Harry R. Buller

Oral rivaroxaban for symptomatic venous thromboembolism.

BACKGROUND Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. METHODS We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. RESULTS The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). CONCLUSIONS Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).

Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects

Background— Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. Methods and Results— In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline; P<0.001) that was immediately and completely reversed by PCC (12.8±1.0; P<0.001). The endogenous thrombin potential was inhibited by rivaroxaban (51±22%; baseline, 92±22%; P=0.002) and normalized with PCC (114±26%; P<0.001), whereas saline had no effect. Dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time. Administration of PCC did not restore these coagulation tests. Conclusion— Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study. Clinical Trial Registration— URL: http://www.trialregister.nl. Unique identifier: NTR2272.Background— Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. Methods and Results— In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline; P <0.001) that was immediately and completely reversed by PCC (12.8±1.0; P <0.001). The endogenous thrombin potential was inhibited by rivaroxaban (51±22%; baseline, 92±22%; P =0.002) and normalized with PCC (114±26%; P <0.001), whereas saline had no effect. Dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time. Administration of PCC did not restore these coagulation tests. Conclusion— Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study. Clinical Trial Registration— URL: . Unique identifier: NTR2272. # Clinical Perspective {#article-title-32}

Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial

BACKGROUND After hip replacement surgery, prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism. Our aim was to assess the oral, direct thrombin inhibitor dabigatran etexilate for such prophylaxis. METHODS In this double-blind study, we randomised 3494 patients undergoing total hip replacement to treatment for 28-35 days with dabigatran etexilate 220 mg (n=1157) or 150 mg (1174) once daily, starting with a half-dose 1-4 h after surgery, or subcutaneous enoxaparin 40 mg once daily (1162), starting the evening before surgery. The primary efficacy outcome was the composite of total venous thromboembolism (venographic or symptomatic) and death from all causes during treatment. On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo, the non-inferiority margin for the difference in rates of thromboembolism was defined as 7.7%. Efficacy analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00168818. FINDINGS Median treatment duration was 33 days. 880 patients in the dabigatran etexilate 220 mg group, 874 in the dabigatran etexilate 150 mg group, and 897 in the enoxaparin group were available for the primary efficacy outcome analysis; the main reasons for exclusion in all three groups were the lack of adequate venographic data. The primary efficacy outcome occurred in 60 (6.7%) of 897 individuals in the enoxaparin group versus 53 (6.0%) of 880 patients in the dabigatran etexilate 220 mg group (absolute difference -0.7%, 95% CI -2.9 to 1.6%) and 75 (8.6%) of 874 people in the 150 mg group (1.9%, -0.6 to 4.4%). Both doses were thus non-inferior to enoxaparin. There was no significant difference in major bleeding rates with either dose of dabigatran etexilate compared with enoxaparin (p=0.44 for 220 mg, p=0.60 for 150 mg). The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups. INTERPRETATION Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile.

Oral apixaban for the treatment of acute venous thromboembolism

BACKGROUND Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism. METHODS In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding. RESULTS The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], -0.4 percentage points; 95% CI, -1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups. CONCLUSIONS A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding (Funded by Pfizer and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00643201).

Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE‐MODEL randomized trial

Background: Oral anticoagulants, such as dabigatran etexilate, an oral, direct thrombin inhibitor, that do not require monitoring or dose adjustment offer potential for prophylaxis against venous thromboembolism (VTE) after total knee replacement surgery. Methods: In this randomized, double‐blind study, 2076 patients undergoing total knee replacement received dabigatran etexilate, 150 mg or 220 mg once‐daily, starting with a half‐dose 1–4 h after surgery, or subcutaneous enoxaparin 40 mg once‐daily, starting the evening before surgery, for 6–10 days. Patients were followed up for 3 months. The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events. Results: The primary efficacy outcome occurred in 37.7% (193 of 512) of the enoxaparin group vs. 36.4% (183 of 503) of the dabigatran etexilate 220‐mg group (absolute difference, −1.3%; 95% CI, −7.3 to 4.6) and 40.5% (213 of 526) of the 150‐mg group (2.8%; 95% CI,−3.1 to 8.7). Both doses were non‐inferior to enoxaparin on the basis of the prespecified non‐inferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3% vs. 1.5% and 1.3% respectively). No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow‐up. Conclusions: Dabigatran etexilate (220 mg or 150 mg) was at least as effective as enoxaparin and had a similar safety profile for prevention of VTE after total knee replacement surgery.

Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism

BACKGROUND Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear. METHODS In a randomized, double-blind, noninferiority study, we randomly assigned patients with acute venous thromboembolism, who had initially received heparin, to receive edoxaban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or to receive warfarin. Patients received the study drug for 3 to 12 months. The primary efficacy outcome was recurrent symptomatic venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS A total of 4921 patients presented with deep-vein thrombosis, and 3319 with a pulmonary embolism. Among patients receiving warfarin, the time in the therapeutic range was 63.5%. Edoxaban was noninferior to warfarin with respect to the primary efficacy outcome, which occurred in 130 patients in the edoxaban group (3.2%) and 146 patients in the warfarin group (3.5%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.70 to 1.13; P<0.001 for noninferiority). The safety outcome occurred in 349 patients (8.5%) in the edoxaban group and 423 patients (10.3%) in the warfarin group (hazard ratio, 0.81; 95% CI, 0.71 to 0.94; P=0.004 for superiority). The rates of other adverse events were similar in the two groups. A total of 938 patients with pulmonary embolism had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels; the rate of recurrent venous thromboembolism in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group (hazard ratio, 0.52; 95% CI, 0.28 to 0.98). CONCLUSIONS Edoxaban administered once daily after initial treatment with heparin was noninferior to high-quality standard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism. (Funded by Daiichi-Sankyo; Hokusai-VTE ClinicalTrials.gov number, NCT00986154.).

Detection of Deep-Vein Thrombosis by Real-Time B-Mode Ultrasonography

In 220 consecutive outpatients with clinically suspected deep-vein thrombosis of the leg, we compared contrast venography with real-time B-mode ultrasonography, using the single criterion of vein compressibility with the ultrasound transducer probe. The common femoral and popliteal veins were evaluated for full compressibility (no thrombosis) and noncompressibility (thrombosis). Both veins were fully compressible in 142 of the 143 patients with normal venograms (specificity, 99 percent; 95 percent confidence interval, 97 to 100). All 66 patients with proximal-vein thrombosis had noncompressible femoral veins, popliteal veins, or both (sensitivity, 100 percent; 95 percent confidence interval, 95 to 100). For all patients (including 11 with calf-vein thrombi), sensitivity and specificity were 91 (95 percent confidence interval, 82 to 96) and 99 percent, respectively. The sensitivity for isolated calf-vein thrombosis was only 36 percent. The compression ultrasound test was repeated in a subset of 45 consecutive patients by a second examiner, unaware of the results of the first test, whose results agreed in all patients with those of the first examiner (kappa = 1). We conclude that ultrasonography with the single criterion of vein compressibility is a highly accurate, simple, objective, and reproducible noninvasive method for detecting proximal-vein thrombosis in outpatients with clinically suspected deep-venous thrombosis.

Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis

BACKGROUND Post-thrombotic syndrome varies from mild oedema to incapacitating swelling with pain and ulceration. We investigated the rate of post-thrombotic syndrome after a first episode of deep-vein thrombosis and assessed the preventive effect of direct application of a sized-to-fit graded compression stocking. METHODS Patients with a first episode of venogram-proven proximal deep-vein thrombosis were randomly assigned no stockings (the control group) or made-to-measure graded compression elastic stockings for at least 2 years. Post-thrombotic syndrome was assessed with a standard scoring system that combined clinical characteristics and objective leg measurements. Patients were assessed every 3 months during the first 2 years, and every 6 months thereafter for at least 5 years. The cumulative incidence of mild-to-moderate post-thrombotic syndrome was the primary outcome measure. FINDINGS Of the 315 consecutive outpatients considered for inclusion, 44 were excluded and 77 did not consent to take part. 194 patients were randomly assigned compression stockings (n = 96) or no stockings (n = 98). The median follow-up was 76 months (range 60-96) in both groups. Mild-to-moderate post-thrombotic syndrome (score > or = 3 plus one clinical sign) occurred in 19 (20%) patients in the stocking group and in 46 (47%) control-group patients (p < 0.001). 11 (11%) patients in the stocking group developed severe post-thrombotic syndrome (score > or = 4), compared with 23 (23%) patients in the control group (p < 0.001). In both groups, most cases of post-thrombotic syndrome occurred within 24 months of the acute thrombotic event. INTERPRETATION About 60% of patients with a first episode of proximal deep-vein thrombosis develop post-thrombotic syndrome within 2 years. A sized-to-fit compression stocking reduced this rate by about 50%.

Apixaban for Extended Treatment of Venous Thromboembolism

BACKGROUND Apixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism. METHODS In this randomized, double-blind study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months. RESULTS A total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group. CONCLUSIONS Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding. (Funded by Bristol-Myers Squibb and Pfizer; AMPLIFY-EXT ClinicalTrials.gov number, NCT00633893.).

Activation of Coagulation after Administration of Tumor Necrosis Factor to Normal Subjects

Tumor necrosis factor has been implicated in the activation of blood coagulation in septicemia, a condition commonly associated with intravascular coagulation and disturbances of hemostasis. To evaluate the early dynamics and the route of the in vivo coagulative response to tumor necrosis factor, we performed a controlled study in six healthy men, monitoring the activation of the common and intrinsic pathways of coagulation with highly sensitive and specific radioimmunoassays. Recombinant human tumor necrosis factor, administered as an intravenous bolus injection (50 micrograms per square meter of body-surface area), induced an early and short-lived rise in circulating levels of the activation peptide of factor X, reaching maximal values after 30 to 45 minutes (mean +/- SEM increase after 45 minutes, 34.2 +/- 18.2 percent; tumor necrosis factor vs. saline, P = 0.015). This was followed by a gradual and prolonged increase in the plasma concentration of the prothrombin fragment F1+2, peaking after four to five hours (mean increase after five hours, 348.0 +/- 144.8 percent; tumor necrosis factor vs. saline, P less than 0.0001). These findings signify the formation of factor Xa (activated factor X) and the activation of prothrombin. Activation of the intrinsic pathway could not be detected by a series of measurements of the plasma levels of factor XII, prekallikrein, factor XIIa-C1 inhibitor complexes, kallikrein-C1 inhibitor complexes, and the activation peptide of factor IX. The delay between the maximal activation of factor X and that of prothrombin amounted to several hours, indicating that neutralization of factor Xa activity was slow. We conclude that a single injection of tumor necrosis factor elicits a rapid and sustained activation of the common pathway of coagulation, probably induced through the extrinsic route. Our results suggest that tumor necrosis factor could play an important part in the early activation of the hemostatic mechanism in septicemia.