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Apixaban vs Enoxaparin for Postoperative Prophylaxis: Safety of an Oral Alternative for the Prevention of Venous Thromboembolism

Apixaban vs Enoxaparin for Postoperative Prophylaxis: Safety of an Oral Alternative for the... Invited Commentary | Surgery Apixaban vs Enoxaparin for Postoperative Prophylaxis: Safety of an Oral Alternative for the Prevention of Venous Thromboembolism Elisabeth Diver, MD Postsurgical venous thromboembolism (VTE) pharmacologic prophylaxis is recommended for Related article patients with cancer by the American Society for Clinical Oncology (ASCO) and the American Author affiliations and article information are Academy of Chest Physicians, as well as in the Gynecologic Oncology Enhanced Recovery After listed at the end of this article. 1-3 Surgery (ERAS) recommendations. Malignancy and radical pelvic surgery are known risk factors for the development of VTE, highlighting the distinct need for effective and tolerable prophylactic strategies for women with gynecologic cancers. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are associated with significant morbidity and mortality in this population. Recent investigations have demonstrated that prolonged VTE prophylaxis up to 28 days postoperatively in a gynecologic population was associated with fewer VTE events. The randomized clinical trial of apixaban vs enoxaparin for postsurgical prophylaxis against VTE in women with suspected gynecologic cancer by Guntupalli et al adds valuable data to this emerging practice that may optimize postoperative outcomes for women undergoing gynecologic surgery. Subcutaneous low-molecular-weight heparin is an established standard that has been extensively studied for preoperative and postoperative VTE prophylaxis in surgical populations. A significant limitation to widespread use has been the need for daily subcutaneous injections along with a high cost, leading to decreased patient compliance and satisfaction when compared with oral medication. In another trial, oral apixaban (a factor Xa inhibitor) was compared with injectable fractionated heparins for the treatment of VTE in populations with cancer and demonstrated noninferior recurrence rates of VTE. These data provide rationale for investigating whether oral factor Xa inhibitors may represent a safe and effective option for the prevention of postoperative VTE that could also improve patient compliance and quality of life. Dr Guntupalli and colleagues addressed these questions in this 2-site randomized clinical trial of apixaban vs enoxaparin prophylaxis in a postoperative gynecologic oncology population. This trial enrolled 400 women undergoing surgery for known or suspected gynecologic malignancies. Once deemed stable following surgery, each patient was randomized 1:1 to either apixaban 2.5 mg orally twice a day or enoxaparin 40 mg subcutaneously daily for 28 days. Primary outcomes demonstrated safety of apixaban prophylaxis compared with enoxaparin; both major bleeding events (0.5% vs 0.5%, respectively; P > .99) and clinically relevant nonmajor bleeding events (5.4% vs 9.7%, respectively; P = .11) were not different between the groups. VTE was assessed for drug efficacy and showed no difference between the groups, with 1.0% in the apixaban group and 1.5% in the enoxaparin arm (P = .68). Importantly, patient satisfaction was significantly higher in the apixaban group compared with the enoxaparin group, 98.9% vs 58.8% (P < .001). Guntupalli and colleagues’ trial provides important and provocative pilot data regarding the practice of extended VTE prophylaxis in a gynecologic oncology surgical population. Given the historically high rate of postoperative VTE noted in these women, it is imperative to explore safe and acceptable prophylaxis options. Patients in the past have demonstrated lower adherence with injectable prophylaxis, and patient preference for an oral medication is clear in the findings of this trial. Notably, this study was done in an unselected surgical population without strict inclusion and exclusion criteria for the types of patients undergoing surgery performed by a gynecologic oncologist. While the broad inclusion criteria limits conclusions about apixaban efficacy for a specific Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(6):e208019. doi:10.1001/jamanetworkopen.2020.8019 (Reprinted) June 26, 2020 1/3 JAMA Network Open | Surgery Safety of Apixaban vs Enoxaparin for Postoperative Prevention of Venous Thromboembolism oncology indications, this feature makes these data easy to apply in the clinic and could be extrapolated to a broad oncologic surgical population. These data demonstrate feasibility and likely safety of apixaban for postoperative prophylaxis in women undergoing surgery with gynecologic oncologists. While the very low rate (0.5%) of major bleeding events and postoperative VTE observed in this study suggest safety of both of these prophylaxis choices in this gynecologic oncology population, the unanticipated lack of events makes the trial underpowered to detect any significant differences. The broad surgical case inclusion was likely responsible for the lower observed event rate, and it may be that future trials limited to high risk patients and surgeries may demonstrate differences in apixaban performance. Efficacy is a critical outcome in this population, and because this study was not designed with a primary outcome of efficacy, larger randomized investigations will be required to validate the promising signal observed in this trial. For women who cannot or will not perform self-injection with enoxaparin, Guntupalli and his colleagues have demonstrated that an alternative, oral VTE prevention strategy with apixaban in the postoperative setting is feasible, and possibly as safe with similar VTE outcomes. As more data are acquired through general use and repeated clinical trials, we are likely to see the emergence of a new standard of care for these women that improves patient satisfaction and may improve compliance. In light of these data, a noninferiority trial designed to assess efficacy of VTE prevention will be required to change standard of care for all women in this patient population, and this study provides the scientific rationale to launch such an investigation. ARTICLE INFORMATION Published: June 26, 2020. doi:10.1001/jamanetworkopen.2020.8019 Open Access: This is an open access article distributed under the terms of the CC-BY License.©2020Diver E. JAMA Network Open. Corresponding Author: Elisabeth Diver, MD, Stanford University, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, 300 Pasteur Drive, H-300, Stanford, CA 94305 (elisabeth.diver@stanford.edu). Author Affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California. Conflict of Interest Disclosures: Dr Diver reported personal fees from Clovis Oncology and personal fees from GlaxoSmithKline outside the submitted work. REFERENCES 1. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):7S-47S. doi:10.1378/chest.1412S3 Published correction appears in Chest. 2012;141(4):1129. doi:10.1378/chest.14-2560 2. Key NS, Bohlke K, Falanga A. Venous thromboembolism prophylaxis and treatment in patients with cancer: asco clinical practice guideline update summary. J Oncol Pract. 2019;15(12):661-664. doi:10.1200/JOP.19.00368 3. Nelson G, Bakkum-Gamez J, Kalogera E, et al. Guidelines for perioperative care in gynecologic/oncology: Enhanced Recovery After Surgery (ERAS) Society recommendations-2019 update. Int J Gynecol Cancer. 2019;29 (4):651-668. doi:10.1136/ijgc-2019-000356 4. Graul A, Latif N, Zhang X, et al. Incidence of venous thromboembolism by type of gynecologic malignancy and surgical modality in the national surgical quality improvement program. Int J Gynecol Cancer. 2017;27(3): 581-587. doi:10.1097/IGC.0000000000000912 5. Felder S, Rasmussen MS, King R, et al. Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev. 2019;8:CD004318. doi:10.1002/14651858. CD004318.pub5 6. Guntupalli SR, Brennecke A, Behbakht K, et al. Safety and efficacy of apixaban vs enoxaparin for preventing postoperative venous thromboembolism in women undergoing surgery for gynecologic malignant neoplasm: a randomized clinical trial. JAMA Netw Open. 2020;3(6):e207410. doi:10.1001/jamanetworkopen.2020.7410 JAMA Network Open. 2020;3(6):e208019. doi:10.1001/jamanetworkopen.2020.8019 (Reprinted) June 26, 2020 2/3 JAMA Network Open | Surgery Safety of Apixaban vs Enoxaparin for Postoperative Prevention of Venous Thromboembolism 7. Tang Y, Wang K, Shi Z, Yang P, Dang X. A RCT study of Rivaroxaban, low-molecular-weight heparin, and sequential medication regimens for the prevention of venous thrombosis after internal fixation of hip fracture. Biomed Pharmacother. 2017;92:982-988. doi:10.1016/j.biopha.2017.05.107 8. Agnelli G, Becattini C, Meyer G, et al; Caravaggio Investigators. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020;382(17):1599-1607. doi:10.1056/NEJMoa1915103 JAMA Network Open. 2020;3(6):e208019. doi:10.1001/jamanetworkopen.2020.8019 (Reprinted) June 26, 2020 3/3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Network Open American Medical Association

Apixaban vs Enoxaparin for Postoperative Prophylaxis: Safety of an Oral Alternative for the Prevention of Venous Thromboembolism

JAMA Network Open , Volume 3 (6) – Jun 26, 2020

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References (10)

Publisher
American Medical Association
Copyright
Copyright 2020 Diver E. JAMA Network Open.
eISSN
2574-3805
DOI
10.1001/jamanetworkopen.2020.8019
Publisher site
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Abstract

Invited Commentary | Surgery Apixaban vs Enoxaparin for Postoperative Prophylaxis: Safety of an Oral Alternative for the Prevention of Venous Thromboembolism Elisabeth Diver, MD Postsurgical venous thromboembolism (VTE) pharmacologic prophylaxis is recommended for Related article patients with cancer by the American Society for Clinical Oncology (ASCO) and the American Author affiliations and article information are Academy of Chest Physicians, as well as in the Gynecologic Oncology Enhanced Recovery After listed at the end of this article. 1-3 Surgery (ERAS) recommendations. Malignancy and radical pelvic surgery are known risk factors for the development of VTE, highlighting the distinct need for effective and tolerable prophylactic strategies for women with gynecologic cancers. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are associated with significant morbidity and mortality in this population. Recent investigations have demonstrated that prolonged VTE prophylaxis up to 28 days postoperatively in a gynecologic population was associated with fewer VTE events. The randomized clinical trial of apixaban vs enoxaparin for postsurgical prophylaxis against VTE in women with suspected gynecologic cancer by Guntupalli et al adds valuable data to this emerging practice that may optimize postoperative outcomes for women undergoing gynecologic surgery. Subcutaneous low-molecular-weight heparin is an established standard that has been extensively studied for preoperative and postoperative VTE prophylaxis in surgical populations. A significant limitation to widespread use has been the need for daily subcutaneous injections along with a high cost, leading to decreased patient compliance and satisfaction when compared with oral medication. In another trial, oral apixaban (a factor Xa inhibitor) was compared with injectable fractionated heparins for the treatment of VTE in populations with cancer and demonstrated noninferior recurrence rates of VTE. These data provide rationale for investigating whether oral factor Xa inhibitors may represent a safe and effective option for the prevention of postoperative VTE that could also improve patient compliance and quality of life. Dr Guntupalli and colleagues addressed these questions in this 2-site randomized clinical trial of apixaban vs enoxaparin prophylaxis in a postoperative gynecologic oncology population. This trial enrolled 400 women undergoing surgery for known or suspected gynecologic malignancies. Once deemed stable following surgery, each patient was randomized 1:1 to either apixaban 2.5 mg orally twice a day or enoxaparin 40 mg subcutaneously daily for 28 days. Primary outcomes demonstrated safety of apixaban prophylaxis compared with enoxaparin; both major bleeding events (0.5% vs 0.5%, respectively; P > .99) and clinically relevant nonmajor bleeding events (5.4% vs 9.7%, respectively; P = .11) were not different between the groups. VTE was assessed for drug efficacy and showed no difference between the groups, with 1.0% in the apixaban group and 1.5% in the enoxaparin arm (P = .68). Importantly, patient satisfaction was significantly higher in the apixaban group compared with the enoxaparin group, 98.9% vs 58.8% (P < .001). Guntupalli and colleagues’ trial provides important and provocative pilot data regarding the practice of extended VTE prophylaxis in a gynecologic oncology surgical population. Given the historically high rate of postoperative VTE noted in these women, it is imperative to explore safe and acceptable prophylaxis options. Patients in the past have demonstrated lower adherence with injectable prophylaxis, and patient preference for an oral medication is clear in the findings of this trial. Notably, this study was done in an unselected surgical population without strict inclusion and exclusion criteria for the types of patients undergoing surgery performed by a gynecologic oncologist. While the broad inclusion criteria limits conclusions about apixaban efficacy for a specific Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(6):e208019. doi:10.1001/jamanetworkopen.2020.8019 (Reprinted) June 26, 2020 1/3 JAMA Network Open | Surgery Safety of Apixaban vs Enoxaparin for Postoperative Prevention of Venous Thromboembolism oncology indications, this feature makes these data easy to apply in the clinic and could be extrapolated to a broad oncologic surgical population. These data demonstrate feasibility and likely safety of apixaban for postoperative prophylaxis in women undergoing surgery with gynecologic oncologists. While the very low rate (0.5%) of major bleeding events and postoperative VTE observed in this study suggest safety of both of these prophylaxis choices in this gynecologic oncology population, the unanticipated lack of events makes the trial underpowered to detect any significant differences. The broad surgical case inclusion was likely responsible for the lower observed event rate, and it may be that future trials limited to high risk patients and surgeries may demonstrate differences in apixaban performance. Efficacy is a critical outcome in this population, and because this study was not designed with a primary outcome of efficacy, larger randomized investigations will be required to validate the promising signal observed in this trial. For women who cannot or will not perform self-injection with enoxaparin, Guntupalli and his colleagues have demonstrated that an alternative, oral VTE prevention strategy with apixaban in the postoperative setting is feasible, and possibly as safe with similar VTE outcomes. As more data are acquired through general use and repeated clinical trials, we are likely to see the emergence of a new standard of care for these women that improves patient satisfaction and may improve compliance. In light of these data, a noninferiority trial designed to assess efficacy of VTE prevention will be required to change standard of care for all women in this patient population, and this study provides the scientific rationale to launch such an investigation. ARTICLE INFORMATION Published: June 26, 2020. doi:10.1001/jamanetworkopen.2020.8019 Open Access: This is an open access article distributed under the terms of the CC-BY License.©2020Diver E. JAMA Network Open. Corresponding Author: Elisabeth Diver, MD, Stanford University, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, 300 Pasteur Drive, H-300, Stanford, CA 94305 (elisabeth.diver@stanford.edu). Author Affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California. Conflict of Interest Disclosures: Dr Diver reported personal fees from Clovis Oncology and personal fees from GlaxoSmithKline outside the submitted work. REFERENCES 1. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):7S-47S. doi:10.1378/chest.1412S3 Published correction appears in Chest. 2012;141(4):1129. doi:10.1378/chest.14-2560 2. Key NS, Bohlke K, Falanga A. Venous thromboembolism prophylaxis and treatment in patients with cancer: asco clinical practice guideline update summary. J Oncol Pract. 2019;15(12):661-664. doi:10.1200/JOP.19.00368 3. Nelson G, Bakkum-Gamez J, Kalogera E, et al. Guidelines for perioperative care in gynecologic/oncology: Enhanced Recovery After Surgery (ERAS) Society recommendations-2019 update. Int J Gynecol Cancer. 2019;29 (4):651-668. doi:10.1136/ijgc-2019-000356 4. Graul A, Latif N, Zhang X, et al. Incidence of venous thromboembolism by type of gynecologic malignancy and surgical modality in the national surgical quality improvement program. Int J Gynecol Cancer. 2017;27(3): 581-587. doi:10.1097/IGC.0000000000000912 5. Felder S, Rasmussen MS, King R, et al. Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev. 2019;8:CD004318. doi:10.1002/14651858. CD004318.pub5 6. Guntupalli SR, Brennecke A, Behbakht K, et al. Safety and efficacy of apixaban vs enoxaparin for preventing postoperative venous thromboembolism in women undergoing surgery for gynecologic malignant neoplasm: a randomized clinical trial. JAMA Netw Open. 2020;3(6):e207410. doi:10.1001/jamanetworkopen.2020.7410 JAMA Network Open. 2020;3(6):e208019. doi:10.1001/jamanetworkopen.2020.8019 (Reprinted) June 26, 2020 2/3 JAMA Network Open | Surgery Safety of Apixaban vs Enoxaparin for Postoperative Prevention of Venous Thromboembolism 7. Tang Y, Wang K, Shi Z, Yang P, Dang X. A RCT study of Rivaroxaban, low-molecular-weight heparin, and sequential medication regimens for the prevention of venous thrombosis after internal fixation of hip fracture. Biomed Pharmacother. 2017;92:982-988. doi:10.1016/j.biopha.2017.05.107 8. Agnelli G, Becattini C, Meyer G, et al; Caravaggio Investigators. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020;382(17):1599-1607. doi:10.1056/NEJMoa1915103 JAMA Network Open. 2020;3(6):e208019. doi:10.1001/jamanetworkopen.2020.8019 (Reprinted) June 26, 2020 3/3

Journal

JAMA Network OpenAmerican Medical Association

Published: Jun 26, 2020

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