Direct oral anticoagulants vs LMWH for cancer-associated thrombosis - updated evidence on bleeding risk, recurrence and patient-reported outcomes: A systematic review

Table 1 Characteristics of included studies

Ref.	Design	N	Population	Patient characteristics	Intervention	Comparator	Primary outcome	Key findings
Agnelli et al[4], 2020	RCT	1155	Cancer patients with VTE	Active cancer, mixed tumor types	Apixaban 10 mg BID × 7 days, then 5 mg BID	Dalteparin 200 IU/kg daily	Recurrent VTE or major bleeding	Non-inferiority demonstrated; higher bleeding in GI/GU cancers
McBane et al[6], 2020	RCT	300	Active malignancy with VTE	Predominantly solid tumors	Apixaban 10 mg BID × 7 days, then 5 mg BID	Dalteparin 200 IU/kg daily	Major bleeding	Similar efficacy; increased bleeding risk with apixaban
Raskob et al[8], 2018	RCT	1050	Cancer-associated VTE	Mixed cancer types, active disease	Edoxaban 60 mg daily	Dalteparin 200 IU/kg daily	Composite of VTE recurrence or major bleeding	Non-inferiority shown; higher bleeding with edoxaban
Young et al[10], 2018	RCT	406	Cancer patients with VTE	Mixed solid tumors	Rivaroxaban 15 mg BID × 21 days, then 20 mg daily	Dalteparin 200 IU/kg daily	VTE recurrence	Reduced VTE recurrence; increased bleeding risk
Marshall et al[5], 2020	RCT	406	Cancer patients with VTE	12-month follow-up of SELECT-D	Rivaroxaban vs placebo	Dalteparin	VTE recurrence	Sustained VTE reduction; persistent bleeding concern
Planquette et al[7], 2022	RCT	370	Cancer-associated thrombosis	Mixed cancer types	Rivaroxaban 15 mg BID × 21 days, then 20 mg daily	Dalteparin 200 IU/kg daily	Net clinical benefit	Effective VTE prevention; bleeding concerns in GI cancers
Lee et al[29], 2003	RCT	672	Cancer patients with VTE	Mixed cancer types	Dalteparin	Warfarin	VTE recurrence	LMWH superior to warfarin in cancer patients
Lee et al[2], 2015	RCT	900	Active cancer with VTE	Mixed tumor types	Tinzaparin	Warfarin	VTE recurrence	Tinzaparin effective vs warfarin
Schrag et al[9], 2023	RCT	671	Cancer patients with VTE	Real-world population	DOACs (mixed)	LMWH	VTE recurrence	Comparable effectiveness in broader population
Hull et al[27], 2006	RCT	200	Proximal VTE with cancer	Mixed cancer types	Long-term LMWH	Usual care	VTE recurrence	Long-term LMWH beneficial
Deitcher et al[30], 2006	RCT	102	Active cancer with VTE	Mixed solid tumors	Enoxaparin alone	Enoxaparin→Warfarin	VTE recurrence	LMWH alone superior to transition
Riess et al[23], 2015	RCT	200	Cancer patients with VTE	German population	Rivaroxaban	LMWH	Patient satisfaction	Improved satisfaction with rivaroxaban
Di Nisio et al[21], 2019	Post-hoc RCT	1050	Cancer patients with VTE	Extended treatment analysis	Edoxaban	Dalteparin	Extended treatment outcomes	Benefits maintained with extended treatment
Mulder et al[22], 2020	Post-hoc RCT	1050	Different cancer types	Cancer type-specific analysis	Edoxaban	Dalteparin	Cancer type-specific outcomes	Variable outcomes by cancer type
Kraaijpoel et al[24], 2018	Post-hoc RCT	1050	Cancer patients with bleeding	Bleeding impact analysis	Edoxaban	Dalteparin	Clinical impact of bleeding	Bleeding events clinically significant
Coleman et al[13], 2023	Observational	7441	Cancer-associated VTE	Real-world cohort	Rivaroxaban	LMWH	Effectiveness and safety	Comparable real-world effectiveness
Kang et al[14], 2024	Observational	15656	Cancer-associated VTE	Switching patterns analysis	Continuous LMWH vs switch to DOAC	LMWH	Safety of switching	Continuous LMWH safer than switching
Carney et al[16], 2021	Observational	121	Cancer with thrombocytopenia	Thrombocytopenic patients	DOACs	LMWH	Bleeding in thrombocytopenia	Increased bleeding risk in both groups
Weitz et al[15], 2020	Registry	1162	Cancer-associated thrombosis	Global registry data	Variable DOACs	LMWH	Real-world treatment patterns	Geographic variations in treatment
Guo et al[26], 2020	Observational	18223	Cancer-associated thrombosis	US treatment patterns	DOACs	LMWH	Treatment patterns and costs	Economic implications of treatment choice
Farge et al[11], 2018	Observational	365	Cancer patients on LMWH	Quality of life study	LMWH	N/A	Quality of life	Significant QoL burden with LMWH
Schaefer et al[12], 2021	Observational	3139	Cancer-associated thrombosis	Adherence comparison	DOACs	LMWH	Medication adherence	Improved adherence with DOACs
Caroti et al[25], 2023	Observational	2071	Lower bleeding risk CAT	DOAC comparison	Rivaroxaban vs Apixaban	N/A	DOAC safety comparison	Similar safety between DOACs
Lee et al[17], 2019	Observational	84	Lung cancer with VTE	Lung cancer-specific	Rivaroxaban	Dalteparin	Efficacy and safety	Effective in lung cancer patients
Benzidia et al[19], 2022	Observational	95	Cancer patients with VTE	Multidisciplinary care	Various anticoagulants	Standard care	Care program effectiveness	Improved outcomes with coordinated care
Pelzer et al[28], 2014	Pilot	312	Pancreatic cancer	Pancreatic cancer-specific	Heparin with chemotherapy	Standard care	Safety and feasibility	Feasible in pancreatic cancer
How et al[18], 2024	Observational	486	Myeloproliferative neoplasms	Splanchnic vein thrombosis	Various anticoagulants	Variable	Management in MPN	Specialized considerations for MPN
Font et al[20], 2023	Observational	287	Cancer-associated VTE	Multinational study	Various anticoagulants	Variable	Adherence and QoL	International perspective on outcomes
Zabeida et al[31], 2023	Observational	146	Pediatric COVID-19	Children with coagulopathy	Anticoagulation	Variable	COVID-associated coagulopathy	Pediatric coagulation considerations

COVID-19: Coronavirus disease 2019; RCT: Randomized controlled trial; VTE: Venous thromboembolism; BID: Twice daily; GI: Gastrointestinal; GU: Genitourinary; LMWH: Low molecular weight heparin; DOAC: Direct oral anticoagulant; QoL: Quality of life; MPN: Myeloproliferative neoplasm; CAT: Cancer-associated thrombosis; N/A: Not applicable.

Table 2 Quality assessment for randomized controlled trials (Cochrane risk of bias tool)

Ref.	Randomization process	Deviations from intended interventions	Missing outcome data	Measurement of outcomes	Selection of reported results	Overall risk of bias
Agnelli et al[4]	Low	Some concerns	Low	Low	Low	Some concerns
McBane et al[6]	Low	Some concerns	Low	Low	Low	Some concerns
Raskob et al[8]	Low	Some concerns	Some concerns	Low	Low	Some concerns
Young et al[10]	Low	Some concerns	Low	Low	Low	Some concerns
Marshall et al[5]	Low	Some concerns	Low	Low	Low	Some concerns
Planquette et al[7]	Low	Some concerns	Low	Low	Low	Some concerns
Lee et al[29]	Low	Low	Low	Low	Low	Low
Lee et al[2]	Low	Low	Some concerns	Low	Low	Some concerns
Schrag et al[9]	Low	Some concerns	Low	Low	Low	Some concerns
Hull et al[27]	Some concerns	Some concerns	Some concerns	Low	Low	Some concerns
Deitcher et al[30]	Some concerns	High	Some concerns	Low	Low	High
Riess et al[23]	Some concerns	Some concerns	Low	Some concerns	Low	Some concerns
Di Nisio et al[21]	Low	Some concerns	Low	Low	Low	Some concerns
Mulder et al[22]	Low	Some concerns	Low	Low	Low	Some concerns
Kraaijpoel et al[24]	Low	Some concerns	Low	Low	Low	Some concerns

Low: Low risk of bias; Some concerns: Some concerns about bias; High: High risk of bias.

Table 3 Quality assessment for observational studies (Newcastle-Ottawa Scale)

Ref.	Selection (4 points)	Comparability (2 points)	Outcome (3 points)	Total score	Quality rating
Coleman et al[13]	4	2	3	9/9	High
Kang et al[14]	4	2	3	9/9	High
Carney et al[16]	3	1	2	6/9	Moderate
Weitz et al[15]	4	2	3	9/9	High
Guo et al[26]	4	1	3	8/9	High
Farge et al[11]	3	1	2	6/9	Moderate
Schaefer et al[12]	4	2	3	9/9	High
Caroti et al[25]	3	2	3	8/9	High
Lee et al[17]	2	1	2	5/9	Moderate
Benzidia et al[19]	2	1	2	5/9	Moderate
Pelzer et al[28]	2	1	2	5/9	Moderate
How et al[18]	3	1	3	7/9	High
Font et al[20]	3	2	2	7/9	High
Zabeida et al[31]	2	1	2	5/9	Moderate

Quality ratings: High = 7-9 points; Moderate = 4-6 points; Low = 0-3 points.