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      Extended versus inpatient thromboprophylaxis with heparins following major open abdominopelvic surgery for malignancy: a systematic review of efficacy and safety

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          Abstract

          Background

          Patients undergoing open abdominopelvic procedures for malignancy are at high risk of postoperative venous thromboembolism (VTE). This risk can be mitigated with prophylaxis; however, optimum duration in this population remains unknown. Our objective was to conduct a systematic review of contemporary literature on the use of heparin thromboprophylaxis following major open pelvic surgery for malignancy, comparing the efficacy and safety of extended duration to inpatient treatment.

          Methods

          A study protocol describing search strategy and inclusion and exclusion criteria was developed and registered with PROSPERO. A literature review was conducted in accordance with the protocol.

          Results

          Literature review identified only 4 studies directly comparing extended and inpatient duration prophylaxis, with a combined population of 3198 and 3135 patients for VTE rate and bleeding events, respectively. Despite many studies reporting lower VTE rates in patients receiving extended prophylaxis, no statistically significant difference in rates of postoperative VTE ( p = 0.18) or bleeding complications ( p = 0.43) was identified between patients receiving extended duration prophylaxis and those receiving inpatient only prophylaxis.

          Conclusion

          On the review of contemporary literature, no significant difference was found in rates of postoperative VTE or bleeding complications between patients receiving extended duration heparin VTE prophylaxis and those receiving inpatient prophylaxis after open abdominopelvic surgery for malignancy.

          This raises the question of how extended duration prophylaxis has become common practice in this population, and whether this needs to be re-evaluated.

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          Most cited references18

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          Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer.

          Abdominal surgery for cancer carries a high risk of venous thromboembolism, but the optimal duration of postoperative thromboprophylaxis is unknown. We conducted a double-blind, multicenter trial in which patients undergoing planned curative open surgery for abdominal or pelvic cancer received enoxaparin (40 mg subcutaneously) daily for 6 to 10 days and were then randomly assigned to receive either enoxaparin or placebo for another 21 days. Bilateral venography was performed between days 25 and 31, or sooner if symptoms of venous thromboembolism occurred. The primary end point with respect to efficacy was the incidence of venous thromboembolism between days 25 and 31. The primary safety end point was bleeding during the three-week period after randomization. The patients were followed for three months. The intention-to-treat analysis of efficacy included 332 patients. The rates of venous thromboembolism at the end of the double-blind phase were 12.0 percent in the placebo group and 4.8 percent in the enoxaparin group (P=0.02). This difference persisted at three months (13.8 percent vs. 5.5 percent, P=0.01). Three patients in the enoxaparin group and six in the placebo group died within three months after surgery. There were no significant differences in the rates of bleeding or other complications during the double-blind or follow-up periods. Enoxaparin prophylaxis for four weeks after surgery for abdominal or pelvic cancer is safe and significantly reduces the incidence of venographically demonstrated thrombosis, as compared with enoxaparin prophylaxis for one week.
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            Extended prophylaxis with bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study.

            There is not enough clinical evidence to make a strong recommendation on the optimal duration of thromboprophylaxis using low-molecular weight heparins (LMWH) in patients undergoing major cancer surgery. CANBESURE is a randomized, double-blind study which enrolled patients admitted for abdominal or pelvic surgery for cancer. They received 3500 IU of bemiparin subcutaneously once daily for 8 days and were then randomized to receive either bemiparin or placebo for 20 additional days. Bilateral venography was performed after 20 days and evaluated blinded. The primary efficacy outcome was the composite of deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and all-cause mortality at the end of double-blind period. Major venous thromboembolism (proximal deep-vein thrombosis, non-fatal pulmonary embolism and venous thromboembolism-related deaths) was also evaluated. The primary safety outcome was major bleeding. Six hundred and twenty-five and 488 patients were included in the safety and main efficacy analyzes, respectively. The primary efficacy outcome occurred in 25 out of 248 patients (10.1%) in the bemiparin group and 32 out of 240 (13.3%) in the placebo group (relative risk reduction 24.4%; 95% CI: -23.7-53.8%; P = 0.26). At the end of double-blind period, major venous thromboembolism occurred in 2 (0.8%) and 11 (4.6%) patients, respectively (relative risk reduction 82.4%; 95% CI: 21.5-96.1%; P = 0.010). No significant difference was found in major bleedings. Four weeks compared with 1 week of prophylaxis with bemiparin after abdominal or pelvic cancer surgery did not significantly reduce the primary efficacy outcome, but decreased major venous thromboembolism (VTE) without increasing hemorrhagic complications.
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              Efficacy and safety of enoxaparin in Japanese patients undergoing curative abdominal or pelvic cancer surgery: results from a multicenter, randomized, open-label study.

              Enoxaparin sodium (enoxaparin) is used worldwide for the prevention of venous thromboembolism (VTE). Registration trials of enoxaparin have been conducted primarily in Caucasian populations, and its preventive use in Japanese patients has yet to be established. To address this, we evaluated the efficacy and safety of postoperative enoxaparin in Japanese patients undergoing surgery for abdominal cancer. This multicenter, open-label study randomized 151 Japanese patients undergoing curative surgery for abdominal cancer to enoxaparin 20mg twice daily for 14 days, started 24-36 hours after surgery (n=113) or intermittent pneumatic compression (IPC) as a reference (n=38). IPC was performed at least once in both groups between randomization and surgery. The primary efficacy endpoint was the incidence of VTE in the modified intention-to-treat (mITT) population. The primary safety outcome was the incidence of any bleeding during treatment and follow-up. Incidence of VTE was 1.2% (95% CI, 0.03-6.53%) (1/83 patients) in the enoxaparin group and 19.4% (95% CI, 7.45-37.47%) (6/31 patients) in the IPC group. In the safety population, 10/109 patients in the enoxaparin group (9.2%; 95% CI, 4.49-16.23%) and 3/38 patients in the IPC group (7.9%; 95% CI, 1.66-21.38%) experienced a bleeding event. There were no cases of fatal bleeding or bleeding into any critical organ. These favorable efficacy and safety data support the use of enoxaparin (20mg twice daily for 14 days started 24-36 hours after surgery) in Japanese patients undergoing abdominal or pelvic cancer surgery. (c) 2009 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                bridgetcheijkoop@gmail.com
                Journal
                Perioper Med (Lond)
                Perioper Med (Lond)
                Perioperative Medicine
                BioMed Central (London )
                2047-0525
                3 March 2020
                3 March 2020
                2020
                : 9
                : 7
                Affiliations
                [1 ]ISNI 0000 0004 0486 659X, GRID grid.278859.9, The Queen Elizabeth Hospital, ; Woodville, SA Australia
                [2 ]ISNI 0000 0004 1936 7304, GRID grid.1010.0, Discipline of Surgery, , The University of Adelaide, ; Adelaide, Australia
                [3 ]ISNI 0000 0004 0637 6498, GRID grid.419296.1, Research and Evaluation, Incorporating ASERNIP-S, , Royal Australasian College of Surgeons, ; Adelaide, Australia
                Author information
                http://orcid.org/0000-0001-6348-5445
                Article
                137
                10.1186/s13741-020-0137-8
                7053065
                25ca8c88-66ea-439d-884e-a721ce386c99
                © The Author(s). 2020

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 25 August 2019
                : 29 January 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002678, Adelaide Research and Innovation, University of Adelaide;
                Award ID: 324-15119081
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                venous thromboembolism,malignancy,surgery,heparin,prophylaxis

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