Theodore E. Spiro

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

Rivaroxaban for thromboprophylaxis in acutely ill medical patients.

BACKGROUND The clinically appropriate duration of thromboprophylaxis in hospitalized patients with acute medical illnesses is unknown. In this multicenter, randomized, double-blind trial, we evaluated the efficacy and safety of oral rivaroxaban administered for an extended period, as compared with subcutaneous enoxaparin administered for a standard period, followed by placebo. METHODS We randomly assigned patients 40 years of age or older who were hospitalized for an acute medical illness to receive subcutaneous enoxaparin, 40 mg once daily, for 10±4 days and oral placebo for 35±4 days or to receive subcutaneous placebo for 10±4 days and oral rivaroxaban, 10 mg once daily, for 35±4 days. The primary efficacy outcomes were the composite of asymptomatic proximal or symptomatic venous thromboembolism up to day 10 (noninferiority test) and up to day 35 (superiority test). The principal safety outcome was the composite of major or clinically relevant nonmajor bleeding. RESULTS A total of 8101 patients underwent randomization. A primary efficacy outcome event occurred in 78 of 2938 patients (2.7%) receiving rivaroxaban and 82 of 2993 patients (2.7%) receiving enoxaparin at day 10 (relative risk with rivaroxaban, 0.97; 95% confidence interval [CI], 0.71 to 1.31; P=0.003 for noninferiority) and in 131 of 2967 patients (4.4%) who received rivaroxaban and 175 of 3057 patients (5.7%) who received enoxaparin followed by placebo at day 35 (relative risk, 0.77; 95% CI, 0.62 to 0.96; P=0.02). A principal safety outcome event occurred in 111 of 3997 patients (2.8%) in the rivaroxaban group and 49 of 4001 patients (1.2%) in the enoxaparin group at day 10 (P<0.001) and in 164 patients (4.1%) and 67 patients (1.7%) in the respective groups at day 35 (P<0.001). CONCLUSIONS In acutely ill medical patients, rivaroxaban was noninferior to enoxaparin for standard-duration thromboprophylaxis. Extended-duration rivaroxaban reduced the risk of venous thromboembolism. Rivaroxaban was associated with an increased risk of bleeding. (Funded by Bayer HealthCare Pharmaceuticals and Janssen Research and Development; MAGELLAN ClinicalTrials.gov number, NCT00571649.).

Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls

Rivaroxaban is an oral, direct factor Xa inhibitor. Routine coagulation monitoring is not required, but a quantitative determination of rivaroxaban concentrations might be useful in some clinical circumstances. This multicentre study assessed the suitability of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations (ng/ml) using rivaroxaban calibrators and controls, and the inter-laboratory precision of the measurement. Twenty-four centres in Europe and North America were provided with sets of rivaroxaban calibrators (0, 41, 209 and 422 ng/ml) and a set of rivaroxaban pooled human plasma controls (20, 199 and 662 ng/ml; the concentrations were unknown to the participating laboratories). The evaluation was carried out over 10 days by each laboratory using local anti-factor Xa reagents as well as the centrally provided reagent, a modified STA® Rotachrom® assay. A calibration curve was produced each day, and the day-to-day precision was evaluated by testing three human plasma controls. When using the local anti-factor Xa reagents, the mean rivaroxaban concentrations (measured/actual values) were: 17/20, 205/199 and 668/662 ng/ml, and the coefficient of variance (CV) was 37.0%, 13.7% and 14.1%, respectively. When the modified STA Rotachrom method was used, the measured/actual values were: 18/20, 199/199 and 656/662 ng/ml, and the CV was 19.1%, 10.9% and 10.0%, respectively. The results suggest that, by using rivaroxaban calibrators and controls, the anti-factor Xa chromogenic method is suitable for measuring a wide range of rivaroxaban plasma concentrations (20-660 ng/ml), which covers the expected rivaroxaban plasma levels after therapeutic doses.

Assays for Measuring Rivaroxaban: Their Suitability and Limitations

Several new oral anticoagulants such as rivaroxaban (which targets Factor Xa) and dabigatran etexilate (which targets thrombin) are in advanced stages of clinical development and are already available for clinical use in some countries. Although these agents do not require routine coagulation monitoring, assays to assess the level of anticoagulation may be of assistance in certain circumstances such as in case of overdose, in patients with a hemorrhagic or thromboembolic event during treatment, or to assess compliance. Moreover, the influence of the new oral anticoagulants on routine coagulation tests must be recognized. The prothrombin time is not suitable for rivaroxaban measurement for several reasons, and the routinely used international normalized ratio for monitoring the vitamin K antagonists cannot be applied to rivaroxaban. Development of universal assays is challenging because the new oral anticoagulants have different targets, and even those with the same target have variable effects on routine coagulation assays. Focusing on rivaroxaban, there is emerging evidence that an anti-Factor Xa assay that uses rivaroxaban-containing plasma calibrators may provide the optimal method for determining plasma rivaroxaban concentrations.

Laboratory assessment of rivaroxaban: a review

Research into new anticoagulants for preventing and treating thromboembolic disorders has focused on targeting single enzymes in the coagulation cascade, particularly Factor Xa and thrombin, inhibition of which greatly decreases thrombin generation. Based on the results of phase III clinical trials, rivaroxaban, a direct Factor Xa inhibitor, has been approved in many countries for the management of several thromboembolic disorders. Owing to its predictable pharmacokinetic and pharmacodynamic characteristics, fixed-dose regimens are used without the need for routine coagulation monitoring. In situations where assessment of rivaroxaban exposure may be helpful, anti-Factor Xa chromogenic assays (in tandem with standard calibration curves generated with the use of rivaroxaban calibrators and controls) could be used. It is important to note that test results will be affected by the timing of blood sampling after rivaroxaban intake. In addition, the anti-Factor Xa method measures the drug concentration and not the intensity of the drug’s anticoagulant activity, and a higher than expected rivaroxaban plasma level does not necessarily indicate an increased risk of bleeding complications. Therefore, clinicians need to consider test results in relation to the pharmacokinetics of rivaroxaban and other patient risk factors associated with bleeding.

Evaluation of the Prothrombin Time for Measuring Rivaroxaban Plasma Concentrations Using Calibrators and Controls: Results of a Multicenter Field Trial

This study evaluated the prothrombin time (PT) assay for the measurement of plasma concentrations of rivaroxaban using calibrators and controls. The intra- and interlaboratory precision of the measurement was investigated in a field trial involving 21 laboratories. Each laboratory was provided with rivaroxaban calibrators and control plasma samples containing different concentrations of rivaroxaban, and PT reagents. The evaluation was carried out over 2 consecutive weeks using centrally provided and local PT reagents. A calibration curve was produced each day (for inter-run precision), and day-to-day precision was evaluated by testing 3 control plasma samples. A large interlaboratory variation (in seconds) was observed with local PT reagents. The results were less variable when expressed as rivaroxaban concentrations (ng/mL) or when central PT reagent was used (STA Neoplastine CI Plus). The widely available PT assay, in conjunction with rivaroxaban calibrators, may be useful for the measurement of peak plasma levels of rivaroxaban.

Laboratory testing of rivaroxaban in routine clinical practice: When, how, and which assays

Abstract A number of target-specific oral anticoagulants (TSOAs) have been developed in recent years, and some have shown considerable promise in large-scale, randomized clinical trials in the prevention and treatment of thromboembolism. Unlike traditional anticoagulants, such as vitamin K antagonists, these TSOAs exhibit predictable pharmacokinetics and pharmacodynamics. Among these agents, rivaroxaban, a direct Factor Xa inhibitor, has been approved for clinical use in many countries for the management of several thromboembolic disorders. As with the other TSOAs, rivaroxaban is given at fixed doses without routine coagulation monitoring. However, in certain patient populations or special clinical circumstances, measurement of drug exposure may be useful, such as in suspected overdose, in patients with a haemorrhagic or thromboembolic event during treatment with an anticoagulant, in those with acute renal failure, or in patients who require urgent surgery. This article summarizes the influence of rivaroxaban on commonly used coagulation assays and provides practical guidance on laboratory testing of rivaroxaban in routine practice. Both quantitative measurement (using the anti-Factor Xa method) and qualitative measurement (using prothrombin time, expressed in seconds) are discussed, together with some practical considerations when performing these tests and interpreting the test results.

The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Design, rationale, and clinical implications.

Hospital-associated venous thromboembolism (VTE) is a leading cause of premature death and disability worldwide. Evidence-based guidelines recommend that anticoagulant thromboprophylaxis be given to hospitalised medical patients at risk of VTE, but suggest against routine use of thromboprophylaxis beyond the hospital stay. The MARINER study is a randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of thromboprophylaxis using rivaroxaban, begun at hospital discharge and continued for 45 days, for preventing symptomatic VTE in high-risk medical patients. Eligible patients are identified using the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE VTE) risk score, combined with a laboratory test, D-dimer. The rivaroxaban regimen is 10 mg once daily for patients with CrCl ≥ 50 ml/min, or 7.5 mg once daily for patients with CrCl ≥ 30 ml/min and < 50 ml/min. The primary efficacy outcome is the composite of symptomatic VTE (lower extremity deep-vein thrombosis and non-fatal pulmonary embolism) and VTE-related death. The principal safety outcome is major bleeding. A blinded clinical events committee adjudicates all suspected outcome events. The sample size is event-driven with an estimated total of 8,000 patients to acquire 161 primary outcome events. Study design features that distinguish MARINER from previous and ongoing thromboprophylaxis trials in medically ill patients are: (i) use of a validated risk assessment model (IMPROVE VTE) and D-dimer determination for identifying eligible patients at high risk of VTE, (ii) randomisation at the time of hospital discharge, (iii) a 45-day treatment period and (iv) restriction of the primary efficacy outcome to symptomatic VTE events.

Predicting the Risk of Venous Thromboembolism in Patients Hospitalized with Heart Failure

Background— Whether heart failure (HF) increases the risk of venous thromboembolism (VTE) is not well established. In the phase III MAGELLAN (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically iLL patients comparing rivaroxabAN with enoxaparin) trial, extended-duration rivaroxaban was compared with standard-duration enoxaparin followed by placebo for VTE prevention in 8101 hospitalized acutely ill patients with or without HF. The aim of this analysis was to evaluate the relationship between HF severity and the risk of VTE in MAGELLAN patients. Methods and Results— Hospitalized patients diagnosed with HF were included according to New York Heart Association class III or IV at admission (n=2593). HF severity was determined by N-terminal probrain natriuretic peptide (NT-proBNP) plasma concentrations (median 1904 pg/mL). Baseline plasma D-dimer concentrations ranged from 0.6 to 1.7 &mgr;g/L for the less and more severe HF subgroups. Patients with more severe HF had a greater incidence of VTE versus patients with less severe HF, with a significant trend up to Day 10 (4.3% versus 2.2%; P=0.0108) and Day 35 (7.2% versus 4.1%; P=0.0150). Multivariable analysis confirmed that NT-proBNP concentration was associated with VTE risk up to Day 10 (P=0.017) and D-dimer concentration with VTE risk up to Day 35 (P=0.005). The association between VTE risk and HF severity that was observed in the enoxaparin/placebo group was not seen in the extended-duration rivaroxaban group. Conclusions— Patients with more severe HF, as defined by high NT-proBNP plasma concentration, were at increased risk of VTE. NT-proBNP may be useful to identify high short-term risk, whereas elevated D-dimer may be suggestive of high midterm risk. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00571649.

Rivaroxaban in Patients with Heart Failure, Sinus Rhythm, and Coronary Disease

Background Heart failure is associated with activation of thrombin‐related pathways, which predicts a poor prognosis. We hypothesized that treatment with rivaroxaban, a factor Xa inhibitor, could reduce thrombin generation and improve outcomes for patients with worsening chronic heart failure and underlying coronary artery disease. Methods In this double‐blind, randomized trial, 5022 patients who had chronic heart failure, a left ventricular ejection fraction of 40% or less, coronary artery disease, and elevated plasma concentrations of natriuretic peptides and who did not have atrial fibrillation were randomly assigned to receive rivaroxaban at a dose of 2.5 mg twice daily or placebo in addition to standard care after treatment for an episode of worsening heart failure. The primary efficacy outcome was the composite of death from any cause, myocardial infarction, or stroke. The principal safety outcome was fatal bleeding or bleeding into a critical space with a potential for causing permanent disability. Results Over a median follow‐up period of 21.1 months, the primary end point occurred in 626 (25.0%) of 2507 patients assigned to rivaroxaban and in 658 (26.2%) of 2515 patients assigned to placebo (hazard ratio, 0.94; 95% confidence interval [CI], 0.84 to 1.05; P=0.27). No significant difference in all‐cause mortality was noted between the rivaroxaban group and the placebo group (21.8% and 22.1%, respectively; hazard ratio, 0.98; 95% CI, 0.87 to 1.10). The principal safety outcome occurred in 18 patients who took rivaroxaban and in 23 who took placebo (hazard ratio, 0.80; 95% CI, 0.43 to 1.49; P=0.48). Conclusions Rivaroxaban at a dose of 2.5 mg twice daily was not associated with a significantly lower rate of death, myocardial infarction, or stroke than placebo among patients with worsening chronic heart failure, reduced left ventricular ejection fraction, coronary artery disease, and no atrial fibrillation. (Funded by Janssen Research and Development; COMMANDER HF ClinicalTrials.gov number, NCT01877915.)