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

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.

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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 ◽

10.1182/blood.v110.11.1870.1870 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1870-1870 ◽

Cited By ~ 1

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.

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

Thrombosis and Haemostasis ◽

10.1160/th13-02-0170 ◽

2013 ◽

Vol 110 (12) ◽

pp. 1152-1163 ◽

Cited By ~ 7

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.

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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 ◽

10.1182/blood.v110.11.1862.1862 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1862-1862 ◽

Cited By ~ 2

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.

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