Comparative Efficacy of Direct Oral Anticoagulants and Low-Molecular-Weight Heparin in Cancer-Associated Thromboembolism: A Systematic Review and Meta-Analysis

Abstract

Patients diagnosed with cancer often experience an abnormal occurrence of venous thromboembolism (VTE) and its related complications. In order to evaluate the safety and effectiveness of both treatment approaches, we conducted a comprehensive systematic review and meta-analysis within the realm of cancer-associated thromboembolism. A thorough search was conducted across PubMed, the Cochrane Library, and Embase databases to find studies comparing direct oral anticoagulants (DOACs) with low molecular weight heparins (LMWHs) for the treatment of VTE in patients with malignancy. The analyses utilized the random-effects model. This meta-analysis included 11 studies. The results showed that DOACs were associated with a significantly reduced risk of VTE recurrence (RR: 0.67; 95% CI: 0.55, 0.81, p<0.0001; I2: 0%) and deep vein thrombosis (DVT) (RR: 0.63; 95% CI: 0.46, 0.86, p<0.0001; I2: 0%) compared to LMWHs. However, there was no significant difference in the risk of pulmonary embolism (PE) (RR: 0.76; 95% CI: 0.54, 1.06, p=0.11; I2: 11%) between the two groups. The use of DOACs was also associated with a non-significant increase in the risk of major bleeding events (RR: 1.23; 95% CI: 0.85, 1.78, p: 0.26; I2: 49%), while clinically relevant non-major bleeding (CRNMB) was significantly higher with DOACs (RR: 1.92; 95% CI: 1.11, 3.30, p: 0.02; I2: 81%). Secondary outcomes, such as survival rates and fatal PE, did not show significant differences between the two treatment groups. Our analysis indicates that direct oral anticoagulants exhibit a substantial decrease in the occurrence of VTE recurrence, deep vein thrombosis, and pulmonary embolism when compared to low molecular weight heparin in cancer-associated thromboembolism. However, it should be noted that DOACs carry a higher risk of CRNMB. Based on these findings, DOACs are recommended as a superior therapeutic option for managing cancer-associated thromboembolism compared to LMWH.

Keywords: cancer; direct oral anticoagulants; doacs; lmwhs; low molecular weight heparins; venous thromboembolism.

Figure 1. PRISMA diagram illustrating the selection process for inclusion of studies in the meta-analysis

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram showcases the step-by-step procedure employed to identify and select studies for inclusion in the meta-analysis. Initially, 2500 articles were identified through a literature review. After removing duplicates and carefully evaluating titles and abstracts, 11 studies that met the inclusion criteria were chosen.

Figure 2. Representation of the Cochrane risk of bias assessment for randomized controlled trials

The figure highlights the presence of trials with moderate-to-high quality, indicating a reliable and robust study design. Source: references [15-18,21-23,25].

Figure 3. Funnel plots of primary outcomes

(A) Venous thromboembolism recurrence and (B) deep vein thrombosis. RR: risk ratio, SE: standard error.

Figure 4. Funnel plots of primary outcomes

(A) pulmonary embolism and (B) major bleeding. RR: risk ratio, SE: standard error.

Figure 5. Funnel plots of primary outcomes: clinically relevant non-major bleeding

RR: risk ratio, SE: standard error.

Figure 6. Forest plot of VTE recurrence

The results of the comparative analysis, indicate a significant reduction in the risk of VTE recurrence associated with the use of DOACs compared to LMWH. The findings further revealed that regardless of whether dalteparin or enoxaparin was utilized as the control drug, DOACs consistently exhibited a lower risk of VTE recurrence. VTE: venous thromboembolism, DOACs: direct oral anticoagulants, LMWHs: low molecular weight heparins, RR: relative risk, CI: confidence interval, M-H: Mantel Hansel. Source: references [15-25].

Figure 7. Forest plot of incidence of DVT

The figure illustrates the comparison between the use of DOACs and LMWH, revealing a significantly lower risk of DVT with DOACs. Notably when dalteparin was employed as the control arm, the reduced risk of DVT was particularly pronounced. DVT: deep vein thrombosis, DOACs: direct oral anticoagulants, LMWHs: low molecular weight heparins, RR: relative risk, CI: confidence interval, M-H: Mantel Hansel. Source: references [15,17,21,22,24,25].

Figure 8. Forest plot of the risk of PE

This figure illustrates that the use of DOACs was associated with a non-significant decrease in the risk of PE. PE: pulmonary embolism, DOACs: direct oral anticoagulants, LMWHs: low molecular weight heparins, RR: relative risk, CI: confidence interval, M-H: Mantel Hansel. Source: references [15,18,21,22,24].

Figure 9. Forest plot of the risk of major bleeding

The figure depicts that the use of DOACs was associated with a non-significant increase in the risk of major bleeding. However, subgroup analysis revealed that when enoxaparin was used as the control arm, treatment with DOACs was linked to a non-significant decrease in the risk of major bleeding. In contrast, when dalteparin was used as the control drug, the use of DOACs significantly increased the risk of major bleeding. DOACs: direct oral anticoagulants, LMWHs: low molecular weight heparins, RR: relative risk, CI: confidence interval, M-H: Mantel Hansel. Source: references [15,16,18-25].

Figure 10. Forest plot of the risk of CRNMB

The figure illustrates the association between the use of DOACs for treatment and an increased risk of CRNMB compared to LMWHs. Subgroup analysis indicated that this increased risk remained consistent with DOACs, regardless of whether enoxaparin or dalteparin was used as the control drug. CRNMB: clinically relevant non-major bleeding, DOACs: direct oral anticoagulants, LMWHs: low molecular weight heparins, RR: relative risk, CI: confidence interval, M-H: Mantel Hansel. Source: references [15-19,21-23,25].