|Year : 2019 | Volume
| Issue : 7 | Page : 1541-1546
Comparison between direct factor Xa inhibitors and low-molecular-weight heparin for efficacy and safety in the treatment of cancer-associated venous thromboembolism: A meta-analysis
Min Yang1, Jiang Li2, Rui Sun1, Yanfeng Wang1, Haiyan Xu1, Boyan Yang1, Xiaoming Wu1, Lei Yu1
1 Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
2 Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
|Date of Submission||26-Jan-2019|
|Date of Decision||09-Jul-2019|
|Date of Acceptance||13-Aug-2019|
|Date of Web Publication||13-Jan-2020|
Dr. Min Yang
Comprehensive Oncology Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
Source of Support: None, Conflict of Interest: None
Aim of the Study: The role of direct-acting oral anticoagulants in the treatment of venous thromboembolism (VTE) in cancer patients compared with the current standard of low-molecular-weight heparin (LMWH) treatment remains unclear. This meta-analysis aimed to evaluate the efficacy and safety of direct factor Xa inhibitors compared with those of LMWH in the treatment of cancer-associated VTE.
Materials and Methods: We systematically searched PubMed, EMBASE, Cochrane library, and Web of Science for potential randomized controlled clinical trials and retrospective cohort studies. Data on recurrent VTE (efficacy) and major and minor bleeding events (safety) were extracted, and the odds risks (OR) were analyzed using a random-effect model.
Results: A total of nine studies involving 4208 cancer patients with VTE were included in these analyses. Pooled analysis showed that direct factor Xa inhibitors were significantly superior to LMWH in reducing the risk of recurrent VTE (OR = 0.67; 95% confidence interval [CI]: 0.54–0.82). There was no significant difference in the rate of major bleeding between the direct factor Xa inhibitor and LMWH treatments (OR = 1.25; 95% CI: 0.94–1.65). However, the rate of minor bleeding events was higher when a direct factor Xa inhibitor was used instead of LMWH (OR = 1.80; 95% CI: 1.05–3.07).
Conclusions: Direct factor Xa inhibitors are superior to LMWH in efficacy in the treatment of VTE in cancer patients, and the safety between the two regimens is comparable except for a slightly higher rate of minor bleeding when the former is used.
Keywords: Cancer-related venous thromboembolism, direct-acting oral anticoagulants, efficacy, low-molecular-weight heparin, safety
|How to cite this article:|
Yang M, Li J, Sun R, Wang Y, Xu H, Yang B, Wu X, Yu L. Comparison between direct factor Xa inhibitors and low-molecular-weight heparin for efficacy and safety in the treatment of cancer-associated venous thromboembolism: A meta-analysis. J Can Res Ther 2019;15:1541-6
|How to cite this URL:|
Yang M, Li J, Sun R, Wang Y, Xu H, Yang B, Wu X, Yu L. Comparison between direct factor Xa inhibitors and low-molecular-weight heparin for efficacy and safety in the treatment of cancer-associated venous thromboembolism: A meta-analysis. J Can Res Ther [serial online] 2019 [cited 2020 Apr 4];15:1541-6. Available from: http://www.cancerjournal.net/text.asp?2019/15/7/1541/275564
| > Introduction|| |
Cancer is a well-established hypercoagulable state with a 4–7-fold higher risk of venous thromboembolism (VTE) than the general population., Although direct oral anticoagulants (DOACs) are the first-line treatment for VTE in patients without cancer, low-molecular-weight heparin (LMWH) is recommended for those with cancer., Direct Xa inhibitors have been approved because of their effectiveness and safety.,, Additional benefits include fixed dosing, fewer interactions, and no requirement for blood monitoring compared with warfarin.,, This study aimed to evaluate the efficacy and safety of direct factor Xa inhibitors in comparison with those of LMWH for the treatment of cancer-associated VTE.
| > Materials and Methods|| |
Data sources and search strategy
This analysis was conducted in line with the guidelines for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The registration number in the PROSPERO database is CRD42018107438. PubMed, EMBASE, Cochrane library, and Web of Science were searched by two reviewers (Y. M. and L. J.) independently from each one's inception until August 2018. The terms, such as rivaroxaban, apixaban, edoxaban, neoplasms, and LMWH, were searched as the Medical Subject Heading. Relevant reviews and meta-analyses were also reviewed.
Two reviewers (Y. M. and L. J.) independently conducted the study screening, and disagreements were resolved through group discussion with a third person (S. R.). Studies were included if they met the following predetermined criteria: (a) they had analyzed cancer patients with VTE who underwent an anticoagulant therapy, (b) they had investigated the effect and bleeding risk of direct factor Xa inhibitors versus LMWH, (c) they were full studies reported in English, and (d) they were not limited to random controlled trials (RCTs) but also included eligible observational studies. Studies that met the following criteria were excluded: (a) those reported as letters, abstracts, conference summaries, case reports, reviews, or laboratory studies; (b) those published as duplicate data (only the most complete one was included); and (c) those in which a key information needed for further analysis was missing.
Data extraction and quality assessment
Data were extracted according to the PRISMA criteria. For each study, the following data were independently extracted by two authors (Y. M. and L. J.): country, year of publication, study design, treatment, comparator, follow-up months, and sample size. The following outcomes were collected for the two treatment groups where available: number of VTE recurrences, and major and minor bleedings. The outcomes were reported as defined in the individual studies.
The study quality was assessed by two reviewers (Y. M. and L. J.) using the JADAD score for RCTs and Newcastle-Ottawa Scale (NOS) for cohort studies. The disagreements about study data extraction and quality assessment were resolved by discussion with a third person (S. R.).
We determined pooled odds ratios (ORs) and 95% confidence intervals (CIs) for VTE recurrences in patients with cancer treated with direct Xa inhibitors or LMWH. We also assessed the pooled ORs of major or minor bleeding. Data were pooled by using the Mantel–Haenszel method. Results were reported according to a fixed-effects model in the absence of significant heterogeneity and to a random-effects model in the presence of significant heterogeneity. The appropriateness of pooling data across the studies was assessed using the I 2 test for heterogeneity. In addition, we conducted sensitivity and subgroup analyses. The meta-analyses were performed using Stata software (version 14.0, Stata Corp, College Station, Texas).
| > Results|| |
As shown in [Figure 1], a total of 654 pieces of literature were identified from database searches. Nine studies met the inclusion criteria and were included in this meta-analysis. No publication bias was detected [Figure 2].
Characteristics of the eligible studies and quality assessment
The characteristics of the nine studies included are listed in [Table 1].,,,,,,,, This meta-analysis involved 4208 patients from studies that included 44–1367 patients. Seven (77.78%) studies were from the USA, one study (11.11%) was from the UK, and one study (11.11%) was from Spain. Two studies (22.22%) were RCTs and seven studies (77.78%) were retrospective cohort studies. The regimens of the study treatment group included rivaroxaban, edoxaban, and apixaban, while those of the comparator group included dalteparin, LMWH, and enoxaparin. Results of quality assessment (NOS/JADAD) are shown in [Table 1]. The basic outcomes, including VTE recurrence and major and minor bleeding, are presented in [Table 2].
Venous thromboembolism recurrence
The rates of VTE recurrence in the nine studies are reported in two groups [Table 2]. The aggregated rate of VTE recurrence was 10.41% (179 of 1720 patients) and 12.72% (300 of 2359 patients) in the direct factor Xa inhibitor and LMWH groups, respectively. A significantly lower rate of VTE recurrence was found in the direct factor Xa inhibitor group than that of the LMWH group (OR = 0.67; 95% CI: 0.54–0.82) with no heterogeneity (I 2 = 0%; P = 0.472) [Figure 3].
|Figure 3: Forest plot of the incidence of venous thromboembolism in meta-analysis|
Click here to view
The numbers of the major bleeding events in the nine studies are reported in [Table 2]. The meta-analysis results showed similar rates of major bleeding between the direct factor Xa inhibitor and LMWH treatment groups (OR = 1.25; 95% CI: 0.94–1.65) with no heterogeneity (I 2 = 0%; P = 0.488) [Figure 4].
Minor bleeding data were available from six studies [Table 2]. In the direct factor Xa inhibitor treatment group, 13.29% (135/1016) patients presented with minor bleeding events, significantly higher than that observed in the LMWH treatment group (10.51% [176/1675]) (OR = 1.80; 95% CI: 1.05–3.07) with a moderate heterogeneity (I 2 = 55.8%; P = 0.045) [Figure 5].
”One-by-one study removed” method was used for the sensitivity analysis. The results are stable in the summary OR estimates of the outcomes [Supplementary Figure 1].
Subgroup analyses for the different types of direct factor Xa inhibitors showed that the ORs of the rates of recurrent VTE for rivaroxaban, edoxaban, and rivaroxaban/apixaban groups were 0.67 (95% CI: 0.49–0.93), 0.67 (95% CI: 0.44–1.02), and 0.33 (95% CI: 0.08–1.36), respectively [Figure 6].
|Figure 6: Forest plot of the incidence of venous thromboembolism in subgroup analysis|
Click here to view
The ORs of the rates of major bleeding events in rivaroxaban, edoxaban, and rivaroxaban/apixaban groups were 1.10 (95% CI: 0.79–1.53), 1.78 (95% CI: 1.02–3.08), and 1.47 (95% CI: 0.14–14.92), respectively [Supplementary Figure 1]. There were no significant differences between the rates of minor bleeding events in rivaroxaban and LMWH groups (OR = 2.06; 95% CI: 0.97–4.35) and between edoxaban and LMWH (OR = 1.37; 95% CI: 0.95–1.97) [Supplementary Figure 2].
| > Discussion|| |
The objective of this meta-analysis was to compare direct Xa inhibitors with LMWH for the treatment of VTE in patients with cancer by pooling data from all the available RCTs and retrospective cohort studies. We analyzed data from nine studies including >4000 patients. Our analysis suggested that the use of direct Xa inhibitors was associated with a 33% reduction compared with the use of LMWH in the risk of VTE recurrence in cancer patients. There was no significant difference in the occurrence of major bleeding between the two treatments although direct Xa inhibitors might increase the risk of minor bleeding events. Subgroup analyses showed that only rivaroxaban was associated with a lower rate of recurrent VTE and different direct Xa inhibitors did not significantly differ in terms of bleeding events.
Based on our knowledge, this study is the first that has systematically collected data to directly compare the efficacy and safety outcomes of the use of direct Xa inhibitors and LMWH in the treatment of VTE in cancer patients. A meta-analysis by Brunetti et al. have previously reported no advantageous effect of direct Xa inhibitors compared with LMWH in terms of the recurrence of VTE (OR = 0.96; 95% CI: 0.52–1.75). However, their latest meta-analysis including both direct Xa inhibitors and dabigatran have found a similarly reduced risk of VTE recurrence, as our findings in comparison with that observed with LMWH or warfarin (relative risk [RR] = 0.64; 95% CI: 0.46–0.88). The guidelines recommend the use of direct Xa inhibitors in preventing the recurrence of VTE based on evidence from patients with no cancer., The findings in our study provide updated evidence to support the use of direct Xa inhibitors in cancer patients as well.
The occurrence of bleeding events is the main side effect of direct Xa inhibitors. Our study found no significant difference in major bleeding events between the uses of direct Xa inhibitors and LMWH in both overall and subgroup analyses, consistent with the comparisons between all DOACS and LMWH or warfarin in cancer patients (RR = 1.31; 95% CI: 0.71–2.44). However, Brunetti et al. have reported that the OR of major bleedings is 2.72 (95% CI: 1.05–7.01) with direct Xa inhibitors relative to LMWH. Notably, our study found that the rate of minor bleeding events in the use of direct Xa inhibitors was significantly higher than that in the LMWH group, while the significance disappeared in the subgroup analyses. The reason could be attributed to the moderate heterogeneity of the included studies. In addition, the dose of direct Xa inhibitors may make a difference in the efficacy and safety outcomes. A previous meta-analysis has demonstrated that, in comparison with LMWH, low doses of oral factor Xa inhibitors can achieve a small absolute risk reduction in venous thrombosis without increasing bleeding, whereas high doses increase bleeding.
There are some limitations when interpreting the findings in our study. All the studies included in this meta-analysis were from Post hoc analyses of RCTs or retrospective cohort studies. It is noteworthy that there were differences in the enrollment of the participants, follow-up period, and definition of major and minor bleedings, potentially causing the heterogeneity of our findings. Second, although the original aim of this study was to analyze the effects of all the direct Xa inhibitors, seven of the nine studies included in our study adopted rivaroxaban as the treatment therapy, and thus somewhat limited us to analyze the rivaroxaban treatment. Third, only patients from the USA, UK, and Spain were enrolled in these nine studies, hampering a global generalization. Last but not least, even though we systematically searched the electronic databases and also investigated the references in the included studies, we may have nevertheless missed some studies.
| > Conclusions|| |
This meta-analysis suggests that direct Xa inhibitors are superior to LMWH in reducing the incidence of VTE recurrence in cancer patients without putting the patients at high risk for major bleeding. Meanwhile, our findings should be interpreted with caution because rivaroxaban has been adopted in most studies. Future studies might assess the efficacy and safety data of other direct Xa inhibitors for the treatment of VTE in patients with different types of cancer.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Ay C, Pabinger I, Cohen AT. Cancer-associated venous thromboembolism: Burden, mechanisms, and management. Thromb Haemost 2017;117:219-30.
Linkins LA. Management of venous thromboembolism in patients with cancer: Role of dalteparin. Vasc Health Risk Manag 2008;4:279-87.
Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al.
Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016;149:315-52.
Streiff MB, Holmstrom B, Ashrani A, Bockenstedt PL, Chesney C, Eby C, et al.
Cancer-associated venous thromboembolic disease, version 1.2015. J Natl Compr Canc Netw 2015;13:1079-95.
Liu ZL, Wang Q, Wang M, Wang B, Huang LN. Low molecular weight heparin in treating patients with lung cancer received chemotherapy: A meta-analysis. J Cancer Res Ther 2018;14:S437-43.
Jun M, Lix LM, Durand M, Dahl M, Paterson JM, Dormuth CR, et al.
Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: Multicentre, population based, observational study. BMJ 2017;359:j4323.
Nagata N, Yasunaga H, Matsui H, Fushimi K, Watanabe K, Akiyama J, et al.
Therapeutic endoscopy-related GI bleeding and thromboembolic events in patients using warfarin or direct oral anticoagulants: Results from a large nationwide database analysis. Gut 2018;67:1805-12.
Agnelli G, Buller HR, Cohen A. Oral apixaban for the treatment of acute venous thromboembolism. J Vasc Surg 2014;59:269.
EINSTEIN-PE Investigators, Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, et al.
Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97.
Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, et al.
Edoxaban for venous thromboembolism in patients with cancer: Results from a non-inferiority subgroup analysis of the hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol 2016;3:e379-87.
Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, 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). J Clin Oncol 2018;36:2017-23.
Streiff MB, Milentijevic D, McCrae K, Yannicelli D, Fortier J, Nelson WW, et al.
Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol 2018;93:664-71.
Simmons B, Wysokinski W, Saadiq RA, Bott-Kitslaar D, Henkin S, Casanegra A, et al.
Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. Eur J Haematol 2018;101:136-42.
Nicklaus MD, Ludwig SL, Kettle JK. Recurrence of malignancy-associated venous thromboembolism among patients treated with rivaroxaban compared to enoxaparin. J Oncol Pharm Pract 2018;24:185-9.
Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, et al.
Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615-24.
Chaudhury A, Balakrishnan A, Thai C, Holmstrom B, Nanjappa S, Ma Z, et al.
The efficacy and safety of rivaroxaban and dalteparin in the treatment of cancer associated venous thrombosis. Indian J Hematol Blood Transfus 2018;34:530-4.
Alzghari SK, Seago SE, Garza JE, Hashimie YF, Baty KA, Evans MF, et al.
Retrospective comparison of low molecular weight heparin vs. Warfarin vs. Oral xa inhibitors for the prevention of recurrent venous thromboembolism in oncology patients: The re-CLOT study. J Oncol Pharm Pract 2018;24:494-500.
Signorelli JR, Gandhi AS. Evaluation of rivaroxaban use in patients with gynecologic malignancies at an academic medical center: A pilot study. J Oncol Pharm Pract 2017. 107815521773968, Doi: dx.doi.org/10.1177/1078155217739683.
Xavier FD, Hoff PM, Braghiroli MI, Paterlini AC, Souza KT, Faria LD, et al.
Rivaroxaban: An affordable and effective alternative in cancer-related thrombosis? J Glob Oncol 2017;3:15-22.
Brunetti ND, Gesuete E, De Gennaro L, Correale M, Caldarola P, Gaglione A, et al.
Direct oral anti-coagulants compared with Vitamin K inhibitors and low-molecular-weight-heparin for the prevention of venous thromboembolism in patients with cancer: A meta-analysis study. Int J Cardiol 2017;230:214-21.
Al Yami MS, Badreldin HA, Mohammed AH, Elmubark AM, Alzahrani MY, Alshehri AM, et al.
Direct oral anticoagulants for the treatment of venous thromboembolism in patients with active malignancy: A systematic review and meta-analysis. J Thromb Thrombolysis 2018;46:145-53.
Streiff MB, Holmstrom B, Angelini D, Ashrani A, Bockenstedt PL, Chesney C, et al.
NCCN guidelines insights: Cancer-associated venous thromboembolic disease, version 2.2018. J Natl Compr Canc Netw 2018;16:1289-303.
Neumann I, Rada G, Claro JC, Carrasco-Labra A, Thorlund K, Akl EA, et al.
Oral direct factor xa inhibitors versus low-molecular-weight heparin to prevent venous thromboembolism in patients undergoing total hip or knee replacement: A systematic review and meta-analysis. Ann Intern Med 2012;156:710-9.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]