Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism

Moshe Vardi; Eran Zittan; Haim Bitterman

doi:10.1002/14651858.CD006771.pub2

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Figure 1

Adapted QUOROM flow chart of studies selection

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Figure 2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Figure 3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Figure 4

Funnel plot of comparison: Recurrent DVT during 3 months follow up.

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Figure 5

Funnel plot of comparison: New clinical pulmonary embolism.

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Analysis 1.1

Comparison 1 Clinical efficacy, Outcome 1 DVT resolution (partial/full) ‐ end of heparin treatment.

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Analysis 1.2

Comparison 1 Clinical efficacy, Outcome 2 Recurrent DVT during 3 months follow up.

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Analysis 1.3

Comparison 1 Clinical efficacy, Outcome 3 New clinical pulmonary embolism.

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Analysis 1.4

Comparison 1 Clinical efficacy, Outcome 4 New pulmonary embolism on routine lung scan ‐ end of heparin therapy.

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Analysis 2.1

Comparison 2 Laboratory measures, Outcome 1 Anticoagulation measures (aPTT, anti‐Xa) ‐ after titration.

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Analysis 2.2

Comparison 2 Laboratory measures, Outcome 2 Number of patients below therapeutic range.

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Analysis 3.1

Comparison 3 Adverse events, Outcome 1 Major bleeding.

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Analysis 3.2

Comparison 3 Adverse events, Outcome 2 Minor bleeding.

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Analysis 3.3

Comparison 3 Adverse events, Outcome 3 Platelet fall.

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Analysis 3.4

Comparison 3 Adverse events, Outcome 4 Hemoglobin fall.

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Analysis 4.1

Comparison 4 Death, Outcome 1 Total death.

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Analysis 4.2

Comparison 4 Death, Outcome 2 VTE or bleeding related death.

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Analysis 5.1

Comparison 5 Clinical efficacy ‐ by control, Outcome 1 DVT resolution (partial/full) ‐ end of heparin treatment.

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Analysis 5.2

Comparison 5 Clinical efficacy ‐ by control, Outcome 2 Recurrent DVT during 3 months follow up.

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Analysis 5.3

Comparison 5 Clinical efficacy ‐ by control, Outcome 3 New clinical pulmonary embolism.

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Analysis 5.4

Comparison 5 Clinical efficacy ‐ by control, Outcome 4 New pulmonary embolism on routine lung scan ‐ end of heparin therapy.

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Analysis 6.1

Comparison 6 Laboratory measures ‐ by control, Outcome 1 Anticoagulation measures (aPTT, anti‐Xa) ‐ after titration.

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Analysis 6.2

Comparison 6 Laboratory measures ‐ by control, Outcome 2 Number of patients below therapeutic range.

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Analysis 7.1

Comparison 7 Adverse events ‐ by control, Outcome 1 Major bleeding.

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Analysis 7.2

Comparison 7 Adverse events ‐ by control, Outcome 2 Minor bleeding.

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Analysis 7.3

Comparison 7 Adverse events ‐ by control, Outcome 3 Platelet fall.

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Analysis 8.1

Comparison 8 Death ‐ by control, Outcome 1 Total death.

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Analysis 8.2

Comparison 8 Death ‐ by control, Outcome 2 VTE or bleeding‐related death.

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Summary of findings for the main comparison. Subcutaneous unfractionated heparin compared to Other treatment modalities for Venous thromboembolism‐ clinical efficacy

Subcutaneous unfractionated heparin compared to Other treatment modalities for Venous thromboembolism‐ clinical efficacy
Patient or population: Venous thromboembolism‐ clinical efficacy Settings: Intervention: Subcutaneous unfractionated heparin Comparison: Other treatment modalities
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Other treatment modalities	Subcutaneous unfractionated heparin
Recurrent DVT during 3 months follow up Follow‐up: 0‐3 months	Medium risk population		OR 1.68 (0.92 to 3.04)	1628 (4 studies)	⊕⊕⊕⊝ moderate¹
	23 per 1000	38 per 1000 (21 to 67)
New clinical pulmonary embolism during heparin treatment Follow‐up: 0‐10 days	Medium risk population		OR 1.1 (0.46 to 2.62)	958 (8 studies)	⊕⊕⊕⊝ moderate¹
	18 per 1000	20 per 1000 (8 to 46)
New clinical pulmonary embolism during 3 months follow up Follow‐up: 0‐3 months	Medium risk population		OR 1.18 (0.54 to 2.56)	1626 (4 studies)	⊕⊕⊕⊝ moderate¹
	17 per 1000	20 per 1000 (9 to 42)
Major bleeding Follow‐up: 0‐3 months	Medium risk population		OR 0.9 (0.6 to 1.36)	4390 (14 studies)	⊕⊝⊝⊝ very low
	14 per 1000	13 per 1000 (8 to 19)
Minor bleeding Follow‐up: 0‐3 months	Medium risk population		OR 0.98 (0.71 to 1.36)	2755 (10 studies)	⊕⊕⊕⊝ moderate
	40 per 1000	39 per 1000 (29 to 54)
Total death ‐ During 3 months follow up (including acute phase)	Medium risk population		OR 1.02 (0.67 to 1.55)	1887 (6 studies)	⊕⊕⊕⊝ moderate
	43 per 1000	44 per 1000 (29 to 65)
VTE or bleeding related death during 3 months follow‐up (including acute phase) Follow‐up: 0‐3 months	Medium risk population		RD 0.0 (‐0.01 to 0.01)	2181 (7 studies)	⊕⊕⊕⊝ moderate
	0 per 1000	0 per 1000 (0 to 0)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Selection, performance, attrition and detection bias exist in some of the trials assessed.

Summary of findings for the main comparison. Subcutaneous unfractionated heparin compared to Other treatment modalities for Venous thromboembolism‐ clinical efficacy

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Table 1. Overall quality of included studies ‐ three point scale

Study	Selection bias	Performance bias	Attrition bias	Detection bias	Overall quality
Andersson 1982	Unclear	No	No	No	C
Belcaro 1999	Unclear	Unclear	No	No	C
Bentley 1980	Yes	No	No	+/‐	C
Doyle 1987	Yes	No	No	+/‐	C
Faivre 1987	Unclear	No	No	+/‐	C
Holm 1986	Unclear	Yes	No	+/‐	C
Hull 1986	Yes	Yes	Unclear	Unclear	B
Kearon 2006	Yes	No	No	Yes	C
Krähenbühl 1979	Unclear	No	No	Yes	C
Lopaciuk 1990	Yes	No	No	Yes	C
Lopaciuk 1992	Unclear	No	No	Yes	C
Peternel 2002	Unclear	No	No	Unclear	C
Pini 1990	Unclear	No	No	Unclear	C
Prandoni 2004	Unclear	No	Yes	Yes	C
Walker 1987	Unclear	No	No	Yes	C

Table 1. Overall quality of included studies ‐ three point scale

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Comparison 1. Clinical efficacy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 DVT resolution (partial/full) ‐ end of heparin treatment Show forest plot	9	886	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [1.06, 1.84]

2 Recurrent DVT during 3 months follow up Show forest plot	4	1628	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [0.92, 3.04]

3 New clinical pulmonary embolism Show forest plot	11		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 During heparin treatment	8	958	Odds Ratio (M‐H, Fixed, 95% CI)	1.10 [0.46, 2.62]
3.2 During 3 months follow up	4	1626	Odds Ratio (M‐H, Fixed, 95% CI)	1.18 [0.54, 2.56]
4 New pulmonary embolism on routine lung scan ‐ end of heparin therapy Show forest plot	2	109	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.25, 2.81]

Comparison 1. Clinical efficacy

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Comparison 2. Laboratory measures

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Anticoagulation measures (aPTT, anti‐Xa) ‐ after titration Show forest plot	5		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 SC UFH vs. IV UFH	3	489	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.14 [‐0.32, 0.04]
1.2 SC UFH vs. SC LMWH	2	92	Std. Mean Difference (IV, Fixed, 95% CI)	‐1.15 [‐1.61, ‐0.69]
2 Number of patients below therapeutic range Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 SC UFH vs. IV UFH	3	434	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [0.89, 1.92]

Comparison 2. Laboratory measures

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Comparison 3. Adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding Show forest plot	14	4390	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.60, 1.36]

1.1 During heparin treatment	14	2721	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.64, 1.79]
1.2 During 3 months follow up (including acute phase)	4	1669	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.33, 1.32]
2 Minor bleeding Show forest plot	10	2755	Odds Ratio (M‐H, Fixed, 95% CI)	0.98 [0.71, 1.36]

2.1 During heparin treatment	10	1806	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.64, 1.59]
2.2 During 3 months follow up (including acute phase)	3	949	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.61, 1.52]
3 Platelet fall Show forest plot	5	1343	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.40, 3.11]

4 Hemoglobin fall Show forest plot	2	200	Odds Ratio (M‐H, Fixed, 95% CI)	0.74 [0.16, 3.41]

Comparison 3. Adverse events

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Comparison 4. Death

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total death Show forest plot	10		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

1.1 During heparin treatment	7	1349	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.01, 0.01]
1.2 During 3 months follow up (including acute phase)	6	1887	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.02, 0.02]
2 VTE or bleeding related death Show forest plot	13		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

2.1 During heparin treatment	9	1549	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]
2.2 During 3 months follow up (including acute phase)	7	2181	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]

Comparison 4. Death

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Comparison 5. Clinical efficacy ‐ by control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 DVT resolution (partial/full) ‐ end of heparin treatment Show forest plot	9	886	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [1.06, 1.84]

1.1 IV UFH as control	6	641	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.31, 2.56]
1.2 SC LMWH as control	3	245	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.46, 1.26]
2 Recurrent DVT during 3 months follow up Show forest plot	4	1628	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [0.92, 3.04]

2.1 IV UFH as control	1	115	Odds Ratio (M‐H, Fixed, 95% CI)	3.29 [0.64, 17.06]
2.2 SC LMWH as control	3	1513	Odds Ratio (M‐H, Fixed, 95% CI)	1.49 [0.78, 2.84]
3 New clinical pulmonary embolism Show forest plot	11		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 During heparin treatment ‐ IV UFH as control	6	756	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.42, 2.92]
3.2 During heparin treatment ‐ SC LMWH as control	2	202	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.14, 7.63]
3.3 During 3 months follow up ‐ IV UFH as control	2	209	Odds Ratio (M‐H, Fixed, 95% CI)	3.11 [0.62, 15.61]
3.4 During 3 months follow up ‐ SC LMWH as control	2	1417	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.31, 2.05]
4 New pulmonary embolism on routine lung scan ‐ end of heparin therapy Show forest plot	2	109	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.25, 2.81]

Comparison 5. Clinical efficacy ‐ by control

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Comparison 6. Laboratory measures ‐ by control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Anticoagulation measures (aPTT, anti‐Xa) ‐ after titration Show forest plot	5		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 SC UFH vs. IV UFH	3	489	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.14 [‐0.32, 0.04]
1.2 SC UFH vs. SC LMWH	2	92	Std. Mean Difference (IV, Fixed, 95% CI)	‐1.15 [‐1.61, ‐0.69]
2 Number of patients below therapeutic range Show forest plot	3	434	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [0.89, 1.92]

2.1 SC UFH vs. IV UFHp	3	434	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [0.89, 1.92]

Comparison 6. Laboratory measures ‐ by control

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Comparison 7. Adverse events ‐ by control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding Show forest plot	14	4390	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.60, 1.36]

1.1 During heparin treatment ‐ IV UFH as control	8	972	Odds Ratio (M‐H, Fixed, 95% CI)	0.83 [0.42, 1.61]
1.2 During heparin treatment ‐ SC LMWH as control	6	1749	Odds Ratio (M‐H, Fixed, 95% CI)	1.57 [0.69, 3.58]
1.3 During 3 months follow up ‐ IV UFH as control	1	94	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.06, 15.77]
1.4 During 3 months follow up ‐ SC LMWH as control	3	1575	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.31, 1.32]
2 Minor bleeding Show forest plot	9	2461	Odds Ratio (M‐H, Fixed, 95% CI)	1.03 [0.74, 1.43]

2.1 During heparin treatment ‐ IV UFH as control	6	601	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.32, 1.27]
2.2 During heparin treatment ‐ SC LMWH as control	3	911	Odds Ratio (M‐H, Fixed, 95% CI)	1.94 [0.96, 3.89]
2.3 During 3 months follow up ‐ IV UFH as control	1	94	Odds Ratio (M‐H, Fixed, 95% CI)	3.0 [0.30, 29.94]
2.4 During 3 months follow up ‐ SC LMWH as control	2	855	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.56, 1.45]
3 Platelet fall Show forest plot	5	1343	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.40, 3.11]

3.1 IV UFH as control	3	465	Odds Ratio (M‐H, Fixed, 95% CI)	0.61 [0.15, 2.37]
3.2 SC LMWH as control	2	878	Odds Ratio (M‐H, Fixed, 95% CI)	2.98 [0.47, 18.95]

Comparison 7. Adverse events ‐ by control

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Comparison 8. Death ‐ by control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total death Show forest plot	10		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

1.1 During heparin treatment	7	1349	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.01, 0.01]
1.2 During 3 months follow up (including acute phase)	6	1887	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.02, 0.02]
2 VTE or bleeding‐related death Show forest plot	12		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

2.1 During heparin treatment	8	1490	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]
2.2 During 3 months follow up (including acute phase)	7	2181	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]

Comparison 8. Death ‐ by control

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