Oral Rivaroxaban Compared with Subcutaneous Enoxaparin for Extended Thromboprophylaxis after Total Hip Arthroplasty: The RECORD1 Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 6-6 ◽  
Author(s):  
Bengt I. Eriksson ◽  
Lars C. Borris ◽  
Richard J. Friedman ◽  
Sylvia Haas ◽  
Menno V. Huisman ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Efficacy And Safety ◽  
Direct Factor ◽  
Mitt Population ◽  
All Cause Mortality ◽  
Subcutaneous Enoxaparin

Abstract Background Thromboprophylaxis for at least 10 days and for up to 4–5 weeks is recommended after total hip arthroplasty (THA). Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. RECORD1 was a phase III, multinational, randomized, double-blind, double-dummy trial, conducted to determine the efficacy and safety of oral rivaroxaban, compared with subcutaneous enoxaparin, for 5 weeks of thromboprophylaxis in patients undergoing THA. Methods Patients received rivaroxaban 10 mg beginning 6–8 hours after surgery and once daily (od) thereafter, or enoxaparin 40 mg od, beginning the evening before surgery (restarting 6–8 hours after surgery). Therapy continued for 35±4 days and mandatory, bilateral venography was conducted the next day. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The primary efficacy analysis was a test for non-inferiority in the per-protocol (PP) population, followed by a test for superiority in the modified intention-to-treat (mITT) population. The main secondary efficacy endpoint was major venous thromboembolism (VTE): the composite of proximal DVT, non-fatal PE and VTE-related death. Major and non-major bleeding during the active treatment period were the primary and secondary safety endpoints, respectively. Results A total of 4541 patients were randomized; 4433 were eligible for the safety population, 3153 for the mITT population, and 3029 for the PP population. The criteria for non-inferiority were met and testing for superiority was performed. Rivaroxaban significantly reduced the incidence of the primary efficacy endpoint (p<0.001) and major VTE (p<0.001), compared with enoxaparin, in the mITT population (Table). The incidence of major and non-major bleeding events was similar in both groups (Table). Conclusions Rivaroxaban was significantly more effective than enoxaparin for extended prophylaxis after THA, with a similar safety profile. This is the first pivotal trial to demonstrate the efficacy and safety of a fixed, unmonitored dose of an oral, direct Factor Xa inhibitor - rivaroxaban - for extended thromboprophylaxis after THA. Rivaroxaban 10mg od % (n/N) Enoxaparin 40 mg od % (n/N) Relative risk reduction % (95% CI) P-value for difference DVT, non-fatal PE, and all-cause mortality 1.1% (18/1595) 3.7% (58/1558) 70% (49–82%) P<0.001 Major VTE 0.2% (4/1686) 2.0% (33/1678) 88% (66–96%) P<0.001 Major bleeding 0.3% (6/2209) 0.1% (2/2224) - P=0.178 Non-major bleeding 5.8% (128/2209) 5.8% (129/2224) - P=1.000

Extended Thromboprophylaxis with Rivaroxaban Compared with Short-Term Thromboprophylaxis with Enoxaparin after Total Hip Arthroplasty: The RECORD2 Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 307-307 ◽  
Author(s):  
Ajay K. Kakkar ◽  
Benjamin Brenner ◽  
Ola E. Dahl ◽  
Bengt I. Eriksson ◽  
Patrick Mouret ◽  
...  
Keyword(s):  
Total Hip Arthroplasty ◽  
Hip Arthroplasty ◽  
Major Bleeding ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Direct Factor ◽  
Short Term ◽  
Double Blind

Abstract Venous thromboembolism (VTE) is a common, potentially fatal complication of major orthopaedic surgery. Pharmacologic thromboprophylaxis is recommended for patients undergoing total hip arthroplasty (THA) for a minimum of 10 days, and up to 35 days. However, extended thromboprophylaxis is not universally used. Therefore, this trial was conducted to evaluate the potential benefits of extended thromboprophylaxis after THA. RECORD2 is the largest, prospective, randomized clinical trial conducted to date, in this indication. This global, phase III, double-blind trial, was designed to compare short-term thromboprophylaxis with a low molecular weight heparin - enoxaparin - with extended thromboprophylaxis for up to 5 weeks with a novel, oral, direct Factor Xa inhibitor - rivaroxaban after THA. Patients received subcutaneous enoxaparin 40 mg once daily (od), beginning the evening before surgery, continuing for 10–14 days (short-term prophylaxis), and followed by placebo until day 35±4, or oral rivaroxaban 10 mg od beginning 6–8 hours after surgery and continuing for 35±4 days (extended prophylaxis). Mandatory, bilateral venography was conducted at the end of the extended treatment period. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The main secondary efficacy endpoint was major VTE; the composite of proximal DVT, non-fatal PE, and VTE-related death. Major and non-major bleeding during double-blind treatment were the primary and secondary safety endpoints, respectively. A total of 2509 patients were randomized; 2457 were included in the safety population and 1733 in the modified intention-to-treat (mITT) population. Extended thromboprophylaxis with rivaroxaban was associated with a significant reduction in the incidence of the primary efficacy endpoint and major VTE, compared with short-term thromboprophylaxis with enoxaparin (Table). The incidences of major and non-major bleeding were similar in both groups (Table). In conclusion, extended duration rivaroxaban was significantly more effective than short term enoxaparin for the prevention of VTE, including major VTE, in patients undergoing THA. Furthermore, this large trial demonstrated that extended thromboprophylaxis provides substantial benefits for patients undergoing THA, and that the oral, direct Factor Xa inhibitor rivaroxaban provides a safe and effective option for such a strategy. Short-term s.c. enoxaparin 40 mg od % (n/N) Extended oral rivaroxaban 10 mg od % (n/N) Relative risk reduction (%) P-value for difference DVT, non-fatal PE, and all-cause mortalitya 9.3% (81/869) 2.0% (17/864) 79% P<0.001 Major VTEb 5.1% (49/962) 0.6% (6/961) 88% P<0.001 Major bleedingc 0.1% (1/1229) 0.1% (1/1228) - P=0.980 Non-major bleedingc 5.5% (67/1229) 6.5% (80/1228) - P=0.246

A dose-finding study with TAK-442, an oral factor Xa inhibitor, in patients undergoing elective total knee replacement surgery

2010 ◽  
Vol 104 (12) ◽  
pp. 1150-1157 ◽  
Author(s):  
Charlie Cao ◽  
Bengt I. Eriksson ◽  
William Fisher ◽  
Stuart Kupfer ◽  
Gary Raskob ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Factor Xa ◽  
Study Drug ◽  
Dose Finding ◽  
Factor Xa Inhibitor ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Open Label ◽  
Finding Study ◽  
Dose Finding Study

SummaryThis multicentre dose-finding study compared TAK-442, an oral factor Xa inhibitor, with enoxaparin for thromboprophylaxis after knee arthroplasty. In this parallel group study, patients were randomised to oral TAK-442 (40 or 80 mg once-daily [QD] or 10, 20, 40, or 80 mg twice-daily [BID] started 6–8 hours postoperatively), which was blinded as to dose, or to open-label subcutaneous enoxaparin (30 mg BID starting 12–24 hours postoperatively) for 10 days. Treatments were continued until bilateral venography was performed (maximum of 14 days). The primary efficacy endpoint was the composite of any deep-vein thrombosis, non-fatal pulmonary embolism or all-cause mortality, while the primary safety endpoint was major bleeding. Of 1,038 patients randomised who received at least one dose of study drug, 949 completed the study and 730 (76.9%) were evaluable for the primary efficacy analysis. Recruitment into the 10 and 20 mg BID dose groups was stopped early because the incidences of the primary efficacy endpoint were significantly higher than that with enoxaparin. The primary efficacy endpoint occurred in 22.0% of patients given enoxaparin and in 39.0%, 38.4%, 23.5%, 21.4%, 26.8%, and 14.3% of those receiving TAK-442 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, and 80 mg BID, respectively. The incidences of major and clinically relevant non-major bleeding with TAK-442 were not dose-dependent or different from that with enoxaparin. All TAK-442 doses except 10 and 20 mg BID displayed similar efficacy and safety profiles to enoxaparin.

scholarly journals Management of direct factor Xa inhibitor–related major bleeding with prothrombin complex concentrate: a meta-analysis

2019 ◽  
Vol 3 (2) ◽  
pp. 158-167 ◽  
Author(s):  
Siavash Piran ◽  
Rasha Khatib ◽  
Sam Schulman ◽  
Ammar Majeed ◽  
Anne Holbrook ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Prothrombin Complex Concentrate ◽  
Meta Analysis ◽  
Case Series ◽  
Factor Xa ◽  
The United States ◽  
Effective Management ◽  
Direct Factor ◽  
All Cause Mortality ◽  
Fxa Inhibitor

Abstract A targeted antidote for reversal of direct factor Xa (FXa) inhibitors is now available for clinical use in the United States, but it is costly and has limited availability. In a systematic review, we evaluated the safety and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) as an alternative for managing direct FXa inhibitor–related major bleeding. A systematic literature search was conducted using Medline, Embase, and the Cochrane Register of Controlled Trials up to September 2018. No comparative studies were found. Ten case series with 340 patients who received PCC for direct FXa inhibitor–related major bleeding were included. The pooled proportion of patients with effective management of major bleeding was 0.69 (95% confidence interval [CI], 0.61-0.76) in 2 studies using the International Society on Thrombosis and Haemostasis (ISTH) criteria and 0.77 (95% CI, 0.63-0.92) in 8 studies that did not use the ISTH criteria; all-cause mortality was 0.16 (95% CI, 0.07-0.26), and thromboembolism rate was 0.04 (95% CI, 0.01-0.08). On the basis of evidence with very low certainty from single-arm case series, it is difficult to determine whether 4F-PCC in addition to cessation of direct oral FXa inhibitor is more effective than cessation of direct oral FXa inhibitor alone in patients with direct FXa inhibitor–related major bleeding.

Extended treatment of venous thromboembolism: a systematic review and network meta-analysis

Heart ◽  
2018 ◽  
Vol 105 (7) ◽  
pp. 545-552 ◽  
Author(s):  
Kang-Ling Wang ◽  
Nick van Es ◽  
Chris Cameron ◽  
Lana A Castellucci ◽  
Harry R Büller ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Major Bleeding ◽  
Low Dose ◽  
Meta Analysis ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Efficacy And Safety ◽  
Standard Intensity ◽  
All Cause Mortality ◽  
Dose Factor

ObjectiveTo evaluate efficacy and safety of oral anticoagulant regimens and aspirin for extended venous thromboembolism (VTE) treatment.MethodsWe searched MEDLINE, Embase, CENTRAL and conference proceedings for randomised controlled trials studying vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or aspirin for secondary prevention of VTE beyond 3 months. ORs (95% credible intervals) between treatments were estimated using random-effects Bayesian network meta-analysis.ResultsSixteen studies, totaling more than 22 000 patients, were included. Compared with placebo or observation and with aspirin, respectively, the risk of recurrent VTE was lower with standard-intensity VKAs (0.15 (0.08 to 0.24) and 0.23 (0.09 to 0.54)), low-dose factor Xa inhibitors (0.16 (0.06 to 0.38) and 0.25 (0.09 to 0.66)), standard-dose factor Xa inhibitors (0.17 (0.08 to 0.33) and 0.27 (0.11 to 0.65)) and the direct thrombin inhibitor (0.15 (0.04 to 0.37) and 0.23 (0.06 to 0.74)) although the risk of major bleeding was higher with standard-intensity VKAs (4.42 (1.99 to 12.24) and 4.14 (1.17 to 18.86)). Effect estimates were consistent in male patients and those with index pulmonary embolism or with unprovoked VTE and in sensitivity analyses. In addition, compared with placebo or observation, the risk of all-cause mortality was reduced with standard-intensity VKAs (0.44 (0.20 to 0.87)) and low-dose factor Xa inhibitors (0.38 (0.12 to 0.995)).ConclusionsStandard-intensity VKAs and DOACs are more efficacious than aspirin for extended VTE treatment. Despite a higher risk of major bleeding, standard-intensity VKAs was associated with a lower risk of all-cause mortality. Since overall efficacy and safety of standard-intensity VKAs and DOACs are in equipoise, patient factors, costs and patient preferences should be considered when recommending extending anticoagulation treatment.

Rivaroxaban - An Oral, Direct Factor Xa Inhibitor - for Thromboprophylaxis after Total Knee Arthoplasty: The RECORD3 Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 308-308 ◽  
Author(s):  
Michael R. Lassen ◽  
Alexander G.G. Turpie ◽  
Nadia Rosencher ◽  
Lars C. Borris ◽  
Walter Ageno ◽  
...  
Keyword(s):  
Relative Risk ◽  
Risk Reduction ◽  
Major Bleeding ◽  
Relative Risk Reduction ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Intention To Treat ◽  
Total Knee ◽  
Treat Population

Abstract Introduction Rivaroxaban is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. In RECORD3, a phase III trial, the efficacy and safety of once-daily (od) rivaroxaban was compared with od enoxaparin for the prevention of venous thromboembolism (VTE) in patients undergoing total knee arthroplasty (TKA). MethodsIn this multicenter, double-blind, double-dummy trial, patients undergoing TKA were randomized to receive either oral rivaroxaban 10 mg od or subcutaneous enoxaparin 40 mg od. Enoxaparin was initiated 12 hours before surgery, and rivaroxaban 6–8 hours after surgery; both were continued for 10–14 days. The primary outcome was the composite of deep vein thrombosis (DVT), pulmonary embolism (PE), and all-cause mortality. Secondary efficacy outcomes included major VTE (the composite of proximal DVT, PE and VTE-related death) and symptomatic VTE. The main safety outcome was major bleeding, and secondary outcomes included non-major bleeding and adverse events. Results A total of 2531 patients were randomized; 2459 were eligible for inclusion in the safety population and 1702 for the modified intention-to-treat population. The primary efficacy outcome occurred in 9.6% of patients receiving rivaroxaban compared with 18.9% of those receiving enoxaparin (relative risk reduction 49%; p<0.001; Table). Rivaroxaban was also significantly more effective than enoxaparin at reducing major VTE, with a relative risk reduction of 62%. Symptomatic VTE was also lower with rivaroxaban than with enoxaparin. The incidences of major and non-major bleeding were similar in both the rivaroxaban and enoxaparin groups, as was the incidence of other adverse events. During the treatment period, there were no deaths or PEs in the rivaroxaban group, and two deaths and four PEs occurred in the enoxaparin group. Conclusions Rivaroxaban was superior to enoxaparin for the prevention of VTE after TKA in this study, with a similar, low rate of bleeding. This is the first study to demonstrate the safety and efficacy of a fixed, unmonitored regimen of an oral, direct Factor Xa inhibitor - rivaroxaban - for the prevention of VTE after major orthopaedic surgery. Rivaroxaban 10 mg od % (n/N) Enoxaparin 40 mg od % (n/N) Relative risk reduction (%) p -value for difference aModified intention-to-treat-population; bModified intention-to-treat population valid for major VTE analysis; cSafety population who underwent surgery; dSafety population; *Calculated for the absolute risk difference DVT, non-fatal PE, and all-cause mortalitya 9.6% (79/824) 18.9% (166/878) 49% p <0.001 Major VTEb 1.0% (9/908) 2.6% (24/925) 62% p =0.016 Symptomatic VTEc 0.7% (8/1201) 2.0% (24/1217) 66% p =0.005 Major bleedingd 0.6% (7/1220) 0.5% (6/1239) - p =0.774* Non-major bleedingd 4.3% (53/1220) 4.4% (54/1239) - p =0.990*

scholarly journals Edoxaban in patients with atrial fibrillation

2016 ◽  
Vol 11 (3) ◽  
pp. 81-90 ◽  
Author(s):  
Alon Eisen ◽  
Christian T. Ruff
Keyword(s):  
Atrial Fibrillation ◽  
Factor Xa ◽  
Phase Iii ◽  
Factor Xa Inhibitor ◽  
Efficacy And Safety ◽  
Direct Factor ◽  
Nonvalvular Atrial Fibrillation ◽  
Preclinical Development ◽  
Phase Iii Trial ◽  
Prevention And Treatment

Edoxaban, a direct factor Xa inhibitor, was extensively studied in the prevention and treatment of venous thromboembolism and in patients with nonvalvular atrial fibrillation (AF). The aim of this review is to focus specifically on the efficacy and safety profile of edoxaban in patients with AF from preclinical development through the phase III trial that led to regulatory approval.

Thromboprophylaxis after Orthopaedic Surgery with an Oral, Direct Factor Xa Inhibitor: Pooled Results of Two Phase Iib Clinical Trials.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 277-277
Author(s):  
Alexander G.G. Turpie ◽  
Kenneth Alan Bauer ◽  
Lars Borris ◽  
Ola E. Dahl ◽  
William D. Fisher ◽  
...  
Keyword(s):  
Orthopaedic Surgery ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Efficacy And Safety ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Replacement Surgery ◽  
All Cause Mortality ◽  
Major Orthopaedic Surgery ◽  
Surgery Trial

Abstract Thromboembolic events, such as deep vein thrombosis (DVT) and pulmonary embolism (PE), are a serious risk after surgical procedures, such as major orthopaedic surgery. BAY 59-7939 is an oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. The efficacy and safety of BAY 59-7939 for thromboprophylaxis have been determined relative to enoxaparin in two clinical trials, one after elective total hip replacement surgery, and one after elective total knee replacement surgery. Both trials were multicenter, multinational, double-blind, dose-ranging studies; the hip surgery trial was performed in Europe, and the knee surgery trial in North America. This pre-specified analysis combines data from both trials. Patients (n=1343) were randomized to oral BAY 59-7939 at 2.5, 5, 10, 20, or 30 mg twice daily (bid), or subcutaneous enoxaparin (40 mg once daily starting 12 hours before hip surgery, or 30 mg bid starting 12 hours after knee surgery). Treatment continued until mandatory bilateral venography was performed 5–9 days after surgery. The primary efficacy endpoint was a composite of DVT, PE, and all-cause mortality, and was analyzed in 914 per-protocol patients. The secondary efficacy endpoint was major venous thromboembolism (VTE) - proximal DVT, PE, and VTE-related death. The primary safety endpoint was major, post-operative bleeding, and was analyzed in 1317 patients. Observed pooled event rates are shown in the table. No significant dose-response relationship for efficacy was observed with BAY 59-7939 (P=0.39 and P=0.46 for primary and secondary endpoints, respectively) in logistic regression models using total daily dose and adjusting for study, age and gender effects; this was potentially due to the efficacy achieved with the lower BAY 59-7939 doses. A significant dose-response relationship was observed for major, post-operative bleeding with BAY 59-7939 (P&lt;0.001). In conclusion, this analysis showed that for the prevention of VTE following major orthopaedic surgery, BAY 59-7939 has a wide therapeutic window and, at doses of 2.5 to 10 mg bid, has similar efficacy and safety to the enoxaparin regimens. BAY 59-7939 (mg bid) Endpoint 2.5 5 10 20 30 Enoxaparin DVT, PE, all-cause mortality 36/167 (21.6%) 38/166 (22.9%) 26/161 (16.1%) 38/156 (24.4%) 17/88 (19.3%) 49/176 (27.8%) Major VTE 5/167 (3.0%) 4/166 (2.4%) 5/161 (3.1%) 5/156 (3.2%) 1/88 (1.1%) 8/176 (4.5%) Major, post-operative bleeding 2/232 (0.9%) 3/238 (1.3%) 5/236 (2.1%) 9/232 (3.9%) 10/143 (7.0%) 4/236 (1.7%)

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