Parenteral anticoagulation in ambulatory patients with cancer

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

doi:10.1002/14651858.CD006652.pub5

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Figure 1

Study flow diagram.

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Figure 2

'Risk of bias' graph: review authors' judgements 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' judgements about each risk of bias item for each included study.

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Figure 4

Funnel plot of comparison: 1 Heparin versus placebo, outcome: 1.1 Mortality at 12 months‐ Main analysis.

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Figure 5

Funnel plot of comparison: 1 Heparin versus placebo, outcome: 1.7 Symptomatic VTE‐ Main analysis.

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Analysis 1.1

Comparison 1: Heparin versus placebo, Outcome 1: Mortality at 12 months‐ Main analysis

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Analysis 1.2

Comparison 1: Heparin versus placebo, Outcome 2: Mortality at 12 months‐ Subgroups Lung vs non‐Lung Cancer

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Analysis 1.3

Comparison 1: Heparin versus placebo, Outcome 3: Mortality at 12 months‐ Subgroups Advanced vs non‐Advanced

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Analysis 1.4

Comparison 1: Heparin versus placebo, Outcome 4: Mortality at 24 months‐ Main Analysis

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Analysis 1.5

Comparison 1: Heparin versus placebo, Outcome 5: Mortality at 24 months‐ Subgroups Advanced vs non‐Advanced

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Analysis 1.6

Comparison 1: Heparin versus placebo, Outcome 6: Mortality over duration of study

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Analysis 1.7

Comparison 1: Heparin versus placebo, Outcome 7: Symptomatic VTE‐ Main analysis

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Analysis 1.8

Comparison 1: Heparin versus placebo, Outcome 8: Symptomatic VTE‐ Subgroups Lung vs non‐Lung Cancer

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Analysis 1.9

Comparison 1: Heparin versus placebo, Outcome 9: PE

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Analysis 1.10

Comparison 1: Heparin versus placebo, Outcome 10: Symptomatic DVT

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Analysis 1.11

Comparison 1: Heparin versus placebo, Outcome 11: Major bleeding‐ Main analysis

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Analysis 1.12

Comparison 1: Heparin versus placebo, Outcome 12: Major bleeding‐ Subgroups Lung vs non‐Lung Cancer

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Analysis 1.13

Comparison 1: Heparin versus placebo, Outcome 13: Minor bleeding

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Analysis 1.14

Comparison 1: Heparin versus placebo, Outcome 14: Thrombocytopenia

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Summary of findings 1. Heparin prophylaxis compared with no prophylaxis in ambulatory patients with cancer without VTE receiving systemic therapy

Outcomes	№ of participants (studies) Follow‐up	Quality of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Heparin prophylaxis compared with no prophylaxis in ambulatory patients with cancer without VTE receiving systemic therapy P: Ambulatory patients with cancer without VTE receiving systemic therapy I: Heparin prophylaxis C: No prophylaxis S: Outpatient
Outcomes	№ of participants (studies) Follow‐up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with No prophylaxis	Risk difference with Heparin prophylaxis
Mortality follow‐up: 12 months	9575 (18 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 0.98 (0.93 to 1.03)	Study population
Mortality follow‐up: 12 months	9575 (18 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 0.98 (0.93 to 1.03)	504 per 1000	10 fewer per 1000 (35 fewer to 15 more)
Mortality follow‐up: 24 months	5229 (14 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 0.99 (0.96 to 1.01)	Study population
Mortality follow‐up: 24 months	5229 (14 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 0.99 (0.96 to 1.01)	778 per 1000	8 fewer per 1000 (31 fewer to 8 more)
Symptomatic VTE follow‐up: 12 months	9036 (16 RCTs)	⊕⊕⊕⊕ HIGH	RR 0.56 (0.47 to 0.68)	Study population
Symptomatic VTE follow‐up: 12 months	9036 (16 RCTs)	⊕⊕⊕⊕ HIGH	RR 0.56 (0.47 to 0.68)	68 per 1000	30 fewer per 1000 (36 fewer to 22 fewer)
Major bleeding follow‐up: 12 months	9592 (18 RCTs)	⊕⊕⊕⊝ MODERATE ²	RR 1.30 (0.94 to 1.79)	Study population
Major bleeding follow‐up: 12 months	9592 (18 RCTs)	⊕⊕⊕⊝ MODERATE ²	RR 1.30 (0.94 to 1.79)	14 per 1000	4 more per 1000 (1 fewer to 11 more)
Minor bleeding follow‐up: 12 months	9245 (16 RCTs)	⊕⊕⊕⊕ HIGH	RR 1.70 (1.13 to 2.55)	Study population
Minor bleeding follow‐up: 12 months	9245 (16 RCTs)	⊕⊕⊕⊕ HIGH	RR 1.70 (1.13 to 2.55)	24 per 1000	17 more per 1000 (3 more to 37 more)
Thrombocytopenia	5832 (12 RCTs)	⊕⊕⊕⊝ MODERATE ³	RR 0.69 (0.37 to 1.27)	Study population
Thrombocytopenia	5832 (12 RCTs)	⊕⊕⊕⊝ MODERATE ³	RR 0.69 (0.37 to 1.27)	105 per 1000	33 fewer per 1000 (66 fewer to 28 more)
Quality of life impairment	2241 (2 RCTs)	⊕⊕⊕⊝ MODERATE ⁴	‐	Macbeth 2016 (FRAGMATIC): " There was no difference between the two groups with respect to quality‐adjusted life years gained in the first year... No difference in overall quality of life at 6 months (P = .94) or at 12 months (P = .89)... Overall quality of life did not change significantly over the study period".Sideras 2006: "The QOL and SDS scores were similar, both at baseline and during the protocol period, in patients randomized to receive LMWH vs those not randomized to receive LMWH."
*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 quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: 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 quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: 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 one level due to serious imprecision: Confidence interval includes values suggesting clinically significant benefit and values suggesting no effect. ² Downgraded one level due to serious imprecision: Confidence interval includes values suggesting clinically significant harm and values suggesting no effect. ³ Downgraded one level due to serious imprecision: Confidence interval includes values suggesting clinically significant benefit and values suggesting harm. ⁴ Downgraded one level due to serious risk of bias: Both studies were open‐label studies (lack of blinding may impact the patient‐reported subjective outcomes)

Summary of findings 1. Heparin prophylaxis compared with no prophylaxis in ambulatory patients with cancer without VTE receiving systemic therapy

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Table 1. Glossary

Term	Definition
Adjuvant therapy	Assisting in the amelioration or cure of disease
Anticoagulation	The process of hindering the clotting of blood especially by treatment with an anticoagulant
Antithrombotic	Used against or tending to prevent thrombosis (clotting)
Bacteremia	The presence of bacteria in the blood
Central venous line	Synthetic tube that is inserted into a central (large) vein of a patient to provide temporary intravenous access for the administration of fluid, medication or nutrients
Coagulation	Clotting
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 (such as swelling and pain) and that is potentially life‐threatening if dislodgment of the thrombus results in pulmonary embolism
Fibrin	A 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	An enzyme occurring especially in the liver and lungs that prolongs the clotting time of blood by preventing the formation of fibrin. Two 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 statistics	A measure of degree of non‐random agreement between observers and/or measurements of a specific categorical variable
Metastasis	The spread of cancer cells from the initial or primary site of disease to another part of the body
Oncogene	A gene having the potential to cause a normal cell to become cancerous
Osteoporosis	A condition that especially affects older women and is characterized by a decrease in bone mass with decreased density and enlargement of bone spaces producing porosity and brittleness
Parenteral nutrition	The practice of feeding a patient intravenously, circumventing the gut
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
Stroma	The supporting framework of an organ typically consisting of connective tissue
Thrombin	A 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
Thrombosis	The formation or presence of a blood clot within a blood vessel
Vitamin K antagonists	Anticoagulant medications that are used for anticoagulation. Warfarin is a vitamin K antagonist
Warfarin	An anticoagulant medication that is a vitamin K antagonist, which is used for anticoagulation
Ximelagatran	An anticoagulant medication

Table 1. Glossary

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Table 2. LMWH: definitions of prophylactic and therapeutic dosages

LMWH	Generic name	Prophylactic dose	Therapeutic dose
Lovenox	Enoxaparin	40 mg once daily	1 mg/kg twice daily
Fragmin	Dalteparin	2500 to 5000 units once daily	200 U/kg once daily or 100 U/kg twice daily
Innohep, Logiparin	Tinzaparin	4500 units once daily	90 U/kg twice daily
Fraxiparine	Nadroparin	35 to 75 anti‐Xa international units/kg once daily	175 anti‐Xa int. units/kg once daily
Certoparin	Sandoparin	3000 anti‐Xa international units once daily	—

Table 2. LMWH: definitions of prophylactic and therapeutic dosages

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Comparison 1. Heparin versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Mortality at 12 months‐ Main analysis Show forest plot	18	9575	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.93, 1.03]

1.2 Mortality at 12 months‐ Subgroups Lung vs non‐Lung Cancer Show forest plot	12	4768	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.86, 1.03]

1.2.1 Lung Cancer (SCLC or NSCLC)	6	3204	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.73, 1.08]
1.2.2 non‐Lung Cancer	7	1564	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.88, 1.03]
1.3 Mortality at 12 months‐ Subgroups Advanced vs non‐Advanced Show forest plot	18	9575	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.94, 1.03]

1.3.1 Advanced cancer	12	6115	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.93, 1.02]
1.3.2 Non‐advanced cancer	8	3460	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.75, 1.12]
1.4 Mortality at 24 months‐ Main Analysis Show forest plot	14	5229	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.96, 1.01]

1.5 Mortality at 24 months‐ Subgroups Advanced vs non‐Advanced Show forest plot	14	5229	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.96, 1.01]

1.5.1 Advanced cancer	6	1554	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.93, 1.03]
1.5.2 Non‐advanced cancer	8	3675	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.93, 1.04]
1.6 Mortality over duration of study Show forest plot	15		Hazard Ratio (IV, Random, 95% CI)	0.93 [0.84, 1.03]

1.7 Symptomatic VTE‐ Main analysis Show forest plot	16	9036	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.47, 0.68]

1.8 Symptomatic VTE‐ Subgroups Lung vs non‐Lung Cancer Show forest plot	11	8090	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.43, 0.63]

1.8.1 Lung Cancer (SCLC or NSCLC)	6	4217	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.41, 0.68]
1.8.2 Non‐lung cancer	7	3873	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.37, 0.70]
1.9 PE Show forest plot	14	8867	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.47, 0.80]

1.10 Symptomatic DVT Show forest plot	14	8867	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.33, 0.63]

1.11 Major bleeding‐ Main analysis Show forest plot	18	9592	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.94, 1.79]

1.12 Major bleeding‐ Subgroups Lung vs non‐Lung Cancer Show forest plot	10	4163	Risk Ratio (M‐H, Random, 95% CI)	1.62 [1.02, 2.56]

1.12.1 Lung Cancer (SCLC or NSCLC)	5	3035	Risk Ratio (M‐H, Random, 95% CI)	1.45 [0.77, 2.73]
1.12.2 Non‐lung cancer	5	1128	Risk Ratio (M‐H, Random, 95% CI)	1.84 [0.94, 3.58]
1.13 Minor bleeding Show forest plot	16	9245	Risk Ratio (M‐H, Random, 95% CI)	1.70 [1.13, 2.55]

1.14 Thrombocytopenia Show forest plot	12	5832	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.37, 1.27]

Comparison 1. Heparin versus placebo

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