Anticoagulation for the long‐term treatment of venous thromboembolism in people with cancer

Lara A Kahale; Maram B Hakoum; Ibrahim G Tsolakian; Fadel Alturki; Charbel F Matar; Irene Terrenato; Francesca Sperati; Maddalena Barba; Victor ED Yosuico; Holger Schünemann; Elie A Akl

doi:10.1002/14651858.CD006650.pub5

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgments about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 1: All‐cause mortality (up to 6 months) (main analysis ‐ active cancer)

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Analysis 1.2

Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 2: All‐cause mortality (time‐to‐event)

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Analysis 1.3

Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 3: Recurrent venous thromboembolism (up to 6 months) (main analysis ‐ active cancer)

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Analysis 1.4

Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 4: Recurrent venous thromboembolism (time‐to‐event)

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Analysis 1.5

Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 5: Major bleeding (up to 6 months) (main analysis ‐ active cancer)

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Analysis 1.6

Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 6: Minor bleeding (up to 6 months) (main analysis ‐ active cancer)

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Analysis 1.7

Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 7: Thrombocytopenia (up to 6 months) (main analysis‐ active cancer)

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Analysis 2.1

Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 1: All‐cause mortality (6‐12 months)

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Analysis 2.2

Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 2: Recurrent venous thromboembolism (6‐12 months)

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Analysis 2.3

Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 3: Major bleeding (6‐12 months)

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Analysis 2.4

Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 4: Minor bleeding (6‐12 months)

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Analysis 3.1

Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 1: All‐cause mortality (6 months)

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Analysis 3.2

Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 2: Recurrent VTE (6 months)

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Analysis 3.3

Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 3: Major bleeding (6 months)

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Analysis 3.4

Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 4: Major GI bleeding (6 months)

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Analysis 3.5

Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 5: Major upper GI bleeding (6 months)

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Analysis 3.6

Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 6: Major lower GI bleeding (6 months)

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Analysis 3.7

Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 7: Major non‐GI bleeding (6 months)

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Analysis 3.8

Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 8: Minor bleeding (6 months)

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Analysis 3.9

Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 9: Minor GI bleeding (6 months)

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Analysis 3.10

Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 10: Minor upper GI bleeding (6 months)

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Analysis 3.11

Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 11: Minor lower GI bleeding (6 months)

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Analysis 3.12

Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 12: Minor non‐GI bleeding (6 months)

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Analysis 4.1

Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 1: All‐cause mortality (up to 6 months)

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Analysis 4.2

Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 2: Recurrent VTE (up to 6 months)

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Analysis 4.3

Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 3: Major bleeding (up to 6 months)

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Analysis 4.4

Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 4: Minor bleeding (up to 6 months)

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Summary of findings 1. Low molecular weight heparin secondary prophylaxis compared to vitamin K antagonist secondary prophylaxis in people with cancer with venous thromboembolism

Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Low molecular weight heparin secondary prophylaxis compared to vitamin K antagonist secondary prophylaxis in patients with cancer with venous thromboembolism
Population: People with cancer with venous thromboembolism Setting: Outpatient Intervention: LMWH secondary prophylaxis Comparison: VKA secondary prophylaxis
Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with VKA secondary prophylaxis	Risk difference with LMWH secondary prophylaxis
All‐cause mortality (main analysis ‐ active cancer) follow up: 6 months	1712 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.99 (0.88 to 1.12)	Study population
	1712 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.99 (0.88 to 1.12)	374 per 1,000	4 fewer per 1,000 (45 fewer to 45 more)
All‐cause mortality (time‐to‐event)	1243 (2 RCTs)	⊕⊕⊝⊝ LOW ^{2 3}	HR 0.94 (0.74 to 1.20)	Study population
All‐cause mortality (time‐to‐event)	1243 (2 RCTs)	⊕⊕⊝⊝ LOW ^{2 3}	HR 0.94 (0.74 to 1.20)	374 per 1,000	18 fewer per 1,000 (81 fewer to 56 more)
Recurrent venous thromboembolism (main analysis ‐ active cancer) follow up: 6 months	1712 (4 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 0.59 (0.44 to 0.80)	Study population
	1712 (4 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 0.59 (0.44 to 0.80)	124 per 1,000	51 fewer per 1,000 (69 fewer to 25 fewer)
Recurrent venous thromboembolism (time‐to‐event)	1243 (2 RCTs)	⊕⊕⊕⊝ MODERATE ³	HR 0.49 (0.31 to 0.78)	Study population
Recurrent venous thromboembolism (time‐to‐event)	1243 (2 RCTs)	⊕⊕⊕⊝ MODERATE ³	HR 0.49 (0.31 to 0.78)	124 per 1,000	61 fewer per 1,000 (84 fewer to 26 fewer)
Major bleeding (main analysis ‐ active cancer) follow up: 6 months	1712 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 2 4}	RR 1.09 (0.55 to 2.12)	Study population
	1712 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 2 4}	RR 1.09 (0.55 to 2.12)	43 per 1,000	4 more per 1,000 (19 fewer to 48 more)
Minor bleeding (main analysis ‐ active cancer) follow up: 6 months	1712 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 2 5}	RR 0.78 (0.47 to 1.27)	Study population
	1712 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 2 5}	RR 0.78 (0.47 to 1.27)	174 per 1,000	38 fewer per 1,000 (92 fewer to 47 more)
Thrombocytopenia (main analysis‐ active cancer) follow up: 6 months	138 (1 RCT)	⊕⊕⊝⊝ LOW ^{3 6}	RR 0.94 (0.52 to 1.69)	Study population
	138 (1 RCT)	⊕⊕⊝⊝ LOW ^{3 6}	RR 0.94 (0.52 to 1.69)	254 per 1,000	15 fewer per 1,000 (122 fewer to 175 more)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by one level due to serious risk of bias (allocation concealment unclear in one study, lack of blinding of participants and personnel in all the four studies, high risk of incomplete outcome data in one study, and high risk of selective reporting in one study). ² Downgraded by one level due to serious imprecision. Confidence interval includes suggests both potential harm and potential benefit. ³ Some concern with lack of blinding of patients and personnel. ⁴ Some concern with inconsistency. I2= 46% ⁵ Downgraded by one level due to serious inconsistency (I2= 78%) ⁶ Downgraded by two levels due to very serious imprecision. Confidence interval includes suggests both potential harm and potential benefit. Low number of events.

Summary of findings 1. Low molecular weight heparin secondary prophylaxis compared to vitamin K antagonist secondary prophylaxis in people with cancer with venous thromboembolism

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Summary of findings 2. Direct oral anticoagulant secondary prophylaxis compared to Vitamin K antagonist secondary prophylaxis in patients with active cancer with venous thromboembolism

Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Direct oral anticoagulant secondary prophylaxis compared to Vitamin K antagonist secondary prophylaxis in patients with active cancer with venous thromboembolism
Population: patients with active cancer with venous thromboembolism Setting: Outpatient Intervention: DOAC secondary prophylaxis Comparison: VKA secondary prophylaxis
Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Vitamin K antagonist (VKA) secondary prophylaxis	Risk difference with Direct oral anticoagulant (DOAC) secondary prophylaxis
All‐cause mortality follow up: range 6 months to 12 months	1060 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.94 (0.72 to 1.23)	Study population
All‐cause mortality follow up: range 6 months to 12 months	1060 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.94 (0.72 to 1.23)	171 per 1,000	10 fewer per 1,000 (48 fewer to 39 more)
Recurrent venous thromboembolism follow up: range 6 months to 12 months	1050 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 3}	RR 0.63 (0.34 to 1.15)	Study population
	1050 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 3}	RR 0.63 (0.34 to 1.15)	49 per 1,000	18 fewer per 1,000 (32 fewer to 7 more)
Major bleeding follow up: range 6 months to 12 months	1055 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.77 (0.39 to 1.53)	Study population
Major bleeding follow up: range 6 months to 12 months	1055 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.77 (0.39 to 1.53)	37 per 1,000	8 fewer per 1,000 (23 fewer to 20 more)
Minor bleeding follow up: range 6 months to 12 months	1055 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.83 (0.57 to 1.23)	Study population
Minor bleeding follow up: range 6 months to 12 months	1055 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.83 (0.57 to 1.23)	127 per 1,000	22 fewer per 1,000 (55 fewer to 29 more)
Thrombocytopenia ‐ not reported	‐	‐	‐	‐	‐
Health related quality of life follow up: range 3 months to 12 months	8485 (1 RCT)	⊕⊕⊕⊝ MODERATE ⁴	‐	Prins 2014 (EINSTEIN DVT‐PE; n=8485 ): "in the general population of the EINSTEIN studies, patient‐reported satisfaction and quality of life was better in the rivaroxaban‐treated patients than in the group treated with enoxaparin and vitamin K antagonist, although we have not yet examined whether this is the same in patients with active cancer. Hence, it can be expected that quality of life will also be improved with rivaroxaban compared with long‐term injected low molecular‐weight heparin." The tool used was validated measure of treatment satisfaction – the Anti‐Clot Treatment Scale (ACTS))
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Some concern with indirectness (study by Schulman et al (RECOVER I‐II) included patients with a diagnosis of cancer within five years before enrollment), however the weight of these studies was low and heterogeneity was very low. ² Downgraded by two levels due to very serious imprecision. Confidence interval suggests both potential benefit and potential harm. ³ Downgraded by two levels due to very serious imprecision. Confidence interval suggests both potential benefit and potential no effect. Low number of events. ⁴ Downgraded by one level for serious indirectness. The study by Prins and colleagues (Prins 2014 ( EINSTEIN n=8485)) reports health related quality of life for the whole study population, without providing data for the cancer subgroup

Summary of findings 2. Direct oral anticoagulant secondary prophylaxis compared to Vitamin K antagonist secondary prophylaxis in patients with active cancer with venous thromboembolism

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Summary of findings 4. Direct oral anticoagulant secondary prophylaxis compared to Low molecular weight heparin secondary prophylaxis in patients with cancer with venous thromboembolism

Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Direct oral anticoagulant secondary prophylaxis compared to Low molecular weight heparin secondary prophylaxis in patients with cancer with venous thromboembolism
Patient or population: patients with cancer with venous thromboembolism Setting: Outpatient Intervention: DOAC secondary prophylaxis Comparison: LMWH secondary prophylaxis
Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Low molecular weight heparin (LMWH) secondary prophylaxis	Risk difference with Direct oral anticoagulant (DOAC) secondary prophylaxis
All‐cause mortality follow up: mean 6 months	2854 (5 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.97 (0.83 to 1.14)	Study population
All‐cause mortality follow up: mean 6 months	2854 (5 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.97 (0.83 to 1.14)	248 per 1,000	7 fewer per 1,000 (42 fewer to 35 more)
Recurrent VTE follow up: mean 6 months	2854 (5 RCTs)	⊕⊕⊝⊝ LOW ^{1 3}	RR 0.63 (0.45 to 0.88)	Study population
Recurrent VTE follow up: mean 6 months	2854 (5 RCTs)	⊕⊕⊝⊝ LOW ^{1 3}	RR 0.63 (0.45 to 0.88)	87 per 1,000	32 fewer per 1,000 (48 fewer to 10 fewer)
Major bleeding follow up: mean 6 months	2994 (5 RCTs)	⊕⊕⊝⊝ LOW ^{1 4}	RR 1.20 (0.83 to 1.73)	Study population
Major bleeding follow up: mean 6 months	2994 (5 RCTs)	⊕⊕⊝⊝ LOW ^{1 4}	RR 1.20 (0.83 to 1.73)	35 per 1,000	7 more per 1,000 (6 fewer to 25 more)
Major GI bleeding follow up: mean 6 months	1838 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 4}	RR 1.16 (0.62 to 2.17)	Study population
Major GI bleeding follow up: mean 6 months	1838 (4 RCTs)	⊕⊕⊝⊝ LOW ^{1 4}	RR 1.16 (0.62 to 2.17)	20 per 1,000	3 more per 1,000 (8 fewer to 23 more)
Major upper GI bleeding follow up: mean 6 months	1838 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 5}	RR 1.18 (0.51 to 2.76)	Study population
Major upper GI bleeding follow up: mean 6 months	1838 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 5}	RR 1.18 (0.51 to 2.76)	11 per 1,000	2 more per 1,000 (5 fewer to 19 more)
Major lower GI bleeding follow up: mean 6 months	1838 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 5}	RR 1.10 (0.43 to 2.80)	Study population
Major lower GI bleeding follow up: mean 6 months	1838 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 5}	RR 1.10 (0.43 to 2.80)	9 per 1,000	1 more per 1,000 (5 fewer to 16 more)
Major non‐GI bleeding follow up: mean 6 months	1838 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 6}	RR 0.84 (0.42 to 1.68)	Study population
Major non‐GI bleeding follow up: mean 6 months	1838 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 6}	RR 0.84 (0.42 to 1.68)	19 per 1,000	3 fewer per 1,000 (11 fewer to 13 more)
Minor bleeding follow up: mean 6 months	2854 (5 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 1.58 (1.15 to 2.16)	Study population
Minor bleeding follow up: mean 6 months	2854 (5 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 1.58 (1.15 to 2.16)	67 per 1,000	39 more per 1,000 (10 more to 78 more)
Minor GI bleeding follow up: mean 6 months	1495 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{6 7 8}	RR 1.37 (0.41 to 4.64)	Study population
Minor GI bleeding follow up: mean 6 months	1495 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{6 7 8}	RR 1.37 (0.41 to 4.64)	25 per 1,000	9 more per 1,000 (15 fewer to 92 more)
Minor upper GI bleeding follow up: mean 6 months	1495 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{6 7 9}	RR 1.03 (0.04 to 25.97)	Study population
Minor upper GI bleeding follow up: mean 6 months	1495 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{6 7 9}	RR 1.03 (0.04 to 25.97)	11 per 1,000	0 fewer per 1,000 (10 fewer to 267 more)
Minor lower GI bleeding follow up: mean 6 months	1495 (2 RCTs)	⊕⊕⊝⊝ LOW ^{5 7}	RR 1.54 (0.72 to 3.27)	Study population
Minor lower GI bleeding follow up: mean 6 months	1495 (2 RCTs)	⊕⊕⊝⊝ LOW ^{5 7}	RR 1.54 (0.72 to 3.27)	15 per 1,000	8 more per 1,000 (4 fewer to 33 more)
Minor non‐GI bleeding follow up: mean 6 months	1495 (2 RCTs)	⊕⊕⊕⊝ MODERATE ^{7 10}	RR 2.37 (1.44 to 3.89)	Study population
Minor non‐GI bleeding follow up: mean 6 months	1495 (2 RCTs)	⊕⊕⊕⊝ MODERATE ^{7 10}	RR 2.37 (1.44 to 3.89)	31 per 1,000	42 more per 1,000 (14 more to 89 more)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by one level due to serious risk of bias. Allocation concealment was not reported in one study, lack of blinding of patients and personnel in all studies, and high risk of bias related to incomplete outcome data. ² Downgraded by one level due to serious imprecision. Confidence interval suggests both potential benefit and potential harm. ³ Downgraded by one level due to serious imprecision. Confidence interval suggests both potential benefit and potential no effect. ⁴ Downgraded by one level due to serious imprecision. Confidence interval suggests both potential harm and potential no effect. ⁵ Downgraded by two levels due to very serious imprecision. Confidence interval suggests both potential harm and potential no effect. Low number of events. ⁶ Downgraded by two levels due to very serious imprecision. Confidence interval suggests both potential harm and potential benefit. Low number of events. ⁷ Some concern with risk of bias. Lack of blinding of patients and personnel in both studies. ⁸ Downgraded by one level due to serious inconsistency (unexplained heterogeneity I2=64%) and due to some concern with risk of bias. ⁹ Downgraded by two levels due to very serious inconsistency (unexplained heterogeneity I2=74%.) and due to some concern with risk of bias. ¹⁰ Downgraded by one level due to serious imprecision. Low number of events.

Summary of findings 4. Direct oral anticoagulant secondary prophylaxis compared to Low molecular weight heparin secondary prophylaxis in patients with cancer with venous thromboembolism

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Summary of findings 5. Idraparinux secondary prophylaxis compared to vitamin K antagonist secondary prophylaxis in people with cancer with venous thromboembolism

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects (95% CI)**
Idraparinux secondary prophylaxis compared to VKA secondary prophylaxis in people with cancer with VTE
Population: people with cancer with VTE receiving secondary prophylaxis Setting: outpatient Intervention: idraparinux prophylaxis Control: VKA prophylaxis
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with VKA secondary prophylaxis	Risk difference with idraparinux secondary prophylaxis
All‐cause mortality follow‐up: mean 6 months	284 (1 RCT)	⊕⊕⊕⊝ Moderate^a	RR 1.11 (0.78 to 1.59)	Study population
All‐cause mortality follow‐up: mean 6 months	284 (1 RCT)	⊕⊕⊕⊝ Moderate^a	RR 1.11 (0.78 to 1.59)	283 per 1000	31 more per 1000 (62 fewer to 167 more)
Recurrent VTE follow‐up: mean 6 months	270 (1 RCT)	⊕⊕⊝⊝ Low^b	RR 0.46 (0.16 to 1.32)	Study population
Recurrent VTE follow‐up: mean 6 months	270 (1 RCT)	⊕⊕⊝⊝ Low^b	RR 0.46 (0.16 to 1.32)	77 per 1000	42 fewer per 1000 (65 fewer to 25 more)
Major bleeding follow‐up: mean 6 months	270 (1 RCT)	⊕⊕⊝⊝ Low^c	RR 1.11 (0.35 to 3.56)	Study population
Major bleeding follow‐up: mean 6 months	270 (1 RCT)	⊕⊕⊝⊝ Low^c	RR 1.11 (0.35 to 3.56)	38 per 1000	4 more per 1000 (25 fewer to 98 more)
Minor bleeding – not reported	—	—	—	—	—
Health‐related quality of life – not reported	—	—	—	—	—
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; VKA: vitamin K antagonist; VTE: venous thromboembolism.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate‐certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low‐certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low‐certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level due to serious imprecision, 95% CI was consistent with the possibility for important benefit (62 per 1000 absolute reduction) and possibility of important harm (167 per 1000 absolute increase), included 85 events. ^bDowngraded two level due to very serious imprecision, 95% CI was consistent with the possibility of important benefit (65 fewer per 1000) and possibility of important harm (25 more per 1000); included 15 events. ^cDowngraded two levels due to very serious imprecision, 95% CI was consistent with the possibility for important benefit (25 per 1000 absolute reduction) and possibility of important harm (98 per 1000 absolute increase), included 11 events.

Summary of findings 5. Idraparinux secondary prophylaxis compared to vitamin K antagonist secondary prophylaxis in people with cancer with venous thromboembolism

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Table 1. Glossary

Term	Definition
Adjuvant therapy	A therapy given in addition to the primary treatment to decrease the risk of the cancer recurrence or to assist in the cure.
Anticoagulation	The process of hindering the clotting of blood especially by treatment with an anticoagulant.
Antithrombotic	Used against or tending to prevent thrombosis (clotting)
Coagulation	Clotting
Direct oral anticoagulants (DOAC)	Also known as NOACs are anticoagulant medications that require less monitoring compared to the traditional anticoagulants.
Deep vein thrombosis (DVT)	A condition marked by the formation of a thrombus within a deep vein (as of the leg or pelvis) that may be asymptomatic or be accompanied by symptoms (as swelling and pain) and that is potentially life‐threatening if dislodgment of the thrombus results in pulmonary embolism.
Fondaparinux	An anticoagulant medication
Hemostatic system	The system that shortens the clotting time of blood and stops bleeding.
Heparin	An enzyme occurring especially in the liver and lungs that prolongs the clotting time of blood by preventing the formation of fibrin. 2 forms of heparin that are used as anticoagulant medications are: unfractionated heparin (UFH) and low molecular weight heparins (LMWH).
Impedance plethysmography	A technique that measures the change in blood volume (venous blood volume as well as the pulsation of the arteries) for a specific body segment
Kappa statistic	A measure of degree of nonrandom agreement between observers, measurements of a specific categorical variable, or both.
Metastasis	The spread of a cancer cells from the initial or primary site of disease to another part of the body.
Parenteral nutrition	The practice of feeding a person intravenously, circumventing the gastrointestinal tract.
Pulmonary embolism (PE)	Embolism of a pulmonary artery or one of its branches that is produced by foreign matter and most often a blood clot originating in a vein of the leg or pelvis and that is marked by labored breathing, chest pain, fainting, rapid heart rate, cyanosis, shock and sometimes death.
Thrombocytopenia	Persistent decrease in the number of blood platelets that is often associated with hemorrhagic conditions.
Thrombosis	The formation or presence of a blood clot within a blood vessel.
Vitamin K antagonists	Anticoagulant medications. Warfarin is a vitamin K antagonist.
Warfarin	An anticoagulant medication that is a vitamin K antagonist that is used for anticoagulation.

Table 1. Glossary

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Comparison 1. Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 All‐cause mortality (up to 6 months) (main analysis ‐ active cancer) Show forest plot	4	1712	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.88, 1.12]

1.2 All‐cause mortality (time‐to‐event) Show forest plot	2	810	HR (IV, Random, 95% CI)	0.94 [0.74, 1.20]

1.3 Recurrent venous thromboembolism (up to 6 months) (main analysis ‐ active cancer) Show forest plot	4	1712	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.44, 0.80]

1.4 Recurrent venous thromboembolism (time‐to‐event) Show forest plot	2	810	HR (IV, Random, 95% CI)	0.49 [0.31, 0.78]

1.5 Major bleeding (up to 6 months) (main analysis ‐ active cancer) Show forest plot	4	1712	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.55, 2.12]

1.6 Minor bleeding (up to 6 months) (main analysis ‐ active cancer) Show forest plot	4	1712	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.47, 1.27]

1.7 Thrombocytopenia (up to 6 months) (main analysis‐ active cancer) Show forest plot	1	138	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.52, 1.69]

Comparison 1. Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA)

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Comparison 2. Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 All‐cause mortality (6‐12 months) Show forest plot	4	1060	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.72, 1.23]

2.2 Recurrent venous thromboembolism (6‐12 months) Show forest plot	4	1050	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.34, 1.15]

2.3 Major bleeding (6‐12 months) Show forest plot	4	1055	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.39, 1.53]

2.4 Minor bleeding (6‐12 months) Show forest plot	4	1055	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.57, 1.23]

Comparison 2. Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA)

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Comparison 3. Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 All‐cause mortality (6 months) Show forest plot	5	2854	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.83, 1.14]

3.2 Recurrent VTE (6 months) Show forest plot	5	2854	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.45, 0.88]

3.3 Major bleeding (6 months) Show forest plot	5	2994	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.83, 1.73]

3.3.1 GI tract cancer	4	854	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.76, 2.84]
3.3.2 Non‐GI tract cancer	4	1853	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.63, 1.73]
3.3.3 GI tract cancer not specified	1	287	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 4.04]
3.4 Major GI bleeding (6 months) Show forest plot	4	1838	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.62, 2.17]

3.5 Major upper GI bleeding (6 months) Show forest plot	4	1838	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.51, 2.76]

3.6 Major lower GI bleeding (6 months) Show forest plot	4	1838	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.43, 2.80]

3.7 Major non‐GI bleeding (6 months) Show forest plot	4	1838	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.42, 1.68]

3.8 Minor bleeding (6 months) Show forest plot	5	2854	Risk Ratio (M‐H, Random, 95% CI)	1.58 [1.15, 2.16]

3.9 Minor GI bleeding (6 months) Show forest plot	2	1495	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.41, 4.64]

3.10 Minor upper GI bleeding (6 months) Show forest plot	2	1495	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.04, 25.97]

3.11 Minor lower GI bleeding (6 months) Show forest plot	2	1495	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.72, 3.27]

3.12 Minor non‐GI bleeding (6 months) Show forest plot	2	1495	Risk Ratio (M‐H, Random, 95% CI)	2.37 [1.44, 3.89]

Comparison 3. Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH)

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Comparison 4. Idraparinux versus vitamin K antagonists (VKA)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 All‐cause mortality (up to 6 months) Show forest plot	1	284	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.78, 1.59]

4.2 Recurrent VTE (up to 6 months) Show forest plot	1	270	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.16, 1.32]

4.3 Major bleeding (up to 6 months) Show forest plot	1	270	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.35, 3.56]

4.4 Minor bleeding (up to 6 months) Show forest plot	1	270	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.30, 1.60]

Comparison 4. Idraparinux versus vitamin K antagonists (VKA)

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