Systematic review and meta-analysis of outcomes in patients with suspected deep vein thrombosis

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Article

Reference

Systematic review and meta-analysis of outcomes in patients with suspected deep vein thrombosis

PATEL, Payal, et al.

Abstract

After deep vein thrombosis (DVT) is diagnosed, prompt evaluation and therapeutic intervention are of paramount importance for improvement in patient-important outcomes. We systematically reviewed patient-important outcomes in patients with suspected DVT, including mortality, incidence of pulmonary embolism (PE) and DVT, major bleeding, intracranial hemorrhage, and postthrombotic sequelae. We searched the Cochrane Central Register of Controlled Trials, Ovid Medline, Embase for eligible studies, references lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Nine studies with 5126 patients were included for lower extremity DVT.

Three studies with 500 patients were included for upper extremity DVT. Among patients with lower extremity DVT, 0.85% (95% confidence interval [CI], 0% to 2.10%) and 0% developed recurrent DVT and PE, respectively, at 3 months. Among patients with upper extremity DVT, 0.49% (95% CI, 0% to 1.16%) and 1.98% (95% CI, 0.62% to 3.33%) developed recurrent DVT and PE, respectively, at 3 months. No major bleeding events were [...]

PATEL, Payal, et al . Systematic review and meta-analysis of outcomes in patients with suspected deep vein thrombosis. Blood advances , 2020, vol. 4, no. 12, p. 2779-2788

DOI : 10.1182/bloodadvances.2020001558 PMID : 32569377

Available at:

http://archive-ouverte.unige.ch/unige:155630

Disclaimer: layout of this document may differ from the published version.

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Supplementary Material 1. Diagnostic Pathway Diagrams

Diagnosis of Lower Extremity Deep Vein Thrombosis: Diagnostic Pathways Assessed

a. Whole leg US

• Positive whole leg US  anticoagulate

• Negative whole leg US  no treatment

b. Proximal CUS

• Positive proximal CUS  anticoagulate

• Negative proximal CUS  no treatment

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c. Proximal CUS

• Negative proximal CUS  D-Dimer o Positive D-Dimer  anticoagulate o Negative D-Dimer  no treatment

d. Proximal CUS

• Negative proximal CUS  D-dimer o Positive D-dimer  serial US

 Positive serial US  anticoagulate

 Negative serial US  no treatment o Negative D-dimer  no treatment

(4)

e. Proximal CUS

• Negative proximal CUS  Serial US o Positive Serial US  anticoagulate o Negative Serial US  no treatment

f. Proximal CUS

• Positive proximal CUS anticoagulate

• Negative proximal CUS  D-Dimer o Positive D-Dimer  venography

 Positive venography  anticoagulate

 Negative venography  No treatment o Negative D-Dimer No treatment

*Venography was deemed not suitable as a follow-up test due to the use of ultrasound as the accepted reference standard for DVT diagnosis.

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g. D-dimer

• Positive D-dimer  anticoagulate

• Negative D-dimer  no treatment

h. D-dimer

• Positive D-dimer  proximal CUS

o Positive proximal CUS  anticoagulate o Negative proximal CUS  no treatment

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i. D-dimer

• Positive D-dimer  whole leg/serial US

o Positive whole leg/serial US  anticoagulate o Negative whole leg/serial US  no treatment

** Whole Leg US sensitivity and specificity estimates were used to model Pathway I.

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Diagnosis of Upper Extremity DVT: Diagnostic Pathways Assessed a. Duplex US

• Positive duplex US  anticoagulate

• Negative duplex US  no treatment

b. Duplex US

• Negative duplex US  serial US

o Positive serial US  anticoagulate o Negative serial US  no treatment

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c. Duplex US

• Negative duplex US  D-dimer

o Positive D-dimer  anticoagulate o Negative D-dimer  no treatment

d. Duplex US

• Negative duplex US  D-dimer o Positive D-dimer  serial US

 Negative serial US  no treatment o Negative D-dimer  no treatment

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e. D-dimer

f. D-dimer

• Positive D-dimer  duplex US

o Positive duplex US  anticoagulate o Negative duplex US  no treatment

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g. D-dimer

• Positive D-dimer  duplex US

o Positive duplex US  anticoagulate o Negative duplex US  serial US

 Negative serial US  no treatment

h. D-dimer

• Negative D-dimer  duplex US

o Positive duplex US  anticoagulate o Negative duplex US  no treatment

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American Society of Hematology Guidelines for Management of Venous Thromboembolism: Diagnosis of Venous Thromboembolism

Supplementary Material 2. Search Strategies

Recommendations 1-10: Diagnosis of Venous Thromboembolism

OVERVIEW

Interface: Ovid

Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present

Date of Search: May 9th, 2016

Study Types: Systematic reviews; diagnostic test accuracy studies; randomized trials

Limits: None

Search Strategy: search terms (number of results) Any diagnostic intervention (CTPA, CUS, D-dimer, VQ):

1 ultrasonography/ or ultrasonography, doppler/ (77097) 2 (ultrasound$ or ultrason$ or sonograph$).mp. (365834) 3 or/1-2 (365834)

4 Fibrin Fibrinogen Degradation Products/ (7338) 5 (D-dimer or d dimer).mp. (7096)

6 (label$ adj2 (fibrogen or fibrinogen)).mp. (631) 7 4 or 5 or 6 (11390)

8 exp Cone-Beam Computed Tomography/ (5051) 9 Tomography, Spiral Computed/ (6878)

10 Tomography, X-Ray Computed/ (317079)

11 (compute* tomograph* or compute*-tomograph*).mp. (222821) 12 or/8-11 (431702)

13 exp Ventilation-Perfusion Ratio/ (5575)

14 (lung adj1 (ventilation or perfusion)).ti,ab,kw. (5817) 15 (lung adj ventilation adj scan).ti,ab,kw. (1)

16 (lung adj perfusion adj scan).ti,ab,kw. (146) 17 (lung adj1 scan).ti,ab,kw. (1081)

18 VQ scan.mp. (25)

19 13 or 14 or 15 or 16 or 17 or 18 (11400) 20 3 or 7 or 12 or 19 (773789)

VTE terms:

21 exp Thromboembolism/ or exp Venous Thromboembolism/ (47568) 22 exp Pulmonary Embolism/ (33893)

23 exp Venous Thrombosis/ (48320) 24 Thrombophlebitis/ (21375) 25 (DVT or VTE or PE).mp. (39840)

26 ((Pulmon$ or vein or venous or lung) adj (Emboli$ or thromb$)).mp. (92654)

27 (thrombus* or thrombotic* or thrombolic* or thromboemboli* or thrombos* or embol*).mp. (326912) 28 (((deep or thromb* or stasis) adj2 (vein* or venous)) or (blood flow stasis or blood clot)).mp. (67667) 29 or/21-28 (368661)

Diagnosis filter:

30 exp "Sensitivity and Specificity"/ (469183) 31 (sensitivity or specificity).tw. (809446) 32 (predictive adj3 value$).tw. (81055)

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American Society of Hematology Guidelines for Management of Venous Thromboembolism: Diagnosis of Venous Thromboembolism

33 exp diagnostic errors/ (101771)

34 ((false adj positiv$) or (false adj negativ$)).tw. (62229) 35 (observer adj variation$).tw. (1026)

36 (roc adj curve$).tw. (18740) 37 (likelihood adj3 ratio$).tw. (11054) 38 likelihood functions/ (18752)

39 *Thromboembolism/di, ra, ri, us (798) 40 *Thrombophlebitis/di, ra, ri, us (3026) 41 *Venous Thrombosis/di, ra, ri, us (3030) 42 or/30-41 (1283612)

43 20 and 29 and 42 (8812) Annotation: Any diagnostic intervention AND VTE AND Diagnosis filter Systematic review filter:

44 meta-analysis/ (65208) 45 meta-analysis as topic/ (14831)

46 (meta analy* or metanaly* or metaanaly*).ti,ab. (90932)

47 (reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab. (30721) 48 ((systematic* or evidence*) adj2 (review* or overview*)).ti,ab. (105255)

49 (search strategy or search criteria or systematic search or study selection or data extraction).ab. (33398) 50 (search* adj4 literature).ab. (37180)

51 (medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab. (119376)

52 ((pool* or combined) adj2 (data or trials or studies or results)).ab. (38566) 53 cochrane.jw. (12302)

54 or/44-53 (287349)

55 animals/ not humans/ (4203767) 56 exp Animals, Laboratory/ (770845) 57 exp Animal Experimentation/ (7910) 58 exp Models, Animal/ (464566) 59 exp Rodentia/ (2869455)

60 (rat or rats or mouse or mice).ti. (1189636) 61 or/55-60 (4963714)

62 54 not 61 (274387) 63 43 and 62 (254) 64 43 not 63 (8558) Records Retrieved:

Systematic review = 254 Other study design = 8558

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American Society of Hematology Guidelines for Management of Venous Thromboembolism: Diagnosis of Venous Thromboembolism

OVERVIEW

Interface: Ovid

Database: Embase 1974 to 2016 Week 07 Date of Search: May 9th, 2016

Study Types: Systematic reviews; diagnostic test accuracy studies; randomized trials

Limits: None

Search Strategy: search terms (number of results) Any diagnostic intervention (CTPA, CUS, D-dimer, VQ):

1 ultrasonography/ or ultrasonography, doppler/ (195494) 2 (ultrasound$ or ultrason$ or sonograph$).mp. (479288) 3 1 or 2 (554916)

4 fibrin degradation product/ (3142) 5 D dimer/ (13156)

6 (D-dimer or d dimer).mp. (16014)

7 (label$ adj2 (fibrogen or fibrinogen)).mp. (557) 8 4 or 5 or 6 or 7 (18440)

9 exp cone beam computed tomography/ (8539) 10 spiral computer assisted tomography/ (10925) 11 computer assisted tomography/ (580883)

12 (compute* tomograph* or compute*-tomograph*).mp. (360312) 13 or/9-12 (744247)

14 exp lung scintiscanning/ (6764) 15 exp Ventilation-Perfusion Ratio/ (6101)

16 (lung adj1 (ventilation or perfusion)).ti,ab,kw. (7981) 17 (lung adj ventilation adj scan).ti,ab,kw. (3)

18 (lung adj perfusion adj scan).ti,ab,kw. (218) 19 (lung adj1 scan).ti,ab,kw. (1348)

20 VQ scan.mp. (105)

21 14 or 15 or 16 or 17 or 18 or 19 or 20 (18644)

22 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 (1239511)

VTE terms:

23 exp vein thrombosis/ (100825)

24 exp Venous Thromboembolism/ (111295) 25 exp 'lung embolism'/ (70029)

26 Thrombophlebitis/ (16025) 27 (PE or DVT or VTE).mp. (62340)

28 ((Pulmon$ or vein or venous or lung) adj (Emboli$ or thromb$)).mp. (166579)

29 (thrombus* or thrombotic* or thrombolic* or thromboemboli* or thrombos* or embol*).mp. (527773) 30 (((deep or thromb* or stasis) adj2 (vein* or venous)) or (blood flow stasis or blood clot)).mp. (158324) 31 or/23-30 (597688)

Diagnosis filter:

32 exp "sensitivity and specificity"/ (245520) 33 (sensitivity or specificity).tw. (958912) 34 (predictive adj3 value$).tw. (114518)

35 ((false adj positiv$) or (false adj negativ$)).tw. (77829)

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American Society of Hematology Guidelines for Management of Venous Thromboembolism: Diagnosis of Venous Thromboembolism

36 (observer adj variation$).tw. (1345) 37 (roc adj curve$).tw. (33158) 38 (likelihood adj3 ratio$).tw. (14400) 39 *Diagnostic Accuracy/ (6352) 40 *Thromboembolism/di (2018) 41 *Thrombophlebitis/di (1624) 42 *Venous Thrombosis/di (926)

43 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 (1192770)

44 22 and 31 and 43 (8959) Annotation: Any diagnostic intervention AND VTE AND Diagnosis filter Systematic review filter:

45 systematic review/ (105938) 46 meta-analysis/ (108354)

47 (meta analy* or metanaly* or metaanaly*).ti,ab. (119945)

48 (reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab. (35710) 49 ((systematic* or evidence*) adj2 (review* or overview*)).ti,ab. (129874)

50 (search strategy or search criteria or systematic search or study selection or data extraction).ab. (38947) 51 (search* adj4 literature).ab. (46763)

52 (medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab. (147674)

53 ((pool* or combined) adj2 (data or trials or studies or results)).ab. (49701) 54 cochrane.jw. (13184)

55 or/45-54 (384419)

56 animals/ not humans/ (1150971) 57 nonhuman/ (4742930)

58 exp Animal Experiment/ (1824805) 59 exp Experimental Animal/ (508398) 60 animal model/ (868145)

61 exp Rodent/ (3009466)

62 (rat or rats or mouse or mice).ti. (1283287) 63 56 or 57 or 58 or 59 or 60 or 61 or 62 (6713559) 64 55 not 63 (347559)

65 44 and 64 (367) 66 44 not 65 (8592) Records Retrieved:

Systematic review = 367 Other study design = 8592

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American Society of Hematology Guidelines for Management of Venous Thromboembolism: Diagnosis of Venous Thromboembolism

OVERVIEW

Interface: Cochrane Library

Database: Cochrane Database of Systematic Reviews Date of Search: May 9th, 2016

Study Types: Systematic reviews Limits: Publication date from 2006 Search Strategy: search terms (number of results) Any diagnostic intervention (CTPA, CUS, D-dimer, VQ):

#1 MeSH descriptor: [Ultrasonography] this term only 940

#2 MeSH descriptor: [Ultrasonography, Doppler] this term only 542

#3 (ultrasound* or ultrason* or sonograph*) 24608

#4 #1 or #2 or #3 24608

#5 MeSH descriptor: [Ventilation-Perfusion Ratio] explode all trees 132

#6 (lung near/1 (ventilation or perfusion)):ti,ab,kw 1068

#7 (lung near ventilation near scan):ti,ab,kw 19

#8 (lung near perfusion near scan):ti,ab,kw 42

#9 (lung near/1 scan):ti,ab,kw 66

#10 (VQ scan) 11

#11 #5 or #6 or #7 or #8 or #9 or #10 1218

#12 MeSH descriptor: [Fibrin Fibrinogen Degradation Products] this term only 488

#13 (D-dimer or d dimer) 1190

#14 (label* near/2 (fibrogen or fibrinogen)) 63

#15 #12 or #13 or #14 1400

#16 MeSH descriptor: [Tomography, X-Ray Computed] this term only 4171

#17 MeSH descriptor: [Cone-Beam Computed Tomography] explode all trees 139

#18 MeSH descriptor: [Tomography, Spiral Computed] this term only 215

#19 (compute* tomograph* or compute*-tomograph*) 13501

#20 (CT or CAT or CAPT):ti,ab 10276

#21 #16 or #17 or #18 or #19 or #20 18898

#22 #4 or #11 or #15 or 21 130946 VTE terms:

#23 MeSH descriptor: [Venous Thrombosis] explode all trees 2448

#24 MeSH descriptor: [Thromboembolism] explode all trees 1892

#25 MeSH descriptor: [Venous Thromboembolism] explode all trees 513

#26 MeSH descriptor: [Pulmonary Embolism] explode all trees 982

#27 MeSH descriptor: [Thrombophlebitis] this term only 1095

#28 (DVT or VTE or PE) 9108

#29 ((Pulmon* or vein or venous or lung) near (Emboli* or thromb*)) 9413

#30 (Thrombus* or thrombotic* or thrombolic* or thromboemboli* or thrombos* or embol*) 22668

#31 (((deep or thromb* or stasis) near/2 (vein* or venous)) or (blood flow stasis or blood clot)) 8726

#32 #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 30977

#33 #22 and #32 7717 Diagnosis filter:

#34 MeSH descriptor: [Sensitivity and Specificity] explode all trees 17846

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American Society of Hematology Guidelines for Management of Venous Thromboembolism: Diagnosis of Venous Thromboembolism

#35 (sensitivity or specificity) 59020

#36 (predictive adj3 value$) 157

#37 MeSH descriptor: [Diagnostic Errors] explode all trees 2854

#38 (false adj positiv*) or (false adj negativ*) 202

#39 (observer adj variation*) 263

#40 (roc adj curve*) 43

#41 (likelihood adj3 ratio*) 638

#42 MeSH descriptor: [Likelihood Functions] explode all trees 393

#43 MeSH descriptor: [Thromboembolism] explode all trees and with qualifier(s): [Diagnosis - DI, Radiography - RA, Radionuclide imaging - RI, Ultrasonography - US] 229

#44 MeSH descriptor: [Thrombophlebitis] explode all trees and with qualifier(s): [Diagnosis - DI, Radiography - RA, Radionuclide imaging - RI, Ultrasonography - US] 260

#45 MeSH descriptor: [Venous Thrombosis] explode all trees and with qualifier(s): [Diagnosis - DI, Radiography - RA, Radionuclide imaging - RI, Ultrasonography - US] 537

#46 #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 67078

#47 #33 and #46 Publication Year from 2006 to 2016 1935 Annotation: Any diagnostic intervention AND VTE AND Diagnosis filter

All Results (1935) Cochrane Reviews (1443) Review (1206)

Protocol

Other Reviews (87) Trials (342)

Methods Studies (2) Technology Assessments (1) Economic Evaluations (48) Cochrane Groups (12) Records Retrieved: 1294

Cochrane reviews: 1206 Other reviews: 87

Technology Assessments: 1

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Supplementary Material 3. Detailed Outcomes Tables

Table 1: Outcomes in treated patients with low clinical probability of LE DVT – (TP and FP) Studies Patients

with LEDVT/

Total patients

Clinical probab ility or prevale nce

Pathway Number of patients with positive XXX/

Total patients tested with XXX

Patients anticoa gulated

Lost to follo w up

Mortalit y: all cause

Mortalit y: from VTE at 3 months

Recurre nce of VTE on AC at 3 months

Post thrombotic sequelae

Major

bleeding Hemorr hagic Stroke

Anderson

1999 45/344

(6/190 (low prob group)

Low CUS positive 5/190: TP

0/190: FP 5/190 0/5 0/5 0/5 0/5 0/5 0/5 0/5

Anderson

1999 45/344

(15/105 mod prob group)

Mod CUS positive 13/105: TP

0/105: FP 13/105 0/13 0/13 0/13 0/13 0/13 0/13 0/13

TOTAL 0/18 0/18

(0%) 0/18

(0%) 0/18 (0%) 0/18

(0%) 0/18 (0%) Anderson

1999 45/344

(24/49 high prob group)

High CUS positive 20/49: TP

0/49: FP 20/49 0/20 2/24 0/24 0/24 0/24 0/24 0/24

TOTAL 0/20 2/24

(8.33%;

95%CI:

0%-19.39%) 0/24

(0%) 0/24

(0%) 0/24 (0%) 0/24

(0%) 0/24 (0%)

Anderson

1999 45/344

Mod CUS positive or CUS negative

 serial US positive

14/105: TP

0/105: FP 14/105 0/14 0/14 0/14 0/14 0/14 0/14 0/14

Birdwell

1998 66/405 16.3% CUS positive or CUS negative

63/405 (CUS positive) 7/342 (CUS negative, serial US positive) Overall TP:

65/70 Overall FP: 5/70

65/70 0/70 7/70 0/70 4/65 NR NR NR

Birdwell

2000 104/709 14.6% CUS positive or CUS negative

104/709: TP 104/709 0/10

4 NR 0/104 7/104

(DVT) 0/104 (PE)

NR NR NR

TOTAL 0/84 7/84

(8.33%;

95%CI:

2.42%- 14.24%)

0/84

(0%) 4/79 (DVT) (5.06%;

95%CI:

0.23%- 9.90%)

0/14 (0%) 0/14

(0%) 0/14 (0%)

Cornuz

2002 82/278 Low:14

/278 Mod:3 6/278 High:32 /278 Overall :29.4%

D-Dimer positive  CUS positive

80/278: TP

0/278: FP 80/278 0/80 5/80 0/80 0/80 NR NR NR

TOTAL 0/80 5/80

(6.25%;

95%CI:

0.95%- 11.55%)

0/80

(0%) 0/80

(0%) NR NR NR

Legnani

2010 90/401

(7/106 low prob group)

Low D-Dimer

positive 7/106: TP

54/106: FP 7/106 NR NR 0/61 0/61 0/61 0/61 0/61

Legnani

2010 90/401

Mod D-Dimer

positive 38/216: TP

103/216: FP 38/216 NR NR 0/141 0/141 0/141 0/141 0/141

TOTAL NR NR 0/202

(0%) 0/202

(0%) 0/202 (0%) 0/202

(0%) 0/202 (0%)

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Legnani

2010 90/401

(45/79 high prob group)

High D-Dimer

positive 45/79 TP

23/79: FP 45/79 NR NR 0/68 0/68 0/68 0/68 0/68

TOTAL NR NR 0/68

(0%) 0/68

(0%) 0/68 (0%) 0/68

(0%) 0/68 (0%) NR = not reported

Table 2:Outcomes in patients not treated with low clinical probability of LE DVT – (TN and FN) Studies Patients with

LEDVT/ Total patients

Clinical probabili ty or prevalen ce

Pathway Number of patients with negative XXX/

Total patients tested with XXX

Lost to follow up

Mortali ty: all cause

Mortalit y: from VTE at 3 months

VTE events at 3 months Post

thromb otic sequela e

Major bleedi ng

Hemorrha gic Stroke

Anderson

1999 45/344 (6/190

low prob group) Low/

3.16% Negative

CUS 185/190 0/185 2/185 0/185 1/185 (DVT) 0/185 0/185 0/185 Anderson

1999 45/344 (15/105

mod prob group) Mod/

14.3% Negative

CUS 92/105 0/92 0/92 0/92 2/92 (DVT) 0/92 0/92 0/92 Birdwell

1998 66/405 16.3% Negative

CUS 342/405 0/342 8/335 0/335 7/335 (DVT)

1/335 (PE) NR NR NR

Wells

2003 16/284 Unlikely/

5.63% Negative

CUS 272/284 5/272 NR 0/272 4/272 (PE) NR NR NR

TOTAL 5/891 10/612

(1.63%;

95%CI 0.63%- 2.64%)

0/884

(0%) 10/884 (DVT) (1.13%;

95%CI:

0.43%- 1.83%) 5/884 (PE) (0.57%;

95%CI:

0.07%- 1.06%) 15/844 (Overall) (1.70%95%

CI: 0.89%- 2.67%)

0/277

(0%) 0/277

(0%) 0/277 (0%)

Wells

2003 67/246 Likely/

27.2% Negative

CUS 182/246 5/182 NR 0/182 2/182 (PE)

1/182 (DVT) NR NR NR

Wells

2003 71/249 Likely/

28.5% Negative

CUS 181/249 2/181 NR 0/181 3/181 (DVT) NR NR NR

TOTAL 7/363 NR 0/363

(0%) 2/363 (PE) (0.55%;

95%CI: 0%- 1.31%) 4/363 (DVT) (1.10%;

95%CI 0.03%- 2.18%) 6/363 (Overall) (1.65%;

95CI:0.34%- 2.96%)

NR NR NR

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Anderson

1999 45/344 (24/49

high prob group) High/

49% Negative

CUS 29/49 0/29 0/25 0/25 4/29 (DVT) 0/29 0/29 0/29

TOTAL 0/29 0/25

(0%) 0/25

(0%) 4/29 (DVT) (13.8%;

95%CI 1.24%- 26.34%) 0/29 (PE) (0%)

0/29

(0%) 0/29

(0%) 0/29 (0%)

Luxembou

rg 2012 90/243 37.0% Negative

whole leg US

154/243 6/154 2/154 0/148 1/148 (DVT) NR NR NR

TOTAL 6/154 2/154

(1.30%;

95%CI:

0%-2.18%)

0/148

(0%) 1/148 (DVT) (0.68%;

95%CI: 0%- 2.0%) 0/148 (PE) (0%)

NR NR NR

Anderson

1999 45/344 (15/105

14.3% Negative CUS  negative serial US

91/92 0/91 0/91 0/91 1/91 (DVT) 0/91 0/91 0/91

Birdwell

1998 66/405 16.3% Negative

CUS  negative serial US

335/342 0/335 8/335 0/335 1/335 (DVT)

1/355 (PE) NR NR NR

Birdwell

2000 104/709 14.6% Negative

CUS  negative serial US

605/709 1/605 NR 0/605 4/605 (DVT) NR NR NR

Wells

2003 67/246 Likely/

27.2% Negative CUS  negative serial US

181/182 5/181 NR 0/181 2/181 (PE) NR NR NR

TOTAL 6/121

2 8/426

(1.88%;

95%CI:

0.59%- 3.17%)

0/1212

(0%) 6/1212 (DVT) (0.50%;

95%CI:

0.10%- 0.89%) 3/1212 (PE) (0.25%;

95%CI: 0%- 0.53%) 9/1212 (Overall) (0.74%;

95%CI:

0.26%- 1.23%)

0/91

(0%) 0/91

(0%) 0/91 (0%)

Legnani

2010 90/401 (7/106

low prob group) Low/

6.60% Negative

DD 45/106 NR 0/45 0/45 0/45 (VTE) 0/45 0/45 0/45

Legnani

2010 90/401 (38/216

17.6% Negative

DD 75/216 NR 0/75 0/75 0/75 (VTE) 0/75 0/75 0/75

Wells

2003 16/317 Unlikely/

5.04% Negative

DD 218/317 0/218 NR 0/218 2/218 (DVT) NR NR NR

TOTAL 0/218 0/120

(0%) 0/338

(0%) 2/338 (DVT) (1.03%;

95%CI 0%- 1.41%) 0/338 (PE) (0%)

0/120

(0%) 0/120

(0%) 0/120 (0%)

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Cornuz

2002 82/278 Low:

14/278 Mod:

36/278 High:

32/278 Overall:2 9.4%

Negative

DD 49/227 0/49 0/49 0/49 2/49 (DVT) NR NR NR

TOTAL 0/49 0/49

(0%) 0/49

(0%) 2/49 (DVT) (4.08%;

95%CI 0%- 9.62%) 0/49 (PE) (0%)

NR NR NR

Legnani

2010 90/401 (45/79

high prob group) High/

57% Negative

DD 11/79 NR 0/11 0/11 0/11 (VTE) 0/11 0/11 0/11

TOTAL NR 0/11

(0%) 0/11

(0%) 0/11 (DVT) (0%) 0/11 (PE) (0%)

0/11

(0%) 0/11

(0%) 0/11 (0%) Bernardi

1998 268/946 28.3% Negative

CUS  Negative DD

598/686 2/598 4/598 0/598 1/598 (DVT) NR NR NR

Wells

2003 71/249 Likely/

28.5% Negative CUS  Negative DD

81/181 0/81 NR 0/81 0/81 (VTE) NR NR NR

TOTAL 2/679 4/598

(0.67%;

95%CI:

0.02%- 1.32%)

0/679

(0%) 1/679 (DVT) (0.15%;

95%CI: 0%- 0.44%) 0/679 (PE) (0%)

NR NR NR

Bernardi

1998 268/946 28.3% Negative

CUS  Positive DD

 negative serial US

83/88 0/83 1/83 1/83 2/83 (PE) NR NR NR

Wells

2003 71/249 Likely/

28.5% Negative CUS  positive DD

 negative serial US

97/100 0/97 NR 0/97 0/97 (VTE) NR NR NR

TOTAL 0/180 1/83

(1.20%;

95%CI:

0%-3.55%)

1/180 (0.56%;

95%CI:

0%-1.64%)

2/180 (PE) (1.11%;

95%CI; 0%- 2.64%) 0/180 (DVT) (0%)

NR NR NR

Schutgens

2002 254/704 36% Positive DD

 negative whole leg US

464/704 0/464 NR NR 13/464

(DVT) NR NR NR

TOTAL 0/464 NR NR 13/464

(DVT) (2.80%;

95%CI:

1.30%- 4.30%) 0/464 (PE) (0%)

NR NR NR

(21)

Wells

2003 16/317 Unlikely/

5.04% Positive DD

 negative CUS

85/99 2/85 NR 0/85 0/85 (VTE) NR NR NR

TOTAL 2/85 NR 0/85 0/85 (DVT)

(0%) 0/85 (PE) (0%)

NR NR NR

Cornuz

2002 82/278 Low:14/

278 Mod:36/

278 High:32/

278 Overall:2 9.4%

D-Dimer negative and/or CUS negative

198/278 0/198 0/198 0/198 2/198 (DVT) NR NR NR

NR = not reported

Table 3: Outcomes in treated patients with low clinical probability of UE DVT – (TP and FP) Studies Patients

UEDVT/

Clinical probab ility or prevale nce

Pathway Number of patients with positive XXX/ Total patients tested with XXX

Lost to follo w up

Patient anticoa gulated

Mortalit y: from UE DVT at 3 months

Develop ment of PE at 3 months

Mortalit y from PE at 3 months

Recurr ent UE DVT

Post throm botic syndro me/se quelae

Major bleedi ng

Hemorr hagic Stroke

Kleinjei

n 2014 12/200 0.06% D-Dimer

positive 12/200: TP

100/200: FP 0/112 12/200 2/203 0/112 0/112 0/112 0/112 NR NR NR

TOTAL 2/203

(0.99%;

95%CI:

0%-2.34%)

0/112 0/112 0/112 0/112 NR NR NR

Kleinjei

n 2014 12/200 0.06% D-Dimer positive

 US positive

12/200: TP

25/200: FP 0/37 12/112 2/203 0/37 0/37 0/37 0/37 NR NR NR

TOTAL 2/203

(0.99%;

95%CI;

0.37%- 2.34%)

0/37

(0%) 0/37

(0%) NR NR NR

Prando

ni 1997 27/58 47% US

positive 27/58: TP

2/58: FP 0/29 27/58 5/58 0/29 8/22 pts 0/58 at 3mo (1/58 at 4 mo)

2/27 0/58 at 3 mo (4/58 within 2 years)

NR NR

Kleinjei

n 2014 91/203 44% US

positive 86/203: TP

29/203: FP 0/115 86/203 5/203 0/115 0/115 0/115 0/115 NR NR NR

TOTAL ^10/261

(3.83%;9 5%CI:1.5 0%-6.16%)

0/144

(0%) 8/137 (5.84%;9 5%CI:1.9 1%-9.76%)

0/173

(0%) ^2/142^(1.41%;

95%CI:0

%-3.34%)

Overall VTE 10/142 (7.04%;

95% CI:2.83

%-11.25%) 0/58

(0%) NR NR

Kleinjei

n 2014 91/203 44% US positive OR US negative

 DD positive

86/203 (US positive) 4/88 (US neg, DD pos, serial US pos) Overall TP:

0/119 90/203 5/203 0/119 0/119 0/119 0/119 NR NR NR

(22)

90/203 Overall FP:

29/203

TOTAL 5/203

(2.46%;

95%CI:

0.33%- 4.59%)

0/119

(0%) 0/119

(0%) NR NR NR

NR = not reported

Table 4: Outcomes in patients not treated with low clinical probability of UE DVT – (TN and FN) Studies Patients

with UE DVT/

Clinical probabil ity or prevalen ce

Pathway Number of patients with positive XXX/

Total patients tested with XXX

Lost to follow up

Mortali ty: from UE DVT at 3 months

Develo pment of PE at 3 month s

Mortali ty from PE at 3 months

VTE events at 3 months

Post throm botic syndro me/se quelae

Major bleed ing

Hemor rhagic Stroke

Sartori

2015 25/239 10% D-Dimer

negative 117/239 0/117 0/117 0/117 0/117 0/117 2/117 (DVT) 0/117 (PE)

0/117 NR NR

Kleinjein

2014 12/200 0.06 D-Dimer

negative 87/200 0/87 NR 0/87 0/87 0/87 0/87 (DVT)

0/87 (PE) NR NR NR

TOTAL 0/117

(0%) 0/204

(0%) 2/204 (0.98%;

95%CI:0%- 2.33%) (DVT) 0/204 (0%) (PE)

0/117

(0%) NR NR

Sartori

2015 25/239 10% US negative 182/239 0/182 0/182 0/182 0/182 0/182 3/182

(DVT) 0/182 (PE)

0/182 NR NR

TOTAL 0/182

(0%) 0/182

(0%) 3/182 (1.65%;95

%CI:0%- 3.49%) (DVT) 0/182 (PE)

0/182

(0%) NR NR

Sartori

2015 25/239 10% US negative, serial US negative

180/239 0/180 0/180 0/180 0/180 0/180 1/180

(DVT) 0/180 (PE)

0/180 NR NR

TOTAL 0/180

(0%) 0/180

(0%) 1/180 (0.56%;95

%CI:0%- 1.64%) (DVT) 0/180 (PE)

0/180

(0%) NR NR

Kleinjein

2014 12/200 0.06% D-Dimer

negative OR D-dimer positive  US negative

87/200 (DD neg) 75/112 (DD pos, US neg) Overall:

162/200

0/162 2/203 0/162 0/162 0/162 0/162 (DVT) 0/162 (PE)

NR NR NR

TOTAL 2/203

(0.99%;

95%CI:0

%-2.34%)

0/162

(0%) 0/162

(0%) 0/162 (DVT) (0%) 0/162 (PE) (0%)

NR NR NR

Prandoni

1997 27/58 47% US negative 31/58 0/31 5/58 0/31 0/31 0/31 0/31 (DVT)

0/31 (PE) 0/58 at 3 mo (4/58 within 2 years)

NR NR

Kleinjein

2014 91/203 44% US negative 88/203 0/88 5/203 0/88 0/88 0/88 5/88 (DVT)

0/88 (PE) NR NR NR

TOTAL 10/261

(3.83%; 0/119

(0%) 0/119

(0%) 5/119

(4.20%;95 0/58

(0%) NR NR

(23)

95%CI:1 .50%- 6.16%)

%CI:0.59%- 7.80%) (DVT) 0/119 (0%) (PE) Kleinjein

2014 91/203 44% US negative

 DD positive

serial US negative

84/203 0/84 5/203 0/84 0/84 0/84 1/84 (DVT)

0/84 (PE) NR NR NR

TOTAL 5/203

(2.46%;

95%CI:0 .33%- 4.59%)

0/84

(0%) 0/84

(0%) 1/84 (1.19%;95

%CI:0%- 3.50%) (DVT) 0/84 (0%) (PE)

NR NR NR

NR = not reported

(24)

Supplementary Material 4. Outcomes in patients with suspected upper extremity deep vein thrombosis from additional sources

Outcomes in patients with suspected upper extremity deep vein thrombosis from various sources Test

accuracy results

Consequences Results from

published SR¹ Results from treatment guideline²

Targeted search of outcomes studies³

Panel survey results

TP Mortality: all cause NR NR 22% (3 months) 14% (1 year)

Mortality: from DVT at 3-12 months NR NR NR 10.4% (1 year)

Recurrent Upper Extremity DVT NR NR 6.7% (3 months) 3.0% (1 year)

Development of PE NR NR 0% (3 months) 3.0% (1 year)

Major bleeding NR NR 6.0% (3 months) 4.0% (1 year)

Fatal major bleeding NR NR NR NR

Hemorrhagic stroke NR NR NR 1.4% (ICH; 1 year)

FP Mortality: all cause NR NR NR NR

Major bleeding NR NR NR 4.0% (1 year)

Fatal major bleeding NR NR NR NR

TN Mortality: from DVT at 3-12 months NR NR NR NR

FN Mortality: all cause NR NR NR 12.5% (1 year)

Mortality: from DVT at 3-12 months NR NR NR 9.5% (1 year)

Recurrence of DVT at 3-12 months NR NR NR 19.25% (1 year)

DVT = deep vein thrombosis, PE = pulmonary embolism, NR = not reported, SR = systematic review

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