Efficacy and safety of Direct Oral Anticoagulants versus Low Molecular Weight Heparin in treatment for cancer-asociated venous thromboembolism: An updated meta-analysis
Tóm tắt
Background
Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE) is a common complication of malignancy1,2. Studies have shown that the risk of developing VTE in patients with active malignancy is seven-fold, with an annual incidence of 0.5% in cancer patients as compared to 0.1% in the general population3-4. A systematic review by Lee et al. regarding epidemiology in Asia showed prevalence of VTE in cancer patients at 0.5-44.6% and cancer prevalence among VTE patients at 6.1-65%5. Cancer has been shown to be a major cause of mortality in patients with VTE and vice versa6. Data from the Global Anticoagulant Registry in the Field (GARFIELD)-VTE registry involving a cohort of 10,315 VTE patients from 419 centers in 28 countries showed 9.7% overall mortality within 6 months, with more than half of these deaths being cancer-related7.
The pathophysiology of cancer-associated VTE (CAVTE) is different than the formation of thrombosis in the general population. Cancer cells produce a variety of substances that promote VTE formation, one of which is the tissue factor which activates the extrinsic coagulation pathway resulting in factor X activation. Cancer cells can also produce 1) pro-coagulant factors which can stimulate factor Xa directly, 2) plasminogen activator inhibitor-1 which interferes with the fibrinolytic system, and 3) mucins which affect the coagulation cascade pathway.8
Rudolf Virchow postulated in 1856 a triad of factors that can predispose a patient to develop thrombosis, namely: endothelial injury, circulatory stasis, and a hypercoagulable state9. Cancer and subsequent treatment modalities can present with conditions that can cause these factors. Surgical procedures and chemotherapy may cause endothelial injury. Tumors can cause circulatory stasis through compression of local blood flow. Pain can also result in impaired mobility in cancer patients, impairing venous drainage even further.6 Genetic profiling studies have also shown the association of mutations that increase the risk of developing VTE such as K-ras mutations in colon and lung cancer and JAK2 V617F which is commonly present in cases of myoproliferative cancer10-12
Methods
- Search Strategy
Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines were used. An update of the previous study by Kahale et al.22 was done. The literature search done in PubMed, MEDLINE, and Google Scholar included studies published from inception until October 2022. Keywords such as “Cancer’ OR “Malignancy” AND “Venous thrombosis” OR “Venous thromboembolism” AND “Direct oral anticoagulant” OR “New oral anticoagulant” AND “Heparin OR “Low molecular weight heparin” AND “Randomized controlled trial” were utilized in different word combinations to obtain published journals and articles. Hand search was also used.
- Study Design
This meta-analysis involves review of randomized controlled trials among cancer patients with VTE given DOAC or LMWH, with efficacy outcome of VTE recurrence and safety outcomes of major bleeding, clinically relevant non-major bleeding, and all-cause mortality. Presence of bias in the obtained data was assessed by heterogeneity analysis.
- Data Collection
The studies reviewed and evaluated in this meta-analysis were those with the following criteria: 1) randomized controlled trials; 2) adult patients (aged 18 years old and above) diagnosed with cancer and VTE; 3) with a data of usage of DOAC as intervention with LMWH alone as comparator; and 4) with d
Results
In this updated meta-analysis, a total of 1,614 patients were treated with DOAC and 1,628 patients were treated with LMWH. With regards to the outcome of VTE recurrence in patients with CAVTE, the calculated risk ratio at 95% confidence interval was 0.65 (0.50, 0.84) favoring the use of DOAC. For the outcomes of major bleeding and clinically relevant non-major bleeding in patients with CAVTE, the calculated risk ratios at 95% confidence interval were 1.32 (0.96, 1.83) and 1.53 (1.22, 1.90) respectively, favoring the use of LMWH. For the outcome of mortality, the calculated risk ratio at 95% confidence interval was 1.00 (0.89, 1.11) favoring neither DOAC or LMWH. The test of overall estimate effect for all of the outcomes were as follows: P = 0.001 for VTE recurrence, P = 0.09 for major bleeding, P = 0.0002 for clinically relevant non-major bleeding, and P = 0.94 for all-cause mortality. Calculated I2 values were as follows: 0% for VTE recurrence (P = 0.64), 33% for major bleeding (P = 0.18), 7% for clinically relevant non-major bleeding (P = 0.38), and 0% for all-cause mortality (P = 0.43). Funnel plots (Fig. 6) were also generated to see for publication bias.
Analyses of the randomized controlled trials included showed that in terms of efficacy, which in this study was represented by the outcome of VTE recurrence, use of DOAC for CAVTE would be favored over LMWH, with a calculated risk ratio of less than 1 at 0.65 (0.50, 0.84) at 95% confidence interval. With regards to the outcomes of major bleeding and clinically relevant non-major bleeding, with calculated risk ratios of more than 1 at 1.32 (0.96, 1.83) and 1.53 (1.22, 1.90) respectively at 95% confidence interval, use of LMWH for CAVTE would result in less bleeding episodes. In terms of all-cause mortality, the calculated risk ratio at 95% confidence interval was 1.00 (0.89, 1.11), showing that the safety profile in terms of mortality of DOAC use as compared to LMWH use is comparable. These calculated risk ratios align with results from the meta-analysis performed by Kahale et al.22, reinforcing that use of DOAC would be comparable to use of LMWH, the first-line treatment for CAVTE. The calculated I2 statistics for all outcomes were all less than 50% indicating low heterogeneity. Funnel plots generated (Fig. 6) showed symmetrical appearance for all graphs except for the outcome of VTE recurrence. The asymmetry for the VTE recurrence Funnel plot indicates publication bias.
Conclusion
Venous thromboembolism, encompassing deep venous thrombosis and pulmonary embolism, is a common complication of malignancy. As clinicians, it is important to assess which management may be done for patients who present with cancer-associated VTE. This updated meta-analysis showed that DOAC use for CAVTE treatment showed better efficacy in terms of VTE recurrence compared to LMWH use and had comparable all-cause mortality rates. However, DOAC use for CAVTE treatment may result in more bleeding episodes compared to LMWH use.
It is recommended that more randomized controlled trials must be done to explore the optimum treatment for CAVTE in terms of safety and efficacy, preferably large-scale studies with head-to-head comparisons of DOAC and LMWH agents. At present, the findings of this updated meta-analysis reinforce the use of DOAC as an alternative first-line treatment for LMWH in CAVTE.
