scholarly journals P5599Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis

2017 ◽  
Vol 38 (suppl_1) ◽  
Author(s):  
G. Chi ◽  
T. Nafee ◽  
S. Korjian ◽  
Y. Daaboul ◽  
R.A. Harrington ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Major Bleeding ◽  
Bivariate Analysis ◽  
Medical Patients ◽  
Extended Duration

scholarly journals The Safety and Efficacy of Full Versus Reduced Dose Betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3824-3824
Author(s):  
Alexander T Cohen ◽  
Rim Halaby ◽  
Serge Korjian ◽  
Yazan Daaboul ◽  
Donald Szlosek ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Major Bleeding ◽  
Primary Analysis ◽  
Advisory Committees ◽  
Medically Ill ◽  
Reduced Dose ◽  
Efficacy Outcome ◽  
Venous Thromboembolism Prevention ◽  
Extended Duration

Abstract Background: The exposure of all the currently licenced DOACs is increased in renal impairment and by certain drug interactions. The Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among acutely ill medical patients. The full 80 mg dose of betrixaban was halved to 40 mg among subjects with severe renal insufficiency (calculated creatinine clearance <30ml/min), or receiving a concomitant strong P-glycoprotein (P-gp) inhibitor. Objectives and Methods: The goal of this analysis is to assess the efficacy and safety of full (80 mg) and reduced dose (40 mg) betrixaban relative to enoxaparin in the APEX trial. Subjects were stratified into the two dose groups prior to randomization according to the pre-specified dosing criteria. The primary efficacy outcome was the composite of asymptomatic proximal and symptomatic venous thromboembolism (proximal or distal deep-vein thrombosis, symptomatic nonfatal pulmonary embolism, or death from venous thromboembolism). The principal safety outcome was major bleeding. Results: The median concentration of betrixaban among subjects administered the 80 mg dose was higher than that of the 40 mg dose (19 ng/ml vs 11 ng/ml, p<0.0001). In the primary analysis Cohort 1 (the elevated D-dimer +ve patients), the primary efficacy outcome was significantly reduced among subjects treated with 80 mg of extended dose betrixaban vs enoxaparin [6.3% (95/1516) vs 8.4% (130/1549), RRR = 0.26 (0.04-0.42), p=0.023]. A similar reduction was observed in the entire modified Intention to Treat (mITT) population [4.87% (122/2506) vs 7.06% (181/2562), RRR = 0.30 (0.13 - 0.44), p=0.001]. In contrast, among subjects receiving 40 mg of betrixaban there was no significant difference in the primary outcomes compared with enoxaparin across Cohorts 1, 2, and 3. There was no excess of major bleeding associated with administration of either the full 80 mg dose or the reduced 40 mg dose of betrixaban as compared with enoxaparin. Conclusion: For extended duration prophylaxis against VTE in hospitalized medically ill patients, the full 80 mg dose of extended duration betrixaban achieves higher serum concentrations than the 40 mg dose and is associated with improved efficacy across all cohorts relative to standard dose enoxaparin, without an excess risk of major bleeding. Based upon the approximate halving of plasma concentrations in this analysis and the lack of improvement in clinical outcomes, the reduced 40 mg dose may have been excessively downwardly adjusted. Conversely, the 80 mg dose was efficacious in all cohorts, including cohort 1. The inclusion of the 40 mg dose in the primary analysis may explain at least in part the marginal statistical result in the original report. Disclosures Cohen: Takeda: Consultancy; Medscape: Speakers Bureau; XO1: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Portola: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; NHS: Membership on an entity's Board of Directors or advisory committees; Lifeblood: Membership on an entity's Board of Directors or advisory committees; Department of Health: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Janssen: Consultancy; Aspen: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; Colation to Prevent Venous Thromboembolism: Other: Founder; Leo Pharma: Consultancy; UK Government Health Select Committee: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria. Goldhaber:Portola: Consultancy. Hull:Portola: Consultancy. Hernandez:Portola: Consultancy. Gold:Portola Pharmaceuticals: Employment. Wiens:Portola: Employment, Equity Ownership. Harrington:Portola: Consultancy. Gibson:Portola: Consultancy.

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

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.

Does Thromboprophylaxis Reduce Mortality in Medical Patients? A Systematic Review and Meta-Analysis of Randomized Cntrolled Tials.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 905-905
Author(s):  
Francesco Dentali ◽  
Monica Gianni ◽  
Wendy Lim ◽  
James D. Douketis
Keyword(s):  
Venous Thromboembolism ◽  
Major Bleeding ◽  
Meta Analysis ◽  
Good Evidence ◽  
Controlled Trials ◽  
Cochrane Central Register ◽  
Medical Patients ◽  
Central Register ◽  
Increased Risk ◽  
Patients At Risk

Abstract Background: Despite good evidence that anticoagulants are effective in preventing venous thromboembolism in medical patients at risk for this disease, only one-third of such patients are receiving thromboprophylaxis. Underutilization of thromboprophylaxis in medical patients may be due to lack of evidence that thromboprophylaxis reduces mortality, concerns about anticoagulant-related bleeding, and questions about the clinical significance of surrogate (venographic) outcomes to assess efficacy in these trials. We performed a meta-analysis of randomized, placebo-controlled trials of anticoagulant thromboprophylaxis in medical patients to assess effects on mortality and bleeding. Methods: The MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases were searched until June 2005. Studies were included that were randomized, placebo-controlled trials investigated a prophylactic dose of unfractionated heparin, low-molecular-weight heparin, or fondaparinux in medical patients. Meta-analysis was done to obtain pooled estimates of the effects of anticoagulant thromboprophylaxis on mortality and clinically important (major) bleeding. The effect of treatment on venous thromboembolism was not pooled because of across-study difference in methods used to diagnose this, and use of asymptomatic (venographic) outcomes in some studies. Results: There were 8 studies of 20,631 patients in the assessment of mortality and 4 studies of 5,428 patients in the assessment of major bleeding. Death occurred in 536 of 10,321 (5.2%) patients who received thromboprophylaxis, and in 608 of 10,510 (5.8%) who received placebo. Thromboprophylaxis was associated with 10% decreased risk for all-cause mortality, although this effect was not quite statistically significant (odds ratio [OR] = 0.90; 95% confidence interval [CI]: 0.81, 1.01). Major bleeding occurred in 22 of 2,726 (0.8%) patients who received thromboprophylaxis, and in 11 of 2,702 (0.4%) patients who received placebo. Thromboprophylaxis was associated with 2-fold increased risk for major bleeding, although this effect was not quite statistically significant (OR = 2.04; 95% CI: 0.98, 4.23). Conclusion: In medical patients who are at increased risk for venous thromboembolism, anticoagulant thromboprophylaxis appears to confer a small reduction in mortality; this benefit should be balanced against an increased risk for major bleeding.

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.

Transfusions, major bleeding, and prevention of venous thromboembolism with enoxaparin or fondaparinux in thoracic surgery

2011 ◽  
Vol 106 (12) ◽  
pp. 1109-1116 ◽  
Author(s):  
Joelle Demaria ◽  
Agnès Lillo-Le Louët ◽  
Raffaele Caliandro ◽  
Jean-Luc Guillou ◽  
Malvina Crespin ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Thoracic Surgery ◽  
Major Bleeding ◽  
Surgical Patients ◽  
Transfusion Rate ◽  
Medical Patients ◽  
Bleeding Events ◽  
Hospitalised Patients ◽  
Before And After ◽  
Patients At Risk

SummaryEnoxaparin 40 mg/day (E) or fondaparinux 2.5 mg/day (F) are recommended to prevent venous thromboembolism (VTE) in medical and surgical patients at risk. Over the two years after switching from E to F in our 35-bed department of pulmonology and thoracic surgery, an increase in the number of transfusions was observed. A retrospective explanatory investigation was undertaken. Hospitalised patients in the two years before and after switching from E to F were compared. The files of all transfused patients were reviewed. A blinded independent committee adjudicated major bleeding events. In the investigated time period, the overall transfusion rate increased from 1.8% of 2,989 patients to 3.1% of 3,085 patients (p=0.002). Mean ages (58.4 vs. 59.1 years), proportions of surgical patients (63.6% vs. 58.4%), cancer patients (72.1% vs. 69.5%), and treated patients (≥1 dose of E or F: 51.8% vs. 52.5%) were similar. The number of medical patients transfused while receiving E or F did not increase significantly (0.9% vs. 1.3%, RR=1.45 [0.66–3.17], p=0.35). The number of surgical patients trans-fused postoperatively while receiving E or F increased significantly (0.7% vs. 1.9% of all surgical patients, relative risk [RR]=2.75 [1.45–5.23], p=0.001), including a significant increase in transfusions for major bleeding (0.2% vs. 0.9%, RR=5.97 [1.74–20.4], p<0.001). A multivariate analysis did not find confounding factors. The incidence of symptomatic postoperative pulmonary embolism remained very low (0.05% vs. 0.17%). In conclusion, in thoracic surgery patients, switch-ing from enoxaparin to fondaparinux to prevent VTE was associated with a significant increase in the risk of postoperative major bleeding. A causal relationship appears plausible.

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