Extended-Duration Enoxaparin for Venous Thromboembolism Prophylaxis in Acutely Ill Medical Patients: An Evaluation of the EXCLAIM Study Based on a Recently Recommended Composite Efficacy Endpoint.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1870-1870 ◽  
Author(s):  
Sebastian M. Schellong ◽  
Russell D. Hull ◽  
Victor F. Tapson ◽  
Manuel Monreal ◽  
Meyer-Michel Samama ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Composite Endpoint ◽  
Medical Patients ◽  
Double Blind ◽  
Once Daily ◽  
All Cause Mortality ◽  
Standard Duration ◽  
Extended Duration ◽  
Level 1 ◽  
Reduced Mobility

Abstract Introduction The EXCLAIM study has shown that in acutely ill medical patients who have received a standard 10-day period of prophylaxis with enoxaparin, extended-duration prophylaxis with enoxaparin for 4 weeks reduces the relative risk of the primary composite endpoint of asymptomatic proximal deep-vein thrombosis (DVT), symptomatic DVT or pulmonary embolism (PE), and fatal PE by 44% compared with placebo (2.8% vs 4.9%; RR 0.56; 95% CI 0.39–0.80; p=0.0011). We assessed the consistency of these results using the composite efficacy endpoint recently proposed for venous thromboembolism (VTE) prophylaxis studies by the European Committee for Medicinal Products for Human Use (CHMP) which, in addition, takes all-cause mortality into account. Methods Patients enrolled in the EXCLAIM study had a recent reduced mobility (≤3 days) due to a medical illness, were aged 40 years or older, and had anticipated level 1 (total bed rest or sedentary without bathroom privileges) or level 2 (level 1 with bathroom privileges) reduced mobility with further risk factors. Eligible patients received enoxaparin 40mg SC once-daily for 10±4 days. Patients were then double-blind randomized and received either enoxaparin 40mg SC once-daily or placebo for a further 28±4 days. Asymptomatic DVT were diagnosed by bilateral compression ultrasound after completion of the randomized treatment period. Suspected cases of symptomatic DVT or PE were confirmed by objective tests. Fatal PE were confirmed by autopsy where possible. Data were analyzed using the CHMP-recommended composite efficacy endpoint of proximal DVT, adjudicated PE and all-cause mortality. Results Eligible patients enrolled at 370 sites in 20 countries received standard-duration prophylaxis with enoxaparin. Of these, 4114 patients were double-blind randomized and 4040 received extended-duration prophylaxis with enoxaparin (n=2013) and placebo (n=2027), respectively. Extended-duration enoxaparin reduced the relative risk of the CHMP composite endpoint by 26% compared with placebo (5.8% vs 7.9%; RR 0.74; 95% CI 0.58–0.95; p=0.018). Conclusion The significant reduction in the incidence of the primary efficacy endpoint associated with the use of extended-duration enoxaparin compared with placebo, following standard duration enoxaparin, was consistent when applying both the pre-defined EXCLAIM and the CHMP-recommended composite endpoints, the latter of which included all-cause mortality in addition to proximal DVT and adjudicated PE.

Consistent Venous Thromboembolism Risk Reduction by Extended- Versus Standard-Duration Enoxaparin Prophylaxis in Subgroups of Acutely Ill Medical Patients in the EXCLAIM Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1863-1863 ◽  
Author(s):  
Victor F. Tapson ◽  
Russell D. Hull ◽  
Sebastian M. Schellong ◽  
Manuel Monreal ◽  
Meyer-Michel Samama ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Odds Ratio ◽  
Primary Diagnosis ◽  
Medical Patients ◽  
Once Daily ◽  
Standard Duration ◽  
Extended Duration ◽  
Level 1 ◽  
Reduced Mobility ◽  
Patient Subgroups

Abstract Introduction In the EXCLAIM study, extended-duration enoxaparin prophylaxis reduced the relative risk of VTE in acutely ill medical patients by 44% compared with placebo, following standard-duration prophylaxis (2.8% vs 4.9%; RR 0.56; 95% CI 0.39–0.80; p=0.0011). We assessed the benefits of extended-duration enoxaparin prophylaxis in subgroups of acutely ill medical patients with the most prominent primary diagnoses enrolled in EXCLAIM. Methods Patients enrolled in EXCLAIM had: recent reduced mobility (≤3 days) due to a medical illness, age ≥40 years, and anticipated level 1 (total bed rest or sedentary without bathroom privileges) or level 2 (level 1 with bathroom privileges) reduced mobility with further risk factors. Eligible patients received enoxaparin 40mg SC once-daily for 10±4 days, and were then double-blind randomized and received enoxaparin 40mg SC once-daily (n=2013) or placebo (n=2027) for a further 28±4 days. Asymptomatic DVT were diagnosed by bilateral compression ultrasound after completion of the randomized treatment. Suspected cases of symptomatic DVT or PE were confirmed by objective tests. Fatal PE were confirmed by autopsy where possible. Univariate logistic regressions were conducted to estimate treatment effects in patient subgroups. The primary safety endpoint was major bleeding. Results Baseline characteristics were similar between treatments within each primary diagnosis subgroup, and the considered primary diagnoses accounted for >80% of the enrolled population. The reduced VTE incidence associated with extended-duration enoxaparin prophylaxis was consistent across subgroups of patients with different primary diagnoses (Table). The incidence of major bleeding was generally higher in patients receiving extended-duration prophylaxis (Table). Table: VTE and major bleeding in patient subgroups receiving extended-duration vs standard-duration prophylaxis/placebo Primary diagnosis Incidence of VTE (%)* Odds Ratio [95% CI]** Incidence of Major Bleeding (%)*** Odds Ratio [95% CI] Extended Enox Standard Enox/Placebo Extended Enox Standard Enox/Placebo *N=3347 evaluable patients; **Alpha adjustment for an interim analysis; ***N=4040 treated patients Heart failure, NYHA class III or IV 3.1 4.7 0.64 [0.29–1.39] 0.0 0.2 N/A Acute respiratory insufficiency 2.2 3.7 0.60 [0.27–1.34] 0.6 0.2 3.15 [0.33–30.4] Post ischemic stroke 2.1 8.3 0.24 [0.06–0.91] 0.6 0.0 N/A Acute infection without septic shock 3.6 5.3 0.66 [0.36–1.22] 0.8 0.2 5.16 [0.60–44.3] Conclusion Extended enoxaparin prophylaxis consistently reduced VTE risk in acutely ill medical patients with the most prominent primary diagnoses compared with placebo following standard-duration prophylaxis. Major bleeding was generally higher in the extended-duration enoxaparin arm, but rates of bleeding were low. These findings are consistent with the primary findings of the EXCLAIM study which demonstrated the clinical benefit of the extended-duration enoxaparin regimen.

The Impact of Age on the Efficacy and Safety of Extended-Duration Thromboprophylaxis in Acutely Ill Medical Patients with Recent Immobility: A Sub-Group Analysis from the EXCLAIM Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 438-438 ◽  
Author(s):  
Roger D Yusen ◽  
Russell D Hull ◽  
Sebastian M Schellong ◽  
Victor F Tapson ◽  
Manuel Monreal ◽  
...  
Keyword(s):  
Placebo Group ◽  
Major Bleeding ◽  
Medical Patients ◽  
Efficacy And Safety ◽  
Double Blind ◽  
End Point ◽  
Standard Duration ◽  
Extended Duration ◽  
Level 1 ◽  
Level 2

Abstract Background: The EXtended CLinical prophylaxis in Acutely Ill Medical patients (EXCLAIM) trial was a randomized, double-blind, placebo-controlled, multicenter, international study that demonstrated a 38% relative risk reduction (RRR) for venous thromboembolism (VTE) with extended-duration enoxaparin prophylaxis compared with placebo (2.5% vs 4.0%; absolute difference [AD], −1.5% 95.8% CI −2.5 to −0.5%; P=0.002). Major bleeding occurred in 0.7% (20/2975) and 0.2% (7/2988) of patients who received enoxaparin and placebo, respectively (AD, 0.4% [CI 0.1% to 0.8%]; P=0.012). As age is a known independent risk factor for VTE, we conducted a pre-specified sub-analysis of the EXCLAIM trial to compare the efficacy and safety of extended-duration enoxaparin prophylaxis in patients >75 years old with patients ≤75 years old. Methods: EXCLAIM eligibility required a recent (≤3 days) reduction in mobility due to acute medical illness, an anticipated level 1 (total bed rest/sedentary) or level 2 (level 1 with bathroom privileges) decreased mobility, and age ≥40 years. During the latter part of the study, a protocol amendment required patients with level 2 mobility to have ≥1 of 3 additional pre-specified risk factors (i.e., active or prior cancer, history of VTE, age >75 years). Of the 7500 patients enrolled, 7415 received open-label enoxaparin 40 mg SC od for 10±4 days. Of these, 6085 were randomized to double-blind therapy (enoxaparin 40mg SC od or placebo) of 28±4 additional days duration. The incidence of VTE, the primary efficacy end point, was defined as the composite of symptomatic or asymptomatic proximal deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE), or fatal PE during the double-blind treatment period. Patients were screened for DVT with bilateral proximal lower extremity compression ultrasound at the end of randomized therapy. The incidence of major bleeding, the primary safety end point, was assessed through 48 hours after the last dose of study treatment. Results: Of the 5963 randomized patients that received at least one dose of double-blind therapy, 29.9% (1781) were >75 years of age (mean age 81.5 years) and 70.1% (4182) were ≤75 years old (mean age 61.8 years). In patients >75 years old, the incidence of VTE was 2.5% (18/725) in the enoxaparin group compared with 6.7% (50/743) in the placebo group (AD −4.2% [95.8% CI −6.5 to −2.0%]; P<0.001). In patients ≤75 years old, the incidence of VTE was 2.4% (43/1760) with extended-duration enoxaparin treatment and 2.8% (50/1767) in the placebo group (AD −0.4%, 95.8% CI −1.5 to 0.7%; P=0.474). The incidence of major bleeding was low, but non-significantly higher with extended prophylaxis compared to placebo in patients >75 years old (0.6% vs 0.2%; AD 0.3%, 95% CI −0.2 to 0.9%; P=0.282) and significantly higher in patients ≤75 years old (0.7% vs 0.2%; AD 0.5%, 95%CI 0.1 to 0.9%; P=0.041). Though the older group had a higher death rate compared to the younger group (3.2% vs 1.6%), the survival between the treatment groups was similar within the two age groups. Without extended prophylaxis (i.e., placebo group), patients >75 years old had a significantly higher risk of VTE than those <75 years old (6.7 % vs 2.8 %; AD 3.9%, 95.8% CI 1.9 to 5.9%; p<0.001) during the first month after completing a standard 10±4 day course of enoxaparin VTE prophylaxis. Conclusions: Despite standard-duration prophylaxis with enoxaparin for 6 to 14 days, acutely ill patients >75 years of age have a significantly higher risk of VTE in the following month, compared to patients ≤75 years of age. The risk-to-benefit ratio of extended-duration enoxaparin following standard-duration prophylaxis in acutely ill medical patients appears most favorable in patients >75 years of age.

The Effects of the Degree of Mobility Reduction and Prespecified Risk Factors on Venous Thromboembolism Rates in Acutely Ill Medical Patients in the EXCLAIM Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1862-1862 ◽  
Author(s):  
Roger D. Yusen ◽  
Russell D. Hull ◽  
Sebastian M. Schellong ◽  
Victor F. Tapson ◽  
Manuel Monreal ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Major Bleeding ◽  
P Value ◽  
Medical Patients ◽  
Standard Duration ◽  
Extended Duration ◽  
Level 1 ◽  
Reduced Mobility ◽  
Level 2

Abstract Introduction EXCLAIM showed a 44% reduction of the relative risk of venous thromboembolism (VTE) with extended-duration enoxaparin prophylaxis compared with placebo, following standard-duration prophylaxis in acutely ill medical patients (2.8% vs 4.9%; RR 0.56; 95% CI 0.39–0.80; p=0.001). We retrospectively assessed the effects of degree of reduced mobility and prespecified risk factors on the incidence of VTE in EXCLAIM. Methods EXCLAIM eligibility required a recent (≤3 days) reduction in mobility due to acute medical illness, an anticipated level 1 (total bed rest/sedentary; no bathroom privileges) or level 2 (level 1 with bathroom privileges) decreased mobility, and age ≥40 years. During the latter part of the study, a protocol amendment required patients with level 2 mobility to have ≥1 of 3 additional prespecified risk factors (history of cancer, history of VTE, age >75 years). Enrolled patients received enoxaparin 40mg SC od for 10±4 days. Randomized patients received double-blind therapy (enoxaparin 40mg SC od or placebo) for 28±4 additional days. Patients were screened for deep vein thrombosis with bilateral proximal lower extremity compression ultrasound after randomized therapy. A blinded committee adjudicated cases of suspected VTE and major bleeding. Results Of patients evaluable for VTE (pre- and post-amendment; n=4995), 42% had level 1 mobility. 43% with level 2 mobility met the amended eligibility criteria. The incidence of VTE was 3.2%. Treatment effects on VTE incidence and major bleeding rates were consistent within mobility groups, regardless of the presence of prespecified risk factors (Table). In patients with level 1 mobility, those with ≥1 prespecified risk factors had a higher VTE incidence than those without (4.8% vs 2.6%; p=0.007). In patients with level 2 mobility, those with ≥1 risk factors had a higher VTE incidence than those without (4.6% vs 1.9%; p<0.0001). Table: Effect of level of reduced mobility and prespecified risk factors on incidence of VTE and major bleeding in patients receiving extended-duration prophylaxis or placebo, following standard-duration prophylaxis Level of mobility and number of prespecified risk factors Extended-duration enoxaparin Extended-duration placebo p-value for interaction* *Non-significant p-value denotes consistent treatment effect among subgroups; n=5963 for assessment of bleeding VTE (%) Level 1 - no risk factors 2.1 3.0 0.36 Level + ≥1 risk factor 2.7 6.8 Level 2 - no risk factors 1.9 2.0 Level 2 + ≥1 risk factor 3.5 5.6 Major bleeding (%) Level 1 - no risk factors 0.4 0.0 1.00 Level 1 + ≥1 risk factor 0.6 0.0 Level 2 - no risk factors 0.8 0.4 Level 2 + ≥1 risk factor 0.8 0.4 Conclusion After acutely ill medical patients with reduced mobility received standard-duration VTE prophylaxis, the presence of prespecified risk factors was associated with an increased incidence of VTE, independent of the level of reduced mobility. The treatment effects of extended-duration prophylaxis with enoxaparin compared with placebo were consistent among subgroups.

Impact of age on the efficacy and safety of extended-duration thromboprophylaxis in medical patients

2013 ◽  
Vol 110 (12) ◽  
pp. 1152-1163 ◽  
Author(s):  
Russell D. Hull ◽  
Sebastian M. Schellong ◽  
Victor F. Tapson ◽  
Manuel Monreal ◽  
Meyer-Michel Samama ◽  
...  
Keyword(s):  
Bleeding Risk ◽  
Absolute Difference ◽  
Medical Patients ◽  
Open Label ◽  
Double Blind ◽  
Vein Thrombosis ◽  
Extended Duration ◽  
Post Hoc ◽  
Reduced Mobility ◽  
The Impact

SummaryThe EXCLAIM study enrolled hospitalised acutely ill medical patients with age >40 years and recently-reduced mobility into a trial of extended-duration anticoagulant thromboprophylaxis. This post-hoc analysis evaluated the impact of age on patient outcomes. After completion of open-label therapy with enoxaparin 40 mg once-daily (10 ± 4 days), eligible patients underwent randomisation to receive double-blind therapy of enoxaparin (n=2,975) or placebo (n=2,988) for 28 ± 4 days. During follow-up, the venous thromboembolism (VTE) risk increased with age in both treatment groups. In patients with age >75 years, those who received extended-duration enoxaparin had lower incidence of VTE (2.5% vs 6.7%; absolute difference [AD] [95% confidence interval]: −4.2% [−6.5, −2.0]), proximal deep-vein thrombosis (2.5% vs 6.6%; AD −4.1 % [−6.2, −2.0]), and symptomatic VTE (0.3% vs 1.5%; AD −1.2% [−2.2, −0.3]), in comparison to those who received placebo. In patients with age ≤75 years, those who received enoxaparin had reduced VTE (2.4% vs 2.8%; AD −0.4% [−1.5, 0.7]) and symptomatic VTE (0.2% vs 0.7%; AD −0.6% [−1.0, −0.1]) in comparison to those who received placebo. In both age subgroups, patients who received enoxaparin had increased rates of major bleeding versus those who received placebo: age >75 years (0.6% vs 0.2%; AD +0.3% [−0.2, 0.9], respectively); age ≤75 years (0.7% vs 0.2%; AD +0.5% [0.1, 0.9]). Patients in both age subgroups that received enoxaparin had similar low bleeding rates (0.6% and 0.7%, respectively). VTE risk increased with age, though the bleeding risk did not. Patients with age >75 years had a more favourable benefit-to-harm profile than younger patients.

scholarly journals Extended-Duration Betrixaban Reduces the Risk of Rehospitalization Associated With Venous Thromboembolism Among Acutely Ill Hospitalized Medical Patients

Circulation ◽  
2018 ◽  
Vol 137 (1) ◽  
pp. 91-94 ◽  
Author(s):  
Gerald Chi ◽  
Megan K. Yee ◽  
Alpesh N. Amin ◽  
Samuel Z. Goldhaber ◽  
Adrian F. Hernandez ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Medical Patients ◽  
Extended Duration

Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism

2015 ◽  
Vol 114 (09) ◽  
pp. 645-650 ◽  
Author(s):  
Rupert Bauersachs ◽  
Jan Beyer-Westendorf ◽  
Henri Bounameaux ◽  
Timothy Brighton ◽  
Alexander Cohen ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Anticoagulant Therapy ◽  
Low Dose ◽  
Double Blind ◽  
Once Daily ◽  
Safety Outcome ◽  
Dose Aspirin ◽  
Recurrent Venous Thromboembolism ◽  
Low Dose Aspirin ◽  
Recurrent Vte

SummaryPatients with unprovoked venous thromboembolism (VTE) are at high risk for recurrence. Although rivaroxaban is effective for extended VTE treatment at a dose of 20 mg once daily, use of the 10 mg dose may further improve its benefit-to-risk ratio. Low-dose aspirin also reduces rates of recurrent VTE, but has not been compared with anticoagulant therapy. The EINSTEIN CHOICE study is a multicentre, randomised, double-blind, active-controlled, event-driven study comparing the efficacy and safety of two once daily doses of rivaroxaban (20 and 10 mg) with aspirin (100 mg daily) for the prevention of recurrent VTE in patients who completed 6–12 months of anticoagulant therapy for their index acute VTE event. All treatments will be given for 12 months. The primary efficacy objective is to determine whether both doses of rivaroxaban are superior to aspirin for the prevention of symptomatic recurrent VTE, while the principal safety outcome is the incidence of major bleeding. The trial is anticipated to enrol 2,850 patients from 230 sites in 31 countries over a period of 27 months. In conclusion, the EINSTEIN CHOICE study will provide new insights into the optimal antithrombotic strategy for extended VTE treatment by comparing two doses of rivaroxaban with aspirin (clinicaltrials.gov NCT02064439).

Extended-duration thromboprophylaxis in acutely ill medical patients with recent reduced mobility: Methodology for the EXCLAIM study

2006 ◽  
Vol 22 (1) ◽  
pp. 31-38 ◽  
Author(s):  
Russell D. Hull ◽  
Sebastian M. Schellong ◽  
Victor F. Tapson ◽  
Manuel Monreal ◽  
Meyer-Michel Samama ◽  
...  
Keyword(s):  
Medical Patients ◽  
Extended Duration ◽  
Reduced Mobility

Edoxaban Versus Enoxaparin for the Prevention of Venous Thromboembolism: Pooled Analysis of Coagulation Biomarkers From Stars E-3 and Stars J-V.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2260-2260
Author(s):  
Takeshi Fuji ◽  
Satoru Fujita ◽  
Shintaro Tachibana ◽  
Yohko Kawai
Keyword(s):  
Venous Thromboembolism ◽  
Factor Xa ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Bleeding Events ◽  
Double Blind ◽  
Once Daily ◽  
Treatment Groups ◽  
Post Operation ◽  
D Dimer

Abstract Abstract 2260 Introduction: Edoxaban is an oral, once-daily, direct factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic events. Two randomized, double-blind, double-dummy, phase III studies (STARS E-3 and STARS J-V) have been conducted to evaluate the efficacy and safety of edoxaban compared to enoxaparin for the prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) or total hip arthroplasty (THA). The objective of this pooled analysis was to investigate the effects of edoxaban on key coagulation biomarkers. Methods: Patients (N=1,326) undergoing TKA or THA in Japan and Taiwan were randomized to receive oral edoxaban 30 mg once daily (qd) or subcutaneous enoxaparin 2,000 IU twice daily (bid; equivalent to 20 mg bid) for 11–14 days. Edoxaban was initiated 6–24 hours after surgery and enoxaparin was initiated 24–36 hours after surgery, which is the standard of care in Japan. Blood samples were collected for coagulation biomarker measurements pre-operation, post-operation (pre-treatment, Day 0), Day 7 (prior to administration of the next dose) and completion day (Day 11–14). The primary efficacy outcome was the composite of symptomatic and asymptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE). The principal safety outcome was the incidence of major and clinically relevant non-major (CRNM) bleeding. Pharmacodynamic endpoints included key coagulation biomarkers such as D-dimer, prothrombin fragment F1+2 (F1+2) and soluble fibrin monomer complex (SFMC). Results: A total of 1,307 patients received at least 1 dose of edoxaban or enoxaparin. There were no clinically relevant differences in baseline characteristics between the treatment groups. The mean age was 68 years, mean body weight was 58.8 kg and 83% of patients were female. Overall, edoxaban significantly reduced the incidence of the composite of symptomatic and asymptomatic DVT and PE compared with enoxaparin (5.1% vs 10.7%, P<0.001). The incidence of major and CRNM bleeding events was 4.6% vs 3.7% in the edoxaban and enoxaparin groups, respectively (P=0.427). For both treatment groups, D-dimer and SFMC levels were reduced at Day 7 compared to post-operation/pretreatment levels, then increased slightly by Day 11–14. Levels of F1+2 also decreased by Day 7 in both treatment groups and further decreased by Day 11–14. However, for each coagulation biomarker, levels were significantly lower in the edoxaban group compared to the enoxaparin group at both Day 7 and Day 11–14. (Table, P<0.001). Conclusion: Edoxaban 30 mg qd is superior to enoxaparin 20 mg bid in the prevention of VTE events with significant reduction of D-dimer, F1+2 and SFMC following TKA and THA. Disclosures: Fuji: Daiichi Sankyo: Consultancy; Bayer: Consultancy; Century Medical: Consultancy; Showa Ikakogyo: Consultancy. Fujita:Daiichi Sankyo: Consultancy; Bayer: Consultancy. Tachibana:Daiichi Sankyo: Consultancy. Kawai:Daiichi Sankyo: Consultancy; Bayer: Consultancy; Toyama Chemical: Consultancy.

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