Bruce L. Davidson

Oral rivaroxaban for the treatment of symptomatic pulmonary embolism

BACKGROUND A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism. METHODS In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups. CONCLUSIONS A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile. (Funded by Bayer HealthCare and Janssen Pharmaceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.).

Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial

BACKGROUND Prophylaxis for venous thromboembolism is recommended for at least 10 days after total knee arthroplasty; oral regimens could enable shorter hospital stays. We aimed to test the efficacy and safety of oral rivaroxaban for the prevention of venous thromboembolism after total knee arthroplasty. METHODS In a randomised, double-blind, phase III study, 3148 patients undergoing knee arthroplasty received either oral rivaroxaban 10 mg once daily, beginning 6-8 h after surgery, or subcutaneous enoxaparin 30 mg every 12 h, starting 12-24 h after surgery. Patients had mandatory bilateral venography between days 11 and 15. The primary efficacy outcome was the composite of any deep-vein thrombosis, non-fatal pulmonary embolism, or death from any cause up to day 17 after surgery. Efficacy was assessed as non-inferiority of rivaroxaban compared with enoxaparin in the per-protocol population (absolute non-inferiority limit -4%); if non-inferiority was shown, we assessed whether rivaroxaban had superior efficacy in the modified intention-to-treat population. The primary safety outcome was major bleeding. This trial is registered with ClinicalTrials.gov, number NCT00362232. FINDINGS The primary efficacy outcome occurred in 67 (6.9%) of 965 patients given rivaroxaban and in 97 (10.1%) of 959 given enoxaparin (absolute risk reduction 3.19%, 95% CI 0.71-5.67; p=0.0118). Ten (0.7%) of 1526 patients given rivaroxaban and four (0.3%) of 1508 given enoxaparin had major bleeding (p=0.1096). INTERPRETATION Oral rivaroxaban 10 mg once daily for 10-14 days was significantly superior to subcutaneous enoxaparin 30 mg given every 12 h for the prevention of venous thromboembolism after total knee arthroplasty. FUNDING Bayer Schering Pharma AG, Johnson & Johnson Pharmaceutical Research & Development.

Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.

Abstract Objective To determine the efficacy and safety of the anticoagulant fondaparinux in older acute medical inpatients at moderate to high risk of venous thromboembolism. Design Double blind randomised placebo controlled trial. Setting 35 centres in eight countries. Participants 849 medical patients aged 60 or more admitted to hospital for congestive heart failure, acute respiratory illness in the presence of chronic lung disease, or acute infectious or inflammatory disease and expected to remain in bed for at least four days. Interventions 2.5 mg fondaparinux or placebo subcutaneously once daily for six to 14 days. Outcome measure The primary efficacy outcome was venous thromboembolism detected by routine bilateral venography along with symptomatic venous thromboembolism up to day 15. Secondary outcomes were bleeding and death. Patients were followed up at one month. Results 425 patients in the fondaparinux group and 414 patients in the placebo group were evaluable for safety analysis (10 were not treated). 644 patients (75.9%) were available for the primary efficacy analysis. Venous thrombembolism was detected in 5.6% (18/321) of patients treated with fondaparinux and 10.5% (34/323) of patients given placebo, a relative risk reduction of 46.7% (95% confidence interval 7.7% to 69.3%). Symptomatic venous thromboembolism occurred in five patients in the placebo group and none in the fondaparinux group (P = 0.029). Major bleeding occurred in one patient (0.2%) in each group. At the end of follow-up, 14 patients in the fondaparinux group (3.3%) and 25 in the placebo group (6.0%) had died. Conclusion Fondaparinux is effective in the prevention of asymptomatic and symptomatic venous thromboembolic events in older acute medical patients. The frequency of major bleeding was similar for both fondaparinux and placebo treated patients.

Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery.

Dabigatran, an oral once-daily unmonitored thrombin inhibitor, has been tested elsewhere using enoxaparin 40 mg once daily. We used the North American enoxaparin 30 mg BID regimen as the comparator. This was a double-blind, centrally randomized trial. Unilateral total knee arthroplasty patients were randomized to receive oral dabigatran etexilate 220 or 150 mg once daily, or enoxaparin 30 mg SC BID after surgery, blinded. Dosing stopped at contrast venography, 12 to 15 days after surgery. Among 1896 patients, dabigatran 220 and 110 mg showed inferior efficacy to enoxaparin (venous thromboembolism rates of 31% [P = .02 vs enoxaparin], 34% [P < .001 vs enoxaparin], and 25%, respectively). Bleeding rates were similar, and no drug-related hepatic illness was recognized. Dabigatran, effective compared to once-daily enoxaparin, showed inferior efficacy to the twice-daily North American enoxaparin regimen, probably because of the latters more intense and prolonged dosing.

Fondaparinux or Enoxaparin for the Initial Treatment of Symptomatic Deep Venous Thrombosis: A Randomized Trial

Context Are selective inhibitors of factor Xa as good as low-molecular-weight heparin in treating deep venous thrombosis? Contribution In this large, multicenter, double-blind trial, patients with symptomatic deep venous thrombosis were randomly assigned to receive either fondaparinux ( a selective inhibitor of factor Xa) or enoxaparin given subcutaneously for at least 5 days plus an oral vitamin K antagonist for 3 months. In both groups, about 1% of the patients experienced major bleeding during initial treatment and about 4% had recurrent thromboembolic events within 3 months. Implications Fondaparinux and enoxaparin have similar safety and efficacy for initial treatment of symptomatic deep venous thrombosis. The Editors Low-molecular-weight heparin (LMWH) therapy has expanded the options for initial management of patients presenting with deep venous thrombosis (1, 2). Low-molecular-weight heparin treatment is simple and consists of once- or twice-daily subcutaneous injection of a dose adjusted only for body weight. Treating suitable patients at home, often with self-injection, is effective and safe and has become standard practice in many settings (2-4). Clinically relevant aspects of LMWH treatment of venous thromboembolism remain uncertain, which may influence usage and recurrence or bleeding. First, LMWHs differ among themselves. Second, data on whether once- or twice-daily LMWH may be superior are conflicting (5, 6), suggesting that a once-daily regimen of enoxaparin may be less effective in patients with higher body mass index and patients with cancer (7). Third, since LMWHs are eliminated in the urine and plasma levels are higher in patients with even modest renal insufficiency (8), some clinicians administer lower dosages when the patients creatinine clearance is less than 0.84 mL/s (9), despite few outcome data to guide such alterations. Finally, in addition to the clinical and economic circumstances, practical issues surround drug administration, including the patients capacity to administer the desired dosage from a fixed-volume syringe or multidose vial; these issues can affect the feasibility of early discharge and home treatment. Fondaparinux is a synthetic and selective inhibitor of factor Xa that has proven efficacy and safety for preventing venous thromboembolism in orthopedic surgery. Although laboratory observations and theory suggested that such a compound might not be effective for treating established thrombosis (10), a dose-ranging study of deep venous thrombosis treatment found that a once-daily subcutaneous injection of fondaparinux, 7.5 mg, may be effective and safe across a broad range of body weights (50 kg and 100 kg) (11). Pharmacokinetic analyses suggested that daily doses of 5 mg and 10 mg are appropriate for patients less than and more than that weight range, respectively. Moreover, the predictable and sustained anticoagulant effect of fondaparinux for 24 hours allows once-daily injection, and since fondaparinux does not cross-react with heparin-induced antibodies, platelet count monitoring may no longer be needed (12). This may further simplify treatment. Therefore, we designed this randomized, double-blind study of 2205 symptomatic patients to determine whether the efficacy and safety of a once-daily subcutaneous fixed-dose regimen of fondaparinux are similar to those of the standard therapy of a twice-daily, subcutaneous, body weightadjusted regimen of enoxaparin. Early discharge was encouraged in both treatment groups. The large sample size allowed outcome assessment in patients with a broad range of body weights and renal function. Methods Patients Consecutive patients (>18 years of age) who presented with acute symptomatic deep venous thrombosis involving the popliteal, femoral, or iliac veins or the trifurcation of the calf veins and who required antithrombotic therapy were eligible for the study. Diagnostic criteria for deep venous thrombosis were a noncompressible vein found on ultrasonography or an intraluminal filling defect found on venography (11, 13). Patients were ineligible for the study if they had symptomatic pulmonary embolism; received therapeutic doses of anticoagulants or oral anticoagulant therapy for more than 24 hours; required thrombolysis, thrombectomy, or a vena cava filter; had contraindication to anticoagulant therapy (for example, active bleeding, thrombocytopenia [platelet count < 100 109 cells/L]); had elevated serum creatinine levels (>177 mol/L [>2 mg/dL]); had contraindication to contrast medium; had uncontrolled hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg); were pregnant; or had a life expectancy of less than 3 months. After giving informed consent, patients were randomly assigned by a computerized interactive voice response system that recorded information about patients before treatment assignment. Randomization was stratified by center in balanced blocks of 4 patients. The respective institutional review boards approved the study protocol, and an independent data safety monitoring board monitored the study. We assessed 5141 patients for eligibility: 2205 patients were randomly assigned to study groups, 2416 patients were excluded, and 520 patients declined to participate (Figure). The most common reasons for exclusion were the use of therapeutic anticoagulation for more than 24 hours, thrombolytic therapy, or vena cava filter (580 patients); contraindication to anticoagulant therapy (395 patients); symptomatic pulmonary embolism (387 patients); and a life expectancy of less than 3 months (228 patients). Figure. Flow of patients through the study. Treatment Regimens The patients allocated to fondaparinux (Arixtra, NV Organon, Oss, the Netherlands, and Sanofi-Synthlabo, Paris, France) received a once-daily subcutaneous injection of 5.0 mg if they weighed less than 50 kg, 7.5 mg if they weighed between 50 and 100 kg, or 10.0 mg if they weighed more than 100 kg. They also received twice-daily subcutaneous injections of placebo that appeared identical to enoxaparin. The patients allocated to enoxaparin (Lovenox, Clexane, Aventis Pharmaceuticals, Bridgewater, New Jersey) received a twice-daily subcutaneous dose of 1 mg/kg of body weight and a once-daily subcutaneous injection of placebo that appeared identical to fondaparinux. Although home treatment with the study drug was allowed, the treating physician made this decision and the drug had to be administered by a home care service. In both groups, vitamin K antagonist therapy was started as soon as possible but within 72 hours of initiation of fondaparinux or enoxaparin therapy. The investigator chose the type of vitamin K antagonist therapy according to local hospital practice. The same type of vitamin K antagonist was recommended for all patients in a particular center. During initial treatment, prothrombin times were measured at least every other day and the dose of vitamin K antagonist was adjusted to maintain the international normalized ratio between 2.0 and 3.0. Double-blind, initial treatment was continued for at least 5 days and until the international normalized ratio was greater than 2.0 for 2 consecutive days. Treatment with vitamin K antagonists was continued for 3 months, and the international normalized ratio was determined at least once per month. Surveillance and Follow-up All patients were contacted daily during initial treatment and at 1 and 3 months. At each contact, patients were evaluated for symptomatic recurrence of deep venous thrombosis or pulmonary embolism and bleeding and were informed about the symptoms and signs of these conditions. They were instructed to report to the study center on an emergency basis if any of these conditions occurred. If recurrent deep venous thrombosis or pulmonary embolism was suspected, the protocol required objective testing for confirmation. Outcome Assessment The primary efficacy outcome was the incidence of symptomatic recurrent venous thromboembolism during the 3-month study period. Symptomatic recurrent venous thromboembolism was defined as objectively documented recurrent deep venous thrombosis or pulmonary embolism or death in which pulmonary embolism was a contributing cause or could not be excluded. Without objective test results to adequately confirm or exclude recurrent venous thromboembolism, this diagnosis was accepted if the physician managed the patient with therapeutic doses of LMWH for more than 2 days, thrombolysis, a vena cava filter, or thrombectomy (3, 13). The criteria for the objective diagnosis of recurrent deep venous thrombosis were a new noncompressible venous segment or a substantial increase ( 4 mm) in diameter of the thrombus during full compression in a previously abnormal segment on ultrasonography (14, 15) or a new intraluminal filling defect found on venography. The criteria for the objective diagnosis of pulmonary embolism were an intraluminal filling defect on spiral computed tomography or pulmonary angiography, cut-off of a vessel of more than 2.5 mm in diameter on pulmonary angiography, perfusion defect of at least 75% of a segment with corresponding normal ventilation (high-probability lung scan), nondiagnostic lung scan associated with new deep venous thrombosis documented by ultrasonography or venography, or pulmonary embolism confirmed by autopsy. The main safety outcomes were major bleeding during the initial treatment period and 3-month mortality. Bleeding was defined as major if it was clinically overt and associated with a decrease in the hemoglobin level of 20 g/L or more, led to transfusion of 2 or more units of red blood cells or whole blood cells, was retroperitoneal or intracranial, occurred in a critical organ, or contributed to death. Bleeding episodes that were clinically relevant but not major (for example, epistaxis that required intervention or spontaneous macroscopic hematuria) were an additional safety outcome. The cause of deat

Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can lead to devastating thromboembolic complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke. METHODS The methods of this guideline follow the 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 Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored (Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants or heparin plus antiplatelet agents (Grade 2C). CONCLUSIONS Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed.

Subcutaneous Enoxaparin Once or Twice Daily Compared with Intravenous Unfractionated Heparin for Treatment of Venous Thromboembolic Disease

Venous thromboembolic disease causes significant morbidity and mortality in both hospitalized and nonhospitalized patients. The mean annual incidence in the United States is 48 per 100 000 for deep venous thrombosis and 23 per 100 000 for pulmonary embolism, according to an epidemiologic study conducted in Massachusetts (1). A similar study in Sweden showed an annual incidence of 160 new cases of deep venous thrombosis per 100 000 inhabitants (2). Five to 10 days of unfractionated heparin is a common recommended initial treatment for deep venous thrombosis. This treatment maintains the activated partial thromboplastin time above 1.5 times its control value (3, 4), as calibrated by protamine titration or an antifactor Xa assay. Another recommended initial treatment is 5 to 10 days of weight-adjusted low-molecular-weight heparin followed by at least 3 months of oral anticoagulant therapy (3-7). Low-molecular-weight heparins are now frequently being used in place of unfractionated heparin for both prevention and treatment of venous thromboembolism (3, 8). Randomized trials and meta-analyses have shown subcutaneously administered low-molecular-weight heparins to have antithrombotic efficacy equal to (9-12) or greater than (13-16) that of continuously infused unfractionated heparin in the initial treatment of deep venous thrombosis and equal to that of unfractionated heparin in the treatment of pulmonary embolism (17, 18). However, many of these studies enrolled small numbers of patients (9-13, 15, 16), used primarily venographic plethysmographic or scintigraphic end points (9-11, 13, 16), and sometimes excluded patients with pulmonary embolism (11, 15). Most trials of twice-daily low-molecular-weight heparin adjusted treatment regimens according to patient weight without laboratory monitoring. However, several studies suggest that once-daily weight-adjusted dosage of a low-molecular-weight heparin is as effective in the treatment of proximal deep venous thrombosis as adjusted dosages of intravenous unfractionated heparin (14, 19) or twice-daily low-molecular-weight heparin (20). Since low-molecular-weight heparins differ in their physicochemical and pharmacologic characteristics, study results that apply to one cannot be extended to another (21, 22). We conducted the present study to determine whether enoxaparin administered subcutaneously once or twice per day is as effective as continuously infused unfractionated heparin in the treatment of patients with acute, symptomatic venous thromboembolic disease. Methods Study Description This parallel-group, randomized, partially blinded, international, multicenter clinical trial compared continuously infused unfractionated heparin (adjusted to maintain activated partial thromboplastin time within a defined range) with two weight-adjusted dosages of enoxaparin administered subcutaneously once or twice daily. The study was conducted in 74 hospitals in 16 countries, including the United States, several European countries, Australia, and Israel, and was approved by the institutional review board or ethics committees at each location. Written informed consent was obtained from each patient. Four committees participated in this study: an Advisory Committee; an Outcome Adjudication Committee, which provided blinded outcome assignments for incidence of recurrent venous thromboembolic disease, major or minor hemorrhage, immune thrombocytopenia, and cause of death; an independent Safety Committee; and a Vascular Imaging Committee, which reviewed all baseline venograms and all vascular imaging studies in a blinded manner to determine whether deep venous thrombosis was present at baseline and whether objective evidence of recurrence existed. Patient Characteristics Patients were required to be at least 18 years of age and willing to remain hospitalized during randomized therapy. The primary inclusion criteria were symptomatic lower-extremity deep venous thrombosis confirmed by venography or ultrasonography (if venography was inconclusive), symptomatic pulmonary embolism confirmed by high-probability ventilationperfusion scanning, or positive pulmonary angiography with confirmation of lower-extremity deep venous thrombosis. All eligible patients underwent baseline lung scanning or angiography. Exclusion criteria were more than 24 hours of previous treatment with heparin or warfarin; need for thrombolytic therapy; known hemorrhagic risk, including active hemorrhage, active intestinal ulcerative disease, known angiodysplasia, or eye, spinal, or central nervous system surgery within the previous month; renal insufficiency (serum creatinine concentration>180 mol/L [2.03 mg/dL]); severe hepatic insufficiency; allergy to heparin, protamine, porcine products (both heparin and enoxaparin are derived from pork intestinal mucosa), iodine, or contrast media; history of heparin-associated thrombocytopenia or heparin- or warfarin-associated skin necrosis; treatment with other investigational therapeutic agents within the previous 4 weeks; inferior vena cava interruption; or known pregnancy or lactation. Treatments Within each center, consecutive eligible patients were randomly assigned sequentially to one of three treatment groups. Randomization was done without stratification in blocks of six, according to ascending randomization number. The numbers were affixed to sealed treatment kits that contained study medication and were provided by the study sponsor. Patients assigned to enoxaparin received a weight-adjusted subcutaneous dose. Two blinded regimens were tested: 1.0 mg/kg of body weight twice daily or 1.5 mg/kg once daily. Several clinical trials have shown the twice-daily regimen to be effective and safe (16, 23, 24). The once-daily dosage was chosen on the basis of results of pharmacokinetic studies that showed it to have a suitable pharmacokinetic profile in healthy volunteers and to be well tolerated in the treatment of patients with venous thromboembolism (25, 26). In these previous studies, therapeutic antifactor Xa levels were present for up to 18 hours in both volunteers and patients, and measurable levels were present for up to 24 hours. A total of three injections, study drug and placebo, were given each day to maintain blinding for volume of solutions and frequency of administration. Patients assigned to the nonblinded unfractionated heparin group received an intravenous bolus dose and infusion on the basis of an approved institution-specific nomogram. In most cases, administration was as follows: Six hours after the initial bolus, the activated partial thromboplastin time was measured and the dose was adjusted to maintain the specified value, which was between 55 and 80 seconds in most centers (4-7). Activated partial thromboplastin time was measured at least daily during unfractionated heparin treatment. Enoxaparin and heparin treatments were continued for at least 5 days, and warfarin was started within 72 hours of initial study drug administration. Forty-three patients received phenprocoumon in place of warfarin sodium. Prothrombin time was measured daily, and patients could be discharged from the hospital after the international normalized ratio was found to be between 2.0 and 3.0 on 2 consecutive days. Oral anticoagulation was continued for at least 3 months. Study Assessments Observers who were aware of treatment assignment assessed patients daily and monthly during the 3-month follow-up for worsening or recurrence of deep venous thrombosis or pulmonary embolism, hemorrhage, adverse events, changes in concomitant medications and adequacy of warfarin use, and warfarin adherence. For patients receiving unfractionated heparin, adherence was defined as an activated partial thromboplastin time within or above the therapeutic range on the second day of treatment. For patients receiving enoxaparin, adherence was defined as at least 10 doses of study medication given with no dosing errors. Adherence to warfarin therapy was defined as having at least one international normalized ratio value greater than or equal to 2.0 between day 4 and the last dose of study treatment during the initial treatment period. These definitions of treatment adherence were established before the analysis of the study outcomes. Efficacy Analysis The efficacy analysis was performed on two study samples: all treated patients, who received at least one dose of study medication, and evaluable patients, which excluded all patients who met at least one of the criteria for nonevaluability. These criteria were no confirmed deep venous thrombosis at baseline, insufficient study therapy, placement of an inferior vena cava filter, two random assignments, and no 3-month follow-up. Insufficient study therapy was defined as one or more missed enoxaparin doses among at least eight consecutive enoxaparin doses or less than 4 consecutive days of heparin infusion. The definition of insufficient study therapy was established before analysis of study outcomes. These two study samples were analyzed to strengthen the conclusion of equivalence among the treatment groups. The homogeneity of the results of the two analyses is considered to be more supportive of the conclusion of equivalence than the results of either analysis alone. Primary clinical end points were recurrent deep venous thrombosis or pulmonary embolism within 3 months of randomization. Patients with symptoms of recurrent thrombosis underwent confirmatory testing with venography, ultrasonography, or both. Patients presenting with signs or symptoms of pulmonary embolism underwent lung perfusion scanning, pulmonary angiography, or both. Clinical symptoms and supportive findings on objective tests; extension of existing thrombi or new thrombi for venography, angiography, or ultrasonography; or high-probability defect patterns on perfusion scans were required to confirm recurrent thrombosis. Prespecified subgroup analyses were performed on the basis of patient demog

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.

Accuracy of Ultrasound for the Diagnosis of Deep Venous Thrombosis in Asymptomatic Patients after Orthopedic Surgery: A Meta-Analysis

Patients who have major orthopedic operations have an increased risk for deep venous thrombosis; without prophylaxis, the incidence of deep venous thrombosis is about 50% after hip replacement and about 65% after major knee surgery [1]. In both of these groups, the incidence of the more dangerous proximal venous thrombosis (thrombosis in the popliteal or more proximal veins) is approximately 20%. Most of these thrombi are asymptomatic. Nevertheless, the risk for pulmonary embolism from asymptomatic proximal venous thrombosis is substantial, about 25%, and fatal pulmonary embolism occurs in 1% to 2% of this group [2]. Several effective prophylactic methods are available. However, even with the most effective methods, the incidence of postoperative thrombosis is 15% to 20% for elective hip surgery and the incidence of thrombosis is 20% to 30% for major knee surgery detected by routine venography done at the time of discharge from hospital [1]. Because of this relatively high incidence of thrombosis despite primary prophylaxis, some authorities [3] advocate routine venography before hospital discharge in addition to primary prophylaxis to detect silent deep venous thrombosis in patients who have major orthopedic procedures. Thrombi that are detected are usually treated with anticoagulant agents. Venography is expensive, can be painful, and can produce other side effects [4]; it is therefore not an ideal screening test. Radioactive fibrinogen leg scanning and impedance plethysmography have been used as screening tests but are much less sensitive than venography [5-7]. More recently, venous ultrasound imaging has been evaluated as a screening test after hip surgery and has been recommended as a substitute for venography [8]. The initial studies with venous ultrasound used real-time B-mode imaging and lack of venous compressibility with gentle probe pressure as the diagnostic criterion for venous thrombosis [9-11]. Subsequently, a Doppler component (duplex) and then a color Doppler component were added as adjuncts to the original B-mode imaging. These modifications facilitate the identification of veins, but the definitive diagnostic criterion with both of these newer techniques is generally considered to be noncompressibility of the vein under gentle probe pressure. Studies [9-17] in symptomatic patients have consistently shown a high sensitivity and specificity (97% and 97%, respectively) for all three methods of ultrasound imaging. In contrast, studies evaluating the sensitivity of venous ultrasound imaging for detecting thrombi in asymptomatic patients after surgery have produced inconsistent results, with reported sensitivities ranging from 38% to 100%. The reason for the marked differences in the sensitivity among studies evaluating venous ultrasound imaging for asymptomatic proximal venous thrombosis is uncertain. Possible explanations for the observed differences in sensitivity among studies include 1) falsely high estimates of sensitivity because of bias resulting from shortcomings in the study design, 2) falsely low estimates of accuracy because of background noise caused by inadequate technique, 3) dependence of accuracy on the type of ultrasound method used, and 4) chance. In a previous study [5] addressing the variation in the sensitivity of radioactive fibrinogen leg scanning as a screening test for postoperative deep venous thrombosis, we provided evidence that wide differences were probably caused by bias in study design. Bias can result either from inappropriate patient selection or from diagnostic suspicion bias. To avoid a biased selection of patients, a study should include consecutive patients. To avoid diagnostic suspicion bias, the diagnostic tests should be done and their results interpreted by blinded observers using validated and explicit diagnostic criteria to ensure that the results can be reproduced by other investigators [18]. To critically evaluate the accuracy of ultrasound screening for deep venous thrombosis, we did a systematic overview of the literature. Studies in which the potential for bias was minimized were evaluated separately from those in which bias was not minimized. We determined the accuracy for detecting asymptomatic proximal venous thrombosis of each of the three ultrasound imaging methods (real-time B-mode, duplex, and color Doppler ultrasonography) by doing a meta-analysis (combining the results of studies regardless of the modality used and then analyzing the results separately for each of the three modalities). We also examined the accuracy of ultrasound as a screening test for isolated calf venous thrombosis. Methods The review was initiated by a computer search of the English-language medical literature using the MEDLINE database from January 1982 to October 1993. We used combinations of the medical subject headings ultrasound, orthopedics, postoperative period, and thrombophlebitis to identify all articles that evaluated screening with venous ultrasound imaging. Bibliographies of retrieved articles were checked for any additional studies. Recent journals were searched independently and using Current Contents to find new reports that were not identified in the computer search. Early reports of data that were later published in full were excluded from the analysis. Abstracts were also excluded because it is usually not possible to completely evaluate the methods and data. Remaining articles were then critically reviewed for the presence of three key methodologic criteria for the evaluation of the accuracy of diagnostic tests. Two of the authors independently checked the articles for the following methodologic standards: 1) previous establishment of objective criteria for normal and abnormal venographic and ultrasonographic results, 2) an independent comparison of the ultrasound result with contrast venography [the reference standard for diagnosis of venous thrombosis] by investigators blinded to the other test result, and 3) the prospective evaluation of consecutive eligible patients. A study was considered to have included consecutive patients if this was explicitly mentioned in the article or if the article stated that patients were excluded only if they refused consent or were allergic to contrast medium. Reports satisfying all three methodologic standards were classified as level 1 studies; otherwise, reports were classified as level 2 studies. Sensitivity, specificity, and positive predictive values for proximal and isolated calf venous thrombosis were calculated for the studies individually and were then calculated for the results of the pooled level 1 and pooled level 2 studies. Separate analyses were done for each of the three different ultrasound modalities (real-time B-mode, duplex, or color Doppler ultrasonography). A statistical test of homogeneity was calculated for the sensitivity and specificity of the three modalities in the pooled level 1 analysis. The 95% CIs for sensitivity and specificity were calculated according to the binomial distribution, adjusting for heterogeneity among studies using a random-effects model. The calculation of the 95% CIs for positive predictive value took into account sampling error in the sensitivities and specificities [19]. Likelihood ratios, and their 95% CIs, for abnormal ultrasound results were calculated for each study using the modification of adding 0.5 to each cell when zero entries occurred in the 2 2 table [20, 21]. Accuracy data were compared between level 1 and level 2 studies by using the normal approximation to the binomial distribution and by adjusting for between-study heterogeneity with a random-effects model [22]. Two-tailed P values are reported, and values of less than 0.05 were considered to be statistically significant. Results We identified 30 studies, all in patients who had had orthopedic surgery. Thirteen of these studies were excluded from analysis: Two studies were excluded because venography was not done or was done only in patients with abnormal ultrasound results [23, 24], 4 studies were excluded because it was impossible to distinguish the data on asymptomatic patients from those on symptomatic patients [25-28], and 7 studies were excluded because they were abstracts or early reports of studies later reported in full [29-35]. Sixteen of the remaining 17 reports evaluated proximal venous thrombi; real-time B-mode ultrasonography was evaluated in 7 reports [7, 36-41], duplex ultrasonography was evaluated in 7 reports [42-48], and color Doppler ultrasonography was evaluated in 2 reports [49, 50]. The last eligible report evaluated color Doppler ultrasonography only for the detection of isolated calf venous thrombosis, and, consequently, this report is included only in that analysis [51]. When level 1 and level 2 studies were combined, 2001 patients were studied. Two hundred seventeen proximal deep venous thrombi were detected by venography for an overall prevalence of no more than 10.8%. (Some studies reported deep venous thromboses by limbs only.) Table 1 shows the characteristics of the 16 analyzed studies, including documentation of the presence or absence of the three criteria necessary to minimize bias when evaluating the accuracy of diagnostic tests. In general, the timing of the ultrasound assessment, mean patient age, and prevalence of proximal venous thrombosis were similar. Studies with the highest rates of deep venous thrombosis did not provide information about whether or not prophylaxis was used or about the method of prophylaxis. Table 1. Summary of Trials Included in the Meta-Analysis* Accuracy of Ultrasonography for Proximal Venous Thrombosis In the level 1 studies Table 2, ultrasonography detected 95 of 153 proximal thrombi, for a sensitivity of 62% (95% CI, 54% to 70%). A falsely abnormal ultrasonographic result was found for 49 of 1463 venograms, for a specificity of 97% (CI, 96% to 98%). Accordingly, the positive predictive value was 66% (95 of 144; CI, 58% to 74%). Th

Ximelagatran versus Warfarin for the Prevention of Venous Thromboembolism after Total Knee Arthroplasty: A Randomized, Double-Blind Trial

Context Warfarin is associated with rates of deep venous thrombosis of 38% to 55% when prescribed during total knee arthroplasty and requires frequent monitoring and dose adjustment. The oral thrombin inhibitor ximelagatran has shown promise in prophylaxis of venous thromboembolism in patients undergoing hip and knee arthroplasty. Ximelagatran does not require monitoring or dose adjustment. Contribution This randomized, controlled trial compared ximelagatran with warfarin in 680 patients undergoing total knee arthroplasty and found that ximelagatran was at least as effective as warfarin. Implications Ximelagatran is an option for prophylaxis of venous thromboembolism in patients undergoing total knee arthroplasty, but this study had limited power to compare adverse effects. The Editors Venous thromboembolism is common after major orthopedic surgery. Meta-analysis has indicated that without prophylaxis, the incidence of deep venous thrombosis (DVT) is 50% to 60% (1). Prophylaxis with low-molecular-weight heparin (LMWH) or warfarin is recommended, but the incidence of venographically confirmed DVT at the time of hospital discharge remains approximately 31% with the former and 47% with the latter (1). In addition, proximal DVT is found in 7% to 12% of patients who receive prophylaxis with either regimen (1). Currently, the use of LMWH and warfarin is approximately evenly divided in North America (2, 3). Warfarin has a slow onset of action and is inconvenient because it requires frequent coagulation monitoring and dose adjustment (3, 4). Low-molecular-weight heparin does not require monitoring but must be administered parenterally, which can be difficult after hospital discharge. Ximelagatran is a novel oral direct thrombin inhibitor. After administration, it is rapidly absorbed and transformed to its active form, melagatran (5), which provides competitive, direct inhibition of both free and clot-bound thrombin. Administration of ximelagatran results in predictable plasma concentrations of melagatran that increase linearly in relation to dose in healthy volunteers (5) and surgical patients (6, 7). Fixed doses of ximelagatran without coagulation monitoring have been studied in phase II trials and have shown promising results in prophylaxis of venous thromboembolism after total hip or knee arthroplasty (8, 9). In this phase III trial, we compared the efficacy and safety of ximelagatran and warfarin for the prevention of venous thromboembolism after total knee arthroplasty. Methods Study Design We performed a randomized, double-blind study comparing ximelagatran with warfarin for the prevention of venous thromboembolism after total knee arthroplasty. Patients were recruited from 74 hospitals in the United States and Canada. The study was performed in accordance with the Declaration of Helsinki and was approved by the institutional review board at each hospital. Patients were evaluated for eligibility 1 to 30 days before surgery and were randomly assigned to treatment postoperatively on the day of surgery. Those that appeared to meet the inclusion criteria were approached before surgery to discuss the study and to sign consent forms if they were interested. Those who agreed to participate were reevaluated after surgery and before randomization to ensure that they still met entry criteria. Randomization was stratified by unilateral or bilateral surgery at each center and was implemented through an interactive voice response system. Treatment was given for 7 to 12 days, and venography was performed within 12 hours of the final dose. Patients were followed clinically for 4 to 8 weeks after surgery. Patients Patients were eligible if they were scheduled for elective total knee arthroplasty, were at least 18 years of age, weighed 40 to 125 kg, and provided consent. Women had to be surgically sterile, postmenopausal for at least 2 years, or using reliable contraception. Criteria for exclusion were scheduled hemiarthroplasty, surface repair, or revisionary surgery; planned external pneumatic compression prophylaxis; immobilization for 3 or more days before surgery; major surgery, ischemic stroke, myocardial infarction, or administration of any investigational drug within 30 days before surgery; a history of intracranial, retroperitoneal, or intraocular bleeding or any other disorder associated with increased risk for bleeding; gastrointestinal bleeding within 90 days before surgery or endoscopically verified ulcer disease within 30 days before surgery; uncontrolled hypertension; cytotoxic treatment for active malignancy; clinically significant liver disease; thrombocytopenia; drug or alcohol abuse in the past 6 months; allergy to contrast media or iodine; contraindication to warfarin; severe renal impairment (defined as estimated creatinine clearance < 0.5 mL/s [<30 mL/min]); or traumatic epidural or spinal puncture before surgery. Metformin was stopped before administration of contrast media for venography and was restarted after 48 hours if renal function was normal. If an epidural or spinal catheter was used, it had to be removed within 36 hours after surgery and at expected trough levels of melagatran. Treatment with thrombolytic drugs and the following anticoagulants or antiplatelet agents was not allowed within 7 days before surgery or during administration of the study drug: heparins, warfarin, dipyridamole, sulfinpyrazone, ticlopidine, clopidogrel, nonselective cyclooxygenase anti-inflammatory drugs with half-life exceeding 20 hours, at least 500 mg of aspirin per day, or dextran. Treatment Regimens Tablets containing 24 mg of ximelagatran (AstraZeneca, Wilmington, Delaware) or placebo were given in the morning and evening, with the first dose given on the morning after surgery and at least 12 hours after surgery. Capsules containing warfarin (Coumadin, DuPont Pharmaceuticals, Wilmington, Delaware) or placebo were given each evening, starting on the day of surgery after hemostasis was adequate. Warfarin was started at a minimum dose of 5 mg and was then titrated to achieve a target international normalized ratio (INR) of 2.5 (range, 1.8 to 3.0). Patients remained in the hospital according to local practice, usually for 3 to 4 days, after which they self-administered the medication. To guide dosing, INRs were measured locally by using a point-of-care device or a laboratory on postoperative days 1 to 3 and as needed in the interim and after discharge until the day of venography. The point-of-care devices were preprogrammed to encrypt INR values, which could be decrypted only by the central anticoagulation management center (Omnicare Clinical Research, Lake Bluff, Illinois). International normalized ratios from local laboratories were reported to the Center, which then faxed real or sham INR values to the investigator. The investigator used these values to determine the next dose of warfarin or placebo. Sham INR values were generated to mimic usual values in persons receiving warfarin. Treatment adherence was assessed by counting tablets and capsules used in the hospital, dispensed at discharge, and returned at the end of the study. Efficacy Assessments The primary efficacy variable was the incidence of DVT (proximal or distal) or pulmonary embolism. The secondary efficacy variable was the incidence of proximal DVT or pulmonary embolism. Both variables considered events that occurred during treatment. Deep venous thrombosis was evaluated by ascending venography on the leg or legs that had undergone surgery (10, 11). Standardized film documentation contained no more than nine images per leg. The Central Adjudication Committee assessed venograms for the primary efficacy end point. The criterion for DVT was a consistent intraluminal filling defect on at least two images. Evaluable venograms required visualization of all of the deep veins except the muscular veins and the anterior tibial veins, although DVT was counted if these veins were seen and thrombus was detected. Non-evaluable venograms were defined as those that showed a lack of filling in a region of the deep system of the leg without the presence of an intraluminal filling defect elsewhere in the same region. Ultrasound diagnosis was sufficient for symptomatic proximal DVT, but venography was required for diagnosis of symptomatic distal DVT. Analysis of local interpretations of venograms was included in the statistical analysis plan before unblinding. Pulmonary embolism was diagnosed when a lung scan showed high probability, defined as one or more segmental perfusion defects seen in at least two views with corresponding normal ventilation. Pulmonary embolism was also diagnosed by pulmonary angiography showing a persistent intraluminal defect or abrupt cutoff of a vessel greater than 2.5 mm in diameter. All cases of suspected pulmonary embolism were adjudicated centrally. Patients with thrombosis were treated according to local practice. Safety Assessments All bleeding events were recorded, including bleeding at the site of surgery, volumes of blood loss and transfusion, and wound appearance. Independent experts classified bleeding events as major if they were clinically overt and showed one or more of the following: critical site involvement (intracranial, retroperitoneal, intraocular, intraspinal, or pericardial), bleeding index of 2.0 or greater (calculated as the number of units of red blood cells transfused plus the difference between prebleeding hemoglobin level minus postbleeding event hemoglobin level [g/dL]), medical or surgical intervention at the operative site, or fatal bleeding. The bleeding index provides a measure of hemoglobin change as modified by transfusion and has been used in other studies of prophylaxis after orthopedic procedures (12, 13). Clinically overt bleeding with none of the other characteristics was classified as minor. The investigators also classified the overall appearance and characteristics of the surgical wound as being as expe