RANDOMIZED CONTROLLED TRIAL
Preoperative Enoxaparin Versus Postoperative Semuloparin Thromboprophylaxis in Major Abdominal Surgery A Randomized Controlled Trial Ajay K. Kakkar, MBBS,∗ Giancarlo Agnelli, MD,† William Fisher, MD,‡ Daniel George, MD,§ Michael R. Lassen, MD,¶ Patrick Mismetti, MD, Patrick Mouret, MD,∗∗ Judith Murphy, MD,†† Francesca Lawson, MD,†† and Alexander G.G. Turpie, MD‡‡; for the SAVE-ABDO Investigators Objective: To compare efficacy and safety of thromboprophylaxis with semuloparin started postoperatively versus enoxaparin started preoperatively in major abdominal surgery. Background: Venous thromboembolism is an important complication following major abdominal surgery. Semuloparin is a novel ultra-low-molecularweight heparin with high antifactor Xa and minimal antifactor IIa activity. Methods: In this double-blind noninferiority trial, adult patients undergoing major abdominal or pelvic operation under general anesthesia lasting more than 45 minutes were assigned to either daily enoxaparin 40 mg commenced preoperatively or daily semuloparin 20 mg commenced postoperatively, for 7 to 10 days. Patients underwent bilateral leg venography between 7 and 11 days postsurgery. The primary efficacy end point was the composite of any deep vein thrombosis, nonfatal pulmonary embolism, or all-cause death. The primary safety outcome was bleeding. Both were independently adjudicated.
Results: In total, 4413 patients were randomized; 3030 (1499 in the enoxaparin and 1531 in the semuloparin groups) were evaluable for the primary efficacy end point, which occurred in 97 patients (6.3%) in the semuloparin group and 82 patients (5.5%) in the enoxaparin group [odds ratio (OR) = 1.16, 95% confidence interval (CI): 0.84–1.59]. On the basis of a noninferiority margin of 1.25, postoperative semuloparin did not demonstrate noninferiority to preoperative enoxaparin. Major bleeding occurred in 63 of 2175 patients (2.9%) in the semuloparin group and 98 of 2177 patients (4.5%) in the enoxaparin group (OR = 0.63, 95% CI: 0.46–0.87). Conclusions: Semuloparin commenced postoperatively did not demonstrate noninferiority to enoxaparin initiated preoperatively for thromboprophylaxis after major abdominal surgery. Study registered with clinicaltrials.gov: NCT00679588. Keywords: abdominal surgery, semuloparin, thromboprophylaxis (Ann Surg 2014;259:1073–1079)
From the ∗ Thrombosis Research Institute and University College London, London, UK; †Stroke Unit and Division of Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Perugia, Italy; ‡Department of Orthopaedic Surgery, McGill University Health Centre, Montreal, QC, Canada; §Duke University Medical Center, Durham, NC; ¶Spine Center Copenhagen, Copenhagen University Hospital, Glostrup, Denmark; University of Saint´ ´ Etienne, Saint-Etienne, France; ∗∗ Klinikum Frankfurt H¨oechst, Frankfurt, Germany; ††Sanofi, Bridgewater, NJ; and ‡‡Hamilton Health Sciences General Hospital, McMaster University, Hamilton, ON, Canada. The detailed list of members of the SAVE-ABDO group is given in the “Acknowledgement” section. Disclosure: A.K.K. has received research funding from and has served on advisory boards with Bayer HealthCare, Sanofi-Aventis, Boehringer-Ingelheim, Pfizer Inc, Bristol-Myers Squibb, and Eisai; has been a consultant for Bayer HealthCare, Sanofi-Aventis, Boehringer-Ingelheim, Pfizer Inc, Bristol-Myers Squibb, Eisai, Adventrx, Novartis, Daiichi Sankyo, and Shire Pharmaceuticals; and has received honoraria from Bayer HealthCare, Sanofi-Aventis, BoehringerIngelheim, Pfizer Inc, Bristol-Myers Squibb, Eisai, and GlaxoSmithKline. G.A. has had a consultant or advisory role for Bayer and Boehringer-Ingelheim and has received honoraria from Bayer, Boehringer-Ingelheim, GlaxoSmithKline, and Sanofi. W.F. has received honoraria and expenses, and research funding, from Sanofi, Bayer, Pfizer Inc, and Boehringer-Ingelheim. D.G. has had a consultant or advisory role for Astellas, Bayer, Dendreon, Genentech/Roche, Medivation, Novartis, Pfizer Inc, Sanofi, and Viamet; has been on the Speakers Bureau for Dendreon Novartis, Pfizer Inc, and Sanofi; and received research support from Dendreon, Exelixis, GlaxoSmithKline, Janssen, Millennium, Novartis, and Pfizer Inc. M.R.L. has served as a consultant for Astellas Pharma Europe, Bayer HealthCare AG, Bristol-Myers Squibb, Boehringer-Ingelheim, GlaxoSmithKline, Merck Serono, Pfizer Inc, Protola Pharma, and Sanofi. P. Mismetti has served as a member of Steering Committees for Sanofi, GlaxoSmithKline, and Boehringer Ingelheim and has received honoraria from Bayer Healthcare and Pfizer/BMS. P. Mouret has been a consultant for and has received honoraria from Bayer HealthCare, Sanofi, and Bristol-Myers Squibb. J.M. is an employee of Sanofi. F.L. is an employee of Sanofi. A.G.G.T. has served as a consultant for Astellas Pharma Europe, Bayer HealthCare AG, Portola Pharma, and Sanofi. This study was funded by Sanofi. Reprints: Ajay K. Kakkar, MBBS, Thrombosis Research Institute, Emmanuel Kaye Building, Manresa Road, Chelsea, London SW3 6LR, UK. E-mail: [email protected]. C 2013 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/13/25906-1073 DOI: 10.1097/SLA.0000000000000430
Annals of Surgery r Volume 259, Number 6, June 2014
P
atients undergoing major operation are at high risk for the development of venous thromboembolism (VTE).1 Pharmacological thromboprophylaxis reduces the risk of both deep vein thrombosis (DVT) and pulmonary embolism (PE).2,3 Although prophylaxis is generally commenced after operation in patients undergoing hip or knee arthroplasty,4 guidelines recommend heparin-based prophylaxis be commenced before operation for patients undergoing laparotomy.5,6 Considering the fear of intraoperative bleeding, restrictions associated with epidural anesthesia, and logistical challenges in administering preoperative prophylaxis when patients are admitted on the day of operation, an effective and safe pharmacological regimen, commenced postoperatively, may be a useful alternative strategy. Semuloparin is a novel ultra-low-molecular-weight heparin with a molecular weight of approximately 2000 to 3000 Daltons, with high antifactor Xa and minimal antifactor IIa activity,7 and a peak plasma concentration reached 3 hours after subcutaneous administration. These characteristics as well as a 58% relative risk reduction of any VTE, when compared with enoxaparin in a phase II study,8 suggest semuloparin might be a good candidate for starting thromboprophylaxis postsurgery. We compared the efficacy and safety of semuloparin started postoperatively with enoxaparin started preoperatively in accordance with the local enoxaparin labeling, for the prevention of VTE in patients undergoing major abdominal surgery.
METHODS Study Oversight The trial was designed and led by an independent steering committee, the principal author wrote the first draft of the manuscript, and subsequent drafts were based on input from coauthors all of www.annalsofsurgery.com | 1073
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 259, Number 6, June 2014
Kakkar et al
whom approved submission of the final version of the manuscript. The study was performed in accordance with the provisions of the Declaration of Helsinki and local regulations. The protocol was approved by the institutional review board or ethics committee at each participating site, and written informed consent was obtained from all patients before randomization. The data were collected by a clinical research organization (ICON Clinical Research Ltd, Leopardstown, Dublin, Ireland), and analyzed by the study sponsor (Sanofi). A Data Monitoring Committee monitored patient safety and efficacy. Primary efficacy and safety outcomes, including cause of death, were assessed by a blinded Central Independent Adjudication Committee.
Patients In this multinational, randomized, double-blind, double dummy, parallel group study, male and female patients 18 years or older, scheduled for major laparotomy under general anesthesia lasting longer than 45 minutes in the peritoneal and/or retroperitoneal space and/or pelvis were included. Patients younger than 60 years had to have one of the following additional risk factors for VTE: previous VTE, obesity (body mass index ≥30 kg/m2 ), chronic heart failure (New York Heart Association class III or IV), chronic respiratory failure (hypoxemia, hypercarbia, or both, due to chronic obstructive pulmonary disease, restrictive parenchymal, or extraparenchymal lung disease), inflammatory bowel disease, or surgery for cancer. The major exclusion criteria were life expectancy of less than 3 months; known pelvic venous obstruction; major orthopedic or general surgery within the previous 3 months; clinical signs or symptoms of DVT or PE within the previous 12 months, or known postphlebitic syndrome; contraindications to venography; treatment with other antithrombotic drugs within 2 weeks before randomization or planned during the course of the study treatment period; active major bleeding; conditions with an increased risk of hemorrhage; thrombocytopenia; known hypersensitivity to enoxaparin sodium, heparin, or pork products; or end-stage renal disease (estimated creatinine clearance 80 mL/min Creatinine clearance >50–80 mL/min Creatinine clearance 30–50 mL/min Creatinine clearance 3 × ULN and total bilirubin >2 × ULN∗ Death on-study,† n (%) On-treatment death‡ Fatal pulmonary embolism Fatal bleeding Cardiovascular death Other Posttreatment death Fatal pulmonary embolism Fatal bleeding Cardiovascular death Other Not adjudicated
Enoxaparin (n = 2177)
Semuloparin (n = 2175)
1462 (67.2) 205 (9.4) 125 (5.7) 27 (1.2) 52 (2.4)
1429 (65.7) 186 (8.6) 107 (4.9) 31 (1.4) 36 (1.7)
133/2136 (6.2) 119/2136 (5.6) 17/2135 (0.8) 43 (2.0) 16 (0.7) 1 (
Preoperative Enoxaparin Versus Postoperative Semuloparin Thromboprophylaxis in Major Abdominal Surgery A Randomized Controlled Trial Ajay K. Kakkar, MBBS,∗ Giancarlo Agnelli, MD,† William Fisher, MD,‡ Daniel George, MD,§ Michael R. Lassen, MD,¶ Patrick Mismetti, MD, Patrick Mouret, MD,∗∗ Judith Murphy, MD,†† Francesca Lawson, MD,†† and Alexander G.G. Turpie, MD‡‡; for the SAVE-ABDO Investigators Objective: To compare efficacy and safety of thromboprophylaxis with semuloparin started postoperatively versus enoxaparin started preoperatively in major abdominal surgery. Background: Venous thromboembolism is an important complication following major abdominal surgery. Semuloparin is a novel ultra-low-molecularweight heparin with high antifactor Xa and minimal antifactor IIa activity. Methods: In this double-blind noninferiority trial, adult patients undergoing major abdominal or pelvic operation under general anesthesia lasting more than 45 minutes were assigned to either daily enoxaparin 40 mg commenced preoperatively or daily semuloparin 20 mg commenced postoperatively, for 7 to 10 days. Patients underwent bilateral leg venography between 7 and 11 days postsurgery. The primary efficacy end point was the composite of any deep vein thrombosis, nonfatal pulmonary embolism, or all-cause death. The primary safety outcome was bleeding. Both were independently adjudicated.
Results: In total, 4413 patients were randomized; 3030 (1499 in the enoxaparin and 1531 in the semuloparin groups) were evaluable for the primary efficacy end point, which occurred in 97 patients (6.3%) in the semuloparin group and 82 patients (5.5%) in the enoxaparin group [odds ratio (OR) = 1.16, 95% confidence interval (CI): 0.84–1.59]. On the basis of a noninferiority margin of 1.25, postoperative semuloparin did not demonstrate noninferiority to preoperative enoxaparin. Major bleeding occurred in 63 of 2175 patients (2.9%) in the semuloparin group and 98 of 2177 patients (4.5%) in the enoxaparin group (OR = 0.63, 95% CI: 0.46–0.87). Conclusions: Semuloparin commenced postoperatively did not demonstrate noninferiority to enoxaparin initiated preoperatively for thromboprophylaxis after major abdominal surgery. Study registered with clinicaltrials.gov: NCT00679588. Keywords: abdominal surgery, semuloparin, thromboprophylaxis (Ann Surg 2014;259:1073–1079)
From the ∗ Thrombosis Research Institute and University College London, London, UK; †Stroke Unit and Division of Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Perugia, Italy; ‡Department of Orthopaedic Surgery, McGill University Health Centre, Montreal, QC, Canada; §Duke University Medical Center, Durham, NC; ¶Spine Center Copenhagen, Copenhagen University Hospital, Glostrup, Denmark; University of Saint´ ´ Etienne, Saint-Etienne, France; ∗∗ Klinikum Frankfurt H¨oechst, Frankfurt, Germany; ††Sanofi, Bridgewater, NJ; and ‡‡Hamilton Health Sciences General Hospital, McMaster University, Hamilton, ON, Canada. The detailed list of members of the SAVE-ABDO group is given in the “Acknowledgement” section. Disclosure: A.K.K. has received research funding from and has served on advisory boards with Bayer HealthCare, Sanofi-Aventis, Boehringer-Ingelheim, Pfizer Inc, Bristol-Myers Squibb, and Eisai; has been a consultant for Bayer HealthCare, Sanofi-Aventis, Boehringer-Ingelheim, Pfizer Inc, Bristol-Myers Squibb, Eisai, Adventrx, Novartis, Daiichi Sankyo, and Shire Pharmaceuticals; and has received honoraria from Bayer HealthCare, Sanofi-Aventis, BoehringerIngelheim, Pfizer Inc, Bristol-Myers Squibb, Eisai, and GlaxoSmithKline. G.A. has had a consultant or advisory role for Bayer and Boehringer-Ingelheim and has received honoraria from Bayer, Boehringer-Ingelheim, GlaxoSmithKline, and Sanofi. W.F. has received honoraria and expenses, and research funding, from Sanofi, Bayer, Pfizer Inc, and Boehringer-Ingelheim. D.G. has had a consultant or advisory role for Astellas, Bayer, Dendreon, Genentech/Roche, Medivation, Novartis, Pfizer Inc, Sanofi, and Viamet; has been on the Speakers Bureau for Dendreon Novartis, Pfizer Inc, and Sanofi; and received research support from Dendreon, Exelixis, GlaxoSmithKline, Janssen, Millennium, Novartis, and Pfizer Inc. M.R.L. has served as a consultant for Astellas Pharma Europe, Bayer HealthCare AG, Bristol-Myers Squibb, Boehringer-Ingelheim, GlaxoSmithKline, Merck Serono, Pfizer Inc, Protola Pharma, and Sanofi. P. Mismetti has served as a member of Steering Committees for Sanofi, GlaxoSmithKline, and Boehringer Ingelheim and has received honoraria from Bayer Healthcare and Pfizer/BMS. P. Mouret has been a consultant for and has received honoraria from Bayer HealthCare, Sanofi, and Bristol-Myers Squibb. J.M. is an employee of Sanofi. F.L. is an employee of Sanofi. A.G.G.T. has served as a consultant for Astellas Pharma Europe, Bayer HealthCare AG, Portola Pharma, and Sanofi. This study was funded by Sanofi. Reprints: Ajay K. Kakkar, MBBS, Thrombosis Research Institute, Emmanuel Kaye Building, Manresa Road, Chelsea, London SW3 6LR, UK. E-mail: [email protected]. C 2013 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/13/25906-1073 DOI: 10.1097/SLA.0000000000000430
Annals of Surgery r Volume 259, Number 6, June 2014
P
atients undergoing major operation are at high risk for the development of venous thromboembolism (VTE).1 Pharmacological thromboprophylaxis reduces the risk of both deep vein thrombosis (DVT) and pulmonary embolism (PE).2,3 Although prophylaxis is generally commenced after operation in patients undergoing hip or knee arthroplasty,4 guidelines recommend heparin-based prophylaxis be commenced before operation for patients undergoing laparotomy.5,6 Considering the fear of intraoperative bleeding, restrictions associated with epidural anesthesia, and logistical challenges in administering preoperative prophylaxis when patients are admitted on the day of operation, an effective and safe pharmacological regimen, commenced postoperatively, may be a useful alternative strategy. Semuloparin is a novel ultra-low-molecular-weight heparin with a molecular weight of approximately 2000 to 3000 Daltons, with high antifactor Xa and minimal antifactor IIa activity,7 and a peak plasma concentration reached 3 hours after subcutaneous administration. These characteristics as well as a 58% relative risk reduction of any VTE, when compared with enoxaparin in a phase II study,8 suggest semuloparin might be a good candidate for starting thromboprophylaxis postsurgery. We compared the efficacy and safety of semuloparin started postoperatively with enoxaparin started preoperatively in accordance with the local enoxaparin labeling, for the prevention of VTE in patients undergoing major abdominal surgery.
METHODS Study Oversight The trial was designed and led by an independent steering committee, the principal author wrote the first draft of the manuscript, and subsequent drafts were based on input from coauthors all of www.annalsofsurgery.com | 1073
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 259, Number 6, June 2014
Kakkar et al
whom approved submission of the final version of the manuscript. The study was performed in accordance with the provisions of the Declaration of Helsinki and local regulations. The protocol was approved by the institutional review board or ethics committee at each participating site, and written informed consent was obtained from all patients before randomization. The data were collected by a clinical research organization (ICON Clinical Research Ltd, Leopardstown, Dublin, Ireland), and analyzed by the study sponsor (Sanofi). A Data Monitoring Committee monitored patient safety and efficacy. Primary efficacy and safety outcomes, including cause of death, were assessed by a blinded Central Independent Adjudication Committee.
Patients In this multinational, randomized, double-blind, double dummy, parallel group study, male and female patients 18 years or older, scheduled for major laparotomy under general anesthesia lasting longer than 45 minutes in the peritoneal and/or retroperitoneal space and/or pelvis were included. Patients younger than 60 years had to have one of the following additional risk factors for VTE: previous VTE, obesity (body mass index ≥30 kg/m2 ), chronic heart failure (New York Heart Association class III or IV), chronic respiratory failure (hypoxemia, hypercarbia, or both, due to chronic obstructive pulmonary disease, restrictive parenchymal, or extraparenchymal lung disease), inflammatory bowel disease, or surgery for cancer. The major exclusion criteria were life expectancy of less than 3 months; known pelvic venous obstruction; major orthopedic or general surgery within the previous 3 months; clinical signs or symptoms of DVT or PE within the previous 12 months, or known postphlebitic syndrome; contraindications to venography; treatment with other antithrombotic drugs within 2 weeks before randomization or planned during the course of the study treatment period; active major bleeding; conditions with an increased risk of hemorrhage; thrombocytopenia; known hypersensitivity to enoxaparin sodium, heparin, or pork products; or end-stage renal disease (estimated creatinine clearance 80 mL/min Creatinine clearance >50–80 mL/min Creatinine clearance 30–50 mL/min Creatinine clearance 3 × ULN and total bilirubin >2 × ULN∗ Death on-study,† n (%) On-treatment death‡ Fatal pulmonary embolism Fatal bleeding Cardiovascular death Other Posttreatment death Fatal pulmonary embolism Fatal bleeding Cardiovascular death Other Not adjudicated
Enoxaparin (n = 2177)
Semuloparin (n = 2175)
1462 (67.2) 205 (9.4) 125 (5.7) 27 (1.2) 52 (2.4)
1429 (65.7) 186 (8.6) 107 (4.9) 31 (1.4) 36 (1.7)
133/2136 (6.2) 119/2136 (5.6) 17/2135 (0.8) 43 (2.0) 16 (0.7) 1 (
