Rivaroxaban in comparison with low molecular weight heparin for the treatment of cancer-associated thrombosis: a systematic review and meta-analysis
AbstractBackground. Apixaban, edoxaban, and rivaroxaban are now recommended over low-molecular-weight heparins (LMWH) for long-term treatment of cancer-associated thrombosis (CAT).
Objective. Our study was aimed at comparing efficacy, safety and effect of rivaroxaban and LMWH on all-cause mortality in patients with cancer-associated thrombosis.
Methods. A systematic literature search was performed through the Medline and Cochrane libraries according to the previously developed in compliance with the PRISMA guidelines protocol (CRD42022310908). Randomized controlled trials comparing full-therapeutic dose of rivaroxaban with full-therapeutic and/or the intermediate dose of LMWH in patients with verified CAT were included. The main outcomes were: VTE recurrence, major bleeding, and all-cause mortality. Individual study events were converted into rates per patient-years of follow-up and combined using a pooled proportion meta-analysis with a random-effect model or fixed effect model according to the heterogeneity. The final results are reported as per 100 patient-years.
Results. The systematic search was performed in March 2022 and revealed 715 records. Of these, 16 full-text papers were screened for eligibility and two RCTs (SELECT-D and CASTA DIVA) combining the data on 564 patients were included into the analysis. The pooled event rate of VTE recurrence in those who received rivaroxaban and dalteparin was estimated as 10.0 and 19.6 per 100 patient-years, respectively. The pooled event rate for major bleeding and all-cause mortality amounted to 10.0 vs. 7.3 and 55.8 vs. 62.0 per 100 patient-years for those treated with rivaroxaban vs. dalteparin, respectively. The odds ratio (OR) for VTE recurrence was in favor of rivaroxaban (OR 0.45; 95% CI 0.22–0.96; p=0.04; I2=0.0%), with no differences in the risk of major bleeding (OR 1.12; 95% CI 0.23–5.53; p=0.136; I2=44.5%) and all-cause mortality (OR 0.77; 95% CI 0.45–1.31; p=0.330; I2=0.0%) observed.
Conclusion. In patients with cancer-associated thrombosis, the use of rivaroxaban in comparison with LMWH is associated with a reduced risk of VTE recurrence without an increase in the risk of major bleeding and does not affect all-cause mortality.
Keywords: venous thrombosis; pulmonary embolism; venous thromboembolism; malignancy; rivaroxaban
Funding. The study had no financial support.
Conflict of interest. Lobastov K.V. and Schastlivtsev I.V. received payments from Bayer AG for lectures, Pyatskaya A.V. and Navasardyan A.R. at the moment of writing the article were employed at Bayer AG, Kovalchuk A.V. has no conflicts of interest to declare.
Authors’ contribution. Study conception and design – Lobastov K.V., Pyatskaya A.V.; data collection and handling – Pyatskaya A.V., Kovalchuk A.V., Schastlivtsev I.V., Navasardyan A.R.; statistical processing – Lobastov K.V.; draft manuscript preparation – Lobastov K.V.; manuscript revision – Lobastov K.V., Schastlivtsev I.V., Pyatskaya A.V., Navasardyan A.R.
For citation: Lobastov K.V., Schastlivtsev I.V., Kovalchuk A.V., Pyatskaya A.V., Navasardyan A.R. Rivaroxaban in comparison with low molecular weight heparin for the treatment of cancer-associated thrombosis: a systematic review and meta-analysis. Angiology and Vascular Surgery. 2022; 28 (4): 126–34. DOI: https://doi.org/10.33029/1027-6661-2022-28-4-126-134 (in Russian)
References
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2. Blom J.W., Vanderschoot J.P., Oostindier M.J., et al. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. Journal of Thrombosis and Haemostasis. 2006; 4 (3): 529–535. DOI: https://doi.org/10.1111/j.1538-7836.2006.01804.x
3. Bergqvist D. Risk of venous thromboembolism in patients undergoing cancer surgery and options for thromboprophylaxis. Journal of Surgical Oncology. 2007; 5 (2): 167–174. DOI: https://doi.org/10.1002/jso.20625
4. Barsam S.J., Patel R., Arya R. Anticoagulation for prevention and treatment of cancer-related venous thromboembolism. British Journal of Haematology. 2013; 161 (6): 764–777. DOI: https://doi.org/10.1111/bjh.12314
5. Agnelli G., Bolis G., Capussotti L., et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Annals of Surgery. 2006; 243 (1): 89–95. DOI: https://doi.org/10.1097/01.sla.0000193959.44677.48
6. Levitan N., Dowlati A., Remick S.C., et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore). 1999; 78 (5): 285–291. DOI: https://doi.org/10.1097/00005792-199909000-00002
7. Monreal M., Falgá C., Valdés M., et al. Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings from the RIETE registry. Journal of Thrombosis and Haemostasis. 2006; 4 (9): 1950–1956. DOI: https://doi.org/10.1111/j.1538-7836.2006.02082.x
8. Prandoni P., Lensing A.W., Piccioli A., et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002; 100 (10): 3484–3488. DOI: https://doi.org/10.1182/blood-2002-01-0108
9. Carrier M., Prandoni P. Controversies in the management of cancer-associated thrombosis. Expert Review of Hematology. 2017; 10 (1): 15–22. DOI: https://doi.org/10.1080/17474086.2017.1257935
10. Kirkilesis G.I., Kakkos S.K., Tsolakis I.A. Editor’s Choice – A Systematic Review and Meta-Analysis of the Efficacy and Safety of Anticoagulation in the Treatment of Venous Thromboembolism in Patients with Cancer. European Journal of Vascular and Endovascular Surgery. 2019; 57 (5): 685–701. DOI: https://doi.org/10.1016/j.ejvs.2018.11.004
11. Khorana A.A., McCrae K.R., Milentijevic D., et al. Current practice patterns and patient persistence with anticoagulant treatments for cancer-associated thrombosis. Research and Practice in Thrombosis and Haemostasis. 2017; 1 (1): 14–22. DOI: https://doi.org/10.1002/rth2.12002
12. Dong S., Zhang Y., Li Y., et al. Direct Oral Anticoagulant for the Treatment of VTE in Cancer Patients: A Systematic Review and Meta-analysis. Annals of Pharmacotherapy. 2021; 55 (4): 430–439. DOI: https://doi.org/10.1177/1060028020960037
13. Lobastov К.V., Schastlivtsev I.V. The Current Status of Direct Oral Anticoagulants in Cancer-Related Venous Thromboembolism Treatment. Rational Pharmacotherapy in Cardiology. 2020; 16 (2): 286–295. DOI: https://doi.org/10.20996/1819-6446-2020-04-10. (in Russian)
14. Riaz I.B., Fuentes H.E., Naqvi S.A.A., et al. Direct Oral Anticoagulants Compared With Dalteparin for Treatment of Cancer-Associated Thrombosis: A Living, Interactive Systematic Review and Network Meta-analysis. Mayo Clinic Proceedings. 2022; 97 (2): 308–324. DOI: https://doi.org/10.1016/j.mayocp.2020.10.041
15. Giustozzi M., Agnelli G., Del Toro-Cervera J., et al. Direct Oral Anticoagulants for the Treatment of Acute Venous Thromboembolism Associated with Cancer: A Systematic Review and Meta-Analysis. Thrombosis and Haemostasis. 2020; 120 (7): 1128–1136. DOI: https://doi.org/10.1055/s-0040-1712098
16. Desai R., Koipallil G.K., Thomas N., et al. Efficacy and safety of direct oral anticoagulants for secondary prevention of cancer associated thrombosis: a meta-analysis of randomized controlled trials. Scientific Reports. 2020; 10 (1): 18945. DOI: https://doi.org/10.1038/s41598-020-75863-3
17. Stevens S.M., Woller S.C., Baumann Kreuziger L., et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report – Executive Summary. Chest. 2021; 160 (6): 545–608. DOI: https://doi.org/10.1016/j.chest.2021.07.056
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19. Young A.M., Marshall A., Thirlwall J., et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). Journal of Clinical Oncology. 2018; 36 (20): 2017–2023. DOI: https://doi.org/10.1200/JCO.2018.78.8034
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21. Moher D., Liberati A., Tetzlaff J., Altman D.G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLOS Medicine. 2009; 6 (7): 1000097. DOI: https://doi.org/10.1371/journal.pmed.1000097
22. Sterne J.A.C., Savović J., Page M.J., et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. British Medical Journal. 2019; 366: l4898. DOI: https://doi.org/10.1136/bmj.l4898
23. Current version of RoB 2. 2019. Available from: https://www.riskofbias.info/welcome/rob-2-0-tool/current-version-of-rob-2.
24. Planquette B., Bertoletti L., Charles-Nelson A., et al. Rivaroxaban vs Dalteparin in Cancer-Associated Thromboembolism: A Randomized Trial. Chest. 2022; 161 (3): 781–790. DOI: https://doi.org/10.1016/j.chest.2021.09.037
25. Schulman S., Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. Journal of Thrombosis and Haemostasis. 2005; 3 (4): 692–694. DOI: https://doi.org/10.1111/j.1538-7836.2005.01204.x
26. Raskob G.E., van Es N., Verhamme P., et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. New England Journal of Medicine. 2018; 378 (7): 615–624. DOI: https://doi.org/10.1056/nejmoa1711948
27. Agnelli G., Becattini C., Meyer G., et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. New England Journal of Medicine. 2020; 382: 1599–1607. DOI: https://doi.org/10.1056/nejmoa1915103
28. Houghton D.E., Vlazny D.T., Casanegra A.I., et al. Bleeding in Patients With Gastrointestinal Cancer Compared With Nongastrointestinal Cancer Treated With Apixaban, Rivaroxaban, or Enoxaparin for Acute Venous Thromboembolism. Mayo Clinic Proceedings. 2021; 96 (11): 2793–2805. DOI: https://doi.org/10.1016/j.mayocp.2021.04.026
29. Kim J.H., Yoo C., Seo S., et al. A Phase II Study to Compare the Safety and Efficacy of Direct Oral Anticoagulants versus Subcutaneous Dalteparin for Cancer-Associated Venous Thromboembolism in Patients with Advanced Upper Gastrointestinal, Hepatobiliary and Pancreatic Cancer: PRIORITY. Cancers (Basel). 2022; 14 (3): 559. DOI: https://doi.org/10.3390/cancers14030559
В настоящий момент существуют определенные опасения в отношении применения ПОАК у пациентов с полостными опухолями пищеварительного тракта, что находит отражение в актуальных клинических рекомендациях [17, 18]. Это связано с тем, что при раке подобной локализации наблюдается повышенный риск развития больших геморрагических осложнений, преимущественно желудочно-кишечных кровотечений из верхних отделов пищеварительного тракта [13]. Подобная тенденция прослеживалась в исследовании SELECT D [19] и достигала статистической значимости в исследовании HOKUSAI VTE Cancer [26]. В то же время в исследовании CARAVAGGIO при сравнении апиксабана с далтепарином не наблюдали увеличения риска развития больших желудочно-кишечных кровотечений, которые, однако, составляли около половины всех больших кровотечений [27]. Следует иметь в виду, что преобладание в популяции больных с полостными опухолями верхних отделов пищеварительного тракта может накладывать определенный отпечаток на профиль безопасности ПОАК. Этот эффект наглядно прослеживается при сравнении исследований SELECT D (10% участников с раком верхних отделов ЖКТ) и CASTA DIVA (менее 2% больных с раком аналогичной локализации). Если в первом исследовании имеется тенденция к увеличению риска развития больших кровотечений и отмечается достоверное повышение угрозы НБКЗ кровотечений, то во втором подобные тренды отсутствуют. Аналогичный эффект можно наблюдать в условиях реальной клинической практики. Так, в рамках анализа проспективно собранных данных, включающих результаты лечения 1392 больных с онко-ассоциированным тромбозом, среди которых полостные опухоли ЖКТ наблюдались в 272 случаях, было отмечено достоверное увеличение риска развития больших кровотечений при раке пищеварительного тракта только на фоне использования апиксабана, но не ривароксабана или эноксапарина [28]. Это может быть связано с представлениями о высокой безопасности апиксабана, которые подталкивают клиницистов к назначению препарата в более сложных и опасных ситуациях, что приводит к возникновению закономерных осложнений. Повышенный риск развития больших кровотечений при использовании апиксабана и ривароксабана по сравнению с далтепарином у пациентов с опухолями верхних отделов пищеварительного тракта был также продемонстрирован в рамках самостоятельного РКИ [29]. Данное исследование не включено в метаанализ в связи с наличием смешанной группы пациентов, получавших оба препарата, и невозможностью выделить подгруппу больных, принимавших ривароксабан. По результатам работы риск возникновения больших кровотечений при использовании ПОАК был увеличен в 4,32 раза (95% ДИ 0,92-20,36). Таким образом, принятие решение о назначении ПОАК у названной группы пациентов требует взвешенного подхода. В остальных случаях прямые оральные антикоагулянты являются препаратами выбора для лечения онко-ассоциированного тромбоза.
Заключение
Применение ривароксабана в сравнении с НМГ у пациентов с онко-ассоциированным тромбозом приводит к снижению риска рецидива ВТЭО и не влияет на опасность развития большого кровотечения и общую смертность.
Литература
1. Blom J.W., Doggen C.J., Osanto S., Rosendaal F.R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005; 293 (6): 715-722. DOI: https://doi.org/10.1001/jama.293.6.715
2. Blom J.W., Vanderschoot J.P., Oostindier M.J., et al. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. Journal of Thrombosis and Haemostasis. 2006; 4 (3): 529-535. DOI: https://doi.org/10.1111/j.1538-7836.2006.01804.x
3. Bergqvist D. Risk of venous thromboembolism in patients undergoing cancer surgery and options for thromboprophylaxis. Journal of Surgical Oncology. 2007; 5 (2): 167-174. DOI: https://doi.org/10.1002/jso.20625
4. Barsam S.J., Patel R., Arya R. Anticoagulation for prevention and treatment of cancer-related venous thromboembolism. British Journal of Haematology. 2013; 161 (6): 764-777. DOI: https://doi.org/10.1111/bjh.12314
5. Agnelli G., Bolis G., Capussotti L., et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Annals of Surgery. 2006; 243 (1): 89-95. DOI: https://doi.org/10.1097/01.sla.0000193959.44677.48
6. Levitan N., Dowlati A., Remick S.C., et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore). 1999; 78 (5): 285-291. DOI: https://doi.org/10.1097/00005792-199909000-00002
7. Monreal M., Falgá C., Valdés M., et al. Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings from the RIETE registry. Journal of Thrombosis and Haemostasis. 2006; 4 (9): 1950-1956. DOI: https://doi.org/10.1111/j.1538-7836.2006.02082.x
8. Prandoni P., Lensing A.W., Piccioli A., et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002; 100 (10): 3484-3488. DOI: https://doi.org/10.1182/blood-2002-01-0108
9. Carrier M., Prandoni P. Controversies in the management of cancer-associated thrombosis. Expert Review of Hematology. 2017; 10 (1): 15-22. DOI: https://doi.org/10.1080/17474086.2017.1257935
10. Kirkilesis G.I., Kakkos S.K., Tsolakis I.A. Editor’s Choice - A Systematic Review and Meta-Analysis of the Efficacy and Safety of Anticoagulation in the Treatment of Venous Thromboembolism in Patients with Cancer. European Journal of Vascular and Endovascular Surgery. 2019; 57 (5): 685-701. DOI: https://doi.org/10.1016/j.ejvs.2018.11.004
11. Khorana A.A., McCrae K.R., Milentijevic D., et al. Current practice patterns and patient persistence with anticoagulant treatments for cancer-associated thrombosis. Research and Practice in Thrombosis and Haemostasis. 2017; 1 (1): 14-22. DOI: https://doi.org/10.1002/rth2.12002
12. Dong S., Zhang Y., Li Y., et al. Direct Oral Anticoagulant for the Treatment of VTE in Cancer Patients: A Systematic Review and Meta-analysis. Annals of Pharmacotherapy. 2021; 55 (4): 430-439. DOI: https://doi.org/10.1177/1060028020960037
13. Лобастов К.В., Счастливцев И.В. Актуальный статус прямых оральных антикоагулянтов при лечении венозных тромбоэмболических осложнений у онкологических больных. Рациональная фармакотерапия в кардиологии. 2020; 16 (2): 286-295. DOI: https://doi.org/10.20996/1819-6446-2020-04-10
14. Riaz I.B., Fuentes H.E., Naqvi S.A.A., et al. Direct Oral Anticoagulants Compared With Dalteparin for Treatment of Cancer-Associated Thrombosis: A Living, Interactive Systematic Review and Network Meta-analysis. Mayo Clinic Proceedings. 2022; 97 (2): 308-324. DOI: https://doi.org/10.1016/j.mayocp.2020.10.041
15. Giustozzi M., Agnelli G., Del Toro-Cervera J., et al. Direct Oral Anticoagulants for the Treatment of Acute Venous Thromboembolism Associated with Cancer: A Systematic Review and Meta-Analysis. Thrombosis and Haemostasis. 2020; 120 (7): 1128-1136. DOI: https://doi.org/10.1055/s-0040-1712098
16. Desai R., Koipallil G.K., Thomas N., et al. Efficacy and safety of direct oral anticoagulants for secondary prevention of cancer associated thrombosis: a meta-analysis of randomized controlled trials. Scientific Reports. 2020; 10 (1): 18945. DOI: https://doi.org/10.1038/s41598-020-75863-3
17. Stevens S.M., Woller S.C., Baumann Kreuziger L., et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report - Executive Summary. Chest. 2021; 160 (6): 545-608. DOI: https://doi.org/10.1016/j.chest.2021.07.056
18. Lyman G.H., Carrier M., Ay C., et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Advances. 2021; 5 (4): 927-974. DOI: https://doi.org/10.1182/bloodadvances.2020003442
19. Young A.M., Marshall A., Thirlwall J., et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). Journal of Clinical Oncology. 2018; 36 (20): 2017-2023. DOI: https://doi.org/10.1200/JCO.2018.78.8034
20. Мареев В.Ю., Мареев Ю.В. Роль антикоагулянтов в лечении и профилактике рецидивов венозных тромбоэмболических осложнений у пациентов со злокачественными новообразованиями: метаанализ рандомизированных исследований с апиксабаном. Кардиология. 2022; 62 (3): 4-15. DOI: https://doi.org/10.18087/cardio.2022.3.n1987
21. Moher D., Liberati A., Tetzlaff J., Altman D.G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLOS Medicine. 2009; 6 (7): 1000097. DOI: https://doi.org/10.1371/journal.pmed.1000097
22. Sterne J.A.C., Savović J., Page M.J., et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. British Medical Journal. 2019; 366: l4898. DOI: https://doi.org/10.1136/bmj.l4898
23. Current version of RoB 2. 2019. Available from: https://www.riskofbias.info/welcome/rob-2-0-tool/current-version-of-rob-2.
24. Planquette B., Bertoletti L., Charles-Nelson A., et al. Rivaroxaban vs Dalteparin in Cancer-Associated Thromboembolism: A Randomized Trial. Chest. 2022; 161 (3): 781-790. DOI: https://doi.org/10.1016/j.chest.2021.09.037
25. Schulman S., Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. Journal of Thrombosis and Haemostasis. 2005; 3 (4): 692-694. DOI: https://doi.org/10.1111/j.1538-7836.2005.01204.x
26. Raskob G.E., van Es N., Verhamme P., et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. New England Journal of Medicine. 2018; 378 (7): 615-624. DOI: https://doi.org/10.1056/nejmoa1711948
27. Agnelli G., Becattini C., Meyer G., et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. New England Journal of Medicine. 2020; 382: 1599-1607. DOI: https://doi.org/10.1056/nejmoa1915103
28. Houghton D.E., Vlazny D.T., Casanegra A.I., et al. Bleeding in Patients With Gastrointestinal Cancer Compared With Nongastrointestinal Cancer Treated With Apixaban, Rivaroxaban, or Enoxaparin for Acute Venous Thromboembolism. Mayo Clinic Proceedings. 2021; 96 (11): 2793-2805. DOI: https://doi.org/10.1016/j.mayocp.2021.04.026
29. Kim J.H., Yoo C., Seo S., et al. A Phase II Study to Compare the Safety and Efficacy of Direct Oral Anticoagulants versus Subcutaneous Dalteparin for Cancer-Associated Venous Thromboembolism in Patients with Advanced Upper Gastrointestinal, Hepatobiliary and Pancreatic Cancer: PRIORITY. Cancers (Basel). 2022; 14 (3): 559. DOI: https://doi.org/10.3390/cancers14030559
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