Direct Oral Anticoagulant for the Treatment of VTE in Cancer Patients: A Systematic Review and Meta-analysis

Abstract

Background: Recent clinical guidelines suggest direct oral anticoagulants (DOACs) as treatment for cancer-associated thrombosis (CAT), but the strength of such recommendations was not clear. Newly released trials add uncertainties to the benefit and risk assessment between DOACs and conventional therapy (low-molecular-weight heparin [LMWH] or vitamin K antagonists [VKAs]). Objective: To evaluate the efficacy and safety of DOACs in patients with CAT, as compared with LMWH and VKAs. Methods: PubMed, EMBASE, Cochrane Library, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched. Randomized controlled trials (RCTs) that reported outcomes of DOACs for treating CAT were included. Relative risk (RR), risk difference, and 95% CIs were pooled using the Mantel-Haenszel method. Results: A total of 8 RCTs were included. DOACs significantly reduced VTE recurrence (RR = 0.59; 95% CI = 0.48-0.73) compared with conventional therapy. Results were similar in the LMWH and VKA subgroups. DOACs had a higher, though nonsignificant, risk of major bleeding compared with LMWH (RR = 1.33; 95% CI = 0.94-1.89) but lower risk of major bleeding compared with VKAs (RR = 0.60; 95% CI = 0.39-0.93). Findings were consistent across patients with active cancer and history of cancer. Conclusion and Relevance: DOACs have better efficacy to prevent recurrent VTE compared with conventional therapy. Regarding the safety profile, DOACs may carry higher risk of bleeding compared with LMWH but lower risk of bleeding compared with VKAs. Further studies are needed to inform the optimal anticoagulation approach for different types of cancers.

An epidemic of redundant meta‐analyses

“…At the time the search was ended (October 6, 2020), 46 records were identified, of which 26 were discarded on title and abstract ( n = 24) or full‐text ( n = 2). The 20 remaining meta‐analyses were published in nonpredatory peer‐reviewed journals: five studies pooled the data of two RCTs, 6‐10 four studies pooled the data of three RCTs, 11‐14 and 11 studies pooled the data of four RCTs 15‐25 . The main characteristics of the 20 meta‐analyses are described in Table 1 and the results of the 20 meta‐analyses for efficacy and safety endpoint are shown Figure 1.…”

“…The 20 remaining meta-analyses were published in nonpredatory peer-reviewed journals: five studies pooled the data of two RCTs, 6-10 four studies pooled the data of three RCTs, [11][12][13][14] and 11 studies pooled the data of four RCTs. [15][16][17][18][19][20][21][22][23][24][25] The main characteristics of the 20 meta-analyses are described in Table 1 and the results of the 20 meta-analyses for efficacy and safety endpoint are shown Figure 1. Within each category of meta-analysis (two, three, or 4 RCTs), the results were similar regarding the risks of VTE recurrence (differences in pooled relative…”

Current status of treatment of cancer-associated venous thromboembolism

“…In recent years, with respect to DOACs vs LMWH, besides SELECT-D trial [ 37 ], six meta-analyses indicated that DOACs were more efficacious in the treatment of cancer-associated VTE with an increase of bleeding risk, compared with LMWH [ 11 , 20 , 38 – 41 ], whereas a retrospective study [ 7 ] and another five meta-analyses [ 10 , 15 , 16 , 42 , 43 ] indicated that DOACs were more efficacious with a comparable bleeding risk, compared with LMWH. In the ADAM VTE trial, major bleeding and VTE recurrence rates were both lower in cancer patients with VTE receiving oral apixaban than those receiving dalteparin [ 44 ].…”

“…With regard to DOACs vs VKA in recent years, one retrospective study [ 7 ] and two meta-analyses [ 10 , 42 ] reported that DOACs were more efficacious in the treatment of cancer-associated VTE with similar bleeding risk compared to VKA, whereas another two meta-analyses [ 11 , 38 ] indicated that DOACs were more efficacious with a decrease of bleeding risk, compared to VKA. Besides, the Hokusai-VTE trial reported that DOAC (edoxaban) was as effective as VKA (warfarin) for the treatment of patients with cancer-associated VTE with less bleeding risk [ 48 ].…”

“…As for LMWH vs VKA, two meta-analyses [ 11 , 20 ] and one retrospective study [ 34 ] reported that LMWH was more efficacious in the treatment of cancer-associated VTE with similar bleeding risk compared with VKA, whereas the CATCH trial [ 49 ] and one meta-analysis indicated that the therapeutic efficacy for cancer-associated VTE and bleeding risk were both similar between LMWH and VKA [ 38 ].…”