Oral anticoagulation in people with cancer who have no therapeutic or prophylactic indication for anticoagulation

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

doi:10.1002/14651858.CD006466.pub6

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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: Vitamin K antagonist (VKA) versus no VKA, Outcome 1: Mortality at 6 months: main analysis

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Analysis 1.2

Comparison 1: Vitamin K antagonist (VKA) versus no VKA, Outcome 2: Mortality at 6 months: subgroup analysis (lung cancer)

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Analysis 1.3

Comparison 1: Vitamin K antagonist (VKA) versus no VKA, Outcome 3: Mortality at 12 months: main analysis

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Analysis 1.4

Comparison 1: Vitamin K antagonist (VKA) versus no VKA, Outcome 4: Mortality at 12 months: subgroup analysis (lung cancer)

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Analysis 1.5

Comparison 1: Vitamin K antagonist (VKA) versus no VKA, Outcome 5: Mortality at 2 years

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Analysis 1.6

Comparison 1: Vitamin K antagonist (VKA) versus no VKA, Outcome 6: Mortality at 5 years

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Analysis 1.7

Comparison 1: Vitamin K antagonist (VKA) versus no VKA, Outcome 7: Symptomatic deep vein thrombosis

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Analysis 1.8

Comparison 1: Vitamin K antagonist (VKA) versus no VKA, Outcome 8: Pulmonary embolism

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Analysis 1.9

Comparison 1: Vitamin K antagonist (VKA) versus no VKA, Outcome 9: Major bleeding: main analysis

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Analysis 1.10

Comparison 1: Vitamin K antagonist (VKA) versus no VKA, Outcome 10: Major bleeding: subgroup analysis (lung cancer)

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Analysis 1.11

Comparison 1: Vitamin K antagonist (VKA) versus no VKA, Outcome 11: Minor bleeding: main analysis

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Analysis 1.12

Comparison 1: Vitamin K antagonist (VKA) versus no VKA, Outcome 12: Minor bleeding: subgroup analysis (lung cancer)

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Analysis 2.1

Comparison 2: Direct oral anticoagulants (DOAC) versus no DOAC, Outcome 1: Mortality at 3 months

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Analysis 2.2

Comparison 2: Direct oral anticoagulants (DOAC) versus no DOAC, Outcome 2: Symptomatic deep vein thrombosis

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Analysis 2.3

Comparison 2: Direct oral anticoagulants (DOAC) versus no DOAC, Outcome 3: Pulmonary embolism

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Analysis 2.4

Comparison 2: Direct oral anticoagulants (DOAC) versus no DOAC, Outcome 4: Major bleeding

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Analysis 2.5

Comparison 2: Direct oral anticoagulants (DOAC) versus no DOAC, Outcome 5: Minor bleeding

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Summary of findings 1. VKA prophylaxis compared to No prophylaxis in ambulatory patients with cancer without VTE receiving systemic therapy

Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
VKA prophylaxis compared to No prophylaxis in ambulatory patients with cancer without VTE receiving systemic therapy
Patient or population: ambulatory people with cancer without VTE receiving systemic therapy Setting: outpatient Intervention: VKA prophylaxis Control: no prophylaxis
Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with No prophylaxis	Risk difference with VKA prophylaxis
Mortality follow up: 12 months	1281 (5 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 0.95 (0.87 to 1.03)	Study population
Mortality follow up: 12 months	1281 (5 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 0.95 (0.87 to 1.03)	574 per 1,000	29 fewer per 1,000 (75 fewer to 17 more)
PE follow up: 12 months	311 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{2 3}	RR 1.05 (0.07 to 16.58)	Study population
PE follow up: 12 months	311 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{2 3}	RR 1.05 (0.07 to 16.58)	6 per 1,000	0 fewer per 1,000 (6 fewer to 98 more)
Symptomatic DVT follow up: 12 months	311 (1 RCT)	⊕⊕⊝⊝ LOW ^{4 5}	RR 0.08 (0.00 to 1.42)	Study population
Symptomatic DVT follow up: 12 months	311 (1 RCT)	⊕⊕⊝⊝ LOW ^{4 5}	RR 0.08 (0.00 to 1.42)	38 per 1,000	35 fewer per 1,000 (38 fewer to 16 more)
Major bleeding follow up: 12 months	1281 (5 RCTs)	⊕⊕⊕⊝ MODERATE ⁶	RR 2.93 (1.86 to 4.62)	Study population
Major bleeding follow up: 12 months	1281 (5 RCTs)	⊕⊕⊕⊝ MODERATE ⁶	RR 2.93 (1.86 to 4.62)	55 per 1,000	107 more per 1,000 (48 more to 201 more)
Minor bleeding follow up: 12 months	863 (4 RCTs)	⊕⊕⊕⊝ MODERATE ⁷	RR 3.14 (1.85 to 5.32)	Study population
Minor bleeding follow up: 12 months	863 (4 RCTs)	⊕⊕⊕⊝ MODERATE ⁷	RR 3.14 (1.85 to 5.32)	78 per 1,000	167 more per 1,000 (66 more to 337 more)
HRQoL ‐ 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; DVT: deep vein thrombosis; HRQoL: health‐related quality of life; PE: pulmonary embolism; RCT: randomized controlled trial; RR: risk ratio; VKA: vitamin K antagonist.
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 concern about both risk of bias (lack of blinding in patients and personnel and unclear allocation concealment in 4 out of 5 studies) and imprecision (95% CI is consistent with the possibility for important benefit (75 per 1000 absolute reduction) and the possibility of important harm (17 per 1000 absolute increase), large event rate) ² Downgraded by one level due to indirectness. Levine 1994 used fixed dose of VKA instead of adjusted dose which is not representative of the current practice. This study was the only trial that reported on PE and symptomatic DVT. ³ Downgraded by two levels due to very serious imprecision. 95% CI is consistent with the possibility for important benefit (6 per 1000 absolute reduction) and the possibility of important harm (98 per 1000 absolute increase), including only 2 events. ⁴Levine 1994 used fixed dose of VKA instead of adjusted dose which is not representative of the current practice. This study was the only trial that reported on PE and symptomatic DVT. We do not think that this indirectness has underestimated the effect on symptomatic DVT (RR 0.08) ⁵ Downgraded by two levels due to very serious imprecision. Only 6 events among 311 participants. ⁶ Downgraded by one level due to concern about risk of bias (lack of blinding in patients and personnel and unclear allocation concealment in 4 out of 5 studies) ⁷ Downgraded by one level due to concern about risk of bias (lack of blinding in patients and personnel and unclear allocation concealment in 3 out of 4 studies)

Summary of findings 1. VKA prophylaxis compared to No prophylaxis in ambulatory patients with cancer without VTE receiving systemic therapy

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Summary of findings 2. DOAC prophylaxis compared to No prophylaxis in ambulatory patients with cancer without VTE receiving systemic therapy (Q6b‐ Oral)

Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
DOAC prophylaxis compared to No prophylaxis in ambulatory patients with cancer without VTE receiving systemic therapy
Patient or population: ambulatory people with cancer without VTE receiving systemic therapy Setting: outpatient Intervention: DOAC prophylaxis Control: no prophylaxis
Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with No prophylaxis	Risk difference with DOAC prophylaxis
Mortality follow up: 3 months	92 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.24 (0.02 to 2.56)	Study population
Mortality follow up: 3 months	92 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.24 (0.02 to 2.56)	67 per 1,000	51 fewer per 1,000 (65 fewer to 104 more)
PE follow up: 3 months	92 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 3}	RR 0.16 (0.01 to 3.91)	Study population
PE follow up: 3 months	92 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 3}	RR 0.16 (0.01 to 3.91)	33 per 1,000	28 fewer per 1,000 (33 fewer to 97 more)
Symptomatic DVT follow up: 3 months	92 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 4}	RR 0.07 (0.00 to 1.32)	Study population
Symptomatic DVT follow up: 3 months	92 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 4}	RR 0.07 (0.00 to 1.32)	100 per 1,000	93 fewer per 1,000 (100 fewer to 32 more)
Major bleeding follow up: 3 months	92 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 3}	RR 0.16 (0.01 to 3.91)	Study population
Major bleeding follow up: 3 months	92 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 3}	RR 0.16 (0.01 to 3.91)	33 per 1,000	28 fewer per 1,000 (33 fewer to 97 more)
Minor bleeding follow up: 3 months	92 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 5}	RR 4.43 (0.25 to 79.68)	Low
Minor bleeding follow up: 3 months	92 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 5}	RR 4.43 (0.25 to 79.68)	0 per 1,000	0 fewer per 1,000 (0 fewer to 8 more)
HRQoL ‐ 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; DOAC: direct oral anticoagulant; DVT: deep vein thrombosis; HRQoL: health‐related quality of life; PE: pulmonary embolism; RCT: randomized controlled trial; RR: risk 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 Concern due to unclear allocation concealment ² Downgraded by two levels due to very serious imprecision: 95% CI is consistent with the possibility for important benefit (65 per 1000 absolute reduction) and the possibility of important harm (104 per 1000 absolute increase), including only 3 events among 92 participants. ³ Downgraded by two levels due to very serious imprecision: 95% CI is consistent with the possibility for important benefit (33 per 1000 absolute reduction) and the possibility of important harm (97 per 1000 absolute increase), including only 1 events among 92 participants. ⁴ Downgraded by two levels due to very serious imprecision: Including only 3 events among 92 participants. ⁵ Downgraded by two levels due to very serious imprecision: Including only 4 events among 92 participants.

Summary of findings 2. DOAC prophylaxis compared to No prophylaxis in ambulatory patients with cancer without VTE receiving systemic therapy (Q6b‐ Oral)

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Table 1. Glossary

Term	Meaning
Adjuvant therapy	Assisting in the amelioration or cure of disease.
Anticoagulation	Process of hindering the clotting of blood especially by treatment with an anticoagulant.
Antithrombotic	Used against or tending to prevent thrombosis (clotting).
Apixaban	Oral direct factor Xa inhibitor used for anticoagulation.
Coagulation	Clotting.
Direct factor Xa inhibitor	Anticoagulant medications used for anticoagulation. Apixaban is an oral direct factor Xa inhibitor.
Deep vein thrombosis (DVT)	Condition marked by the formation of a thrombus within a deep vein (e.g. leg or pelvis) that may be asymptomatic or symptomatic (as swelling and pain) and that is potentially life‐threatening if dislodgment of the thrombus results in pulmonary embolism.
Fibrin	White insoluble fibrous protein formed from fibrinogen by the action of thrombin especially in the clotting of blood.
Fondaparinux	An anticoagulant medication.
Hemostatic system	The system that shortens the clotting time of blood and stops bleeding.
Heparin	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).
Major bleeding	Bleeding that is intracranial or retroperitoneal, if it leads directly to death, or if results in hospitalization or transfusion.
Metastasis	Spread of a cancer cells from the initial or primary site of disease to another part of the body.
Minor bleeding	Any bleeding not classified as major bleeding.
Oncogene	Gene having the potential to cause a normal cell to become cancerous.
Osteoporosis	Condition that affects mainly older women and is characterized by decrease in bone mass with decreased density and enlargement of bone spaces producing porosity and brittleness.
Pulmonary embolism (PE)	Embolism of a pulmonary artery or 1 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.
Stroma	The supporting framework of an organ typically consisting of connective tissue.
Thrombin	Proteolytic enzyme formed from prothrombin that facilitates the clotting of blood by catalyzing conversion of fibrinogen to fibrin.
Thrombocytopenia	Persistent decrease in the number of blood platelets that is often associated with hemorrhagic conditions.
Vitamin K antagonist (VKA)	Anticoagulant medications. Warfarin is a vitamin K antagonist.
Warfarin	Anticoagulant medication that is a vitamin K antagonist.
Ximelagatran	Anticoagulant medication.

Table 1. Glossary

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Comparison 1. Vitamin K antagonist (VKA) versus no VKA

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Mortality at 6 months: main analysis Show forest plot	3	946	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.77, 1.13]

1.2 Mortality at 6 months: subgroup analysis (lung cancer) Show forest plot	3	946	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.77, 1.14]

1.2.1 Lung cancer (small cell and non‐small cell)	3	813	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.72, 1.06]
1.2.2 Non‐lung cancer	1	133	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.82, 1.82]
1.3 Mortality at 12 months: main analysis Show forest plot	5	1281	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.87, 1.03]

1.4 Mortality at 12 months: subgroup analysis (lung cancer) Show forest plot	5	1281	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.87, 1.03]

1.4.1 Lung cancer (small cell and non‐small cell)	4	837	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.85, 1.05]
1.4.2 Non‐lung cancer	2	444	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.81, 1.10]
1.5 Mortality at 2 years Show forest plot	2	528	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.70, 1.30]

1.6 Mortality at 5 years Show forest plot	1	344	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.83, 1.03]

1.7 Symptomatic deep vein thrombosis Show forest plot	1	311	Risk Ratio (M‐H, Random, 95% CI)	0.08 [0.00, 1.42]

1.8 Pulmonary embolism Show forest plot	1	311	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.07, 16.58]

1.9 Major bleeding: main analysis Show forest plot	5	1281	Risk Ratio (M‐H, Random, 95% CI)	2.93 [1.86, 4.62]

1.10 Major bleeding: subgroup analysis (lung cancer) Show forest plot	5	1281	Risk Ratio (M‐H, Random, 95% CI)	2.85 [1.76, 4.62]

1.10.1 Lung cancer (small cell and non‐small cell)	4	837	Risk Ratio (M‐H, Random, 95% CI)	3.95 [2.38, 6.55]
1.10.2 Non‐lung cancer	2	444	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.63, 4.89]
1.11 Minor bleeding: main analysis Show forest plot	4	863	Risk Ratio (M‐H, Random, 95% CI)	3.14 [1.85, 5.32]

1.12 Minor bleeding: subgroup analysis (lung cancer) Show forest plot	4	865	Risk Ratio (M‐H, Random, 95% CI)	3.19 [1.83, 5.55]

1.12.1 Lung cancer (small cell and non‐small cell)	3	554	Risk Ratio (M‐H, Random, 95% CI)	3.79 [1.55, 9.24]
1.12.2 Non‐lung cancer	1	311	Risk Ratio (M‐H, Random, 95% CI)	2.44 [0.64, 9.27]

Comparison 1. Vitamin K antagonist (VKA) versus no VKA

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Comparison 2. Direct oral anticoagulants (DOAC) versus no DOAC

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Mortality at 3 months Show forest plot	1	92	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.02, 2.56]

2.2 Symptomatic deep vein thrombosis Show forest plot	1	92	Risk Ratio (M‐H, Random, 95% CI)	0.07 [0.00, 1.32]

2.3 Pulmonary embolism Show forest plot	1	92	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.01, 3.91]

2.4 Major bleeding Show forest plot	1	92	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.01, 3.91]

2.5 Minor bleeding Show forest plot	1	92	Risk Ratio (M‐H, Random, 95% CI)	4.43 [0.25, 79.68]

Comparison 2. Direct oral anticoagulants (DOAC) versus no DOAC

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