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

Prevención secundaria de la tromboembolia venosa recurrente después del tratamiento de anticoagulación oral inicial en pacientes con tromboembolia venosa sin causa aparente

Appendices

Appendix 1. CRS search strategy

Search run on Mon Mar 27 2017

#1	MESH DESCRIPTOR Thrombosis	1267
#2	MESH DESCRIPTOR Thromboembolism	921
#3	MESH DESCRIPTOR Venous Thromboembolism	258
#4	MESH DESCRIPTOR Venous Thrombosis EXPLODE ALL TREES	2041
#5	(thrombus* or thrombopro* or thrombotic* or thrombolic* or thromboemboli* or thrombos* or embol* or microembol*):TI,AB,KY	19072
#6	MESH DESCRIPTOR Pulmonary Embolism EXPLODE ALL TREES	748
#7	(PE or DVT or VTE):TI,AB,KY	4988
#8	((vein* or ven) near thromb):TI,AB,KY	6717
#9	(blood near3 clot*):TI,AB,KY	2966
#10	(pulmonary near3 clot*):TI,AB,KY	5
#11	(lung near3 clot*):TI,AB,KY	4
#12	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11	24711
#13	MESH DESCRIPTOR Anticoagulants	3362
#14	MESH DESCRIPTOR Warfarin EXPLODE ALL TREES	1168
#15	warfarin*:TI,AB,KY	3007
#16	(vitamin near3 antagonist*):TI,AB,KY	447
#17	VKA:TI,AB,KY	182
#18	couma:TI,AB,KY	746
#19	indobufen	82
#20	MESH DESCRIPTOR Platelet Aggregation Inhibitors EXPLODE ALL TREES	8563
#21	MESH DESCRIPTOR Phosphodiesterase Inhibitors EXPLODE ALL TREES	5590
#22	MESH DESCRIPTOR Tetrazoles	1857
#23	(antiplatelet* or anti‐platelet* or antiaggreg* or anti‐aggreg*):TI,AB,KY	3484
#24	(((platelet or thromboxane or thrombocyte or cyclooxygenase or cyclo‐oxygenase or phosphodiesterase or fibrinogen or PAR‐1) near3 (antagonist or inhibitor))):TI,AB,KY	2436
#25	((gp* or glycoprotein* or protease or P2Y12 or TXA2) near3 inhibit*):TI,AB,KY	3327
#26	thienopyridine:TI,AB,KY	284
#27	(ticlopidine or Ticlid):TI,AB,KY	1817
#28	(clopidogrel or Plavix):TI,AB,KY	3217
#29	(Prasugrel or Effient or Efient or Prasita):TI,AB,KY	561
#30	(ticagrelor or AZD6140 or Brilinta):TI,AB,KY	521
#31	(elinogrel or PRT060128 or PRT‐060128):TI,AB,KY	8
#32	(cangrelor or AR‐C6993* or ARC6993*):TI,AB,KY	55
#33	(SCH530348 or SCH‐530348):TI,AB,KY	21
#34	E5555:TI,AB,KY	6
#35	(terutroban or Triplion):TI,AB,KY	14
#36	(aspirin* or nitroaspirin or ASA):TI,AB,KY	17514
#37	(acetylsalicylic acid):TI,AB,KY	5169
#38	(acetyl salicylic acid*):TI,AB,KY	114
#39	(triflusal or disgren):TI,AB,KY	99
#40	(Cilostazol or Pletal or Pletaal):TI,AB,KY	481
#41	(dipyridamol* or Persantine):TI,AB,KY	1136
#42	(OPC‐13013 or OPC13013):TI,AB,KY	5
#43	(picotamide or picotinamide):TI,AB,KY	41
#44	satigrel:TI,AB,KY	3
#45	vorapaxar:TI,AB,KY	90
#46	indobufen:TI,AB,KY	82
#47	MESH DESCRIPTOR Antithrombins EXPLODE ALL TREES	1290
#48	MESH DESCRIPTOR Hirudin Therapy	75
#49	(thrombin near3 inhib*):TI,AB,KY	528
#50	hirudin*:TI,AB,KY	369
#51	(BIBR‐953* or BIBR953* or BIBR‐1048 or BIBR1048):TI,AB,KY	9
#52	(AZD0837 or AZD‐0837):TI,AB,KY	14
#53	MESH DESCRIPTOR Factor Xa Inhibitors	326
#54	(Factor X* near4 (antag* or inhib* or block*)):TI,AB,KY	634
#55	(FX* near4 (antag* or inhib* or block*)):TI,AB,KY	50
#56	(10* near4 (antag* or inhib* or block*) ):TI,AB,KY	1129
#57	*igatran:TI,AB,KY	458
#58	*agatran:TI,AB,KY	157
#59	*ixaban:TI,AB,KY	388
#60	*oxaban:TI,AB,KY	748
#61	*axaban:TI,AB,KY	7
#62	((DU‐176b or DU176b)):TI,AB,KY	11
#63	((PRT‐054021 or PRT054021)):TI,AB,KY	1
#64	((YM150 or YM‐150 or LY517717 or LY‐517717 or DU‐176b or DU176*)):TI,AB,KY	41
#65	((GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK‐813893 or GSK813893)):TI,AB,KY	3
#66	#13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #60 OR #61 OR #62 OR #63 OR #64 OR #65	42400
#67	MESH DESCRIPTOR Secondary Prevention	2531
#68	MESH DESCRIPTOR Recurrence	10094
#69	secondary:TI,AB,KY	67519
#70	recurr*:TI,AB,KY	38684
#71	reoccur*:TI,AB,KY	129
#72	duration:TI,AB,KY	78656
#73	extended:TI,AB,KY	10203
#74	prolong:TI,AB,KY	2299
#75	(month* or year*):TI,AB,KY	318293
#76	#67 OR #68 OR #69 OR #70 OR #71 OR #72 OR #73 OR #74 OR #75	400159
#77	#12 AND #66 AND #76	3837

Appendix 2. Trials registry searches

CinicalTrials.gov

196 studies found for

thromboembolism OR embolism OR thrombosis/Condition

AND

recurrence OR reoccurrence OR recurrent/Outcome measures

World Health Organization International Clinical Trials Registry Platform

80 records for 18 trials found for: thromboembolism AND recurrence AND prevent*

72 records for 25 trials found for: thrombosis AND recurrent AND prevent*

82 records for 18 trials found for: embolism AND recurrent AND prevent*

75 records for 16 trials found for: embolism AND recurrence AND prevent*

ISRCTN Register

98 results (recurrence OR reoccurrence OR recurrent) AND (thromboembolism OR embolism OR thrombosis)

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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Prevención secundaria de la tromboembolia venosa recurrente después del tratamiento de anticoagulación oral inicial en pacientes con tromboembolia venosa sin causa aparente

Appendices

Appendix 1. CRS search strategy

Appendix 2. Trials registry searches

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Appendices

Appendix 1. CRS search strategy

Appendix 2. Trials registry searches

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