Direct Oral Anti-Coagulants compared to Dalteparin for treatment of Cancer Associated Thrombosis: A Living, Interactive Systematic Review and Network Meta-Analysis

We have maintained a living systematic review and network meta-analysis for treatment of cancer associated thrombosis (CAT) since our original publication in 2019. This current update includes results from CASTA-DIVA and CANVAS clinical trials. The results of ongoing trials - PRIORITY (NCT03139487) and CONKO-011(NCT02583191) are pending and will be considered for addition to living analysis as they become available.


INTERACTIVE, MODIFIED PRISMA

Search strategy is developed in consultation with an information specialist. Search strategy is implemented through PubMed and OVID (Medline, Embase, Cochrane Central Register of Controlled trials) search engines to constantly strategy to maintain a “living search” The numbers in the flowsheet are dynamically updated as new studies are considered for inclusion. Red limb on the right side of the flowsheet represent the living updates. Users can click the colored boxes for additional details.

How to use this flowsheet? Video demonstration


INTERACTIVE TABLE

Interactive table summarizes study characteristics, population characteristics and results from the clinical trials included in systematic review and meta-analysis. This table will be dynamically updated as new studies are included in this living review. Users can choose to visualize the studies with certain characteristics (using filters) or interactively construct the results table from the available menu.

How to use this table? Video demonstration


PAIRWISE META-ANALYSIS

Results are summarized as forest plots for primary analysis, sensitivity analysis and subgroup analysis.
Users can use dropdown (select outcome) to select the outcome of interest.


Primary Analysis


Sensitivity Analysis


Subgroup Analysis


NETWORK META-ANALYSIS

Results are summarized in league tables, interactive forest plots, SUCRA curves and Ranking for each clinically important outcome. Forest Plots are interactive, choose the reference treatment (select reference treatment) for relevant clinical decision making.



SUMMARY OF FINDINGS: PAIRWISE META-ANALYSIS

A Summary of Findings (SoF) table is designed to summarize the key results of a pairwise meta-analysis and to evaluate your confidence in the estimates of effect. The table summarizes the results for patient important outcomes for patients receiving direct acting anti-coagulant (DOACs) as compared to low molecular weight heparin (LMWH). User can interactively select or deselect SoF for a given clinical outcome by clicking the options in the outcome list (panel on left). The first click selects the clinical outcome and second select deselects the clinical outcome.

Choose measure of effect and denominator for absolute effect.


SUMMARY OF FINDINGS: NETWORK META-ANALYSIS

A Summary of Findings (SoF) table is designed to display multiple comparisons in an interactive manner. All possible combinations in network meta-analysis can be compared using this framework. User can interactively select or deselect SoF for a given clinical outcome by clicking the options in the outcome list (panel on left). The first click selects the clinical outcome and second select deselects the clinical outcome.

Choose comparator (reference treatment), measure of effect, and denominator for absolute effect


EVIDENCE MAPS

Evidence map is a visual depiction of evidence which presents synthesized data in user friendly illustration (figures or graphs) facilitating evidence based clinical guidelines, policies and decisions, and identifying evidence gaps that warrant future research.


Evidence Map comparing DOACs vs LMWH using standard method

Evidence map summarizing benefits of direct oral anticoagulants compared to dalteparin.

Outcomes Recurrent venous thromboembolism Major bleeding Clinically relevant non-major bleeding Net clinical benefit Mortality Major gastrointestinal bleeding Major genitourinary bleeding Intracranial bleeding Fatal bleeding
DOACs vs Dalteparin 4 4 4 4 4 3 3 2 2
Certainty of Evidence
Method: REM using DerSimonian and Laird (DS)
(n=number of studies included in analysis)
n High
Significant Harm n Moderate
No Significant Effect n Low
Significant Benefit n Very Low

Evidence Map comparing DOACs vs LMWH using different random effects methods

Evidence map illustrating the influence of choice of Random effects model on significance of results.

Arms Method Recurrent venous thromboembolism Major bleeding Clinically relevant non-major bleeding Net clinical benefit Mortality Major gastrointestinal bleeding Major genitourinary bleeding Intracranial bleeding Fatal bleeding
DOACs vs Dalteparin DL 4 4 4 4 4 3 3 2 2
DL with HK adjustment 4 4 4 4 4 3 3 2 2
SJ 4 4 4 4 4 3 3 2 2
SJ with HK adjustment 4 4 4 4 4 3 3 2 2
REML with HK adjustment 4 4 4 4 4 3 3 2 2
  Significant Harm No Significant Effect Significant Benefit  
  Certainty of Evidence
Method: Random effects model
Tau2 estimator: DerSimonian and Laird (DL)
Adjustment: None
(n=number of studies included in analysis) 		Certainty of Evidence
Method: Random effects model
Tau2 estimator: DerSimonian and Laird (DL)
Adjustment: Hartung-Knapp (HK)
(n=number of studies included in analysis) 		Certainty of Evidence
Method: Random effects model
Tau2 estimator: Sidik-Jonkman (SJ)
Adjustment: None
(n=number of studies included in analysis) 		Certainty of Evidence
Method: Random effects model
Tau2 estimator: Sidik-Jonkman (SJ)
Adjustment: Hartung-Knapp (HK)
(n=number of studies included in analysis) 		Certainty of Evidence
Method: Random effects model
Tau2 estimator: Restricted Maximum Likelihood (REML)
Adjustment: Hartung-Knap (HK)
(n=number of studies included in analysis)
n High n High n High n High n High
n Moderate n Moderate n Moderate n Moderate n Moderate
n Low n Low n Low n Low n Low
n Very Low n Very Low n Very Low n Very Low n Very Low

Evidence map comparing all individual drugs

Evidence map illustrating benefits and harms of individual direct oral anticoagulants and dalteparin as compared to each other.

Outcomes Recurrent venous thromboembolism Major bleeding Clinically relevant non-major bleeding Net clinical benefit Mortality   Certainty of Evidence
Apixaban vs Dalteparin 4 4 4 4 4 n High
Apixaban vs Edoxaban 4 4 4 4 4 n Moderate
Apixaban vs Rivaroxaban 4 4 4 4 4 n Low
n Very Low
Edoxaban vs Dalteparin 4 4 4 4 4 n=number of studies included in the analysis
Edoxaban vs Apixaban 4 4 4 4 4
Edoxaban vs Rivaroxaban 4 4 4 4 4
 
Rivaroxaban vs Dalteparin 4 4 4 4 4 Significant Harm
Rivaroxaban vs Apixaban 4 4 4 4 4 No Significant Effect
Rivaroxaban vs Edoxaban 4 4 4 4 4 Significant Benefit

PUBLICATIONS

Direct Oral Factor Xa Inhibitors for the Treatment of Acute Cancer-Associated Venous Thromboembolism: A Systematic Review and Network Meta-analysis. Mayo Clinic Proceedings. 2019 Dec; 94(12): 2444-2454.
Harry E Fuentes, Robert D McBane 2nd, Waldemar E Wysokinski, Alfonso J Tafur, Charles L Loprinzi, Mohammad H Murad, Irbaz Bin Riaz.
PMID: 31685262   DOI: 10.1016/j.mayocp.2019.05.035

Direct Oral Anticoagulants Compared With Dalteparin for Treatment of Cancer-Associated Thrombosis: A Living, Interactive Systematic Review and Network Meta-analysis. Mayo Clinic Proceedings. 2022 Feb; 97(2): 308-324.
Irbaz Bin Riaz, Harry E Fuentes, Syed Arsalan Ahmed Naqvi, Huan He, Qurat-Ul-Ain Riaz Sipra, Alfonso J Tafur, Leslie Padranos, Waldemar E Wysokinski, Ariela L Marshall, Per Olav Vandvik, Victor Montori, Alan H Bryce, Hongfang Liu, Robert G Badgett, Mohammad Hassan Murad, Robert D McBane 2nd.
PMID: 34172290   DOI: 10.1016/j.mayocp.2020.10.041