Direct oral anticoagulants compared to low‐molecular‐weight heparin for the treatment of cancer‐associated thrombosis: Updated systematic review and meta‐analysis of randomized controlled trials

Abstract Background Low‐molecular‐weight‐heparins (LMWHs) have been established for the treatment of cancer‐associated venous thromboembolism (VTE). Recently published randomized controlled trials (RCTs) have compared direct oral anticoagulants (DOACs) with LMWHs. The aim of this systematic review and meta‐analysis was to evaluate efficacy and safety of DOACs versus LMWHs and update the evidence for treatment of VTE in cancer. Methods Biomedical databases were screened for RCTs evaluating DOACs for cancer‐associated VTE. Primary efficacy and safety outcomes of this meta‐analysis were recurrent VTE and major bleeding at 6 months. Secondary outcomes comprised clinically relevant nonmajor bleeding (CRNMB), major gastrointestinal (GI) and genitourinary bleeding, mortality, fatal bleeding/pulmonary embolism, and treatment discontinuation rate. We performed prespecified subgroup analyses. Pooled relative risk (RR) and 95% confidence intervals (CIs) were obtained by the Mantel‐Haenszel method within a random‐effect model. Results We screened 759 articles and included 4 RCTs (n = 2894). DOACs significantly reduced recurrent VTEs compared to LMWHs (5.2% vs 8.2%; RR, 0.62 [95% CI, 0.43‐0.91]), but were associated with a nonsignificant increase in major bleedings (4.3% vs 3.3%; RR, 1.31 [95% CI, 0.83‐2.08]) and a significant increase in CRNMB (10.4% vs 6.4%; RR, 1.65 [95% CI, 1.19‐2.28]). Mortality risks were comparable between groups (RR, 0.99 [95% CI, 0.83‐1.18]). Preterm treatment discontinuation was less common with DOACs (RR, 0.88 [95% CI, 0.81‐0.96]). Major bleeding was more frequent in patients with GI cancer treated with DOACs (RR, 2.30 [95% CI, 1.08‐4.88]). Conclusion In patients with cancer‐associated VTE, DOACs are more effective in preventing recurrent VTE compared to LMWH. However, risk of bleeding is increased with DOACs, especially in patients with GI cancer.


| INTRODUCTION
Patients with cancer are at an increased risk of developing venous thromboembolism (VTE), which is a major contributor to morbidity and mortality. [1][2][3][4] As compared to VTE in the noncancer setting, managing cancer-associated VTE is challenged by a higher risk of recurrence and increased risk of major bleeding during anticoagulant treatment. 5 The Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in CLOT (Patients With Cancer ) study and subsequent trials have tested the efficacy and safety of lowmolecular-weight heparins (LMWHs) versus vitamin K antagonists (VKAs) for the treatment of VTE in patients with cancer, with favorable results for LMWH (ie, reduced risk of recurrence and no increase in risk of bleeding). [6][7][8] Based on these studies, guidelines have uniformly endorsed LMWH monotherapy as the standard-ofcare treatment of VTE in cancer-associated VTE for 3-6 months until recently. 3,7 Direct oral anticoagulants (DOACs), such as apixaban, edoxaban, rivaroxaban, and dabigatran, have emerged as the preferred treatment option for VTE in the general population. [9][10][11] However, the subgroup of patients with cancer included in trials testing DOACs for VTE was limited, and the control treatment in these trials was VKA.
As the preferred treatment for cancer-associated VTE at that time was LMWH, no robust data for efficacy and safety of DOACs for patients with cancer-associated VTE were available until recently. Therefore, no definitive conclusion could be drawn for the use of DOACs in patients with active cancer and a direct comparison of DOACs to LMWHs was urgently needed. 5 Recently, DOACs have been tested for the treatment and secondary prevention of VTE in patients with cancer head-to-head against LMWHs according to the CLOT regimen (dalteparin 200 IU/ kg for 1 month, followed by dalteparin 150 IE/kg) in 4 studies, which provide evidence for the efficacy and safety of DOACs, in particular factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban). [12][13][14][15] DOACs have been shown to be at least noninferior compared to LMWH monotherapy for the treatment of cancer-associated VTE.
Relevant safety outcomes such as rates of bleeding events differed in these studies. Further, these trials also included patients with incidentally diagnosed asymptomatic VTE, which is frequently observed in patients with cancer.
Previous meta-analyses have been performed comparing DOACs to LMWHs for the treatment of cancer-associated VTE aggregating data from 2 or 3 of the now 4 available randomized controlled trials (RCTs) and showed a nonsignificant decrease in risk of VTE accompanied by an increase in risk of bleeding in patients treated with a DOAC. [16][17][18][19] The aim of this systematic review and updated meta-analysis was to compare efficacy and safety of DOACs versus LMWHs for the treatment of acute cancer-associated VTE by aggregating results from all available RCTs and to assess their relative benefit in specific subgroups.

| METHODS
We conducted a systematic review of the literature and meta-analysis to identified RCTs comparing DOACs with LMWHs specifically in patients with cancer. The study was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. 20 The proposal of the systematic review, including strategy of literature research, was submitted online to the International Prospective Register of Systematic Reviews prior to the initiation of literature review and identification of eligible studies.

| Literature research and study selection
Two researchers (FM and CA) independently conducted a review of the literature (April 1, 2020), using the biomedical databases EMBASE, MEDLINE, and CENTRAL. Predefined search terms were used combined with filters to identify clinical trials (complete search strategy is provided in Appendix S1). Titles and abstracts of primarily identified publications matching search criteria were screened for conformity with inclusion and exclusion criteria. The remainder of studies underwent full-text evaluation for eligibility.
To be eligible for inclusion, studies had to fulfil all predefined inclusion criteria and not match any exclusion criteria. Criteria for inclusion were defined as follows: (i) prospective clinical trials testing DOACs specifically for the treatment of cancer-associated VTE, (ii) control arm of patients treated with LMWHs, (iii) randomized study group allocation, (iv) adult patients only (≥18 years of age), and (v) anticoagulants, factor Xa inhibitors, low molecular weight heparin, neoplasms, venous thromboembolism, venous thrombosis qualifying VTE event must include symptomatic or asymptomatic/ incidental pulmonary embolism (PE) or deep vein thrombosis (DVT).
Exclusion criteria were (i) observational cohort study, (ii) lack of control group, (iii) no randomization process for study group allocation, and (iv) inclusion of patients <18 years of age.
Any disagreements between the 2 reviewers were resolved by discussion, involving also the co-authors.

| Data extraction and study outcomes
Identified studies that were found eligible for inclusion underwent data extraction. Baseline information of our selected studies including characteristics on study design, and respective inclusion and exclusion criteria were collected. Baseline characteristics of individual patient cohorts including age, sex, stage and type of cancer, and specifics regarding qualifying VTE diagnosis were gathered.
Extracted outcome data comprised efficacy and safety results of included studies. The primary efficacy outcome of the meta-analysis was defined as the aggregated rate of recurrent VTE at 6 months, and the primary safety outcome was defined as the 6-month rate of major bleeding. Secondary outcomes included rates of clinically relevant nonmajor bleeding (CRNMB), any bleeding, major gastrointestinal (GI) bleeding, major genitourinary (GU) bleeding, intracranial bleeding, mortality, fatal bleeding, PE-related mortality, and rate of preterm discontinuation of anticoagulation. All extracted outcome variables were defined as within the respective study. For calculating aggregated rates of outcomes, we used modified intention to treat populations of the selected studies. Prespecified subgroup analyses were conducted in patients with GI cancer and incidental VTE as index event.
Risk of bias of included studies was evaluated with the modified Cochrane risk-of-bias tool. 21 Risk of publication bias was assessed within a funnel plot for the primary efficacy outcome.

| Statistical analysis
Aggregated summary statistics were calculated by weighted means and proportions, as suitable according to type of variable.
Pooled relative risk (RR) and corresponding 95% confidence intervals (CIs) of outcome variables were obtained by combining results from selected studies by the Mantel-Haenszel method within a random-effects model. Assessment of heterogeneity was conducted graphically from forest plots and tested by assessing the I 2 as a measure of variation in RR attributable to heterogeneity among included studies. In the case of a substantial degree of heterogeneity between studies, outcome analysis was repeated after exclusion of selected studies.

| Study identification
A total of 759 published records, matching the predefined search terms, were found by systematic database search (EMBASE, 396; CENTRAL, 147; MEDLINE, 216). After removal of duplicates, 755 records were screened for eligibility. After exclusion of 716 records based on information drawn from title and abstract, 39 records were selected for full-text assessment. Of those, we identified 4 clinical trials contributing to 9 different publications, including 5 publications on specific subgroups or post hoc analysis or on outcomes during extended treatment beyond 6 months. [12][13][14][15][22][23][24][25][26] Figure 1 shows a Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram, which summarizes the process of study identification and selection. 27  Cancer) study. [12][13][14][15] These studies all represent RCTs, which compared DOACs with LMWHs for the treatment of VTE in patients with cancer. Specifics on study design and corresponding inclusion and exclusion criteria are presented in Table 1 and the rates of outcome variables within selected studies in Table 2.

| Study characteristics
Overall, 2894 patients with acute VTE were included in the meta-analysis. Of those, 1446 were allocated to treatment with a DOAC and 1448 to LMWH (50% each). Incidental VTE was reported as the index event in 30.0% of patients, ranging from 19.9% in Caravaggio, 27.8% in SELECT-D to 32.5% in Hokusai VTE Cancer, with no reported rates of presence or absence of symptoms of the qualifying VTE events in ADAM VTE. [12][13][14][15] Patients allocated to the control group of all 4 studies were treated with dalteparin at a dose of 200 IU/kg once daily for

| Risk of bias
Risk of bias was assessed by the Revised Cochrane risk-of-bias tool for randomized trials. 21 Low risk of bias was suspected for all included studies ( Figure 2). Visual inspection of a funnel plot revealed no suspicion for publication bias ( Figure S1).   Forest plots and corresponding RRs of the primary outcome analysis are displayed in Figure 3A.

| Secondary outcomes of the meta-analysis
For the analysis of major GI bleeding, major GU bleeding, fatal bleeding events, and intracranial bleeding, 12-month rates from Hokusai VTE Cancer were used due to the unavailability of 6-month rates. Figure 3B depicts forest plots and corresponding RR for key secondary outcome events (CRNMB, mortality, treatment discontinuation). Forest plots for the remaining secondary outcomes (any bleeding, fatal bleeding, fatal PE, major GI bleeding, major GU bleeding, and intracranial bleeding are provided in the Appendix S1 ( Figure S2).  Figure S4).

| Subgroup analyses
We conducted a subgroup analysis of risk of major bleeding in pa- We also analyzed efficacy and safety outcomes in the sub-

| DISCUSSION
In this meta-analysis of 4 RCTs including 2894 patients, we com- and low I 2 values (ie, the percentage of variation in RR attributable to differences between studies), it appears reasonable to come to the general conclusion that factor Xa inhibitors are effective in preventing recurrent VTE.
On the contrary, DOACs seem to be associated with an increased risk of bleeding. We found a numerically elevated rate of major bleed- One strength of our meta-analysis is its scale, with the recent publication of the Caravaggio trial, adding a significant number of patients for aggregating data. Thereby, the power is higher compared to previous meta-analyses, which enhances the generalizability of the results.
Further, updated guideline recommendations for the treatment of cancer-associated VTE, naming DOACs as alternative to LMWHs as first-line therapeutic option, are supported by our meta-analysis. [29][30][31] Due to the improved efficacy reported in our meta-analysis and its practical advantages beyond efficacy and safety leading to improved patient adherence, superiority of DOACs to LMWHs in the setting of acute cancer-associated VTE should be evaluated in updated guidelines in the future.

| CONCLUSION
In patients with cancer-associated VTE, DOACs significantly reduce