Secondary prevention of recurrent venous thromboembolism after initial oral anticoagulation therapy in patients with unprovoked venous thromboembolism

Lindsay Robertson; Su Ern Yeoh; Ahmad Ramli

doi:10.1002/14651858.CD011088.pub2

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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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Analysis 1.1

Comparison 1 Extended VTE prophylaxis versus placebo, Outcome 1 VTE‐related mortality.

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Analysis 1.2

Comparison 1 Extended VTE prophylaxis versus placebo, Outcome 2 Recurrent VTE.

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Analysis 1.3

Comparison 1 Extended VTE prophylaxis versus placebo, Outcome 3 Major bleeding.

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Analysis 1.4

Comparison 1 Extended VTE prophylaxis versus placebo, Outcome 4 All‐cause mortality.

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Analysis 1.5

Comparison 1 Extended VTE prophylaxis versus placebo, Outcome 5 Clinically relevant non‐major bleeding.

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Analysis 1.6

Comparison 1 Extended VTE prophylaxis versus placebo, Outcome 6 Stroke.

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Analysis 1.7

Comparison 1 Extended VTE prophylaxis versus placebo, Outcome 7 Serious adverse events (myocardial infarction).

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Analysis 2.1

Comparison 2 Extended VTE prophylaxis versus another extended VTE prophylaxis, Outcome 1 Recurrent VTE.

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Analysis 2.2

Comparison 2 Extended VTE prophylaxis versus another extended VTE prophylaxis, Outcome 2 Major bleeding.

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Analysis 2.3

Comparison 2 Extended VTE prophylaxis versus another extended VTE prophylaxis, Outcome 3 Clinically relevant non‐major bleeding.

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Summary of findings for the main comparison. Extended prophylaxis compared to placebo in patients with unprovoked venous thromboembolism

Extended prophylaxis compared to placebo in patients with unprovoked venous thromboembolism
Patient or population: patients with unprovoked venous thromboembolism Setting: hospital Intervention: extended prophylaxis Comparison: placebo
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo	Risk with extended prophylaxis
VTE‐related mortality^a	Study population		OR 0.98 (0.14 to 6.98)	1862 (4 RCTs)	⊕⊕⊝⊝ LOW^b	Two of the four studies reported no cases of VTE‐related mortality.
	2 per 1000	2 per 1000 (0 to 15)
Recurrent VTE^c	Study population		OR 0.63 (0.38 to 1.03)	2043 (5 RCTs)	⊕⊕⊕⊝ MODERATE^d
	170 per 1000	114 per 1000 (72 to 174)
Major bleeding^e	Study population		OR 1.84 (0.87 to 3.85)	2043 (5 RCTs)	⊕⊕⊝⊝ LOW^f
	11 per 1000	20 per 1000 (9 to 40)
All‐cause mortality^g	Study population		OR 1.00 (0.63 to 1.57)	2043 (5 RCTs)	⊕⊕⊕⊝ MODERATE^d
	38 per 1000	38 per 1000 (24 to 59)
Clinically relevant non‐major bleeding^h	Study population		OR 1.78 (0.59 to 5.33)	1672 (4 RCTs)	⊕⊕⊝⊝ LOW^f	Two of the four studies reported no cases of clinically relevant non‐major bleeding.
	6 per 1000	11 per 1000 (4 to 31)
Strokeⁱ	Study population		OR 1.15 (0.39 to 3.46)	1224 (2 RCTs)	⊕⊕⊕⊝ LOW^j
	10 per 1000	11 per 1000 (4 to 33)
Myocardial infarction	Study population		OR 1.00 (0.35 to 2.87)	1495 (3 RCTs)	⊕⊕⊕⊝ LOW^b
	9 per 1000	9 per 1000 (3 to 27)
*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; OR: odds ratio; RCT: randomised controlled trial; 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.
^aVTE‐related mortality ‐ death due to fatal PE. ^bDowngraded as high risk of selection bias in one study (WARFASA) and high risk of performance bias in another study (WODIT DVT). The evidence was downgraded further owing to imprecision, reflected by the small number of outcome events and wide confidence intervals around the estimate of effect. ^cRecurrence rate of symptomatic, objectively confirmed VTE (DVT or PE) during follow‐up. ^dDowngraded as high risk of selection bias in one study (WARFASA) and high risk of performance bias in two studies (WODIT DVT; WODIT PE). ^eMajor bleeding events: A major bleeding episode is defined as clinically overt bleeding that is associated with at least one of a fall in haemoglobin levels of 20 g/L or more; transfusion of at least 2 units of packed red blood cells; involvement of the intracranial or retroperitoneal space or a body cavity; or death (International Society on Thrombosis and Haemostasis definition) (Schulman 2005); or as defined by the investigators of each trial. ^fDowngraded as high risk of selection bias in one study (WARFASA) and high risk of performance bias in two studies (WODIT DVT; WODIT PE). The evidence was downgraded further owing to imprecision, reflected by the small number of outcome events and wide confidence intervals around the estimate of effect. ^gAll‐cause mortality ‐ death due to any cause. ^hClinically relevant non‐major bleeding as defined in each individual trial. ⁱStroke (both ischaemic and haemorrhagic). ^jDowngraded as high risk of selection bias in one study (WARFASA). The evidence was downgraded further owing to imprecision, reflected by the small number of outcome events and wide confidence intervals around the estimate of effect.

Summary of findings for the main comparison. Extended prophylaxis compared to placebo in patients with unprovoked venous thromboembolism

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Summary of findings 2. VTE extended prophylaxis compared to another VTE extended prophylaxis in patients with unprovoked venous thromboembolism

VTE extended prophylaxis compared to another VTE extended prophylaxis in patients with unprovoked venous thromboembolism
Patient or population: patients with unprovoked venous thromboembolism Setting: hospital Intervention: extended prophylaxis (rivaroxaban) Comparison: extended prophylaxis (aspirin)
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with aspirin	Risk with rivaroxaban
VTE‐related mortality^a	See comments.	See comments.	See comments.	See comments.		Data on VTE‐related mortality are yet available for participants with unprovoked VTE.
Recurrent VTE^b	Study population		OR 0.28 (0.15 to 0.54)	1389 (1 RCT)	⊕⊕⊕⊝ MODERATE^c
	56 per 1000	16 per 1000 (9 to 31)
Major bleeding^d	Study population		OR 3.06 (0.37 to 25.51)	1389 (1 RCT)	⊕⊕⊕⊝ MODERATE^c
	2 per 1000	7 per 1000 (1 to 52)
All‐cause mortality^e	See comments.	See comments.	See comments.	See comments.		Data on all‐cause mortality are not yet available for participants with unprovoked VTE.
Clinically relevant non‐major bleeding^f	19 per 1000	16 per 1000 (7 to 37)	OR 0.84 (0.37 to 1.94)	1389 (1 RCT)	⊕⊕⊕⊝ MODERATE^c
Stroke^g	See comments.	See comments.	See comments.	See comments.		Data on stroke are not yet available for participants with unprovoked VTE.
Myocardial infarction	See comments.	See comments.	See comments.	See comments.		Data on myocardial infarction are not yet available for participants with unprovoked VTE.
*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; OR: odds ratio; RCT: randomised controlled trial; 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.
^aVTE‐related mortality ‐ death due to fatal PE. ^bRecurrence rate of symptomatic, objectively confirmed VTE (DVT or PE) during follow‐up. ^cThe evidence was downgraded owing to imprecision, reflected by the small number of outcome events and wide confidence intervals around the estimate of effect. ^dMajor bleeding events: A major bleeding episode is defined as clinically overt bleeding that is associated with at least one of a fall in haemoglobin levels of 20 g/L or more; transfusion of at least 2 units of packed red blood cells; involvement of the intracranial or retroperitoneal space or a body cavity; or death (International Society on Thrombosis and Haemostasis definition) (Schulman 2005); or as defined by the investigators of each trial. ^eAll‐cause mortality ‐ death due to any cause. ^fClinically relevant non‐major bleeding as defined in each individual trial. ^gStroke (both ischaemic and haemorrhagic).

Summary of findings 2. VTE extended prophylaxis compared to another VTE extended prophylaxis in patients with unprovoked venous thromboembolism

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Comparison 1. Extended VTE prophylaxis versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 VTE‐related mortality Show forest plot	4	1862	Odds Ratio (M‐H, Fixed, 95% CI)	0.98 [0.14, 6.98]

1.1 Warfarin vs placebo	2	638	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Aspirin vs placebo	2	1224	Odds Ratio (M‐H, Fixed, 95% CI)	0.98 [0.14, 6.98]
2 Recurrent VTE Show forest plot	5	2043	Odds Ratio (M‐H, Random, 95% CI)	0.63 [0.38, 1.03]

2.1 Warfarin vs placebo	3	819	Odds Ratio (M‐H, Random, 95% CI)	0.52 [0.15, 1.80]
2.2 Aspirin vs placebo	2	1224	Odds Ratio (M‐H, Random, 95% CI)	0.68 [0.50, 0.92]
3 Major bleeding Show forest plot	5	2043	Odds Ratio (M‐H, Fixed, 95% CI)	1.84 [0.87, 3.85]

3.1 Warfarin vs placebo	3	819	Odds Ratio (M‐H, Fixed, 95% CI)	2.81 [0.89, 8.92]
3.2 Aspirin vs placebo	2	1224	Odds Ratio (M‐H, Fixed, 95% CI)	1.28 [0.47, 3.47]
4 All‐cause mortality Show forest plot	5	2043	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.63, 1.57]

4.1 Warfarin vs placebo	3	819	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.53, 2.17]
4.2 Aspirin vs placebo	2	1224	Odds Ratio (M‐H, Fixed, 95% CI)	0.95 [0.52, 1.72]
5 Clinically relevant non‐major bleeding Show forest plot	4	1672	Odds Ratio (M‐H, Fixed, 95% CI)	1.78 [0.59, 5.33]

5.1 Warfarin vs placebo	2	448	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Aspirin vs placebo	2	1224	Odds Ratio (M‐H, Fixed, 95% CI)	1.78 [0.59, 5.33]
6 Stroke Show forest plot	2	1224	Odds Ratio (M‐H, Fixed, 95% CI)	1.15 [0.39, 3.46]

6.1 Aspirin vs placebo	2	1224	Odds Ratio (M‐H, Fixed, 95% CI)	1.15 [0.39, 3.46]
7 Serious adverse events (myocardial infarction) Show forest plot	3	1495	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.35, 2.87]

7.1 Warfarin vs placebo	1	271	Odds Ratio (M‐H, Fixed, 95% CI)	1.02 [0.20, 5.16]
7.2 Aspirin vs placebo	2	1224	Odds Ratio (M‐H, Fixed, 95% CI)	0.98 [0.24, 3.94]

Comparison 1. Extended VTE prophylaxis versus placebo

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Comparison 2. Extended VTE prophylaxis versus another extended VTE prophylaxis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Recurrent VTE Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Major bleeding Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Clinically relevant non‐major bleeding Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Extended VTE prophylaxis versus another extended VTE prophylaxis

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