Efficacy of Factor Xa Inhibitors Versus Placebo in Thromboprophylaxis for Cancer-Associated Thromboembolism: A Systematic Review and Meta-analysis

Abstract

Background

Cancer patients are at significantly increased risk of venous thromboembolism (VTE), a leading cause of morbidity and mortality in this population. While traditional anticoagulants like low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKAs) are commonly used, their limitations have prompted growing interest in direct oral anticoagulants (DOACs), particularly Factor Xa inhibitors. However, concerns about bleeding risks persist. This meta-analysis aims to evaluate the efficacy of Factor Xa inhibitors versus placebo for thromboprophylaxis in cancer-associated VTE.

Methods

This systematic review and meta-analysis followed PRISMA guidelines and was registered with PROSPERO (CRD42024574869). A comprehensive search of PubMed, Cochrane Library, Scopus, Google Scholar, and ClinicalTrials.gov was conducted without language or demographic restrictions. Data were extracted independently by two reviewers and analyzed using a random-effects model.

Results

Six RCTs with a total of 2330 participants met the inclusion criteria. The pooled analysis showed a non-significant reduction in VTE incidence with Factor Xa inhibitors (RR = 0.33, 95% CI: 0.05-2.10, P = .24). However, there was a nearly twofold increased risk of major bleeding (RR = 1.90, 95% CI: 1.00-3.62, P = .05). No significant effect was found for clinically relevant non-major bleeding (CRNMB) (RR = 1.28, 95% CI: 0.73-2.22, P = .39).

Conclusion

Factor Xa inhibitors may reduce the risk of VTE in cancer patients but appear to increase the risk of major bleeding. The evidence remains inconclusive due to limited event numbers and wide confidence intervals, highlighting the need for larger trials to better assess safety and efficacy.

Keywords

cancer-associated thrombosis factor Xa inhibitors venous thromboembolism anticoagulation thromboprophylaxis apixaban rivaroxaban randomized controlled trials

Introduction

Venous thromboembolism (VTE), which comprises both deep vein thrombosis (DVT) and pulmonary embolism (PE), is one of the major complications in cancer patients and is responsible for significant morbidity and mortality. After disease progression, cancer-associated thrombosis (CAT) remains a leading cause of death among cancer patients.¹ Cancer patients are 7 times more likely to develop VTE compared to the general population. This could be because of the propensity of cancer itself to promote blood clot formation and the treatment processes, like chemotherapy. Patients can also have other co-morbidities, which enhance the possibility of developing VTE.^2-4

Cancer predisposes a patient to VTE as it creates a hypercoagulable state. The release of procoagulant substances from cancer cells initiates the clotting cascade, ultimately forming clot.^5-7 Furthermore, widely used treatment modalities for cancer, which include chemotherapy, hormonal therapy, and surgical interventions, are known to cause damage to endothelial cells, affect platelet function and promote inflammation.⁸ Consequently, it becomes essential to put strategies that effectively balance the need for anticoagulation and the adverse effects of associated bleeding.

Traditionally, low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKAs) have been the mainstays of VTE prophylaxis and treatment in cancer patients.⁹ LMWH is often favoured because it is easier to use, has predictable pharmacokinetics, and no dietary restrictions are associated with it, which are common challenges with VKAs like warfarin.¹⁰ However, LMWH has its challenges, as it requires daily injections. This can be inconvenient for some patients, especially those who are undergoing outpatient chemotherapy. On the contrary, VKAs are taken orally which can be desired by the patients who find injecting LMWH difficult. However, VKAs are widely known to be affected by dietary changes and drug interactions. Hence, frequent monitoring is required so that a dose within the therapeutic range can be adjusted accordingly.^11,12

Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban, have recently become a promising alternative for managing VTE in cancer patients. As these drugs work by inhibiting Factor Xa, they decrease thrombin production and, eventually, clot formation.¹³ Compared to VKAs, advantages offered by DOACs include lesser dietary and drug interactions, no monitoring required and predictable pharmacokinetics.¹⁴ Factor Xa inhibitors, administered orally, have shown efficacy in preventing VTE recurrence in non-cancer populations, further supporting their potential in cancer-associated thrombosis.¹⁵

However, the safety profile of Factor Xa inhibitors remains a critical area of investigation, particularly in the context of cancer. Cancer patients are inherently at higher risk for bleeding due to factors like thrombocytopenia, tumour invasion, and chemotherapy-induced vascular toxicity.¹⁵ Previous studies have shown mixed results regarding the bleeding risk associated with Factor Xa inhibitors. For example, a recent study found that apixaban significantly reduced the risk of VTE but was associated with a higher rate of major bleeding events.¹⁵ In contrast, some analyses suggested that the bleeding risk of Factor Xa inhibitors was comparable to, or even lower than, that of VKAs, highlighting the need for further research in this area.¹⁶

Considering these complexities, recent guidelines and clinical trials have explored Factor Xa inhibitors as a thromboprophylaxis option in cancer patients, focusing on optimizing the risk-benefit ratio. Early evidence, including data from the AVERT and CASSINI trials, has suggested that these agents may reduce VTE risk in high-risk cancer patients, such as those with metastatic disease or those undergoing chemotherapy. However, bleeding risks remain a concern.¹⁷ Additionally, the Khorana score, a validated tool for VTE risk stratification in cancer patients, has been proposed to identify patients who might benefit most from thromboprophylaxis.¹⁸ The Khorana score evaluates factors like cancer type, body mass index, and hematologic parameters to gauge an individual's risk, facilitating personalized risk management strategies.^19,20

Given the complex interplay between thrombosis and bleeding in cancer patients, this meta-analysis aims to update and extend existing evidence on the efficacy and safety of Factor Xa inhibitors compared to placebo. By synthesizing findings from recent RCTs, we aim to clarify whether these agents can effectively reduce VTE incidence without disproportionately increasing bleeding risk, thereby informing clinical decision-making for thromboprophylaxis in this vulnerable population.

Methods

This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria and registered with PROSPERO (CRD42024574869) accessible at https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024574869.

Data Source and Search Strategy

This meta-analysis was conducted according to PRISMA guidelines. PubMed, Cochrane Library, Google Scholar, and Scopus were extensively searched for relevant literature. The relevant studies compared the efficacy of Factor Xa inhibitors versus placebo for cancer-associated thromboembolism. There were no restrictions on language, demographics, or publication date. Apart from that, the team searched ClinicalTrials.gov for ongoing or unpublished trials. Search terms included “Thromboembolism,” “thromboprophylaxis,” “cancer,” “Factor Xa inhibitors,” and “placebo,” with no restrictions on language, race, ethnicity, or date. A manual search was performed to acquire any additional studies.

Study Selection and Inclusion Criteria

In this meta-analysis, we included randomized controlled trials (RCTs) or cluster RCTs, comparing Factor Xa inhibitors with placebo in adults with ambulatory cancer patients at high risk of thromboembolism. The selection criteria involved the adults with cancer, using apixaban or similar anticoagulants in either the control or intervention groups. The exclusion criteria included reviews, observational studies, trials involving children, therapies that included intervention and small sample size. Studies with crossover designs were included only up to the first randomization period to avoid potential carryover effects.

Data Extraction and Assessment of Study Quality

To maintain accuracy, two independent reviewers extracted the data. This extracted data included the number of participants, intervention types, primary and secondary outcomes (eg, VTE-related death, major bleeding, treatment tolerability, and serious adverse events), and any effect measures such as relative risk or odds ratios. In cases of incomplete data, corresponding authors were contacted to retrieve missing information. Discrepancies between reviewers were resolved through consensus or by consulting a third reviewer. Study quality was assessed using the Cochrane Collaboration's Risk of Bias Tool, which evaluated domains such as randomization, deviations from intended interventions, missing data, measurement of outcomes, and selective reporting. Studies were rated as “low risk,” “some concerns,” or “high risk” for each bias domain and overall.

Statistical Analysis

The data were analyzed using a random-effects model to account for differences in data across the studies. The studies mainly consisted of dichotomous outcomes; hence, relative risk (RR) with 95% confidence intervals (CI) were used. We used I² and P-values to assess the heterogeneity across studies. For our analysis, I² values above 50% indicated high heterogeneity. While a P-value less than .10 indicated significant differences between studies. In cases of homogeneity across studies, a standard pairwise meta-analysis was conducted. The team utilized subgroup analysis to find differences between studies, such as control type variations and Factor Xa inhibitors. The team also used sensitivity analysis to exclude high-risk studies, making the results more reliable. All statistical analyses were conducted using RevMan (V5.1). Using CMA Version 4 software, a funnel plot was created to assess publication bias visually.

Results

Study Selection

A total of 3577 records were identified through databases and registers. After removing 525 duplicates, 3052 records were screened, out of which 3032 were excluded due to different and irrelevant study designs like observational studies, commentaries, editorials, reviews and letters to the editor. Twenty reports were sought for retrieval, but 14 were not retrieved, leaving 6 reports for eligibility assessment. All 6 were deemed eligible and included in the final review. Thus, 6 studies were included in the systematic review. The PRISMA flow diagram illustrates the study selection process for the review in Figure 1.

Figure 1.

PRISMA Flowchart.

Baseline Characteristics

A total of six RCTs were included in this systematic review and meta-analysis, encompassing a cumulative sample size of 2330 participants. The baseline characteristics of these trials are comprehensively summarized in Table 1. These studies varied in sample size, intervention design, geographical location, and clinical settings, reflecting a diverse representation of populations and methodologies.

Table 1.

Characteristics of Included Studies.

Study Title	Study Design	Year of Publication	First Author	Intervention	Control	Sample Size (Total:Intervention:Placebo)	Age (Intervention:Placebo)	Incidence of Venous Thromboembolism (VTE)(Intervention: Placebo)	Outcomes (Intervention:Placebo)
Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer	Randomized, placebo-controlled, double-blind trial	2019	Alok A. Khorana	Rivaroxaban	Placebo	420 : 421	(62 [54-72]) : (64 [56-73])	25 (6.0%) : 37 (8.8%)	Major bleeding: 8 (2.0%) : 4 (1.0%)
									CRNMB: 12 (2.7%) : 8 (2.0%)
									VTE related deaths: 10 (2.3%) : 18 (4.3%)
A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer	Randomized, double-blind, placebo-controlled, clinical trial	2012	M. N. LEVINE	Apixaban	Placebo	125 : 63 : 62	60 (26-86) : 59 (24-86)	0 (0%) : 3 (10.3%)	Major bleeding: 2 (2.6%) : 1 (1.6%)
									CRNMB: 4 (4.2%) : 0 (0%)
									VTE related deaths: No death occurred due to VTE
Apixaban to Prevent Venous Thromboembolism in Patients with Cancer	Randomized, placebo-controlled, double-blind, clinical trial	2019	Marc Carrier	Apixaban	Placebo	558: 288 : 275	62 ± 12.4 : 61.7 ± 11.3	12 (4.2%) : 28 (10.2%)	Major bleeding: 10 (3.5%) : 5 (1.8%)
									CRNMB: 21 (7.3%) : 15 (5.5%)
									VTE related deaths: Not Reported
A Single-Center, Randomized, Double-Blind Study of 94 Patients Undergoing Surgery for Cerebral Glioma to Compare Postoperative Thromboprophylaxis with and without Rivaroxaban	Randomized, placebo-controlled, double-blind, clinical trial	2022	Zi-Yan Wang	Rivaroxaban	Placebo	94 : 50 : 44	56 ± 14.0 : 54 ± 10.6	1 (2.0%) : 10 (21.3%)	Major bleeding: 1 (2.1%) : 1 (2.1%)
									CRNMB: 3 (6.4%) : 1 (2.1%)
									VTE related deaths: 0 (0%) : 1 (2.1%)
Rivaroxaban versus placebo for extended antithrombotic prophylaxis after laparoscopic surgery for colorectal cancer	Randomized, placebo-controlled, double-blind, clinical trial	2022	Cecilia Becattini	Rivaroxaban	Placebo	568 : 287 : 282	68 ± 11.3 : 65.1 ± 11.1	6 (1.2%) : 4 (0.7%)	Major bleeding: 2 (0.7%) : 0 (0%)
									CRNMB: 3 (1.0%) : 5 (1.8%)
									VTE related deaths: No death occurred due to VTE
Safety and efficacy of apixaban thromboprophylaxis in cancer patients with metastatic disease: A post-hoc analysis of the AVERT trial	Randomized, placebo-controlled, double-blind, clinical trial	2020	William Knoll	Apixaban	Placebo	−	−	4 (3.7%) : 14 (11.6%)	Major bleeding: Not Reported
						In Non-Metastatic 207 : 121	(Non-Metastatic) 68 [24-90]	(In Non-Metastatic) 21 (9.9%) : 3 (3.5%)	CRNMB: Not Reported
						In Metastatic 138 : 79	(Metastatic) 73 : 65	(In Metastatic) 6 (4.2%) : 6 (7.6%)	VTE related deaths: No death occurred due to VTE

Risk of Bias Assessment

Each study is assessed for five specific bias domains, shown in Figure 2:

Figure 2.

Risk of Bias Assessment.

D1: Randomization process

D2: Deviations from intended interventions

D3: Missing outcome data

D4: Measurement of the outcome

D5: Selection of the reported result

Green indicates a “Low risk” of bias.

Yellow represents “Some concerns” for potential bias. Red indicates “High risk” of bias. The final column gives an overall risk of bias for each study, a summary based on the individual domain assessments. This is crucial in meta-analysis as it affects the confidence in the pooled estimate of the effect. The table includes a Weight column that likely represents the relative weight each study contributes to the meta-analysis based on factors like study size and variance. This bias assessment interprets the pooled effect of Factor Xa inhibitors on significant bleeding risk, considering each study's quality and potential bias. Lower-risk studies contribute to more reliable estimates, while high-risk studies may introduce bias.

Publication Bias

Using CMA Version 4 software, a funnel plot was created to assess publication bias visually. A P-value less than .05 is considered statistically significant, suggesting that the funnel plot shows evidence of publication bias or asymmetry. The funnel plot shows a fairly symmetrical distribution of studies around the central line, suggesting no significant publication bias. Studies are spread on both sides of the mean log risk ratio, with no clear asymmetry. However, the small number of studies (n = 5) limits the reliability of this assessment. (Supplementary Figure 1).

Meta-analysis of Study Outcomes

Incidence of VTE

Figure 3 presents a forest plot comparing the risk of venous thromboembolism (VTE) between patients receiving anti-Xa factor agents and placebo. The analysis included 1210 participants in the anti-Xa group and 1120 in the placebo group, with 50 VTE events occurring in the anti-Xa group compared to 100 in the placebo group. The pooled risk ratio (RR) was 0.47 (95% CI: 0.30-0.73), demonstrating a statistically significant 53% reduction in VTE risk with anti-Xa agents (Z = 3.34, P = .0008). All individual studies favored anti-Xa therapy, with particularly strong risk reductions in Zi-Yan Wang 2022 (RR = 0.10) and M.N. Levine 2012 (RR = 0.05), though the latter had limited events. The largest weighted study, Alok A. Khorana 2019 (35.4%), showed a non-significant trend toward benefit (RR = 0.68, 95% CI: 0.42-1.10). Heterogeneity was low-to-moderate (I² = 28%, P = .22), supporting consistent findings across studies. These results confirm that anti-Xa agents significantly reduce VTE risk compared to placebo.

Figure 3.

Forest Plot of Incidence of VTE.

CRNMB

Figure 4 shows a forest plot summarizing a meta-analysis evaluating the risk of CRNMB associated with anti-Xa factor agents compared to placebo across five studies. The pooled risk ratio (RR) is 1.28 with a 95% confidence interval (CI) of 0.73 to 2.22, indicating a 28% increased risk in the anti-Xa group; however, this result is not statistically significant as the CI crosses 1 and the P-value is .39. Individual study results vary, with some showing increased risk and others showing no effect or reduced risk, though most have wide CIs reflecting limited precision. The test for heterogeneity shows no significant variation among studies (I² = 0%, P = .57), supporting the consistency of findings. Overall, the analysis suggests that anti-Xa factor agents do not significantly alter the risk of CRNMB compared to placebo.

Figure 4.

Forest Plot of Risk of CRNMB.

Major Bleeding

Figure 5 shows a forest plot comparing the risk of major bleeding between patients receiving anti-Xa factor agents and those on placebo. A total of 1210 participants were included in the anti-Xa group and 1120 in the placebo group. There were 29 major bleeding events in the anti-Xa group compared to 13 in the placebo group. The pooled risk ratio (RR) was 1.90 (95% CI: 1.00 to 3.62), indicating a nearly twofold increased risk of major bleeding with anti-Xa agents. This result is on the threshold of statistical significance, with a Z-score of 1.96 and a P-value of .05. Among individual studies, most reported increased risk ratios, although with wide confidence intervals, and one study (M.N. Levine 2012) showed a reduced bleeding risk (RR = 0.63). The largest weight in the analysis was from Marc Carrier 2019 (37.6%), which also showed an elevated bleeding risk (RR = 1.96). There was no significant heterogeneity across studies (I² = 0%, Chi² = 1.61, P = .90), indicating consistent findings. Overall, the results suggest that anti-Xa factor agents may be associated with a significantly increased risk of major bleeding.

Figure 5.

Forest Plot of Major Bleeding.

VTE-Related Deaths

Supplementary Figure 2 shows a forest plot that compares the incidence of deaths due to VTE between patients receiving anti-Xa factor agents and those given a placebo, based on data from two studies: Alok A. Khorana (2019) and Zi-Yan Wang (2022). In total, 467 patients were included in the anti-Xa group and 468 in the placebo group, with 1 and 4 VTE events reported, respectively. The pooled risk ratio (RR) was 0.33 with a 95% confidence interval (CI) of 0.05 to 2.10, suggesting a potential 67% reduction in VTE risk in the anti-Xa group. However, the result was not statistically significant (Z = 1.17, P = .24). There was no heterogeneity between studies (I² = 0%, Chi² = 0.00, P = 1.00), indicating consistent findings. Despite a favorable trend, the small number of events and wide confidence intervals limit the strength of the conclusions. Therefore, while anti-Xa agents may reduce the risk of VTE-related deaths, the evidence is currently inconclusive and warrants further investigation through larger, high-powered studies.

Discussion

Our meta-analysis shows the effectiveness and efficacy of Factor Xa inhibitors in reducing VTE among cancer patients. However, it also emphasizes the risks associated with Factor Xa, the major being bleeding. Our analysis provides increasing evidence for using direct oral anticoagulants (DOACs), like Factor Xa inhibitors, for thromboprophylaxis in high-risk cancer populations. Although the DOACs helped lower VTE risk, they carry significant patient bleeding risks.^21,22 Due to this, proper evaluation of cancer patients needs to be performed, considering their bleeding and clotting profiles before proceeding with DOACs.

Our findings show that Factor Xa inhibitors are effective against VTE in cancer patients. Factor Xa inhibitors block vital constituents in the blood clotting process, preventing VTE.²³ They are more effective than other treatments like vitamin K antagonists.^24,25 Our analysis has shown that Factor Xa inhibitors can provide far better benefits compared to other agents when treating cancer patients who are susceptible to blood clots because of cancer or treatments like chemotherapy and surgery. Although Factor Xa inhibitors provide benefits in treating VTE, they raise a significant concern regarding bleeding.^21,22 Cancer patients are highly susceptible to bleeding due to thrombocytopenia, tumour invasion into vascular structures, and chemotherapy-related mucosal injury.^26,27 It is shown in this study that the significant bleeding risk was almost twice as high in patients being treated with Factor Xa compared to the control group. While the statistical significance value was borderline, it is still a primary concern since bleeding complications can lead to significant morbidity and mortality in this population.

Several studies have shown that the bleeding risk with DOACs varies significantly based on cancer type. For instance, patients with gastrointestinal (GI) and genitourinary (GU) malignancies are at higher risk of bleeding complications when treated with DOACs, due to mucosal involvement.^16,17,26 In contrast, patients with non-mucosal cancers such as breast or hematologic malignancies may experience lower bleeding rates. In the AVERT and CASSINI trials, a considerable proportion of bleeding events occurred in patients with GI cancers, reinforcing the importance of individualized therapy.^1,2 This heterogeneity underscores that the benefit of VTE reduction must be weighed carefully against bleeding risk, particularly in mucosal tumors where the net clinical benefit may be reduced or even negative.

This study shows that results are consistent with previous studies showing the benefits of Factor Xa in thromboprophylaxis among cancer patients.^28-30 For instance, trials such as AVERT and CASSINI highlighted similar trends, where apixaban and rivaroxaban reduced VTE incidence but were associated with a higher rate of bleeding events.³¹ The AVERT trial used apixaban to reduce VTE, demonstrating a 60% reduction. However, it was associated with a higher risk of significant bleeding in cancer patients.¹ Similarly, the CASSINI trial used rivaroxaban for treating VTE, but it also showed a substantial risk of bleeding.² These findings show that a thorough study needs to be conducted for the safety of Factor Xa.

Furthermore, comparisons with low-molecular-weight heparin (LMWH) studies reveal differences in bleeding patterns between LMWH and Factor Xa inhibitors.²⁹ LMWHs, while associated with bleeding risks, have a shorter half-life and can be reversed more easily than DOACs, which may be beneficial in managing bleeding complications. Additionally, LMWH's subcutaneous administration is less convenient than oral Factor Xa inhibitors, making adherence challenging, especially for outpatients. Our findings support the shift toward DOACs, given their convenience and similar efficacy; however, they also highlight the need to carefully weigh the bleeding risks.

The findings from this meta-analysis carry several implications for clinical practice and policy. In clinical practice, the choice of anticoagulant should involve an individualized assessment of both clotting and bleeding risks, especially in cancer patients who already have complex hematologic profiles. Factor Xa inhibitors may offer a viable option for patients with high VTE risk and lower bleeding risk, particularly in settings where daily injections of LMWH are impractical. For patients at a higher risk of bleeding, however, LMWH or even a conservative approach without anticoagulation might be safer, highlighting the importance of shared decision-making between patients and providers.

Although the relative risk reduction in VTE was significant (RR = 0.47), the absolute risk reduction was modest. Based on pooled data, the absolute benefit translates into preventing VTE in approximately 5 out of every 100 patients treated, yielding a number needed to treat (NNT) of 20. This means that for every 20 patients given DOACs, only one VTE event is prevented. In contrast, the number needed to harm (NNH) for major bleeding in high-risk cancers like GI or GU may be much lower, thus tipping the balance against their use in such populations. Therefore, the clinical impact must be contextualized based on both relative and absolute effects, with cancer subtype playing a critical role in the risk-benefit calculus.^16,29

From a policy perspective, guidelines for thromboprophylaxis in cancer patients should be updated to include considerations for Factor Xa inhibitors, particularly for patients with a high thrombotic risk. However, policies should also emphasize the need for monitoring protocols to identify and manage bleeding risks early. For instance, periodic monitoring of haemoglobin and platelet levels, especially in patients on cytotoxic therapies, may allow clinicians to detect early signs of bleeding complications. There needs to be tools to assess the risk associated with Factor Xa. This can help doctors treat patients safely and reduce the side effects of treatment with Factor Xa.

Clinicians should consider implementing bleeding mitigation strategies when prescribing DOACs in cancer patients. These include: (1) careful patient selection like avoiding use in those with mucosal tumors or active lesions; (2) routine monitoring for occult bleeding and trends in hemoglobin levels; (3) use of prophylactic proton pump inhibitors in patients with upper GI cancers; and (4) temporary discontinuation during invasive procedures or when platelet counts fall below a safe threshold. These approaches are supported by current international guidelines^12,17 and expert consensus aimed at reducing bleeding-related complications without sacrificing thromboprophylactic efficacy.

The Khorana score is used to assess VTE risk in cancer patients.³² However, it does not consider bleeding risk, which is vital when treating with Factor Xa inhibitors. More studies are needed to refine the Khorana score, and new methods are needed to consider bleeding risk factors, such as thrombocytopenia and tumour location. Furthermore, future research must be done to find safe doses of Factor Xa tailored for individual cancer patients that could lower the bleeding risks associated with Factor Xa.³²

Doctors could more effectively use Factor Xa for treatment if future research could focus on different types of cancers. Additionally, if more treatments are created to mitigate the bleeding risks, more doctors can use Factor Xa. Finally, new studies comparing Factor Xa inhibitors directly with LMWH, focusing on long-term benefits and quality of life, would help find the best ways to prevent blood clots in cancer patients.¹²

Strengths and Limitations

One of the strengths of this meta-analysis is that it included multiple randomized controlled trials (RCTs) with different cancer types, stages, and patient groups. Hence, it provides a broad view of Factor Xa in many patients. Furthermore, the effectiveness and risks of Factor Xa remain consistent throughout each RCT.

However, some limitations should be acknowledged. First, the meta-analysis relies on studies with a range of inclusion criteria and designs, potentially introducing heterogeneity that could affect the interpretation of results. While statistical measures indicated low heterogeneity, variations in cancer type, stage, and patient characteristics could still impact outcomes in ways that are not fully captured by the pooled analysis.³³ Second, bleeding risk assessment is complex in cancer patients due to overlapping factors like thrombocytopenia, tumour location, and treatment regimens. The meta-analysis does not account for all these variables, and further research is needed to clarify how these factors influence bleeding risk in patients receiving Factor Xa inhibitors. Another limitation is the relatively short follow-up periods in the included studies. Cancer patients often require long-term anticoagulation, and short-term studies may not adequately capture the risks associated with extended use of Factor Xa inhibitors.³⁴ Longitudinal studies with extended follow-up would help provide insights into the long-term balance of risks and benefits. Finally, publication bias may also impact our results, as studies with non-significant or unfavourable outcomes may be underreported.

Conclusion

Our meta-analysis highlights the benefits and efficacy of using Factor Xa inhibitors in treating VTE in cancer patients. However, there are certain complications that are associated with it. Our study shows that DOACs, like Factor Xa, hold significant promise in treating cancer patients with VTE. However, before proceeding forward, a thorough risk assessment is needed to mitigate any adverse effects, particularly major bleeding complications. Our findings support the use of Factor Xa inhibitors as a potentially valuable option for cancer-associated thromboprophylaxis but highlight the need for individualized treatment plans that account for each patient's cancer type, stage, and overall risk profile. Future research should focus on optimizing patient selection criteria, investigating dose adjustments, and integrating predictive tools such as the Khorana score to improve the safety and efficacy of Factor Xa inhibitors in this high-risk population.

Supplemental Material

sj-jpg-1-cat-10.1177_10760296251372947 - Supplemental material for Efficacy of Factor Xa Inhibitors Versus Placebo in Thromboprophylaxis for Cancer-Associated Thromboembolism: A Systematic Review and Meta-analysis

Supplemental material, sj-jpg-1-cat-10.1177_10760296251372947 for Efficacy of Factor Xa Inhibitors Versus Placebo in Thromboprophylaxis for Cancer-Associated Thromboembolism: A Systematic Review and Meta-analysis by Amna Kamil, Sandhiya Prem Kumar, Rumaisa Zulfiqar, Eiman Araib, Bibi Samia Khan, Muhammad Saad Khan, Muhammad Mohsin Khan, Umaimah Naeem and Aminath Waafira in Clinical and Applied Thrombosis/Hemostasis

Supplemental Material

sj-jpg-2-cat-10.1177_10760296251372947 - Supplemental material for Efficacy of Factor Xa Inhibitors Versus Placebo in Thromboprophylaxis for Cancer-Associated Thromboembolism: A Systematic Review and Meta-analysis

Supplemental material, sj-jpg-2-cat-10.1177_10760296251372947 for Efficacy of Factor Xa Inhibitors Versus Placebo in Thromboprophylaxis for Cancer-Associated Thromboembolism: A Systematic Review and Meta-analysis by Amna Kamil, Sandhiya Prem Kumar, Rumaisa Zulfiqar, Eiman Araib, Bibi Samia Khan, Muhammad Saad Khan, Muhammad Mohsin Khan, Umaimah Naeem and Aminath Waafira in Clinical and Applied Thrombosis/Hemostasis

Footnotes

ORCID iDs

Sandhiya Prem Kumar

Muhammad Saad Khan

Umaimah Naeem

Aminath Waafira

Author Contributions

Amna Kamil: Data Curation, Formal analysis, Methodology, Writing-the original draft, Writing- review & editing. Sandhiya Prem Kumar: Data Curation, Formal analysis, Methodology, Writing-the original draft, Writing- review & editing. Rumaisa Zulfiqar: Data Curation, Formal analysis, Methodology, Writing-the original draft, Writing- review & editing. Eiman Araib: Data Curation, Formal analysis, Methodology, Writing-the original draft, Writing- review & editing. Bibi Samia Khan: Data Curation, Formal analysis, Methodology, Writing-the original draft, Writing- review & editing. Muhammad Saad Khan: Writing-the original draft, Final reviewer as supervisor of study and agreement on the accuracy of the work. Muhammad Mohsin Khan: Data Curation, Formal analysis, Methodology, Writing-the original draft, Writing- review & editing and Final Review of study. Umaimah Naeem: Data Curation, Formal analysis, Methodology, Writing-the original draft, Writing- review & editing and Final Review of study. Aminath Waafira: Data Curation, Formal analysis, Methodology, Writing-the original draft, Writing- review & editing and Final Review of study.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental Material

Supplemental material for this article is available online.

References

Khorana

Soff

Kakkar

, et al. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019;380(8):720‐728. doi:10.1056/NEJMoa1814630

Carrier

Abou-Nassar

Mallick

, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380(8):711‐719. doi:10.1056/NEJMoa1814468

Becattini

Pace

Pirozzi

, et al. Rivaroxaban vs placebo for extended antithrombotic prophylaxis after laparoscopic surgery for colorectal cancer. Blood. 2022;140(8):900‐908. doi:10.1182/blood.2022015796

Levine

Liebman

, et al. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost. 2012;10(5):807‐814. doi:10.1111/j.1538-7836.2012.04693.x

Wang

Wan

Liu

Wang

Jiang

Yang

. A single-center, randomized, double-blind study of 94 patients undergoing surgery for cerebral glioma to compare postoperative thromboprophylaxis with and without rivaroxaban. Med Sci Monit. 2022;28:e934341. doi:10.12659/MSM.934341. Published 2022 Feb 10.

Knoll

Mallick

Wells

Carrier

. Safety and efficacy of apixaban thromboprophylaxis in cancer patients with metastatic disease: A post-hoc analysis of the AVERT trial. Thromb Res. 2020;197:13‐15. doi:10.1016/j.thromres.2020.10.026

Connolly

Ezekowitz

Yusuf

, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139‐1151. doi:10.1056/nejmoa0905561

Key

Khorana

Mackman

, et al. Thrombosis in cancer: Research priorities identified by a national cancer institute/national heart, lung, and blood institute strategic working group. Cancer Res. 2016;76(13):3671‐3675. doi:10.1158/0008-5472.CAN-15-3100

Blom

Vanderschoot

Oostindiër

Osanto

van der Meer

Rosendaal

. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: Results of a record linkage study. J Thromb Haemost. 2006;4(3):529‐535. doi:10.1111/j.1538-7836.2006.01804.x

10.

Douketis

Spyropoulos

Spencer

, et al. Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines [published correction appears in Chest. 2012 Apr;141(4):1129]. Chest. 2012;141(2 Suppl):e326S‐e350S. doi:10.1378/chest.11-2298.

11.

Lyman

Khorana

Kuderer

, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American society of clinical oncology clinical practice guideline update. J Clin Oncol. 2013;31(17):2189‐2204. doi:10.1200/JCO.2013.49.1118

12.

Farge

Frere

Connors

, et al. 2019 International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol. 2019;20(10):e566‐e581. doi:10.1016/S1470-2045(19)30336-5

13.

Dranitsaris

Shane

Woodruff

. Low-molecular-weight heparins for the prevention of recurrent venous thromboembolism in patients with cancer: A systematic literature review of efficacy and cost-effectiveness. J Oncol Pharm Pract. 2019;25(1):68‐75. doi:10.1177/1078155217727140

14.

Steuber

. The role of direct oral anticoagulants in the management of venous thromboembolism. Am J Manag Care. 2017;23(20 Suppl):S383‐S390.

15.

Cabral

Ansell

. The role of factor Xa inhibitors in venous thromboembolism treatment. Vasc Health Risk Manag. 2015;11:117‐123. doi:10.2147/VHRM.S39726. Published 2015 Jan 30.

16.

Masini

Toma

Spallarossa

Porto

Ameri

. Direct oral anticoagulants for cancer-associated venous thromboembolism. Curr Oncol Rep. 2023;25(9):979‐987. doi:10.1007/s11912-023-01428-y

17.

Frere

Font

Esposito

Crichi

Girard

Janus

. Incidence, risk factors, and management of bleeding in patients receiving anticoagulants for the treatment of cancer-associated thrombosis. Support Care Cancer. 2022;30(4):2919‐2931. doi:10.1007/s00520-021-06598-8

18.

Bosch

FTM

Mulder

Kamphuisen

, et al. Primary thromboprophylaxis in ambulatory cancer patients with a high Khorana score: A systematic review and meta-analysis. Blood Adv. 2020;4(20):5215‐5225. doi:10.1182/bloodadvances.2020003115

19.

Mulder

Candeloro

Kamphuisen

, et al. The Khorana score for prediction of venous thromboembolism in cancer patients: A systematic review and meta-analysis. Haematologica. 2019;104(6):1277‐1287. doi:10.3324/haematol.2018.209114

20.

Overvad

Ording

Nielsen

, et al. Validation of the Khorana score for predicting venous thromboembolism in 40 218 patients with cancer initiating chemotherapy. Blood Adv. 2022;6(10):2967‐2976. doi:10.1182/bloodadvances.2021006484

21.

Gómez-Lumbreras

Tan

Moorman-Bishir

Ilham

Malone

. Risk of bleeding among individuals on direct-acting oral anticoagulants: An academic medical center cohort study. J Cardiovasc Pharmacol. 2022;80:813‐819. https://doi.org/10.1097/FJC.0000000000001347

22.

Chang

K-H

Chen

C-M

Wang

C-L

, et al. Major bleeding risk in patients with non-valvular atrial fibrillation concurrently taking direct oral anticoagulants and antidepressants. Front Aging Neurosci. 2022;14. https://doi.org/10.3389/fnagi.2022.791285

23.

Costa

Felix

Richter

. ‘X’ marks the spot! Utilising factor Xa inhibitors to optimise thromboprophylaxis in multiple myeloma. Br J Haematol. 2024. https://doi.org/10.1111/bjh.19640

24.

Diener

Grosse

Hüsing

, et al. Efficacy and safety of oral factor Xa inhibitors versus vitamin-K antagonists in the early phase after acute ischemic stroke or TIA in the real-world setting: The PRODAST study. Eur Stroke J. 2024:23969873241242239. https://doi.org/10.1177/23969873241242239

25.

Xiong

Guo

Wan

. Factor Xa inhibitors versus vitamin K antagonists in atrial fibrillation patients with end-stage kidney disease on dialysis: A meta-analysis. Clin Appl Thromb-Hemost. 2024;30. https://doi.org/10.1177/10760296241271423

26.

Ruch

Sood

. Bleeding Disorders in Cancer Patients. Elsevier Inc.; 2013:763‐773. https://doi.org/10.1016/B978-0-12-397164-7.00119-1

27.

DeLoughery

Calverley

. Bleeding and Thrombosis in Cancer Patients. Springer International Publishing; 2015:235‐242. https://doi.org/10.1007/978-3-319-09312-3_28

28.

Giustozzi

Agnelli

Del Toro-Cervera

, et al. Direct oral anticoagulants for the treatment of acute venous thromboembolism associated with cancer: A systematic review and meta-analysis. Thromb Haemostasis. 2020;120(7):1128‐1136. https://doi.org/10.1055/s-0040-1712098

29.

Hussain

Ali

Verghese

, et al. Factor Xa inhibitors versus low molecular weight heparin for the treatment of cancer associated venous thromboembolism; A meta-analysis of randomized controlled trials and non-randomized studies. Crit Rev Oncol Hematol 2022;169:103526‐103526. https://doi.org/10.1016/j.critrevonc.2021.103526

30.

Putranto

JNE

Wardhana

Noor

Yosua Siahaan

PLM

Al Farabi

. Factor Xa Inhibitor for Venous Thromboembolism Management in Patient with Cancer: a Systematic Review and Meta-Analysis . n.d. https://doi.org/10.12688/f1000research.73883.1

31.

Piel-Julian

Mahévas

Germain

, et al. Risk factors for bleeding, including platelet count threshold, in newly diagnosed immune thrombocytopenia adults. J Thromb Haemost. 2018;16(9):1830‐1842. doi:10.1111/jth.14227

32.

van Es

Ventresca

Di Nisio

, et al. The Khorana score for prediction of venous thromboembolism in cancer patients: An individual patient data meta-analysis. J Thromb Haemost: JTH 2020;18(8):1940‐1951. https://doi.org/10.1111/jth.14824

33.

Song

Liu

Zeng

, et al. Treatment of venous thromboembolism in cancer patients: A systematic review and meta-analysis on the efficacy and safety of different direct oral anticoagulants (DOACs). Ann Transl Med. 2021;9(2):162. doi:10.21037/atm-20-8156

34.

Van Hylckama Vlieg

MAM

Nasserinejad

Visser

, et al. The risk of recurrent venous thromboembolism after discontinuation of anticoagulant therapy in patients with cancer-associated thrombosis: A systematic review and meta-analysis. EClinicalMedicine. 2023;64:102194. doi:10.1016/j.eclinm.2023.102194

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.08 MB

0.03 MB