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

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.