The Ultra-Low-Molecular-Weight Heparin Semuloparin for Prevention of Venous Thromboembolism In Patients Undergoing Major Abdominal Surgery

Venous thromboembolism (VTE) remains a common and potentially fatal complication of major abdominal surgery. Semuloparin is a novel ultra-low-molecular-weight heparin (ULMWH) with high anti-factor Xa and residual anti-factor IIa activities currently under development for prevention of VTE. We have conducted a study to assess the efficacy and safety of semuloparin compared to enoxaparin for the prevention of VTE in patients undergoing major abdominal surgery.

SAVE-ABDO is a multinational, randomized, double-blind phase III study of patients undergoing major abdominal or pelvic operation. Patients were randomized to receive either once-daily enoxaparin 40 mg commenced pre-operatively or semuloparin 20 mg commenced post-operatively, both agents continued for 7–10 days. Patients were eligible for inclusion if they were aged > 60 years, had undergone major surgery in the peritoneal or the retroperitoneal space, and/or pelvis under general anesthesia lasting more than 45 minutes. For patients under the age of 60 years old, an additional risk factor (history of VTE, body mass index ≥ 30 kg/m², chronic heart failure, chronic respiratory failure, inflammatory bowel disease, or operation for malignancy) was required. For patients with severe renal impairment, defined as a creatinine clearance < 30 mL/min, the dose of semuloparin was reduced to 10 mg once-daily, and that of enoxaparin to 20 mg once-daily. Randomization was stratified by indication for operation (cancer versus non-cancer), renal function (creatinine clearance ≥ or < 30 mL/min), and geographic region. Mandatory bilateral venography was performed between day 7 and 11. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. Secondary efficacy endpoints included the composite of any VTE and VTE-related mortality, and the composite of any proximal DVT, symptomatic distal DVT, non-fatal pulmonary embolism, and all-cause mortality. The main safety endpoint was major bleeding, with main secondary safety endpoints of clinically-relevant non-major (CRNM) bleeding, and the composite of major and CRNM bleeding. All study endpoints were independently and blinded adjudicated. The non-inferiority will be reached if the upper limit of the confidence interval of the odds ratio for the primary analysis is < 1.25. If the non-inferiority is demonstrated the superiority will be tested using a stratified exact test on the primary efficacy endpoint.

4414 patients were randomized between May 2008 and June 2010. The mean age was 61 years (±13 years) and 57% of subjects were male. 81% of patients underwent an operation for malignant disease. The majority of patients underwent gastro-intestinal procedures, with 59% having colon or colo-rectal surgery, and 20% gastric surgery. Final data will be available for presentation at the meeting.

Kakkar:Bayer Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; sanofi-aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Agnelli:sanofi-aventis: Research Funding. Fisher:sanofi-aventis: Honoraria, Research Funding; Bayer Healthcare: Honoraria, Research Funding; Takeda Pharmaceuticals: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees. George:sanofi-aventis: Honoraria. Mouret:Bayer Healthcare: Consultancy, Honoraria; sanofi-aventis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Lassen:Astellas Pharma Europe: Consultancy; Bayer Healthcare: Consultancy; Bristol-Myers Squibb: Consultancy; GlaxoSmithKline: Consultancy; Merck Serono: Consultancy; Pfizer: Consultancy; sanofi-aventis: Consultancy. Mismetti:sanofi-aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Honoraria; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria. Murphy:sanofi-aventis: Employment. Turpie:Astellas Pharma Europe: Consultancy; Bayer Healthcare: Consultancy; Portola Pharma: Consultancy; sanofi-aventis: Consultancy.