Abstract

Abstract 1160

Background:

Dabigatran etexilate (DE) 220 mg once daily (qd) was as effective as enoxaparin 40 mg qd in phase III trials for the prevention of venous thromboembolism (VTE) in orthopaedic surgery patients, with a favourable safety profile. Recommendations from the European Medicines Agency state that DE 110 mg should be administered 1–4 hours after surgery and 220 mg thereafter, in patients ≤ 75 years and without moderate renal impairment or concomitant verapamil, amiodarone or quinidine. The aim of this prospective, international, observational, single-arm study was to evaluate the safety and efficacy of DE in a real-world setting, with a particular focus on pre-specified subgroups that may represent an increased risk of bleeding and/or VTE. We report here a prespecified analysis of the results for additional subgroups with different body mass index (BMI), creatinine clearance (CrCL) and age.

Methods:

Patients were included if aged ≥ 18 years and undergoing elective total hip or knee replacement (THR, TKR). Patients also had to be eligible for DE 220 mg qd according to the European label. The primary safety endpoint was the incidence of major bleeding events (MBEs) as defined in the pivotal clinical trials of DE; the primary efficacy endpoint was documented symptomatic VTE (sVTE) (the composite of symptomatic proximal and distal deep vein thrombosis and symptomatic non-fatal pulmonary embolism) and all-cause mortality. The observation period was from the first dose to 24 hours after the last dose of DE. We examined the incidence of these endpoints stratified by baseline BMI, CrCL and age, all characteristics with potential influence on bleeding and/or efficacy.

Results:

5292 patients were included in the study. Median BMI was 28.4 kg/m2. Median CrCL was 95.4 mL/min, with 70.4% of patients having CrCL ≥ 80 mL/min and 26.0% with CrCL 50 to < 80 mL/min. Median age was 64 years. A small proportion of patients were treated who had moderate renal impairment (1.1%) or were > 75 years old (0.8%); no differences in primary efficacy or safety results were seen in these underpowered groups.

The incidence of MBEs for all patients was 0.72% (95% CI: 0.51, 0.98%).Occurrence of MBEs was comparable for subgroups of patients with BMI ≤ 35 kg/m2 and numerically higher for severely obese patients with BMI > 35 kg/m2 (1.47%). The rate of MBE was not affected by age < 65 or ≥ 65 years. There were no differences for patients with CrCL ≥ 80 or those with CrCL 50 to < 80 mL/min.

Incidence of sVTE and all-cause mortality in patients treated in the total population was 1.04% (95% CI: 0.78, 1.35%). The rates were comparable in patients stratified according to their BMI, age and CrCL.

Overall, the type of surgery, THR or TKR, did not impact on the incidence of MBEs (0.69% [95% CI 0.42%, 1.08%] and 0.74% [95% CI 0.45%, 1.16%], respectively), whereas the composite of sVTE and death was more common in the TKR group (1.56% [95% CI 1.12%, 2.12%]) than the THR group (0.55% [95% CI 0.31%, 0.90%]), as expected. The stratified analysis by surgery type did not show differences in incidence rates of the primary efficacy or safety endpoints across BMI, age or CrCL sugroups.

Conclusion:

DE 220 mg qd administered to patients undergoing TKR or THR according to the European label showed a favourable safety profile in a real-world clinical setting irrespective of their BMI, renal function and age.

Table 1.

Incidence of primary safety and efficacy endpoints in the combined TKR and THR population

Subgroup Incidence of MBE, n; % (95% CI, %) Incidence of sVTE and all-cause mortality, n, % (95% CI, %) 
Body mass index, kg/m2    
< 25 1131 8; 0.71% (0.31, 1.39) 11; 0.97% (0.49, 1.73) 
25 ≤ BMI < 30 2180 15; 0.69% (0.39, 1.13) 20; 0.92% (0.56, 1.41) 
30 ≤ BMI ≤ 35 1292 5; 0.39% (0.13, 0.90) 15; 1.16% (0.65, 1.91) 
> 35 678 10; 1.47% (0.71, 2.70) 9; 1.33% (0.61, 2.50) 
Creatinine clearance, mL/min    
30 ≤ CrCL < 50 60 0; 0% (0.00, 5.96) 2; 3.33% (0.41, 11.53) 
50 ≤ CrCL < 80 1374 10; 0.73% (0.35, 1.33) 11; 0.80% (0.40%, 1.43) 
≥ 80 3726 28; 0.75% (0.50, 1.08) 39; 1.05% (0.75%, 1.43) 
Age, years    
< 65 2703 17; 0.63% (0.37, 1.01) 26; 0.96% (0.63%, 1.41) 
≥ 65 2589 21; 0.81% (0.50, 1.24) 29; 1.12% (0.75%, 1.60%) 
Subgroup Incidence of MBE, n; % (95% CI, %) Incidence of sVTE and all-cause mortality, n, % (95% CI, %) 
Body mass index, kg/m2    
< 25 1131 8; 0.71% (0.31, 1.39) 11; 0.97% (0.49, 1.73) 
25 ≤ BMI < 30 2180 15; 0.69% (0.39, 1.13) 20; 0.92% (0.56, 1.41) 
30 ≤ BMI ≤ 35 1292 5; 0.39% (0.13, 0.90) 15; 1.16% (0.65, 1.91) 
> 35 678 10; 1.47% (0.71, 2.70) 9; 1.33% (0.61, 2.50) 
Creatinine clearance, mL/min    
30 ≤ CrCL < 50 60 0; 0% (0.00, 5.96) 2; 3.33% (0.41, 11.53) 
50 ≤ CrCL < 80 1374 10; 0.73% (0.35, 1.33) 11; 0.80% (0.40%, 1.43) 
≥ 80 3726 28; 0.75% (0.50, 1.08) 39; 1.05% (0.75%, 1.43) 
Age, years    
< 65 2703 17; 0.63% (0.37, 1.01) 26; 0.96% (0.63%, 1.41) 
≥ 65 2589 21; 0.81% (0.50, 1.24) 29; 1.12% (0.75%, 1.60%) 

BMI was missing for 11 patients; CrCL was missing for 132 patients.

Disclosures:

Rosencher:BMS (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Pfizer (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Sanofi (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; GSK (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Bayer (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees. Frostick:DePuy: Research Funding; Pfizer: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Biomet: Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; DePuy: Consultancy; Boehringer Ingelheim: Consultancy; Biomet: Consultancy; Johnson & Johnson: Research Funding. Feuring:Boehringer Ingelheim (Anticoagulant Therapy): Employment. Kleine:Boehringer Ingelheim (Anticoagulant Therapy): Employment. Brueckmann:Boehringer Ingelheim Pharma GmbH & cO.kg: Employment. Clemens:Boehringer Ingelheim (Anticoagulant Therapy): Employment. Samama:Cordis (product development and education): Honoraria; LFB (anticoagulant therapy): Honoraria; Boehringer Ingelheim (anticoagulant therapy): Honoraria; Bayer (anticoagulant therapy): Honoraria; Biotest (anticoagulant therapy): Honoraria; CSL Behring (anticoagulant therapy): Honoraria; Sanofi-Aventis (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; GSK (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Pfizer (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; BMS (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Lilly (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Baxter (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Bayer (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Curacyte (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Fresenius: Membership on an entity's Board of Directors or advisory committees; LFB (anticoagulant therapy): Primary Investigator, Primary Investigator Other; GSK (anticoagulant therapy): Primary Investigator Other; Sanofi (anticoagulant therapy): Primary Investigator, Primary Investigator Other.

Author notes

*

Asterisk with author names denotes non-ASH members.