Role of anticoagulants in therapy and prevention of recurrent venous thromboembolism in patients with cancer: a meta-analysis of randomized trials with apixaban

Abstract

Background    Venous thromboembolic complications (VTEC) are a major non-oncological cause of death of patients with malignant neoplasm (MNP). This determines the high significance of antithrombotic therapy for the treatment and secondary prevention of VTEC in this population. During recent years, low-molecular weight heparins (LMWH) have been a “gold standard” for the treatment of cancer-associated venous thrombosis (CAVT). In the recent decade, direct oral anticoagulants (DOACs) have become extensively used for the treatment and prevention of VTEC relapse in non-oncological patients and also for primary prevention of VTEC following orthopedic surgery. Taking into account the oral route of administration, the predictable and convenient pharmacokinetic profile, and the absence of need for coagulation monitoring, it seems possible to use DOACs for the treatment and secondary prevention of VTEС in oncological patients. A meta-analysis of 4 randomized clinical trials (RCTs) showed a higher efficacy of DOACs compared to LMWHs, however, with a greater risk of bleedings in CAVT. In two of four studies using apixaban (more than 40% of weight in meta-analysis), no increase in bleedings was noted.Aim    The aim of this study was to perform a systematic search for comparative clinical studies with apixaban and to perform a meta-analysis to answer the question on clinical efficacy and safety of apixaban in the treatment and secondary prevention of recurrent VTEC in patients with CAVT.Material and methods    The systematic search was performed in three reference databases, Medline (PubMed), Cochrane Library (CENTRAL), and eLibrary. The search was aimed at publications containing results of RCTs using apixaban for the treatment and prevention of VTEC in patients with MNP. A totality of 678 titles was found; 15 articles were selected for detailed studying, and 4 RCTs were included into the final analysis. The meta-analysis was performed according to the criteria of PRISMA guidelines. Relative risk (RR) was used as a measure of the effect. The meta-analysis was performed by the Mantel-Haenszel method using the R software. Statistical heterogeneity was evaluated with the Cochran criterion (I2); heterogeneity was considered significant at I2 ≥50 %, which was a reason for performing a random-effects meta-analysis. For this meta-analysis, the primary outcome measure was new VTECs (symptomatic or detected proximal deep vein thrombosis and/or symptomatic, detected or fatal pulmonary thromboembolism plus symptomatic upper extremity thromboses, celiac veinous thromboses, and cerebral veinous thromboses if they were included into the efficacy endpoint of the primary studies). The primary safety measure was major bleeding according to ISTH criteria. Other variables included major and clinically significant minor bleedings as well as overall death rate.Results    During the systematic search, 4 RCTs were selected. The meta-analysis of the treatment and secondary prevention of VTEC in patients with MNP showed that apixaban was more effective than the active control (88% of LMWHs) in prevention of VTEC relapse. The RR was 0.59; 95 % confidence interval (CI): 0.40–0.86 in the absence of statistically significant differences from the control in the risk of major bleedings (statistically non-significant decrease by 21%), the sum of major and clinically significant minor bleedings, and overall death rate.Conclusion    According to the results of the meta-analysis, the DOAC apixaban may be a drug of choice for the treatment and prevention of VTEC relapse in patients with MNO.