Direct versus conventional anticoagulants for treatment of cancer associated thrombosis: a pooled and interaction analysis between observational studies and randomized clinical trials

Introduction

Patients with cancer, due to their pathological hypercoagulability, have a 4 to 7-fold increased risk of venous thromboembolism (VTE) relative to those without cancer (1). Among malignancy, VTE patients were 3 times more likely to be hospitalized, with an additional 7 hospital days and around 24% decreased 1-year survival rate compared to those without VTE (2,3). Anticoagulation regimen is the cornerstone for the management of cancer-associated thrombosis (CAT), yet its use is challenging in these fragile patients due to a delicate balance between high risk of recurrent VTE and bleeding (4). Current practice guidelines are unanimous in their recommendation of low molecular-weight heparins (LMWHs) as first-line treatment for CAT. The landmark CLOT trial reveals that LMWH is more effective than vitamin-K antagonists (VKAs) in reducing recurrent VTE risk, without increasing major bleeding risk (5). However, in the real-world practice, LMWH use is burdensome as the requirement of daily subcutaneous injections, which inevitably limits its long-term adoption (6). Of late, direct oral anticoagulants (DOACs) represent a convenient and effective alternative to VKAs for the prevention of stroke in atrial fibrillation and the prophylaxis or treatment in VTE (7,8). Whereas, clinical trials of DOACs that specially aimed at patients with cancer remain scarce. Previous several meta-analyses have addressed this issue but were limited by inclusion of only post-hoc analysis from Randomized controlled trials (RCTs), thereby leading to an insufficient sample size estimation for the reduction in recurrent VTE from 3% to 5% (9-15). Publication of several pivotal RCTs, such as Hokusai VTE Cancer and SELECT-D, fueled systematical reassessment of DOACs treatment in CAT patients (16,17).

RCTs and their meta-analyses certainly represent the highest quality of evidence and are the basis for guidelines by healthcare organizations (18). However, RCTs are often conduced on specific populations or in specialized scenarios that differ from real clinical settings, yielding high internal validity (i.e., reliable relative treatment effect estimates) but low external validity (i.e., generalizability to real-world practice) (18). Observational studies (OSs) have traditionally been considered methodologically weaker than RCTs (19). However, there is increased awareness that OSs support and extend RCT findings to large patient populations in real-world clinical practice and, as such, are complementary to RCTs. Therefore, the evidence derived from OSs and their meta-analyses may facilitate validation of conclusions drawn from RCTs and reassure decision-makers that findings can be extrapolated to real-world populations. This study therefore assesses the effectiveness and safety of DOACs in CAT between OSs and RCTs.

Methods

Literature search and study selection

This systematic review was reported in line with a prespecified protocol (PROSPERO: CRD42019132607, https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=132607) and standards in PRISMA Statement and Cochrane Collaboration (20,21). Databases of PUBMED, EMBASE, and Cochrane Library was systematically searched from inception to May 15, 2019, with the language restriction of English, to identify potentially eligible OSs and RCTs comparing DOACs with conventional anticoagulants (LMWH or VKAs) in CAT and reporting data on recurrent VTE and major bleeding. Full details of search strategy were presented in Table S1. Any potential studies from bibliographies of pertinent articles were also identified. As for OSs, when several studies used the same data source from an overlapping period, the one that reported interested data with the longest study period was included. Studies that published only in conference abstract or letter form were excluded. Two reviewers (ZC Gu, YD Yan) independently assessed the study titles and abstracts to determine eligibility, and full articles were thereafter retrieved and assessed according to inclusion criteria, with any disagreements being resolved by corresponding authors (Z Li, XH Wang).

Table S1 Search strategy used in May 15, 2019
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Study outcomes, data extraction, and quality evaluation

The primary outcomes of this study were recurrent VTE and major bleeding, and the secondary outcome was clinical related non-major bleeding (CRNMB), according to International Society on Thrombosis and Hemostasis (ISTH) criteria (22). A prespecified form was used to extract data with the following items: study characteristics, patient demographics and clinical characteristics, data on recurrent VTE, major bleeding and CRNMB. The methodological quality of included RCTs was evaluated according to Cochrane Collaboration Risk of Bias Tool (23). Because OSs have a higher risk of bias than RCTs, several important factors in design and methods have been considered to mitigate bias when comparing study outcomes between DOAC and comparator in OS (24). Low, moderate, or high risk of bias was allocated to each citation within the following items: (I) use of adjusted method to deal with selection bias; (II) potential for residual confounding; (III) use of methods to handle time-varying covariates and information censoring, and (IV) reporting detailed baseline characteristics and outcome measures.

Data analysis

Forest plots were used to measure the primary and secondary outcomes for included OSs and RCTs. Relative risks (RRs) and their 95% CI were calculated using random-effects models. Statistical heterogeneity was assessed using I² test, and a value of >50% represented considerable heterogeneity (25). Subgroup analyses were thereafter conducted on the basis of individual DOACs (rivaroxaban, dabigatran, apixaban, edoxaban), bleeding types (fatal, intracranial, gastrointestinal, urogenital bleeding), comparison (VKAs and LMWH), and follow-up duration (≤6 and >6 months). Finally, interaction analyses were used to assess the comparability between OSs and RCTs. In addition, to test the robustness of primary results, series sensitivity analyses were performed by sequential eliminating each study from the pool, merging OSs and RCTs simultaneously, or using adjusted effective size as the measurement. Afterward, interaction analyses were also used to compare the difference between result of sensitivity analyses and result of primacy analyses. Publication bias was evaluated by visual funnel plots and quantitative Egger’s test if available (21). All the Statistics were performed employing STATA software (version13, Statacorp, College Station, Texas, USA), and a P value of <0.05 indicated a statistically significant difference.

Results

Search results and study evaluation

The initial search yielded 1,754 records, among them 1,720 records were excluded by screening titles and abstracts. The remaining 34 full-text articles were reviewed and 16 articles were excluded for reasons listed in Figure 1 and Table S2. Finally, a total of 18 studies involving 37,744 CAT patients met the inclusion criteria (16,17,26-41); 10 were OSs (5 for rivaroxaban and 5 for DOACs) and 8 were RCTs (3 for rivaroxaban; 2 for dabigatran; 2 for edoxaban; and 1 for apixaban); 35,142 patients (8,855 with DOACs and 26,287 with conventional anticoagulants) in OSs and 2,602 patients (1,338 with DOACs and 1,264 with conventional anticoagulants) in RCTs were included. Table 1 showed the characteristics of OSs. All of included OSs were conducted in the USA and follow-up duration wildly ranged from 3 to 12 months. The characteristics of RCTs were outlined in Table 2. The publication period ranged from 2010 to 2018, with the up-to-date Hokusai VTE Cancer and SELECT-D trials published in 2018. Detailed patients and clinical characteristics were summarized in Tables S3,S4. As shown in Table 3, baseline characteristic was comparable between included OSs and RCTs (P>0.05 for each characteristic). No high-risk bias tool items were detected in OSs (Table 4). The included RCTs satisfied all bias tool items except for 4 open-label trials (Table 5). Thus, the included studies were of modest to high quality.

Figure 1 Flow diagram for the selection of eligible studies. VTE, venous thromboembolism; DOACs, direct oral anticoagulants; RCTs, randomized controlled trials.

Table S2 Excluded studies with reasons
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Table 1 Characteristics of included observational studies
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Table 2 Characteristics of included RCTs
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Table S3 Patient demographics and clinical characteristics of observational studies
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Table S4 Patient demographics and clinical characteristics of RCTs
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Table 3 Baseline characteristic of observational studies and included RCTs
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Table 4 Quality assessment of observational studies
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Table 5 Quality assessment of RCTs
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Comparison of recurrent VTE and bleeding risk between OSs and RCTs

The incidence of recurrent VTE was 12.3% (613/4,990) after pooling 10 OSs data: 10.8% (252/2,339) in DOACs group and 13.6% (361/2,651) in conventional anticoagulants group, indicating a lower risk of recurrent VTE in patients allocated to DOACs than those assigned to conventional anticoagulants (RR: 0.74, 95% CI: 0.63–0.86, I²: 0%). Similarly, decreased risk of VTE recurrence was found in RCTs (RR: 0.65, 95% CI: 0.49–0.86; I²: 0%). No significant difference for recurrent VTE was observed between OSs and RCTs (P_interaction: 0.42) (Figures 2A,S1,S2). As for individual DOACs, rivaroxaban (RR: 0.73, 95% CI: 0.63–0.86, I²: 0% for OSs; RR: 0.51, 95% CI: 0.27–0.97, I²: 0% for RCTs; P_interaction: 0.24) and edoxaban (RR: 0.68, 95% CI: 0.47–0.98, I²: 0% for RCTs) conferred a lower risk of recurrent VTE in CAT patients (Figures 2A,S3,S4). Regarding major bleeding risk, 35,142 patients from 10 OSs were included, amongst them 4.4% (393/8,855) of DOACs users and 4.8% (1,266/26,287) of conventional anticoagulants users experienced major bleeding, with a similar risk between DOACs and conventional anticoagulants (RR: 0.90, 95% CI: 0.76–1.07, I²: 24.0%). The result of RCTs was in line with that from OSs (RR: 1.17, 95% CI: 0.72–1.88, I²: 26.2%). The difference for major bleeding between OSs and RCTs was not significant (P_interaction: 0.38) (Figures 2B,S5,S6). With regards to individual DOACs, rivaroxaban appeared at similar risk of major bleeding (RR: 1.18, 95% CI: 0.92–1.52, I²: 0% for OSs; RR: 0.98, 95% CI: 0.27–3.53, I²: 67.2% for RCTs; P_interaction: 0.80), whereas edoxaban might associated with an increased risk of major bleeding (RR: 1.69, 95% CI: 1.04–2.77, I²: 0% for RCTs) (Figures 2B,S7,S8). Likewise, patients receiving DOACs carried a similar risk of CRNMB compared to those taking conventional anticoagulants (RR: 1.73, 95% CI: 1.16–2.57, I²: 0% for OSs; RR: 1.17, 95% CI: 0.76–1.78, I²: 66.9% for RCTs; P_interaction: 0.21) (Figure 2B,S9,S10).

Figure 2 (A) Risk of recurrent VTE by DOACs and individuals and (B) risk of bleeding by DOACs and individuals. VTE, venous thromboembolism; DOACs, direct oral anticoagulants; RCTs, randomized controlled trials; OSs, observational studies; MB, major bleeding; CRNMB, clinical related non-major bleeding; RR, relative risk; No., number of included studies.

Figure S1 Recurrent VTE of OSs. VTE, venous thromboembolism; OSs, observational studies.

Figure S2 Recurrent VTE of RCTs. VTE, venous thromboembolism; RCTs, randomized controlled trials.

Figure S3 Recurrent VTE by drugs (OSs). VTE, venous thromboembolism; OSs, observational studies.

Figure S4 Recurrent VTE by drugs (RCTs). VTE, venous thromboembolism; RCTs, randomized controlled trials.

Figure S5 Major bleeding of OSs. OSs, observational studies.

Figure S6 Major bleeding of RCTs. RCTs, randomized controlled trials.

Figure S7 Major bleeding by drugs (OSs). OSs, observational studies.

Figure S8 Major bleeding by drugs (RCTs). RCTs, randomized controlled trials.

Figure S9 Clinical relative non-major bleeding of OSs. OSs, observational

Figure S10 Clinical relative non-major bleeding of RCTs. RCTs, randomized controlled trials.

Comparison of major bleeding types between OSs and RCTs

Further analysis on the types of major bleeding were summarized in Figures 3,S11,S12. Data from OSs and RCTs showed a similar risk of fatal bleeding (RR: 3.33, 95% CI: 0.68–16.26 for OSs; RR: 0.20, 95% CI: 0.01–4.17 for RCTs) as well as risk of urogenital bleeding (RR: 0.72, 95% CI: 0.37–1.39, I²: 0% for OSs; RR: 6.14, 95% CI: 0.72–52.4, I²: 0% for RCTs) in patients with DOACs versus conventional anticoagulants. No significant difference of the treatment effect estimates was found between OSs and RCTs (P_interaction: 0.45 for fatal bleeding; P_interaction: 0.68 for urogenital bleeding). Merged result from OSs showed that DOACs associated with reduced risk of intracranial bleeding (RR: 0.59, 95% CI: 0.38–0.91, I²: 0%). By contrast, after summing 2 RCTs, patients allocated to DOACs significantly increased the risk of major gastrointestinal bleeding (GIB) when compared to conventional anticoagulants (RR: 2.77, 95% CI: 1.35–5.68, I²: 0%).

Figure 3 Risk of major bleeding by types. RCTs, randomized controlled trials; OSs, observational studies; RR, relative risk; No., number of included studies.

Figure S11 Major bleeding by bleeding type (OSs). OSs, observational studies.

Figure S12 Major bleeding by bleeding type (RCTs). RCTs, randomized controlled trials.

Recurrent VTE and major bleeding risk based on comparators and follow-up

Similar with the primacy results, reduced risk of recurrent VTE was also observed in patients receiving DOACs versus warfarin (RR: 0.75, 95% CI: 0.61–0.93, I²: 0% for OSs; RR: 0.66, 95% CI: 0.39–1.11, I²: 0% for RCTs; P_interaction: 0.65) or versus LMWH (RR: 0.72, 95% CI: 0.58–0.89, I²: 0% for OSs; RR: 0.64, 95% CI: 0.46–0.91, I²: 0% for RCTs; P_interaction: 0.57) (Figures 4A,S13,S14). Regarding major bleeding, 2 RCTs involving 1,452 patients were identified, and the incidence of major bleeding was 6.48% (47/725) in DOACs group compared to 3.71% (27/727) in LMWH group, indicating increased risk between DOACs and LMWH (RR: 1.75, 95% CI: 1.10–2.77, I²: 0%). Nevertheless, compared with warfarin, data from OSs showed that DOACs were at decreased risk of major bleeding (RR: 0.79, 95% CI: 0.67–0.92, I²: 0%) (Figures 4B,S15,S16). In terms of different follow-up duration, decreased risk of VTE recurrence of DOACs versus conventional anticoagulants was found in both short-term follow up (RR: 0.71, 95% CI: 0.43–1.17, I²: 0% for OSs; RR: 0.59, 95% CI: 0.35–1.00, I²: 0% for RCTs; P_interaction: 0.63) and long-term follow up (RR: 0.70, 95% CI: 0.42–1.17, I²: 0% for OSs; RR: 0.67, 95% CI: 0.48–0.95, I²: 0% for RCTs; P_interaction: 0.89). Also, no significant difference for major bleeding between OSs and RCTs was found in short-term follow up subgroup (P_interaction: 0.52) and long-term follow up subgroup (P_interaction: 0.67) (Figures 4,S17-S20).

Figure 4 (A) Risk of recurrent VTE by comparison and follow-up and (B) risk of major bleeding by comparison and follow-up. LMWH, low molecular-weight heparins; RCTs, randomized controlled trials; OSs, observational studies; RR, relative risk; No., number of included studies.

Figure S13 Recurrent VTE by comparison (OSs). VTE, venous thromboembolism; OSs, observational studies.

Figure S14 Recurrent VTE by comparison (RCTs). VTE, venous thromboembolism; RCTs, randomized controlled trials.

Figure S15 Major bleeding by comparison (OSs). OSs, observational studies.

Figure S16 Major bleeding by comparison (RCTs). RCTs, randomized controlled trials.

Figure S17 Recurrent VTE by follow-up (OSs). VTE, venous thromboembolism; OSs, observational studies.

Figure S18 Recurrent VTE by follow-up (RCTs). VTE, venous thromboembolism; RCTs, randomized controlled trials.

Figure S19 Major bleeding by comparison (OSs). OSs, observational studies.

Figure S20 Major bleeding by follow-up (RCTs). RCTs, randomized controlled trials.

Sensitivity analysis and publication bias

Sensitivity analyses failed to identify any individual trial as having influenced the primacy outcome (Tables S5,S6). Also, further analyses by pooling OSs and RCTs (VTE outcome: P_interaction=0.79 for comparing with OSs; P_interaction=0.51 for comparing with RCTs; major bleeding outcome: P_interaction=0.56 for comparing with OSs; P_interaction=0.52 for comparing with RCTs) or using adjusted effective size as the measurement (VTE outcome: P_interaction=0.74 for comparing with OSs; major bleeding outcome: P_interaction=0.62 for comparing with OSs) robust the primary results (Table S7). Funnel plot was not performed as the limited number of included studies for OSs (10 studies) and RCTs (8 trials).

Table S5 Sensitivity analysis of OSs and RCTs in recurrent VTE
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Table S6 Sensitivity analysis of OSs and RCTs in major bleeding
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Table S7 Sensitivity analysis by pooling OSs and RCTs, and using adjusted effective size as the measurement
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Discussion

To our best knowledge, present study is the first to evaluate the effectiveness and safety of DOACs versus conventional anticoagulants in CAT patients between OSs and RCTs. No significant difference in estimates for benefit outcome and safety outcome between OSs and RCTs was observed. Merged results from 10 OSs and 8 RCTs validated the reduced risk of VTE recurrence and comparable risk of major bleeding between patients receiving DOACs and conventional anticoagulants. Furthermore, it is worth noting that DOACs might associated with lowered risk of intracranial bleeding but increased risk of major GIB when compared to conventional anticoagulants.

Prior several systematic review and meta-analysis have assessed the benefits and harms of DOACs in patients with cancer, revealing that the use of DOACs conferred the similar risk of recurrent VTE and major bleeding when compared to conventional anticoagulants (9-15). However, these studies had limited value because of the inclusion of only minor proportion of cancer patients from phase III trials, therefore inevitably leading to the insufficient sample size estimation for the reduced risk of recurrent VTE from 3% to 5%. In 2018, an updated meta-analysis of 8 RCTs, including latest Hokusai VTE Cancer trial, reported a significantly reduced risk of VTE recurrence in cancer patients with DOACs versus conventional anticoagulants, without increasing risk of major bleeding (42). While Li and colleagues recently reported an opposite result to previous meta-analysis (43). Another emerging RCTs (SELECT-D trial) that directly compared rivaroxaban to dalteparin were also involved. The investigators emphasized that patients treated with DOACs were at lower risk of recurrent VTE but at higher risk of major bleeding than those assigned to LMWH (43). Given the above limitation and controversial results, it is necessary to reassess this issue by a rigorous method.

It is well-known that RCTs and their meta-analyses represent the highest quality of evidence. Whereas, the stringent inclusion and exclusion criteria of RCTs might lead to the enrollment of population with relatively low risk of VTE and bleeding when on anticoagulants, thus inevitably restricting the generalizability of results. On the contrary, OSs could enroll more representative patients than RCTs and provide more crucial evidence for the benefits and risks of an intervention, especially when there are gaps in evidence from RCTs (44). Thus, a comprehensive analysis of RCTs and OSs data would provide more robust evidence on drug efficacy and safety. In current study, we have collected all available evidences from 10 OSs and 8 RCTs to simultaneously evaluate the risk of recurrent VTE and major bleeding on DOACs, and perceived sources of heterogeneity were addressed by prior designed subgroup analyses. Patients characteristic and distribution of cancer types were comparable between OSs and RCTs. The pooled result from OSs was consistent with those from RCTs, thereby validating the reduced risk of recurrent VTE in CAT patients with DOACs versus conventional anticoagulants. Remarkably, the consistent results from OSs and RCTs conformed the conclusion of comparable risk of major bleeding between DOACs and conventional anticoagulants, which presented controversial in previous meta-analysis (42,43).

As the serious medical condition, intracranial bleeding and GIB, has always been the main focus because they are the most frequent cause of major bleeding, mortality, as well as enormous burden on global health care utilization (45,46). Current evidence has confirmed that DOACs use significantly reduced the risk of intracranial bleeding compared to warfarin in patients with atrial fibrillation (47). In present study, CAT patients treated with DOACs were also associated with decreased risk of intracranial bleeding, but at the expense of increase in the risk of major GIB. Given a variability of intracranial bleeding and GIB risk, screening for the risk of GIB should be considered before initiating anticoagulant therapy.

Regarding different comparators, patients receiving DOACs carried a decreased risk of recurrent VTE compared to those taking warfarin or LMWH. For major bleeding, our results from OSs documented that DOACs lowered the risk of major bleeding than warfarin, which might be explained by frequent interactions between warfarin and anticancer agents (including chemotherapeutic and immunosuppressive agents) and the poor control of time in therapeutic range (TTR) of warfarin in real world practice (48). By contrast, compared to LMWH, DOACs seems to be associated with a higher risk of major bleeding. The positive result was derived mainly from two latest RCTs that compared DOACs with dalteparin (Hokusai VTE Cancer and SELECT-D trial), which indicated that DOACs decreased the rate of recurrent VTE at the expense of more major GIB bleeding (16,17). As the limited number of included studies, more RCTs and OSs are warranted to make definitive conclusions about the latter association.

To date, trials of head-to-head comparison between edoxaban/rivaroxaban and LMWH have been published. Due to the importance in field of CAT, growing trials related to other individual DOACs, including one for dabigatran (NCT03240120) and five for apixaban (NCT03692065, NCT02581176, NCT02366871, NCT02585713 and NCT03045406), are also actively underway. These ongoing RCTs will further our understanding of the optimal anticoagulation approach to management of VTE in cancer patients.

Several limitations should be addressed in our study. Firstly, among 8 RCTs, only two (Hokusai VTE Cancer and SELECT-D trials) were especially designed to assess VTE and bleeding risk of DOACs in patients with cancer. Therefore, the difference in the baseline characteristics in patients with DOACs and VKAs/LMWH could not be excluded. Secondly, unlike RCT, OS has a high risk of bias due to unmeasured confounders or inadequate control for measured confounders, and only two included OSs provided the adjusted data by using authorized method to minimize confounding. Thirdly, half of included OSs was not especially designed to assess the individual DOACs in patients with CAT. Fourthly, we have not got access to patient-level data in relation to the type, the stage or the location of cancer, making powerful subgroup analysis unavailable. Finally, we did not have the resources to review the non-English articles. However, we included studies identified in a comprehensive search of broad databases and are confident that this study covered the majority of studies in these special patients.

Conclusions

In summary, effectiveness and safety of DOACs versus conventional anticoagulants in CAT from OSs are in agreement with those from RCTs, confirming the reduced risk of recurrent VTE and similar risk of major bleeding between CAT patients receiving DOACs compared with those taking conventional anticoagulants. Furthermore, the use of DOACs might associated with lowered risk of intracranial bleeding but increased risk of major GIB. This discrepancy might be used to select oral anticoagulant regimen.

Acknowledgments

Funding: This study was funded by Research Funds of Shanghai Health and Family Planning commission (20184Y0022), Cultivation fund of clinical research of Renji hospital (PY2018-III-06), Clinical Pharmacy Innovation Research Institute of Shanghai Jiao Tong University School of Medicine (CXYJY2019ZD001, CXYJY2019QN004), and Program for Key but Weak Disciplines of Shanghai Municipal Commission of Health and Family Planning (2016ZB0304).

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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