Haider F, Ahmed F, Junaid Y, Khalid M, Dar A, Arham M, Ullah A, Aliha S, Arshad MU, Naeem K, Ali Hashim MM, Gohar N, Ricciuti A, Bhanderi V, Alenezi F, Patel B. Direct oral anticoagulants vs low-molecular-weight heparins for cancer-associated thromboembolism. World J Clin Cases 2026; 14(17): 118087 [DOI: 10.12998/wjcc.v14.i17.118087]
Corresponding Author of This Article
Faseeh Haider, Researcher, Department of Internal Medicine, Allama Iqbal Medical College, Allama Shabbir Ahmed Usmani Road, Lahore 54550, Punjab, Pakistan. faseehhaidermd@gmail.com
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Oncology
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Haider F, Ahmed F, Junaid Y, Khalid M, Dar A, Arham M, Ullah A, Aliha S, Arshad MU, Naeem K, Ali Hashim MM, Gohar N, Ricciuti A, Bhanderi V, Alenezi F, Patel B. Direct oral anticoagulants vs low-molecular-weight heparins for cancer-associated thromboembolism. World J Clin Cases 2026; 14(17): 118087 [DOI: 10.12998/wjcc.v14.i17.118087]
Author contributions: Haider F designed the research study; Haider F and Junaid Y led the project; Khalid M, Dar A, Aliha S, Naeem K, Ali M, Arham M and Arshad U screened the articles and extracted the data; Khalid M, Dar A, Aliha S and Naeem K wrote the manuscript; Hashim MMA, Arham M, Ullah A, Gohar N analyzed the data; Ahmed F, Ricciuti A, Bhanderi V, Alenezi F, Patel B reviewed the manuscript. All authors have read and approved the final manuscript.
AI contribution statement: We did use AI tools solely for paraphrasing certain sentences to improve clarity and readability. All content, data analysis, study design, results, and interpretations are original, based on our own research and writing. No AI was involved in generating ideas, methods, or conclusions. We are happy to provide further details or revised sections if needed.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Corresponding author: Faseeh Haider, Researcher, Department of Internal Medicine, Allama Iqbal Medical College, Allama Shabbir Ahmed Usmani Road, Lahore 54550, Punjab, Pakistan. faseehhaidermd@gmail.com
Received: December 23, 2025 Revised: March 11, 2026 Accepted: May 12, 2026 Published online: June 16, 2026 Processing time: 162 Days and 13.1 Hours
Abstract
BACKGROUND
Direct oral anticoagulants (DOACs) have demonstrated great potential in preventing recurrent cancer-related thromboembolism and offer an alternative to low-molecular-weight heparins (LMWHs) in active cancer patients.
AIM
To compare DOACs versus LMWH for venous thromboembolism (VTE), mortality, and bleeding risks in cancer-associated thrombosis, and identify outcome moderators.
METHODS
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we retrieved relevant literature from MEDLINE, the Cochrane Library, EMBASE, ScienceDirect, and Scopus up to April 2025. We performed subgroup analyses by anticoagulation regimen and study design. Meta-regression was used to assess the impact of the clinical variables age, body mass index, sex, metastasis, thrombocytopenia, and creatinine levels (> 60 μmol/L vs < 60 μmol/L). The study analysis was performed using the (rma) R (v2025.05.0+49) meta package via Restricted Maximum Likelihood estimation.
RESULTS
Twenty-nine studies (n = 42379) were analyzed. DOACs lowered VTE risk vs LMWHs [risk ratio (RR) = 0.76; 95% confidence interval (CI): 0.64-0.90; I2 = 41.9%], with the greatest reduction with apixaban (RR = 0.55; 95%CI: 0.40-0.76; I2 = 3.4%; P = 0.008). Deep vein thrombosis decreased (RR = 0.61; 95%CI: 0.42-0.89; P = 0.02; I2 = 0%). Clinically relevant non-major bleeding increased with rivaroxaban (RR = 1.66; 95%CI: 1.19-2.30; P = 0.04). Metastasis predicted major bleeding (β = 1.91; P = 0.008) and mortality (β = 0.668; P = 0.026); female sex predicted minor bleeding (β = 3.13; P = 0.04). Excluding McBane et al, mortality decreased (RR = 0.73; 95%CI: 0.55-0.97; I2 = 94.4%).
CONCLUSION
DOACs, especially apixaban, are associated with reduced risk of VTE and mortality vs LMWHs. Overall, bleeding was similar; rivaroxaban increased clinically relevant non-major bleeding. Female sex, metastasis, and thrombocytopenia affected bleeding and mortality.
Core Tip: Cancer-associated thrombosis continues to be a major cause of morbidity and mortality in oncology patients, necessitating the selection of anticoagulation medication. This study examined the efficacy and safety of direct oral anticoagulants vs low-molecular-weight heparins. Direct oral anticoagulants showed comparable protection against venous thromboembolism and severe bleeding, with apixaban demonstrating a significant reduction in venous thromboembolism recurrence. Metastasis and platelet count were found as major moderators of bleeding and mortality outcomes in study, indicating the need for personalized anticoagulation methods in cancer treatment.
Citation: Haider F, Ahmed F, Junaid Y, Khalid M, Dar A, Arham M, Ullah A, Aliha S, Arshad MU, Naeem K, Ali Hashim MM, Gohar N, Ricciuti A, Bhanderi V, Alenezi F, Patel B. Direct oral anticoagulants vs low-molecular-weight heparins for cancer-associated thromboembolism. World J Clin Cases 2026; 14(17): 118087
Cancer-associated thrombosis (CAT) is the formation of blood clots in people with active cancer. These clots most often occur in the deep veins of the legs [deep vein thrombosis (DVT)] or travel to the lungs [pulmonary embolism (PE)], which can be life-threatening[1]. CAT is one of the most common and serious complications for cancer patients, causing up to 1 in 5 cases of all blood clots and being a leading cause of death after cancer progression[2]. For patients with cancer, CAT is a significant and life-threatening complication, accounting for over 20% of venous thrombosis (VTE) cases[3]. Cancer treatment often causes a hypercoagulable state, which can be further triggered by tumor biology, systemic inflammation, endothelial injury, and some treatment-related factors, such as chemotherapy, surgery, and central venous catheters[4]. To manage CAT, clinicians and surgeons need to approach it with nuance because of the delicate balance between preventing thromboembolic recurrence and limiting bleeding risk, both of which remain elevated in these populations. Historically, low molecular weight heparin (LMWH) has been the standard treatment for CAT, demonstrating proven efficacy and reduced interactions with other medications in patients undergoing treatment[5]. However, daily subcutaneous administration, high cost, and issues with long-term adherence pose significant challenges, especially for patients undergoing palliative or outpatient care. Recent clinical data have highlighted the use of direct oral anticoagulants (DOACs) like rivaroxaban and apixaban, which have gained attention as alternatives due to their oral administration, fixed dosing, and lack of laboratory monitoring[6]. Previous studies, including randomized controlled trials (RCTs) and observational studies, have compared DOACs and LMWH in CAT, showing generally comparable efficacy in preventing VTE recurrence. Some studies have even reported lower recurrence rates with DOACs[7]. However, increased bleeding risk, particularly in patients with genitourinary or gastrointestinal cancers, remains a significant concern for clinicians. These results have led to the use of DOACs in clinical practice and ongoing debate about which treatment is the optimal choice for management[8]. Our primary concern in conducting this study was to clearly define the rationale for conducting an analysis on a topic that has been extensively studied and to address existing gaps. Although several meta-analyses have examined the safety and efficacy of DOACs and LMWH in CAT, most have limitations. Previous analyses have often pooled data without stratifying by cancer type, omitting observational data, or failing to account for variability across different DOAC agents. Importantly, few have performed study analysis to systematically explore how patient and treatment-related variables may influence clinical outcomes[9]. This has left a gap in understanding how the heterogeneity of these treatments affects different subgroups and settings. Our study, along with meta-regression, aims to fill this gap by stratifying data by cancer, regimen, and study type and using meta-regression techniques to further analyze heterogeneity.
Addressing these limitations, our systematic review and analyses aim to synthesize evidence from all relevant RCTs and high-quality non-RCTs, enabling researchers to investigate additional variables and explore how treatment effects influence key outcomes, including recurrent VTE, major bleeding, clinically relevant non-major bleeding (CRNMB), and mortality. Our expanded clinical and analytical approach is crucial for two reasons. First, with the growing diversity of clinical trial designs, cancer types, and DOACs used, simple pooled effects can mask important effect modifiers[10]. Second, clinicians need guidance not only on whether DOACs or LMWH are better overall, but also on which drug is best for which patient under which circumstances[11,12]. By identifying these effect-modifying variables, this review can provide insights to support individualized treatment decisions. Our study will also stratify outcomes by specific DOAC agents rather than treating them as a single class, offering clarity on whether certain agents are safer or more effective in specific cancer populations. Additionally, by including both trial and real-world data, we aim to enhance generalizability and reflect the diversity of patients encountered in routine oncology practice[13].
In summary, this study will provide a comprehensive comparison of DOACs and LMWHs for CAT, integrating cumulative evidence across drug subtypes and patient populations. Through our study techniques, we aim to identify key clinical variables that influence treatment outcomes, ultimately informing more personalized, evidence-based approaches to anticoagulation in cancer care.
MATERIALS AND METHODS
Our study followed the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions and was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines[14]. Additionally, the study protocol was registered with the PROSPERO - International Prospective Register of Systematic Reviews.
Data sources and search
For this study, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, ScienceDirect, and Scopus for relevant studies from their inception to April 2025. We also reviewed the reference lists of the included studies and of similar systematic reviews to identify additional relevant studies. Our search terms included “cancer” or “neoplasm” or “carcinoma” or “tumor” or “oncology” combined with “venous thromboembolism” or “thromboembolism” or “venous thrombosis” or “DVT” or “pulmonary embolism” or “thrombosis” and “direct oral anticoagulants” or “non-vitamin K antagonist oral anticoagulants” or apixaban or rivaroxaban or edoxaban or dabigatran, as well as LMWH, enoxaparin, dalteparin, or tinzaparin. The detailed search strategy is provided in Supplementary Table 1.
Eligibility criteria
Our study included RCTs, prospective and retrospective cohort studies that compared DOACs with LMWH in CAT. We looked at both effectiveness and safety outcomes. We excluded reviews, case reports, letters, editorials, case series, cross-sectional studies without cancer-specific outcomes, non-comparative studies, and animal studies. We did not impose any language or date restrictions.
Study selection and data extraction
We used Rayyan software to filter and remove duplicate articles from our online search results. Two authors independently reviewed titles and abstracts to exclude irrelevant studies. Followed by a full-text review of the remaining studies to ensure they met our eligibility criteria. A third author resolved any discrepancies in study selection. We extracted relevant data into a pre-piloted Excel spreadsheet, including author name, publication year, country, sample size, mean age, cancer type, index VTE, platelet count, serum albumin, creatinine clearance, Eastern Cooperative Oncology Group performance status, metastasis, and other comorbidities.
Outcomes
Our primary outcomes were recurrence of VTE, DVT, and PE. Secondary goals included major bleeding, minor bleeding, clinically relevant bleeding, all-cause mortality, and adverse events. We performed a study analysis on all-cause mortality, bleeding events, and VTE to identify clinical modifiers.
Quality assessment
The Risk of Bias 2.0 (ROB 2) tool was used to assess the quality of RCTs by evaluating biases across five domains: D1 - randomization process; D2 - deviations from interventions; D3 - missing outcome data; D4 - outcome measurement; and D5 - selection of reported results[15]. Judgments were categorized as “low risk”, “high risk”, or “some concerns”. For case-control and cohort studies, the Newcastle-Ottawa Scale was used, assigning a maximum of nine points across three domains: (1) Selection of study groups (four points); (2) Comparability of groups (two points); and (3) Assessment of exposure and outcomes (three points)[16].
Statistical analysis
For dichotomous two-arm data, we used the inverse-variance method and log-transformed hazard ratios. We conducted a study with the DerSimonian-Laird random-effects model and Hartung-Knapp confidence intervals. Subgroup analyses were conducted based on anticoagulant type and study design. We performed study using restricted maximum likelihood estimation. We then ran a regression using log-transformed risk ratio (logRR) as the dependent variable and a moderator variable, and referred to the results file for both dependent and independent variables.
RESULTS
Result of literature search
Our literature search followed the PRISMA 2020 guidelines (Figure 1), focusing on databases and registries. We initially found records in PubMed (n = 408), Cochrane (n = 212), Scopus (n = 442), EMBASE (n = 827), and ScienceDirect (n = 107). After removing duplicates and records for other reasons (n = 926 and n = 12, respectively), we screened 1071 articles and excluded 769. We sought 109 full-text reports, but 12 were not retrieved. After assessing eligibility, we included 29 studies in our final review, which comprised both RCTs and observational studies.
Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analysis flowchart of the included studies.1Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). 2If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.
Study characteristics and baseline data
A total of 29 studies were conducted across multiple countries, including France, the United States, Brazil, Iran, Korea, Sweden, Thailand, Italy, China, Canada, Egypt, and the United Kingdom. These studies included both observational research and RCTs. Sample sizes ranged from 42 to 16372, with a total population of 42379. The mean age of participants ranged from 52.67 years to 73 years. A summary of all baseline characteristics is shown in Table 1.
Assessing the quality of 11 RCTs using the Cochrane Risk of Bias 2.0 tool revealed that two studies (Borsi et al[17] and Lee et al[18]) had a high risk of bias, while four others had some concerns. In contrast, the remaining five RCTs were deemed to have a low risk of bias or some concerns, indicating generally acceptable methodological quality, as shown in Supplementary Figure 1. For the 18 non-randomized studies and observational studies, we assessed quality using the Newcastle-Ottawa Scale. Four non-RCTs showed some concerns, while the rest showed low bias across all domains, as shown in Supplementary Figure 2.
Thrombosis
Venous thromboembolism: A total of 27 studies involving 40121 patients were analyzed to assess the risk of VTE. The combined results showed no statistically significant difference, with an overall RR of 0.88 (0.68; 1.14) (P = 0.327), but high heterogeneity (I2 = 97.0%) (Supplementary Figure 3). Given the substantial heterogeneity observed (I2 = 97.0%), we further explored potential sources of variability. The leave-one-out sensitivity analysis identified the study by Linder et al[19] as the primary contributor to heterogeneity. This study differed from others in terms of patient characteristics, including a higher proportion of advanced or metastatic disease, potential differences in baseline bleeding and thrombotic risk, and variations in anticoagulation regimen or follow-up duration. These clinical differences may have amplified between-study variability and contributed disproportionately to the pooled heterogeneity.
Subgroup analysis showed no significant differences according to study type. When the regimens were further broken down, apixaban was associated with a significant reduction in VTE risk [RR = 0.55 (0.40; 0.76), I2 = 3.4%], whereas other regimens showed non-significant results (Figure 2). A sensitivity analysis, where one study was removed at a time, confirmed the overall effect size and found that removing Linder et al[19], had the greatest impact on reducing heterogeneity (I2 = 41.9%) (Supplementary Figure 4). Importantly, excluding this study did not materially alter the direction or magnitude of the pooled effect estimate, suggesting that although it contributed to statistical heterogeneity, it did not bias the overall conclusion regarding comparative VTE risk.
Figure 2 Forest plot of subgroup analysis of venous thromboembolism by regimen type.
RR: Risk ratio; CI: Confidence interval.
DVT: A total of 9 studies were analyzed for DVT, with a total population of 1867. The pooled RR was 0.61 [95% confidence interval (CI): 0.42-0.89], with a statistically significant P-value (P = 0.016) and no observed heterogeneity (I2 = 0.0%) (Figure 3). When we looked at the results by treatment regimen, we found that the 'others/not-specified' group had a significant effect (RR = 0.55; 95%CI: 0.39-0.78) compared to other regimens. However, the results by study type remained non-significant (Supplementary Figures 5 and 6).
Figure 3 Forest plot of deep venous thrombosis.
RR: Risk ratio; CI: Confidence interval.
PE: Eleven studies, including a total of 2184 participants, were analyzed for PE. Using a random-effects model, the pooled RR was calculated as 0.54 (95%CI: 0.18-1.63, I2 = 85.9%), with a non-significant P-value (P = 0.235). Subgroup analyses did not show any significant results.
All-cause mortality
Eighteen studies, including 7122 patients, were analyzed for all-cause mortality. The pooled RR was 0.76 (95%CI: 0.58-1.00, I2 = 94.2%), with a P-value of 0.053, indicating no significant difference in mortality (Supplementary Figure 7). A leave-one-out sensitivity analysis showed that the overall estimate remained robust, even after excluding the study by Linder et al[19]. This reduced heterogeneity to I2 = 67.2% (Supplementary Figure 8). The influence of Linder et al[19] on heterogeneity may be attributable to differences in patient selection, including a potentially higher prevalence of advanced malignancy, variable thrombocytopenia rates, and differences in cancer subtype distribution. These factors may have modified baseline mortality risk independent of anticoagulant strategy, thereby influencing the pooled estimate. Nevertheless, exclusion of this study did not substantially alter the overall direction of effect, supporting the stability of the mortality findings.
Bleeding outcomes
Major bleed: Analysis of major bleeding included 24 studies with a total of 20407 patients. The pooled RR was 0.86 (95%CI: 0.67-1.12), with a non-significant result (P = 0.254) and moderate heterogeneity (I2 = 67.0%). Subgroup and leave-one-out analyses also yielded non-significant results.
CRNMB: Overall, 19 studies with a total of 16961 patients were analyzed for CRNMB. The pooled RR was 1.24 (95%CI: 0.99-1.55; P = 0.055; I2 = 53.3%), which was not significant with moderate heterogeneity (Supplementary Figure 9). When looking at the different regimens, Rivaroxaban showed a RR of 1.66 (95%CI: 1.19-2.31) that favored the control group significantly, while other regimens did not show a significant difference (Figure 4).
Figure 4 Forest plot of subgroup analysis of clinically relevant non-major bleeding by regimen type.
RR: Risk ratio; CI: Confidence interval.
Minor bleed: A total of 7 studies with a total population of 697 patients were included in the analysis of minor bleeding that revealed a pooled RR of 1.01 (95%CI: 0.58-1.75; P = 0.958; I2 = 26.0%), indicating non-significant results in both groups and low heterogeneity. The subgroup difference between regimens and stratification by study type remained non-significant throughout. Leave-one-out sensitivity analysis indicated that the pooled estimate dropped significantly to (I2 = 0.0%) after the exclusion of two studies.
Meta-regression analysis
Study analyses were performed for major bleeding, all-cause mortality, and venous thromboembolism. Minor bleeding was additionally included as an exploratory analysis, given the limited number of available studies, to ensure a comprehensive evaluation of bleeding events. The covariates included platelets, age, metastasis, female population, body mass index, and serum creatinine levels, which were assessed across all studies.
Our study found that metastasis was associated with a higher risk of major bleeding β = 1.90, SE = 0.71, P = 0.008, 95%CI: 0.49-3.31Other factors weren’t significant. We also saw that female sex was significantly associated with increased minor bleeding risk (β = 3.13, SE = 1.49, P = 0.036, 95%CI: 0.204-6.055). In all-cause mortality, higher platelet counts were linked to a lower risk of all-cause mortality (β = -0.27, SE = 0.11, P = 0.009, 95%CI: -0.48 to -0.06), compared to the presence of metastasis, which was linked to a higher risk of mortality (β = 0.66, SE = 0.30, P = 0.026, 95%CI: 0.07-1.25). No other covariates were statistically significant (Table 2).
Publication bias was assessed through a visual analysis of funnel plots and a formal evaluation using Egger’s regression test for all primary outcomes. We observed asymmetry in four outcomes (CRNMB, major bleeding, VTE, and all-cause mortality) on visual inspection. However, only the major bleeding outcome showed statistically significant evidence of publication bias, with a P-value of 0.012, suggesting small-study effects. The other outcomes displayed asymmetry on visual inspection but non-significant P-values, suggesting that the observed asymmetry might be due to heterogeneity or small study effects rather than true publication bias.
DISCUSSION
This study reviewed the safety and effectiveness of DOACs and LMWH for the treatment of CAT. The combined data revealed that both DOACs and LMWH were equally effective in preventing all VTE events, with similar reductions in the risk of DVT across studies. However, there was no significant benefit in preventing PE, and mortality reduction was only seen in RCTs. In terms of safety, DOACs had a risk of major bleeding comparable to LMWH, but a slightly higher rate of CRNMB. This increased bleeding risk may be attributable to chemotherapy-induced mucosal injury, thrombocytopenia, and local tumor invasion, particularly in gastrointestinal and genitourinary malignancies, where anticoagulation may predispose to mucosal bleeding[20,21]. These findings emphasize the need to balance thrombotic protection with tailored bleeding risk when selecting an anticoagulant approach in oncology.
When comparing the overall impact of DOACs and LMWH in preventing VTE among cancer patients, combined study results showed no significant difference [RR = 0.88 (0.68-1.14), P = 0.327]. The included studies were heterogeneous, possibly due to differences in patient populations, cancer conditions, study designs, and follow-up periods. Notably, when analyzing single DOACs, apixaban was associated with a great reduction in VTE events. This could be attributed to its better pharmacokinetic profile, tolerability, and likely lower bleeding risk, which may lead to better patient compliance and more stable anticoagulation[22,23]. In contrast, medications like Rivaroxaban did not show similar benefits, likely due to differences in dosing, absorption, or drug interactions[24]. The study design type also appeared to have a limited impact on the direction of effect, suggesting that both randomized and non-randomized data showed similar patterns. Excluding a single powerful study narrowed the range, but the direction of the effect remained unchanged, further supporting the stability of the findings. DOACs were found to be significantly effective in reducing the risk of DVT, with consistent results across studies. The consistent reduction in DVT risk may reflect the targeted pharmacologic mechanisms and predictable pharmacokinetic profiles of DOACs[25]. By directly inhibiting the coagulation cascade, DOACs effectively inhibit clot formation in deep veins[26]. Their linear and predictable pharmacokinetics also lead to consistent anticoagulant effects without frequent monitoring or dosingadjustments[6]. This consistency across various patient populations and clinical situations likely contributes to the consistent DVT risk-reduction results observed in the included studies.
Our findings align with previous meta-analyses, such as those by Sabatino et al[27] and Vedovati et al[28], which reported similar efficacy of DOACs and LMWH in preventing overall VTE. However, our subgroup analysis provides new insights by highlighting apixaban’s association with decreased VTE risk, a finding not previously emphasized. This could be related to its pharmacokinetic benefits, such as lower peak-trough variability and less gastrointestinal exposure, which may improve safety and compliance in cancer patients[29,30]. These observations suggest that DOACs could be an effective alternative to LMWH for cancer-related thrombosis, but with caution to avoid increased bleeding risk. Nevertheless, when examining subgroups by study design or specific DOAC drugs, the protective effect was not consistently evident, possibly due to the smaller number of studies and patients per subgroup, which reduced statistical power to detect differences[31]. Interestingly, studies that did not report the type of DOAC still showed a robust effect, suggesting that unreported combinations or underreported agents contributed to the observed benefit[32].
Notably, while studies showed uniform reductions in DVT, this was not observed for PE, aligning with previous research by Young et al[31] and suggesting a potential pharmacologic deficiency in preventing large proximal clots or embolic extension[33]. This may be due to differences in the pathophysiology of DVT and PE or the impact of cancer-related hypercoagulability on embolization. Variations in PE diagnostic testing methods across studies could also have contributed to this discrepancy. Since PE often results from more significant, more proximal thrombi, its prevention may require more aggressive or prolonged anticoagulation[34]. It’s possible that in certain patient populations, particularly those with comorbidities or advanced cancer, DOACs may be less effective at preventing embolic migration. The significant variability between studies also suggests that differences in diagnostic criteria, surveillance, or PE definitions could explain the differing results. The small number of studies in this outcome makes it harder to draw solid conclusions.
There was a non-significant trend towards lower all-cause mortality by DOACs in cancer patients compared to LMWH, although the finding fell just short of statistical significance[35]. When considering randomized trials alone, the survival advantage became significant, implying that when study designs reduce confounding and bias, the mortality advantage of DOACs may become evident. This could be due to several factors, including the ease of administering DOACs orally, reducing the need for injections, which can improve quality of life and compliance[36,37]. Additionally, the predictable anticoagulant effect of DOACs may lower the risk of fatal thrombotic events[38]. Variation in non-randomized studies may be due to selection bias or residual confounding, with sicker patients potentially more likely to receive one treatment rather than another. Furthermore, one study appeared to contribute much of the variance, and removing it made the results more comparable, suggesting that outlier effects can bias pooled estimates.
When assessing safety outcomes, the analysis found that DOAC use was roughly equivalent to LMWH in terms of the risk of major bleeding. These findings suggest that DOACs do not significantly increase the risk of life-threatening bleeding events in cancer patients with VTE[39]. Meta-regression analysis demonstrated that the presence of metastatic disease was significantly associated with increased major bleeding risk. This finding is clinically plausible, as metastatic disease often reflects greater tumor burden, increased mucosal invasion, particularly in gastrointestinal and genitourinary malignancies, and heightened systemic inflammation. Advanced cancer may also impair vascular integrity and hemostatic balance, predisposing patients to bleeding complications during anticoagulation therapy. These findings underscore the importance of incorporating disease stage and tumor burden into anticoagulation risk assessment. However, when considering CRNMB events, those that require medical attention but are not life-threatening, DOACs show a slight trend toward a higher risk[40]. This can be attributed to their systemic action and longer half-life compared to LMWH, which can sometimes be easier to control or reverse[41]. For minor bleeding events, the outcomes were similar between the two groups, indicating that neither therapy has a significant disadvantage in causing mild, self-limiting bleeding episodes. Interestingly, study revealed that a higher proportion of female participants within studies was significantly associated with increased minor bleeding risk. The positive regression coefficient suggests that female sex may be an effect modifier for minor bleeding outcomes. Potential explanations include sex-related pharmacokinetic differences, variations in body composition, hormonal influences on vascular fragility, or differences in bleeding reporting patterns. Although exploratory, this finding underscores the need for sex-specific analyses in anticoagulation trials in oncology populations. Our results align with earlier large trials, such as Hokusai-VTE Cancer and Caravaggio, which found no significant difference in major bleeding between DOACs and LMWH[28,42,43]. However, our combined analysis did identify a slight increase in CRNMB with DOACs, particularly in trials involving genitourinary or gastrointestinal malignancies. This risk is consistent with previous subgroup analyses by Kraaijpoel et al[42], highlighting the importance of tumor location in predicting mucosal bleeding[43]. Our study also revealed cancer site to be a significant moderator of CRNMB risk, emphasizing the value of tumor-specific bleeding profiles in treatment planning (Table 1)[17-19,31,40-64].
Results on mortality were less clear. Although a non-significant trend toward DOACs was seen in the overall pooled analysis, a significant survival benefit was found when limited to RCTs. This could be due to RCTs controlling for fewer confounding factors and biases, or better patient allocation. Our findings aligned with those of Riaz et al[43], who showed survival benefits with DOACs compared to LMWHs. The better adherence and quality of life of oral agents likely contributed to this advantage. Notably, the study showed that trial design and sample size were strong moderators of mortality endpoints; smaller observational studies with high heterogeneity weakened the effect seen in larger, well-designed trials. Looking at overall adverse events, DOACs were similar to LMWH in terms of adverse effects, with the key takeaway that both treatments are generally safe and well-tolerated in most patients. Notably, the results didn’t vary much by patient characteristics, suggesting a consistent safety profile across cancer types. Despite this, DOACs seem like a viable alternative to LMWH for cancer patients with VTE, possibly offering benefits like oral treatment and improved quality of life. Future studies should explore which anticoagulant is the best choice for this population.
From a clinical perspective, our findings support individualized anticoagulation strategies in CAT. Apixaban showed a significant reduction in VTE with minor heterogeneity, suggesting it may be a preferred option in selected oncology populations. Conversely, caution may be warranted with certain DOACs in patients with gastrointestinal or genitourinary malignancies due to potential bleeding risk. The presence of metastatic disease emerged as an important modifier of major bleeding risk, underscoring the need to incorporate tumor stage and disease burden into anticoagulation decision-making. Ultimately, treatment selection should balance thrombotic protection against bleeding risk, integrating patient-specific oncologic and hematologic factors.
Limitations
Although these findings are encouraging, several limitations should be noted. First, the analysis included both RCTs and observational studies, which may introduce differences in study quality and patient selection. The studies presented their data inconsistently, and some had smaller sample sizes or focused on specific cancer types, which could limit the generalizability of the results. Additionally, most trials did not systematically categorize by tumor location or stage, which are critical factors in predicting bleeding and clot risk. Many cancer patients have complex clinical presentations, including advanced disease, organ dysfunction, and multiple comorbidities, all of which could impact anticoagulant safety and efficacy. These complexities are often underrepresented in clinical trial populations, potentially reducing the generalizability of the results to real-world settings. The generalizability of these findings may also be limited in patients with very high bleeding risk malignancies, such as gastrointestinal or genitourinary cancer, where clinical judgment may still favor LMWH. Also, variations in the types of DOAC prescribed, treatment durations, and definitions of bleeding outcomes between studies make it challenging to conclude individual agents or optimal treatment regimens. Although outcomes such as DVT (n = 9), PE (n = 11), and minor bleeding (n = 7) were reported in a limited number of studies. The significant pooled effect for DVT supports its systematic evaluation as a primary outcome in future studies. Minor bleeding study, based on < 10 studies, showed a potential association with female sex (β = 3.13), but this should be considered exploratory and confirmed in adequately powered, gender-stratified studies.
CONCLUSION
Our study indicates that DOACs are a valid alternative to LMWH in the treatment of thrombosis in cancer patients. Although there was no significant difference in the primary outcome of VTE prevention, DOACs were non-inferior to LMWH in the prevention of DVT and had a similar risk of major bleeding. The oral route of administration for DOACs remains a significant advantage in terms of patient convenience and compliance. Nevertheless, the presence of heterogeneity among studies, the effect of metastatic disease on the risk of bleeding, and the slightly higher risk of CRNMB suggest the importance of individualized treatment strategies. Treatment choices should take into account the type of cancer, the extent of metastatic disease, the risk of bleeding, and patient preference. Additional high-quality randomized trials are required to better define patient selection and treatment strategies in this challenging patient population.
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Specialty type: Medicine, research and experimental
Country of origin: Pakistan
Peer-review report’s classification
Scientific quality: Grade B, Grade B, Grade C
Novelty: Grade B, Grade B, Grade C
Creativity or innovation: Grade B, Grade B, Grade B
Scientific significance: Grade B, Grade B, Grade C
P-Reviewer: Ali A, PhD, Associate Research Scientist, Pakistan; Shukla A, MD, Assistant Professor, India S-Editor: Bai SR L-Editor: A P-Editor: Yang YQ
