Vitamin K antagonists versus low‐molecular‐weight heparin for the long term treatment of symptomatic venous thromboembolism

Alina Andras; Adriano Sala Tenna; Marlene Stewart

doi:10.1002/14651858.CD002001.pub3

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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 trials.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.

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Figure 4

Funnel plot of comparison: 2 LMWH versus VKA during three months of allocated treatment (category I and II trials); outcome: 2.1 incidence of recurrent VTE.

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Figure 5

Funnel plot of comparison: 2 LMWH versus VKA during three months of allocated treatment (category I and II trials); outcome: 2.2 incidence of major bleeding.

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Figure 6

Funnel plot of comparison: 2 LMWH versus VKA during three months of allocated treatment (category I and II trials), outcome; 2.3 mortality.

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Analysis 1.1

Comparison 1 LMWH versus VKA during allocated treatment (category I and II trials) in participants with VTE, Outcome 1 Incidence of recurrent VTE.

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Analysis 1.2

Comparison 1 LMWH versus VKA during allocated treatment (category I and II trials) in participants with VTE, Outcome 2 Incidence of major bleeding.

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Analysis 1.3

Comparison 1 LMWH versus VKA during allocated treatment (category I and II trials) in participants with VTE, Outcome 3 Mortality.

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Analysis 2.1

Comparison 2 LMWH versus VKA during allocated treatment (category I and II trials) in participants with DVT, Outcome 1 Incidence of recurrent VTE.

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Analysis 2.2

Comparison 2 LMWH versus VKA during allocated treatment (category I and II trials) in participants with DVT, Outcome 2 Incidence of major bleeding.

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Analysis 2.3

Comparison 2 LMWH versus VKA during allocated treatment (category I and II trials) in participants with DVT, Outcome 3 Mortality.

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Analysis 3.1

Comparison 3 LMWH versus VKA during allocated treatment (category I and II trials) in participants with PE, Outcome 1 Incidence of recurrent VTE.

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Analysis 3.2

Comparison 3 LMWH versus VKA during allocated treatment (category I and II trials) in participants with PE, Outcome 2 Incidence of major bleeding.

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Analysis 3.3

Comparison 3 LMWH versus VKA during allocated treatment (category I and II trials) in participants with PE, Outcome 3 Mortality.

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Analysis 4.1

Comparison 4 LMWH versus VKA during allocated treatment (category I trials) in participants with VTE, Outcome 1 Incidence of recurrent VTE.

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Analysis 4.2

Comparison 4 LMWH versus VKA during allocated treatment (category I trials) in participants with VTE, Outcome 2 Incidence of major bleeding.

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Analysis 4.3

Comparison 4 LMWH versus VKA during allocated treatment (category I trials) in participants with VTE, Outcome 3 Mortality.

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$Comparison 5 Category I trials and the same initial treatment in both groups (unfractionated heparin or LMWH), Outcome 1 Incidence of recurrent VTE.$

Analysis 5.1

Comparison 5 Category I trials and the same initial treatment in both groups (unfractionated heparin or LMWH), Outcome 1 Incidence of recurrent VTE.

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$Comparison 5 Category I trials and the same initial treatment in both groups (unfractionated heparin or LMWH), Outcome 2 Incidence of major bleeding.$

Analysis 5.2

Comparison 5 Category I trials and the same initial treatment in both groups (unfractionated heparin or LMWH), Outcome 2 Incidence of major bleeding.

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$Comparison 5 Category I trials and the same initial treatment in both groups (unfractionated heparin or LMWH), Outcome 3 Mortality.$

Analysis 5.3

Comparison 5 Category I trials and the same initial treatment in both groups (unfractionated heparin or LMWH), Outcome 3 Mortality.

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$Comparison 6 Category I trials and initial treatment not the same in both groups (unfractionated heparin compared with LMWH), Outcome 1 Incidence of recurrent VTE.$

Analysis 6.1

Comparison 6 Category I trials and initial treatment not the same in both groups (unfractionated heparin compared with LMWH), Outcome 1 Incidence of recurrent VTE.

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$Comparison 6 Category I trials and initial treatment not the same in both groups (unfractionated heparin compared with LMWH), Outcome 2 Incidence of major bleeding.$

Analysis 6.2

Comparison 6 Category I trials and initial treatment not the same in both groups (unfractionated heparin compared with LMWH), Outcome 2 Incidence of major bleeding.

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$Comparison 6 Category I trials and initial treatment not the same in both groups (unfractionated heparin compared with LMWH), Outcome 3 Mortality.$

Analysis 6.3

Comparison 6 Category I trials and initial treatment not the same in both groups (unfractionated heparin compared with LMWH), Outcome 3 Mortality.

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Analysis 7.1

Comparison 7 LMWH versus VKA during additional follow‐up (category I and II trials), Outcome 1 Incidence of recurrent VTE.

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Analysis 7.2

Comparison 7 LMWH versus VKA during additional follow‐up (category I and II trials), Outcome 2 Incidence of major bleeding.

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Analysis 7.3

Comparison 7 LMWH versus VKA during additional follow‐up (category I and II trials), Outcome 3 Mortality.

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Analysis 8.1

Comparison 8 LMWH versus VKA during additional nine months of follow‐up (category I trials), Outcome 1 Incidence of recurrent VTE.

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Analysis 8.2

Comparison 8 LMWH versus VKA during additional nine months of follow‐up (category I trials), Outcome 2 Incidence of major bleeding.

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Analysis 8.3

Comparison 8 LMWH versus VKA during additional nine months of follow‐up (category I trials), Outcome 3 Mortality.

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Analysis 9.1

Comparison 9 LMWH versus VKA for total period of 12 months of follow‐up (category I and II trials), Outcome 1 Incidence of recurrent VTE.

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Analysis 9.2

Comparison 9 LMWH versus VKA for total period of 12 months of follow‐up (category I and II trials), Outcome 2 Incidence of major bleeding.

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Analysis 9.3

Comparison 9 LMWH versus VKA for total period of 12 months of follow‐up (category I and II trials), Outcome 3 Mortality.

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Analysis 10.1

Comparison 10 LMWH versus VKA for total period of 12 months of follow‐up (category I trials), Outcome 1 Incidence of recurrent VTE.

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Analysis 10.2

Comparison 10 LMWH versus VKA for total period of 12 months of follow‐up (category I trials), Outcome 2 Incidence of major bleeding.

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Analysis 10.3

Comparison 10 LMWH versus VKA for total period of 12 months of follow‐up (category I trials), Outcome 3 Mortality.

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Summary of findings for the main comparison. LMWH compared with VKA for long term treatment of symptomatic VTE

LMWH compared with VKA for long term treatment of symptomatic VTE
Patient or population: patients with symptomatic VTE requiring long term treatment (3 months) for symptomatic VTE Setting: hospital and outpatient Intervention: LMWH Comparison: VKA
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with VKA	Risk with LMWH
Incidence of recurrent VTE (treatment duration 3 months)	Study population		Peto OR 0.83 (0.60 to 1.15)	3299 (16 RCTs)	⊕⊕⊕⊝ MODERATE^a,b
	51 per 1000	42 per 1000 (31 to 58)
Incidence of major bleeding (treatment duration 3 months)	Study population		Peto OR 0.51 (0.32 to 0.80)	3299 (16 RCTs)	⊕⊕⊝⊝ LOW^c,d
	29 per 1000	15 per 1000 (10 to 24)
Mortality (treatment duration 3 months)	Study population		Peto OR 1.08 (0.75 to 1.56)	3299 (16 RCTs)	⊕⊕⊕⊝ MODERATE^a,b
	35 per 1000	37 per 1000 (26 to 53)
* The basis for the assumed risk with VKA for 'Study population' was the average risk in the VKA group (i.e. total number of participants with events divided by total number of participants in the VKA group included in the meta‐analysis). The risk in the LMWH group (and its 95% confidence interval) is based on assumed risk in the VKA group and the relative effect of the intervention (and its 95% CI) CI: confidence interval; LMWH: low‐molecular‐weight heparin; OR: odds ratio; VKA: vitamin K antagonist; VTE: venous thromboembolism
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
^aHigh risk of bias due to no blinding but not downgraded, as analysis excluding studies deemed of low methodological quality confirms no clear differences between LMWH and VKA ^bDowngraded by one level owing to imprecision, small number of events, and relatively large confidence interval ^cDowngraded by one level for risk of bias, as sensitivity analysis based on category I trials (clearly concealed randomisation, double‐blind or blinded outcome assessment) shows no clear differences between VKA and LMWH. Bleeding outcomes are more susceptible to biased outcome reporting than outcomes such as VTE and mortality ^dDowngraded by one level for inconsistency: only two studies (studies of low methodological quality) reported less bleeding for LMWH, and the remainder showed no clear differences, with confidence intervals crossing the line of no effect

Summary of findings for the main comparison. LMWH compared with VKA for long term treatment of symptomatic VTE

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Comparison 1. LMWH versus VKA during allocated treatment (category I and II trials) in participants with VTE

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of recurrent VTE Show forest plot	16	3299	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.83 [0.60, 1.15]

2 Incidence of major bleeding Show forest plot	16	3299	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.51 [0.32, 0.80]

3 Mortality Show forest plot	16	3299	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.08 [0.75, 1.56]

Comparison 1. LMWH versus VKA during allocated treatment (category I and II trials) in participants with VTE

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Comparison 2. LMWH versus VKA during allocated treatment (category I and II trials) in participants with DVT

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of recurrent VTE Show forest plot	12	3021	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.79 [0.57, 1.11]

2 Incidence of major bleeding Show forest plot	12	3021	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.54 [0.33, 0.88]

3 Mortality Show forest plot	12	3021	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.10 [0.75, 1.60]

Comparison 2. LMWH versus VKA during allocated treatment (category I and II trials) in participants with DVT

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Comparison 3. LMWH versus VKA during allocated treatment (category I and II trials) in participants with PE

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of recurrent VTE Show forest plot	3	202	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.70 [0.91, 35.60]

2 Incidence of major bleeding Show forest plot	3	202	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.23 [0.03, 1.78]

3 Mortality Show forest plot	3	202	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.39 [0.51, 57.36]

Comparison 3. LMWH versus VKA during allocated treatment (category I and II trials) in participants with PE

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Comparison 4. LMWH versus VKA during allocated treatment (category I trials) in participants with VTE

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of recurrent VTE Show forest plot	7	1872	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.80 [0.54, 1.18]

2 Incidence of major bleeding Show forest plot	7	1872	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.62 [0.36, 1.07]

3 Mortality Show forest plot	7	1872	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.61, 1.41]

Comparison 4. LMWH versus VKA during allocated treatment (category I trials) in participants with VTE

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Comparison 5. Category I trials and the same initial treatment in both groups (unfractionated heparin or LMWH)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of recurrent VTE Show forest plot	2	292	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.95 [0.74, 5.19]

2 Incidence of major bleeding Show forest plot	2	292	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.01 [0.20, 5.12]

3 Mortality Show forest plot	2	292	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.89 [0.29, 2.68]

Comparison 5. Category I trials and the same initial treatment in both groups (unfractionated heparin or LMWH)

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Comparison 6. Category I trials and initial treatment not the same in both groups (unfractionated heparin compared with LMWH)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of recurrent VTE Show forest plot	5	1580	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.68 [0.44, 1.03]

2 Incidence of major bleeding Show forest plot	5	1580	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.59 [0.33, 1.04]

3 Mortality Show forest plot	5	1580	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.93 [0.59, 1.46]

Comparison 6. Category I trials and initial treatment not the same in both groups (unfractionated heparin compared with LMWH)

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Comparison 7. LMWH versus VKA during additional follow‐up (category I and II trials)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of recurrent VTE Show forest plot	10	2592	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.12 [0.77, 1.64]

2 Incidence of major bleeding Show forest plot	9	2112	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]

3 Mortality Show forest plot	10	2592	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.00 [0.71, 1.40]

Comparison 7. LMWH versus VKA during additional follow‐up (category I and II trials)

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Comparison 8. LMWH versus VKA during additional nine months of follow‐up (category I trials)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of recurrent VTE Show forest plot	5	1691	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.26 [0.81, 1.98]

2 Incidence of major bleeding Show forest plot	4	1211	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]

3 Mortality Show forest plot	5	1691	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.06 [0.72, 1.55]

Comparison 8. LMWH versus VKA during additional nine months of follow‐up (category I trials)

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Comparison 9. LMWH versus VKA for total period of 12 months of follow‐up (category I and II trials)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of recurrent VTE Show forest plot	10	2592	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.88 [0.67, 1.15]

2 Incidence of major bleeding Show forest plot	9	2112	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.56 [0.33, 0.95]

3 Mortality Show forest plot	10	2592	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.09 [0.84, 1.43]

Comparison 9. LMWH versus VKA for total period of 12 months of follow‐up (category I and II trials)

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Comparison 10. LMWH versus VKA for total period of 12 months of follow‐up (category I trials)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of recurrent VTE Show forest plot	5	1691	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.95 [0.70, 1.30]

2 Incidence of major bleeding Show forest plot	4	1211	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.72 [0.39, 1.32]

3 Mortality Show forest plot	5	1691	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.05 [0.78, 1.42]

Comparison 10. LMWH versus VKA for total period of 12 months of follow‐up (category I trials)

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