg twice daily, starting on the morning after total knee replacement, offers a convenient and more effective orally administered alternative to 40 mg per day enoxaparin, without increased bleeding. FUNDING Bristol-Myers Squibb; Pfizer.

A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation.

BACKGROUND Deep-vein thrombosis is a potentially life-threatening complication of total hip or knee replacement. There are few data on the effectiveness and safety of warfarin as compared with low-molecular-weight heparin as prophylaxis against this problem. METHODS We therefore performed a randomized, double-blind trial in 1436 patients to evaluate the effectiveness and safety of low-molecular-weight heparin (given subcutaneously once daily) as compared with adjusted-dose warfarin to prevent venous thrombosis after hip or knee replacement. Treatment with the drugs was started postoperatively. The primary end point was deep-vein thrombosis as detected by contrast venography (performed a mean of 9.4 days after surgery in each group). RESULTS Among the 1207 patients with interpretable venograms, 231 of 617 patients (37.4 percent) in the warfarin group and 185 of 590 patients (31.4 percent) in the low-molecular-weight-heparin group had deep-vein thrombosis (P = 0.03). The reduction in risk with low-molecular-weight heparin as compared with warfarin was 16 percent, and the absolute difference in the incidence of venous thrombosis was 6 percent in favor of low-molecular-weight heparin (95 percent confidence interval, 0.8 to 11.4 percent). The incidence of major bleeding was 1.2 percent (9 of 721 patients) in the warfarin group and 2.8 percent (20 of 715 patients) in the low-molecular-weight-heparin group (P = 0.04), and the absolute difference was 1.5 percent in favor of warfarin (95 percent confidence interval, 0.1 to 3.0 percent). CONCLUSIONS Our data demonstrate that the small reduction in the incidence of venous thrombosis with low-molecular-weight heparin, as compared with warfarin, was offset by an increase in bleeding complications. Although the use of low-molecular-weight heparin is simpler, because it is administered subcutaneously without the need for monitoring, it may be more costly than warfarin. Warfarin is inexpensive, but the overall cost of its use is increased by the need to monitor the intensity of anticoagulation. At this time it is unclear which of these approaches is the most cost effective.

The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement

Summary.  Background: Heparins and warfarin are currently used as venous thromboembolism (VTE) prophylaxis in surgery. Inhibition of factor (F) Xa provides a specific mechanism of anticoagulation and the potential for an improved benefit–risk profile. Objectives: To evaluate the safety and efficacy of apixaban, a potent, direct, oral inhibitor of FXa, in patients following total knee replacement (TKR), and to investigate dose–response relationships. Patients/methods: A total of 1238 patients were randomized to one of six double‐blind apixaban doses [5, 10 or 20 mg day–1 administered as a single (q.d.) or a twice‐daily divided dose (b.i.d.)], enoxaparin (30 mg b.i.d.) or open‐label warfarin (titrated to an International Normalized Ratio of 1.8–3.0). Treatment lasted 10–14 days, commencing 12–24 h after surgery with apixaban or enoxaparin, and on the evening of surgery with warfarin. The primary efficacy outcome was a composite of VTE (mandatory venography) and all‐cause mortality during treatment. The primary safety outcome was major bleeding. Results: A total of 1217 patients were eligible for safety and 856 patients for efficacy analysis. All apixaban groups had lower primary efficacy event rates than either comparator. The primary outcome rate decreased with increasing apixaban dose (P = 0.09 with q.d./b.i.d. regimens combined, P = 0.19 for q.d. and P = 0.13 for b.i.d. dosing).A significant dose‐related increase in the incidence of total adjudicated bleeding events was noted in the q.d. (P = 0.01) and b.i.d. (P = 0.02) apixaban groups; there was no difference between q.d. and b.i.d. regimens. Conclusions: Apixaban in doses of 2.5 mg b.i.d. or 5 mg q.d. has a promising benefit–risk profile compared with the current standards of care following TKR.

Prevention and Treatment of Venous Thromboembolism

SummaryAll patients at moderate to high risk for the development of venous thrombo- embolism should receive prophylaxis. The approaches of proven value include low-dose heparin, low molecular weight heparin, oral anticoagulants and intermittent pneumatic compression.The use of one of the cited heparin nomograms will ensure that all patients are rapidly brought within the therapeutic range. Because of the varying sensitivities of thromboplastins, each laboratory should establish a therapeutic range using the activated partial thromboplastin time (APTT) which will correspond to 0.2 to 0.4 U/ml of heparin. Constant vigilance and a high level of suspicion are necessary to establish the clinical diagnosis of heparin-induced thrombocytopenia, and to institute appropriate therapy. Physicians should be aware of the sensitivity of the thromboplastin being used in the performance of the International Normalised Ratio (INR). Care must be taken to ensure that patients are maintained within the target therapeutic range for INR (in most cases 2 to 3) by frequent determination of the INR and appropriate adjustments of warfarin dosage.Low molecular weight heparin is the recommended approach to the initial management of venous thromboembolism where these agents are available.Patients with an acute episode of venous thromboembolism should receive warfarin therapy for at least 3 months. At the present time it is reasonable to treat the first recurrence with oral anticoagulants for a period of 12 months and indefinitely for more than 1 recurrence.For selected patients with acute massive pulmonary embolism, thrombolytic therapy with one of the available agents is recommended. However, the role of thrombolytic therapy in patients with proximal venous thrombosis remains unclear. In selected patients with acute venous thromboembolism who have contraindications to anticoagulant therapy or who have objectively documented recurrent disease while on adequate therapy, the insertion of an inferior vena cava filter is recommended.

Venous Thromboembolism in Neurosurgery and Neurology Patients

Thromboembolism is a common problem in neurosurgery and neurology patients. Within this diverse population are subpopulations of patients with varying degrees of thromboembolic risk: low, moderate, and high. Patients at substantial risk for deep vein thrombosis and pulmonary embolism include those with spinal cord injury, brain tumor, subarachnoid hemorrhage, head trauma, stroke, and patients undergoing a neurosurgical operation. There are prophylactic strategies that can be applied to these various risk groups that will dramatically reduce the incidence of thromboembolism. The risk of pulmonary embolism or fatal pulmonary embolism typically exceeds the risk of severe or fatal bleeding from adequate prophylaxis, and these techniques should be applied on a routine basis. To adequately care for patients with deep venous thrombosis and pulmonary embolism, the physician requires a thorough understanding of the methods of diagnosis, the pharmacokinetics of heparin and warfarin, and a knowledge of their role in the treatment strategies that have proven efficacy and safety. In addition, an awareness of the low molecular weight heparins and heparinoids is becoming essential. These new agents have a potentially promising role in both the prophylaxis and treatment of patients with neurological disease. The principles concerning the prophylaxis, diagnosis, and clinical management of venous thromboembolic disease in neurosurgery and neurology patients are dealt with in this review.

Therapeutic Use of Low-Molecular-Weight Heparins

Accumulating evidence indicates that certain low-molecular-weight (LMW) heparins administered subcutaneously may replace classic intravenous heparin therapy. LMW heparins do not require monitoring and may be safer and more effective than unfractionated heparin. The decreased mortality rate, evident in two randomized trials, which was particularly striking in patients with metastatic carcinoma, requires confirmation. The simplified care offered by LMW heparin therapy raises the possibility of transferring care from in-hospital to out of hospital in uncomplicated patients with deep-vein thrombosis [Salzman EW: Low-molecular weight heparin and other new antithrombotic drugs. N Engl J Med 1992;326: 1017-1019]. The advantages to the patient of avoiding in-hospital care and its associated hazards are obvious. Outpatient LMW heparin therapy will likely prove to be highly cost-effective. It is uncertain at present whether the findings associated with an individual LMW heparin preparation can be extrapolated to a different LMW heparin. For this reason the findings of clinical trials apply only to the particular LMW heparin evaluated and cannot be generalized to the LMW heparins at large.

Adverse Effects of Coumarin Anticoagulants

SummaryThe biochemistry of vitamin K metabolism and the role of vitamin K-dependent γ-carboxylation of the vitamin K-dependent coagulation factors are now well understood. Likewise, there is a clear understanding of the role of oral anticoagulants in the inhibition of these coagulation factors. However, the effect of oral anticoagulants on extrahepatic γ-carboxylated proteins such as osteocalcin and matrix γ-carboxyglutamate (Gla)-protein (MOP), and the effects of long term anticoagulants on bone mineral metabolism are just now being recognised. The relevance of these observations on mineral metabolism for elderly individuals, and in particular postmenopausal women who are on long term anticoagulants, is still unknown but worthy of continued close observation.The most significant hazard of oral anticoagulants is haemorrhage. Clinical trials continue to demonstrate that less intense (lower dosage) warfarin therapy can significantly decrease this risk of haemorrhage while at the same time providing equal efficacy when compared to more intense warfarin therapy. The more widespread use of the International Normalised Ratio (INR) for the control of anticoagulants will undoubtedly further decrease the risk of haemorrhage, but new innovations such as the use of ultra low-dose warfarin or newer techniques for the continued monitoring of oral anticoagulants are still required, particularly as the indications for oral anticoagulants continue to expand.

Economic impact of enoxaparin versus unfractionated heparin for venous thromboembolism prophylaxis in patients with acute ischemic stroke: a hospital perspective of the PREVAIL trial.

BACKGROUND The PREVAIL (Prevention of VTE [venous thromboembolism] after acute ischemic stroke with LMWH [low-molecular-weight heparin] and UFH [unfractionated heparin]) study demonstrated a 43% VTE risk reduction with enoxaparin versus UFH in patients with acute ischemic stroke (AIS). A 1% rate of symptomatic intracranial and major extracranial hemorrhage was observed in both groups. OBJECTIVE To determine the economic impact, from a hospital perspective, of enoxaparin versus UFH for VTE prophylaxis after AIS. DESIGN A decision-analytic model was constructed and hospital-based costs analyzed using clinical information from PREVAIL. Total hospital costs were calculated based on mean costs in the Premier™ database and from wholesalers acquisition data. Costs were also compared in patients with severe stroke (National Institutes of Health Stroke Scale [NIHSS] score ≥14) and less severe stroke (NIHSS score <14). RESULTS The average cost per patient due to VTE or bleeding events was lower with enoxaparin versus UFH (

Economic Impact of Enoxaparin After Acute Ischemic Stroke Based on PREVAIL

422 vs

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

662, respectively; net savings