Prevention of VTE in Nonsurgical Patients : Antithrombotic ...umg.umdnj.edu/gim/consult_manual/VTE...

DOI 10.1378/chest.11-2296 2012;141;e195S-e226SChest

Russell C. Klein, Hoang Le, Sam Schulman and M. Hassan MuradFrancesco Dentali, Elie A. Akl, Deborah J. Cook, Alex A. Balekian, Susan R. Kahn, Wendy Lim, Andrew S. Dunn, Mary Cushman, Practice GuidelinesChest Physicians Evidence-Based Clinical Thrombosis, 9th ed: American College ofAntithrombotic Therapy and Prevention of Prevention of VTE in Nonsurgical Patients :

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CHEST Supplement

www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e195S

ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES

Background: This guideline addressed VTE prevention in hospitalized medical patients, outpa-tients with cancer, the chronically immobilized, long-distance travelers, and those with asymp-tomatic thrombophilia. Methods: This guideline follows methods described in Methodology for the Development of Anti-thrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Pre-vention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. Results: For acutely ill hospitalized medical patients at increased risk of thrombosis, we recom-mend anticoagulant thromboprophylaxis with low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B) and suggest against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B). For acutely ill hospitalized medical patients at low risk of throm-bosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B). For acutely ill hospitalized medical patients at increased risk of thrombosis who are bleeding or are at high risk for major bleeding, we suggest mechanical thromboprophylaxis with graduated compression stockings (GCS) (Grade 2C) or intermittent pneumatic compression (IPC) (Grade 2C). For critically ill patients, we suggest using LMWH or LDUH thromboprophylaxis (Grade 2C). For critically ill patients who are bleeding or are at high risk for major bleeding, we suggest mechanical thromboprophylaxis with GCS and/or IPC at least until the bleeding risk decreases (Grade 2C). In outpatients with cancer who have no additional risk factors for VTE we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and recommend against the prophylactic use of vitamin K antagonists (Grade 1B). Conclusions: Decisions regarding prophylaxis in nonsurgical patients should be made after con-sideration of risk factors for both thrombosis and bleeding, clinical context, and patients’ values and preferences. CHEST 2012; 141(2)(Suppl):e195S–e226S

Abbreviations: APLA 5 antiphospholipid antibodies; ASA 5 acetylsalicylic acid; CVC 5 central venous catheter; GCS 5 graduated compression stockings; HIT 5 heparin-induced thrombocytopenia; HR 5 hazard ratio; INR 5 international normalized ratio; IPC 5 intermittent pneumatic compression; LDUH 5 low-dose unfractionated heparin; LMWH 5 low-molecular-weight heparin; PE 5 pulmonary embolism; RAM 5 risk assessment model; RCT 5 randomized controlled trial; RR 5 risk ratio; SCLC 5 small cell lung cancer; UFH 5 unfractionated heparin; VFP 5 venous foot pump; VKA 5 vitamin K antagonist

Prevention of VTE in Nonsurgical Patients Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Susan R. Kahn, MD; Wendy Lim, MD; Andrew S. Dunn, MD ; Mary Cushman, MD; Francesco Dentali, MD; Elie A. Akl , MD , MPH , PhD; Deborah J. Cook, MD , MSc ( Epi ); Alex A. Balekian , MD , MSHS ; Russell C. Klein, MD ; Hoang Le , MD , FCCP ; Sam Schulman, MD ; and M. Hassan Murad , MD , MPH


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e196S Prevention of VTE in Nonsurgical Patients

Revision accepted August 31, 2011 . Affi liations: From the Department of Medicine (Dr Kahn), McGill University, Montreal, QC, Canada; the Department of Medicine (Drs Lim and Cook), Division of Hematology and Thromboembolism (Dr Schulman), and the Department of Clin ical Epidemiology and Biostatistics (Drs Akl and Cook), McMaster University, Hamilton, ON, Canada; the Depart-ment of Medicine (Dr Dunn), Mount Sinai School of Medicine, New York, NY; the Department of Medicine (Dr Cushman), Uni-versity of Vermont and Fletcher Allen Health Care, Burlington, VT; the Department of Clinical Medicine (Dr Dentali), Univer-sity of Insubria, Varese, Italy; the Department of Medicine (Dr Akl), University at Buffalo, Buffalo, NY; the Division of Pul-monary and Critical Care Medicine (Dr Balekian), Keck School of Medicine, University of Southern California, Los Angeles, CA; the Huntington Beach Internal Medicine Group (Dr Klein), Newport Beach, CA; the Department of Pulmonary and Critical Care Medicine (Dr Klein), University of California Irvine School of Medicine, Orange, CA; the Hoag Memorial Hospital Presbyterian (Dr Le), Newport Beach, CA; the Pulmonary Division (Dr Le), Fountain Valley Regional Hospital, Fountain Valley, CA; and the Division of Preventive Medicine and the Knowledge and Evalua-tion Research Unit (Dr Murad), Mayo Clinic, Rochester, MN . Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants were also provided by Bristol-Myers Squibb; Pfi zer, Inc; Canyon Pharmaceuticals; and sanofi -aventis US. Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S. Correspondence to: M. Hassan Murad, MD, MPH, 200 First St SW, Rochester, MN 55905; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http://www.chestpubs.org/site/misc/reprints.xhtml ). DOI: 10.1378/chest.11-2296

Summary of Recommendations

Note on Shaded Text: Throughout this guideline, shading is used within the summary of recommenda-tions sections to indicate recommendations that are newly added or have been changed since the pub-lication of Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Recommendations that remain unchanged are not shaded.

2.3. For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with low-molecular-weight heparin [LMWH], low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B) .

Remarks: In choosing the specifi c anticoagulant drug to be used for pharmacoprophylaxis, choices should be based on patient preference, compliance, and ease

of administration (eg, daily vs bid vs tid dosing), as well as on local factors affecting acquisition costs (eg, prices of various pharmacologic agents in individual hospital formularies).

2.4. For acutely ill hospitalized medical patients at low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechan-ical prophylaxis (Grade 1B) .

2.7.1. For acutely ill hospitalized medical patients who are bleeding or at high risk for bleeding, we recommend against anticoagulant thrombo-prophylaxis (Grade 1B) .

2.7.2. For acutely ill hospitalized medical patients at increased risk of thrombosis who are bleed-ing or at high risk for major bleeding, we suggest the optimal use of mechanical thrombo-prophylaxis with graduated compression stock-ings (GCS) (Grade 2C) or intermittent pneumatic compression (IPC) (Grade 2C) , rather than no mechanical thromboprophylaxis. When bleeding risk decreases, and if VTE risk persists, we sug-gest that pharmacologic thromboprophylaxis be substituted for mechanical thromboprophy-laxis (Grade 2B) .

Remarks: Patients who are particularly averse to the potential for skin complications, cost, and need for clinical monitoring of GCS and IPC use are likely to decline mechanical prophylaxis.

2.8. In acutely ill hospitalized medical patients who receive an initial course of thromboprophy-laxis, we suggest against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B) .

3.2. In critically ill patients, we suggest against routine ultrasound screening for DVT (Grade 2C) .

3.4.3. For critically ill patients, we suggest using LMWH or LDUH thromboprophylaxis over no prophylaxis (Grade 2C) .

3.4.4. For critically ill patients who are bleeding, or are at high risk for major bleeding, we sug-gest mechanical thromboprophylaxis with GCS (Grade 2C) or IPC (Grade 2C) until the bleeding risk decreases, rather than no mechanical throm-boprophylaxis. When bleeding risk decreases, we suggest that pharmacologic thromboprophy-laxis be substituted for mechanical thrombo-prophylaxis (Grade 2C) .

4.2.1. In outpatients with cancer who have no additional risk factors for VTE, we suggest against


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This article focuses on prevention of VTE in non-surgical populations. Because they are addressed

in other chapters in these guidelines, 1,2 we do not include prevention of VTE in patients with trauma and spinal cord injury and in patients with ischemic and hemorrhagic stroke.

Adverse consequences of unprevented VTE include symptomatic DVT and pulmonary embolism (PE), fatal PE, chronic postthrombotic syndrome, and increased risk of recurrent VTE. We consider the desir-able and undesirable consequences of antithrombotic prophylaxis to prevent VTE in the following popula-tions/patient groups: (1) hospitalized acutely ill med-ical patients, (2) critically ill patients, (3) patients with cancer receiving cancer treatment in the outpatient setting, (4) patients with cancer with indwelling central venous catheters (CVCs), (5) Chronically immobilized patients, (6) long-distance travelers, and (7) asymptomatic persons with thrombophilia. We also consider the use of statins (HMG-CoA reduc-tase inhibitors) to prevent VTE. Table 1 describes the question defi nition (population, intervention, com-parator, and outcome) and eligibility criteria for studies considered in each section of this article.

1.0 Methods

The methodology of these guidelines follows the general approach of Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrom-botic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. 3 In brief, panel members con-ducted literature searches to update the existing evidence base, seeking systematic reviews and trials published since the previous iteration of the guidelines, and rated the quality of the evidence using the Grading of Recommendations Assessment, Develop-ment, and Evaluation framework. The panel considered the bal-ance of benefi ts and harm, patients’ values and preferences, and patients’ context and resources to develop weak or strong recom-mendations. In this article, we identifi ed three areas with sparse high-quality evidence: (1) the benefi ts of prophylaxis as mea-sured by reduction of the incidence of symptomatic VTE events, (2) resource use and cost-effectiveness, and (3) the benefi ts of screening strategies for VTE in nonsurgical patients.

1.1 Outcomes of Interest

We selected similar patient-important outcomes across recom-mendations. These include symptomatic DVT, PE, death from PE, major bleeding, heparin-induced thrombocytopenia (HIT), and mechanical thromboprophylaxis complications (when appli-cable). In addition, for patients with CVCs, we include catheter failure as an outcome.

As the mortal outcome of greatest interest, when data were available, we have chosen treatment-related mortality (PE deaths, hemorrhagic deaths). For pharmacologic interventions, when available, we provide data on fatal bleeding and fatal intracranial

routine prophylaxis with LMWH or LDUH (Grade 2B) and recommend against the prophy-lactic use of vitamin K antagonists (Grade 1B) .

Remarks: Additional risk factors for venous throm-bosis in cancer outpatients include previous venous thrombosis, immobilization, hormonal therapy, angio-genesis inhibitors, thalidomide, and lenali domide.

4.2.2. In outpatients with solid tumors who have additional risk factors for VTE and who are at low risk of bleeding, we suggest prophylactic-dose LMWH or LDUH over no prophylaxis (Grade 2B) .

Remarks: Additional risk factors for venous throm-bosis in cancer outpatients include previous venous thrombosis, immobilization, hormonal therapy, angio-genesis inhibitors, thalidomide, and lenali domide.

4.4. In outpatients with cancer and indwelling central venous catheters, we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and suggest against the prophylactic use of vitamin K antagonists (Grade 2C) .

5.1. In chronically immobilized persons resid-ing at home or at a nursing home, we suggest against the routine use of thromboprophylaxis (Grade 2C) .

6.1.1. For long-distance travelers at increased risk of VTE (including previous VTE, recent surgery or trauma, active malignancy, preg-nancy, estrogen use, advanced age, limited mobility, severe obesity, or known thrombo-philic disorder), we suggest frequent ambula-tion, calf muscle exercise, or sitting in an aisle seat if feasible (Grade 2C) .

6.1.2. For long-distance travelers at increased risk of VTE (including previous VTE, recent surgery or trauma, active malignancy, preg-nancy, estrogen use, advanced age, limited mobility, severe obesity, or known thrombo-philic disorder), we suggest use of properly fi tted, below-knee GCS providing 15 to 30 mm Hg of pressure at the ankle during travel (Grade 2C) . For all other long-distance travelers, we suggest against the use of GCS (Grade 2C) .

6.1.3. For long-distance travelers, we suggest against the use of aspirin or anticoagulants to prevent VTE (Grade 2C) .

7.1. In persons with asymptomatic thrombo-philia (ie, without a previous history of VTE), we recommend against the long-term daily use

of mechanical or pharmacologic thrombopro-phylaxis to prevent VTE (Grade 1C) .





Tabl

e 1—

[Int

rodu

ctio

n] S

tru

ctu

red

Cli

nica

l Q

ues

tion

s

Popu

latio

nIn

terv

entio

n(s)

Com

para

tor

Out

com

eM

etho

dolo

gy

Hos

pita

lized

acu

tely

ill m

edic

al

patie

nts

Mec

hani

cal p

roph

ylax

is (G

CS,

IPC

, IV

C fi

lter)

and

/or

phar

mac

olog

ic

prop

hyla

xis

(ASA

, LD

UH

, L

MW

H, f

onda

pari

nux,

VK

A, o

ral

DT

I, o

ral d

irec

t Xa

inhi

bito

rs)

No

trea

tmen

t, pl

aceb

o,

mec

hani

cal p

roph

ylax

is, a

nd/o

r ph

arm

acol

ogic

pro

phyl

axis

Sym

ptom

atic

DV

T a

nd P

E,

deat

h, m

ajor

ble

edin

g ev

ents

, m

echa

nica

l pro

phyl

axis

co

mpl

icat

ions

RC

Ts

LD

UH

bid

LD

UH

tid

Ext

ende

d-du

ratio

n ph

arm

acol

ogic

pr

ophy

laxi

s, a

fter

initi

al

shor

t-du

ratio

n pr

ophy

laxi

s

Shor

t-du

ratio

n pr

ophy

laxi

s

Any

scr

eeni

ng fo

r as

ympt

omat

ic

VT

E w

ith u

ltras

ound

No

scre

enin

g

All

patie

nts

adm

itted

to a

cri

tical

ca

re u

nit

Rou

tine

scre

enin

g w

ith u

ltras

ound

fo

r as

ympt

omat

ic V

TE

No

scre

enin

gSy

mpt

omat

ic D

VT,

PE

, dea

th,

maj

or b

leed

ing

even

tsR

CTs

and

obs

erva

tiona

l stu

dies

LM

WH

, LD

UH

No

trea

tmen

t, pl

aceb

o,

mec

hani

cal p

roph

ylax

is, a

nd/o

r ph

arm

acol

ogic

pro

phyl

axis

Sym

ptom

atic

DV

T a

nd P

E, d

eath

, m

ajor

ble

edin

g ev

ents

, m

echa

nica

l pro

phyl

axis

co

mpl

icat

ions

RC

Ts a

nd o

bser

vatio

nal s

tudi

es

Patie

nts

with

can

cer

R

ecei

ving

can

cer

trea

tmen

t in

ou

tpat

ient

set

ting

Mec

hani

cal p

roph

ylax

is (G

CS)

an

d/or

pha

rmac

olog

ic p

roph

ylax

is (A

SA,

LD

UH

, LM

WH

, fon

dapa

rinu

x, V

KA

, or

al D

TI,

oral

dire

ct X

a in

hibi

tors

)

No

trea

tmen

t, pl

aceb

o,

mec

hani

cal p

roph

ylax

is, a

nd/o

r ph

arm

acol

ogic

pro

phyl

axis

Sym

ptom

atic

DV

T a

nd P

E, d

eath

, m

ajor

ble

edin

g ev

ents

, m

echa

nica

l pro

phyl

axis

co

mpl

icat

ions

RC

Ts a

nd o

bser

vatio

nal s

tudi

es

W

ith in

dwel

ling

cent

ral

ve

nous

cat

hete

rsPh

arm

acol

ogic

pro

phyl

axis

(ASA

, L

DU

H, L

MW

H, f

onda

pari

nux,

V

KA

, ora

l DT

I, o

ral d

irec

t Xa

inhi

bito

rs)

No

trea

tmen

t, pl

aceb

o, o

r ph

arm

acol

ogic

pro

phyl

axis

Sym

ptom

atic

DV

T a

nd P

E, d

eath

, m

ajor

ble

edin

g ev

ents

, cat

hete

r fa

ilure

RC

Ts a

nd o

bser

vatio

nal s

tudi

es

Chr

onic

ally

imm

obili

zed

patie

nts

(e.g

. nur

sing

hom

e or

reh

ab r

esid

ents

, im

mob

ilize

d pe

rson

s liv

ing

at h

ome)

Mec

hani

cal p

roph

ylax

is (G

CS)

and

/or

pha

rmac

olog

ic p

roph

ylax

is

(ASA

, LD

UH

, LM

WH

, fo

ndap

arin

ux, V

KA

, ora

l DT

I,

oral

dir

ect X

a in

hibi

tors

)

No

trea

tmen

t, pl

aceb

o,

mec

hani

cal p

roph

ylax

is, a

nd/o

r ph

arm

acol

ogic

pro

phyl

axis

Sym

ptom

atic

DV

T a

nd P

E, d

eath

, m

ajor

ble

edin

g ev

ents

, m

echa

nica

l pro

phyl

axis

co

mpl

icat

ions

RC

Ts a

nd o

bser

vatio

nal s

tudi

es

Lon

g-di

stan

ce tr

avel

ers

GC

S, L

MW

H, A

SAN

o tr

eatm

ent,

plac

ebo,

m

echa

nica

l pro

phyl

axis

, and

/or

phar

mac

olog

ic p

roph

ylax

is

Sym

ptom

atic

DV

T, P

E, d

eath

, m

ajor

ble

edin

g ev

ents

RC

Ts a

nd o

bser

vatio

nal s

tudi

es

All

patie

nts

Prog

nost

ic fa

ctor

s as

soci

ated

with

ri

sk o

f VT

EN

/ASy

mpt

omat

ic D

VT

and

PE

, dea

th

from

PE

RC

Ts a

nd o

bser

vatio

nal s

tudi

es

All

patie

nts

Prog

nost

ic fa

ctor

s as

soci

ated

with

ri

sk o

f ble

edin

gN

/AM

ajor

ble

edin

g ev

ents

, dea

th fr

om

blee

ding

RC

Ts a

nd o

bser

vatio

nal s

tudi

es

Asy

mpt

omat

ic p

erso

ns w

ith

thro

mbo

phili

a (in

heri

ted

thro

mbo

phili

a, L

AC

, APL

A)

Mec

hani

cal p

roph

ylax

is (G

CS)

and

/or

pha

rmac

olog

ic p

roph

ylax

is

(ASA

, LD

UH

, LM

WH

, VK

A)

No

trea

tmen

t or

plac

ebo

Sym

ptom

atic

DV

T, P

E, d

eath

, maj

or

blee

ding

eve

nts

RC

Ts a

nd o

bser

vatio

nal s

tudi

es

Asy

mpt

omat

ic p

erso

ns (i

e, n

o pr

evio

us V

TE

)St

atin

sN

o tr

eatm

ent o

r pl

aceb

oSy

mpt

omat

ic D

VT,

PE

, dea

thR

CTs

and

obs

erva

tiona

l stu

dies

For

tra

deof

f of

ben

efi ts

and

har

ms,

onl

y sy

mpt

omat

ic V

TE

eve

nts

are

cons

ider

ed.

APL

A 5

antip

hosp

holip

id a

ntib

odie

s; A

SA 5

acet

ylsa

licyl

ic a

cid;

DT

I 5 d

irec

t th

rom

bin

inhi

bito

r; G

CS

5 g

radu

ated

co

mpr

essi

on s

tock

ings

; IP

C 5

inte

rmitt

ent

pneu

mat

ic c

ompr

essi

on;

IVC

5 in

feri

or v

ena

cava

; L

AC

5 lu

pus

antic

oagu

lant

; L

DU

H 5

low

-dos

e un

frac

tiona

ted

hepa

rin;

LM

WH

5 lo

w-m

olec

ular

-wei

ght

hepa

rin;

PE

5 p

ulm

onar

y em

bolis

m; R

CT

5 ra

ndom

ized

con

trol

led

tria

l; V

KA

5 vi

tam

in K

ant

agon

ist.




supplementary tables not contained in the body of the article and available online. See the “Acknowledgments” for more informa-tion.). Also, there is uncertainty about the generalizability of trial results to other populations, as in many of the trials the ratio of patients screened to patients enrolled was very high (eg, � 100), and probable underestimation of absolute numbers of symptom-atic events, as patients diagnosed with asymptomatic DVT via trial-mandated screening tests are typically treated with anticoag-ulants. Incidence estimates from most observational studies were unsatisfactory because they were not stratifi ed by the use of thrombo-prophylaxis and were also reported in very heterogenous popula-tions (Table S2).

To estimate baseline risk for patients with low and high VTE risk, we used data from risk assessment models (RAMs). Several RAMs have been proposed for use in hospitalized medical patients (Table S3). 5-7 Limitations of most RAMs include lack of prospec-tive validation, applicability only to high-risk subgroups, inade-quate follow-up time, and excessive complexity.

In a prospective observational study of 1,180 inpatients, a predefi ned RAM (Padua Prediction Score, modifi ed after Kucher 8 ) assigned points to 11 common VTE risk factors ( Table 2 ) 9 and categorized hospitalized medical patients as low risk ( , 4 points; 60.3% of patients) or high risk ( � 4 points; 39.7% of patients) for VTE. Attending physicians were not notifi ed of their patients’ risk categories. Patients were followed for symp-tomatic VTE for 90 days. VTE occurred in 11.0% of high-risk patients who did not receive prophylaxis vs 0.3% of low-risk patients, a . 30-fold difference in risk (hazard ratio [HR], 32.0; 95% CI, 4.1-251.0). Among 711 low-risk patients, two (0.3%) developed VTE (1 PE, 1 PE with DVT). Among 283 high-risk patients who did not receive prophylaxis, the risk of DVT was 6.7%, nonfatal PE 3.9%, and fatal PE 0.4%. Hence, for base-line risk for low- and high-risk strata, we used risk estimates provided by the Padua Prediction Score. 9 Despite the limita-tions of this risk model (small number of events, suboptimal

bleeding as a subset of all-cause mortality, and for the outcome of major bleeding, when available, we provide data on intracranial bleeding and GI bleeding (the most common type of “critical organ” bleeding expected in nonsurgical populations). Given that anticoagulants used to prevent VTE are administered for short periods of time, major bleeding and fatal bleeding are likely to be rare events, except during critical illness.

1.2 Values and Preferences

Little is known about the distribution of patients’ values and preferences in the context of VTE prevention in nonsurgical set-tings. In developing the recommendations for this guideline, pan-elists made estimates of patients’ values and preferences often using indirect data from other settings (eg, values and preferences that pertain to anticoagulation in atrial fi brillation).

In our populations, the weights (relative importance) given to the harmful effects (disutilities) of the most representative types of critical organ bleeding, namely GI or, less commonly, intracranial bleeding, will greatly impact the tradeoff between desirable and undesirable consequences of antithrombotic therapy. There are limited data to guide us with respect to the relative impact of VTE events vs bleeding events on patient-perceived state of health; available evidence suggests values and preferences for treatments and for health states vary appreciably between individuals. 4

In a values rating exercise, Antithrombotic Therapy and Pre-vention of Thrombosis, 9th ed: American College of Chest Physi-cians Evidence-Based Clinical Practice Guidelines panelists used a “feeling thermometer” with anchors at 0 (representing death) and 100 (representing full health) to rate patient scenarios for var-ious clinical outcomes in terms of the value placed on a year in which the events depicted in the scenario occurred. 3 Median rat-ings were similar for the outcomes of symptomatic DVT, PE, and catheter thrombosis (80, 75, and 80, respectively) and severe GI bleeding (75), whereas the median rating for intracranial bleeding (stroke scenario) was 40. Therefore, we used 1:1 ratio of symp-tomatic VTE to major extracranial bleeding and 2.5:1 ratio of symptomatic VTE to intracranial bleeding for tradeoffs.

We considered that preventative and screening recommenda-tions require higher-quality evidence supporting benefi t than therapy recommendations. This decision is a value-based judg-ment. In making our recommendations, when there is uncertain benefi t and an appreciable probability of important harm or patient burden associated with treatment, we recommend against such treatments.

1.3 Estimating Baseline Risk

In making clinical recommendations, guideline developers need to consider the balance of benefi ts and harms in terms of absolute treatment effect on patient-important symptomatic events in addition to relative measures of risk. The panelists of the four articles dealing with VTE prevention faced challenges in fi nding these data and developed several possible approaches for estimating the effect of prophylaxis on the incidence of symptom-atic VTE events. In this article, we used two different approaches for hospitalized patients in non-critical care settings and for criti-cally ill patients, based on the availability of data.

1.3.1 Baseline Risk in Hospitalized Medical Patients: Since medical patients have a signifi cantly heterogeneous risk for VTE, the guideline panel sought to evaluate preventive strategies in two different strata of patients (low risk and high risk). We decided against simply using as the baseline estimate the pooled average risk of DVT (0.8%) and PE (0.4%) reported in the control arms of the randomized controlled trials (RCTs) of thromboprophylaxis in hospitalized medical patients, as it is evident from the trials’ eligi-bility criteria that patients with heterogeneous risk were enrolled (Table S1) (Tables that contain an “S” before the number denote

Table 2—Risk Factors for VTE in Hospitalized Medical Patients9

Risk Factor Points

Active cancera 3Previous VTE (with the exclusion of superfi cial vein

thrombosis)3

Reduced mobilityb 3Already known thrombophilic conditionc 3Recent (� 1 mo) trauma and/or surgery 2Elderly age (� 70 y) 1Heart and/or respiratory failure 1Acute myocardial infarction or ischemic stroke 1Acute infection and/or rheumatologic disorder 1Obesity (BMI � 30) 1Ongoing hormonal treatment 1

In the Padua Prediction Score risk assessment model, high risk of VTE is defi ned by a cumulative score � 4 points. In a prospective observational study of 1,180 medical inpatients, 60.3% of patients were low risk and 39.7% were high risk. Among patients who did not receive prophylaxis, VTE occurred in 11.0% of high-risk patients vs 0.3% of low-risk patients (HR, 32.0; 95% CI, 4.1-251.0). Among high-risk patients, the risk of DVT was 6.7%, nonfatal PE 3.9%, and fatal PE 0.4%.9 HR 5 hazard ratio.aPatients with local or distant metastases and/or in whom chemotherapy or radiotherapy had been performed in the previous 6 mo.bAnticipated bed rest with bathroom privileges (either because of patient’s limitations or on physician’s order) for at least 3 d.cCarriage of defects of antithrombin, protein C or S, factor V Leiden, G20210A prothrombin mutation, antiphospholipid syndrome.





accounts for about one-fourth of all VTE events in the community. 17,18 Among hospitalized patients, 50% to 75% of VTE events, including fatal PE, occur in those hospitalized on the medical service. 16,19 Risk factors for VTE in hospitalized medical patients include intrinsic factors, such as increasing age (espe-cially . 70 years), previous VTE, known thrombo-philia, and various comorbid illnesses, such as cancer, heart failure, or respiratory failure, and extrinsic fac-tors, such as immobilization for � 3 days and hor-monal medications 5,20-22 ( Table 2 ). 9

2.2 Risk Factors for Bleeding in Hospitalized Medical Patients

A recent multinational observational study reported on risk factors at admission that were indepen-dently predictive of in-hospital bleeding (the analysis combined major and nonmajor clinically relevant bleeding) among 10,866 hospitalized medical patients. The strongest risk factors were active gastroduo-denal ulcer, bleeding in 3 months before admission, and platelet count , 50 3 10 9 /L, followed by age . 85 years, hepatic failure, severe renal failure, and ICU or critical care unit admission ( Table 3 ). 10 Although data on incidence of bleeding were not provided separately by use vs nonuse of prophylaxis (overall rate of major bleeding was 0.76%), the above vari-ables remained predictive of bleeding when the model was adjusted for pharmacologic prophylaxis. A bleeding risk score that included these and addi-tional variables was developed by the authors, who reported that more than one-half of all major bleeding episodes occurred in the 10% of hospital-ized medical patients who had a bleeding risk score � 7.0.

Although this risk score is complex and has not yet been validated, the panel considered patients to have an excessive risk of bleeding if they had multiple risk factors or had one of the three risk factors with

validation), this model provides the best available basis for judging hospitalized patients’ risk.

We considered a number of options for baseline risk of major bleeding. We considered bleeding events reported in the Padua prediction score study. However, this study stratifi ed bleeding events according to thrombosis risk, not bleeding risk (1 of 283 in the low VTE risk group [0.4%; 95% CI, 0.0-2.0] and 1 of 711 in the high VTE risk group [0.1%; 95% CI, 0.0-0.8]). 9 We also considered bleeding events in a large observational study by Decousus 10 ; however, this study did not report bleeding according to use of pharmacoprophylaxis. Therefore, we chose to use 0.4% (19 of 4,304) derived from the control arm of trials of thromboprophylaxis in medical patients as the estimate of baseline risk of major bleeding (section 2.1). Where possible, we presented data on intracranial bleeding separately from major bleeding events.

1.3.2 Baseline Risk in Critically Ill Patients: Critical care trials have routinely screened patients for asymptomatic DVT, which are usually promptly treated if detected. Hence, an accurate estimate of risk of symptomatic DVT is not available from trials of critically ill patients receiving no prophylaxis, and PE events are generally rare. We used two approaches to esti-mate the baseline risk and absolute risk difference in critically ill patients. When symptomatic events were reported, such as DVT in the trials by Shorr et al 11 and in PROTECT, 12 we used these data directly to estimate the baseline risk, relative risk (RR), and risk difference. When symptomatic events were not reported in the trials, such as the PE outcome in trials that compared unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) vs placebo, we opted to use a base-line risk derived from symptomatic PEs reported in three observational studies. 13-15 The risk ratio (RR) was derived from the trials in which events were likely a mix of symptomatic and asymptomatic events . The former approach has the advantage of directness but may suffer from imprecision and poor appli-cability. The latter approach requires imputations that make the evidence indirect.

2.0. Hospitalized Acutely Ill Medical Patients

2.1 Risk Factors for VTE in Hospitalized Medical Patients

Hospitalization for acute medical illness is associ-ated with an eightfold increased risk of VTE 16 and

Table 3—Independent Risk Factors for Bleeding in 10,866 Hospitalized Medical Patient10

Risk Factora Total Patients, No. (%) (N 5 10,866) OR (95% CI)

Active gastroduodenal ulcer 236 (2.2) 4.15 (2.21-7.77)Bleeding in 3 mo before admission 231 (2.2) 3.64 (2.21-5.99)Platelet count , 50 3 109/L 179 (1.7) 3.37 (1.84-6.18)Age � 85 y (vs , 40 y) 1,178 (10.8) 2.96 (1.43-6.15)Hepatic failure (INR . 1.5) 219 (2.0) 2.18 (1.10-4.33)Severe renal failure (GFR , 30 mL/min/m2) 1,084 (11.0) 2.14 (1.44-3.20)ICU or CCU admission 923 (8.5) 2.10 (1.42-3.10)Central venous catheter 820 (7.5) 1.85 (1.18-2.90)Rheumatic disease 740 (6.8) 1.78 (1.09-2.89)Current cancer 1,166 (10.7) 1.78 (1.20-2.63)Male sex 5,367 (49.4) 1.48 (1.10-1.99)

Data shown were obtained by multiple logistic regression analysis for characteristics at admission independently associated with in-hospital bleeding (major bleeding and clinically relevant nonmajor bleeding combined). GFR 5 glomerular fi ltration rate; INR 5 international normalized ratio.aAlthough not specifi cally studied in medical patients, one would also expect dual antiplatelet therapy to increase the risk of bleeding.




the strongest association with bleeding (OR . 3.0): active gastroduodenal ulcer, bleeding in 3 months before admission, and platelet count , 50 3 10 9 /L.

2.3 Any Anticoagulant vs None to Prevent VTE

We used data from three contemporary, high-quality systematic reviews to assess the benefi ts and harms of anticoagulant prophylaxis vs no prophylaxis in hospi-talized, acutely ill medical patients. 23-25 In general, the trials included acutely ill hospitalized patients (typi-cally, the mean age of enrolled patients was . 65 years) admitted for congestive heart failure, severe respi-ratory disease, or acute infectious, rheumatic, or infl ammatory conditions, who were immobilized and had one or more additional VTE risk factors including but not limited to age . 40 years, active cancer, pre-vious VTE, or serious infection (Table S2). Prophy-lactic anticoagulant regimens included low-dose unfractionated heparin (LDUH) tid, LDUH bid, var-ious LMWHs, and fondaparinux. Duration of use of prophylaxis ranged from 6-21 days or discharge from hospital, whichever came fi rst. In all trials, routine screening for DVT was performed.

Meta-analysis of these trials demonstrates that anticoagulant thromboprophylaxis is associated with signifi cant reduction in fatal PEs (RR, 0.41; 95% CI, 0.22-0.76; two fewer per 1,000 [95% CI, from one fewer to three fewer]). When we apply the relative effect of anticoagulant thromboprophylaxis obtained from these meta-analyses to baseline risks obtained from risk assessment models, we fi nd that throm-boprophylaxis is associated with a reduction in symp-tomatic DVT (RR, 0.47; 95% CI, 0.22-1; one fewer per 1,000 [95% CI, from one fewer to 0 fewer] in low-risk patients; 34 fewer per 1,000 [95% CI, from 51 fewer to 0 fewer] in high-risk patients). The effect on non-fatal PE, major bleeding, and all-cause mortality was not statistically signifi cant and is described in terms of relative and absolute effects ( Table 4 , Table S4). No trial reported the incidence of HIT.

Based on these data, the panel judged that moderate-quality evidence suggests that thromboprophylaxis is effective in reducing symptomatic DVT and fatal PE in acutely ill, hospitalized, immobilized medical patients who have characteristics similar to those enrolled in the above RCTs, and moderate-quality evidence suggests a modest relative and very small absolute increase in bleeding risk. Based on the above RCTs, the panel considered that providing prophy-laxis for 6 to 21 days, until full mobility is restored or until discharge from hospital, whichever comes fi rst, is a reasonable approach. The recommendation to prophylax applies only to the higher-risk patients ( Table 2 ). In low-risk patients, VTE is too infrequent to warrant prophylaxis.

Tabl

e 4—

[Sec

tion

2.3

] Su

mm

ary

of F

indi

ngs:

Sho

uld

Ant

icoa

gula

nt P

roph

ylax

is (

LM

WH

, UF

H, F

onda

pari

nux)

vs

Pla

ceb

o/N

o T

reat

men

t B

e U

sed

in

Hos

pita

lize

d M

edic

al P

atie

nts?

24-2

6

Out

com

es

Ant

icip

ated

Abs

olut

e E

ffec

ts

Rel

ativ

e E

ffec

t (95

% C

I)N

o. o

f Par

ticip

ants

(S

tudi

es) F

ollo

w-u

pQ

ualit

y of

the

Evi

denc

e (G

RA

DE

)B

asel

ine

Ris

kaR

isk

Diff

eren

ce W

ith A

ntic

oagu

lant

Pro

phyl

axis

(95%

CI)

Sym

ptom

atic

DV

TL

ow r

isk

RR

, 0.4

7 (0

.22-

1)5,

206

(4 R

CTs

) 1-1

4 d

Mod

erat

e du

e to

im

prec

isio

nb2

per

1,00

01

few

er p

er 1

,000

(fro

m 1

few

er to

0 m

ore)

Hig

h ri

sk67

per

1,0

0034

few

er p

er 1

,000

(fro

m 5

1 fe

wer

to 0

mor

e)N

onfa

tal p

ulm

onar

y em

bolis

mL

ow r

isk

RR

, 0.6

1 (0

.23-

1.67

)5,

206

(6 R

CTs

) 1-2

2 d

Mod

erat

e du

e to

im

prec

isio

nb2

per

1,00

01

few

er p

er 1

,000

(fro

m 1

few

er to

1 m

ore)

Hig

h ri

sk39

per

1,0

0015

few

er p

er 1

,000

(fro

m 3

0 fe

wer

to 2

6 m

ore)

Maj

or b

leed

ing

4 pe

r 1,

000

1 m

ore

per

1,00

0 (f

rom

1 fe

wer

to 6

mor

e)O

R, 1

.32

(0.7

3-2.

37)

8,60

5 (8

RC

Ts) 1

0-11

0 d

Mod

erat

e du

e to

im

prec

isio

nb

Ove

rall

mor

talit

y45

per

1,0

001

few

er p

er 1

,000

(fro

m 9

few

er to

8 m

ore)

OR

, 0.9

7 (0

.79-

1.19

)7,

355

(5 R

CTs

) 1-2

2 d

Mod

erat

e du

e to

im

prec

isio

nb

Thr

ombo

cyto

peni

a13

per

1,0

001

few

er p

er 1

,000

(fro

m 6

few

er to

7 m

ore)

OR

, 0.9

1 (0

.54-

1.53

)4,

624

(3 R

CTs

) 6-2

1 d

Low

due

to r

isk

of b

ias

and

impr

ecis

ionb

GR

AD

E 5

Gra

des

of R

ecom

men

datio

ns, A

sses

smen

t, D

evel

opm

ent,

and

Eva

luat

ion;

RR

5 ri

sk r

atio

; UF

H 5

unf

ract

iona

ted

hepa

rin.

See

Tab

le 1

lege

nd fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a Bas

elin

e ris

k fo

r DV

T a

nd P

E in

low

-risk

pop

ulat

ion

wer

e de

rived

from

the

RA

M b

y B

arba

r et a

l.9 Bas

elin

e ris

k fo

r mor

talit

y an

d bl

eedi

ng is

der

ived

from

the

cont

rol a

rm o

f med

ical

pat

ient

s in

a m

eta-

anal

ysis

(Den

tali

et a

l).24

b We

will

con

side

r th

e pr

esen

ce o

f ser

ious

impr

ecis

ion

whe

n th

ere

are

, 3

00 e

vent

s in

tota

l (ev

ents

in tr

eatm

ent a

nd c

ontr

ol p

atie

nts)

or

whe

n C

Is in

clud

e ap

prec

iabl

e ha

rms

and

bene

fi ts.





of 15,156 acutely ill hospitalized medical patients enrolled at 52 hospitals in 12 countries, docu-mented marked variation in practices in dosing frequency of LDUH used to prevent VTE. LDUH was prescribed tid in 54% of patients from the United States compared with bid in 85% of non-US patients. 31

There have been no head-to-head trials comparing bid vs tid LDUH to prevent VTE in hospitalized medical patients. We conducted a mixed-treatment comparison meta-analysis of 16 RCTs that enrolled hospitalized nonsurgical patients at risk for VTE and compared LDUH bid, LDUH tid, or LMWH to each other or to an inactive control. 32 The RR and 95% credible intervals comparing LDUH tid to LDUH bid for DVT, PE, death, and major bleeding (all were indirect comparisons) were 1.56 (0.64-4.33), 1.67 (0.49-208.09), 1.17 (0.72-1.95), and 0.89 (0.08-7.05), respectively. Due to a lack of reporting, we could not perform this analysis for the outcome HIT. The low-quality evidence from these indirect comparisons provides no compelling evidence that LDUH tid dosing, compared with bid dosing, reduces VTE or causes more bleeding. A future randomized trial comparing these agents is unlikely, considering the large sample size that would be required to demon-strate a signifi cant difference, which, if it exists, is undoubtedly small. From a patient preference per-spective, twice daily injections are likely to be preferred and better tolerated than thrice daily injections.

2.4 LDUH vs LMWH to Prevent VTE

LDUH and LMWH (enoxaparin, nadroparin, or certoparin) have been directly compared in fi ve RCTs. 26-30 Eligibility criteria for RCTs of LDUH vs LMWH in hospitalized medical patients were sim-ilar to trials of any anticoagulant vs none to prevent VTE and are shown in Table S5. In all trials, routine screening for DVT was performed. Dosing of LDUH was tid in four trials and bid in one trial. 26

Pooled results failed to exclude benefi t or harm for LMWH vs LDUH for the outcomes DVT (RR, 0.77; 95% CI, 0.50-1.19), PE (RR, 1.00; 95% CI, 0.28-3.59), overall mortality (RR, 0.89; 95% CI, 0.65-1.23), and HIT (RR, 0.50; 95% CI, 0.05-5.48) ( Table 5 , Table S6). Pooled results for major bleeding suggest a large relative protective effect of LMWH (RR, 0.48; 95% CI, 0.24-0.99) and small absolute (fi ve fewer; 95% CI, 0-7 fewer) reduction in bleed-ing events per 1,000 patients treated. Evidence is consistent with a similar effect of LMWH and UFH on reduction in thrombosis in acutely ill hos-pitalized medical patients (though imprecision is such that effects could, in relative terms, be appre-ciably greater in one treatment or the other). The potential for less bleeding with LMWH represents a benefi t that is small, and it may be very small.

2.5 LDUH bid vs tid to Prevent VTE

The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE), a registry

Table 5—[Section 2.4] Summary of Findings: Should Anticoagulant Prophylaxis With LMWH vs UFH be Used in Hospitalized Medical Patients?23,171

Outcomes No. of Participants (Studies) Follow-up

Quality of the Evidence (GRADE)

Relative Effect (95% CI)

Anticipated Absolute Effects

Risk With UFHa

Risk Difference With LMWH (95% CI)

Symptomatic DVT 5,371 (5 RCTs) 1-28 d Low due to imprecisionb and indirectnessc

RR, 0.77 (0.50-1.19) 3 per 1,000 1 fewer per 1,000 (from 2 fewer to 1 more)

Nonfatal pulmonary embolism

5,386 (5 RCTs) 1-28 d Low due to imprecisionb and indirectnessc


Major bleeding 5,597 (5 RCTs) 1-28 d Moderate due to imprecisionb

RR, 0.48 (0.24-0.99) 9 per 1,000 5 fewer per 1,000 (from 0 fewer to 7 fewer)

Overall mortality 5,597 (5 RCTs) 1-28 d Moderate due to imprecisionb


Heparin-induced thrombocytopenia

3,239 (1 RCT) 1-28 d Low due to risk of imprecisionb and reporting biasd


See Table 1 and 4 legends for expansion of abbreviations.aBaseline risk is derived from the median control group risk across studies.bWe will consider the presence of serious imprecision when there are , 300 events in total (events in treatment and control patients) or when confi dence intervals include appreciable harms and benefi ts.cThe RR used to estimate risk difference included a mix of symptomatic and asymptomatic events, whereas the baseline risk (risk with UFH) was derived from symptomatic events (Riess et al30).dOnly one study (Riess et al30) reported this outcome, suggesting possible reporting bias.




Medical Patients with Enoxaparin (MEDENOX) trial, which did not directly compare LMWH to LDUH 42 and enrolled a very small proportion of patients screened for eligibility, thereby limiting generalizability. Third, although the acquisition costs of LMWH are higher up front (or similar, depending on individual hospital formulary pricing), the eventual cost savings come from treating fewer adverse events—primarily HIT and, possibly, major bleeding—farther downstream. A recent thromboprophylaxis trial in 3,764 critically ill patients reported that the incidence of HIT was 0.3% in patients who received LMWH vs 0.7% in patients who received LDUH; 12 however, a meta-analysis of HIT in patients being treated for acute DVT or PE found no difference in incidence when using LMWH or LDUH. 43 Although the popu-lation of this meta-analysis is different from those in the critical care trial; adding the trial data to the meta-analysis does not change its conclusion (RR, 0.71; 95% CI, 0.45-1.11).

In summary, there is no clear evidence in the current literature to support choosing one form of pharma-coprophylaxis over another in the medical popula-tion based on outcomes or from a cost-effectiveness standpoint. It would be reasonable to make choices based on patient preference, compliance, and ease of

2.6 Anticoagulant Thromboprophylaxis in Acutely Ill Hospitalized Medical Patients From a Resource Perspective

Almost all cost-effectiveness analyses in this popu-lation have reported costs per VTE or death averted with the use of anticoagulant prophylaxis, but few studies have reported costs per quality-adjusted life-year gained to compare against preexisting bench-marks. Two studies that reported incremental costs of $65 to $2,534 per quality-adjusted life-year gained over no prophylaxis were both sponsored by the pharmaceutical industry. 33,34 In populations at suffi -ciently high risk ( Tables 2, 6 , Table S7), pharmaco-prophylaxis is likely to be favorable from a resource standpoint for preventing VTE. 35,36 The comparison between different types of prophylaxis, however, is less clear.

Several studies have suggested that choosing LMWH over LDUH is cost neutral, or even cost saving. 37-41 However, the quality of these analyses is moderate at best. First, many of the authors have had fi nancial disclosures with the pharmaceutical indus-try, and whether these ties infl uence the cost-neutral or cost-saving results of LMWH over LDUH is unclear. Second, the performance estimates used in most of these studies have been extracted from the

Table 6—[Section 2.6] Summary of Findings: Should Aspirin or Other Antiplatelet Drugs Be Used in Hospitalized Medical Patients?59

OutcomeParticipants (Studies)

Follow-upQuality of the

Evidence (GRADE)Relative Effect

(95% CI)


Baseline Riska

Risk Difference With Aspirin Prophylaxis (95% CI)

Symptomatic DVT

Imputed data (1 RCT) up to 35 d

Low due to very serious indirectnessb

RR, 0.71 (0.52-0.97) Low risk2 per 1,000 1 fewer per 1,000

(from 1 fewer to 1 fewer)High risk

67 per 1,000 19 fewer per 1,000 (from 32 fewer to 2 fewer)


Imputed data (64 RCTs) up to 35 d





Major bleeding Imputed data (1 RCT) up to 35 d


RR, 1.42 (1.16-1.74) 4 per 1,000 2 more per 1,000 (from 1 more to 3 more)

Overall mortality Imputed data (1 RCT) up to 35 d

Very low due to very serious indirectnessb and imprecisionc


See Table 1 and 4 legends for expansion of abbreviations.aBaseline risk for DVT and PE are derived from the RAM by Barbar et al.9 Baseline risk for mortality and bleeding is derived from the control arm of medical patients in a meta-analysis (Dentali et al).24

bEvidence is indirect because the relative effect is primarily derived from surgical patients (555 of the 26,890 patients included in PEP trial report meta-analysis were high-risk medical patients). DVT and PE baseline risk estimates are derived from a risk assessment model derived in a cohort with a small number of outcome events, hence have uncertainty about them. This uncertainty can be labeled as imprecision or indirectness. Some of the PE events in this meta-analysis may have been fatal.cWe will consider the presence of serious imprecision when there are , 300 events in total (events in treatment and control patients) or when CIs include appreciable harms and benefi ts.





administration (eg, daily vs bid vs tid dosing), as well as on local factors affecting acquisition costs.

2.7 Mechanical Methods of Thromboprophylaxis in Hospitalized Medical Patients

Mechanical methods of thromboprophylaxis include graduated compression stockings (GCS), intermittent pneumatic compression devices (IPCs), and venous foot pumps (VFPs). These devices reduce venous stasis, a risk factor for VTE, by displacing blood from the superfi cial to the deep venous system via the per-forating veins, thereby increasing the velocity and volume of fl ow in the deep system. 44 Most studies of mechanical thromboprophylaxis have been conducted in surgical patients. The primary attraction of mechan-ical methods is that they do not cause bleeding; hence they may have advantages for patients at risk for VTE who cannot receive anticoagulant-based thrombo-

prophylaxis because they are bleeding or are at risk for bleeding.

2.7.1 Stockings to Prevent VTE: Direct evidence from hospitalized nonsurgical patients is available from three randomized trials that have evaluated the use of thigh-length GCS to prevent VTE in patients with myocardial infarction (one trial) 45 and stroke (two trials) 46,47 ( Table 7 , Table S8). In pooled analyses, results failed to demonstrate or exclude a benefi cial effect on symptomatic DVT or PE. Stocking use increased the risk of skin breaks/ulcers but failed to demonstrate or exclude an effect on lower limb ischemia or amputation. It is not known if hospital-ized medical patients have a similar risk of skin com-plications as hospitalized stroke patients.

In a recent multicenter RCT that compared knee-length to thigh-length GCS to prevent VTE in immo-bilized patients with acute stroke, proximal DVT

Table 7—[Section 2.7.1] Summary of Findings: Should Graduated Compression Stockings vs No Stockings Be Used in Hospitalized Medical Patients?45,47,48

OutcomeNo. of Participants (Studies) Follow-up




Baseline Riska

Risk Difference With Graduated Compression

Stockings (95% CI)

Symptomatic DVT 1,256 (1 RCT) 1-30 d Moderate due to imprecisionb


(from 1 fewer to 1 more)High risk

67 per 1,000 6 fewer per 1,000 (from 25 fewer to 19 more)


1,256 (1 RCT) 1-30 d Low due to very serious imprecisionb




Overall mortality 1,321 (2 RCTs) 1-30 d Moderate due to imprecisionb

RR, 1.06 (0.94-1.20) 45 per 1,000 3 more per 1,000 (from 3 fewer to 9 more)

Skin breaks/ulcers/blisters/skin necrosis

1,256 (1 RCT) 1-30 d Very low due to imprecision,b indirectness,c and methodologic limitationsd


Lower limb ischemia/amputation

1,256 (1 RCT) 1-30 d Very low due to very serious imprecisionb and methodologic limitationsd


Number of participants is the number of patients who received graduated compression stockings. See Table 1 and 4 legends for expansion of abbreviations.aBaseline risk for DVT and PE are derived from the RAM by Barbar et al.9 Baseline risk for mortality and bleeding is derived from the control arm of medical patients in a meta-analysis (Dentali et al24). Baseline risk for lower leg ischemia and skin breaks (derived from the control arms of CLOTS trial 1).bWe will consider the presence of serious imprecision when there are , 300 events in total (events in treatment and control patients) or when confi dence intervals include appreciable harms and benefi ts. The exception is for low-risk patients in whom the absolute difference in PE and DVT is fairly small and precise.cData on skin breaks are from stroke patients.dAssessment of outcomes was based on case-note review and was not blinded to treatment allocation.




skin complications of IPC use, but one might plausi-bly expect rates to be similar to those of GCS. The panel considered that the evidence for the different outcomes should be rated down due to indirectness because the RR estimates are derived from surgical populations, in whom effects of IPC may be different than in medical patients, and from a mix of symptom-atic and asymptomatic events.

2.7.3 Mechanical Compression vs Heparin: There are no studies that have compared mechanical com-pression vs anticoagulants to prevent VTE in hos-pitalized medical patients. Indirect evidence from various orthopedic and nonorthopedic surgical popu-lations was provided in a recent meta-analysis by Eppsteiner of 16 trials (3,887 patients) of various compression modalities tested against LDUH or LMWH. 51 Pooled results for mechanical compres-sion compared with heparin failed to show or to exclude a benefi cial or detrimental effect for DVT (RR, 1.07; 95% CI, 0.72-1.61) or PE (RR, 1.03; 95% CI, 0.48-2.22). Mechanical compression was associated with a reduced risk of postoperative bleeding com-pared with heparin (RR, 0.47; 95% CI 0.31-0.70). The median rate of major bleeding within the study

(symptomatic or asymptomatic) occurred in 98 of 1,552 (6.3%) patients who received thigh-length stockings vs 138 of 1,562 (8.8%) who received below-knee stockings (RR, 0.71; 95% CI, 0.56-0.92), with no differences between groups in rates of deaths or PE. 48 Skin breaks occurred in 3.9% and 2.9% of patients allocated to thigh-length and knee-length GCS, respectively. These results are diffi cult to inter-pret alongside evidence from the CLOTS1 trial that thigh-length GCS were not effective to prevent VTE but suggest that if GCS are used, thigh length is pre-ferred to knee length. 49

2.7.2 Intermittent Pneumatic Compression Devices to Prevent VTE: An international registry of 15,156 hos-pitalized acutely ill medical patients found that 22% of US patients received IPC to prevent VTE compared with only 0.2% of patients in other coun-tries. 31 There are no published studies of IPC or VFP devices in hospitalized medical patients. Data are available from a meta-analysis of 22 trials that assessed IPC and VFP, primarily in surgical patients. 50 IPC devices failed to demonstrate or to exclude a benefi -cial effect on mortality or PE but reduced the risk of DVT ( Table 8 , Table S9). No data are available on

Table 8—[Section 2.7.2] Summary of Findings: Should Intermittent Pneumatic Compression Be Used in Hospitalized Nonsurgical Patients With Restricted Mobility?25,51,172,173

Outcome Source of Data




Baseline Riska

Risk Difference with IPC (95% CI)

Symptomatic DVT Imputed data Moderate due to serious indirectnessb





Imputed data Low due to indirectnessb and imprecisionc




Overall mortality Imputed data Low due to indirectnessb and imprecisionc


Skin complications Not reported … … … …

See Table 1 and 4 legends for expansion of abbreviations.aBaseline risk for DVT and PE are derived from the RAM by Barbar et al.9 Baseline risk for mortality is derived from the control arm of medical patients in a meta-analysis (Dentali et al24).bSerious indirectness is considered because: RR for PE is derived from surgical patients (Roderick et al50). RR data are presented for IPC used as monotherapy because this is most relevant to the way IPCs are used in medical patients (ie, in patients who cannot receive anticoagulation). If IPCs are used alone or as adjunct to anticoagulant/antiplatelet therapy, RR is 0.77 (0.41-1.43). This does not change the conclusions of this evidence profi le. Another element of indirectness is that DVT in these surgical patients was primarily asymptomatic DVT as ascertained by systematic imaging tests. RR for proximal asymptomatic DVT was similar (0.52; 95% CI, 0.37-0.73). RR data are presented for IPC used as monotherapy because this is most relevant to the way IPCs are used in medical patients (ie, in patients who cannot receive anticoagulation). If IPCs are used alone or as adjunct to anticoagulant/antiplatelet therapy, RR is 0.49 (0.37-0.63). This does not change the conclusions of this evidence profi le.cWe will consider the presence of serious imprecision when there are , 300 events in total (events in treatment and control patients) or when CIs include appreciable harms and benefi ts.





IPC devices are often not functioning when patients are out of bed or being transported, either due to improperly applied sleeves or nonfunctioning com-pression pump (not plugged in, power switch not turned on, or air hose compressed). Devices were properly functioning in , 50% of postoperative patients in one study 52 and only 19% of trauma patients in another. 53 Newer battery-powered por-table devices are available, and a recent study reported better compliance with these devices than with tra-ditional plug-in devices. 54

2.8 Extended-Duration Anticoagulant Thromboprophylaxis to Prevent VTE in Hospitalized Medical Patients

Hospitalized medical patients may have risk fac-tors for VTE that persist for weeks to months after hospital discharge. In a medical records review of 1,897 patients diagnosed with VTE in the Worcester, Massachusetts, area, 73.7% of episodes occurred in the outpatient setting; of these, 36.8% occurred in persons hospitalized for medical illness in the pre-ceding 3 months. Among these, two-thirds were diagnosed with VTE within 1 month after hospital-ization and one-third between 2 to 3 months after hospitalization. 18 In the MEDENOX RCT in which patients received enoxaparin prophylaxis or pla-cebo for up to 14 days, eight VTE events (8% of the total) occurred between days 15 and 110, of which four were fatal PEs. 42

Extended-duration thromboprophylaxis refers to prophylaxis that is continued beyond the initial (eg, 5-14 days) course, for up to approximately 35 days total. Evidence from RCTs in hospitalized surgical patients suggests that extended-duration thrombo-prophylaxis reduces VTE in patients undergoing hip replacement surgery, hip fracture surgery, and sur-gery for abdominal malignancy. 1,55

The Extended Prophylaxis for Venous Thrombo-embolism in Acutely Ill Medical Patients With Pro-longed Immobilization (EXCLAIM) study is the only published RCT of extended duration throm-boprophylaxis in hospitalized medical patients. 56 The study population consisted of 6,085 hospital-ized patients aged . 40 years with acute medical illness (eg, heart failure, respiratory insuffi ciency, infection) and reduced mobility. All patients received initial open-label enoxaparin (40 mg daily for 10 � 4 days ), and were then randomized to receive extended-duration enoxaparin (40 mg daily for 38 � 4 days) or placebo. Extended-duration enoxaparin, compared with placebo, reduced the incidence of overall VTE (composite of asymptomatic and symptomatic events) (RR, 0.62; 95% CI, 0.45-0.84) and symptomatic prox-imal DVT (RR, 0.25; 95% CI, 0.09-0.67) but failed to

populations was 1.5%, but bleeding rates were not provided by intervention. Subgroup analyses by hep-arin type suggested that LMWH may reduce risk of DVT compared with compression (RR for compres-sion, 1.80; 95% CI, 1.16-2.79), but remains associ-ated with increased bleeding risk.

2.7.4 Mechanical Compression and Pharmacologic Prophylaxis: Trials in postsurgical patients that com-pared the combination of intermittent pneumatic compression devices with a pharmacologic method to pharmacologic therapy used alone showed a strong trend toward fewer DVTs with combination therapy (OR, 0.45; 95% CI, 0.20-1.03). 1 Studies that compared the combination of elastic stockings and pharmaco-logic prophylaxis to pharmacologic therapy alone showed a reduction in symptomatic or asymptomatic DVT (OR, 0.40; 95% CI, 0.25-0.65), but this benefi t should be weighed against the increase in skin com-plications (RR, 4.18; 95% CI, 2.4-7.3) that has been observed in stroke patients treated with elastic com-pression stockings. 2,3,46

In summary, indirect data derived primarily from surgical populations suggest that GCS may be mod-estly effective at preventing asymptomatic DVT and possibly PE in hospitalized medical patients. Direct evidence of low to moderate quality in nonsurgical patients (primarily stroke patients) does not support benefi t, and their use in stroke patients is associated with a 5% risk of skin breakdown. IPCs failed to reduce PE in surgical patients but reduced DVT. Of the two methods, GCS has lower cost and greater ease of use and application than IPCs.

Despite the uncertain benefi t, mechanical throm-boprophylaxis with GCS or IPCs may be preferable to no prophylaxis in patients at appreciable risk for VTE who are also at high risk for bleeding, as the Eppsteiner meta-analysis showed similar effective-ness but reduced rates of bleeding with mechanical compared with heparin prophylaxis among surgical patients. 51 However, as subgroup analysis in that meta-analysis suggested that LMWH may be more effective than compression, and taking into account that the baseline rate of bleeding is lower among medical patients (average from RCTs, 0.4%) than surgical patients, if the bleeding risk is temporary and if patients remain at high risk of VTE ( Table 2 ), pharmacologic thromboprophylaxis should be initi-ated once the bleeding risk has decreased.

The panel also noted that the use of all mechanical methods of thromboprophylaxis are associated with costs related to purchase and maintenance and the time and vigilance required to ensure optimal com-pliance. Clinical staff must ensure that the correct size is used, that they are properly applied, and that they are worn at all times. Studies have shown that




antiplatelet drugs to prevent VTE has been stud-ied in relatively few hospitalized medical patients (nine trials, total of 555 patients). These trial data are limited by small numbers of outcome events; report-ing of asymptomatic DVT of uncertain clinical rele-vance, often diagnosed with radiolabeled fi brinogen uptake testing, which has limitations in both sen-sitivity and specifi city; wide variety of antiplatelet drugs studied, including drugs that are no longer in use and that were administered for a mean of 8 weeks; and lack of reporting of rates of bleeding. 57 Among the nine trials, antiplatelet agents were asso-ciated with reduced risk of asymptomatic DVT (RR, 0.65; 95% CI, 0.45-0.94) based on 39 of 261 vs 61 of 266 events). Results failed to demonstrate or to exclude a benefi cial effect of antiplatelet agents on PE (RR, 0.38; 95% CI, 0.10-1.42) based on three of 275 vs eight of 280 events, respectively. Bleeding rates were not reported.

Our summary of ASA to prevent VTE in hospital-ized medical patients (section 2.9) is based on indi-rect evidence from the PEP (Pulmonary Embolism Prevention) trial, a multicenter trial of ASA 160 mg daily vs placebo for 35 days in hip fracture surgery or elective hip or knee arthroplasty patients 58 for the

exclude benefi ts or harm for fatal PE (RR, 0.34; 95% CI, 0.01-8.26) and overall mortality (RR, 1.00; 95% CI, 0.7-1.43). The risk of major bleeding was signifi cantly increased with extended-duration enox-aparin (RR, 2.51; 95% CI, 1.21-5.22), and there were four intracranial bleeding events (one fatal) in the extended enoxaparin group compared with none in the placebo group. In terms of absolute effects, extended-duration enoxaparin prevented six fewer symptomatic proximal DVT per 1,000 (95% CI, from three fewer to seven fewer) at a cost of fi ve more major bleeding events per 1,000 (95% CI, from one more to 14 more) ( Table 9 , Tables S10, S11). In addi-tion to the bleeding risk, extended prophylaxis also entails the burden and cost of daily injection.

2.9 Aspirin or Other Antiplatelet Drugs to Prevent VTE in Hospitalized Medical Patients

The contribution of platelet activation to the path-ogenesis of venous thrombosis is less clear than for arterial thrombosis. Although the use of acetylsali-cylic acid (ASA) for VTE prevention is appealing because of its low cost, oral administration, and low bleeding rates, the effectiveness of ASA or other

Table 9—[Section 2.8] Summary of Findings: Should Extended-Duration Thromboprophylaxis vs Standard Short-Duration Thromboprophylaxis Be Used for Prevention of VTE in Hospitalized Medical Patients With Reduced Mobility?57





Risk With Standard Short-Duration

Thromboprophylaxis

Risk Difference With Extended-Duration

Prophylaxis (95% CI)

Symptomatic DVT 4,995 (1 RCT) 24-32 d

Moderate due to methodologic limitationsa



Not reported … … … …

Fatal pulmonary embolism

4,995 (1 RCT) 24-32 d



Major bleeding 4,995 (1 RCT) 24-32 d



Overall mortality 4,995 (1 RCT) 24-32 d

Low due to methodologic limitationsa and imprecisionb



4,624 (1 RCT) 24-32 d

Very low due to methodologic limitationsa and very serious imprecisionb


ITT 5 intention to treat. See Table 1 and 4 legends for expansion of other abbreviations.aMethodologic limitations: change in eligibility criteria part way through the trial and seemed “data-driven”; did not use ITT analysis.bWe will consider the presence of serious imprecision when there are , 300 events in total (events in treatment and control patients) or when CIs include appreciable harms and benefi ts. We did not rate down for imprecision in the outcome of fatal PE because the absolute difference was small and precise.





suggest that passive strategies, such as dissemination of guidelines or educational events, are ineffective. Multicomponent approaches, audit and feedback, and use of automatic reminders, such as preprinted orders, computer alerts, and human alerts, have been shown to be effective strategies; however, VTE prophylaxis continues to be underused or used inappropriately, even with such interventions. 8,64-66

Recommendations

2.3. For acutely ill hospitalized medical patients at increased risk of thrombosis ( Table 2 ), we recommend anticoagulant thromboprophylaxis With LMWH, LDUH bid, LDUH tid, or fonda-parinux (Grade 1B) .

Remarks: In choosing the specifi c anticoagulant drug to be used for pharmacoprophylaxis, choices should be based on patient preference, compliance, and ease of administration (eg, daily vs bid vs tid dosing), as well as on local factors affecting acquisition costs (eg, prices of various pharmacologic agents in individual hospital formularies).

2.4. For acutely ill hospitalized medical patients at low risk of thrombosis ( Table 2 ), we recom-mend against the use of pharmacologic prophy-laxis or mechanical prophylaxis (Grade 1B) .

2.7.1. For acutely ill hospitalized medical patients who are bleeding or at high risk for bleeding ( Table 3 ), we recommend against anti-coagulant thromboprophylaxis (Grade 1B) .

2.7.2. For acutely ill hospitalized medical patients at increased risk of thrombosis who are bleeding or at high risk for major bleeding, we suggest the optimal use of mechanical thromboprophylaxis with GCS (Grade 2C) or IPC (Grade 2C) , rather than no mechanical throm-boprophylaxis. When bleeding risk decreases, and if VTE risk persists, we suggest that pharmacologic thromboprophylaxis be sub-stituted for mechanical thromboprophylaxis (Grade 2B) .

Remarks: Patients who are particularly averse to the potential for skin complications, cost, and need for clinical monitoring of GCS and IPC use are likely to decline mechanical prophylaxis.

2.8. In acutely ill hospitalized medical patients who receive an initial course of thrombopro-phylaxis, we suggest against extending the dura-tion of thromboprophylaxis beyond the period

outcomes mortality, symptomatic DVT, and bleeding; and the PEP trial meta-analysis of 53 randomized trials (nine trials conducted in medical patients, as discussed above) of antiplatelet therapy to prevent VTE for the outcome PE. Use of ASA/antiplatelet drugs, compared with placebo, had little or no effect on mortality (RR, 0.97; 95% CI, 0.85-1.10) and was associated with a reduced risk of PE (RR, 0.47; 95% CI, 0.37-0.59), a reduced risk of DVT (RR, 0.71; 95% CI, 0.52-0.97), and an increased risk of nonsur-gical site-related bleeding events (RR, 1.42; 95% CI, 1.16-1.74).

The quality of the evidence was rated down for indirectness based on relative effects derived pri-marily from surgical patients (only 555 of the 26,890 patients included in PEP trial report meta-analysis were high-risk medical patients, and all PEP trials participants were orthopedic surgery patients). The panel judged that based on the low quality of available evidence pertaining to use of ASA to pre-vent VTE in hospitalized medical patients, no rec-ommendation could be made. There have been no studies of antiplatelet therapy compared with anti-thrombotic therapy to prevent VTE in acutely ill medical patients.

2.10 Screening for DVT in Hospitalized Medical Patients

Ultrasound screening in medical patients has not been systematically studied. Indirect evidence from hospitalized orthopedic patients 59 and spinal cord injury patients 60 suggests that routine screening is not of benefi t to reduce symptomatic VTE events. For example, in a population of patients who had joint arthroplasty and were receiving warfarin prophylaxis, screening compression ultrasonography with subse-quent treatment of identifi ed asymptomatic DVT did not reduce the rate of subsequent symptomatic VTE. 59 In a population with a low prevalence of DVT, such as medical patients, even with a highly-specifi c test such as ultrasound, one would anticipate a sub-stantial number of false-positive results. Moreover, even without considering false-positive results, rou-tine ultrasound screening would be associated with appreciable cost and inconvenience without evidence of benefi t.

2.11 Gaps in Care

Low rates of adherence to recommended thrombo-prophylaxis regimens have been documented world-wide. 31,61-64 In the last few years, research efforts have focused on evaluating strategies to improve uptake of evidence-based VTE prophylaxis regimens in hospi-talized patients, including medical patients. Results




specifi cally evaluated prognostic factors associated with bleeding complications in critically ill patients ( Table 12 ). 70

3.4 Randomized Trials of Thromboprophylaxis

Five RCTs have examined pharmacologic prophy-laxis in critically ill patients: one of LDUH vs pla-cebo, 71 one of LMWH vs placebo, 69 and three of LDUH vs LMWH (one also included a placebo arm) 11,12,72 (Table S13). LDUH prophylaxis has been studied only in doses of 5,000 units bid.

The trial of LDUH vs placebo reported that LDUH was associated with a reduced risk of asymptomatic DVT (13% vs 29%, respectively; RR, 0.46; 95% CI, 0.22-0.99). Rates of bleeding, PE, and mortality were not reported. The trial of LMWH (nadroparin) vs placebo showed a trend toward reduced asymp-tomatic DVT with nadroparin (16% vs 28%, respec-tively; RR, 0.55; 95% CI, 0.30-1.00) but failed to demonstrate or exclude a benefi cial or detrimental effect of nadroparin on major bleeding (RR, 2.09; 95% CI, 0.54-8.16; 29 more per 1,000; 95% CI, from 12 fewer to 190 more) or mortality (RR, 1.01; 95% CI, 0.4-2.57). PE was not systematically evaluated.

As both of these trials routinely screened patients for asymptomatic DVT (which are usually treated if detected), and neither study reported PE, a direct estimate of effects on symptomatic VTE is only avail-able from one trial with a very small number of events. 11 For the comparison of LDUH vs placebo, results failed to demonstrate or exclude a benefi cial or detrimental effect on symptomatic DVT (RR, 0.89; 95% CI, 0.57-1.41; six fewer per 1,000; 95% CI, from 25 fewer to 24 more) or PE (RR, 0.48; 95% CI, 0.10-2.26; 22 fewer per 1,000 (95% CI, from 38 fewer to 53 more) (Table S14). Similarly, comparing LMWH

of patient immobilization or acute hospital stay (Grade 2B) .

3.0 Critically Ill Patients

3.1 Risk of VTE

The risk of VTE in patients who are admitted to an ICU varies, depending on their acute illness (eg, sepsis), chronic illnesses (eg, congestive heart failure), prehospi-tal diagnoses (eg, prior VTE), and ICU-specifi c expo-sures and events (eg, immobilization, surgery, and other invasive procedures [such as central venous catheteriza-tion] mechanical ventilation, and drugs such as vaso-pressors and paralytic agents) ( Table 10 , Table S12). 67 There are no validated risk assessment models to stratify VTE risk in critically ill patients.

3.2 Screening for VTE

There are no studies in critically ill patients of the effectiveness of screening compression ultrasonography and subsequent treatment of identifi ed DVT in reduc-ing the rate of subsequent symptomatic thromboem-bolic complications ( Table 11 ). Indirect evidence provides no support for ultrasonographic screening. 59,60

3.3 Risk of Bleeding

Although critically ill patients are at increased risk for VTE, they frequently develop bleeding complica-tions in the ICU. Up to 80% of critically ill patients have one or more episodes of bleeding, although most bleeding is minor. 68 The risk of major bleeding in the untreated arm of a prophylaxis trial in critical care patients was 2.7%, 69 but the range in practice is dependent on the case mix. Only few studies have

Table 10—[Section 3.1] Summary of Findings: Should Unfractionated Heparin vs Placebo Be Used for DVT Prevention in Critically Ill Adult Patients?71


Quality of the Evidence (GRADE) Relative Effect (95% CI)c


Baseline RiskRisk Difference With

UFH (95% CI)

Symptomatic DVT 1,457 (1 RCT) up to 28 d Moderate due to imprecisiona

RR, 0.89 (0.57-1.41) 58 per 1,000 6 fewer per 1,000 (25 fewer to 24 more)

Pulmonary embolus 1,457 (1 RCT) up to 28 d Low due to indirectnessb and imprecisiona

RR, 0.48 (0.10-2.26) 42 per 1,000 22 fewer per 1,000 (38 fewer to 53 more)

Death No data … … … …Major bleeding No data … … … …

See Table 1 and 4 legends for expansion of abbreviations.aWe will consider the presence of serious imprecision when there are , 300 events in total (events in treatment and control patients) or when CIs include appreciable harms and benefi ts.bPulmonary embolus baseline risk was obtained from observational studies whereas the relative risk is from RCT (mix of symptomatic and asymptomatic events)cRR estimated from a mix of symptomatic and asymptomatic events.





The panel considered suggesting LMWH over LDUH; however, the benefi t was small enough in magnitude (eight PEs per 1,000 patients prevented by LMWH with lower boundary of the CI of 0.6 PE per 1,000), and the treatment effect was only driven by a difference of 16 events. In addition, this trial performed screening compression ultrasonography on all enrolled patients, which differs from real world practice. If DVTs detected on ultrasonog-raphy remained undiagnosed and untreated and progressed to symptomatic PE, the treatment effect would likely be different. The panel decided to not issue this recommendation in the absence of evi-dence from other future trials and reliable cost-effective data.

There are no randomized trials comparing mechan-ical methods of prophylaxis (GCS, IPC) with no pro-phylaxis in critically ill patients. Although combined mechanical and pharmacologic prophylaxis appears to be more effective in reducing symptomatic and asymptomatic VTE events than mechanical methods alone in surgical ICU patients, it is not known whether this is the same in medical ICU patients. 73

Recommendations

3.2. In critically ill patients, we suggest against routine ultrasound screening for DVT (Grade 2C) .

3.4.3. For critically ill patients, we suggest using LMWH or LDUH thromboprophylaxis over no prophylaxis (Grade 2C) .

3.4.4. For critically ill patients who are bleeding, or are at high risk for major bleeding ( Table 4 ), we suggest mechanical thromboprophylaxis

vs placebo, results failed to demonstrate or exclude a benefi cial or detrimental effect of LMWH on symptomatic DVT (RR, 0.82; 95% CI, 0.51-1.32), PE (RR, 1.01; 95% CI, 0.31-3.31), bleeding (RR, 2.09; 95% CI, 0.54-8.16), or mortality (RR, 1.01; 95% CI, 0.4-2.57) (Table S15). Combining data from the above com parisons, 11,69,71 the use of any heparin (LMWH or LDUH) compared with placebo was associated with similar risks of symptomatic DVT, symptom-atic PE, major bleeding, and mortality (Table S16; Table 13 ).

A large randomized, blinded, placebo-controlled trial compared the LMWH dalteparin 5,000 Inter-national Units daily vs LDUH 5,000 International Units bid in 3,764 critically ill patients expected to remain in the ICU for � 3 d. The trial failed to demonstrate or exclude difference in the rate of proximal leg asymptomatic DVT (5.1% vs 5.8%, respectively; HR, 0.92; 95% CI, 0.68-1.23). 12 PE was not systematically screened, and PE events were classifi ed by a blinded, independent adjudi-cation committee as defi nite, probable, possible, or absent. Symptomatic PE occurred in signifi cantly fewer patients receiving dalteparin compared with LDUH (22 of 1,873 [1.2%] vs 38 of 1,873 [2%]; RR, 0.58; 95% CI, 0.34-0.97). The study failed to show differences in major bleeding, rates of HIT, ICU mortality, and hospital mortality in the dalteparin and LDUH groups (major bleeding, 5.5% vs 5.6%; HR, 1.00; 95% CI, 0.75-1.34; HIT, 0.3% vs 0.6%; HR, 0.47; 95% CI, 0.16-1.35; ICU mortality, 15.2% vs 16.2%; HR, 0.97; 95% CI, 0.82-1.15; hospital mortality, 22.1% vs 24.5%; HR, 0.92; 95% CI, 0.80-1.05). Two other trials 11,72 conducted this com-parison with variable reporting of symptomatic outcomes ( Table 14 , Table S17).

Table 11—[Section 3.2] Summary of Findings: Should LMWH vs Placebo Be Used for DVT Prevention in Critically Ill Adult Patients?12,70


Quality of the Evidence (GRADE) Relative Effect (95% CI)


Baseline RiskRisk difference with LMWH (95% CI)


Moderate due to serious imprecisiona

RR, 0.82 (0.51-1.32) 58 per 1,000 6 fewer (from 23 fewer to 22 more)

Pulmonary embolus 1,437 (1 RCT) 5-28 d

Very low due to very serious imprecisionb and indirectnessc

RR, 1.01 (0.31-3.31) 42 per 1,000 1 more (from 29 fewer to 97 more)

Death 169 (1 RCT) 5-28 d

Low due to very serious imprecisiona


Major bleeding 221 (1 RCT) 5-28 d


RR, 2.09 (0.54 -8.16) 27 per 1,000 29 more per 1,000 (from 12 fewer to 190 more)

See Table 1 and 4 legends for expansion of abbreviations.aCIs include appreciable harms and benefi ts.b The RR of the outcome of PE is considered very imprecise due to small number of events (4 of 478 LMWH vs 8 of 959 placebo).cRR estimated from a mix of symptomatic and asymptomatic events.




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in the article about prevention of VTE in surgical patients in this supplement. 1

4.1 Risk of VTE

Patients with cancer have at least a sixfold increased risk of VTE, 16,74 and the development of DVT is asso ciated with a signifi cant reduction in survival in this population. 75-77 VTE risk is higher with certain cancers (malignant brain tumors; adenocarcinomas of the lung, ovary, pancreas, colon, stomach, prostate, and kidney; and hematologic malignancies). 78

Nonsurgical therapies for cancer, such as chemo-therapy and hormonal manipulation, also increase

with GCS (Grade 2C) or IPC (Grade 2C) until the bleeding risk decreases, rather than no mechan-ical thromboprophylaxis. When bleeding risk decreases, we suggest that pharmacologic throm-boprophylaxis be substituted for mechanical thromboprophylaxis (Grade 2C) .

4.0 Patients With Cancer in the Outpatient Setting

The role of thromboprophylaxis to prevent VTE in patients with cancer undergoing surgery is addressed

Table 13—[Section 3.4.3] Summary of Findings: Should Any Heparin (LDUH, LMWH) vs Placebo Be Used for DVT Prophylaxis in Critically Ill Adult Patients?12,70,71

Outcome

No. of Participants

(Studies) Follow-up Quality of the

Evidence (GRADE) Relative Effect (95% CI)


Baseline RiskRisk Difference With Any

Heparin (95% CI)


Moderate due to serious imprecisiona


Pulmonary embolus 1,935 (1 RCT) 5-28 d

Low due to serious imprecisiona and indirectnessb


Death 169 (1 RCT) 5-28 d



Major bleeding 221 (1 RCT) 5-28 d



See Table 1 and 4 legends for expansion of abbreviations.aWe will consider the presence of serious imprecision when there are , 300 events in total (events in treatment and control patients) or when CIs include appreciable harms and benefi ts.bRR estimated from a mix of symptomatic and asymptomatic events.

Table 14—[Section 3.4.4] Summary of Findings: Should LMWH vs Unfractionated Heparin Be Used for DVT Prevention in Critically Ill Adult Patients?12,13,72

Outcome


Relative Effect (95% CI)No. of Participants (Studies) Follow-up

Quality of the Evidence (GRADE)Risk with UFH

Risk Difference With LMWH (95% CI)

Symptomatic DVT 25 per 1,000 3 fewer per 1,000 (from 10 fewer

to 6 more)

RR, 0.87 (0.60-1.25) 4,722 (2 RCTs) 7-28 d Moderate due to imprecisiona

Symptomatic pulmonary embolism

20 per 1,000 8 fewer per 1,000 (13.2 fewer

to 0.6 fewer)

RR, 0.58 (0.34-0.97) 3,746 (1 RCT) 7 d Moderate due to imprecisiona

Major bleeding 55 per 1,000 2 fewer per 1,000 (from 14 fewer

to 14 more)


Death 159 per 1,000 10 fewer per 1,000 (from 30 fewer

to 14 more)



6 per 1,000 3 fewer per 1,000 (from 5 fewer

to 1 more)

RR, 0.42 (0.15-1.18) 3,746 (1 RCT) 7 d Moderate due to imprecisiona

See Table 1 and 4 legends for expansion of abbreviations.aWe will consider the presence of serious imprecision when there are , 300 events in total (events in treatment and control patients) or when CIs include appreciable harms and benefi ts.




one study and LMWH in the remaining studies; all studies used prophylactic doses. Type of chemo-therapy, duration of treatment, and duration of antithrombotic prophylaxis varied widely among the studies. A number of studies administered hep-arin for the duration of chemotherapy, whereas other studies administered it for fi xed durations of heparin (eg, 6 weeks, 12 months).

Overall, the effect of heparin therapy on mortality was not statistically signifi cant at 12 months (RR, 0.93; 95% CI, 0.85-1.02), but it was statistically signif-icant at 24 months (RR, 0.92; 95% CI, 0.88-0.97) ( Table 15 , Table S18). Heparin therapy also reduced symptomatic VTE (RR, 0.55; 95% CI, 0.37-0.82). The results failed to confi rm or to exclude benefi cial or detrimental effects of heparin therapy on major bleeding (RR, 1.30; 95% CI, 0.59-2.88), minor bleed-ing (RR, 1.05; 95% CI, 0.75-1.46), and quality of life (assessed in only one study 103 ). The quality of evi-dence was high for symptomatic VTE; moderate for mortality, major bleeding, and minor bleeding; and low for quality of life.

In a subgroup analysis of patients with small cell lung cancer (SCLC) 104,105 vs other types of cancer, the test for subgroup effect was statistically signifi cant for mortality at 12 months ( P 5 .03) (RR, 0.86; 95% CI, 0.75-0.98 for SCLC vs RR, 0.96; 95% CI, 0.86-1.07

the risk of VTE. 16,79-86 The rate of VTE increases by twofold to fi vefold among women whose breast cancer has been treated with the selective estrogen receptor modulator tamoxifen. 85,87 This risk was even greater in postmenopausal women when tamoxifen was combined with chemotherapy. 88 The use of aro-matase inhibitors anastrozole, letrozole, or exemes-tane is associated with about one-half the risk of VTE compared with tamoxifen. 89-92 Angiogenesis inhibitors have also been shown to increase thromboembolic complications in patients with cancer. 93 Thalidomide and lenalidomide increase the risk of venous throm-bosis, especially when combined with chemotherapy or high-dose dexamethasone. 94-97 A recent meta-analysis reported a high risk of VTE in patients with cancer receiving bevacizumab. 98 Finally, the presence of a CVC in patients with cancer predisposes to upper extremity DVT. 99-101

4.2 Parenteral Anticoagulants

A recent systematic review evaluated the effi cacy and safety of parenteral anticoagulants in outpa-tients with cancer. 102 The review identifi ed nine eligible RCTs enrolling 2,857 patients with meta-static or locally advanced solid cancers of different tissue types. The intervention consisted of UFH in

Table 15—[Section 4.2] Summary of Findings: Should Heparin Compared With No Heparin Be Used for Patients With Cancer Who Have No Other Therapeutic or Prophylactic Indication for Anticoagulation?102

Outcomes

Illustrative Comparative Risksa (95% CI)


No. of Participants (Studies)


Assumed Risk, No Heparin

Corresponding Risk, Heparin

Mortality; follow-up: 12 mo

Medium-risk population RR, 0.93 (0.85-1.02) 2,531 (8) Moderateb-d

649 per 1,000 604 per 1,000 (552 to 662)Symptomatic VTE;

follow-up: 12 moMedium-risk population RR, 0.55 (0.37-0.82) 2,264 (7) Highb

29 per 1,000 16 per 1,000 (11 to 24)Major bleeding;

follow-up: 12 moMedium-risk population RR, 1.3 (0.59-2.88) 2,843 (9) Moderateb,e

7 per 1,000 9 per 1,000 (4 to 20)Minor bleeding;

follow-up: 12 wkMedium-risk population RR, 1.05 (0.75-1.46) 2,345 (7) Moderateb,e

27 per 1,000 28 per 1,000 (20 to 39)Health-related quality of

life: the Uniscale and the Symptom Distress Scale; better indicated by lower values. Follow-up: 12 mo

Not estimable Not estimable Not estimablef 0 (1) Lowg

See Table 4 legend for expansion of abbreviations.aThe basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).bVast majority of studies had allocation concealment and used blinded outcome and adjudication. We did not downgrade, although there was some concern about lack of blinding in some studies; the overall risk of bias was believed to be very low.cThere is moderate heterogeneity among studies included in the analysis of death at 12 mo (I2 5 41%). The subgroup analysis for mortality at 12 mo was statistically signifi cant and suggested survival benefi t in patients with small cell lung cancer but not in patients with advanced cancer. Overall we decided to downgrade by one level when considering these issues along with imprecision.dCI interval includes effects suggesting benefi t as well as no benefi t.eCI includes possibility of both harms and benefi ts.fThe scores for the two scales were similar for the two study groups, both at baseline and at follow-up.gHigh risk of bias and only 138 patients enrolled.





ing (RR, 4.24; 95% CI, 1.85-9.68; 23 more per 1,000 [from six more to 61 more]) and minor bleeding (RR, 3.34; 95% CI, 1.66-6.74). The quality of evidence was moderate for all outcomes ( Table 16 , Table S19). In summary, the absolute risk increase of bleeding with warfarin outweighs the absolute risk reduction of VTE.

4.4 Patients With Cancer With Indwelling CVCs

CVCs may result in arm swelling and discomfort, PE, predisposition to catheter-related sepsis, and the need to replace the catheter. 107,108 Peripherally inserted CVCs are associated with a greater risk of thrombosis than subclavian vein or internal jugular vein access. 109,110 If the CVC tip is placed in the upper superior vena cava or more peripherally, the DVT risk is higher than when placed at or just above the right atrium. 111 Other potential risk factors include left-sided CVC insertion, chest radiotherapy, more than one insertion attempt, and previous CVC insertion. 112,113

A systematic review identifi ed 12 eligible RCTs that enrolled 3,611 patients with cancer and an indwelling CVC 114 and compared prophylactic-dose heparin (LDUH or LMWH) or low-dose VKAs to each other or to no anticoagulation. Most studies administered treatments for a specifi ed fi xed period or until CVC removal or thrombosis diagnosis.

Prophylactic-dose heparin was associated with a trend toward reduction in symptomatic DVT (RR, 0.54; 95% CI, 0.28-1.05) ( Table 17 , Table S20). The results failed to confi rm or to exclude benefi cial or detrimental effects of prophylactic-dose heparin on

for other types of cancer) but not statistically signifi -cant at 24 months ( P 5 .88). In a subgroup analysis of patients with advanced cancer vs patients with non-advanced cancer, the review found no signifi cant dif-ference between the effects of heparin in the two subgroups ( P 5 .51).

In summary, there is moderate-quality evidence of a reduction in mortality and high-quality evidence of a reduction in VTE with larger absolute effects than any plausible increase in risk of major bleeding. There is a possible but not convincing increased mortality benefi t in the subgroup of patients with SCLC.

4.3 Oral Anticoagulants

A recent systematic review evaluated the effi cacy and safety of oral anticoagulants in patients with can-cer and no therapeutic or prophylactic indication for anticoagulation. 106 The review identifi ed fi ve eligible RCTs that enrolled 1,656 patients. The intervention consisted of warfarin in all fi ve studies; started within a month before, or at the time of, initiating chemo-therapy; and continued until the end of chemotherapy or up to a few weeks later.

Warfarin had little or no effect on reducing mortality at 6 months (RR, 0.96; 95% CI, 0.80-1.16), at 1 year (RR, 0.94; 95% CI, 0.8-1.03), at 2 years (RR, 0.97; 95% CI, 0.87-1.08), or at 5 years (RR, 0.91; 95% CI, 0.83-1.01). One study assessed the effect of warfarin on VTE and showed an RR reduction of 85% (RR, 0.15; 95% CI, 0.02-1.2; 25 fewer per 1,000 [from 28 fewer to six more]). Warfarin increased both major bleed-

Table 16—[Section 4.3] Summary of Findings: Should Oral Anticoagulation Be Used in Patients With Cancer With No Therapeutic or Prophylactic Indication for Anticoagulation?102

Outcomes


Assumed Risk, Control

Corresponding Risk, Oral Anticoagulation Relative Effect (95% CI)

No of Participants (Studies)


Death; follow-up: median 1 y

457 per 1,000 430 per 1,000 (398- 471) RR, 0.94 (0.87-1.03) 1,604 (5) Moderateb

VTE; follow-up: 1 y 43 per 1,000 6 per 1,000 (1-52) RR, 0.15 (0.02-1.2) 315 (1) Moderatec

Major bleeding; follow-up: median 1 y

22 per 1,000 93 per 1,000 (41-213) RR, 4.24 (1.85-9.68) 1,282 (4) Moderated

Minor bleeding; follow-up: 1 y

79 per 1,000 264 per 1,000 (131-532) RR, 3.34 (1.66-6.74) 851 (3) Moderated

Health-related quality of life: not reported

Not estimable Not estimable Not estimable … Not estimable

See Table 1 and 4 legends for expansion of abbreviations.aThe basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).bWe downgraded because of lack of blinding of patients and providers in four out of fi ve studies, it was unclear whether allocation was concealed in two studies, and only one study clearly used ITT analysis.cWe downgraded because the precision of the estimate does not exclude a patient-important benefi t (the lower limit of RR still suggests a benefi t that might be relevant given the high baseline risk).dWe downgraded because lack of blinding of patients and providers in three out of four studies, it was unclear whether allocation was concealed in two studies, and only one study clearly used ITT analysis.




and low risk of bleeding are more likely to benefi t than be harmed from heparin prophylaxis.

Recommendations

4.2.1. In outpatients with cancer who have no additional risk factors for VTE, we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and recommend against the prophylactic use of VKAs (Grade 1B) .

Remarks : Additional risk factors for venous thrombosis in outpatients with cancer include previous venous thrombosis, immobilization, hormonal therapy, angio-genesis inhibitors, thalidomide, and lenalidomide.

4.2.2. In outpatients with solid tumors who have additional risk factors for VTE and who are at low risk of bleeding, we suggest prophylactic-dose LMWH or LDUH over no prophylaxis (Grade 2B) .

Remarks : Additional risk factors for venous thrombosis in outpatients with cancer include previous venous thrombosis, immobilization, hormonal therapy, angio-genesis inhibitors, thalidomide, and lenalidomide.

4.4. In outpatients with cancer and indwelling CVCs, we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and suggest against the prophylactic use of VKAs (Grade 2C) .

5.0 Chronically Immobilized Outpatients

5.1 Risk of VTE

The recognition that bedbound hospitalized patients are at increased risk for VTE has led many clinicians

death (RR, 0.85; 95% CI, 0.53-1.37), major bleeding (RR, 0.68; 95% CI, 0.10-4.78), thrombocytopenia (RR, 0.85; 95% CI, 0.49-1.46), and infection (RR, 0.91; 95% CI, 0.49-1.68). No data were available for HIT, heparin-induced thrombocytopenia and throm-bosis , PE, or catheter failure. The quality of evidence was moderate for all outcomes.

Results failed to confi rm or to exclude benefi cial or detrimental effects of low-dose VKAs on death (RR, 0.97; 95% CI, 0.82-1.15), symptomatic DVT (RR, 0.63; 95% CI, 0.35-1.11), or major bleeding (RR, 6.93; 95% CI, 0.86-56.08) ( Table 18 , Table S21). However, low-dose VKAs were associated with a statistically signifi cant reduction in asymptomatic DVT (RR, 0.42; 95% CI, 0.28-0.61).

Studies comparing heparin to VKA found no effects on any of the outcomes of interest. The quality of evidence was low for all these outcomes ( Table 19 , Table S22).

In summary, prophylactic-dose heparin in patients with cancer and CVCs is potentially associated with more benefi ts than harms. It is uncertain whether the potential benefi ts of low-dose VKAs outweigh the associated potential increase in bleeding.

Despite evidence of benefi t of prophylactic-dose heparin in some outpatients with cancer and some patients with cancer with CVCs, the substantial clin-ical heterogeneity of the patients studied (different cancer types, different cancer treatments, and dif-ferent durations of prophylaxis) raises questions about which groups of outpatients with cancer will benefi t. More evidence will be available over the next few years on the effectiveness, cost-effectiveness, and specifi c patient groups most likely to benefi t from prophylaxis. Considering the selection criteria of the studies, patients with solid cancer, high risk for VTE,

Table 17—[Section 4.4] Summary of Findings: Should Heparin Compared With No Heparin Be Used for Thrombosis Prophylaxis in Patients With Cancer With Central Venous Catheters?114

Outcomes


Relative Effect (95% CI)No. of Participants

(Studies)


Assumed Risk, No Heparin

Corresponding Risk, Heparin

Death 65 per 1,000 55 per 1,000 (34-89) RR, 0.85 (0.53-1.37) 1,192 (5) Moderateb-d

Symptomatic DVT 49 per 1,000 26 per 1,000 (14-51) RR, 0.54 (0.28-1.05) 1,173 (6) Moderateb-d

Major bleeding 5 per 1,000 3 per 1,000 (1-24) RR, 0.68 (0.1-4.78) 891 (4) Moderateb-d

Infection 71 per 1,000 65 per 1,000 (35-119) RR, 0.91 (0.49-1.68) 626 (3) Moderateb,c

Thrombocytopenia 66 per 1,000 56 per 1,000 (32-96) RR, 0.85 (0.49-1.46) 836 (3) Moderateb-d

Quality of life: not reported

Not estimable Not estimable Not estimable … Not estimable

See Table 4 for expansion of abbreviations.aThe basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).bAllocation clearly concealed in three of the six studies. Four studies blinded patients and providers and all studies blinded outcome adjudicators. Three studies had no problem with incomplete data. None of the studies was suspected of selective reporting. Two studies clearly used ITT.cRelatively small number of events.dCI includes both values suggesting no effect and values suggesting either benefi t or harm.





ical condition reducing mobility for at least 48 h. 115 Anticoagulant prophylaxis was administered to 35% of patients. The study found a 1.2% incidence of symptomatic VTE in the 3 weeks after the onset of the acute condition. This incidence is similar to studies examining patients hospitalized with acute medical conditions, but the pattern of immobility (acute rather than chronic) does not allow extrapolation to home-bound patients.

Several observational studies have examined the incidence of VTE in nursing home patients, including two large studies using the Minimum Data Set, a mandatory questionnaire completed for all Medicare-licensed long-term facilities in the United States. 116,117 Liperoti and colleagues retrospectively assessed 132,018 nursing home patients across fi ve states

to consider whether chronically immobilized outpa-tients are at similar increased risk, and whether they may also benefi t from VTE prophylaxis. The chroni-cally immobile population is large and includes patients who are homebound, as well as residents of nursing homes and postacute care facilities. Despite their similarities to medical inpatients, there have been few studies and no placebo-controlled trials investi-gating VTE prophylaxis for chronically immobilized outpatients.

Although the population at risk is clearly large, the scope of the problem and incidence of symptomatic VTE is uncertain. One study of outpatients examined the incidence of symptomatic VTE in 16,532 outpa-tients . 40 years of age (median age, 71 years) who were not immobile at baseline and had an acute med-

Table 18—[Section 4.5] Summary of Findings: Should VKA Compared With No VKA Be Used for Thrombosis Prophylaxis in Patients With Cancer With Central Venous Catheters?114

Outcomes



(Studies)Quality of the

Evidence (GRADE)Assumed Risk,

no VKA Corresponding Risk, VKA

Death 312 per 1,000 303 per 1,000 (256-359) RR, 0.97 (0.82-1.15) 1,093 (2) Moderate due to imprecisionb,c

Symptomatic DVT 90 per 1,000 57 per 1,000 (31-100) RR, 0.63 (0.35-1.11) 1,235 (4) Moderate due to imprecisionb,c

Major bleeding 2 per 1,000 14 per 1,000 (2-112) RR, 6.93 (0.86-56.08) 1,093 (2) Moderate due to imprecisionb,c; high-quality evidence in other populations

See Table 1 and 4 legends for expansion of abbreviations.aThe basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).bWe did not rate down for methodologic limitations. Allocation clearly concealed in three of the four studies. None of studies blinded patients, providers, or data collectors, and three studies blinded outcome adjudicators. Three studies had no problem with incomplete data. The presence of selective reporting was unclear in one study. Two studies clearly used ITT.cRelatively small number of events. CI includes both values suggesting no effect and values suggesting either benefi t or harm.

Table 19—[Section 4.6] Summary of Findings: Should LMWH Compared With VKA Be Used for Thrombosis Prophylaxis in Patients With Cancer With Central Venous Catheters?114

Outcomes



(Studies)


Assumed Risk, VKA

Corresponding Risk, LMWH

Death 110 per 1,000 140 per 1,000 (61-326) RR, 1.27 (0.55-2.96) 343 (2) Lowb-d

Symptomatic DVT 22 per 1,000 28 per 1,000 (6-143) RR, 1.28 (0.25-6.5) 280 (2) Lowb-d

Major bleeding 0 per 1,000 0 per 1,000 (0-0) RR, 3.1 (0.13-73.14) 343 (2) Lowb-d

Thrombocytopenia 0 per 1,000 0 per 1,000 (0-0) RR, 5.17 (0.26-103.21) 59 (1) Lowb-d

Quality of life: not reported Not estimable Not estimable Not estimable … Not estimable

See Table 1 and 4 legends for expansion of abbreviations.aThe basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).bAllocation clearly concealed in one of the two studies. None of the studies blinded patients, providers, or data collectors, but both studies blinded outcome adjudicators. One study did not address incomplete data reporting. None of the studies was suspected of selective reporting. One study clearly used ITT.cRelatively small number of events.dCI includes both values suggesting no effect and values suggesting either benefi t or harm.




6.0 Long-Distance Travel

6.1 Risk of VTE

Prolonged air travel results in a very small absolute incidence of VTE. A systematic review and meta-analysis of 14 studies (11 case-control, two cohort, and one case-crossover) of risk for VTE in travelers demonstrated a pooled RR of 2.8 (95% CI, 2.2-3.7). A dose-response relationship was identifi ed, with an 18% higher risk of VTE for each 2-h increase in travel duration. 122,123 However, the overall absolute inci-dence of a symptomatic VTE in the month following a fl ight . 4 h is 1 in 4,600 fl ights, 124 with a reported incidence of asymptomatic VTE on arrival from a trip ranging from 0% to 1.5%. 123 The incidence varies by the type and duration of travel and by individual risk factors. 125-127 Thrombosis risk also appears to be increased for travel by car, bus, or train. 128-130

The association between air travel and VTE is strongest for fl ights . 8 to 10 h 125-128,131-133 and is increased in the presence of VTE risk factors such as recent surgery. 123 For those on fl ights . 4 h, immo-bility during the fl ight and window seating (especially for obese persons) also increase the risk of VTE. 134 Especially tall or short passengers may have an increased risk. 130 There is no defi nitive evidence that dehydration, travel in economy class, and drink-ing alcoholic beverages on the fl ight are related to VTE risk.

Most individuals with travel-associated VTE have one or more known risk factors for thrombosis, including previous VTE, recent surgery or trauma, active malignancy, pregnancy, estrogen use, advanced age, limited mobility, severe obesity, or a thrombo-philic disorder. 129,130,132,135-140 Among healthy volunteers, coagulation activation observed after an 8-h fl ight was greater in carriers of factor V Leiden and in women taking oral contraceptives. 141 Case-control studies have reported an increased risk of VTE in travelers who have thrombophilia and use oral contraceptives. 130,136

We identifi ed a Cochrane review 142 of nine RCTs of thromboprophylaxis in long-distance air travelers (Tables S24, S25). All but one of these trials was con-ducted by a single group of investigators. 140,143-150 Trials enrolled a mix of low- and increased-risk subjects based on risk factors for VTE, and most studies included persons taking fl ights of . 7 h. Asymptomatic DVT detected by screening ultrasound examination was the primary end point. All of the trials have meth-odologic limitations that compromise their interpre-tation. Further, the UK General Medical Council’s Fitness to Practice Panel judged that these papers included coauthors who had not approved the papers and erased the principal investigator from the register of the General Medical Council. 151 Regardless, as there

and found a symptomatic VTE incidence of 0.91 per 100 person-years. Similarly, a retrospective study of 18,661 nursing home patients in Kansas found a VTE incidence of 1.30 per 100 person-years. 116 These studies suggest that the best estimate of the annual incidence of symptomatic VTE in nursing home patients is approximately 1%. The use of anticoagu-lant prophylaxis has not been examined adequately in this population to draw conclusions on whether the benefi ts outweigh the risks and costs.

The incidence of VTE in postacute care facil-ities was examined in a prospective cohort study of 3,039 patients admitted for rehabilitation after acute medical illness or surgery. 118 Reasons for admission to the facility included medical illness (54.7%), stroke (21.1%), and surgery (31.7%). Most patients (75.1%) received anticoagulant thromboprophylaxis, which was primarily LMWH. The incidence of symptom-atic VTE was 2.4% during the stay at the facility (median duration 26 days). Risk factors for VTE were cancer and prior VTE.

Two cross-sectional studies examined the preva-lence of asymptomatic DVT in elderly patients in postacute care facilities in France and detected asymptomatic DVT in 14.0% and 15.8% of patients, respectively. 119,120 A subsequent analysis that com-bined data from these two studies noted that although proximal DVT was not signifi cantly reduced among patients who received LMWH prophylaxis (5.7% vs 4.0%; P 5 .16), this difference became statistically signifi cant with the use of propensity analysis to con-trol for potentially confounding variables (OR, 0.56; P 5 .03). 121 These studies suggest that the incidence of asymptomatic DVT in elderly patients in postacute care facilities is similar to that of hospitalized patients. However, their observational designs and lack of patient-important end points does not allow for any conclusions to be drawn on whether thromboprophy-laxis is of benefi t in this population (Table S23).

The available data suggest that nursing home patients have an incidence of symptomatic VTE of 1% annually and postacute care patients have an incidence of 1.0% to 2.4% during their stay at the facility. These data offer some indirect support for prophylaxis of immobile patients in postacute or subacute care facilities, as their incidence of VTE may be similar to that of acutely ill hospitalized patients. Randomized trials are needed to determine if the benefi ts of anticoagulant thromboprophylaxis outweigh the risks in this population.

Recommendation

5.1. In chronically immobilized persons resid-ing at home or at a nursing home, we suggest against the routine use of thromboprophylaxis (Grade 2C) .





or trauma, active malignancy, pregnancy, estro-gen use, advanced age, limited mobility, severe obesity, or known thrombophilic disorder), we suggest frequent ambulation, calf muscle exercise or sitting in an aisle seat if feasible (Grade 2C) .

6.1.2. For long-distance travelers at increased risk of VTE (including previous VTE, recent surgery or trauma, active malignancy, preg-nancy, estrogen use, advanced age, limited mobility, severe obesity, or known thrombophilic disorder), we suggest use of properly fi tted, below-knee GCS providing 15 to 30 mm Hg of pressure at the ankle stockings during travel (Grade 2C) . For all other long-distance travelers, we suggest against the use of GCS (Grade 2C) .

6.1.3. For long-distance travelers, we suggest against the use of aspirin or anticoagulants to prevent VTE (Grade 2C) .

7.0 Thromboprophylaxis to Prevent VTE in Asymptomatic Persons

With Thrombophilia

7.1 Risk of VTE

Thrombophilia refers to inherited or acquired con-ditions, measurable in the blood, that are associated with an increased risk of developing venous throm-bosis. Inherited conditions include factor V Leiden (R506Q) mutation (average population prevalence, 5%; RR of a fi rst venous thrombosis, compared with the general population, 5-7), prothrombin gene (G20210A) mutation (2%; RR, 2-3), antithrombin defi ciency (0.04%; RR, 15-20), protein C defi ciency (0.3%; RR, 15-20), and protein S defi ciency (0.3%; RR, 15-20). Acquired thrombophilic conditions include antiphospholipid antibodies (APLA) (1%-5.6%; RR, 3-10), 9,152 which may be associated with both venous and arterial thrombosis.

Thrombophilia is most often tested for and detected in patients who have been diagnosed with VTE. However, in some situations, asymptomatic persons (ie, without a previous history of VTE) may undergo testing for thrombophilia for reasons potentially related (eg, family member had VTE) or unrelated (eg, as part of a workup for autoim-mune disease) to risk of VTE. The absolute annual incidence of VTE in asymptomatic persons with thrombophilia who are relatives of probands with VTE is low, ranging from 0.1% per year for carriers of factor V Leiden, to 1.7% per year for those with antithrombin defi ciency or mixed thrombophilic defects. 153,154

A pertinent clinical question is whether long-term antithrombotic therapy should be offered to such

was no evidence presented suggesting falsifi cation of data, we include discussion of these trials in this article.

A meta-analysis of the above trials found that among nine randomized trials, 142 the use of various brands of below-knee GCS (providing 15-30 mm Hg compression at the ankle) reduced the rate of asymp-tomatic DVT detected by screening from 3.6% (47 of 1,323 control subjects) to 0.2% (three of 1,314 stocking users) (RR, 0.10; 95% CI, 0.04-0.25); abso-lute estimated effects in a low-risk population were 4.5 fewer symptomatic DVT per 10,000 (95% CI, from four fewer to fi ve fewer) and 24 fewer PE per 1,000,000 (95% CI, from 20 fewer to 26 fewer), and in a high-risk population, 16.2 fewer symptomatic DVT per 10,000 (95% CI, from 14 fewer to 17.5 fewer) and 87 fewer PE per 1,000,000 (95% CI, from 76 fewer to 94 fewer) ( Table 20 , Table S26). Among eight trials that reported superfi cial throm-bophlebitis as an end point, results failed to show or exclude a benefi cial or detrimental effect of stockings (RR, 0.45; 95% CI, 0.18-1.13). Stockings reduced postfl ight leg edema in six trials in which this out-come was assessed; however, lack of blinding and use of unvalidated measures of edema reduce con-fi dence in this result.

In a small study of high-dose enoxaparin (1 mg/kg), administered once 2 to 4 h before travel lasting 7 to 8 h, vs aspirin, one dose daily for 3 days starting 12 h before the beginning of the fl ight, vs control, there were zero of 82, three of 84, and four of 83 asymp-tomatic DVT in the three groups, respectively, but no symptomatic DVT or PE events in any group, although follow-up ended after the subjects left the airport. 149

In summary, symptomatic VTE is rare in passen-gers returning from long fl ights. Travelers at increased risk of VTE, defi ned as persons with previous VTE, thrombophilic disorders, severe obesity, recently active cancer, or recent major surgery, who are trav-eling on fl ights . 6 h, may want to consider reducing their risk of VTE by frequent ambulation or sitting in an aisle seat if feasible and avoiding dehydration, although these measures have not been assessed in clinical trials. Light compression stockings appear to have a protective effect in reducing asymptomatic DVT in travelers, are inexpensive, and are unlikely to cause harm. Until further, methodologically appro-priate studies are available, decisions regarding phar-macologic thromboprophylaxis for travelers who are considered to be at particularly high risk for VTE must be made on an individual basis, considering that adverse effects may outweigh any benefi t.

Recommendations

6.1.1. For long-distance travelers at increased risk of VTE (including previous VTE, recent surgery




vs placebo to prevent arterial or venous thrombosis. 159 A total of 98 asymptomatic individuals with persistently positive APLA ( . 95% female; 60% had systemic lupus erythematosus) who were not receiving warfa-rin were randomized. The study failed to demon-strate or exclude a benefi cial or detrimental effect of ASA (HR, 1.04; 95% CI, 0.69-1.56). In asymptomatic persons with other types of thrombophilia (factor V Leiden, prothrombin G20210A mutation), a subgroup analysis of the Women’s Health Study also failed to demonstrate or exclude an effect of ASA on VTE (HR, 0.83; 95% CI, 0.50-1.39) 160 ( Table 21 , Tables S27-S30). There are no published studies of the

patients to prevent VTE (consideration of antithrom-botic therapy to prevent VTE in pregnant women with thrombophilia is addressed in Bates et al 155 ). Observational studies have addressed the effects of ASA in asymptomatic persons with APLA, or ASA and hydroxychloroquine in persons with systemic lupus erythematosus and APLA 156-158 ; some suggest that these drugs may be effective.

Only one published RCT has addressed this issue. The Antiphospholipid Antibody Acetylsalicylic Acid (APLASA) study was a randomized, blinded, placebo-controlled clinical trial in asymptomatic patients with APLA comparing the effi cacy of aspirin 81 mg daily

Table 20—[Section 6.1] Summary of Findings: Should Compression Stockings Compared With No Compression Stockings Be Used by People Taking Long Flights?142

OutcomeNo. of Patients

(Studies)Quality of the

Evidence (GRADE)Relative Effect (95% CI)


Baseline Risk Without StockingRisk Difference With

Stocking (95% CI)

Symptomatic DVT 2,637 (9) Moderate due to imprecisiona

Not estimable 0 per 1,000 21.5% to 1.5%

Pulmonary embolism 2,637 (9) Not estimable Not estimable 0 per 1,000 21.5% to 1.5%Symptomatic DVT

(inferred from surrogate, symptomless DVT)

2,637 (9) Moderate due to indirectnessb

RR, 0.10 (0.04-0.25)

Low-risk populationc

5 per 10,000 0.5 per 10,000 (0 to 1.25)

High-risk populationc

18 per 10,000 1.8 per 10,000 (1 fewer to 8 fewer)

Symptomatic pulmonary embolism (inferred from surrogate, symptomless DVT)

2,637 (9) Moderate due to indirectnessb

RR, 0.10 (0.04-0.25)

Low-risk populationc

27 per million 3 per million (1 fewer to 7 fewer)

High-risk populationc

97 per million 10 per million (4 fewer to 95 fewer)

Superfi cial vein thrombosis

1,804 (8) Moderate due to imprecision

RR, 0.45 (0.18-1.13)

13 per 1,000 6 per 1,000 (2 fewer to 15 more)

Edema postfl ight values measured on a scale from 0, no edema, to 10, maximum edema.

1,246 (6) Lowb due to risk of bias (unblinded, unvalidated measure)

Not estimable The mean edema score ranged across control groups from 6.4 to 8.9

The mean edema score in the intervention groups was on average 4.72 lower (95% CI, 4.91-4.52).

Death 2,637 (9) Not estimabled Not estimable Estimates not available, but risk extremely low

Adverse effects 1,182 (4) Not estimabled Not estimable Not estimable Not estimable

All the stockings in the nine trials included in this review were below-knee compression stockings. In four trials the compression strength was 20-30 mm Hg at the ankle. It was 10-20 mm Hg in the other four trials. Stockings come in different sizes. If a stocking is too tight around the knee it can prevent essential venous return, causing the blood to pool around the knee. Compression stockings should be fi tted properly. A stocking that is too tight could cut into the skin on a long fl ight and potentially cause ulceration and increased risk of DVT. Some stockings can be slightly thicker than normal leg covering and can be potentially restrictive with tight footwear. It is a good idea to wear stockings around the house prior to travel to ensure a good, comfortable fi tting. Stockings were put on 2 to 3 h before the fl ight in most of the trials. The availability and cost of stockings can vary. See Table 4 legend for expansion of abbreviations.aThe imprecision refers to absolute measures, not the relative. For the relative, it is not possible to make an estimate. This is also true for pulmonary embolism.bThere are two reasons for indirectness: estimates of relative risk reduction come from the surrogate, and there is uncertainty regarding the baseline risk.cEstimates for control event rates for venous thrombosis and for pulmonary embolism come from Philbrick et al.131 Defi nition of high risk includes previous episodes of DVT, coagulation disorders, severe obesity, limited mobility due to bone or joint problems, neoplastic disease within the previous 2 years, or large varicose veins.dNone of the other trials reported adverse effects, apart from four cases of superfi cial vein thrombosis in varicose veins in the knee region that were compressed by the upper edge of the stocking in one trial.131





VTE in three prospective cohort studies, six case-control studies, and one clinical trial (Tables S31, S32). Considering DVT and PE together, the pooled risk estimate with statin use vs nonuse from several case-control studies 162-166 was 0.61 (95% CI, 0.48-0.81). Two observational studies based on administrative data 166,167 reported no signifi cant difference in the adjusted OR of VTE comparing statin users and nonusers. In contrast, another observational study 168 reported a lower risk of DVT with statin use, with an RR of 0.78 (95% CI, 0.69-0.87). The Heart and Estro-gen/Progestin Replacement (HERS) clinical trial 169 of women with coronary artery disease also reported a lower risk of VTE with statin use (not randomized) in women (HR, 0.45; 95% CI, 0.23-0.88).

A single RCT comparing statin to placebo reported a lower risk of VTE with the statin. 170 The Justifi ca-tion for the Use of Statins in Primary Prevention: an Intervention Trial Using Rosuvastatin (JUPITER) was designed to assess the effi cacy of rosuvastatin in preventing arterial vascular events in those not other-wise eligible for statins based on existing guidelines. Thus, it included a large sample of healthy people with low-density lipoprotein cholesterol , 130 mg/dL and C-reactive protein . 2 mg/L, without diabetes

effectiveness of thromboprophylaxis in asymptom-atic persons with thrombophilia types other than APLA, factor V Leiden, or prothrombin mutation, and no studies of anticoagulants such as LMWH, UFH, or VKA, or of mechanical thromboprophy-laxis such as GCS to prevent VTE in asymptomatic persons with thrombophilia.

Recommendation

7.1. In persons with asymptomatic thrombo-philia (ie, without a previous history of VTE), we recommend against the long-term daily use of mechanical or pharmacologic thrombopro-phylaxis to prevent VTE (Grade 1C) .

8.0 Statins to Prevent VTE in Asymptomatic Persons

8.1 Risk of VTE

Statins reduce coagulation potential by decreasing tissue factor expression and decreasing thrombin generation, 161 leading to consideration of statin use to prevent VTE. Statin use has been related to risk of

Table 21—[Section 7.1] Summary of Findings: Should Aspirin vs No Treatment Be Used for Prevention of VTE in Persons With Asymptomatic Thrombophilia?157-160


(Studies) Follow-upQuality of the

Evidence (GRADE)

Relative Effect (95%

CI)



Aspirin (95% CI)

Symptomatic nonfatal DVT and PE

98 (2 RCTs) 2.3-10.1 y Low due to very serious imprecisiona

RR, 2.08 (0.20-22.23)

20 per 1,000 22 more per 1,000 (from 16 fewer to 425 more)

Mortality 98 (1 RCT) 2.3 y Very low due to very serious imprecisiona and methodologic limitationsb

RR, 1.04 (0.07-16.19)

21 per 1,000 1 more per 1,000 (from 19 fewer to 316 more)

Major bleeding 207 (3 Observational studies) 2.3-8 y

Very low due to very serious imprecisiona

Not estimable, no events in either arm

0 per 1,000 Not estimable

See Table 1 and 4 legends for expansion of abbreviations.aVery small number of events.bErkan et al159 terminated early as event rates were lower than expected and larger sample size was infeasible.

Table 22—[Section 8.1] Summary of Findings: Should Statins Be Used to Prevent VTE?170


(Studies) Follow-upQuality of the

Evidence (GRADE) Relative Effect (95% CI)



Statins (95% CI)

Symptomatic DVT 17,802 (1 RCT) 1.9 y

High HR, 0.45 (0.25-0.79) 4 per 1,000 2 fewer per 1,000 (from 1 fewer to 3 fewer)

Nonfatal PE 17,802 (1 RCT) 1.9 y

High HR, 0.77 (0.41-1.45) 2 per 1,000 0 fewer per 1,000 (from 1 fewer to 1 more)

See Table 1 and 2 legends for expansion of abbreviations.




panies/orga nizations whose products or services may be dis-cussed in this article . Role of sponsors: The sponsors played no role in the develop-ment of these guidelines. Sponsoring organizations cannot recom-mend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Sci-ence Policy Committee are blinded to the funding sources. Fur-ther details on the Confl ict of Interest Policy are available online at http://chestnet.org. Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clin-ical Pharmacy, the American Society of Health-System Pharma-cists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis. Additional information: The supplemental Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e195S/suppl/DC1.

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and other conditions. Considering symptomatic VTE, a secondary end point of the trial, assignment to the statin was associated with a 55% lower DVT risk and 23% lower PE risk. There was no increased risk of bleeding. The absolute rates of VTE were 2 per 1,000 in statin users compared with 4 per 1,000 in nonus-ers. The number needed to treat to prevent one DVT was 500 ( Table 22 , Table S33).

The panel considered that it was premature to issue a recommendation concerning the use of statins to prevent VTE in light of the paucity of data and the availability of more established effective treat-ments. In addition, the patients included in this trial were not at increased risk of thrombosis and are not the patients for whom thromboprophylaxis would be recommended.

This area is in need of further research. Trials that enroll patients at high risk of VTE (eg, those with previous VTE) who require thromboprophylaxis are needed. Such trials should have a comparative effec-tiveness design to better inform guideline developers; to that extent, these trials should have an active treat-ment of comparison, focus on symptomatic events that matter the most to patients, and report cost effec-tiveness analyses.

Acknowledgments Author contributions : As Topic Editor, Dr Murad oversaw the development of this article, including the data analysis and subse-quent development of the recommendations contained herein. Dr Murad: contributed as Topic Editor. Dr Kahn: contributed as Deputy Editor. Dr Lim: contributed as a panelist. Dr Dunn: contributed as a panelist. Dr Cushman: contributed as a panelist. Dr Dentali: contributed as a panelist. Dr Akl: contributed as a panelist. Dr Cook: contributed as a panelist. Dr Balekian: contributed as a resource consultant. Dr Klein: contributed as a frontline clinician. Dr Le: contributed as a frontline clinician. Dr Schulman: contributed as a panelist. Financial/nonfi nancial disclosures: The authors of this guide-line provided detailed confl ict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e195S/suppl/DC1. In summary, the authors have reported to CHEST the following confl icts of interest: Dr Kahn has received peer-reviewed and investigator-initi-ated industry research funding for projects related to venous thrombosis and postthrombotic syndrome prevention and treat-ment. She has received honoraria for industry-sponsored talks per-taining to venous thrombosis. Dr Balekian received industry research support and served as a consultant in areas relating to venous thrombosis. Dr Cook has received donated study drug (dalteparin) from Pfi zer for a Canadian government-funded trial of thrombo-prophylaxis in the ICU. Dr Cushman is the mentor on a mentored research grant from the Hemophilia and Thrombosis Research Society that is studying risk factors for venous thrombosis among medical inpatients, 2009-2011. No specifi c dollar amount goes toward her salary. Dr Akl is a prominent contributor to the GRADE Working Group. Dr Murad is a member of the GRADE Working Group. Drs Lim, Dunn, Dentali, Klein, Le, and Schulman have reported that no potential confl icts of interest exist with any com-


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1 © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( www . chestjournal . org / site / misc / reprints . xhtml ). DOI: 10.1378/chest.11-2296

Prevention of VTE in Nonsurgical Patients

Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Susan R. Kahn , MD ; Wendy Lim , MD ; Andrew S. Dunn , MD ; Mary Cushman , MD ; Francesco Dentali , MD ; Elie A. Akl , MD, MPH, PhD ; Deborah J. Cook , MD, MSc(Epi) ; Alex A. Balekian , MD, MSHS ; Russell C. Klein , MD ; Hoang Le , MD, FCCP ; Sam Schulman , MD ; and M. Hassan Murad , MD, MPH



2© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2296

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aceb

o gr

oup,

80.

1 �

6.9

y)

Pred

icta

ble

shor

t-te

rm h

ospi

taliz

atio

n ( ,

7 d

)

Hos

pita

lized

Act

ive

blee

ding

Coa

gula

tion

diso

rder

Thy

roid

dis

ease

Ong

oing

ant

icoa

gula

nt o

r an

tipla

tele

t the

rapy

Iodi

ne a

llerg

y

Acu

te m

edic

al il

lnes

s: C

HF

(NYH

A I

II-I

V),

acut

e or

res

pira

tory

infe

ctio

us d

isea

se“A

utop

sy n

ot a

vaila

ble

if ne

cess

ary”

Ibar

ra-P

erez

et a

l 4 /198

8A

ge .

40

y (m

ean

age

not a

vaila

ble)

PE

Pred

icte

d im

mob

iliza

tion

. 3

dM

edic

al h

isto

ry o

f DV

T o

r PE

Hem

orrh

age

CVA

Vasc

uliti

s

Peri

card

itis

Coa

gula

tion

diso

rder

s

Rec

ent p

osto

pera

tive

stat

us

Use

of a

ntic

oagu

lant

s

Hos

pita

lized

Alle

rgy

to io

dine

Pulm

onar

y di

seas

ePa

tient

or

phys

icia

n’s

refu

sal t

o co

oper

ate

(Con

tinu

ed)




Stud

y/Ye

arIn

clus

ion

Cri

teri

aE

xclu

sion

Cri

teri

a

Gar

dlun

d 5 /199

6A

ge .

55

y (m

ean

age

75 y

)A

bilit

y to

be

mob

ile

Rea

dmis

sion

with

in 6

0 d

of r

ando

miz

atio

n

Act

ive

blee

ding

Pers

iste

nt h

emor

rhag

e or

incr

ease

d ri

sk o

f ble

edin

g co

mpl

icat

ions

(eg,

inhe

rite

d bl

eedi

ng d

isor

ders

, pla

tele

t cou

nt ,

70

3 1

0 9 /L,

or h

isto

ry o

f int

raoc

ular

ble

edin

g)

Seve

re r

enal

failu

re (r

equi

ring

dia

lysi

s)

Liv

er fa

ilure

HIV

infe

ctio

n

Term

inal

dis

ease

in w

hich

act

ive

trea

tmen

t was

with

held

Pree

xist

ent a

ntic

oagu

lant

ther

apy

(hep

arin

s or

cou

mar

in)

Hos

pita

lized

Hep

arin

pro

phyl

axis

judg

ed to

be

indi

cate

d by

the

re

spon

sibl

e do

ctor

Infe

ctio

us d

isea

se (p

neum

onia

, ski

n an

d so

ft-t

issu

e in

fect

ions

, fev

er/s

epsi

s,

U

TI,

gas

troe

nter

itis,

upp

er r

espi

rato

ry tr

act i

nfec

tion,

and

so

fort

h)A

sses

smen

t of c

ontr

aind

icat

ions

not

pos

sibl

e (e

g, p

atie

nt

co

mat

ose

and

no n

ext o

f kin

was

ava

ilabl

e)

Ber

gman

n an

d C

aulin

6 /199

6A

ge N

/S (m

ean

age

76 y

)N

ot s

tate

d

Imm

obile

(con

fi ned

to b

ed)

Hos

pita

lized

, 2

4 h

befo

re s

tudy

incl

usio

n

Acu

te m

edic

al il

lnes

s (a

cute

car

diac

dis

ease

, 25%

; acu

te p

ulm

onar

y di

seas

e,

22

%; c

ance

r, 14

%; n

onpu

lmon

ary

seps

is, 2

3%)

Tabl

e S1

—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

arIn

clus

ion

Cri

teri

aE

xclu

sion

Cri

teri

a

Sam

ama

et a

l, 7 ME

DE

NO

X S

tudy

/199

9A

ge .

40

y (m

ean

� S

D a

ge: 2

0 m

g en

oxap

arin

gro

up, 7

2.9

� 1

0.1

y; 4

0 m

g

enox

apar

in g

roup

, 73.

1 �

10.

8 y;

pla

cebo

gro

up, 7

4.1

� 1

0.6

y)K

now

n th

rom

boph

ilia

Imm

obili

zatio

n ,

3 d

at t

ime

of e

nrol

lmen

tSe

rum

cre

atin

ine

conc

entr

atio

n .

1.7

mg/

dL (1

50 m

mol

/L)

Proj

ecte

d ho

spita

l sta

y .

6 d

Unc

ontr

olle

d ar

teri

al h

yper

tens

ion

(sys

tolic

BP

. 2

00 m

m H

g,

di

asto

lic B

P .

120

mm

Hg,

or

both

)

Act

ive

pept

ic u

lcer

, bac

teri

al e

ndoc

ardi

tis, o

r ot

her

cond

ition

s

that

cou

ld in

crea

se th

e ri

sk o

f hem

orrh

age

Plat

elet

cou

nt ,

100

,000

/ m L

, pro

long

ed a

PTT,

pro

thro

mbi

n

ratio

of ,

50%

, or

INR

. 1

.2

HIV

Stro

ke/s

urge

ry w

ithin

pre

viou

s 3

mo

Intu

batio

n

Ant

icoa

gula

nt th

erap

y re

quir

ed/r

ecei

ved

any

type

of

an

ticoa

gula

nt th

erap

y fo

r .

48

h

Con

trai

ndic

atio

ns to

iodi

nate

d co

ntra

st m

edia

Hyp

erse

nsiti

vity

to h

epar

in o

r he

pari

n-in

duce

d

thro

mbo

cyto

peni

a

CH

F (N

YHA

III

-IV

), ac

ute

or c

hron

ic r

espi

rato

ry d

isea

se (i

f acu

te

re

spir

ator

y fa

ilure

doe

s no

t req

uire

ven

tilat

or s

uppo

rt);

or o

ne o

f the

fo

llow

ing

acut

e in

fect

ious

or

rheu

mat

olog

ic d

isea

se, i

f ass

ocia

ted

with

at

leas

t one

add

ition

al r

isk

fact

or a f

or V

TE

: acu

te in

fect

ion

with

out

sept

ic s

hock

; acu

te r

heum

atic

dis

orde

rs (i

nclu

ding

acu

te lu

mba

r pa

in o

r sc

iatic

a or

ver

tebr

al c

ompr

essi

on c

ause

d by

ost

eopo

rosi

s or

a tu

mor

), ac

ute

arth

ritis

of t

he le

gs, o

r an

acu

te e

piso

de o

f rh

eum

atoi

d ar

thri

tis in

the

legs

; or

an e

piso

de o

f in

fl am

mat

ory

bow

el d

isea

se

Preg

nant

/bre

astf

eedi

ng w

omen

Wom

en o

f chi

ldbe

arin

g ag

e no

t usi

ng c

ontr

acep

tion

Tabl

e S1

—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

arIn

clus

ion

Cri

teri

aE

xclu

sion

Cri

teri

a

Fra

isse

et a

l 8 /200

0A

ge 4

0-80

y (m

ean

� S

D a

ge: t

reat

men

t gro

up, 6

9.4

� 7

.7 y

;

plac

ebo

grou

p, 6

6.8

� 8

.2 y

)Pa

tient

on

vent

ilato

r ,

48

h

Hos

pita

lized

(med

ical

IC

U)

His

tory

of a

con

fi rm

ed D

VT

with

in th

e pr

evio

us 6

mo

or

pre

senc

e of

sig

ns o

f a D

VT

on

the

Dop

pler

ul

tras

onog

raph

y at

incl

usio

n

Adm

itted

with

acu

te, r

espi

rato

ry-d

ecom

pens

ated

CO

PD,

an

d re

quir

ing

mec

hani

cal v

entil

atio

nO

rgan

ic le

sion

that

cou

ld b

leed

(ie,

an

activ

e ga

stro

duod

enal

ulce

r or

a r

ecen

t hem

orrh

agic

CVA

)

Wei

ght 4

5-10

0 kg

Seve

re li

ver

failu

re le

adin

g to

a d

ecre

ase

of th

e PT

to ,

50%

(nor

mal

val

ues

70%

-100

%)

Seve

re r

enal

impa

irm

ent (

seru

m c

reat

inin

e .

300

m m

ol/L

)

Con

fi rm

ed o

r un

cont

rolle

d hy

pert

ensi

on (d

iast

olic

BP

. 1

20 m

m H

g)

Con

geni

tal o

r ac

quir

ed c

oagu

latio

n di

sord

er

His

tory

of h

yper

sens

itivi

ty o

r th

rom

bocy

tope

nia

to a

ny ty

pe

of

hep

arin

Con

trai

ndic

atio

n to

ant

icoa

gula

nt th

erap

y, v

enog

raph

y,

or

ang

iogr

aphy

Rec

eivi

ng a

ny fo

rm o

f ace

tyls

alic

ylic

aci

d, ti

clop

idin

e,

or

ora

l ant

icoa

gula

nts

Lei

zoro

vicz

et a

l, 9 PR

EV

EN

T S

tudy

/200

4A

ge �

40

y (m

ean

� S

D a

ge, 6

8.5

� 1

1.7

y)H

igh

risk

of b

leed

ing

� 3

d o

f pre

viou

s im

mob

iliza

tion

Plat

elet

cou

nt ,

100

3 1

0 9 /L

Proj

ecte

d ho

spita

lizat

ion

� 4

dH

epat

ic in

suffi

cien

cy o

r ac

tive

hepa

titis

Acu

te c

oron

ary

synd

rom

e w

ithin

pre

viou

s m

o

Bac

teri

al e

ndoc

ardi

tis

Imm

obili

zed

low

er li

mb

due

to c

ast o

r fr

actu

re

Stro

ke w

ithin

last

3 m

o

Maj

or s

urgi

cal o

r in

vasi

ve p

roce

dure

per

form

ed in

prev

ious

mo

or to

be

unde

rtak

en w

ithin

nex

t 2 w

k

Hep

arin

or

LM

WH

pro

phyl

axis

. 4

8 h

befo

re r

ando

miz

atio

n

Con

trai

ndic

atio

n to

hep

arin

ant

icoa

gula

tion

Cre

atin

ine

. 2

.0 m

g/dL

Acu

te m

edic

al il

lnes

s: a

cute

CH

F (N

YHA

III

-IV

); or

acu

te r

espi

rato

ry fa

ilure

that

did

not

req

uire

ven

tilat

ory

supp

ort;

or a

ny o

f the

follo

win

g, if

com

bine

d w

ith �

1 a

dditi

onal

ris

k fa

ctor

for

VT

E b :

infe

ctio

n w

ithou

t sep

tic s

hock

, acu

te

rheu

mat

olog

ic d

isor

ders

, or

infl a

mm

ator

y bo

wel

dis

ease

Preg

nanc

y or

bre

astf

eedi

ng

Life

exp

ecta

ncy

, 1

mo

Tabl

e S1

—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

arIn

clus

ion

Cri

teri

aE

xclu

sion

Cri

teri

a

Mah

e et

al 10

/200

5A

ge .

40

y (m

ean

age:

trea

tmen

t gro

up, 7

6.1

y; p

lace

bo g

roup

76.

5 y

Syst

olic

BP

. 2

40 m

m H

g, d

iast

olic

BP

. 1

20 m

m H

g

Imm

obili

zed

(una

ble

to w

alk

. 1

0 m

alo

ne)

Plat

elet

leve

l , 5

0,00

0/ m

m, T

CA

. c

ontr

ol 1

10

s

Hos

pita

lized

, 2

4 h

PT ,

50%

Act

ive

gast

rodu

oden

al u

lcer

Ren

al fa

ilure

(cre

atin

ine

leve

l . 3

00 m

mol

/L)

Con

ditio

ns r

equi

ring

full-

dose

ant

icoa

gula

tion

Stro

ke o

r m

ajor

sur

gery

with

in th

e pr

evio

us 3

0 d

Ant

icoa

gula

nt o

r an

tipla

tele

t the

rapy

with

in la

st 7

d

Acu

te m

edic

al il

lnes

s: C

HF

(NYH

A I

II-I

V),

acut

e or

res

pira

tory

dis

ease

,

nonp

ulm

onar

y se

psis

, can

cer

Preg

nanc

y

Led

erle

et a

l 11 /2

006

Age

� 6

0 (m

ean

� S

D a

ge: t

reat

men

t gro

up, 7

1.3

y; p

lace

bo g

roup

, 72.

1 y

Kno

wn

thro

mbo

cyto

peni

a (p

late

let c

ount

, 1

00,0

00/ m

m 3 )

Adm

itted

or

tran

sfer

red

to m

edic

al s

ervi

ceSy

stol

ic B

P .

220

mm

Hg

or d

iast

olic

BP

. 1

10 m

m H

g

Occ

urre

nce

with

in p

ast 3

0 d

of m

yoca

rdia

l inf

arct

ion,

str

oke,

maj

or s

urge

ry (d

efi n

ed a

s re

quir

ing

gene

ral,

spin

al,

or e

pidu

ral a

nest

hesi

a an

d la

stin

g .

30

min

), or

any

eye

sur

gery

Alr

eady

rec

eivi

ng o

r re

quir

ing

antic

oagu

latio

n fo

r re

ason

s

othe

r th

an V

TE

pro

phyl

axis

Oth

er c

ontr

aind

icat

ion

to lo

w-d

ose

hepa

rin

Prev

ious

ran

dom

izat

ion

into

the

stud

y

Pred

icte

d ho

spita

lizat

ion

� 3

d“S

uppo

rtiv

e/pa

lliat

ive

care

onl

y” s

tatu

s

Tabl

e S1

—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

arIn

clus

ion

Cri

teri

aE

xclu

sion

Cri

teri

a

Coh

en e

t al, 12

AR

TE

MIS

Stu

dy/2

006

Age

� 6

0 y

(mea

n �

SD

age

: tre

atm

ent g

roup

, 75.

0 �

8.3

y;

pl

aceb

o gr

oup,

74.

4 �

8.3

y)

Hig

h ri

sk fo

r bl

eedi

ng

Pred

icte

d im

mob

iliza

tion

� 4

dSe

rum

cre

atin

ine

leve

l . 1

80 m

mol

/L in

wel

l-hyd

rate

d pa

tient

Hos

pita

lized

Acu

te b

acte

rial

end

ocar

ditis

Cer

ebra

l met

asta

sis

Rec

ent h

emor

rhag

ic o

r is

chem

ic s

trok

e

Bra

in, s

pina

l, or

oph

thal

mol

ogic

sur

gery

Indw

ellin

g in

trat

heca

l or

epid

ural

cat

hete

r

Ant

icip

ated

intu

batio

n .

24

h

Use

of a

ntith

rom

botic

s ,

48

h be

fore

ran

dom

izat

ion

Indi

catio

n fo

r an

ticoa

gula

nt p

roph

ylax

is o

r th

erap

y

Doc

umen

ted

hype

rsen

sitiv

ity to

con

tras

t med

ia

Acu

te m

edic

al il

lnes

s: C

HF

(NYH

A I

II-I

V);

or a

cute

res

pira

tory

illn

ess

in th

e

pres

ence

of c

hron

ic lu

ng d

isea

se; o

r cl

inic

ally

dia

gnos

ed a

cute

infe

ctio

ns

or in

fl am

mat

ory

diso

rder

s, s

uch

as a

rthr

itis,

con

nect

ive

tissu

e di

seas

es,

or in

fl am

mat

ory

bow

el d

isea

se

Life

exp

ecta

ncy

, 1

mo

aPT

T 5

act

ivat

ed p

artia

l thr

ombo

plas

tin ti

me;

CVA

5 c

ereb

rova

scul

ar a

ccid

ent;

INR

5 in

tern

atio

nal n

orm

aliz

ed r

atio

; LM

WH

5 lo

w-m

olec

ular

-wei

ght h

epar

in; N

/S 5

not

sta

ted

as in

clus

ion

crite

rion

; N

YHA

5 N

ew Y

ork

Hea

rt A

ssoc

iatio

n; P

T 5

pro

thro

mbi

n tim

e; T

CA

5 tr

ichl

oroa

cetic

aci

d; U

TI

5 u

rina

ry tr

act i

nfec

tion .

a A

dditi

onal

ris

k fa

ctor

s: a

ge .

75

y, c

ance

r, pr

evio

us V

TE

, obe

sity

(B

MI

� 3

0 fo

r m

en a

nd �

28.

6 fo

r w

omen

), va

rico

se v

eins

, hor

mon

e th

erap

y (a

ntia

ndro

gen

or e

stro

gen,

exc

ept

for

post

men

opau

sal

horm

one-

repl

acem

ent t

hera

py),

and

chro

nic

hear

t or

resp

irat

ory

failu

re.

b Add

ition

al r

isk

fact

ors

for

VT

E: a

ge �

75

y, c

ance

r, pr

evio

us V

TE

, obe

sity

, var

icos

e ve

ins

and/

or c

hron

ic v

enou

s in

suffi

cien

cy, h

orm

one

repl

acem

ent t

hera

py, h

isto

ry o

f CH

F, c

hron

ic r

espi

rato

ry fa

ilure

, or

mye

lopr

olife

rativ

e sy

ndro

me.

Tabl

e S1

—C

onti

nued




Tabl

e S2

—O

bse

rvat

iona

l St

udi

es o

f R

isk

of V

TE

in

Acu

tely

Ill

or

Hos

pita

lize

d M

edic

al P

atie

nts

Stud

y/Ye

arPa

tient

sD

urat

ion

of F

ollo

w-u

pU

se o

f Thr

ombo

prop

hyla

xis

Sym

ptom

atic

VT

E

Eve

nts

No.

(%) C

umul

ativ

e In

cide

nce

[rat

e]

Bos

son

et a

l 13 /2

006

Patie

nts

� 4

0 y

with

an

acu

te m

edic

al

even

t, an

ticip

ated

to

hav

e re

duce

d m

obili

ty fo

r at

le

ast 4

8 h

(200

2-20

03)

1-28

dIn

itiat

ed in

35%

of

patie

nts

(n 5

5,7

82)

DV

T: c

onfi r

med

by

dup

lex

ultr

ason

ogra

phy

O

vera

ll12

8 (0

.77)

[0.5

eve

nts/

1,00

0 pa

tient

-day

s]

Man

aged

in th

e co

mm

unity

(out

patie

nts)

Tr

eate

d: n

5 4

,163

(h

igh

risk

: 1,6

64;

low

ris

k: 2

,499

)

77 (1

.85)

N 5

16,

532

Hig

h ri

sk 4

2 (2

.52)

Low

ris

k 35

(1.4

0)

U

ntre

ated

: n 5

8,2

47

(hig

h ri

sk: 1

,318

; lo

w r

isk:

6,8

43)

51 (0

.62)

Hig

h ri

sk 1

6 (1

.21)

Low

ris

k 35

(0.5

1)

PE

: con

fi rm

ed

by im

agin

g27

(0.2

)

[0.1

eve

nts/

1,00

0 pa

tient

-day

s]

Dar

ze e

t al 14

/200

5Pa

tient

s w

ith C

HF

(2

001-

2003

)N

ot r

epor

ted

70%

Rec

eive

d 40

mg

enox

apar

inPE

: con

fi rm

ed b

y hi

gh-

prob

abili

ty lu

ng

scin

tigra

phy

or p

ositi

ve

spir

al C

T

N 5

198

O

vera

ll18

(9.1

)

Tr

eate

d: n

5 1

3812

(8.7

)

Unt

reat

ed: n

5 6

06

(10.

0)

Gui

jarr

o et

al 15

/200

5A

ll ho

spita

l inp

atie

nts

(199

8-20

01)

Not

rep

orte

dN

o in

form

atio

n pr

ovid

edD

VT

as

the

seco

ndar

y

di

agno

sis

5,55

9 (0

.25)

N 5

2,2

28,8

94PE

as

the

seco

ndar

y di

agno

sis

at d

isch

arge

2,16

2 (0

.1)

Kis

him

oto

et a

l 16 /2

005

All

hosp

ital i

npat

ient

s (1

987-

1999

)H

ospi

tal s

tay:

mea

n le

ngth

of h

ospi

tal

stay

not

rep

orte

d

Nev

er o

r ra

rely

use

dD

VT:

dia

gnos

ed

by v

enog

raph

y or

ultr

asou

nd

128

(0.1

)

N 5

131

,060

Tim

e fr

om

adm

issi

on to

dia

gnos

is

(mea

n 1

SD

): 21

.3 1

21.

2 d

PE: d

iagn

osed

by

pulm

onar

y pe

rfus

ion

scin

tigra

phy

and/

or

cont

rast

-enh

ance

d C

T s

can

41 (0

.03)

(Con

tinu

ed)




Tabl

e S2

—C

onti

nued

Stud

y/Ye

arPa

tient

sD

urat

ion

of F

ollo

w-u

pU

se o

f Thr

ombo

prop

hyla

xis

Sym

ptom

atic

VT

E

Eve

nts

No.

(%) C

umul

ativ

e In

cide

nce

[rat

e]

Skaf

et a

l 17 /2

005

Isch

emic

or

hem

orrh

agic

str

oke

(197

9-20

03)

Unt

il di

scha

rge

Not

ana

lyze

d; a

utho

rs

assu

me

mos

t pat

ient

s w

ith is

chem

ic s

trok

e re

ceiv

ed a

ntith

rom

botic

th

erap

y

DV

T: m

etho

d

of

dia

gnos

is

not r

epor

ted

Mea

n le

ngth

of

hosp

ital s

tay

not r

epor

ted

O

vera

ll12

6,00

0 (0

.8)

N 5

15,

715,

000

Is

chem

ic s

trok

e

pa

tient

s10

4,00

0 (0

.74)

14,1

09,0

00 (i

sche

mic

), 1,

606,

000

(hem

orrh

agic

)

Hem

orrh

agic

str

oke

patie

nts

22,0

00 (1

.37)

PE: m

etho

d of

dia

gnos

is

not r

epor

ted

O

vera

ll83

,000

(0.5

3)

Is

chem

ic s

trok

e

pa

tient

s72

,000

(0.5

1)

H

emor

rhag

ic s

trok

e

pa

tient

s11

,000

(0.6

8)

Spyr

opou

los

et a

l 18 /2

011

IMPR

OV

E r

egis

try

patie

nts:

� 1

8 y,

ad

mitt

ed to

the

hosp

ital f

or a

n ac

ute

med

ical

ill

ness

, hos

pita

l st

ay �

3 d

(200

2-20

06)

Up

to 3

mo

50%

Rec

eive

d th

rom

bopr

ophy

laxi

s (d

etai

ls p

rovi

ded

in T

apso

n et

al 19

)

VT

E: D

VT

and

PE

da

ta n

ot p

rese

nted

se

para

tely

, or

acco

rdin

g to

whe

ther

th

rom

bopr

ophy

laxi

s w

as r

ecei

ved

143

(0.9

)

N 5

15,

156

Spyr

opou

los

et a

l 20 /2

011

Insu

red

patie

nts

� 4

0 y,

ho

spita

lized

for

canc

er, C

HF,

se

vere

infe

ctio

us

dise

ases

, or

lung

di

seas

es (2

001-

2005

)

� 9

1 d

(rep

orte

d V

TE

by

30-

d w

indo

ws)

No

info

rmat

ion

prov

ided

VT

E: d

isch

arge

rec

ords

8,89

5 (5

.6):

3,22

5 (3

6.3)

ev

ents

occ

urre

d in

the

fi rst

30

d fo

llow

ing

hosp

italiz

atio

n; 4

,107

(46.

2)

even

ts o

ccur

red

. 3

mo

post

disc

harg

e 6,

300

(3.9

8)

(DV

T),

2,32

4 (1

.47)

(PE

), 27

1 (0

.17)

(DV

T/P

E)

DV

T: m

edia

n tim

e to

D

VT,

76

d

PE: m

edia

n tim

e

to

PE

, 73

d

N 5

158

,325

DV

T/P

E: m

edia

n tim

e

to

DV

T/P

E, 3

4 d

(Con

tinu

ed)




Stud

y/Ye

arPa

tient

sD

urat

ion

of F

ollo

w-u

pU

se o

f Thr

ombo

prop

hyla

xis

Sym

ptom

atic

VT

E

Eve

nts

No.

(%) C

umul

ativ

e In

cide

nce

[rat

e]

Bar

bar

et a

l 21 /2

010

Patie

nts

� 1

8 y

adm

itted

to a

de

part

men

t of i

nter

nal

med

icin

e (2

007-

2008

)

3 m

o18

6 (3

9.7%

) of p

atie

nts

at

high

ris

k re

ceiv

ed

appr

opri

ate

prop

hyla

xis;

52

(7.3

%) o

f pat

ient

s at

lo

w r

isk

of V

TE

re

ceiv

ed p

roph

ylax

is

DV

T: c

ompr

essi

on

ultr

ason

ogra

phy

L

ow r

isk:

n 5

711

0 (0

)

H

igh

risk

: n 5

469

22 (4

.7)

Trea

ted:

n 5

186

3 (1

.6)

N 5

118

0

U

ntre

ated

: n 5

283

19 (6

.7)

PE: s

pira

l CT

or

/ s

can

L

ow r

isk:

n 5

711

2 (0

.3)

Trea

ted:

n 5

52

1 (1

.9)

Unt

reat

ed: n

5 6

591

(0.2

)

H

igh

risk

: n 5

469

13 (2

.8)

Trea

ted:

n 5

185

1 (0

.5) (

nonf

atal

)

Unt

reat

ed: n

5 2

8312

(4.2

) (11

non

fata

l w

ith o

r w

ithou

t D

VT,

1 fa

tal P

E)

Ris

k of

sym

ptom

atic

DV

T in

pat

ient

s ho

spita

lized

for

an a

cute

med

ical

eve

nt in

stu

dies

rep

orte

d he

re r

ange

from

0.1

%-6

.7%

. The

low

est e

stim

ate

(0.1

%) w

as d

eriv

ed fr

om a

stu

dy o

f hos

pita

lized

Jap

anes

e pa

tient

s w

ho a

re e

xpec

ted

to h

ave

low

rat

es b

ased

on

prev

ious

rep

orts

in J

apan

ese

pers

ons.

The

hig

hest

est

imat

e (6

.7%

) w

as r

epor

ted

in t

he B

arba

r et

al 21

stu

dy, w

hich

incl

uded

3 m

o of

fol

low

-up

and

repo

rted

eve

nts

with

in th

e tr

eate

d an

d un

trea

ted

grou

ps. T

he n

ext h

ighe

st e

stim

ate

(4.0

%) w

as r

epor

ted

in th

e Sp

yrop

oulo

s et

al 18

,20 s

tudy

, whi

ch a

lso

incl

uded

3 m

o of

follo

w-u

p bu

t did

not

rep

ort b

y pr

o-ph

ylax

is g

roup

. Exc

ludi

ng th

ese

thre

e st

udie

s, ra

tes r

ange

d fr

om 0

.25%

-0.8

%. R

ate

of D

VT

was

onl

y re

port

ed in

one

stud

y (B

osso

n et

al)

as 0

.5 e

vent

s/1,

000

patie

nt-d

ays.

Ris

k of

PE

in p

atie

nts h

ospi

taliz

ed

for a

n ac

ute

med

ical

eve

nt in

stud

ies r

epor

ted

here

rang

e fr

om 0

.03%

-10%

. The

low

est e

stim

ate

(0.0

3%) w

as d

eriv

ed fr

om a

stud

y of

hos

pita

lized

Japa

nese

pat

ient

s who

are

exp

ecte

d to

hav

e lo

w ra

tes b

ased

on

pre

viou

s re

port

s in

Jap

anes

e pe

rson

s. T

he h

ighe

st e

stim

ate

(10%

) was

rep

orte

d in

the

Dar

ze e

t al 14

stu

dy, w

hich

rep

orte

d ev

ents

with

in th

e tr

eate

d an

d un

trea

ted

grou

ps a

nd o

nly

incl

uded

pat

ient

s w

ith

seve

re c

onge

stiv

e he

art f

ailu

re w

ho h

ad h

igh

rate

s of

trad

ition

al r

isk

fact

ors.

The

sec

ond

high

est e

stim

ate

(4.2

%)

was

rep

orte

d in

the

Bar

bar

et a

l 21 s

tudy

, whi

ch in

clud

ed 3

mo

of fo

llow

-up

and

repo

rted

ev

ents

with

in t

he t

reat

ed a

nd u

ntre

ated

gro

ups.

Exc

ludi

ng t

hese

thr

ee s

tudi

es, r

ates

ran

ged

from

0.1

%-1

.5%

. Rat

e of

PE

was

onl

y re

port

ed in

one

stu

dy (

Bos

son

et a

l 13 )

as 0

.1 e

vent

/1,0

00 p

atie

nt-d

ays.

C

HF

5 co

nges

tive

hear

t fai

lure

; PE

5 p

ulm

onar

y em

bolis

m;

/ 5

ven

tilat

ion/

perf

usio

n. Ta

ble

S2—

Con

tinu

ed




Tabl

e S3

— R

AM

s fo

r P

redi

ctin

g Sy

mpt

omat

ic V

TE

in

Med

ical

Pat

ient

s

Stud

y/Ye

arPa

tient

sD

urat

ion

of

Fol

low

-up

Use

of

Thr

ombo

prop

hyla

xis

Des

crip

tion

of R

AM

Ris

k St

rata

VT

E N

o. (%

)

Kuc

her

et a

l 22 /2

005

H

ospi

taliz

ed m

edic

al a

nd

su

rgic

al p

atie

nts

� 1

8 y

who

wer

e at

incr

ease

d ri

sk fo

r V

TE

(200

0-20

04)

3 m

oPr

ophy

lact

ic m

easu

res

w

ere

orde

red

for

24%

of

pat

ient

s in

the

stud

y:

421

of th

e 1,

255

patie

nts

in th

e in

terv

entio

n (e

lect

roni

c al

erts

) gro

up

(33.

5%) a

nd 1

82 o

f th

e 1,

251

patie

nts

in th

e co

ntro

l gr

oup

(14.

5%)

Eig

ht c

omm

on r

isk

fa

ctor

s us

ed to

det

erm

ine

each

hos

pita

lized

pat

ient

’s ri

sk p

rofi l

e fo

r V

TE

. E

ach

risk

fact

or w

as

wei

ghte

d ac

cord

ing

to

a po

int s

cale

:sco

re o

f 3:

canc

er, p

rior

VT

E, a

nd

hype

rcoa

gula

bilit

y; s

core

of

2: m

ajor

sur

gery

; sco

re

of 1

: adv

ance

d ag

e,

obes

ity, b

ed r

est,

and

use

of H

RT

or

OC

.

488

of 1

,574

(5.6

)

Patie

nts

from

neu

rolo

gy,

ne

wbo

rn s

ervi

ce, a

nd th

e N

ICU

wer

e ex

clud

ed, a

s w

ere

thos

e re

ceiv

ing

mec

hani

cal o

r ph

arm

acol

ogic

pr

ophy

laxi

s.

. 4

76 o

f 932

(8.2

)

Part

of a

n R

CT

to a

sses

s

effe

ctiv

enes

s of

ele

ctro

nic

aler

ts to

impr

ove

the

pres

crib

ing

of a

ppro

pria

te

thro

mbo

prop

hyla

xis;

N

5 2

,506

An

incr

ease

d ri

sk o

f VT

E

w

as d

efi n

ed a

s a

cum

ulat

ive

risk

sco

re o

f at l

east

4

Not

e: p

atie

nts

with

a

scor

e ,

4 w

ere

excl

uded

from

this

st

udy

(the

y w

ere

not c

onsi

dere

d to

be

at i

ncre

ased

ri

sk fo

r V

TE

)

Kho

rana

et a

l 23 /2

008

Am

bula

tory

pat

ient

s �

18

y

with

his

tolo

gica

lly

confi

rm

ed d

iagn

osis

of

can

cer;

req

uire

d to

be

at t

he s

tart

of a

new

ch

emot

hera

py r

egim

en,

expe

cted

to c

ompl

ete

four

cy

cles

of c

hem

othe

rapy

(2

002-

2005

)

Med

ian,

2.5

mo

Not

rep

orte

dSc

ore

of 2

: sto

mac

h,

pa

ncre

atic

can

cer

Low

(sco

re 0

)0.

8% a

nd 0

.3%

N 5

2,7

01 (d

eriv

atio

n),

1,

365

(val

idat

ion)

Scor

e of

1: l

ung,

lym

phom

a,

gy

neco

logi

c, G

U e

xclu

ding

pr

osta

te c

ance

r; p

late

let

coun

t � 3

50,0

00 m

m, H

gb

, 1

0 g/

dL o

r us

e of

ESA

, le

ukoc

yte

coun

t . 1

1,00

0 m

m,

BM

I �

35

Inte

rmed

iate

(s

core

1-2

)1.

8% a

nd 2

%

Hig

h (s

core

� 3

)7.

1% a

nd 6

.7%

(ris

k of

VT

E

in d

eriv

atio

n an

d va

lidat

ion

coho

rts,

re

spec

tivel

y)

(Con

tinu

ed)




Stud

y/Ye

arPa

tient

sD

urat

ion

of

Fol

low

-up

Use

of

Thr

ombo

prop

hyla

xis

Des

crip

tion

of R

AM

Ris

k St

rata

VT

E N

o. (%

)

Bar

bar

et a

l 21 /2

010 b

Con

secu

tive

patie

nts

� 1

8 y

ad

mitt

ed to

a d

epar

tmen

t of

inte

rnal

med

icin

e (2

007-

2008

)

3 m

o18

6 of

496

(39.

7%) o

f

patie

nts

at h

igh

risk

re

ceiv

ed a

ppro

pria

te

prop

hyla

xis

(the

re

mai

ning

283

rec

eive

d no

ne o

r in

appr

opri

ate

prop

hyla

xis)

; 52

of

711

(7.3

%) o

f pat

ient

s at

low

ris

k of

VT

E

rece

ived

pro

phyl

axis

Ele

ven

com

mon

ris

k fa

ctor

s

used

to d

eter

min

e ea

ch

hosp

italiz

ed p

atie

nt’s

risk

pr

ofi le

for

VT

E. E

ach

risk

fa

ctor

was

wei

ghte

d ac

cord

ing

to a

poi

nt s

cale

:

, 4

(low

ris

k):

2 of

711

(0.3

)

Scor

e of

3: a

ctiv

e ca

ncer

, pri

or

V

TE

, red

uced

mob

ility

, kno

wn

thro

mbo

phili

c co

nditi

on;

� 4

(hig

h ri

sk):

35 o

f 469

(7.5

)

Patie

nts

wer

e ex

clud

ed

if

they

wer

e on

full-

dose

an

ticoa

gula

tion

ther

apy,

ha

d co

ntra

indi

catio

ns to

ph

arm

acol

ogic

pro

phyl

axis

, or

wer

e pr

egna

nt

Scor

e of

2: r

ecen

t tra

uma

an

d/or

sur

gery

Rec

eive

d pr

ophy

laxi

s4

of 1

86 (2

.2)

N 5

1,1

80Sc

ore

of 1

: age

� 7

0 y,

hea

rt

an

d/or

res

pira

tory

failu

re, a

cute

M

I or

isch

emic

str

oke,

acu

te

infe

ctio

n an

d/or

rhe

umat

olog

ic

diso

rder

, obe

sity

, ong

oing

ho

rmon

al tr

eatm

ent

Did

not

rec

eive

prop

hyla

xis

31 o

f 283

(11.

8)

An

incr

ease

d ri

sk o

f VT

E w

as

de

fi ned

as

a cu

mul

ativ

e ri

sk

scor

e of

at l

east

4 c

Tabl

e S3

—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

arPa

tient

sD

urat

ion

of

Fol

low

-up

Use

of

Thr

ombo

prop

hyla

xis

Des

crip

tion

of R

AM

Ris

k St

rata

VT

E N

o. (%

)

Spyr

opou

los

et a

l 18 /2

011

IMPR

OV

E s

tudy

19 p

atie

nts

ag

ed �

18

y, a

dmis

sion

fo

r an

acu

te m

edic

al

illne

ss, �

3 d

hos

pita

lizat

ion.

F

irst

10

elig

ible

acu

tely

ill

hos

pita

lized

med

ical

pat

ient

s sy

stem

atic

ally

enr

olle

d at

the

star

t of e

ach

mon

th a

t eac

h ho

spita

l.

3 m

oN

ot r

epor

ted

Two

mod

els

deve

lope

d: 4

-fac

tor

m

odel

bas

ed o

n fa

ctor

s av

aila

ble

at h

ospi

tal

adm

issi

on a

nd 7

-fac

tor

mod

el in

clud

ing

fact

ors

avai

labl

e du

ring

hos

pita

l st

ay. F

acto

r sc

ores

(1-3

) ba

sed

on lo

gari

thm

ic H

R.

4-fa

ctor

mod

el:

0 (l

owes

t ris

k)24

of 4

,981

(0.5

)

1

72 o

f 8,4

41 (1

.0)

2

20 o

f 1,1

66 (2

.1)

3

5 of

127

(4.0

)

4-fa

ctor

mod

el: o

lder

age

and

canc

er, 1

poi

nt e

ach;

kno

wn

thro

mbo

phili

a an

d pr

evio

us

VT

E, 3

poi

nts

each

.

4

16 o

f 376

(4.7

)

Patie

nts

excl

uded

if e

nrol

led

in a

ther

apeu

tic c

linic

al tr

ial o

r if

any

of th

e fo

llow

ing

appl

ied:

an

ticoa

gula

nt o

r th

rom

boly

tic

drug

use

at a

dmis

sion

or

with

in

48 h

aft

er a

dmis

sion

; maj

or

surg

ery

or tr

aum

a �

3 m

o be

fore

ad

mis

sion

; adm

issi

on fo

r D

VT

or

PE

(or

diag

nosi

s of

eith

er

with

in 2

4 h

of a

dmis

sion

); fo

llow

-up

deem

ed im

poss

ible

.

5

-8 (h

ighe

st r

isk)

6 of

65

(11)

7-fa

ctor

mod

el: o

lder

age

,

ICU

/CC

U s

tay,

im

mob

iliza

tion

� 7

d,

1 po

int e

ach;

cur

rent

can

cer,

curr

ent L

L p

aral

ysis

, kno

wn

thro

mbo

phili

a, 2

poi

nts

each

; pr

evio

us V

TE

3 p

oint

s.

7-fa

ctor

mod

el:

0 (l

owes

t ris

k)14

of 4

,029

(0.4

)

N 5

15,

156

1

33 o

f 6,3

50 (0

.6)

2

31 o

f 2,4

20 (1

.5)

3

18 o

f 1,3

35 (1

.6)

4

30 o

f 729

(4.8

)

5

-10

(hig

hest

ris

k)17

of 2

62 (8

.1)

Not

at A

CC

P ri

sk50

of 8

,227

(0.7

)

At A

CC

P ri

sk93

of 6

,898

(1.5

)

AC

CP

5 A

mer

ican

Col

lege

of

Che

st P

hysi

cian

s; C

CU

5 c

riti

cal c

are

unit

; ESA

5 e

ryth

ropo

iesi

s-st

imul

atin

g ag

ent;

GU

5 g

enit

ouri

nary

; Hgb

5 h

emog

lobi

n; H

R 5

haz

ard

rati

o; H

RT

5 h

orm

one

repl

acem

ent t

hera

py; L

L 5

low

er li

mb;

MI 5

myo

card

ial i

nfar

ctio

n; N

ICU

5 n

eona

tal I

CU

; OC

5 o

ral c

ontr

acep

tive;

RA

M 5

ris

k as

sess

men

t mod

el; R

CT

5 r

ando

miz

ed c

ontr

olle

d tr

ial .

Oth

er R

AM

s ou

tlin

ed in

Spy

ropo

ulos

24 b

ut e

xclu

ded

from

the

abov

e ta

ble

incl

ude

one

by L

utz

et a

l, 25 w

hich

was

reg

arde

d as

“no

t tho

roug

hly

evid

ence

-bas

ed o

r va

lidat

ed.”

Ano

ther

RA

M th

at w

as

excl

uded

fro

m t

he t

able

was

tha

t by

Coh

en e

t al

, 12 w

hich

was

not

val

idat

ed a

nd a

ssum

ed t

hat

all r

isk

fact

ors

conf

erre

d a

sim

ilar

leve

l of

VT

E r

isk.

Ano

ther

stu

dy e

xclu

ded

was

a v

alid

atio

n st

udy

by

Bah

l et a

l, 26 w

hich

use

d th

e C

apri

ni R

AM

but

was

onl

y as

sess

ed in

sur

gica

l pat

ient

s.

a An

inte

rven

tion

stud

y by

Pia

zza

et a

l 27 u

sed

the

Kuc

her

RA

M t

o cl

assi

fy p

atie

nts

as a

t ri

sk a

nd t

here

fore

elig

ible

for

incl

usio

n. S

ubje

cts

incl

uded

wer

e th

ose

with

a r

isk

scor

e �

4 a

nd t

he s

tudy

fou

nd a

cu

mul

ativ

e ri

sk o

f VT

E o

f 3%

in 9

0 d

of fo

llow

-up.

b B

arba

r et

al 8 :

Not

incl

uded

in th

e Sp

yrop

oulo

s 24 r

evie

w . T

he s

tudy

val

idat

es th

e Pa

dua

Pred

ictio

n Sc

ore

in m

edic

al in

patie

nts.

c N

otes

on

Bar

bar

et a

l 8 RA

M: (

1) a

ctiv

e ca

ncer

: loc

al o

r di

stan

t m

etas

tase

s an

d/or

che

mot

hera

py o

r ra

diot

hera

py in

the

pre

viou

s 6

mo;

(2)

pri

or V

TE

: exc

lude

s su

perfi

cia

l vei

n th

rom

bosi

s; (

3) r

educ

ed

mob

ility

: bed

res

t with

bat

hroo

m p

rivi

lege

s fo

r at

leas

t 3 d

; (4)

rec

ent t

raum

a an

d/or

sur

gery

, � 1

mo;

(5) o

besi

ty: B

MI

� 3

0.

Tabl

e S3

—C

onti

nued




Tabl

e S4

—[S

ecti

on 2

.3]

Evi

denc

e P

rofi l

e: S

hou

ld A

ntic

oagu

lant

Pro

phyl

axis

(L

MW

H, U

FH

, Fon

dapa

rinu

x) v

s P

lace

bo/

No

Tre

atm

ent

Be

Use

d in

Hos

pita

lize

d M

edic

al P

atie

nts?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

N

o. o

f Pat

ient

sE

ffec

t

Qua

lity

No.

of

Stud

ies

Des

ign

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

a Im

prec

isio

nO

ther

C

onsi

dera

tions

Ant

icoa

gula

nt

Prop

hyla

xis

(LM

WH

, UF

H,

Fon

dapa

rinu

x)Pl

aceb

o/N

o Tr

eatm

ent b

Rel

ativ

e (9

5% C

I)A

bsol

ute

Sym

ptom

atic

DV

T (f

ollo

w-u

p 1-

14 d

) c

4 c R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

nsN

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous e

Non

e…

0.15

%R

R, 0

.47

(0.2

2-1)

1 fe

wer

per

1,

000

(fro

m

1 fe

wer

to

0 fe

wer

)

Mod

erat

eC

ritic

al

6.7%

e 34

few

er p

er

1,00

0 (f

rom

51

few

er to

0

few

er)

Non

fata

l PE

(fol

low

-up

1-22

d) f

6 c , g

Ran

dom

ized

tr

ials

No

seri

ous

limita

tions

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s e N

one

…0.

15%

RR

, 0.6

1 (0

.23-

1.67

) h 1

few

er p

er

1,00

0 (f

rom

1

few

er to

1

mor

e

Mod

erat

eC

ritic

al

3.9%

e 15

few

er p

er

1,00

0 (f

rom

30

few

er to

26

mor

e)

Maj

or b

leed

ing

(fol

low

-up

10-1

10 d

)

8 c , i

Ran

dom

ized

tr

ials

No

seri

ous

limita

tions

No

seri

ous

inco

nsis

tenc

y j N

o se

riou

s in

dire

ctne

ssSe

riou

s d N

one

25 o

f 4,3

01

(0.6

%)

19 o

f 4,3

04

(0.4

%)

OR

, 1.3

2 (0

.73-

2.37

)1

mor

e pe

r 1,

000

(fro

m

1 fe

wer

to

6 m

ore)

Mod

erat

eC

ritic

al

(Con

tinu

ed)




Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

N

o. o

f Pat

ient

sE

ffec

t

Qua

lity

No.

of

Stud

ies

Des

ign

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

a Im

prec

isio

nO

ther

C

onsi

dera

tions

Ant

icoa

gula

nt

Prop

hyla

xis

(LM

WH

, UF

H,

Fon

dapa

rinu

x)Pl

aceb

o/N

o Tr

eatm

ent b

Rel

ativ

e (9

5% C

I)A

bsol

ute

Mor

talit

y (f

ollo

w-u

p 1-

22 d

) f

5 c , k

Ran

dom

ized

tr

ials

No

seri

ous

limita

tions

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s l N

one

158

of 3

,676

(4

.3%

)16

5 of

3,

679

(4.5

%)

OR

, 0.9

7 (0

.79-

1.19

)1

few

er p

er

1,00

0 (f

rom

9

few

er to

8

mor

e)

Mod

erat

eC

ritic

al

Thr

ombo

cyto

peni

a (f

ollo

w-u

p 6-

21 d

)

3 m

Ran

dom

ized

tr

ials

No

seri

ous

limita

tions

No

seri

ous

inco

nsis

tenc

y n N

o se

riou

s in

dire

ctne

ssSe

riou

s d N

one

28 o

f 2,3

16

(1.2

%)

31 o

f 2,3

08

(1.3

%)

OR

, 0.9

1 (0

.54-

1.53

)1

few

er p

er

1,00

0 (f

rom

6

few

er to

7

mor

e)

Mod

erat

eC

ritic

al

Bib

liogr

aphy

: D

enta

li F,

Dou

ketis

JD

, G

iann

i M

, L

im W

, C

row

ther

MA

. M

eta-

anal

ysis

: A

ntic

oagu

lant

pro

phyl

axis

to

prev

ent

sym

ptom

atic

ven

ous

thro

mbo

embo

lism

in

hosp

italiz

ed m

edic

al p

atie

nts.

A

nn I

nter

n M

ed .

2007

;146

(4):2

78-2

88.

Llo

yd N

S, D

ouke

tis J

D,

Moi

nudd

in I

, L

im W

, C

row

ther

MA

. A

ntic

oagu

lant

pro

phyl

axis

to

prev

ent

asym

ptom

atic

dee

p ve

in t

hrom

bosi

s in

hos

pita

lized

med

-ic

al p

atie

nts:

A s

yste

mat

ic r

evie

w a

nd m

eta-

anal

ysis

. J T

hrom

b H

aem

ost .

2008

;6(3

):405

-414

. Alik

han

R, C

ohen

AT.

Hep

arin

for

the

pre

vent

ion

of v

enou

s th

rom

boem

bolis

m in

gen

eral

med

ical

pat

ient

s (e

xclu

ding

stro

ke a

nd m

yoca

rdia

l inf

arct

ion)

. Coc

hran

e D

atab

ase

Syst

Rev

. 200

9;(3

):CD

0037

47. U

FH

5 u

nfra

ctio

nate

d he

parin

; RR

5 re

lativ

e ris

k. S

ee T

able

S1

and

S2 le

gend

s for

exp

ansio

n of

oth

er a

bbre

viat

ions

. a F

or m

any

of th

e tr

ials

, the

rat

io o

f pat

ient

s sc

reen

ed to

pat

ient

s in

clud

ed w

as v

ery

high

(eg,

� 1

00),

rais

ing

som

e co

ncer

ns a

bout

the

over

all r

epre

sent

ativ

enes

s of

the

tria

l pop

ulat

ions

. b B

asel

ine

risk

for

DV

T a

nd P

E (l

ow-r

isk

and

high

-ris

k po

pula

tions

) are

der

ived

from

the

RA

M b

y B

arba

r et

al. 8 B

asel

ine

risk

for

mor

talit

y an

d bl

eedi

ng is

der

ived

from

the

cont

rol a

rm o

f med

ical

pat

ient

s in

a m

eta-

anal

ysis

(Den

tali

et a

l).

c Dat

a de

rive

d fr

om D

enta

li et

al.

Stud

ies

som

etim

es r

epor

ted

outc

omes

for

a lo

nger

dur

atio

n of

follo

w-u

p; h

owev

er, t

he D

enta

li et

al r

evie

w o

nly

incl

uded

out

com

es d

urin

g th

e on

-tre

atm

ent p

erio

d.

d We

will

con

side

r th

e pr

esen

ce o

f ser

ious

impr

ecis

ion

whe

n th

ere

are

, 3

00 e

vent

s in

tota

l (ev

ents

in tr

eatm

ent a

nd c

ontr

ol p

atie

nts)

sin

ce it

is d

iffi c

ult t

o ob

tain

pre

cise

est

imat

es in

the

abse

nce

of a

suf

-fi c

ient

num

ber

of o

utco

mes

. e T

his

estim

ate

of th

e ri

sk o

f the

eve

nt in

hig

h-ri

sk p

atie

nts

was

der

ived

from

the

Bar

bar

et a

l 8 stu

dy, w

hich

str

atifi

ed p

atie

nts

acco

rdin

g to

the

Padu

a Pr

edic

tion

Scor

e. T

he e

stim

ate

show

n re

fl ect

s th

e ri

sk

amon

g pa

tient

s w

ho d

id n

ot r

ecei

ve p

roph

ylax

is (s

ympt

omat

ic D

VT

5 1

9 of

238

, non

fata

l PE

5 1

1 of

283

, fat

al P

E 5

1 o

f 283

). f F

atal

PE

: sev

en R

CTs

, ant

icoa

gula

nts

(14

of 9

,902

[0.

1%],

cont

rol 3

9 of

10,

051

[0.4

%];

RR

, 0.4

1 [0

.22-

0.76

]; fo

r lo

w-r

isk

patie

nts:

two

few

er p

er 1

,000

(fr

om o

ne fe

wer

to th

ree

few

er)

and

for

high

-ris

k pa

tient

s tw

o fe

wer

per

1,0

00 (

from

one

few

er to

thre

e fe

wer

). In

four

of t

he tr

ials

with

ava

ilabl

e da

ta th

ere

was

fata

l ble

edin

g in

18

of 8

,249

(0.

22%

) in

the

prop

hyla

xis

grou

p vs

sev

en o

f 8,3

65 (

0.08

%)

in

the

plac

ebo

grou

p.

g The

Den

tali

et a

l rev

iew

did

not

sep

arat

e no

nfat

al a

nd fa

tal P

E; t

here

fore

, we

wen

t to

the

orig

inal

stu

dies

to fi

nd w

hich

had

rep

orte

d no

nfat

al e

vent

s on

ly o

r bo

th n

onfa

tal a

nd fa

tal e

vent

s.

h The

RR

repo

rted

resu

lts fr

om a

met

a-an

alys

is u

sing

the

Der

Sim

onia

n-L

aird

rand

om e

ffec

ts m

odel

. Thi

s mod

el w

as c

hose

n du

e to

the

num

ber o

f stu

dies

( . 3

) and

bec

ause

ther

e w

as n

ot a

sing

le st

udy

that

do

min

ated

the

met

a-an

alys

is.

i GI

blee

ding

and

intr

acra

nial

ble

edin

g w

ere

not r

outin

ely

repo

rted

sep

arat

ely

from

maj

or b

leed

ing

even

ts in

the

indi

vidu

al c

ompo

nent

stu

dies

of t

he D

enta

li et

al s

yste

mat

ic r

evie

w; h

owev

er, a

t lea

st o

ne

stud

y (C

ohen

et a

l 12 ) r

epor

ted

that

GI

blee

ding

eve

nts

acco

unte

d fo

r ze

ro o

f tw

o to

tal a

nd in

trac

rani

al b

leed

ing

even

ts a

ccou

nted

for

zero

of t

wo

tota

l maj

or b

leed

ing

even

ts.

j The

re w

as s

ome

hete

roge

neity

det

ecte

d am

ong

indi

vidu

al s

tudi

es; I

2 5 3

0%.

k Alth

ough

the

Den

tali

et a

l rev

iew

did

not

rep

ort

fata

l ble

edin

g, s

ome

of t

he c

ompo

nent

stu

dies

did

: tw

o of

nin

e bl

eedi

ng o

utco

mes

in t

he t

reat

men

t gr

oup

and

one

of t

hree

in t

he p

lace

bo g

roup

of

the

Lei

zoro

vicz

et a

l 20 s

tudy

wer

e fa

tal b

leed

ing

even

ts. T

here

wer

e no

fata

l ble

edin

g ev

ents

in th

e C

ohen

et a

l 12 s

tudy

(ze

ro o

f tw

o m

ajor

ble

edin

g ou

tcom

es).

One

of s

ix b

leed

ing

outc

omes

in th

e tr

eatm

ent

grou

p an

d ze

ro o

f fou

r in

the

plac

ebo

grou

p of

the

Sam

ama

et a

l 7 stu

dy w

ere

fata

l ble

edin

g ev

ents

. l S

ince

the

confi

den

ce in

terv

al r

ange

s fr

om a

red

uctio

n in

dea

ths

to a

n in

crea

se in

dea

ths,

we

are

not a

ssur

ed th

at th

ere

is tr

uly

no e

ffec

t. m D

ata

deri

ved

from

the

Alik

han

and

Coh

en r

evie

w.

n The

re w

as s

ome

hete

roge

neity

det

ecte

d am

ong

the

indi

vidu

al s

tudi

es; I

2 5 4

2%.

Tabl

e S4

—C

onti

nued




Tabl

e S5

—E

ligi

bil

ity

Cri

teri

a fo

r R

CT

s of

LD

UH

vs

LM

WH

Thr

omb

opro

phyl

axis

in

Hos

pita

lize

d M

edic

al P

atie

nts

Stud

y/Ye

arIn

clus

ion

Cri

teri

aE

xclu

sion

Cri

teri

a

For

ette

and

Wol

mar

k 28 /1

995

Age

N/S

(mea

n ag

e: 8

3 y)

Prev

ious

red

uced

mob

ility

Rec

ent t

rans

ient

red

uced

mob

ility

Exi

sten

ce o

f pre

viou

s D

VT,

con

fi rm

ed b

y ec

ho D

oppl

er 4

8 h

prio

r to

incl

usio

n in

stu

dy

Hos

pita

lized

for

. 4

wk

Acu

te m

edic

al il

lnes

sPr

evio

us D

VT

(with

in la

st 6

mo)

Prev

ious

PE

(with

in la

st y

)

Seve

re a

rter

ial h

yper

tens

ion

Cer

ebra

l hem

orrh

age

with

in p

revi

ous

6 m

o or

any

neu

rosu

rgic

al

inte

rven

tion

Ren

al in

suffi

cien

cy

Seve

re li

ver

dise

ase

Surg

ical

inte

rven

tion

(non

orth

oped

ic 8

d; o

rtho

pedi

c 28

d)

Rec

eivi

ng a

spir

in, t

iclo

pidi

ne, a

ntiin

fl am

mat

orie

s, h

epar

inoi

d,

or v

itam

in K

Con

trai

ndic

atio

n to

hep

arin

, or

veno

grap

hic

or a

ngio

grap

hic

inve

stig

atio

ns

Lec

hler

et a

l, 29 P

RIM

E/1

996

Age

. 1

8 y

(mea

n ag

e: 7

4 �

13

y)B

leed

ing

diso

rder

Exp

ecte

d im

mob

iliza

tion

. 1

/2 d

aytim

e fo

r w

hole

stu

dy p

erio

d (7

d)

Thr

ombo

cyto

peni

a ( ,

100

,000

3 1

0 9 /L)

Hos

pita

lized

Hem

orrh

agic

str

oke

duri

ng th

e pr

eced

ing

4 w

k

Acu

te m

edic

al il

lnes

s pl

us �

1 a

dditi

onal

thro

mbo

embo

lic r

isk

fact

or ( .

60

y, m

alig

nanc

y, o

besi

ty, f

orm

er th

rom

boem

bolic

eve

nt,

card

iac

insu

ffi ci

ency

, par

esis

of t

he lo

wer

lim

bs, h

emip

legi

a,

para

pleg

ia, o

r se

vere

infe

ctio

n)

Hea

d tr

aum

a in

pre

viou

s 6

mo

End

ocar

ditis

Seve

re r

enal

dis

ease

or

rena

l ins

uffi c

ienc

y

Thr

ombo

embo

lism

Reg

iona

l ane

sthe

sia

Trea

tmen

t with

ant

icoa

gula

nts,

ant

ipla

tele

ts o

r N

SAID

s in

the

prec

edin

g 7

d

Preg

nanc

y an

d la

ctat

ion

Part

icip

atio

n in

clin

ical

tria

l in

prec

edin

g 6

wk

(Con

tinu

ed)




Stud

y/Ye

arIn

clus

ion

Cri

teri

aE

xclu

sion

Cri

teri

a

Ber

gman

n an

d N

euha

rt, 30

EM

SG/1

996

Stud

y pa

rtic

ipan

ts w

ere

65-8

0 y;

mea

n ag

e: e

noxa

pari

n gr

oup,

83.

8 y;

UF

H g

roup

, 82.

6 y

Ong

oing

ven

ous,

art

eria

l or

card

iac

dise

ase

requ

irin

g an

ticoa

gula

tion

Abn

orm

al p

late

let c

ount

Red

uced

mob

ility

Ren

al d

isor

ders

Hos

pita

lized

Loc

al d

isor

ders

of t

he lo

wer

lim

b th

at w

ould

inte

rfer

e w

ith F

UT

Acu

te m

edic

al il

lnes

sC

ontr

aind

icat

ion

to a

ntic

oagu

latio

n

His

tory

or

alle

rgy

or th

rom

bocy

tope

nia

indu

ced

by U

FH

or

LM

WH

Any

con

trai

ndic

atio

n to

isot

opic

or

veno

grap

hic

inve

stig

atio

ns

Kle

ber

et a

l 31 /2

003

Age

� 1

8 y

(mea

n ag

e, 7

0 �

14

y)Im

mob

ilize

d .

24

h be

fore

enr

ollm

ent

Con

fi ned

to b

ed fo

r .

2/3

day

time

Acu

te s

igns

of D

VT

or

PE

Hos

pita

lized

Seve

re a

rter

ial h

yper

tens

ion

Hea

rt fa

ilure

(NYH

A I

II o

r IV

; pat

ient

s w

ere

allo

wed

100

mg

daily

of

acet

ylsa

licyl

ic a

cid)

; or

seve

re r

espi

rato

ry d

isea

se (c

hara

cter

ized

by

impa

ired

pul

mon

ary

func

tion

test

s, b

lood

gas

ana

lyse

s ou

tsid

e no

rmal

ra

nge,

or

both

); an

d at

leas

t one

add

ition

al p

atho

logi

c co

nditi

on: s

ever

e fu

nctio

nal l

oss

of �

2 lu

ng s

egm

ents

, sev

ere

seco

ndar

y pu

lmon

ary

hype

rten

sion

, pne

umon

ia, i

nter

stiti

al lu

ng d

isea

se, l

ung

canc

er

and/

or m

etas

tase

s w

ith a

life

exp

ecta

ncy

. 2

mo,

or

exac

erba

tion

of C

OPD

Intr

acra

nial

ble

edin

g or

hem

orrh

agic

str

oke

in th

e pr

eced

ing

6 m

o

Coa

gula

tion

diso

rder

s

GI

ulce

r

Seve

re p

ancr

eatic

, hep

atic

, or

rena

l dis

ease

Adv

ance

d A

IDS

Ocu

lar

or c

entr

al n

ervo

us s

yste

m s

urge

ry in

the

prec

edin

g 4

wk

Dru

g or

alc

ohol

abu

se

Patie

nts

taki

ng a

ntic

oagu

lant

s/pl

atel

et in

hibi

tors

or

NSA

IDs

Con

trai

ndic

atio

ns to

LM

WH

or

UF

H th

erap

y

Alle

rgy

(uns

peci

fi ed)

Hyp

erse

nsiti

vity

to c

ontr

ast m

edia

Tabl

e S5

—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

arIn

clus

ion

Cri

teri

aE

xclu

sion

Cri

teri

a

Rei

ss e

t al, 32

CE

RT

IFY/

2010

Age

. 7

0 y

(mea

n �

SD

age

, 78.

8 �

6.3

y)

Imm

obili

zatio

n .

3 d

pri

or to

ran

dom

izat

ion

Sign

ifi ca

nt d

ecre

ase

in m

obili

ty (b

edri

dden

or

only

abl

e to

wal

k sh

ort d

ista

nces

) exp

ecte

d fo

r �

4 d

Imm

obili

zatio

n du

e to

cas

t or

frac

ture

Hos

pita

lized

A

cute

sym

ptom

atic

DV

T/P

E

Acu

te m

edic

al il

lnes

s (in

fect

ions

and

infe

stat

ions

, 28%

; car

diac

di

sord

ers,

22%

; res

pira

tory

, tho

raci

c, a

nd m

edia

stin

al

diso

rder

s, 1

7%; n

ervo

us s

yste

m d

isor

ders

, 7%

; and

so

fort

h)

Unc

ontr

olle

d hy

pert

ensi

on

Acu

te H

IT-I

I or

his

tory

of t

his

Hem

orrh

agic

str

oke

or in

trac

rani

al b

leed

ing

( , 1

2 m

o)

Acu

te n

onhe

mor

rhag

ic s

trok

e or

his

tory

of t

his

( , 3

mo)

Acu

te o

r on

goin

g in

trac

rani

al d

isea

se

Hig

h ri

sk o

f GI

blee

ding

Acu

te e

ndoc

ardi

tis

Kno

wn

activ

e re

tinop

athy

, or

intr

avitr

eal o

r ot

her

intr

aocu

lar

blee

ding

Seve

re s

epsi

s or

nee

d fo

r ve

ntila

tor

supp

ort (

cont

inuo

us p

ositi

ve a

irw

ay

pres

sure

, oxy

gen

mas

k, a

nd s

o fo

rth,

wer

e pe

rmitt

ed)

Seve

re r

enal

or

liver

dis

ease

Illn

ess

with

ver

y hi

gh a

cute

mor

talit

y ra

te ( .

30%

)

Spin

al o

r ep

idur

al a

nest

hesi

a or

lum

bar

punc

ture

with

in la

st 1

2 h

Exp

ecte

d to

und

ergo

maj

or s

urgi

cal/i

nvas

ive

proc

edur

e w

ithin

3

wk

follo

win

g ra

ndom

izat

ion

Rec

eive

d L

MW

H/h

epar

in fo

r .

48

h in

5 d

pri

or to

ran

dom

izat

ion

Indi

catio

ns fo

r an

ticoa

gula

tion

or th

rom

boly

sis

Life

exp

ecta

ncy

, 6

mo

FU

T 5

fi br

inog

en u

ptak

e; H

IT-I

I 5 h

epar

in-in

duce

d th

rom

bocy

tope

nia

type

2; L

DU

H 5

low

-dos

e un

frac

tiona

ted

hepa

rin;

NSA

IDs 5

ons

tero

idal

ant

iinfl a

mm

ator

y dr

ugs.

See

Tab

le S

1 an

d S2

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

.

Tabl

e S5

—C

onti

nued




Tabl

e S6

—[S

ecti

on 2

.4]

Evi

denc

e P

rofi l

e: S

hou

ld A

ntic

oagu

lant

Pro

phyl

axis

Wit

h L

MW

H v

s U

FH

Be

Use

d in

Hos

pita

lize

d M

edic

al P

atie

nts?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

N

o. o

f Pat

ient

sE

ffec

t

Qua

lity

No.

of

Stud

ies

Des

ign

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

Con

sider

atio

ns

Ant

icoa

gula

nt

Prop

hyla

xis

With

LM

WH

UF

HR

elat

ive

(95%

CI)

Abs

olut

e

Sym

ptom

atic

DV

T (f

ollo

w-u

p, 1

-28

d)

5 a R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

nsN

o se

riou

s in

cons

iste

ncy

Seri

ous b

Seri

ous c

Non

e…

0.33

%R

R, 0

.77

(0.5

0-1.

19)

1 fe

wer

per

1,0

00

(fro

m 2

few

er to

1 m

ore)

Low

Cri

tical

PE (f

ollo

w-u

p, 1

-28

d)

5 a R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

nsN

o se

riou

s in

cons

iste

ncy

Seri

ous b

Seri

ous c

Non

e…

0.20

%R

R, 1

.00

(0.2

8-3.

59)

0 fe

wer

per

1,0

00

(fro

m 1

few

er to

5 m

ore)

Low

Cri

tical

Maj

or b

leed

ing

5 a , d R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

nsN

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous c

Non

e11

of 2

,795

(0.4

%)

26 o

f 2,8

02 (0

.9%

)R

R, 0

.48

(0.2

4-0.

99)

5 fe

wer

per

1,0

00

(fro

m 0

few

er to

7 fe

wer

)M

oder

ate

Cri

tical

Mor

talit

y

5 a , e R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

nsN

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous c

Non

e68

of 2

,795

(2.4

%)

77 o

f 2,8

05 (2

.7%

)R

R, 0

.89

(0.6

5-1.

23)

3 fe

wer

per

1,0

00

(fro

m 1

0 fe

wer

to 6

mor

e)M

oder

ate

Cri

tical

Hep

arin

-indu

ced

thro

mbo

cyto

peni

a

1R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

nsN

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous c , f

Rep

ortin

g bi

as g

1 of

1,6

24 (0

.06%

)2

of 1

,615

(0.1

2%)

RR

, 0.5

0 (0

.05-

5.48

)1

few

er p

er 1

,000

(f

rom

1 fe

wer

to 1

mor

e)L

owC

ritic

al

Bib

liogr

aphy

: A

likha

n R

, C

ohen

AT.

Hep

arin

for

the

pre

vent

ion

of v

enou

s th

rom

boem

bolis

m i

n ge

nera

l m

edic

al p

atie

nts

(exc

ludi

ng s

trok

e an

d m

yoca

rdia

l in

farc

tion)

. C

ochr

ane

Dat

abas

e Sy

st R

ev .

2009

;(3):C

D00

3747

. Rei

ss H

, Haa

s S, T

ebbe

U, e

t al.

A ra

ndom

ized

, dou

ble-

blin

d st

udy

of c

erto

pari

n vs

unf

ract

iona

ted

hepa

rin

to p

reve

nt v

enou

s thr

ombo

embo

lic e

vent

s in

acut

ely

ill, n

on-s

urgi

cal p

atie

nts:

C

ER

TIF

Y St

udy.

J T

hrom

b H

aem

ost.

2009

;8(6

):120

9-12

15. S

ee T

able

S1,

S2,

and

S5

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a One

stu

dy a

sses

sed

UF

H b

id; f

our

stud

ies

asse

ssed

UF

H ti

d.

b The

RR

is d

eriv

ed fr

om a

mix

of s

ympt

omat

ic a

nd a

sym

ptom

atic

eve

nts

and

the

base

line

risk

(ris

k w

ith U

FH

) is

deri

ved

from

sym

ptom

atic

eve

nts

from

the

Rie

ss e

t al s

tudy

. c W

e w

ill c

onsi

der

the

pres

ence

of s

erio

us im

prec

isio

n w

hen

ther

e ar

e ,

300

eve

nts

in to

tal (

even

ts in

trea

tmen

t and

con

trol

pat

ient

s), s

ince

it is

diffi

cul

t to

obta

in p

reci

se e

stim

ates

in th

e ab

senc

e of

a s

uf-

fi cie

nt n

umbe

r of

out

com

es.

d GI

blee

ding

and

intr

acra

nial

ble

edin

g w

ere

not r

outin

ely

repo

rted

sep

arat

ely

from

maj

or b

leed

ing

even

ts in

the

indi

vidu

al c

ompo

nent

stu

dies

of t

he A

likha

n an

d C

ohen

sys

tem

atic

rev

iew

; how

ever

, one

st

udy

(Lec

hler

et a

l 29 ) r

epor

ted

that

GI

blee

ding

eve

nts

acco

unte

d fo

r ni

ne o

f 30

tota

l maj

or b

leed

ing

even

ts, b

ut n

umbe

r of

eve

nts

was

not

rep

orte

d se

para

tely

by

trea

tmen

t gro

up.

e Fat

al b

leed

ing

even

ts n

ot r

epor

ted

sepa

rate

ly.

f Onl

y on

e st

udy

(CE

RT

IFY

tria

l) re

port

ed th

is o

utco

me

and

ther

e w

ere

only

thre

e oc

curr

ence

s of

thro

mbo

cyto

peni

a ov

eral

l; th

eref

ore,

the

sugg

estio

n of

a p

rote

ctiv

e ef

fect

of L

MW

H v

s U

FH

is n

ot w

ell

supp

orte

d.

g Sin

ce o

nly

one

stud

y re

port

ed th

is o

utco

me,

it is

pos

sibl

e th

at th

ere

was

sel

ectiv

e re

port

ing

of th

is o

utco

me,

whi

ch w

ould

indi

cate

pub

licat

ion

bias

.




Tabl

e S7

— [S

ecti

on 2

.6]

Evi

denc

e P

rofi l

e: S

hou

ld A

SA o

r O

ther

Ant

ipla

tele

t D

rugs

Be

Use

d in

Hos

pita

lize

d M

edic

al P

atie

nts?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

No.

of

Stud

ies

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sW

ith A

SAW

ith

Plac

ebo,

a %R

elat

ive

Eff

ect

(95%

CI)

b

Abs

olut

e R

isk

Diff

eren

ce W

ith

ASA

(95%

CI)

Qua

lity

of

Evi

denc

eIm

por-

tanc

e

Sym

ptom

atic

DV

T (f

ollo

w-u

p, 8

wk)

1 R

CT

No

seri

ous

limita

tions

No

seri

ous

limita

tions

Very

ser

ious

lim

itatio

ns c , d

No

seri

ous

limita

tions

Und

etec

ted

…0.

15R

R, 0

.71

(0.5

2-0.

97)

1 fe

wer

per

1,0

00

(fro

m 1

few

er to

1 fe

wer

)L

owIm

port

ant

…6.

719

few

er p

er 1

,000

(f

rom

32

few

er to

2 fe

wer

)

PE (f

ollo

w-u

p, 8

wk)

64 R

CTs

e N

o se

riou

s lim

itatio

nsN

o se

riou

s lim

itatio

nsVe

ry s

erio

us

limita

tions

c , d , f N

o se

riou

s lim

itatio

nsU

ndet

ecte

d…

0.15

RR

, 0.4

7 (0

.37-

0.59

)1

few

er p

er 1

,000

(f

rom

1 fe

wer

to 1

few

er)

Low

Cri

tical

…3.

921

few

er p

er 1

,000

(f

rom

25

few

er to

16

few

er)

Mor

talit

y (f

ollo

w-u

p, 3

5 d)

1 R

CT

No

seri

ous

limita

tions

No

seri

ous

limita

tions

Very

ser

ious

lim

itatio

ns c , d

Seri

ous

limita

tions

g U

ndet

ecte

d…

4.5

RR

, 0.9

7 (0

.85-

1.10

)1

few

er p

er 1

,000

(f

rom

7 fe

wer

to 5

mor

e)Ve

ry lo

wC

ritic

al

Ble

edin

g (f

ollo

w-u

p, 3

5 d)

1 R

CT

No

seri

ous

limita

tions

No

seri

ous

limita

tions

Very

ser

ious

lim

itatio

ns c , d

No

seri

ous

limita

tions

Und

etec

ted

…0.

4R

R, 1

.42

(1.1

6-1.

74) h

2 m

ore

per

1,00

0 (f

rom

1 m

ore

to 3

mor

e)L

owIm

port

ant

Bib

liogr

aphy

: Pul

mon

ary

Em

bolis

m P

reve

ntio

n (P

EP)

Tri

al C

olla

bora

tive

Gro

up. P

reve

ntio

n of

pul

mon

ary

embo

lism

and

dee

p ve

in t

hrom

bosi

s w

ith lo

w d

ose

aspi

rin:

Pul

mon

ary

Em

bolis

m P

reve

ntio

n (P

EP)

tria

l. L

ance

t. 20

00;3

55(9

212)

:129

5-13

02 (

RC

T r

epor

t inc

lude

d a

met

a-an

alys

is).

MI,

an

impo

rtan

t pos

tope

rativ

e co

mpl

icat

ion

that

can

be

impa

cted

by

ASA

, is

not r

epor

ted

in th

is e

vide

nce

profi

le

beca

use

it is

not

a r

elev

ant o

utco

me

in m

edic

al p

opul

atio

ns. A

n al

tern

ativ

e ap

proa

ch to

usi

ng in

dire

ct d

ata

from

sur

gica

l pat

ient

s is

to o

nly

use

data

from

med

ical

pat

ient

s in

clud

ed in

the

PEP

tria

l rep

ort

met

a-an

alys

is. N

ine

tria

ls w

ith a

com

bine

d to

tal p

opul

atio

n of

555

pat

ient

s wer

e co

nduc

ted

in h

igh-

risk

med

ical

pat

ient

s (st

roke

, CH

F, M

I, o

r spi

nal c

ord

inju

ry).

DV

T e

vent

s in

thes

e tr

ials

wer

e as

ympt

om-

atic

and

age

nts

othe

r th

an A

SA w

ere

used

in s

ome

tria

ls. A

ntip

late

let a

gent

s w

ere

asso

ciat

ed w

ith r

educ

ed r

isk

of a

sym

ptom

atic

DV

T (R

R, 0

.65;

95%

CI,

0.4

5-0.

94),

base

d on

39

of 2

61 v

s 61

of 2

66 e

vent

s,

resp

ectiv

ely.

Res

ults

faile

d to

show

or t

o ex

clud

e a

bene

fi cia

l eff

ect o

f ant

ipla

tele

t age

nts o

n PE

(RR

, 0.3

8; 9

5% C

I, 0

.10-

1.42

), ba

sed

on 3

of 2

75 v

s 8 o

f 280

eve

nts,

resp

ectiv

ely)

. Ble

edin

g an

d m

orta

lity

rate

s w

ere

not r

epor

ted.

Usi

ng th

ese

data

will

giv

e si

mila

r co

nclu

sion

reg

ardi

ng D

VT

(sig

nifi c

ant r

educ

tion

but l

ow-q

ualit

y ev

iden

ce d

ue to

sur

roga

cy o

f out

com

es a

nd im

prec

isio

n) a

nd w

ill c

hang

e co

nclu

sion

s re

gard

ing

PE to

bec

ome

a no

n-st

atis

tical

ly s

igni

fi can

t red

uctio

n w

ith v

ery-

low

-qua

lity

evid

ence

due

to s

ever

e im

prec

isio

n an

d th

e in

dire

ctne

ss c

ause

d by

the

base

line

risk

unc

erta

inty

. ASA

5 a

cety

lsal

icyl

ic

acid

. See

Tab

le S

1, S

3, a

nd S

4 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a Bas

elin

e ri

sk fo

r D

VT

and

PE

(low

-ris

k an

d hi

gh-r

isk

popu

latio

ns) a

re d

eriv

ed fr

om th

e R

AM

by

Bar

bar

et a

l. 21 B

asel

ine

risk

for

mor

talit

y an

d bl

eedi

ng is

der

ived

from

the

cont

rol a

rm o

f med

ical

pat

ient

s in

a m

eta-

anal

ysis

(Den

tali

et a

l).

b RR

s in

this

evi

denc

e pr

ofi le

s ar

e de

rive

d fr

om th

e PE

P tr

ial p

ublic

atio

n. F

or P

E, t

he m

eta-

anal

ysis

incl

uded

in P

EP

tria

l rep

ort i

s us

ed, f

or D

VT

the

met

a-an

alys

is w

as n

ot u

sed

beca

use

it m

ainl

y in

clud

ed

asym

ptom

atic

DV

Ts; i

nste

ad, R

R o

f sym

ptom

atic

DV

T e

vent

s fr

om P

EP

was

use

d; fo

r m

orta

lity

and

blee

ding

, PE

P da

ta w

ere

used

bec

ause

the

met

a-an

alys

is d

id n

ot p

ool t

hese

out

com

es.

c Evi

denc

e is

indi

rect

bec

ause

the

rela

tive

effe

ct is

pri

mar

ily d

eriv

ed fr

om s

urgi

cal p

atie

nts

(555

of t

he 2

6,89

0 pa

tient

s in

clud

ed in

PE

P tr

ial r

epor

t met

a-an

alys

is w

ere

high

-ris

k m

edic

al p

atie

nts)

. d D

VT

and

PE

bas

elin

e ri

sk e

stim

ates

are

der

ived

from

an

RA

M d

eriv

ed in

a c

ohor

t with

a s

mal

l num

ber

of o

utco

me

even

ts, h

ence

hav

e un

cert

aint

y ab

out t

hem

. Thi

s un

cert

aint

y ca

n be

labe

led

as im

pre-

cisi

on o

r in

dire

ctne

ss.

e Six

ty-f

our

RC

Ts c

onsi

st o

f 63

from

the

met

a-an

alys

is p

ublis

hed

in th

e PE

P tr

ial r

epor

t and

the

PEP

tria

l. f S

ome

of th

e PE

eve

nts

in th

is m

eta-

anal

ysis

may

hav

e be

en fa

tal.

g Wid

e C

I th

at in

clud

es b

enefi

t an

d ha

rm.

h RR

of

blee

ding

incl

uded

the

fol

low

ing

blee

ding

eve

nts

(fat

al in

trac

rani

al, e

xtra

cran

ial,

and

GI

blee

ding

eve

nts,

and

non

fata

l mel

ena

and

hem

atem

esis

, reg

ardl

ess

of t

rans

fusi

on n

eeds

). L

ocal

ble

edin

g ev

ents

at t

he s

ite o

f sur

gery

wer

e no

t con

side

red

as th

ey a

re ir

rele

vant

to m

edic

al p

opul

atio

ns.




Tabl

e S8

—[S

ecti

on 2

.7.1

] E

vide

nce

Pro

fi le:

Sho

uld

GC

S vs

No

GC

S B

e U

sed

in H

ospi

tali

zed

Med

ical

Pat

ient

s? a

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

No.

of P

atie

nts

Eff

ect

No.

of

Stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

C

onsid

erat

ions

GC

SC

ontr

ol a

Rel

ativ

e (9

5% C

I)A

bsol

ute

Qua

lity

Sym

ptom

atic

DV

T (p

roxi

mal

or d

ista

l) (f

ollo

w-u

p, 1

-30

d; c

onfi r

med

on

imag

ing)

1 b R

ando

miz

ed

tr

ials

No

seri

ous

lim

itatio

nsN

o se

riou

s

inco

nsist

ency

No

seri

ous

in

dire

ctne

ssSe

riou

s c N

one

…0.

15%

RR

, 0.9

1

(0.6

3-1.

29)

1 fe

wer

per

1,0

00 (f

rom

1

few

er to

1 m

ore)

Mod

erat

eIm

port

ant

6.7%

6 fe

wer

per

1,0

00 (f

rom

25

few

er to

19

mor

e)

PE (f

ollo

w-u

p, 1

-30

d; c

onfi r

med

on

imag

ing

or a

utop

sy)

1 b R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

nsN

o se

riou

s in

cons

isten

cyN

o se

riou

s in

dire

ctne

ssSe

riou

s c N

one

…0.

15%

RR

, 0.6

5 (0

.33-

1.31

)1

few

er p

er 1

,000

(fro

m

1 fe

wer

to 1

mor

e)L

owC

ritic

al

3.9%

14 fe

wer

per

1,0

00 (f

rom

26

few

er to

12

mor

e)

Mor

talit

y (f

ollo

w-u

p, 3

0 d)

2R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

nsN

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous c

Non

e13

1 of

1,3

21

(9.9

%)

4.5%

RR

, 1.0

6 (0

.94-

1.20

) d 3

mor

e pe

r 1,

000

(fro

m

3 fe

wer

to 9

mor

e)M

oder

ate

Cri

tical

Skin

bre

aks/

ulce

rs/b

liste

rs/s

kin

necr

osis

(fol

low

-up,

1-3

0 d;

cas

e-no

te r

evie

w)

1 b R

ando

miz

ed

tria

lsSe

riou

s e N

o se

riou

s in

cons

iste

ncy

Seri

ous

indi

rect

ness

b Se

riou

s c N

one

64 o

f 1,2

56

(5.1

%)

16 o

f 1,2

62

(1.3

%)

RR

, 4.0

2 (2

.34-

6.91

)38

mor

e pe

r 1,

000

(fro

m

17 m

ore

to 7

5 m

ore)

Very

low

Impo

rtan

t

Low

er li

mb

isch

emia

/am

puta

tion

(fol

low

-up,

1-3

0 d;

cas

e-no

te r

evie

w)

1 b R

ando

miz

ed

tria

lsSe

riou

s e N

o se

riou

s in

cons

iste

ncy

No

serio

us

indi

rect

ness

Very

se

riou

s c N

one

7 of

1,2

56

(0.6

%)

2 of

1,2

62

(0.2

%)

RR

, 3.5

2 (0

.73-

16.9

0)4

mor

e pe

r 1,

000

(fro

m

0 fe

wer

to 2

5 m

ore)

Very

low

Impo

rtan

t

Bib

liogr

aphy

: Kie

rkeg

aard

A, N

orgr

en L

. Gra

duat

ed c

ompr

essi

on s

tock

ings

in t

he p

reve

ntio

n of

dee

p ve

in t

hrom

bosi

s in

pat

ient

s w

ith a

cute

myo

card

ial i

nfar

ctio

n. E

ur H

eart

J . 1

993;

14(1

0):1

365-

1368

. M

uir

KW

, Wat

t A

, Bax

ter

G, G

ross

et D

G, L

ees

KR

. Ran

dom

ized

tri

al o

f gr

aded

com

pres

sion

sto

ckin

g fo

r pr

even

tion

of d

eep-

vein

thr

ombo

sis

afte

r ac

ute

stro

ke. Q

JM . 2

000;

93(6

):359

-364

. Den

nis

M,

Sand

erco

ck P

A, R

eid

J, e

t al

. The

CL

OT

S Tr

ials

Col

labo

ratio

n. E

ffec

tiven

ess

of t

high

-leng

th g

radu

ated

com

pres

sion

sto

ckin

gs t

o re

duce

the

ris

k of

dee

p ve

in t

hrom

bosi

s af

ter

stro

ke (

CL

OT

S tr

ial 1

): a

mul

ticen

ter,

rand

omiz

ed c

ontr

olle

d tr

ial.

Lan

cet .

2009

;373

(967

9):1

958-

1965

. GC

S 5

gra

duat

ed c

ompr

essi

on s

tock

ings

. See

Tab

les

S1 a

nd S

4 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a Bas

elin

e ri

sk fo

r D

VT

and

PE

(lo

w-r

isk

and

high

-ris

k po

pula

tion

s) a

re d

eriv

ed fr

om th

e R

AM

by

Bar

bar

et a

l. 21 B

asel

ine

risk

for

mor

talit

y an

d bl

eedi

ng is

der

ived

from

the

cont

rol a

rm o

f med

ical

pa

tien

ts in

a m

eta-

anal

ysis

(Den

tali

et a

l). B

asel

ine

risk

for

low

er le

g is

chem

ia a

nd s

kin

brea

ks (d

eriv

ed fr

om th

e co

ntro

l arm

s of

CL

OT

S tr

ial 1

). b D

ata

from

CL

OT

S tr

ial 1

(str

oke

patie

nts)

; hen

ce, w

hen

resu

lts a

pplie

d to

med

ical

pat

ient

s, th

e qu

ality

of e

vide

nce

shou

ld b

e do

wng

rade

d du

e to

indi

rect

ness

c F

or t

he o

utco

mes

of

DV

T a

nd P

E, i

mpr

ecis

ion

refe

rs o

nly

to t

he h

igh-

risk

pat

ient

s (e

stim

ates

in lo

w-r

isk

patie

nts

are

asso

ciat

ed w

ith v

ery

smal

l abs

olut

e di

ffer

ence

tha

t is

fai

rly

prec

ise)

. Im

prec

isio

n ot

herw

ise

is d

ue to

wid

e C

I th

at in

clud

es a

ppre

ciab

le b

enefi

t an

d ha

rm a

nd o

vera

ll sm

all n

umbe

r of

eve

nts.

d T

he e

ffec

t est

imat

e sh

own

here

res

ults

from

a fi

xed-

effe

cts

met

a-an

alys

is o

f tw

o tr

ials

of g

radu

ated

com

pres

sion

sto

ckin

g fo

r pr

even

tion

of D

VT

in h

ospi

taliz

ed m

edic

al p

atie

nts.

The

Mui

r tr

ial r

epor

ted

deat

h in

nin

e of

65

patie

nts w

ith a

cute

stro

ke in

the

trea

tmen

t gro

up a

nd fo

ur o

f 32

patie

nts i

n th

e co

ntro

l gro

up. T

he C

LO

TS

tria

l 1 re

port

ed d

eath

in 1

22 o

f 1,2

56 p

atie

nts w

ith a

cute

stro

ke in

the

trea

tmen

t gr

oup

and

110

of 1

,262

pat

ient

s in

the

cont

rol g

roup

. Sto

ckin

gs w

ere

used

for

1 w

eek

in tw

o st

udie

s (K

ierk

egaa

rd a

nd N

orgr

en; M

uir

et a

l) an

d un

til th

e pa

tient

was

inde

pend

ently

mob

ile, w

as d

isch

arge

d,

refu

sed

to w

ear t

hem

, or d

evel

oped

skin

pro

blem

s in

one

stud

y (D

enni

s et a

l). T

he la

rges

t of t

he st

udie

s, th

e C

LO

TS1

Tri

al c

ondu

cted

in 2

,518

hos

pita

lized

stro

ke p

atie

nts,

was

the

only

one

to p

rovi

de d

ata

on a

dver

se e

ffec

ts o

f gra

duat

ed c

ompr

essi

on s

tock

ings

. e A

sses

smen

t of o

utco

mes

was

bas

ed o

n ca

se-n

ote

revi

ew a

nd w

as n

ot b

linde

d to

trea

tmen

t allo

catio

n.




Tabl

e S9

—[S

ecti

on 2

.7.2

] E

vide

nce

Pro

fi le:

Sho

uld

IP

C B

e U

sed

in H

ospi

tali

zed

Non

surg

ical

Pat

ient

s? S

etti

ngs:

Inp

atie

nts

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

No.

of P

atie

nts

Eff

ect

No

of

Stud

ies

Des

ign

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

Con

side

ratio

nsIP

CC

ontr

ol, a %

Rel

ativ

e (9

5% C

I)A

bsol

ute

Qua

lity

of

Evi

denc

e

Sym

ptom

atic

DV

T (f

ollo

w-u

p, 3

0 d)

19

Ran

dom

ized

tr

ials

No

seri

ous

limita

tions

No

seri

ous

inco

nsis

tenc

ySe

riou

s in

dire

ctne

ss b

No

seri

ous

impr

ecis

ion

Non

e…

0.15

RR

, 0.4

3 (0

.32-

0.58

)1

few

er p

er 1

,000

(f

rom

1 fe

wer

to 1

few

er)

Mod

erat

eIm

port

ant

6.7

38 fe

wer

per

1,0

00

(fro

m 4

6 fe

wer

to 2

8 fe

wer

)

PE (f

ollo

w-u

p, 3

0 d)

8R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

nsN

o se

riou

s in

cons

iste

ncy

Seri

ous

indi

rect

ness

c Se

riou

s im

prec

isio

n d N

one

…0.

15R

R, 0

.82

(0.4

1-1.

62)

1 fe

wer

per

1,0

00 (f

rom

1

few

er to

1 m

ore)

Low

Cri

tical

3.9

7 fe

wer

per

1,0

00 (f

rom

23

few

er to

24

mor

e)

Mor

talit

y (f

ollo

w-u

p, 3

0 d)

2R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

nsN

o se

riou

s in

cons

iste

ncy

Seri

ous

indi

rect

ness

e Se

riou

s im

prec

isio

n d N

one

…4.

5R

R, 1

.03

(0.4

2-2.

57)

1 m

ore

per

1,00

0 (f

rom

76

few

er to

71

mor

e)L

owC

ritic

al

Skin

com

plic

atio

ns (b

reak

s, u

lcer

s, b

liste

rs, a

nd n

ecro

sis)

, not

rep

orte

d in

any

pop

ulat

ion g

0…

……

……

Non

e…

……

…Im

port

ant

Bib

liogr

aphy

: Sys

tem

atic

rev

iew

in s

urgi

cal p

atie

nts:

Rod

eric

k P,

Fer

ris

G, W

ilson

K, e

t al.

Tow

ard

evid

ence

-bas

ed g

uide

lines

for

the

prev

entio

n of

ven

ous

thro

mbo

embo

lism

: sys

tem

atic

rev

iew

s of

mec

hani

cal m

etho

ds,

oral

ant

icoa

gula

tion,

dex

tran

and

reg

iona

l ane

sthe

sia

as t

hrom

bopr

ophy

laxi

s. H

ealth

Tec

hnol

Ass

ess.

200

5;9(

49):1

-78.

Sys

tem

atic

rev

iew

in s

trok

e pa

tient

s: N

acca

rato

M, C

hiod

o G

rand

i F, D

enni

s M

, San

derc

ock

PA.

Phys

ical

met

hods

for

prev

entin

g de

ep v

ein

thro

mbo

sis

in s

trok

e. C

ochr

ane

Dat

abas

e Sy

st R

ev. 2

010;

(8):

CD

0019

22. B

arba

r S,

Nov

enta

F, R

osse

tto

V, e

t al.

A r

isk

asse

ssm

ent m

odel

for

the

iden

tifi c

atio

n of

hos

pita

lized

m

edic

al p

atie

nts

at r

isk

for

veno

us th

rom

boem

bolis

m: T

he P

adua

Pre

dict

ion

Scor

e. J

Thr

omb

Hae

mos

t . 20

10;8

(11)

:245

0-24

57. D

enta

li F,

Dou

ketis

JD

, Gia

nni M

, Lim

W, C

row

ther

MA

. Met

a-an

alys

is: A

ntic

oagu

lant

pr

ophy

laxi

s to

pre

vent

sym

ptom

atic

ven

ous

thro

mbo

embo

lism

in

hosp

italiz

ed m

edic

al p

atie

nts.

Ann

Int

erna

l M

ed.

2007

;146

(4):2

78-2

88.

IPC

5 in

term

itten

t pn

eum

atic

com

pres

sion

. Se

e Ta

bles

S1,

S3,

and

S4

for

expa

nsio

n of

oth

er a

bbre

viat

ions

. a B

asel

ine

risk

for D

VT

and

PE

(low

-ris

k an

d hi

gh-r

isk

popu

latio

ns) a

re d

eriv

ed fr

om th

e R

AM

by

Bar

bar e

t al.

Bas

elin

e ri

sk fo

r mor

talit

y is

der

ived

from

the

cont

rol a

rm o

f med

ical

pat

ient

s in

a m

eta-

anal

ysis

(Den

tali

et a

l).

b RR

for

DV

T is

der

ived

from

sur

gica

l pat

ient

s (R

oder

ick

et a

l). A

noth

er e

lem

ent o

f ind

irec

tnes

s is

that

DV

T in

thes

e su

rgic

al p

atie

nts

was

pri

mar

ily a

sym

ptom

atic

DV

T a

s as

cert

aine

d by

sys

tem

atic

Im

agin

g te

sts.

RR

fo

r pr

oxim

al a

sym

ptom

atic

DV

T w

as s

imila

r (0

.52;

95%

CI,

0.3

7-0.

73).

RR

dat

a ar

e pr

esen

ted

for

IPC

use

d as

mon

othe

rapy

bec

ause

thi

s is

mos

t re

leva

nt t

o th

e w

ay I

PCs

are

used

in m

edic

al p

atie

nts

(ie, i

n pa

tient

s w

ho c

anno

t rec

eive

ant

icoa

gula

tion)

. If I

PCs

are

used

alo

ne o

r as

adj

unct

to a

ntic

oagu

lant

/ant

ipla

tele

t the

rapy

, RR

is 0

.49

(0.3

7-0.

63),

whi

ch le

ads

to a

bsol

ute

effe

ct p

er 1

,000

pat

ient

s of

one

few

er (

from

one

few

er to

on

e fe

wer

) in

low

-ris

k pa

tient

s an

d 32

few

er (f

rom

42

few

er to

25

few

er) i

n hi

gh-r

isk

patie

nts.

c R

R fo

r PE

is d

eriv

ed fr

om s

urgi

cal p

atie

nts

(Rod

eric

k et

al).

RR

dat

a ar

e pr

esen

ted

for

IPC

use

d as

mon

othe

rapy

bec

ause

this

is m

ost r

elev

ant t

o th

e w

ay I

PCs

are

used

in m

edic

al p

atie

nts

(ie, i

n pa

tient

s w

ho c

anno

t re

ceiv

e an

ticoa

gula

tion)

. If I

PCs

are

used

alo

ne o

r as

adj

unct

to a

ntic

oagu

lant

/ant

ipla

tele

t the

rapy

, RR

is 0

.77

(0.4

1-1.

43).

Thi

s do

es n

ot c

hang

e th

e co

nclu

sion

s of

this

evi

denc

e pr

ofi le

. d C

I in

clud

es n

eglig

ible

eff

ect,

appr

ecia

ble

bene

fi t, a

nd a

ppre

ciab

le h

arm

. e R

R is

der

ived

from

RC

Ts in

str

oke

(incl

udin

g on

e st

udy

of p

atie

nts

with

hem

orrh

agic

str

oke)

. RC

Ts o

f IPC

s in

oth

er p

opul

atio

ns d

id n

ot m

easu

re o

r re

port

mor

talit

y.

f Est

imat

es fo

r sk

in c

ompl

icat

ions

in m

edic

al p

atie

nts

usin

g IP

C a

re n

ot a

vaila

ble.

Dat

a fr

om g

radu

ated

com

pres

sion

sto

ckin

gs (s

ectio

n 2.

3) m

ay b

e in

dire

ctly

con

side

red.




Tabl

e S1

0 —E

xten

ded-

Du

rati

on P

roph

ylax

is i

n H

ospi

tali

zed

Med

ical

Pat

ient

s

Stud

y/Ye

arTi

tle, D

esig

nPa

tient

Typ

esE

xclu

ded

Patie

nts

Inte

rven

tion

Con

trol

Out

com

esR

esul

ts a

Len

gth

of

Fol

low

-up

Pote

ntia

l for

Bia

s

Hul

l et a

l 33 /2

010

Para

llel R

CT;

N

5 6

,085

Acu

tely

ill m

edic

al

patie

nts,

� 4

0 y

with

a li

fe

expe

ctan

cy o

f at

leas

t 6 m

o w

ith

rece

ntly

red

uced

m

obili

ty fo

r up

to

3 d

, defi

ned

as

req

uiri

ng

tota

l bed

res

t or

bein

g se

dent

ary

with

(lev

el 2

) or

with

out (

leve

l 1)

bath

room

pr

ivile

ges

Evi

denc

e of

an

activ

e bl

eedi

ng

diso

rder

Subc

utan

eous

en

oxap

arin

, 40

mg/

d fo

r 28

� 4

d

Plac

ebo

for

28 �

4 d

VT

E (c

ompo

site

of

sym

ptom

atic

pr

oxim

al D

VT,

as

ympt

omat

ic

prox

imal

DV

T

dete

cted

on

man

dato

ry b

ilate

ral

com

pres

sion

ul

tras

ound

at e

nd

of d

oubl

e-bl

ind

trea

tmen

t per

iod,

sy

mpt

omat

ic P

E,

or fa

tal P

E) d

urin

g do

uble

-blin

d tr

eatm

ent p

erio

d

VT

E a

t 28

d6

mo

Did

not

use

IT

T

anal

ysis

: –F

or s

afet

y, o

nly

incl

uded

thos

e w

ho h

as a

t lea

st

one

dose

of s

tudy

dr

ug (n

5 5

,963

) – F

or e

ffi ca

cy, o

nly

incl

uded

thos

e w

ho h

ad a

t lea

st

one

dose

of

stud

y dr

ug a

nd

had

an e

valu

able

ul

tras

onog

ram

(n

5 4

,995

)

E

: 61

of 2

,485

For

VT

E:

Aft

er in

itial

op

en-la

bel,

subc

utan

eous

en

oxap

arin

, 40

mg/

d fo

r 10

� 4

d

P:

100

of 2

,510

28 �

4 d

Sym

ptom

atic

prox

imal

DV

T90

� 1

0 d

E

: 5 o

f 2,4

85F

or d

eath

:

Maj

or s

urge

ry

with

in th

e pr

evio

us 3

mo

P:

20

of 2

,510

28 �

4 d

Aft

er in

itial

op

en-la

bel,

subc

utan

eous

en

oxap

arin

, 40

mg/

d fo

r 10

� 4

d

Fat

al P

E

90 �

10

d

E

: 0 o

f 2,4

85

P:

1 o

f 2,5

10

180

� 1

0 d

(Con

tinu

ed)




Stud

y/Ye

arTi

tle, D

esig

nPa

tient

Typ

esE

xclu

ded

Patie

nts

Inte

rven

tion

Con

trol

Out

com

esR

esul

ts a

Len

gth

of

Fol

low

-up

Pote

ntia

l for

Bia

s

VT

E a

t 90

dC

onfl i

ct o

f int

eres

t: fu

nder

invo

lved

in

dat

a m

anag

emen

t, st

atis

tical

an

alys

is, a

nd

prep

arat

ion

of

the

artic

le fo

r pu

blic

atio

n

Spin

al o

r ep

idur

al

anal

gesi

a or

lu

mba

r pu

nctu

re

with

in th

e pr

evio

us 2

4 h

E

: 65

of 2

,485

P:

105

of 2

,510

Mor

talit

y di

d no

t si

gnifi

cant

ly

diff

er a

t 30,

90

, or

180

d K

now

n hy

pers

ensi

tivity

to

UF

H, L

MW

H,

or p

ork-

deri

ved

prod

ucts

Maj

or b

leed

ing

Did

not

rep

ort

num

ber

of

patie

nts

scre

ened

fo

r in

clus

ion

VT

E in

cide

nce

thro

ugh

3 m

o (d

ay 9

0 �

10)

E

: 25

of 2

,975

(4

intr

acra

nial

; 1

fata

l) H

isto

ry o

f he

pari

n-in

duce

d th

rom

bocy

tope

nia

or th

rom

bosi

s

Post

hoc

sub

grou

p an

alys

es

Mor

talit

y at

1 m

o (d

ay 2

8 � 4)

, 3 m

o (d

ay 9

0 �

10)

, an

d 6

mo

(day

18

0 �

10)

P:

10

of 2

,988

(0

intr

acra

nial

; 0

fata

l)

Cha

nge

in

elig

ibili

ty c

rite

ria

part

way

thro

ugh

the

tria

l and

“d

ata-

driv

en”

Tota

l ble

edin

g

E

: 186

of 2

,975

F

ollo

win

g an

am

endm

ent t

o th

e el

igib

ility

cr

iteri

a, p

atie

nts

with

leve

l 2

imm

obili

ty w

ere

requ

ired

to h

ave

at le

ast 1

VT

E

risk

fact

or

Tabl

e S1

0—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

arTi

tle, D

esig

nPa

tient

Typ

esE

xclu

ded

Patie

nts

Inte

rven

tion

Con

trol

Out

com

esR

esul

ts a

Len

gth

of

Fol

low

-up

Pote

ntia

l for

Bia

s

Part

icip

atio

n in

an

othe

r cl

inic

al

stud

y w

ithin

the

prev

ious

30

d

P:

116

of 2

,988

Maj

or b

leed

ing b

duri

ng a

nd u

p to

48

h af

ter

doub

le-b

lind

trea

tmen

t pe

riod

Seri

ous

adve

rse

ev

ents

E

: 216

of 2

,975

P:

218

of 2

,988

Pers

iste

nt r

enal

fa

ilure

HIT

E

: 1 o

f 2,9

75

Kno

wn

or s

uspe

cted

se

vere

ane

mia

of

une

xpla

ined

ca

use

Tota

l (m

ajor

and

m

inor

) ble

edin

g ev

ents

A p

rost

hetic

hea

rt

valv

e

P: 0

of 2

,988

Se

riou

s ad

vers

e ev

ents

(inc

ludi

ng

thro

mbo

cyto

peni

a)

Cer

ebra

l met

asta

ses

Patie

nts

who

are

un

likel

y to

be

com

plia

nt

Post

hoc

ana

lyse

s id

entifi

ed

sign

ifi ca

nt

inte

ract

ion

betw

een

trea

tmen

t eff

ect

and

sex

( P 5

.016

) an

d ag

e .

75

y ( P

5 .0

11).

Fav

orab

le

risk

-ben

efi t

ratio

lik

ely

only

for

fem

ale

patie

nts

with

leve

l 1

imm

obili

ty .

75

y

Wom

en w

ho a

re

brea

st-f

eedi

ng,

preg

nant

, or

of

child

bear

ing

age

and

not

usin

g ef

fect

ive

cont

race

ptio

n

Con

trai

ndic

atio

ns

to p

harm

acol

ogic

an

ticoa

gula

tion

Use

of L

MW

H

or U

FH

at

prop

hyla

ctic

do

ses

for

. 7

2 h

prio

r to

incl

usio

n,

or tr

eatm

ent w

ith

oral

ant

icoa

gula

nt

ther

apy

with

in

72 h

pri

or to

en

rollm

ent

ITT

5 in

tent

ion

to tr

eat.

See

Tabl

e S1

-S5

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

. a E

5 e

noxa

pari

n; P

5 p

lace

bo.

b Ble

edin

g co

nsid

ered

to b

e m

ajor

if o

vert

and

ass

ocia

ted

with

dea

th; a

dec

reas

e in

hem

oglo

bin

leve

l of a

t lea

st 2

0 g/

L, o

r a tr

ansf

usio

n of

at l

east

2 u

nits

of p

acke

d R

BC

or w

hole

blo

od; s

urgi

cal i

nter

vent

ion;

or

ret

rope

rito

neal

, int

racr

ania

l, or

intr

aocu

lar

blee

ding

.

Tabl

e S1

0—C

onti

nued




Tabl

e S1

1 —[S

ecti

on 2

.8]

Evi

denc

e P

rofi l

e: S

hou

ld E

xten

ded-

Du

rati

on T

hrom

bop

roph

ylax

is v

s St

anda

rd S

hort

-Du

rati

on T

hrom

bop

roph

ylax

is B

e U

sed

for

Pre

vent

ion

of V

TE

in

Hos

pita

lize

d M

edic

al P

atie

nts

Wit

h R

edu

ced

Mob

ilit

y?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

N

o. (%

) of P

atie

nts

Eff

ect

No.

of

Stud

ies

Des

ign

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

Con

side

ratio

nsE

xten

ded-

Dur

atio

n T

hrom

bopr

ophy

laxi

s

Stan

dard

Sh

ort-

Dur

atio

n T

hrom

bopr

ophy

laxi

sR

elat

ive

(95%

CI)

Abs

olut

e Q

ualit

y

Sym

ptom

atic

pro

xim

al D

VT

(fol

low

-up,

24-

32 d

; bila

tera

l com

pres

sion

ultr

ason

ogra

phy

or v

enog

raph

y)

1R

ando

miz

ed

tria

lsSe

riou

s a N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Non

eN

one

5 of

2,4

85 (0

.2)

20 o

f 2,5

10 (0

.8)

RR

, 0.2

5 (0

.09-

0.67

)6

few

er p

er 1

,000

(f

rom

3 fe

wer

to

7 fe

wer

)

Mod

erat

eC

ritic

al

Fat

al P

E (f

ollo

w-u

p, 2

4-32

d; a

utop

sy)

1R

ando

miz

ed

tria

lsSe

riou

s a N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Non

e b N

one

0 of

2,4

85 (0

)1

of 2

,510

(0)

RR

, 0.3

4 (0

.01-

8.26

)0

few

er p

er 1

,000

(f

rom

0 fe

wer

to

3 m

ore)

Mod

erat

eC

ritic

al

Mor

talit

y (f

ollo

w-u

p, 2

4-32

d)

1R

ando

miz

ed

tria

lsSe

riou

s a N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous b

Non

e60

of 2

,975

(2)

65 o

f 2,9

88 (2

.2)

RR

, 1.0

0 (0

.7-1

.43)

0 fe

wer

per

1,0

00

(fro

m 7

few

er

to 9

mor

e)

Low

Cri

tical

Maj

or b

leed

ing

(fol

low

-up,

24-

34 d

; hem

orrh

ages

con

side

red

to b

e m

ajor

is th

ey w

ere

over

t and

ass

ocia

te w

ith d

eath

; a d

ecre

ase

in h

emog

lobi

n le

vel o

f at l

east

20g

/L o

r a

tran

sfus

ion

of a

t lea

st 2

uni

ts o

f pa

cked

RB

C o

r w

hole

blo

od; s

urgi

cal i

nter

vent

ion;

or

retr

oper

itone

al, i

ntra

cran

ial,

or in

trao

cula

r bl

eedi

ng)

1R

ando

miz

ed

tria

lsSe

riou

s a N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Non

eN

one

25 o

f 2,9

75 (0

.8) c

10 o

f 2,9

88 (0

.3) d

RR

, 2.5

1 (1

.21-

5.22

)5

mor

e pe

r 1,

000

(fro

m 1

mor

e to

14

mor

e)

Mod

erat

eC

ritic

al

Seri

ous

adve

rse

even

ts (f

ollo

w-u

p, 2

4-32

d e ;

New

illn

ess,

wor

seni

ng o

f pre

exis

ting

illne

ss, o

r st

udy

med

icat

ion

effe

cts

that

res

ulte

d in

dea

th o

r pe

rsis

tent

or

subs

tant

ial d

isab

ility

or

inca

pabi

lity,

wer

e lif

e-th

reat

enin

g or

con

side

red

an im

port

ant m

edic

al e

vent

, or

requ

ired

in-p

atie

nt h

ospi

taliz

atio

n or

pro

long

atio

n of

exi

stin

g ho

spita

lizat

ion f )

1R

ando

miz

ed

tria

lsSe

riou

s b N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous c

Non

e21

6 of

2,9

75 (7

.3)

218

of 2

,988

(7.3

)R

R, 1

.00

(0.8

3-1.

19)

0 fe

wer

per

1,0

00

(fro

m 1

2 fe

wer

to

14

mor

e)

Low

Impo

rtan

t

HIT

(fol

low

-up,

24-

32 d

e )

1R

ando

miz

ed

tria

lsSe

riou

s a N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Very

ser

ious

b N

one

1 of

2,9

75 (0

)0

of 2

,988

(0)

RR

, 3.0

1 (0

.12-

73.9

3)0

mor

e pe

r 1,

000

(fro

m 0

few

er

to 0

mor

e)

Very

low

Cri

tical

Bib

liogr

aphy

: H

ull

RD

, Sc

hello

ng S

M,

Taps

on V

F, e

t al

. E

xten

ded-

dura

tion

veno

us t

hrom

boem

bolis

m p

roph

ylax

is i

n ac

utel

y ill

med

ical

pat

ient

s w

ith r

ecen

tly r

educ

ed m

obili

ty:

a ra

ndom

ized

tri

al.

Ann

Int

ern

Med

. 201

0;15

3(1)

:8-1

8. S

ee T

able

S1,

S4,

and

S5

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Cha

nge

in e

ligib

ility

cri

teri

a pa

rt w

ay th

roug

h th

e tr

ial a

nd “

data

-dri

ven”

; did

not

use

IT

T a

naly

sis.

b W

e co

nsid

ered

impr

ecis

ion

to b

e se

riou

s whe

n C

Is in

clud

ed a

ppre

ciab

le b

enefi

t an

d ha

rm. W

e co

nsid

ered

impr

ecis

ion

very

seri

ous i

n th

e ou

tcom

es o

f fat

al P

E a

nd H

IT b

ecau

se th

e nu

mbe

r of e

vent

s was

ve

ry s

mal

l (1

and

2, r

espe

ctiv

ely)

. c F

our

intr

acra

nial

, one

fata

l. d Z

ero

intr

acra

nial

, zer

o fa

tal.

e The

leng

th o

f fol

low

-up

for

this

out

com

e w

as u

ncle

ar fr

om th

e pu

blis

hed

artic

le.

f Inc

lude

s 13

VT

Es,

one

in e

noxa

pari

n, 1

2 in

pla

cebo

gro

up; i

nclu

des

20 m

ajor

ble

edin

g ev

ents

, 15

in e

noxa

pari

n gr

oup,

fi ve

in p

lace

bo g

roup

.




Tabl

e S1

2 —P

rogn

osti

c F

acto

rs A

ssoc

iate

d W

ith

VT

E i

n IC

U P

atie

nts

Stud

y/Ye

arTy

pe o

f Stu

dyPa

rtic

ipan

tsIn

terv

entio

nO

utco

mes

Fol

low

-up

Res

ults

Com

men

ts

Stud

ies

usin

g m

ultiv

aria

ble

anal

ysis

Shor

r et

al 34

/200

9M

ultic

ente

r R

CT

(X

PRE

SS)

1,93

5 se

psis

pat

ient

s re

ceiv

ing

DA

AL

MW

H (E

noxa

pari

n 40

mg

SC o

d), U

FH

5,

000

Inte

rnat

iona

l U

nits

SC

bid

or

plac

ebo

duri

ng D

AA

infu

sion

pe

riod

DV

T s

cree

ning

with

ul

tras

ound

be

twee

n da

ys 4

-6

28 d

RR

old

er p

atie

nts

(age

. 7

5 y)

, 1.

92 (9

5% C

I, 1

.22-

3.04

; P

5 .0

04);

hist

ory

of V

TE

, 4.

6 (2

.17-

9.79

, P ,

.001

); m

ultiv

aria

ble

anal

ysis

: his

tory

of

VT

E; O

R, 3

.66

(95%

CI,

1.

77-7

.56;

P 5

.005

)

Mul

tivar

iabl

e an

alys

is

adju

sted

for

age,

re

cent

sur

gery

, his

tory

of

VT

E, b

asel

ine

hepa

rin,

use

of

vaso

pres

sors

, nee

d fo

r m

echa

nica

l ven

tilat

ion

Coo

k et

al, 35

D

IRE

CT

/200

8M

ultic

ente

r pr

ospe

ctiv

e co

hort

138

med

ical

-sur

gica

l IC

U p

atie

nts

with

re

nal i

nsuf

fi cie

ncy

Dal

tepa

rin

5,00

0 In

tern

atio

nal U

nits

SC

od

DV

T s

cree

ning

with

ul

tras

ound

on

adm

issi

on a

nd

twic

e w

eekl

y

Up

to 3

0 d

Ele

vate

d A

PAC

HE

II

scor

e;

HR

for

10-u

nit i

ncre

ase,

2.

25 (9

5% C

I, 1

.03-

4.91

)

Inde

pend

ent v

aria

bles

: ba

selin

e V

TE

ris

k fa

ctor

s, a t

rans

fusi

on,

CV

C, i

notr

ope

or

vaso

pres

sor,

mec

hani

cal

vent

ilatio

n

Coo

k et

al, 36

V

ET

EC

/200

5Si

ngle

-cen

ter

pros

pect

ive

coho

rt

261

med

ical

-sur

gica

l IC

U p

atie

nts

Dal

tepa

rin

5,00

0 In

tern

atio

nal U

nits

SC

od

DV

T s

cree

ning

w

ith u

ltras

ound

on

adm

issi

on a

nd

twic

e w

eekl

y

Pers

onal

or

fam

ily h

isto

ry o

f V

TE

, HR

, 4.0

(95%

CI,

1.

5-10

.3);

end-

stag

e re

nal

failu

re, H

R, 3

.7%

(1.2

%-1

1.1%

); pl

atel

et tr

ansf

usio

n, H

R, 3

.2%

(1

.2%

-8.4

%);

vaso

pres

sor

use,

H

R, 2

.8%

(1.1

%-7

.2%

)

Inde

pend

ent v

aria

bles

: ba

selin

e V

TE

ris

k fa

ctor

s, e

xpos

ures

w

ithin

2 w

k an

d du

ring

IC

U a

dmis

sion

, da

ily I

CU

exp

osur

es b

Ibra

him

et a

l 37 /2

002

Pros

pect

ive

coho

rt11

0 m

edic

al I

CU

pa

tient

s re

quir

ing

mec

hani

cal

vent

ilatio

n .

7 d

Scre

enin

g du

plex

ul

tras

ound

of u

pper

an

d lo

wer

ext

rem

ities

ev

ery

7 d

DV

T, m

orta

lity;

als

o ho

spita

l and

IC

U

LO

S, d

urat

ion

of

mec

hani

cal

vent

ilatio

n

N/S

(whi

le

in I

CU

)D

urat

ion

of C

VC

pla

cem

ent

(1-d

incr

emen

ts),

RR

of

DV

T, 1

.04

(95%

CI,

1.

03-1

.05;

P ,

.001

)

Cox

pro

port

iona

l haz

ards

m

odel

Kol

lef 38

/199

8Si

ngle

-cen

ter

pros

pect

ive

coho

rt

323

med

ical

IC

U

patie

nts

Sem

iqua

ntita

tive

d-di

mer

VT

E (n

ot

syst

emat

ical

ly

scre

ened

)

N/S

(whi

le

in I

CU

)In

crea

sed

d-di

mer

inde

pend

ently

as

soci

ated

with

vas

cula

r th

rom

bosi

s, a

djus

ted

OR

, 5.0

6 (9

5% C

I, 2

.96-

8.65

; P 5

.003

)

Mul

tiple

logi

stic

re

gres

sion

Stud

ies

that

use

d un

ivar

iate

ana

lysi

s to

ide

ntify

ris

k fa

ctor

s fo

r V

TE

wer

e no

t in

clud

ed i

n th

e ta

ble.

34,3

9 A

PAC

HE

5 A

cute

Phy

siol

ogy

and

Chr

onic

Hea

lth E

valu

atio

n; C

VC

5 ce

ntra

l ve

nous

cat

hete

r;

DA

A 5

dro

trec

ogin

alfa

(act

ivat

ed);

LO

S 5

leng

th o

f sta

y; o

d 5

onc

e da

ily; S

C 5

subc

utan

eous

. See

Tab

le S

2, S

4, S

5, a

nd S

7 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a Bas

elin

e ri

sk fa

ctor

s: p

erso

nal o

r fa

mily

his

tory

, kno

wn

thro

mbo

phili

c di

sord

er, c

urre

nt o

r re

cent

(with

in 5

y) m

alig

nanc

y.

b Bas

elin

e V

TE

ris

k fa

ctor

s: a

ge; g

ende

r; B

MI;

adm

issi

on d

iagn

osis

; med

ical

or

surg

ical

sta

tus;

APA

CH

E I

I sc

ore;

pre

-IC

U lo

catio

n; p

erso

nal o

r fa

mily

his

tory

of V

TE

; kno

wn

thro

mbo

phili

c di

sord

er; a

ctiv

e or

pre

viou

s m

alig

nanc

y; c

hron

ic c

ardi

ac, r

espi

rato

ry, r

enal

, or

CN

S di

seas

e; s

mok

ing;

hos

pita

lizat

ion

with

in 6

mo;

sur

gery

with

in 1

2 w

k; b

ed r

est o

f � 3

d in

pri

or 4

wk;

act

ivity

leve

l. E

xpos

ures

with

in 2

wk

befo

re I

CU

adm

issi

on a

nd d

aily

ther

eaft

er in

clud

ed C

VC

s, s

ubcu

tane

ous

UF

H, U

FH

for

cath

eter

pat

ency

, the

rape

utic

UF

H o

r L

MW

H, w

arfa

rin

ASA

, NSA

IDS,

ant

ipla

tele

t dru

gs, v

itam

in K

, tra

nsfu

sion

(R

BC

, pla

sma,

pla

tele

ts, c

ryop

reci

pita

te).

Dai

ly I

CU

var

iabl

es in

clud

ed v

asop

ress

ors,

mec

hani

cal v

entil

atio

n, p

ositi

ve e

nd-e

xpir

ator

y pr

essu

re, d

ialy

sis,

sur

gica

l int

erve

ntio

ns, M

ultip

le O

rgan

Dys

func

tion

scor

e, h

emog

lobi

n, p

late

let c

ount

, IN

R, a

PTT,

IV

sed

ativ

es/o

piat

es/p

aral

ytic

s.




Tabl

e S1

3 — D

escr

ipti

on o

f St

udi

es o

f P

roph

ylac

tic

Ant

icoa

gula

tion

in

ICU

Pat

ient

s

Stud

y/Ye

arTy

pe o

f Stu

dyPa

rtic

ipan

tsIn

terv

entio

nO

utco

mes

Fol

low

-up

Res

ults

Com

men

ts

UF

H v

s Pl

aceb

o

Cad

e 40 /1

982

Sing

le-c

ente

r R

CT

119

med

ical

-sur

gica

l IC

U p

atie

nts

UF

H 5

,000

Int

erna

tiona

l U

nits

SC

bid

vs

plac

ebo

DV

T d

etec

ted

by

fi bri

noge

n le

g sc

anni

ng fo

r m

edia

n 7

d (4

-10

d)

Not

spe

cifi e

d (w

hile

in I

CU

)D

VT:

UF

H, 1

3%

vs p

lace

bo 2

9%;

P ,

.05

57%

Dis

tal D

VT,

1/

3 bi

late

ral,

1/5

prox

imal

LM

WH

vs

Plac

ebo

Fra

isse

et a

l 8 /200

0M

ultic

ente

r, do

uble

-blin

d R

CT

223

mec

hani

cally

ve

ntila

ted

patie

nts

with

CO

PD

LM

WH

(nad

ropa

rin

� 6

5 In

tern

atio

nal U

nits

/kg

SC o

d) v

s pl

aceb

o

DV

T (d

etec

ted

by

veno

grap

hy b

efor

e da

y 21

), bl

eedi

ng,

mor

talit

y

Up

to 2

1 d

DV

T: L

MW

H, 1

3 of

84

(15.

5%) v

s pl

aceb

o,

24 o

f 85

(28.

2%);

P 5

.045

Wee

kly

ultr

asou

nd;

prox

imal

DV

T in

3

of 1

3 L

MW

H

and

7 of

24

plac

ebo

Maj

or b

leed

ing:

LM

WH

, 6

of 1

08 (5

.5%

) vs

pla

cebo

, 3 o

f 11

3 (2

.7%

); P

5 .2

8

Mor

talit

y: L

MW

H, 8

of

84 (9

.5%

) vs

plac

ebo,

8

of 8

5 (9

.4%

) (C

onti

nued

)




Stud

y/Ye

arTy

pe o

f Stu

dyPa

rtic

ipan

tsIn

terv

entio

nO

utco

mes

Fol

low

-up

Res

ults

Com

men

ts

LM

WH

vs

UF

H

PRO

TE

CT

in

vest

igat

ors 41

/201

1M

ultic

ente

r, do

uble

-blin

d R

CT

3,76

4 cr

itica

lly il

l pa

tient

s ex

pect

ed

to r

emai

n in

IC

U

for

� 3

d

LM

WH

(dal

tepa

rin

5,00

0 In

tern

atio

nal U

nits

SC

od)

vs

UF

H 5

,000

In

tern

atio

nal U

nits

SC

bid

Prox

imal

DV

T (d

etec

ted

by c

ompr

essi

on

ultr

asou

nd �

3 d

af

ter

rand

omiz

atio

n;

com

pres

sion

ultr

asou

nd

perf

orm

ed w

ithin

2

d of

adm

issi

on, t

wic

e w

eekl

y, a

nd a

s cl

inic

ally

in

dica

ted)

; sec

onda

ry

outc

omes

: any

DV

T,

PE, V

TE

, dea

th, m

ajor

bl

eedi

ng, H

IT

Whi

le in

IC

UPr

oxim

al D

VT:

LM

WH

, 96

of 1

,873

(5.1

%)

vs U

FH

, 109

of

1,87

3 (5

.8%

); H

R,

0.92

(95%

CI,

0.

68-1

.23;

P 5

.57)

All

DV

T o

utco

mes

w

ere

scre

ened

for

by u

ltras

ound

; PE

w

as n

ot s

cree

ned

for,

but w

as c

linic

ally

su

spec

ted

and

clas

sifi e

d as

pos

sibl

e,

prob

able

, or

defi n

ite

Any

DV

T: L

MW

H,

138

of 1

,873

(7.4

%)

vs U

FH

, 161

of

1,87

3 (8

.6%

); H

R, 0

.93

(95%

CI,

0.

72-1

.19;

P 5

.54)

PE: L

MW

H, 2

4 of

1,

873

(1.3

%) v

s U

FH

, 43

of 1

,873

(2.3

%);

HR

, 0.5

1 (9

5% C

I,

0.30

-0.8

8; P

5 .0

1)

VT

E: L

MW

H, 1

54 o

f 1,

873

(8.2

%) v

s U

FH

, 18

6 of

1,8

73 (9

.9%

); H

R, 0

.87

(95%

CI,

0.

69-1

.10;

P 5

.24)

Dea

th (I

CU

): L

MW

H,

284

of 1

,873

(15.

2%)

vs U

FH

, 304

of

1,87

3 (1

6.2%

); H

R, 0

.97

(95%

CI,

0.

82-1

.15;

P 5

.71)

Maj

or b

leed

ing:

LM

WH

, 10

3 of

1,8

73 (5

.5%

), U

FH

, 105

of

1,87

3 (5

.6%

)

HIT

: LM

WH

, 5 o

f 1,8

73

(0.3

%) v

s U

FH

, 12

of

1,87

3 (0

.6%

)

Tabl

e S1

3—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

arTy

pe o

f Stu

dyPa

rtic

ipan

tsIn

terv

entio

nO

utco

mes

Fol

low

-up

Res

ults

Com

men

ts

Shor

r et

al 34

/200

9 M

ultic

ente

r R

CT

(XPR

ESS

)1,

935

seps

is p

atie

nts

rece

ivin

g D

AA

LM

WH

(eno

xapa

rin

40 m

g SC

od)

, UF

H 5

000

Inte

rnat

iona

l Uni

ts

SC b

id o

r pl

aceb

o du

ring

DA

A in

fusi

on

peri

od

DV

T (d

etec

ted

by

com

pres

sion

ul

tras

ound

bet

wee

n da

ys 4

-6)

28 d

VT

E: L

MW

H, 2

3 of

47

8 (5

.9%

), U

FH

, 26

of 4

98 (6

.3%

), pl

aceb

o, 5

6 of

95

9 (5

.8%

)

Mos

t DV

T c

linic

ally

si

lent

PE: L

MW

H, 4

of

478

(0.4

%),

UF

H, 2

of

498

(0.4

%),

plac

ebo,

8

of 9

59 (0

.8%

)

De

et a

l 42 /2

010

Sing

le-c

ente

r R

CT

N 5

156

, cri

tical

ly

ill s

urgi

cal p

atie

nts

unde

rgoi

ng m

ajor

su

rger

y

LM

WH

(eno

xapa

rin

40 m

g od

) vs

UF

H 5

,000

In

tern

atio

nal U

nits

SC

bid

DV

T (d

etec

ted

with

D

oppl

er b

etw

een

post

oper

ativ

e da

ys

5-7

and

clin

ical

su

spic

ion)

, ble

edin

g,

mor

talit

y

� 6

wk

DV

T: L

MW

H, 1

of

81 (1

.2%

) vs

UF

H,

2 of

75

(2.7

%),

Cau

se o

f dea

th n

ot

VT

E o

r bl

eedi

ng

Maj

or b

leed

ing:

LM

WH

, 1

of 8

1 (1

.2%

) vs

UF

H,

2 of

75

(2.7

%)

No

scre

enin

g ul

tras

ound

, D

oppl

er o

nly

Mor

talit

y: L

MW

H, 9

of

81 (1

1%) v

s 6

of 7

5 (8

%)

Sing

le-a

rm c

linic

al s

tudi

es u

sing

LM

WH

/UF

H

Dou

ketis

et a

l 43 /2

008

Mul

ticen

ter,

sin

gle-

arm

cl

inic

al tr

ial

138

criti

cally

ill

med

ical

-sur

gica

l pa

tient

s w

ith s

ever

e re

nal i

nsuf

fi cie

ncy

(CrC

l , 3

0 m

L/m

in)

LM

WH

(dal

tepa

rin

5,00

0 In

tern

atio

nal U

nits

SC

od)

un

til I

CU

dis

char

ge o

r 30

d

DV

T (d

etec

ted

by

twic

e-w

eekl

y sc

reen

ing

ultr

asou

nd),

blee

ding

Unt

il IC

U

disc

harg

e or

up

to 3

0 d

DV

T: 7

of 1

38 (5

.1%

; 95

% C

I, 2

.5%

-10.

1%)

All

DV

T a

sym

ptom

atic

an

d pr

oxim

al; 6

of

7 as

soci

ated

with

fe

mor

al c

athe

ters

M

ajor

ble

edin

g: 1

0 of

13

8 (7

.2%

; 95%

CI,

4.

0%-1

2.8%

)

Rab

bat e

t al 44

/200

5Si

ngle

-cen

ter

pros

pect

ive

coho

rt19

cri

tical

ly il

l m

edic

al-s

urgi

cal

patie

nts

with

C

rCl .

0 m

L/m

in

LM

WH

(dal

tepa

rin

5,00

0 In

tern

atio

nal U

nits

SC

od)

VT

E (t

wic

e w

eekl

y sc

reen

ing

ultr

asou

nd),

blee

ding

Med

ian

12 d

(4

-54

d)V

TE

: 1 o

f 19

(5.3

%)

1 In

tern

al ju

gula

r ve

in th

rom

bosi

s,

1 m

ajor

and

1 m

inor

bl

eedi

ng

Ble

edin

g: 2

of 1

9 (1

0.5%

)

Coo

k et

al 36

/200

5Si

ngle

-cen

ter

pros

pect

ive

coho

rt26

1 m

edic

al-s

urgi

cal

ICU

pat

ient

sU

FH

5,0

00 I

nter

natio

nal

Uni

ts S

C b

idD

VT

det

ecte

d by

co

mpr

essi

on u

ltras

ound

on

adm

issi

on a

nd tw

ice

wee

kly

Unt

il IC

U

disc

harg

e, d

eath

or

dev

elop

men

t of

DV

T

Inci

dent

DV

T: 2

5 of

261

(9

.6%

; 95%

CI,

6.

3%-1

3.8%

)

Mos

t DV

T a

sym

ptom

atic

(n

ot c

linic

ally

sus

pect

ed)

CrC

l 5 cr

eatin

ine

clea

ranc

e. S

ee T

able

S1-

S5 a

nd S

11 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

Tabl

e S1

3—C

onti

nued




Tabl

e S1

4 —[S

ecti

on 3

.4.1

] E

vide

nce

Pro

fi le:

Sho

uld

UF

H v

s P

lace

bo

Be

Use

d fo

r D

VT

Pre

vent

ion

in C

riti

call

y Il

l A

dult

Pat

ient

s?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

N

o. o

f Pat

ient

sE

ffec

t

No.

of

Stud

ies

Des

ign

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

Con

side

ratio

nsU

FH

Plac

ebo

Rel

ativ

e (9

5% C

I)A

bsol

ute

Qua

lity

Sym

ptom

atic

DV

T (u

p to

28

d) a (

impo

rtan

t out

com

e)

1R

CT

Non

eN

one

Non

eSe

riou

s b N

one

26 o

f 498

(5.2

2%)

56 o

f 959

(5.8

4%)

RR

, 0.8

9 (0

.57-

1.41

)6

few

er p

er 1

,000

(f

rom

25

few

er to

24

mor

e)M

oder

ate

Sym

ptom

atic

PE

(up

to 2

8 d)

a (im

port

ant o

utco

me)

1R

CT

Non

eN

one

Seri

ous a

Seri

ous b

Non

e…

4.2%

RR

, 0.4

8 (0

.10-

2.26

)22

few

er p

er 1

,000

(f

rom

38

few

er to

53

mor

e)L

ow

Mor

talit

y (c

ritic

al o

utco

me)

No

data

……

……

……

……

……

…

Maj

or b

leed

ing

(impo

rtan

t out

com

e)

No

data

……

……

……

……

……

…

Bib

liogr

aphy

: Sh

orr

AF,

Will

iam

s M

D.

Veno

us t

hrom

boem

bolis

m i

n cr

itica

lly i

ll pa

tient

s. O

bser

vatio

ns f

rom

a r

ando

miz

ed t

rial

in

seps

is.

Thro

mb

Hae

mos

t. 20

09;1

01(1

):139

-144

. Se

e Ta

ble

S1 a

nd

S4 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a S

ympt

omat

ic D

VT

was

rep

orte

d in

Sho

rr a

nd W

illia

ms,

sym

ptom

atic

PE

was

not

rep

orte

d. T

here

fore

, we

estim

ated

PE

bas

elin

e ri

sk f

rom

obs

erva

tiona

l stu

dies

(4.

2%)

and

used

RR

fro

m S

horr

and

W

illia

ms,

whi

ch w

as li

kely

a m

ix o

f sym

ptom

atic

and

asy

mpt

omat

ic e

vent

s.

b Sm

all n

umbe

r of

pat

ient

s an

d sm

all n

umbe

r of

eve

nts

in e

ach

grou

p; C

I in

clud

e be

nefi t

and

har

m.




Tabl

e S1

5 — [S

ecti

on 3

.4.2

] E

vide

nce

Pro

fi le:

Sho

uld

LM

WH

vs

Pla

ceb

o B

e U

sed

for

DV

T P

reve

ntio

n in

Cri

tica

lly

Ill

Adu

lt P

atie

nts?

Set

ting

: IC

U

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

N

o. o

f Pat

ient

s (%

)E

ffec

t

No.

of

Stud

ies

Des

ign

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

Con

sider

atio

nsL

MW

HPl

aceb

oR

elat

ive

(95%

CI)

Abs

olut

e Q

ualit

y

Sym

ptom

atic

DV

T (5

-28

d) a

1R

CT

No

seri

ous

limita

tions

b N

one c

Non

eSe

riou

s d N

one

23 o

f 478

(4.8

1%)

56 o

f 959

(5.8

4%)

RR

, 0.8

2 (0

.51-

1.32

)9

few

er (f

rom

24

few

er

to15

mor

e)M

oder

ate

Impo

rtan

t

Sym

ptom

atic

PE

(5-2

8 d)

a

1R

CT

No

seri

ous

limita

tions

b N

one c

Seri

ous a

Very

se

riou

s d N

one

…4.

2 e R

R, 1

.01,

(0

.31-

3.31

)0

few

er (f

rom

29

few

er

to 9

7 m

ore)

Very

low

Impo

rtan

t

Maj

or b

leed

ing

(fol

low

-up

mea

n, 1

1.6

d)

1R

CT

No

seri

ous

limita

tions

b N

one c

No

seri

ous

indi

rect

ness

Very

se

riou

s d N

one f

6 of

108

(5.6

%)

3 of

113

(2.7

%)

RR

, 2.0

9 (0

.54

to 8

.16)

29 m

ore

per

1,00

0 (f

rom

12

few

er to

190

mor

e)Ve

ry lo

wIm

port

ant

Mor

talit

y (f

ollo

w-u

p m

ean,

11.

6 d)

1R

CT

No

seri

ous

limita

tions

b N

one c

No

seri

ous

indi

rect

ness

Very

se

riou

s d N

one f f

8 of

84

(9.5

%)

8 of

85

(9.4

%)

RR

, 1.0

1 (0

.4 to

2.5

7)1

mor

e pe

r 1,

000

(fro

m

56 fe

wer

to 1

48 m

ore)

Very

low

Cri

tical

Bib

liogr

aphy

: Fra

isse

F, H

olza

pfel

L, C

oula

nd J

M e

t al.

Nad

ropa

rin

in th

e pr

even

tion

of d

eep

vein

thro

mbo

sis

in a

cute

dec

ompe

nsat

ed C

OPD

. The

Ass

ocia

tion

of N

on-U

nive

rsity

Affi

liate

d In

tens

ive

Car

e Sp

ecia

list P

hysi

cian

s of

Fra

nce.

Am

J R

espi

r C

rit C

are

Med

. 200

0;16

1(4

pt 1

):110

9-11

14. S

horr

AF,

Will

iam

s M

D. V

enou

s th

rom

boem

bolis

m in

cri

tical

ly il

l pat

ient

s. O

bser

vatio

ns fr

om a

ran

dom

ized

tria

l in

sep

sis.

Thr

omb

Hae

mos

t . 20

09;1

01(1

):139

-144

. See

Tab

le S

1-S4

, S10

, and

S11

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Sym

ptom

atic

DV

T w

as r

epor

ted

in S

horr

and

Will

iam

s sy

mpt

omat

ic P

E w

as n

ot r

epor

ted

in S

horr

et a

l (ze

ro e

vent

s in

bot

h st

udy

arm

s by

Fra

isse

et a

l). T

here

fore

, we

estim

ated

PE

bas

elin

e ri

sk fr

om

obse

rvat

iona

l stu

dies

(4.2

%) a

nd u

sed

RR

from

Sho

rr a

nd W

illia

ms,

whi

ch w

as li

kely

a m

ix o

f sym

ptom

atic

and

asy

mpt

omat

ic e

vent

s.

b Bot

h st

udie

s do

uble

-blin

d, I

TT

ana

lysi

s. F

rais

se e

t al

: ven

ogra

phy

coul

d no

t be

per

form

ed in

52

of 2

21 (

23.5

%)

of p

atie

nts;

the

se p

atie

nts

wer

e ex

clud

ed f

rom

the

effi

cacy

ana

lysi

s. S

horr

and

Will

iam

s:

stud

y as

sess

ed e

ffi ca

cy o

f pr

ophy

lact

ic d

oses

of

LM

WH

/UF

H in

pat

ient

s w

ith s

ever

e se

psis

onl

y w

hile

rec

eivi

ng d

rotr

ecog

in a

lfa. F

rais

se e

t al

: stu

dy s

uppo

rted

by

a gr

ant

from

San

ofi (

man

ufac

ture

r of

na

drop

arin

). c C

linic

al h

eter

ogen

eity

of t

he tr

ials

: (1)

Fra

isse

et a

l: N

adro

pari

n do

sed

acco

rdin

g to

wei

ght (

3,80

0 un

its fo

r 45

-70

kg; 5

,700

uni

ts fo

r 71

-110

kg)

; Sho

rr a

nd W

illia

ms:

enox

apar

in 4

0 m

g SC

od;

(2) F

rais

se e

t al:

Patie

nts

with

CO

PD e

xace

rbat

ion

requ

irin

g m

echa

nica

l ven

tilat

ion;

Sho

rr a

nd W

illia

ms:

1,9

35 s

epsi

s pa

tient

s re

ceiv

ing

drot

reco

gin

alfa

; (3)

Met

hod

of D

VT

ass

essm

ent:

Fra

isse

et a

l: ve

nogr

aphy

at e

nd

of s

tudy

per

iod

(max

21

� 1

d);

Shor

r an

d W

illia

ms:

com

pres

sion

ultr

ason

ogra

phy

betw

een

days

4 a

nd 6

; and

(4)

Fra

isse

et

al: r

esul

ts f

rom

Dop

pler

ultr

ason

ogra

phy

and

veno

grap

hy w

as d

iscr

epan

t, bu

t no

furt

her

info

rmat

ion

was

pro

vide

d. V

enog

raph

y (a

t the

end

of t

he s

tudy

per

iod)

was

use

d to

ass

ess

effi c

acy

in th

is s

tudy

, but

ultr

ason

ogra

phy

was

per

form

ed b

efor

e in

clus

ion

and

wee

kly.

d S

mal

l num

ber

of p

atie

nts

and

smal

l num

ber

of e

vent

s in

eac

h gr

oup;

CI

incl

ude

bene

fi t a

nd h

arm

. The

RR

of

the

outc

ome

of P

E is

con

side

red

very

impr

ecis

e du

e to

sm

all n

umbe

r of

eve

nts

(4 o

f 47

8 L

MW

H v

s 8

of 9

59 p

lace

bo).

e No

dire

ct e

vide

nce

rega

rdin

g sy

mpt

omat

ic P

E. T

here

fore

, we

estim

ated

bas

elin

e ri

sk fr

om o

bser

vatio

nal s

tudi

es (4

.2%

) and

use

d R

R fr

om S

horr

and

Will

iam

s, w

hich

was

like

ly a

mix

of s

ympt

omat

ic a

nd

asym

ptom

atic

eve

nts.

f M

ajor

ble

edin

g an

d m

orta

lity

wer

e on

ly a

sses

sed

in F

rais

se e

t al (

adju

dica

ted

by in

depe

nden

t com

mitt

ee).

Ble

edin

g w

as d

efi n

ed a

s ov

ert,

asso

ciat

ed w

ith d

ecre

ase

in H

gb o

f . 2

g/d

L, p

acke

d R

BC

tran

s-fu

sion

, ret

rope

rito

neal

or

intr

acra

nial

or

resu

lted

in d

isco

ntin

uatio

n of

pro

phyl

axis

. Mor

talit

y w

as m

ainl

y du

e to

car

diov

ascu

lar

com

plic

atio

ns a

ssoc

iate

d w

ith in

fect

ion

(not

due

to b

leed

ing)

.




Tabl

e S1

6 —[S

ecti

on 3

.4.3

] E

vide

nce

Pro

fi le:

Sho

uld

Any

Hep

arin

(L

DU

H o

r L

MW

H)

vs P

lace

bo

Be

Use

d fo

r D

VT

Pro

phyl

axis

in

Cri

tica

lly

Ill

Adu

lt P

atie

nts?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

N

o. o

f Pat

ient

s (%

)E

ffec

t

No.

of

Stud

ies

Des

ign

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

Con

side

ratio

nsL

MW

H o

r L

DU

FH

a Pl

aceb

oR

elat

ive

(95%

CI)

Abs

olut

eQ

ualit

y

Sym

ptom

atic

DV

T (5

-28

d) b

1R

CT

No

seri

ous

limita

tions

c N

one

Non

eSe

riou

s d N

one

49 o

f 976

(5.0

%)

56 o

f 959

(5.8

%)

RR

, 0.8

6 (0

.59-

1.25

)4

few

er p

er 1

,000

(f

rom

12

few

er to

8 m

ore)

Mod

erat

eIm

port

ant

Sym

ptom

atic

PE

(5-2

8 d)

e

1R

CT

No

seri

ous

limita

tions

c N

one

Seri

ous e

Seri

ous d

Non

e…

4.2%

RR

, 0.7

3 (0

.26-

2.1

1)11

few

er p

er 1

,000

(f

rom

31

few

er to

47

mor

e)L

owIm

port

ant

Maj

or b

leed

ing

(fol

low

-up

mea

n, 1

1.6

d) f

1R

CT

No

seri

ous

limita

tions

c N

one

No

seri

ous

indi

rect

ness

Very

se

riou

s d N

one f

6 of

108

(5.6

%)

3 of

113

(2.7

%)

RR

, 2.0

9 (0

.54

to 8

.16)

29 m

ore

per

1,00

0 (f

rom

12

few

er to

190

mor

e)Ve

ry lo

wIm

port

ant

Mor

talit

y (f

ollo

w-u

p m

ean,

11.

6 d)

f

1R

CT

No

seri

ous

limita

tions

c N

one

No

seri

ous

indi

rect

ness

Very

se

riou

s d N

one f

8 of

84

(9.5

%)

8 of

85

(9.4

%)

RR

, 1.0

1 (0

.4 to

2.5

7)1

mor

e pe

r 1,

000

(fro

m 5

6 fe

wer

to 1

48 m

ore)

Very

low

Cri

tical

Bib

liogr

aphy

: Sho

rr A

F, W

illia

ms

MD

. Ven

ous

thro

mbo

embo

lism

in c

ritic

ally

ill p

atie

nts.

Obs

erva

tions

fro

m a

ran

dom

ized

tri

al in

sep

sis.

Thr

omb

Hae

mos

t . 20

09;1

01(1

):139

-144

. Fra

isse

F, H

olza

pfel

L,

Cou

land

JM

, et

al. N

adro

pari

n in

the

pre

vent

ion

of d

eep

vein

thr

ombo

sis

in a

cute

dec

ompe

nsat

ed C

OPD

. The

Ass

ocia

tion

of N

on-U

nive

rsity

Affi

liate

d In

tens

ive

Car

e Sp

ecia

list

Phys

icia

ns o

f F

ranc

e.

Am

J R

espi

r C

rit C

are

Med

. 200

0;16

1(4

pt 1

):110

9-11

14. S

ee T

able

S1-

S5 a

nd S

11 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a I

nclu

des

LM

WH

(eno

xapa

rin

40 m

g od

, nad

ropa

rin

base

d on

wei

ght o

d) a

nd u

nfra

ctio

nate

d he

pari

n 5,

000

units

bid

. b D

ata

are

only

ava

ilabl

e on

sym

ptom

atic

DV

T fr

om S

horr

and

Will

iam

s.

c We

did

not r

ate

evid

ence

dow

n fo

r m

etho

dolo

gica

l lim

itatio

ns o

r in

cons

iste

ncy,

alth

ough

ther

e w

ere

som

e po

ssib

le d

efi c

ienc

ies

in th

ese

area

s. S

horr

and

Will

iam

s: p

roph

ylax

is fo

llow

ing

6 d

was

left

to th

e di

scre

tion

of th

e ph

ysic

ian;

Fra

isse

et a

l and

Cad

e: u

ncle

ar d

escr

iptio

n of

ran

dom

izat

ion

and

allo

catio

n co

ncea

lmen

t, an

d th

ere

may

be

poss

ible

clin

ical

(not

sta

tistic

al) h

eter

ogen

eity

in th

e pa

tient

pop

ula-

tions

: sep

sis

patie

nts

rece

ivin

g dr

otre

cogi

n al

fa (S

horr

and

Will

imas

), pa

tient

s w

ith C

OPD

req

uiri

ng v

entil

atio

n (F

rais

se e

t al),

gen

eral

IC

U (C

ade)

; and

in th

e m

etho

ds o

f DV

T a

scer

tain

men

t: co

mpr

essi

on

ultr

asou

nd (S

horr

and

Will

iam

s), v

enog

raph

y (F

rais

se e

t al);

125 I

fi br

inog

en le

g sc

anni

ng (C

ade)

; Sho

rr a

nd W

illia

ms:

28-

d tr

eatm

ent p

erio

d; F

rais

se e

t al:

11.6

-d m

ean

dura

tion

of tr

eatm

ent;

Cad

e: 7

.7 m

ean

days

of l

eg s

cann

ing.

d R

elat

ivel

y sm

all n

umbe

r of

pat

ient

s an

d sm

all n

umbe

r of

eve

nts

in e

ach

grou

p; C

Is in

clud

e be

nefi t

and

har

m.

e No

dire

ct e

vide

nce

rega

rdin

g sy

mpt

omat

ic P

E. T

here

fore

, we

estim

ated

PE

bas

elin

e ri

sk fr

om o

bser

vatio

nal s

tudi

es (4

.2%

) and

use

d R

R fr

om S

horr

and

Will

iam

s, w

hich

was

like

ly a

mix

of s

ympt

omat

ic

and

asym

ptom

atic

eve

nts.

f M

ajor

ble

edin

g an

d m

orta

lity

wer

e on

ly a

sses

sed

in F

rais

se e

t al.




Tabl

e S1

7 —[S

ecti

on 3

.4.4

] E

vide

nce

Pro

fi le:

Sho

uld

LM

WH

vs

UF

H B

e U

sed

for

DV

T P

reve

ntio

n in

Cri

tica

lly

Ill

Adu

lt P

atie

nts?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

N

o. o

f Pat

ient

sE

ffec

t

No.

of

Stud

ies a

Des

ign

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

Con

sider

atio

nsL

MW

HU

FH

Rel

ativ

e (9

5% C

I)A

bsol

ute

Qua

lity

Sym

ptom

atic

DV

T (f

ollo

w-u

p 7-

28 d

) b

2R

CT

Non

e c N

o se

riou

s in

cons

iste

ncy

Non

eSe

riou

s d N

one

51 o

f 2,3

51 (2

.2%

)60

of 2

,371

(2.5

%)

RR

, 0.8

7 (0

.60-

1.25

) e 3

few

er p

er 1

,000

(f

rom

10

few

er to

6 m

ore)

Mod

erat

eIm

port

ant

Sym

ptom

atic

PE

(fol

low

-up

7-28

d)

1R

CT

Non

e c N

o se

riou

s in

cons

iste

ncy

Non

eSe

riou

s d N

one

22 o

f 1,8

73 (1

.2%

)38

of 1

,873

(2.0

%)

RR

, 0.5

8 (0

.34-

0.97

)8

few

er p

er 1

,000

(1

3.2

few

er to

0.6

few

er)

Mod

erat

eIm

port

ant

Maj

or b

leed

ing

(fol

low

-up

7-47

d)

2 f R

CT

Non

e c N

o se

riou

s in

cons

iste

ncy

Non

eSe

riou

s d N

one

104

of 1

,954

(5.3

%)

107

of 1

,948

(5.5

%)

RR

, 0.9

7 (0

.75-

1.26

) e 2

few

er p

er 1

,000

(f

rom

14

few

er to

14

mor

e)M

oder

ate

Impo

rtan

t

Mor

talit

y (f

ollo

w-u

p 7-

47 d

)

2R

CT

Non

e c N

o se

riou

s in

cons

iste

ncy

Non

eSe

riou

s d N

one

293

of 1

,954

(15.

0%)

310

of 1

,948

(15.

9%)

RR

, 0.9

4 (0

.81-

1.09

) e 10

few

er p

er 1

,000

(f

rom

30

few

er to

14

mor

e)M

oder

ate

Cri

tical

HIT

(7 d

)

1R

CT

Non

e c N

o se

riou

s in

cons

iste

ncy

Non

eSe

riou

s d N

one

5 of

1,8

73 (0

.3%

)12

of 1

,873

(0.6

%)

RR

, 0.4

2 (0

.15-

1.18

)3

few

er p

er 1

,000

(f

rom

5 fe

wer

to 1

mor

e)M

oder

ate

Impo

rtan

t

Bib

liogr

aphy

: PR

OT

EC

T I

nves

tigat

ors.

Dal

tepa

rin

vs u

nfra

ctio

nate

d he

pari

n in

cri

tical

ly il

l pat

ient

s. N

Eng

l J M

ed . 2

011;

364(

14):1

305-

1314

. Sho

rr A

F, W

illia

ms M

D. V

enou

s thr

ombo

embo

lism

in c

ritic

ally

ill

pat

ient

s. O

bser

vatio

ns fr

om a

ran

dom

ized

tria

l in

seps

is. T

hrom

b H

aem

ost.

2009

;101

(1):1

39-1

44. D

e A

, Roy

P, G

arg

VK

et a

l. L

ow-m

olec

ular

-wei

ght h

epar

in a

nd u

nfra

ctio

nate

d he

pari

n in

pro

phyl

axis

ag

ains

t dee

p ve

in th

rom

bosi

s in

cri

tical

ly il

l pat

ient

s un

derg

oing

maj

or s

urge

ry. B

lood

Coa

gul F

ibri

noly

sis .

201

0;21

(1):5

7-61

. IQ

R 5

inte

rqua

rtile

ran

ge. S

ee T

able

S1-

S5 a

nd S

11 le

gend

s fo

r ex

pans

ion

of

othe

r ab

brev

iatio

ns.

a The

out

com

e of

sym

ptom

atic

PE

was

rep

orte

d in

PR

OT

EC

T a

nd th

e ou

tcom

e of

sym

ptom

atic

DV

T w

as r

epor

ted

in P

RO

TE

CT

and

Sho

rr a

nd W

illia

ms

stud

ies.

The

out

com

es o

f ble

edin

g an

d m

orta

lity

wer

e re

port

ed in

PR

OT

EC

T a

nd D

e et

al s

tudi

es. T

he o

utco

me

of H

IT w

as re

port

ed in

PR

OT

EC

T. T

he in

terv

entio

ns w

ere:

PR

OT

EC

T: d

alte

pari

n 5,

000

Inte

rnat

iona

l Uni

ts S

C o

d; S

horr

and

Will

iam

s and

D

e et

al:

enox

apar

in 4

0 m

g SC

od;

UF

H 5

,000

uni

ts S

C b

id; a

nd a

ll st

udie

s inc

lude

d pl

aceb

o in

ject

ion.

PR

OT

EC

T: c

ompr

essi

on u

ltras

ound

per

form

ed w

ithin

2 d

of I

CU

adm

issi

on th

en tw

ice

wee

kly

whi

le

in I

CU

; Sho

rr a

nd W

illia

ms:

com

pres

sion

ultr

asou

nd p

erfo

rmed

bet

wee

n da

y 4

and

6 of

dro

trec

ogin

alfa

trea

tmen

t; D

e et

al:

Dop

pler

per

form

ed b

etw

een

post

oper

ativ

e da

y 5

and

7. P

opul

atio

n: P

RO

TE

CT:

3,

764

patie

nts

expe

cted

to r

emai

n in

IC

U a

t lea

st 3

d; S

horr

and

Will

iam

s: 1

,935

sep

sis

patie

nts

rece

ivin

g dr

otre

cogi

n al

fa; D

e et

al:

156

patie

nts

unde

rgoi

ng m

ajor

sur

gery

req

uiri

ng a

t lea

st 2

4 h

in I

CU

. b P

RO

TE

CT:

Med

ian

dura

tion

of s

tudy

per

iod:

7 d

(IQ

R 4

-12

d); S

horr

and

Will

iam

s: 2

8-d

stud

y pe

riod

; De

et a

l: M

edia

n fo

llow

-up:

47

d.

c De

et a

l: U

ncle

ar d

escr

iptio

n of

ran

dom

izat

ion

proc

ess,

blin

ding

, and

loss

es to

follo

w-u

p. P

RO

TE

CT

had

ade

quat

e bi

as p

rote

ctio

n m

easu

res.

d R

elat

ivel

y sm

all n

umbe

r of

eve

nts

and

wid

e C

Is th

at in

clud

e be

nefi t

and

har

m.

e Fix

ed e

ffec

t mod

el u

sed

for

met

a-an

alys

is.

f Maj

or b

leed

ing

defi n

ition

: PR

OT

EC

T: h

emor

rhag

e at

a c

ritic

al si

te, b

leed

ing

resu

lting

in n

eed

for t

hera

peut

ic in

terv

entio

n, c

ausi

ng h

emod

ynam

ic c

ompr

omis

e, re

quir

ing

2 un

its tr

ansf

usio

n or

resu

lting

in

deat

h. D

e et

al:

GI

blee

ding

dia

gnos

ed o

n st

ool t

estin

g or

upp

er G

I en

dosc

opy

or a

ny b

leed

ing

epis

ode

requ

irin

g re

oper

atio

n.




Tabl

e S1

8 —[S

ecti

on 4

.2]

Evi

denc

e P

rofi l

e: S

hou

ld H

epar

in v

s N

o H

epar

in B

e U

sed

in P

atie

nts

Wit

h C

ance

r W

ho H

ave

No

Oth

er T

hera

peu

tic

or P

roph

ylac

tic

Indi

cati

on f

or A

ntic

oagu

lati

on?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

N

o. o

f Pat

ient

sE

ffec

t

No.

of

Stud

ies

Des

ign

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

Con

sider

atio

nsH

epar

inN

o H

epar

in, %

Rel

ativ

e (9

5% C

I)A

bsol

ute

Qua

lity

Mor

talit

y (f

ollo

w-u

p, 1

2 m

o) a

8R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

ns b

Seri

ous c

No

seri

ous

indi

rect

ness

No

seri

ous

impr

ecis

ion d

Non

e73

5 of

1,4

64 (5

0.2%

)64

.9 e

RR

, 0.9

3 (0

.85-

1.02

)45

few

er p

er 1

,000

(f

rom

97

few

er to

13

mor

e)

Mod

erat

eIm

port

ant

Sym

ptom

atic

VT

E (f

ollo

w-u

p, 1

2 m

o)

7R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

ns b

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssN

o se

riou

s im

prec

isio

nN

one

38 o

f 1,3

38 (2

.8%

)2.

9 e R

R, 0

.55

(0.3

7-0.

82)

13 fe

wer

per

1,0

00

(fro

m 5

few

er to

18

few

er)

Hig

hC

ritic

al

Maj

or b

leed

ing

(fol

low

-up,

12

mo)

9R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

ns b

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s f N

one

30 o

f 1,6

24 (1

.8%

)0.

7 b R

R, 1

.3

(0.5

9-2.

88)

2 m

ore

per

1,00

0 (f

rom

3 fe

wer

to

13 m

ore)

Mod

erat

eIm

port

ant

Min

or b

leed

ing

(fol

low

-up,

12

wk)

7R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

ns b

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s f N

one

85 o

f 1,3

65 (6

.2%

)2.

7 e R

R, 1

.05

(0.7

5-1.

46)

1 m

ore

per

1,00

0 (f

rom

7 fe

wer

to

12 m

ore)

Mod

erat

eN

ot im

port

ant

Hea

lth-r

elat

ed q

ualit

y of

life

(fol

low

-up,

12

mo;

the

Uni

scal

e an

d th

e Sy

mpt

om D

istr

ess

Scal

e; b

ette

r in

dica

ted

by lo

wer

val

ues)

1R

ando

miz

ed

tria

lsSe

riou

s g N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous g

Non

eN

ot estim

able

h L

owIm

port

ant

Bib

liogr

aphy

: Akl

EA

, Gun

ukul

a SK

, van

Doo

rmaa

l FF,

et a

l. Pa

rent

eral

ant

icoa

gula

tion

in p

atie

nts

with

can

cer

who

hav

e no

ther

apeu

tic o

r pr

ophy

lact

ic in

dica

tion

for

antic

oagu

latio

n. C

ochr

ane

Dat

abas

e Sy

st R

ev . 2

011;

(4)C

D00

6652

. See

Tab

le S

4 le

gend

for

expa

nsio

n of

abb

revi

atio

n.

a The

out

com

es a

re r

epor

ted

at 1

2-m

o fo

llow

-up.

Mor

talit

y at

2-y

follo

w-u

p in

crea

ses

from

65%

to 8

6%.

b Vas

t m

ajor

ity o

f st

udie

s ha

d al

loca

tion

conc

ealm

ent

and

used

blin

ded

outc

ome

and

adju

dica

tion.

We

did

not

dow

ngra

de, a

lthou

gh t

here

was

som

e co

ncer

n ab

out

lack

of

blin

ding

in s

ome

stud

ies;

the

ov

eral

l ris

k of

bia

s w

as b

elie

ved

to b

e ve

ry lo

w.

c The

re is

mod

erat

e he

tero

gene

ity a

mon

g st

udie

s inc

lude

d in

the

anal

ysis

of d

eath

at 1

2 m

o ( I

2 5 4

1%).

The

subg

roup

ana

lysi

s for

mor

talit

y at

12

mo

was

stat

istic

ally

sign

ifi ca

nt a

nd su

gges

ted

surv

ival

ben

efi t

in p

atie

nts

with

sm

all c

ell l

ung

canc

er b

ut n

ot in

pat

ient

s w

ith a

dvan

ced

canc

er. O

vera

ll w

e de

cide

d to

dow

ngra

de b

y on

e le

vel w

hen

cons

ider

ing

thes

e is

sues

alo

ng w

ith im

prec

isio

n.

d CI

inte

rval

incl

udes

eff

ects

sug

gest

ing

bene

fi t a

s w

ell a

s no

ben

efi t.

e B

asel

ine

risk

is th

e m

edia

n of

ris

k in

con

trol

gro

ups

of tr

ials

incl

uded

in th

e sy

stem

atic

rev

iew

. f C

I in

clud

es p

ossi

bilit

y of

bot

h ha

rms

or b

enefi

ts.

g Hig

h ri

sk o

f bia

s an

d on

ly 1

38 p

atie

nts

enro

lled.

h T

he s

core

s fo

r th

e tw

o sc

ales

wer

e si

mila

r fo

r th

e tw

o st

udy

grou

ps, b

oth

at b

asel

ine

and

at fo

llow

-up.




Tabl

e S1

9 —[S

ecti

on 4

.3]

Evi

denc

e P

rofi l

e: S

hou

ld O

ral

Ant

icoa

gula

tion

Be

Use

d in

Pat

ient

s W

ith

Can

cer

Wit

h N

o T

hera

peu

tic

or P

roph

ylac

tic

Indi

cati

on f

or

Ant

icoa

gula

tion

?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

N

o. o

f Pat

ient

sE

ffec

t

No.

of

Stud

ies

Des

ign

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

Con

side

ratio

nsO

ral

Ant

icoa

gula

tion

Con

trol

, %R

elat

ive

(95%

CI)

Abs

olut

e Q

ualit

y

Mor

talit

y (f

ollo

w-u

p m

edia

n, 1

y)

5R

ando

miz

ed

tria

lsSe

riou

s a N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

No

seri

ous

impr

ecis

ion

Non

e36

0 of

80

1 (4

4.9%

)64

.9 b

RR

, 0.9

4 (0

.87-

1.03

)39

few

er p

er 1

,000

(f

rom

84

few

er

to 1

9 m

ore)

Mod

erat

eIm

port

ant

Sym

ptom

atic

VT

E (f

ollo

w-u

p, 1

y)

1R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

nsN

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous c

Non

e1

of 1

54

(0.6

%)

2.9 b

RR

, 0.1

5 (0

.02-

1.2)

25 fe

wer

per

1,0

00

(fro

m 2

8 fe

wer

to

6 m

ore)

Mod

erat

eIm

port

ant

Maj

or b

leed

ing

(fol

low

-up,

med

ian

1 y)

4R

ando

miz

ed

tria

lsSe

riou

s d N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

No

seri

ous

impr

ecis

ion

Non

e72

of 6

50 (1

1.1%

)0.

7 b R

R, 4

.24

(1.8

5-9.

68)

23 m

ore

per

1,00

0 (f

rom

6 m

ore

to 6

1 m

ore)

Mod

erat

eIm

port

ant

Hea

lth-r

elat

ed q

ualit

y of

life

: not

rep

orte

d

0…

……

……

Non

e0

of 0

(0%

)0

……

Impo

rtan

t B

iblio

grap

hy: A

kl E

A, V

asir

eddi

S, G

unuk

ula

S, e

t al.

Ora

l ant

icoa

gula

tion

for

prol

ongi

ng s

urvi

val i

n pa

tient

s w

ith c

ance

r. C

ochr

ane

Dat

abas

e Sy

st R

ev . 2

010;

(12)

:CD

0064

66.

a We

dow

ngra

ded

beca

use

lack

of b

lindi

ng o

f pat

ient

s an

d pr

ovid

ers

in fo

ur o

ut o

f fi v

e st

udie

s; it

was

unc

lear

whe

ther

allo

catio

n w

as c

once

aled

in tw

o st

udie

s; a

nd o

nly

one

stud

y cl

earl

y us

ed I

TT

ana

lysi

s.

All

stud

ies

used

war

fari

n at

a d

ose

to in

crea

se P

T 1

.5 to

2 ti

mes

(fou

r st

udie

s) o

r to

kee

p IN

R b

etw

een

1.3

and

1.9.

See

Tab

les

S4 a

nd S

10 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. b B

asel

ine

risk

is th

e m

edia

n of

ris

k in

con

trol

gro

ups

of tr

ials

incl

uded

in a

sys

tem

atic

rev

iew

of t

he e

ffec

ts o

f par

ente

ral a

ntic

oagu

latio

n in

pat

ient

s w

ith c

ance

r bu

t no

prop

hyla

ctic

or

ther

apeu

tic in

dica

tion

for

antic

oagu

latio

n (A

kl e

t al).

c W

e do

wng

rade

d be

caus

e th

e pr

ecis

ion

of th

e es

timat

e do

es n

ot e

xclu

de a

pat

ient

impo

rtan

t ben

efi t

(the

low

er li

mit

of R

R s

till s

ugge

sts

a be

nefi t

that

mig

ht b

e re

leva

nt g

iven

the

high

bas

elin

e ri

sk).

d We

dow

ngra

ded

beca

use

lack

of

blin

ding

of

patie

nts

and

prov

ider

s in

thr

ee o

ut o

f fo

ur s

tudi

es; i

t w

as u

ncle

ar w

heth

er a

lloca

tion

was

con

ceal

ed i

n tw

o st

udie

s; a

nd o

nly

one

stud

y cl

earl

y us

ed I

TT

an

alys

is.




Tabl

e S2

0 —[S

ecti

on 4

.4]

Evi

denc

e P

rofi l

e: S

hou

ld H

epar

in v

s N

o H

epar

in B

e U

sed

for

Thr

omb

osis

Pro

phyl

axis

in

Pat

ient

s W

ith

Can

cer

Wit

h C

VC

s?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

N

o. o

f Pat

ient

sE

ffec

t

Qua

lity

No.

of S

tudi

esD

esig

nL

imita

tions

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

C

onsid

erat

ions

Hep

arin

No

Hep

arin

Rel

ativ

e (9

5% C

I)A

bsol

ute

Mor

talit

y

5R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

ns a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s b , c N

one

31 o

f 67

1 (4

.6%

)34

of

521

(6.5

%)

RR

, 0.8

5 (0

.53-

1.37

)10

few

er

per

1,00

0 (f

rom

31

few

er

to 2

4 m

ore)

Mod

erat

eC

ritic

al

Sym

ptom

atic

DV

T

6R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

ns a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s b , c

Non

e17

of

664

(2.6

%)

25 o

f 50

9 (4

.9%

)R

R, 0

.54

(0.2

8-1.

05)

23 fe

wer

pe

r 1,

000

(fro

m 3

5 fe

wer

to

2 m

ore)

Mod

erat

eC

ritic

al

Maj

or b

leed

ing

4R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

ns a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s b , c

Non

e2

of 520

(0.4

%)

2 of

371

(0.5

%)

RR

, 0.6

8 (0

.1-4

.78)

2 fe

wer

pe

r 1,

000

(fro

m 5

few

er

to 2

0 m

ore)

Mod

erat

eC

ritic

al

Infe

ctio

n

3R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

ns a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s b N

one

21 o

f 38

8 (5

.4%

)17

of

238

(7.1

%)

RR

, 0.9

1 (0

.49-

1.68

)6

few

er

per

1,00

0 (f

rom

36

few

er

to 4

9 m

ore)

Mod

erat

eIm

port

ant

Thr

ombo

cyto

peni

a

3R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

ns a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s b , c

Non

e28

of

490

(5.7

%)

23 o

f 34

6 (6

.6%

)R

R, 0

.85

(0.4

9-1.

46)

10 fe

wer

pe

r 1,

000

(fro

m 3

4 fe

wer

to

31

mor

e)

Mod

erat

eN

ot im

port

ant

Qua

lity

of li

fe: n

ot r

epor

ted

0…

……

……

Non

e0

of 0

(0%

)0

of 0

(0%

)…

…Im

port

ant

Bib

liogr

aphy

: Akl

EA

, Vas

ired

di S

R, Y

osui

co V

E, B

arba

M, S

pera

ti F,

Coo

k D

, Sch

ünem

ann

H. A

ntic

oagu

latio

n fo

r th

rom

bosi

s pr

ophy

laxi

s in

can

cer

patie

nts

with

cen

tral

ven

ous

cath

eter

s. C

ochr

ane

Dat

abas

e Sy

st R

ev . 2

011;

4:C

D00

6468

. See

Tab

le S

4 an

d S1

2 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a A

lloca

tion

clea

rly

conc

eale

d in

thre

e of

the

six

stud

ies.

Fou

r stu

dies

blin

ded

patie

nts a

nd p

rovi

ders

and

all

stud

ies b

linde

d ou

tcom

e ad

judi

cato

rs. T

hree

stud

ies h

ad n

o pr

oble

m w

ith in

com

plet

e da

ta. N

one

of th

e st

udie

s w

as s

uspe

cted

of s

elec

tive

repo

rtin

g. T

wo

stud

ies

clea

rly

used

IT

T.

b Rel

ativ

ely

smal

l num

ber

of e

vent

s.

c CI

incl

udes

bot

h va

lues

sug

gest

ing

no e

ffec

t and

val

ues

sugg

estin

g ei

ther

ben

efi t

or h

arm

.




Tabl

e S2

1 —[S

ecti

on 4

.5]

Evi

denc

e P

rofi l

e: S

hou

ld V

KA

vs

No

VK

A B

e U

sed

for

Thr

omb

osis

Pro

phyl

axis

in

Pat

ient

s W

ith

Can

cer

Wit

h C

VC

s?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

N

o. o

f Pat

ient

sE

ffec

t

Qua

lity

No.

of S

tudi

esD

esig

nL

imita

tions

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

C

onsi

dera

tions

VK

AN

o V

KA

Rel

ativ

e (9

5% C

I)A

bsol

ute

Mor

talit

y

2R

ando

miz

ed

tria

lsN

one a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s b N

one

166

of

551

(30.

1%)

169

of

542

(31.

2%)

RR

, 0.9

7 (0

.82-

1.15

)9

few

er

per

1,00

0 (f

rom

56

few

er

to 4

7 m

ore)

Mod

erat

eC

ritic

al

Sym

ptom

atic

DV

T

4R

ando

miz

ed

tria

lsN

one a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s b , c

Non

e37

of

621

(6%

)55

of

614

(9%

)R

R, 0

.63

(0.3

5-1.

11)

33 fe

wer

pe

r 1,

000

(fro

m 5

8 fe

wer

to

10

mor

e)

Mod

erat

eC

ritic

al

Maj

or b

leed

ing

2R

ando

miz

ed

tria

lsN

one a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s b , c

Non

e7

of 551

(1.3

%)

1 of

542

(0.2

%)

RR

, 6.9

3 (0

.86-

56.0

8)11

mor

e pe

r 1,

000

(fro

m 0

few

er

to 1

02 m

ore)

Mod

erat

eC

ritic

al

Indi

rect

ev

iden

ce e

Hig

h

Bib

liogr

aphy

: Akl

EA

, Vas

ired

di S

R, Y

osui

co V

E B

arba

M, S

pera

ti F,

Coo

k D

, Sch

ünem

ann

H. A

ntic

oagu

latio

n fo

r thr

ombo

sis p

roph

ylax

is in

can

cer p

atie

nts w

ith c

entr

al v

enou

s cat

hete

rs. C

ochr

ane

Dat

abas

e Sy

st R

ev . 2

011;

4:C

D00

6468

. VK

A 5

vita

min

K a

ntag

onis

t. Se

e Ta

ble

S4 a

nd S

10 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a Allo

catio

n cl

earl

y co

ncea

led

in t

hree

of

four

stu

dies

. Non

e of

stu

dies

blin

ded

patie

nts,

pro

vide

rs, o

r da

ta c

olle

ctor

s, a

nd t

hree

stu

dies

blin

ded

outc

ome

adju

dica

tors

. Thr

ee s

tudi

es h

ad n

o pr

oble

m w

ith

inco

mpl

ete

data

. The

pre

senc

e of

sel

ectiv

e re

port

ing

was

unc

lear

in o

ne s

tudy

. Tw

o st

udie

s cl

earl

y us

ed I

TT.

b R

elat

ivel

y sm

all n

umbe

r of

eve

nts.

c C

I in

clud

es b

oth

valu

es s

ugge

stin

g no

eff

ect a

nd v

alue

s su

gges

ting

eith

er b

enefi

t or

har

m.

d Alth

ough

dat

a in

this

pop

ulat

ion

are

of lo

wer

qua

lity,

indi

rect

dat

a fr

om m

any

othe

r po

pula

tions

that

use

d V

KA

dem

onst

rate

hig

h-qu

ality

evi

denc

e.




Tabl

e S2

2 —[S

ecti

on 4

.6]

Evi

denc

e P

rofi l

e: S

hou

ld L

MW

H v

s V

KA

Be

Use

d fo

r T

hrom

bos

is P

roph

ylax

is i

n P

atie

nts

Wit

h C

ance

r W

ith

CV

Cs?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

No.

of P

atie

nts

Eff

ect

Qua

lity

No.

of S

tudi

esD

esig

nL

imita

tions

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

C

onsi

dera

tions

LM

WH

VK

AR

elat

ive

(95%

CI)

A

bsol

ute

2R

ando

miz

ed

tria

lsSe

riou

s a N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous b ,

c N

one

22 o

f 170

(1

2.9%

)19

of 1

73 (1

1%)

RR

, 1.2

7 (0

.55-

2.96

)30

mor

e pe

r 1,

000

(fro

m

49 fe

wer

to

215

mor

e)

Low

Cri

tical

Sym

ptom

atic

DV

T

2R

ando

miz

ed

tria

lsSe

riou

s a N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous b ,

c N

one

4 of

142

(2.8

%)

3 of

138

(2.2

%)

RR

, 1.2

8 (0

.25-

6.5)

6 m

ore

per

1,00

0 (f

rom

16

few

er to

12

0 m

ore)

Low

Cri

tical

Maj

or b

leed

ing

2R

ando

miz

ed

tria

lsSe

riou

s a N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous b ,

c N

one

1 of

170

(0.6

%)

0 of

173

(0%

)R

R, 3

.1 (0

.13-

73.1

4)0

mor

e pe

r 1,

000

(fro

m

0 fe

wer

to 0

m

ore)

Low

Cri

tical

Thr

ombo

cyto

peni

a

1R

ando

miz

ed

tria

lsSe

riou

s a N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous b ,

c N

one

2 of

29

(6.9

%)

0 of

30

(0%

)R

R, 5

.17

(0.2

6-10

3.21

)0

mor

e pe

r 1,

000

(fro

m

0 fe

wer

to 0

m

ore)

Low

Not

impo

rtan

t

Qua

lity

of li

fe -

not r

epor

ted

0…

……

……

Non

e0

of 0

(0%

)0

of 0

(0%

)…

…Im

port

ant

Bib

liogr

aphy

: Akl

EA

, Vas

ired

di S

R, Y

osui

co V

E D

, Bar

ba M

, Spe

rati

F, C

ook

D, S

chün

eman

n H

. Ant

icoa

gula

tion

for

thro

mbo

sis

prop

hyla

xis

in c

ance

r pa

tient

s w

ith c

entr

al v

enou

s ca

thet

ers.

Coc

hran

e D

atab

ase

Syst

Rev

. 201

1;4:

CD

0064

68. S

ee T

able

S2,

S4,

S10

, S12

, and

S21

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

. a A

lloca

tion

clea

rly

conc

eale

d in

one

of t

he tw

o st

udie

s. N

one

of th

e st

udie

s bl

inde

d pa

tient

s, p

rovi

ders

, or

data

col

lect

ors,

but

bot

h st

udie

s bl

inde

d ou

tcom

e ad

judi

cato

rs. O

ne s

tudy

did

not

add

ress

Inc

om-

plet

e da

ta r

epor

ting.

Non

e of

the

stud

ies

was

sus

pect

ed o

f sel

ectiv

e re

port

ing.

One

stu

dy c

lear

ly u

sed

ITT.

b R

elat

ivel

y sm

all n

umbe

r of

eve

nts.

c C

I in

clud

es b

oth

valu

es s

ugge

stin

g no

eff

ect a

nd v

alue

s su

gges

ting

eith

er b

enefi

t or

har

m.




Tabl

e S2

3 —O

bse

rvat

iona

l St

udi

es o

f O

utp

atie

nts

wit

h R

estr

icte

d M

obil

ity

and

Nu

rsin

g H

ome

Pat

ient

s

Stud

y/Ye

arTy

pe o

f Stu

dyPa

rtic

ipan

tsIn

terv

entio

nO

utco

mes

Fol

low

-up

Res

ults

Lab

arèr

e et

al 45

/200

9Tw

o cr

oss-

sect

iona

l st

udie

s (B

osso

n et

al47

an

d Se

llier

et a

l46) a

t 50

pos

t-ac

ute

care

fa

cilit

ies

in F

ranc

e

� 6

5 y;

866

LM

WH

and

73

7 no

n-L

MW

HPr

ophy

lact

ic-d

ose

LM

WH

vs

no

LM

WH

(32%

re

ceiv

ed

antip

late

let)

Prox

imal

DV

T b

y sc

reen

ing

ultr

asou

ndN

A; c

ross

-sec

tiona

l st

udy

Prox

imal

DV

T r

educ

ed b

y L

MW

H fr

om 5

.7%

to

4.0%

( P 5

.16)

; pro

pens

ity

anal

ysis

OR

, 0.5

6 ( P

5 .0

3)

Selli

er e

t al 46

/200

8C

ross

-sec

tiona

l stu

dy o

f 40

hos

pita

l-bas

ed

post

-acu

te c

are

faci

litie

s in

Fra

nce

812

Patie

nts

aged

� 6

5 y

Non

ePr

oxim

al D

VT

by

scre

enin

g ul

tras

ound

NA

; cro

ss-s

ectio

nal

stud

yD

VT:

113

of 8

12 (1

4%);

33

(4%

) had

pro

xim

al D

VT;

in

depe

nden

t ris

k fa

ctor

s ag

e .

80

y (O

R, 1

.71)

, pr

evio

us V

TE

(OR

, 2.0

3),

regi

onal

/met

asta

tic c

ance

r (2

.71)

, dep

ende

nt in

� 3

A

DL

(2.1

8), p

ress

ure

ulce

r (1

.85)

Bos

son

et a

l 47 /2

003

Cro

ss-s

ectio

nal s

tudy

of

36 h

ospi

tal-b

ased

pos

t-ac

ute

care

faci

litie

s in

F

ranc

e

852

Patie

nts

aged

� 6

5 y;

52

% h

ad �

2 V

TE

ris

k fa

ctor

s be

side

s ag

e

Non

ePr

oxim

al D

VT

by

scre

enin

g ul

tras

ound

NA

; cro

ss-s

ectio

nal

stud

yD

VT:

135

of 8

52 (1

5.8%

); 50

(5

.9%

) had

pro

xim

al D

VT;

pr

ophy

lact

ic a

ntic

oagu

lant

56

% (r

ange

20.

0%-8

6.9%

);

Bos

son

et a

1 13 /2

006

Pros

pect

ive

obse

rvat

iona

l co

hort

stu

dy16

,532

Out

patie

nts

. 4

0 y

(med

ian

age,

71

y) w

ith

an a

cute

med

ical

co

nditi

on r

educ

ing

mob

ility

for a

t lea

st 4

8 h;

35

% re

ceiv

ed p

roph

ylax

is

Non

eSy

mpt

omat

ic V

TE

3 w

k �

7 d

VT

E in

cide

nce:

197

of

16,5

32 (1

.2%

); re

ceiv

ing

prop

hyla

xis

asso

ciat

ed

with

incr

ease

d in

cide

nce

of V

TE

(con

foun

ding

by

indi

catio

n)

Ben

oist

et a

l 48 /1

994

(Fre

nch)

Cro

ss-s

ectio

nal s

tudy

96 I

nstit

utio

naliz

ed

elde

rly

patie

nts

Non

eD

VT

by

scre

enin

g ul

tras

ound

NA

13 o

f 96

(13.

5%) D

VT;

all

popl

iteal

Gat

t et a

l 49 /2

004

Ret

rosp

ectiv

e ch

art

revi

ew47

1 N

H p

atie

nts

Non

eSy

mpt

omat

ic V

TE

Med

ian,

2.7

5 y

(ran

ge, 0

.25-

18.3

3)26

Pat

ient

s de

velo

ped

DV

T

sym

ptom

s; in

cide

nce

sim

ilar

in im

mob

ile

and

mob

ile g

roup

s (1

3.9

and

15.8

per

1,

000

patie

nt-y

ears

)

Kro

psky

et a

l 50 /2

003

Ret

rosp

ectiv

e ch

art

revi

ew24

6 N

H p

atie

nts

taki

ng

meg

estr

olN

one

Sym

ptom

atic

DV

TN

ot r

epor

ted

10 o

f 246

(4.9

%) D

VT

Gom

es 51

/200

3R

etro

spec

tive

coho

rt

stud

y us

ing

Min

imum

D

ata

Set

18,6

61 N

H p

atie

nts

in

Kan

sas

1997

-199

8;

med

ian

age,

85

y; 9

5%

whi

te; 7

4% w

omen

Non

eSy

mpt

omat

ic V

TE

Med

ian

follo

w-u

p 25

2 d

155

Patie

nts

deve

lope

d V

TE

; 1.3

0 pe

r 1,

00

pers

on-y

ears

(Con

tinu

ed)




Stud

y/Ye

arTy

pe o

f Stu

dyPa

rtic

ipan

tsIn

terv

entio

nO

utco

mes

Fol

low

-up

Res

ults

Vald

erra

ma

et a

l 52 /2

006

Pros

pect

ive

obse

rvat

iona

l co

hort

stu

dy87

NH

pat

ient

sN

one

Asy

mpt

omat

ic D

VT

on

scre

enin

g ul

tras

ound

4 m

o3

of 8

7 (3

.4%

) had

DV

T o

n in

itial

scr

eeni

ng a

t tim

e of

NH

adm

issi

on; 0

of 8

7 (0

%) d

evel

oped

DV

T o

ver

the

stud

y pe

riod

Lip

erot

i et a

l 53 /2

005

Ret

rosp

ectiv

e co

hort

st

udy

usin

g M

inim

um

Dat

a Se

t

132,

018

NH

res

iden

ts in

fi v

e U

S st

ates

Non

eH

ospi

taliz

atio

n fo

r V

TE

6 m

oV

TE

hos

pita

lizat

ion

0.91

pe

r 10

0 pe

rson

-yea

rs; r

ate

was

incr

ease

d fo

r us

ers

of

atyp

ical

ant

ipsy

chot

ics

Hei

t et a

l 54 /2

000

Popu

latio

n-ba

sed

nest

ed

case

-con

trol

stu

dy62

5 Pa

tient

s (in

stitu

tiona

lized

w

ithou

t rec

ent s

urge

ry)

with

a fi

rst V

TE

and

62

5 m

atch

ed c

ontr

ols

with

out a

DV

T

Non

eR

isk

fact

ors

for

VT

EU

niva

riat

e: N

H c

onfi n

emen

t O

R, 1

0.64

; mul

tivar

iate

: “i

nstit

utio

naliz

atio

n w

ithou

t rec

ent s

urge

ry”

OR

, 7.9

8

Hei

t et a

l 55 /2

002

Popu

latio

n-ba

sed

nest

ed

case

-con

trol

stu

dy62

5 Pa

tient

s w

ith a

fi rs

t V

TE

and

625

mat

ched

co

ntro

ls w

ithou

t a D

VT

Non

eA

ttri

buta

ble

risk

of r

isk

fact

ors

for

VT

EN

H r

esid

ence

acc

ount

ed fo

r 13

% o

f cas

es o

f VT

E

Rod

rigu

ez-M

anas

et

al 56

/201

0Pr

ospe

ctiv

e ob

serv

atio

nal

coho

rt s

tudy

Ger

iatr

ic o

utpa

tient

ce

nter

s (n

5 3

58) o

r H

ospi

tal-a

t-H

ome

Uni

ts (n

5 1

49)

bedr

idde

n fo

r at

leas

t 4

d; m

ean

age,

82

y

LM

WH

(b

emip

arin

) 2,

500

or 3

,500

In

tern

atio

nal

Uni

ts/d

; no

cont

rol a

rm

Sym

ptom

atic

DV

T o

r PE

; maj

or b

leed

; m

inor

ble

ed,

thro

mbo

cyto

peni

a

3 m

oTh

ree

of 5

07 (0

.6%

) dev

elop

ed

DV

T; 2

(0.4

%) d

evel

oped

m

ajor

ble

edin

g; 8

(1.6

%)

deve

lope

d m

inor

ble

edin

g (e

xclu

ding

hem

atom

a).

Ove

rall

blee

d ra

te 2

.0%

. M

ild th

rom

bocy

tope

nia

inci

denc

e, 1

.4%

; non

e ,

100

,000

or

requ

ired

di

scon

tinua

tion

Lei

bson

et a

l 57 /2

008

Nes

ted

case

-con

trol

st

udy

with

in

popu

latio

n-ba

sed

coho

rt s

tudy

Olm

sted

Cou

nty

resi

dent

s (n

5 1

24,2

77).

Use

d (1

) M

CM

RP

(whi

ch w

as a

pr

ecur

sor

to th

e M

inim

um D

ata

Set i

n N

Hs)

, and

(2) R

EP

data

set

Non

eV

TE

dia

gnos

is b

ased

on

IC

D-9

cod

es.

Fol

low

ed u

ntil

date

of

last

kno

wn

vita

l st

atus

Yiel

ds a

n in

cide

nce

of V

TE

in

NH

pat

ient

s of 1

2-15

per

1,

000

patie

nt-y

ears

usin

g M

CM

RP

and

a hi

gher

rate

(3

6 pe

r 1,0

00 p

atie

nt-y

ears

) us

ing

RE

P. F

ound

risk

fa

ctor

s are

uni

que

in th

e N

H p

opul

atio

n an

d re

late

to

mob

ility

stat

us (i

e, re

quire

as

sista

nce

with

tran

sfer

ring,

ne

ed fo

r PT,

wou

nd c

are)

ra

ther

than

the

trad

ition

al

risk

fact

ors (

canc

er, C

HF

).

Prie

to 58

/200

7 (S

pani

sh)

0.9%

VT

E in

cide

nce

AD

5 ac

tiviti

es o

f da

ily l

ivin

g; I

CD

-9 5

Inte

rnat

iona

l St

atis

tical

Cla

ssifi

catio

n of

Dis

ease

s an

d R

elat

ed H

ealth

Pro

blem

s, 9

th e

d.; M

CM

RP

5 M

inne

sota

Cas

e M

ix R

evie

w P

rogr

am; N

A, n

ot a

pplic

able

; N

H 5

nur

sing

hom

e; R

EP

5 R

oche

ster

Epi

dem

iolo

gic

Proj

ect.

Tabl

e S2

3—C

onti

nued




Tabl

e S2

4 —Su

mm

ary

Tab

le f

or T

rial

s of

Pha

rmac

olog

ic P

roph

ylax

is t

o P

reve

nt V

TE

in

Air

Tra

vele

rs

Stud

y/Ye

arIn

terv

entio

nsR

isk

Gro

up ,†

Flig

ht D

urat

ion

Patie

nts

Ana

lyze

d (%

)Ti

me

to

Scre

enin

gD

VT,

%, R

R

(95%

CI)

SVT,

%, R

R

(95%

CI)

Ede

ma,

M

ean

(SD

)‡C

omm

ents

LM

WH

vs

no th

rom

bopr

ophy

laxi

s

Ces

aron

e et

al 59

/200

2N

o th

rom

bopr

ophy

laxi

sH

igh,

7-8

hN

o th

rom

bopr

ophy

laxi

s:

83 o

f 100

(83)

On

arri

val

No

thro

mbo

prop

hyla

xis:

4

of 8

3 (5

)N

o th

rom

bopr

ophy

laxi

s:

2 of

83

(2)

NR

Wei

ght-

base

d L

MW

H

dosi

ng r

educ

es

feas

ibili

ty

Eno

xapa

rin:

1 m

g/kg

, 2-

4 h

prefl

ight

Eno

xapa

rin:

0 o

f 82

Eno

xapa

rin:

1 o

f 82

(1)

Eno

xapa

rin:

82

of 1

00 (8

2)R

R, 0

.11

(0.0

0-2.

06)

RR

, 0.5

1 (0

.05-

5.47

)

Asp

irin

vs

no th

rom

bopr

ophy

laxi

s

Ces

aron

e et

al 59

/200

2N

o th

rom

bopr

ophy

laxi

sH

igh,

7-8

hN

o th

rom

bopr

ophy

laxi

s:

83 o

f 100

(83)

On

arri

val

No

thro

mbo

prop

hyla

xis:

4

of 8

3 (5

)N

o th

rom

bopr

ophy

laxi

s:

2 of

83

(2)

NR

Asp

irin

: 400

mg

3 3

d,

star

ting

12 h

pre

fl igh

tA

spir

in: 8

4 of

100

(84)

Asp

irin

: 3 o

f 84

(4%

)A

spir

in: 3

of 8

4 (4

)

RR

, 0.7

4 (0

.17-

3.21

)R

R, 1

.48

(0.2

5-8.

64)

Pycn

ogen

ol (a

bio

fl avo

noid

) vs

plac

ebo

Bel

caro

et

al 60

/200

4Pl

aceb

o ad

min

iste

red

iden

tical

lyM

oder

ate

to h

igh,

7-

12 h

(m

ean,

8 h

)

Plac

ebo

adm

inis

tere

d id

entic

ally

97

of

105

(92)

, 1

20 m

inPl

aceb

o: 1

of 9

7 (1

.0)

Plac

ebo:

4 o

f 97

(4.1

)N

RIn

act

ive

trea

tmen

t gr

oup

1 cl

inic

al

SVT

see

n bu

t not

cl

assi

fi ed

as s

uch—

no th

rom

bosi

s se

en

on u

ltras

ound

Pycn

ogen

ol 2

00 m

g 2-

3 h

befo

re fl

ight

, 20

0 m

g 6

h la

ter,

100

mg

the

next

day

; al

l with

250

mL

wat

er.

Pycn

ogen

ol 2

00 m

g 2-

3 h

befo

re fl

ight

, 200

mg

6 h

late

r, 10

0 m

g th

e ne

xt d

ay; a

ll w

ith

250

mL

wat

er: 1

01 o

f 10

6 (9

5%)

Pycn

ogen

ol: 0

of 1

01 (0

)Py

cnog

enol

: 0 o

f 101

(0)

All

DV

T

asym

ptom

atic

. All

SVT

sym

ptom

atic

.

NR

5 n

ot r

epor

ted;

SV

T 5

supe

rfi c

ial v

ein

thro

mbo

sis.

See

Tab

le S

2 an

d S4

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

.




Tabl

e S2

5 —M

etho

dolo

gic

Qu

alit

y of

Tri

als

Usi

ng P

harm

acol

ogic

Pro

phyl

axis

to

Pre

vent

VT

E i

n A

ir T

rave

lers

Stud

y/Ye

arIn

terv

entio

nR

ando

miz

atio

n C

once

aled

Blin

ding

No

Out

com

e (%

)A

naly

sis

Com

men

ts

LM

WH

vs

no th

rom

bopr

ophy

laxi

s

Ces

aron

e et

al 59

/200

2N

o th

rom

bopr

ophy

laxi

sPr

obab

ly n

ot (N

R)

Subj

ects

: no

No

thro

mbo

prop

hyla

xis:

17

of 1

00 (1

7)Pe

r pr

otoc

olA

bstr

act r

epor

ts a

n ad

ditio

nal s

ubje

ct g

roup

(L

MW

H 1

sock

s) n

ot

men

tione

d in

pub

licat

ion

Subj

ect r

ecru

itmen

t pro

cess

N

R

Eno

xapa

rin

1 m

g/kg

, 2-4

h

prefl

ight

Out

com

e as

sess

ors:

pr

obab

ly n

otF

light

dur

atio

n N

R

Eno

xapa

rin:

18

of 1

00 (1

8)M

etho

d of

ran

dom

izat

ion

NR

DV

T s

cree

ning

test

not

va

lidat

ed

Sour

ce o

f fun

ding

NR

Asp

irin

vs

no th

rom

bopr

ophy

laxi

s

Ces

aron

e et

al 59

/200

2N

o th

rom

bopr

ophy

laxi

sPr

obab

ly n

ot (N

R)

Subj

ects

: no

No

thro

mbo

prop

hyla

xis:

17

of 1

00 (1

7)Pe

r pr

otoc

olA

bstr

act r

epor

ts a

n ad

ditio

nal s

ubje

ct g

roup

(L

MW

H 1

sock

s) n

ot

men

tione

d in

pub

licat

ion

Subj

ect r

ecru

itmen

t pro

cess

N

R

Asp

irin

400

mg

3 3

d,

star

ting

12 h

pre

fl igh

tO

utco

me

asse

ssor

s:

prob

ably

not

Asp

irin

: 16

of 1

00 (1

6)

Flig

ht d

urat

ion

NR

Met

hod

of r

ando

miz

atio

n N

R

DV

T s

cree

ning

test

not

va

lidat

ed

Sour

ce o

f fun

ding

NR

Pycn

ogen

ol v

s pl

aceb

o

Bel

caro

et a

l 60 /2

004

Plac

ebo

adm

inis

tere

d id

entic

ally

Unk

now

nU

nkno

wn

for

subj

ects

or

ass

esso

rsPl

aceb

o: 5

VT

(1 D

VT,

4 S

VT

[w

ith th

rom

bosi

s])

Per

prot

ocol

Out

com

e no

nsta

ndar

dize

d

Prefl

ight

(with

in 9

0 m

in)

and

post

fl igh

t (w

ithin

12

0 m

in) u

ltras

ound

don

e.

Pycn

ogen

ol: 0

DV

T, 1

SV

T b

ut

not c

lass

ifi ed

as

such

Inco

nsis

tent

rep

ortin

g of

com

plet

ion

rate

of

part

icip

ants

.

Pycn

ogen

ol 2

00 m

g 2-

3 h

befo

re fl

ight

, 20

0 m

g 6

h la

ter,

100

mg

the

next

day

; al

l with

250

mL

wat

er.

Exc

lude

d th

ose

. 9

0 kg

or

190

cm

See

Tabl

e S2

, S4,

and

S24

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.




Tabl

e S2

6 —[S

ecti

on 6

.1.1

] E

vide

nce

Pro

fi le:

Sho

uld

Peo

ple

Tak

ing

Lon

g F

ligh

ts U

se C

ompr

essi

on S

tock

ings

vs

No

Com

pres

sion

Sto

ckin

gs?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

No.

of P

atie

nts

RR

(95%

CI)

Abs

olut

e R

isk

Qua

lity

No.

of S

tudi

es

(Des

ign)

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

s

With

out

Com

pres

sion

St

ocki

ngs a

With

C

ompr

essi

on

Stoc

king

sC

ontr

ol R

ate

Ris

k D

iffer

ence

(9

5% C

I)

Sym

ptom

atic

DV

T

Dir

ect e

vide

nce

9 (R

CT

)N

o se

riou

s lim

itatio

ns b

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s im

prec

isio

n c U

ndet

ecte

d0

of 1

,323

0 of

1,3

14N

ot e

stim

able

(n

o ev

ents

)0

per

1,00

00

per

1,00

0 ( 2

1.5

to 1

.5)

Mod

erat

e

Indi

rect

evi

denc

e (b

ased

on

sym

ptom

less

DV

T a

s a

surr

ogat

e ou

tcom

e fo

r sy

mpt

omat

ic D

VT

)

9 (R

CT

)N

o se

riou

s lim

itatio

ns b

No

seri

ous

inco

nsis

tenc

ySe

riou

s in

dire

ctne

ss d

No

seri

ous

impr

ecis

ion

Und

etec

ted

Surr

ogat

e sy

mpt

omle

ss

DV

T: 4

7 of

1,

323

Surr

ogat

e sy

mpt

omle

ss

DV

T: 3

of

1,31

4

RR

, 0.1

0 (0

.04-

0.25

)5

per

10,0

00L

ow r

isk

Mod

erat

e

4.5

per

10,0

00

(4 to

5)

18 p

er 1

0,00

0H

igh

risk

16.2

per

10,

000

(14

to 1

7.5)

PE

Dir

ect e

vide

nce

9 (R

CT

)N

o se

riou

s lim

itatio

ns b

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssN

o se

riou

s im

prec

isio

nU

ndet

ecte

d0

of 1

,323

0 of

1,3

14N

ot e

stim

able

(n

o ev

ents

)0

per

1,00

00

per

1,00

0 ( 2

1.5

to 1

.5)

Hig

h

Indi

rect

evi

denc

e (b

ased

on

sym

ptom

less

DV

T a

s a

surr

ogat

e ou

tcom

e fo

r sy

mpt

omat

ic D

VT

)

9 (R

CT

)N

o se

riou

s lim

itatio

ns b

No

seri

ous

inco

nsis

tenc

ySe

riou

s in

dire

ctne

ss d

No

seri

ous

impr

ecis

ion

Und

etec

ted

Surr

ogat

e sy

mpt

omle

ss

DV

T: 4

7 of

1,

323

Surr

ogat

e sy

mpt

omle

ss

DV

T: 3

of

1,31

4

RR

, 0.1

0 (0

.04-

0.25

)27

per

1 m

illio

nL

ow r

isk

Mod

erat

e

24 p

er 1

mill

ion

(20

to 2

6)

97 p

er 1

mill

ion

Hig

h ri

sk

87 p

er 1

mill

ion

(76

to 9

4)

SVT

8 (R

CT

)N

o se

riou

s lim

itatio

ns b

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s im

prec

isio

n c U

ndet

ecte

d12

of 9

014

of 9

03R

R, 0

.45

(0.1

8-1.

13)

13 p

er 1

,000

Not

sig

nifi c

ant

Mod

erat

e

(Con

tinu

ed)




Tabl

e S2

6—C

onti

nued

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

No.

of P

atie

nts

RR

(95%

CI)

Abs

olut

e R

isk

Qua

lity

No.

of S

tudi

es

(Des

ign)

Lim

itatio

nsIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

s

With

out

Com

pres

sion

St

ocki

ngs a

With

C

ompr

essi

on

Stoc

king

sC

ontr

ol R

ate

Ris

k D

iffer

ence

(9

5% C

I)

Ede

ma

(pos

tfl ig

ht v

alue

s m

easu

red

on a

sca

le fr

om 0

, no

edem

a, to

10,

max

imum

ede

ma)

6 (R

CT

)Ve

ry s

erio

us

limita

tions

e N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

No

seri

ous

impr

ecis

ion

Und

etec

ted

7- o

r 8-

h F

light

…W

eigh

ted

mea

n di

ffer

ence

: 2

4.7

2 ( 2

4.9

1 to

2 4

.52)

Low

Mea

n, 6

.4-6

.9M

ean,

2.2

-2.4

349

Part

icip

ants

348

Part

icip

ants

12-h

Flig

htF

avor

s st

ocki

ngs

Mea

n, 7

.9-8

.9M

ean,

2.6

-3.3

272

Part

icip

ants

277

Part

icip

ants

Adv

erse

eff

ects

f

4 (R

CT

)Ve

ry s

erio

us

limita

tions

e N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

No

seri

ous

impr

ecis

ion

Und

etec

ted

0 of

1,1

820

of 1

,182

Not

ava

ilabl

eT

he to

lera

bilit

y of

th

e st

ocki

ngs

was

des

crib

ed

as v

ery

good

w

ith n

o co

mpl

aint

s of

si

de e

ffec

ts

Low

Bib

liogr

aphy

: C

lark

e M

, H

opew

ell

S, J

uszc

zak

E,

Eis

inga

A,

Kje

ldst

rom

M.

Com

pres

sion

sto

ckin

gs f

or p

reve

ntin

g de

ep v

ein

thro

mbo

sis

in a

irlin

e pa

ssen

gers

. C

ochr

ane

Dat

abas

e Sy

st R

ev .

2006

; (2

):C

D00

4002

. Phi

lbri

ck J

T, S

hum

ate

R, S

iada

ty M

S, e

t al

. Air

tra

vel a

nd v

enou

s th

rom

boem

bolis

m: a

sys

tem

atic

rev

iew

. J G

en I

nter

n M

ed. 2

007;

22:1

07-1

14. A

ll th

e st

ocki

ngs

in t

he n

ine

tria

ls

incl

uded

in th

is r

evie

w w

ere

belo

w-k

nee

com

pres

sion

sto

ckin

gs. I

n fo

ur tr

ials

the

com

pres

sion

str

engt

h w

as 2

0 to

30

mm

Hg

at th

e an

kle.

It w

as 1

0 to

20

mm

Hg

in th

e ot

her

four

tria

ls. S

tock

ings

com

e in

di

ffer

ent s

izes

. If a

sto

ckin

g is

too

tight

aro

und

the

knee

it c

an p

reve

nt e

ssen

tial v

enou

s re

turn

cau

sing

the

bloo

d to

poo

l aro

und

the

knee

. Com

pres

sion

sto

ckin

gs s

houl

d be

fi tt

ed p

rope

rly.

A s

tock

ing

that

is

too

tight

cou

ld c

ut in

to th

e sk

in o

n a

long

fl ig

ht a

nd p

oten

tially

cau

se u

lcer

atio

n an

d in

crea

sed

risk

of D

VT.

Som

e st

ocki

ngs

can

be s

light

ly th

icke

r th

an n

orm

al le

g co

veri

ng a

nd c

an b

e po

tent

ially

res

tric

tive

with

tigh

t foo

t wea

r. It

is a

goo

d id

ea to

wea

r st

ocki

ngs

arou

nd th

e ho

use

prio

r to

trav

el to

ens

ure

a go

od, c

omfo

rtab

le fi

ttin

g. S

tock

ings

wer

e pu

t on

2 to

3 h

bef

ore

the

fl igh

t in

mos

t of t

he tr

ials

. The

ava

il-ab

ility

and

cos

t of s

tock

ings

can

var

y. S

ee T

able

S1,

S3,

S4,

and

S24

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Est

imat

es f

or c

ontr

ol e

vent

rat

es f

or v

enou

s th

rom

bosi

s an

d fo

r PE

com

e fr

om P

hilb

rick

et

al . D

efi n

ition

of

high

ris

k in

clud

es p

revi

ous

epis

odes

of

DV

T, c

oagu

latio

n di

sord

ers,

sev

ere

obes

ity, l

imite

d m

obili

ty d

ue to

bon

e or

join

t pro

blem

s, n

eopl

astic

dis

ease

with

in th

e pr

evio

us 2

yea

rs, l

arge

var

icos

e ve

ins.

b W

e di

d no

t rat

e do

wn

for

met

hodo

logi

cal l

imita

tion,

alth

ough

ther

e w

as in

adeq

uate

con

ceal

men

t of a

lloca

tion

and

blin

ding

. c T

he im

prec

isio

n re

fers

to a

bsol

ute

mea

sure

s, n

ot th

e re

lativ

e. F

or th

e re

lativ

e, it

is n

ot p

ossi

ble

to m

ake

an e

stim

ate.

Thi

s is

als

o tr

ue fo

r PE

. d T

here

are

two

reas

ons

for

indi

rect

ness

. One

is th

at e

stim

ates

of R

R r

educ

tion

com

e fr

om th

e su

rrog

ate.

The

sec

ond

is th

at th

ere

is u

ncer

tain

ty r

egar

ding

the

base

line

risk

. e L

ack

of c

once

alm

ent a

nd b

lindi

ng c

onst

itute

d ve

ry s

erio

us li

mita

tions

in th

e co

ntex

t of a

n un

valid

ated

ede

ma

ratin

g an

d de

scri

ptio

n of

tole

rabi

lity

of s

tock

ings

. f N

one

of th

e ot

her

tria

ls r

epor

ted

adve

rse

effe

cts,

apa

rt fr

om fo

ur c

ases

of S

VT

in v

aric

ose

vein

s in

the

knee

reg

ion

that

wer

e co

mpr

esse

d by

the

uppe

r ed

ge o

f the

sto

ckin

g in

one

tria

l.




Tabl

e S2

7 —St

udi

es o

f T

hrom

bop

roph

ylax

is t

o P

reve

nt V

TE

in

Asy

mpt

omat

ic P

erso

ns W

ith

Thr

omb

ophi

lia:

Cli

nica

l D

escr

ipti

on a

nd R

esu

lts

Stud

y/Ye

ar, C

ount

ry,

Des

ign

Inte

rven

tions

No.

Pat

ient

s A

naly

zed

Len

gth

of

Fol

low

-up

Popu

latio

nD

VT,

PE

, R

R (9

5% C

I)D

eath

s, M

ajor

B

leed

ing,

RR

(95%

CI)

Com

men

ts

Erk

an e

t al 61

/200

2;

Uni

ted

Stat

es;

cros

s-se

ctio

nal,

retr

ospe

ctiv

e,

com

para

tive

coho

rt s

tudy

ASA

, dos

e an

d du

ratio

n N

RG

roup

B: t

otal

56;

A

SA: 1

8 of

56

(32.

1%)

Gro

up B

: 6 m

o pr

ior

to th

e pa

tient

’s la

st

hosp

ital v

isit

Gro

up B

: 56

asym

ptom

atic

aP

L-p

ositi

ve p

atie

nts

(med

ium

to h

igh

titer

of

aC

L a

nd/o

r a

posi

tive

LA

C te

st b

ut

no h

isto

ry o

f vas

cula

r or

pre

gnan

cy e

vent

s)

Eve

nts

wer

e di

vide

d in

to v

enou

s or

ar

teri

al e

vent

s, a

nd

not s

peci

fi cal

ly

cate

gori

zed

as

DV

T o

r PE

Dea

ths:

NR

In w

omen

onl

y, th

e pr

obab

ility

of a

n ev

ent i

ncre

ased

with

th

rom

bocy

tope

nia

and

the

pres

ence

of e

ither

pr

egna

ncy

or s

urgi

cal

proc

edur

es

HC

Q, d

ose

and

dura

tion

NR

Age

: 46.

0 �

13.

8 y

“In

logi

stic

reg

ress

ion

anal

ysis

, the

pr

obab

ility

of a

n ev

ent w

as d

ecre

ased

by

taki

ng A

SA a

nd/o

r H

CQ

” (c

ompa

red

with

taki

ng n

o su

ch tr

eatm

ent)

Maj

or b

leed

ing:

NR

Stud

y ex

clud

ed fr

om

Evi

denc

e Pr

ofi le

s fo

r la

ck o

f app

ropr

iate

da

ta

Sex

(fem

ale)

: 51

of 5

6 (9

1%)

HC

Q: 2

1 of

56

(37.

5%)

Lup

us-li

ke d

isea

se: 3

of

56 (4

%) (

perc

enta

ge is

m

isca

lcul

ated

in a

rtic

le;

it sh

ould

rea

d 5.

4%)

Gro

up A

had

pri

or

vasc

ular

eve

nt,

ther

efor

e da

ta n

ot

appl

icab

le

Thr

ombo

cyto

peni

a: 5

%

Erk

an e

t al 62

/200

7;

Uni

ted

Stat

es;

RC

T (A

PLA

SA

stud

y) a

nd

sing

le-g

roup

co

hort

stu

dy

ASA

, 81m

g/d

RC

T

(no.

ran

dom

ized

)R

CT:

2.3

0 y

(SD

, 0.9

5 y)

Pers

iste

ntly

aPL

-pos

itive

in

divi

dual

s (t

hose

with

po

sitiv

e aP

L b

ut n

o va

scul

ar a

nd/o

r pr

egna

ncy

even

ts)

RC

TM

ajor

ble

edin

g (o

vert

or

clos

ed-s

pace

ble

edin

g w

ith d

ecre

ase

in H

gb

� 2

g/d

L o

ver

24 h

):

Com

posi

te o

utco

mes

on

ly p

rese

nted

No

ASA

Pers

ons

who

de

clin

ed

rand

omiz

atio

n or

al

read

y on

ASA

w

ere

follo

wed

in

an o

bser

vatio

nal

stud

y of

ASA

or

no

trea

tmen

t

ASA

: 48

Plac

ebo:

50

Obs

erva

tiona

l stu

dy:

2.46

y (S

D, 0

.76

y)

Obs

erva

tiona

l stu

dy:

Prim

ary

outc

ome

(inci

dent

acu

te

thro

mbo

sis [

thro

mbo

tic

stro

ke, D

VT,

PE

, acu

te

MI]

con

fi rm

ed b

y im

agin

g st

udie

s),

inci

denc

e ra

te p

er

100

patie

nt-y

ears

:

0 G

roup

s in

bot

h st

udie

s

(Con

tinu

ed)




Tabl

e S2

7—C

onti

nued

Stud

y/Ye

ar, C

ount

ry,

Des

ign

Inte

rven

tions

No.

Pat

ient

s A

naly

zed

Len

gth

of

Fol

low

-up

Popu

latio

nD

VT,

PE

, R

R (9

5% C

I)D

eath

s, M

ajor

B

leed

ing,

RR

(95%

CI)

Com

men

ts

Obs

erva

tiona

l stu

dy

ASA

: 61

of 7

4 (8

2.4%

)

A

ge, m

ean

� S

D

ASA

: 2.7

5

A

SA: 4

7.8

� 1

4.8

y

No

ASA

: 0

No

ASA

: 13

of 7

4 (1

7.6%

)N

o A

SA: 4

6.2

� 1

4.1

yH

R, 1

.04

(95%

CI,

0.6

9-1.

56),

P 5

.83

Sex

(no.

wom

en),

Seco

ndar

y ou

tcom

e

(tra

nsie

nt is

chem

ic

atta

ck),

inci

denc

e ra

te

per 1

00 p

atie

nt-y

ears

:

ASA

: 58

of 6

1 (9

5%)

A

SA: 1

.83

No

ASA

: 13

of

13 (1

00%

)

No

ASA

: 0.8

6

H

R, 1

.08

(95%

CI,

0.

72-1

.62)

, P 5

.68

Obs

erva

tiona

l stu

dy

pr

imar

y ou

tcom

e (a

s ab

ove)

:

A

SA: 2

.70

N

o A

SA: 0

Seco

ndar

y ou

tcom

e:

0 bo

th g

roup

s

Gly

nn e

t al 63

/200

7;

Uni

ted

Stat

es; R

CT

(s

ubgr

oup

anal

yses

of

Wom

en’s

Hea

lth

Stud

y)

ASA

, 100

mg

ever

y 2

days

for

10 y

Tota

l No.

allo

cate

d in

Wom

en’s

Hea

lth S

tudy

:

Med

ian

follo

w-u

p,

10.2

y (I

QR

, 9.

7-10

.6 y

)

Tota

l pop

ulat

ion:

39,

876

initi

ally

hea

lthy

wom

en

age

� 4

5 y

Fac

tor

V L

eide

n pr

esen

t (u

nkno

wn

% h

ad p

rior

V

TE

):

NR

for

thro

mbo

phili

a su

bgro

up3%

of e

ntir

e st

udy

popu

latio

n ha

d pr

ior

VT

E, b

ut in

pop

ulat

ion

of in

tere

st (f

acto

r V

L

eide

n) a

n un

cert

ain

% h

ad p

rior

VT

E

No

ASA

ASA

: 19,

934

(5.2

%

had

fact

or V

L

eide

n 5

1,0

37)

Rat

e di

ffer

ence

per

1,

000

patie

nt-y

ears

, A

SA v

s pla

cebo

: 2 0

.50

(95%

CI,

2 2

.26

to

1.26

)

In p

atie

nts

with

fact

or

V L

eide

n or

the

prot

hrom

bin

mut

atio

n,

the

inci

denc

e of

VT

E

in th

e pl

aceb

o gr

oup

was

2.7

tim

es th

at o

f w

omen

in th

e pl

aceb

o gr

oup

with

out e

ither

ri

sk fa

ctor

No

ASA

: 19,

942

(5.1

% h

ad fa

ctor

V

Lei

den

5 1

,017

)

Tota

l with

fact

or V

L

eide

n pr

esen

t an

d da

ta fo

r A

SA

effe

ct: 1

,370

HR

, 0.8

1 (9

5% C

I,

0.42

-1.5

4)

(Con

tinu

ed)




Stud

y/Ye

ar, C

ount

ry,

Des

ign

Inte

rven

tions

No.

Pat

ient

s A

naly

zed

Len

gth

of

Fol

low

-up

Popu

latio

nD

VT,

PE

, R

R (9

5% C

I)D

eath

s, M

ajor

B

leed

ing,

RR

(95%

CI)

Com

men

ts

Her

eng

et a

l 64 /2

008;

F

ranc

e;

retr

ospe

ctiv

e co

mpa

rativ

e co

hort

stu

dy

ASA

, dos

e an

d du

ratio

n N

RTo

tal c

ohor

t 103

Mea

n, 6

4 �

24.

7 m

oA

ll pa

tient

s w

ere

asym

ptom

atic

aPL

an

tibod

y-po

sitiv

e ca

rrie

rs (A

CL

or

LA

C)

Am

ong

patie

nts

with

SL

E, 4

of 1

0 no

t ta

king

ASA

dev

elop

ed

a th

rom

bosi

s (a

rter

ial

or v

enou

s) v

s 3

of 2

7 ta

king

ASA

( P 5

.03)

Dea

ths:

NR

No

ASA

ASA

: 75

of 1

03

(72.

8%)

Age

, mea

n �

SD

Aut

oim

mun

e th

rom

bocy

tope

nia:

4

of 6

pat

ient

s no

t ta

king

asp

irin

suf

fere

d a

thro

mbo

tic e

vent

vs

1 o

f 10

taki

ng

aspi

rin

( P 5

.01)

“Sev

ere

blee

ding

eve

nt”

(not

defi

ned

):

No

ASA

28

of 1

03

(27.

2%)

ASA

: 40.

1 �

16.

7 y

A

SA: 0

of 7

5 (0

%)

No

ASA

: 44.

7 � 17

.4 y

N

o A

SA: 0

of 2

8 (0

%)

Sex

(no.

wom

en):

ASA

: 67

of 7

5 (8

9.3%

)

No

ASA

: 24

of 2

8 (8

5.7%

)

Ass

ocia

ted

dise

ases

: SL

E (n

5 3

7),

auto

imm

une

thro

mbo

cyto

peni

a (n

5 1

6), R

A (n

5 8

)

Tekt

onid

ou

et a

l 65 /2

009;

G

reec

e;

pros

pect

ive

com

para

tive

coho

rt s

tudy

ASA

, 80-

100

mg/

dA

ll pa

tient

s w

ith

SLE

with

po

sitiv

e aP

L

with

out p

revi

ous

thro

mbo

sis

or

preg

nanc

y m

orbi

dity

: n

5 1

44

Med

ian

dura

tion

of fo

llow

up,

aP

L-p

ositi

ve

patie

nts:

104

mo

(IQ

R, 6

1-15

0 m

o)

aPL

-neg

ativ

e pa

tient

s: 11

2 m

o (I

QR

, 62

-156

mo)

Patie

nts

with

SL

E w

ith

posi

tive

aPL

but

w

ithou

t pre

viou

s th

rom

bosi

s or

pr

egna

ncy

mor

bidi

ty

Thr

ombo

tic e

vent

s,

No.

(%)

Ove

rall

acut

e th

rom

bosi

s in

cide

nce

rate

(eve

nts

per

100

patie

nt-y

ears

):

aP

L-p

ositi

ve: 2

.09

aP

L-n

egat

ive:

0.7

9

No

patie

nt e

xper

ienc

ed

maj

or b

leed

ing

in

eith

er S

LE

gro

up

Vari

able

s as

soci

ated

with

th

rom

botic

eve

nts

in

aPL

-pos

itive

pat

ient

s:

mal

e se

x, L

AC

, co

nsta

ntly

pos

itive

aC

L

HC

Q, d

ose

NR

Age

- and

sex

-m

atch

ed p

atie

nts

with

SL

E w

ith

nega

tive

aPL

: n

5 1

44

aP

L-p

ositi

ve: 2

9 of

14

4 (2

0%)

aP

L-n

egat

ive:

11

of

144

(7.6

%)

11 o

f 87

patie

nts

took

ASA

;(7

art

eria

l, 4

veno

us)

Dea

th: N

R

19 o

f 101

took

H

CQ

(cou

ld

use

both

)

P 5

.003

Tabl

e S2

7—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

ar, C

ount

ry,

Des

ign

Inte

rven

tions

No.

Pat

ient

s A

naly

zed

Len

gth

of

Fol

low

-up

Popu

latio

nD

VT,

PE

, R

R (9

5% C

I)D

eath

s, M

ajor

B

leed

ing,

RR

(95%

CI)

Com

men

ts

Una

djus

ted

RR

in

aPL

-pos

itive

pat

ient

s fo

r tr

eatm

ent:

ASA

vs

no A

SA fo

r th

rom

bosi

s:

HR

, 0.4

3; 9

5% C

I,

0.20

-0.9

1; P

5 .0

27

HC

Q: H

R, 0

.67

(95%

CI,

0.

31-1

.45)

, P 5

.30

Adj

uste

d an

alys

es: H

R

per

1 m

o in

aP

L-p

ositi

ve p

atie

nts

for

risk

of t

hrom

botic

ev

ents

:

ASA

vs

no A

SA: H

R, 0

.98

(95%

CI,

0.9

6-0.

99),

P 5

.05

HC

Q v

s no

ne: H

R, 0

.99

(95%

CI,

0.9

8 to

1.0

0),

P 5

.05

Com

bina

tion

ther

apy

resu

lts N

R

aCL

5 a

ntic

ardi

olip

in; a

PL 5

ant

ipho

spho

lipid

ant

ibod

ies;

HC

Q 5

hyd

roxy

chlo

roqu

ine;

LA

C 5

lupu

s an

ticoa

gula

nt; S

LE

5 s

yste

mic

lupu

s er

ythe

mat

osus

. See

Tab

le S

1, S

3, S

4, S

7, S

17, a

nd S

24 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

.

Tabl

e S2

7—C

onti

nued




Tabl

e S2

8 —R

CT

s of

Thr

omb

opro

phyl

axis

to

Pre

vent

VT

E i

n A

sym

ptom

atic

Per

sons

Wit

h T

hrom

bop

hili

a: M

etho

dolo

gic

Qu

alit

y

Stud

y/Ye

arC

once

alm

ent o

f A

lloca

tion

Blin

ding

of P

atie

nts

Blin

ding

of

Hea

lth-c

are

Prov

ider

sB

lindi

ng o

f Dat

a C

olle

ctor

sB

lindi

ng o

f Out

com

e A

djud

icat

ors

Blin

ding

of D

ata

Ana

lyst

sSt

oppe

d E

arly

F

or B

enefi

tIT

T C

omm

ents

Erk

an e

t al 62

/200

7D

YD

YD

YD

YPY

PYD

YD

Y

Cen

tral

ized

al

loca

tion

with

co

mpu

ter-

gene

rate

d ra

ndom

izat

ion

tabl

e

“Inv

estig

ator

s,

coor

dina

tors

, pa

rtic

ipan

ts w

ere

blin

ded

to th

e tr

eatm

ent

assi

gnm

ents

”

Patie

nt r

ecru

itmen

t te

rmin

ated

ear

ly a

s lo

wer

-tha

n-ex

pect

ed

even

t rat

es in

bot

h gr

oups

; lar

ger

sam

ple

size

unf

easi

ble

Gly

nn e

t al 63

/200

7D

YD

YD

YD

YD

YD

YN

oD

Y

Subg

roup

ana

lysi

s of

R

CT

(Wom

en’s

Hea

lth s

tudy

)

Subg

roup

ana

lyse

s w

ere

pres

peci

fi ed.

In

pop

ulat

ion

of

inte

rest

(fac

tor

V

Lei

den)

an

unce

rtai

n %

had

pri

or V

TE

; in

over

all p

opul

atio

n 2.

9% h

ad p

rior

VT

E,

but i

n pa

tient

s w

ith

fact

or V

Lei

den

or

the

prot

hrom

bin

mut

atio

n th

e in

cide

nce

of V

TE

in

the

plac

ebo

grou

p w

as 2

.7 ti

mes

that

of

wom

en in

the

plac

ebo

grou

p w

ithou

t ei

ther

ris

k fa

ctor

D

Y 5

defi

nite

ly y

es; P

Y 5

pro

babl

y ye

s. S

ee T

able

S3

and

S10

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

.




Tabl

e S2

9 —O

bse

rvat

iona

l St

udi

es o

f T

hrom

bop

roph

ylax

is t

o P

reve

nt V

TE

in

Asy

mpt

omat

ic P

erso

ns W

ith

Thr

omb

ophi

lia:

Met

hodo

logi

c Q

ual

ity

Stud

y/Ye

arIn

terv

entio

n/C

ompa

rato

rSt

udy

Des

ign

Inte

rven

tion/

Con

trol

Se

ttin

g Si

mila

rIn

terv

entio

n/C

ontr

ol

Tim

e F

ram

e Si

mila

rA

djus

tmen

tE

ffec

tivel

y B

linde

d A

sses

smen

t of O

utco

me

Los

s to

Fol

low

-up

Erk

an e

t al 62

/200

7A

SA, 8

1 m

g/d

Pros

pect

ive

com

para

tive

coho

rt s

tudy

(RC

T

qual

ity is

ass

esse

d in

se

para

te ta

ble)

DY

DY

NR

PYA

SA: 2

of 6

1 (3

.3%

); 6

with

draw

als

No

ASA

Fol

low

-up

inte

rval

s si

mila

r, co

ntem

pora

neou

s da

ta c

olle

ctio

n

No

ASA

: 0 o

f 13

(0%

); 2

with

draw

als

Erk

an e

t al 61

/200

2B

oth

ASA

and

H

CQ

exa

min

ed

(stu

dy e

xclu

ded

from

E

vide

nce

Profi

le)

Cro

ss-s

ectio

nal,

retr

ospe

ctiv

e,

com

para

tive

stud

y

PYPY

NR

DN

NA

(ret

rosp

ectiv

e)

ASA

(dos

e an

d du

ratio

n N

R)

vs n

o tr

eatm

ent

HC

Q (d

ose

and

dura

tion

NR

) vs

no

trea

tmen

t

Gro

up A

had

had

an

eve

nt, G

roup

B

was

asy

mpt

omat

ic;

sign

ifi ca

nt d

iffer

ence

s be

twee

n th

e tw

o gr

oups

Her

eng

et a

l 64 /2

008

ASA

: dos

e an

d du

ratio

n N

RR

etro

spec

tive

com

para

tive

coho

rt s

tudy

PY (1

0 pa

tient

s w

ere

not f

ollo

wed

in

sam

e de

part

men

t)

DY

NR

DN

3 of

108

(27.

8%)

othe

r pa

tient

s re

ceiv

ed lo

ng-t

erm

an

ticoa

gula

tion

No

ASA

Gro

ups

diff

ered

on

%

aCL

, IgG

, and

IgM

( P

, .0

5), t

hus

diff

er

in th

rom

bosi

s ri

sk

Tekt

onid

ou e

t al 65

/200

9B

oth

ASA

and

H

CQ

exa

min

edPr

ospe

ctiv

e co

mpa

rativ

e co

hort

stu

dy

DY

DY

Sex,

LA

C,

age,

sm

okin

g,

com

orbi

d co

nditi

ons

PNC

ohor

t was

follo

wed

to

dat

e of

last

vis

it or

to e

vent

A

SA (8

0-10

0 m

g/d)

vs

no

trea

tmen

t

HC

Q (d

ose

NR

) vs

no

trea

tmen

tR

ecru

ited

from

sa

me

clin

ic

DN

5 d

efi n

itely

no;

PN

5 p

roba

bly

no. S

ee T

able

S7,

S24

, S27

, and

S28

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.




Tabl

e S3

0 —[S

ecti

on 7

.1]—

Evi

denc

e P

rofi l

e: S

hou

ld A

SA v

s N

o T

reat

men

t B

e U

sed

for

Pre

vent

ion

of V

TE

in

Per

sons

Wit

h A

sym

ptom

atic

Thr

omb

ophi

lia?

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

N

o. o

f Pat

ient

sE

ffec

t

No.

of S

tudi

esD

esig

nL

imita

tions

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

C

onsi

dera

tions

ASA

No

Trea

tmen

tR

elat

ive

(95%

CI)

Abs

olut

e Q

ualit

y Im

port

ance

VT

E (n

onfa

tal)

(fol

low

-up,

2.3

-10.

1 y)

2 a R

ando

miz

ed

tria

ls b

No

seri

ous

limita

tions

c N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Very

ser

ious

d N

one

2 of

48

(4.2

%) e

1 of

50

(2%

)R

R, 2

.08

(0.2

0-22

.23)

22 m

ore

per

1,00

0 (f

rom

16

few

er

to 4

25 m

ore)

Low

Impo

rtan

t

Mor

talit

y (f

ollo

w-u

p m

ean,

2.3

y) f

1 g R

ando

miz

ed

tria

lsSe

riou

s c N

o se

riou

s in

cons

iste

ncy h

No

seri

ous

indi

rect

ness

Seri

ous d

Non

e1

of 5

0 (2

%) i , j

1 of

48

(2.1

%) k

RR

, 1.0

4 (0

.07-

16.1

9) l , m

1

mor

e pe

r 1,

000

(fro

m 1

9 fe

wer

to

316

mor

e)

Low

Cri

tical

Maj

or b

leed

(non

fata

l) (f

ollo

w-u

p, 2

.3-8

y)

3 g , n O

bser

vatio

nal

stud

ies n

No

seri

ous

limita

tions

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s d N

one

0 of

147

(0%

) o 0

of 6

0 (0

%)

Not

poo

led p

Not

poo

led

Very

low

Impo

rtan

t

Bib

liogr

aphy

: Gly

nn R

J, R

idke

r PM

, Gol

dhab

er S

Z, B

urin

g JE

. Eff

ect

of lo

w-d

ose

aspi

rin

on t

he o

ccur

renc

e of

ven

ous

thro

mbo

embo

lism

: a r

ando

miz

ed t

rial

.[Sum

mar

y fo

r pa

tient

s in

Ann

Int

ern

Med

. 20

07;1

47(8

):I34

; PM

ID: 1

7938

386]

. Ann

Int

ern

Med

. 200

7;14

7(8)

:525

-533

. Erk

an D

, Har

riso

n M

J, L

evy

R, e

t al.

Asp

irin

for p

rim

ary

thro

mbo

sis p

reve

ntio

n in

the

antip

hosp

holip

id sy

ndro

me:

a ra

ndom

ized

, do

uble

-blin

d, p

lace

bo-c

ontr

olle

d tr

ial i

n as

ympt

omat

ic a

ntip

hosp

holip

id a

ntib

ody-

posi

tive

indi

vidu

als.

Art

hrit

is R

heum

. 200

7;56

(7):2

382-

2391

. Her

eng

T, L

ambe

rt M

, Hac

hulla

E, e

t al.

Infl u

ence

of a

spir

in

on th

e cl

inic

al o

utco

mes

of 1

03 a

nti-p

hosp

holip

id a

ntib

odie

s-po

sitiv

e pa

tient

s. L

upus

. 200

8;17

(1):1

1-15

. Tek

toni

dou

MG

, Las

kari

K, P

anag

iota

kos

DB

, Mou

tsop

oulo

s H

M. R

isk

fact

ors

for

thro

mbo

sis

and

prim

ary

thro

mbo

sis

prev

entio

n in

pat

ient

s w

ith s

yste

mic

lupu

s er

ythe

mat

osus

with

or

with

out a

ntip

hosp

holip

id a

ntib

odie

s. A

rthr

itis

Rhe

um. 2

009;

61(1

):29-

36. S

ee T

able

S1,

S3,

S4,

S7,

and

S11

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Erk

an e

t al a

nd G

lynn

et a

l are

RC

Ts; i

n ad

ditio

n, H

eren

g et

al,

Erk

an e

t al,

and

Tekt

onid

ou e

t al p

rovi

ded

obse

rvat

iona

l dat

a.

b Erk

an e

t al a

nd G

lynn

et a

l. c E

rkan

et a

l ter

min

ated

ear

ly a

s ev

ent r

ates

wer

e lo

wer

than

exp

ecte

d an

d la

rger

sam

ple

size

was

infe

asib

le.

d Num

ber

of e

vent

s w

as v

ery

smal

l. e E

vent

rate

s are

from

Erk

an e

t al (

RC

T) (

n 5

98)

, as s

econ

d R

CT

(Gly

nn e

t al)

did

not r

epor

t eve

nt ra

tes.

In E

rkan

et a

l, H

R o

f com

posi

te o

utco

me

(art

eria

l or v

enou

s thr

ombo

sis,

incl

udin

g st

roke

, PE

, DV

T,

acut

e M

I), 1

.04

(95%

CI,

0.6

9-1.

56),

P 5

.83.

Num

ber

of v

enou

s ev

ents

: int

erve

ntio

n 2

of 4

8, p

lace

bo 0

of 5

0. G

lynn

et a

l (R

CT,

n 5

1,3

70),

HR

for

VT

E, 0

.81

(95%

CI,

0.4

2-1.

54).

In a

dditi

on, o

bser

vatio

nal

stud

ies

repo

rted

com

posi

te o

utco

mes

incl

udin

g bo

th a

rter

ial a

nd v

enou

s ev

ents

(Erk

an e

t al,

Her

eng

et a

l, an

d Te

kton

idou

et a

l).

f In

addi

tion

to th

e R

CT,

one

obs

erva

tiona

l stu

dy h

ad fo

llow

-up

of 2

.5 y

(SD

, 0.8

y).

g Erk

an e

t al e

ncom

pass

es b

oth

an R

CT

and

an

obse

rvat

iona

l stu

dy.

h Inc

onsi

sten

cy n

ot a

sses

sed

as is

one

stu

dy, a

lthou

gh E

rkan

et a

l enc

ompa

sses

bot

h a

rele

vant

RC

T a

nd a

n ob

serv

atio

nal c

ompo

nent

. i I

nter

vent

ion

was

81

mg

od.

j Cau

se o

f dea

th w

as n

ot r

epor

ted.

k C

ompa

riso

n gr

oup

rece

ived

no

ASA

. l R

R c

alcu

late

d fr

om e

vent

rat

es (u

nadj

uste

d).

m In

add

ition

, in

the

obse

rvat

iona

l stu

dy (E

rkan

et a

l) th

e m

orta

lity

rate

was

0%

in b

oth

grou

ps.

n Erk

an e

t al,

Her

eng

et a

l, Te

kton

idou

et a

l. In

add

ition

, Erk

an e

t al (

RC

T) r

epor

ted

0 m

ajor

ble

edin

g ev

ents

bot

h gr

oups

. o E

rkan

et a

l als

o in

clud

ed a

n R

CT

(n 5

94)

with

0 m

ajor

non

fata

l ble

edin

g ev

ents

in b

oth

the

ASA

and

no

ASA

gro

ups.

p R

R n

ot e

stim

able

(rat

e of

0 b

oth

grou

ps).




Tabl

e S3

1 —St

udi

es E

xam

inin

g th

e E

ffec

t of

Exp

osu

re t

o St

atin

s on

DV

T, P

E, a

nd d

eath

: Cli

nica

l D

escr

ipti

on a

nd R

esu

lts:

RC

T a

nd C

ohor

t St

udi

es

Stud

y/Ye

ar; T

rial

Nam

e;

Cou

ntry

; Stu

dy D

esig

nIn

terv

entio

n an

d C

ompa

rato

rSa

mpl

e Si

zePo

pula

tion

Cha

ract

eris

tics

Len

gth

of

Fol

low

-up

Res

ults

Com

men

ts

Gra

dy e

t al 66

, 200

0;

Uni

ted

Stat

es;

Pros

pect

ive,

co

mpa

rativ

e co

hort

st

udy

from

H

ER

S tr

ial

Stat

in th

erap

y2,

763

Wom

en r

ando

miz

ed

in H

ER

S tr

ial

(1,3

80 r

ando

miz

ed

to r

ecei

ve e

stro

gen;

1,

383

to p

lace

bo)

Post

men

opau

sal w

omen

,

80

y, w

ith C

HD

but

no

pre

viou

s V

TE

and

no

hys

tere

ctom

y

HE

RS

tria

l: m

ean

follo

w-u

p 4.

1 y

(ran

ge 3

.6-5

.3 y

)

Clin

ical

eve

nts

acco

rdin

g

to s

tatin

use

dur

ing

the

HE

RS

tria

l:

Inte

ract

ion

betw

een

horm

one

repl

acem

ent

ther

apy

and

stat

in

use

for

1-y

even

ts:

P 5

.57

No

stat

in th

erap

y

Mea

n du

ratio

n of

fo

llow

-up:

3.3

yB

asel

ine

use

Mea

n ag

e �

SD

, y

Dur

atio

n of

follo

w-u

p fo

r w

omen

who

us

ed s

tatin

s fo

r � 3

y

(mea

n �

SD

): 5.

7 �

2.4

y

Stat

in th

erap

y: 1

,004

Stat

in th

erap

y: 6

6.9

� 6

.18

No

stat

in th

erap

y: 1

,467

No

stat

in th

erap

y:

66.5

� 7

.04

V

TE

s:

Sex:

100

% w

omen

N

o st

atin

use

: 32

of

1,

467

(5.5

a )

Dur

atio

n of

follo

w-u

p fo

r w

omen

who

use

d st

atin

s fo

r , 3

y

(mea

n �

SD

): 5.

7 �

2.4

y

Bas

elin

e st

atin

use

rs

tend

ed to

be

whi

te,

bett

er e

duca

ted,

he

alth

ier,

with

few

co

mor

bid

cond

ition

s an

d m

ore

likel

y to

ta

ke A

SA

St

atin

use

: 9 o

f

1,00

4 (2

.2 a )

(Con

tinu

ed)




Stud

y/Ye

ar; T

rial

Nam

e;

Cou

ntry

; Stu

dy D

esig

nIn

terv

entio

n an

d C

ompa

rato

rSa

mpl

e Si

zePo

pula

tion

Cha

ract

eris

tics

Len

gth

of

Fol

low

-up

Res

ults

Com

men

ts

A

djus

ted

HR

: 0.4

4

(95%

CI,

0.2

1-0.

94),

P 5

.033

A

ll-ca

use

mor

talit

y

N

o st

atin

use

: 159

of

1,

467

(26.

8 a )

S

tatin

use

: 75

of

1,

004

(18.

4 a )

A

djus

ted

HR

: 0.7

4

(95%

CI,

0.5

6-0.

99),

P 5

.040

Any

sta

tin u

se

V

TE

s:

N

o st

atin

use

: 28

of

1,

467

(6.1

a )

St

atin

use

: 13

of

1,

270

(2.5

a )

A

djus

ted

HR

: 0.4

5

(95%

CI,

0.2

3-0.

88),

P 5

.020

M

orta

lity

N

o st

atin

use

: 134

of

1,

467

(28.

4 a )

St

atin

use

: 100

of

1,

270

(18.

9 a )

A

djus

ted

HR

: 0.6

7

(95%

CI,

0.5

1-0.

87),

P 5

.003

Use

d st

atin

s .

3 y

A

ll-ca

use

mor

talit

y: H

R,

0.

70 (9

5% C

I 0.

52-0

.93)

, P

5 .0

1

V

TE

s: H

R, 0

.40

(9

5% C

I, 0

.18-

0.91

), P

5 .0

3

Tabl

e S3

1—C

onti

nued

(Con

tinu

ed)




Tabl

e S3

1—C

onti

nued

Stud

y/Ye

ar; T

rial

Nam

e;

Cou

ntry

; Stu

dy D

esig

nIn

terv

entio

n an

d C

ompa

rato

rSa

mpl

e Si

zePo

pula

tion

Cha

ract

eris

tics

Len

gth

of

Fol

low

-up

Res

ults

Com

men

ts

Ray

et a

l, 67 2

001;

Can

ada;

R

etro

spec

tive

coho

rt s

tudy

Prim

ary

coho

rt:

Prim

ary

coho

rt: 1

25,8

62

adul

ts; 1

90,6

01

pers

on-y

ears

of

drug

use

Ont

ario

res

iden

ts

aged

� 6

5 y

enro

lled

in th

e O

ntar

io H

ealth

In

sura

nce

Plan

The

ave

rage

dur

atio

n of

ob

serv

atio

n 1.

4 y

for

both

sta

tins

and

thyr

oid

repl

acem

ent t

hera

py

(pri

mar

y co

hort

)

No.

of c

ases

of

D

VT

/1,0

00

patie

nt-y

ears

(a

djus

ted

HR

[95%

CI]

)

Stat

ins

Thy

roid

rep

lace

men

t th

erap

yPr

imar

y co

hort

Seco

ndar

y co

hort

: 89,

508

wom

en; 1

24,5

68

pers

on-y

ears

of

drug

use

Mea

n ag

e (p

rim

ary

coho

rt),

72.9

y

Men

and

wom

en

Mea

n ag

e (s

econ

dary

co

hort

), 73

.5 y

Non

-sta

tin

lipid

-low

erin

g ag

ents

Sinc

e es

trog

en u

se in

th

e se

cond

ary

coho

rt

had

to b

e m

utua

lly

excl

usiv

e, th

ese

part

icip

ants

may

hav

e di

ffer

ed s

light

ly fr

om

wom

en in

the

prim

ary

coho

rt

R

ecei

ving

thyr

oid

re

plac

emen

t the

rapy

: 10

.9 (H

R, 1

.0 [r

efer

ent]

)

Seco

ndar

y co

hort

(w

omen

onl

y): a

s fo

r pr

imar

y co

hort

, plu

s es

trog

ens

R

ecei

ving

non

-sta

tin

lip

id-lo

wer

ing

agen

ts: 9

.3

(HR

, 0.9

7 [0

.79-

1.18

])

R

ecei

ving

sta

tin th

erap

y:

7.

4 (H

R, 0

.78

[0.6

8-0.

87])

Men

(C

onti

nued

)




Tabl

e S3

1—C

onti

nued

(Con

tinu

ed)

Stud

y/Ye

ar; T

rial

Nam

e;

Cou

ntry

; Stu

dy D

esig

nIn

terv

entio

n an

d C

ompa

rato

rSa

mpl

e Si

zePo

pula

tion

Cha

ract

eris

tics

Len

gth

of

Fol

low

-up

Res

ults

Com

men

ts

R

ecei

ving

sta

tin th

erap

y:

6.

7 (H

R, 0

.97

[0.7

8-1.

22])

Wom

en

R

ecei

ving

sta

tin th

erap

y:

8.

1 (H

R, 0

.72

[0.6

3-0.

82])

Seco

ndar

y co

hort

:

Thy

roid

rep

lace

men

t the

rapy

:

11.9

(HR

, 1.0

[ref

eren

t])

Stat

in th

erap

y: 7

.6

(H

R, 0

.68

[0.5

9-0.

79])

Smee

th e

t al 68

/200

9;

Uni

ted

Kin

gdom

; ob

serv

atio

nal s

tudy

, po

pula

tion

base

d

Vari

ous

stat

ins

(fi rs

t pre

scri

ptio

n)

com

pare

d w

ith

non-

stat

in u

sers

(n

o re

cord

of s

tatin

use

)

Tota

l N, 7

29,5

29T

HIN

dat

abas

e:

age

40-8

0 y

betw

een

Janu

ary

1995

and

D

ecem

ber

2006

Med

ian

follo

w-u

p af

ter

inde

x da

te

(dat

e of

fi rs

t use

of

sta

tin):

4.4

y

VT

E r

isk

in e

xpos

ed 1

.1%

,

unex

pose

d 1.

0%; H

R

adju

sted

for

age

and

sex,

1.

18 (9

5% C

I, 1

.06-

1.31

); H

R fu

lly a

djus

ted.

1.

02 (0

.88-

1.18

)

Stat

in u

sers

: 129

,288

Non

-sta

tin u

sers

: 600

,241

5.5

mill

ion

patie

nts

deri

ved

from

303

ge

nera

l pra

ctic

es

Gly

nn e

t al 69

/200

9;

Uni

ted

Stat

es

Ros

uvas

tatin

(20

mg/

d)To

tal:

17,8

02A

ppar

ently

hea

lthy

su

bjec

ts w

ith L

DL

ch

oles

tero

l ( ,

130

mg/

dL)

and

elev

ated

hi

gh-s

ensi

tivity

C

-rea

ctiv

e pr

otei

n ( �

2.0

mg/

L),

men

� 5

0 y

and

wom

en �

60

y

Med

ian

follo

w-u

p: 1

.9 y

(m

axim

um 5

.0 y

)Pr

imar

y ef

fi cac

y an

alys

is b

DV

T d

iagn

osed

with

ul

tras

ound

or

veno

gram

; PE

di

agno

sed

with

an

giog

ram

, CT

sca

n,

or

/ s

can

Ros

uvas

tatin

: 8,9

01

Rid

ker

et a

l 70 /2

008;

U

nite

d St

ates

Pl

aceb

o

Rid

ker

et a

l 71 /2

007;

U

nite

d St

ates

; JU

PIT

ER

tria

l; R

CT

Plac

ebo:

8,9

01

PE

(No.

pat

ient

s,

No.

eve

nts

per

100

pers

on-y

ears

)

Ros

uvas

tatin

: 17,

0.0

9

Plac

ebo:

22,

0.1

2

Am

ong

all 1

7,80

2

JUPI

TE

R p

atie

nts:

HR

(95%

CI)

: 0.7

7

(0

.41-

1.45

), P

5 .4

2




Tabl

e S3

1—C

onti

nued

(Con

tinu

ed)

Stud

y/Ye

ar; T

rial

Nam

e;

Cou

ntry

; Stu

dy D

esig

nIn

terv

entio

n an

d C

ompa

rato

rSa

mpl

e Si

zePo

pula

tion

Cha

ract

eris

tics

Len

gth

of

Fol

low

-up

Res

ults

Com

men

ts

3

2.0%

wer

e �

70

y

of a

ge

DV

T (N

o. p

atie

nts,

N

o. e

vent

s pe

r 10

0 pe

rson

-yea

rs)

3

8.2%

wer

e w

omen

Age

, med

ian

R

osuv

asta

tin: 6

6.0

y

R

osuv

asta

tin: 1

7, 0

.09

Con

sist

ent e

ffec

ts

in a

ll su

bgro

ups

exam

ined

Pl

aceb

o: 6

6.0

y

Sex

(% fe

mal

e)

Pl

aceb

o: 3

8, 0

.20

R

osuv

asta

tin: 3

,426

of

8,

901

(38.

5%)

Pl

aceb

o: 3

,375

of

8,

901

(37.

9%)

HR

(95%

CI)

: 0.4

5

(0

.25-

0.79

), P

5 .0

04B

leed

ing

(not

defi

ned

): ro

suva

stat

in: 2

58 o

f 8,

901

(2.9

%)

Hig

h-se

nsiti

vity

C-r

eact

ive

prot

ein

� 5

mg/

L (%

) R

osuv

asta

tin: 4

0.6%

Plac

ebo:

41.

9%

In b

oth

rosu

vast

atin

and

pl

aceb

o gr

oups

, 37.

6%

had

a B

MI

� 3

0

Plac

ebo:

275

of 8

,901

(3

.1%

), P

5 .4

5

Safe

ty a

naly

sis c

PE

(No.

pat

ient

s,

No.

eve

nts

per

100

pers

on-y

ears

)

Ros

uvas

tatin

: 17,

0.0

9

Plac

ebo:

24,

0.1

2




Stud

y/Ye

ar; T

rial

Nam

e;

Cou

ntry

; Stu

dy D

esig

nIn

terv

entio

n an

d C

ompa

rato

rSa

mpl

e Si

zePo

pula

tion

Cha

ract

eris

tics

Len

gth

of

Fol

low

-up

Res

ults

Com

men

ts

HR

(95%

CI)

: 0.7

1

(0

.38-

1.32

), P

5 .2

7 IC

H (n

umbe

r):

rosu

vast

atin

: 6

(0.1

%)

D

VT

(No.

pat

ient

s,

No.

eve

nts

per

100

pers

on-y

ears

)

Ros

uvas

tatin

: 18,

0.0

9

Plac

ebo:

40,

0.2

1Pl

aceb

o: 9

(0.1

%),

P 5

.44

HR

(95%

CI)

: 0.4

5

(0

.26-

0.78

), P

5 .0

03G

I bl

eedi

ng e

vent

: NR

sp

ecifi

cally

; no

sign

ifi ca

nt d

iffer

ence

be

twee

n gr

oups

in

GI

“sys

tem

s”

Mor

talit

y in

VT

E: A

mon

g

th

e 94

par

ticip

ants

(3

4 in

ros

uvas

tatin

gro

up

and

60 in

pla

cebo

gro

up)

in w

hom

VT

E d

evel

oped

, 21

die

d by

Mar

ch 3

0, 2

008

(14

in th

e pl

aceb

o gr

oup

and

7 in

the

rosu

vast

atin

gr

oup)

(HR

, 0.8

8; 9

5%

CI,

0.3

5-2.

18; P

5 .7

8)

All-

caus

e m

orta

lity:

1.0

0 an

d

1.25

per

100

per

son-

year

s of

follo

w-u

p in

the

rosu

vast

atin

and

pla

cebo

gr

oups

, res

pect

ivel

y (H

R, 0

.80;

95%

C

I, 0

.67-

0.97

; P 5

.02)

C

HD

5 co

rona

ry h

eart

dis

ease

; IC

H 5

intr

acra

nial

hem

orrh

age;

HE

RS

5 H

eart

and

Est

roge

n/Pr

oges

tin R

epla

cem

ent S

tudy

; JU

PIT

ER

5 Ju

stifi

catio

n fo

r th

e U

se o

f Sta

tins

in P

reve

ntio

n: a

n In

terv

entio

n Tr

ial E

valu

atin

g R

osuv

asta

tin; L

DL

5 lo

w-d

ensi

ty li

popr

otei

n; T

HIN

5 T

he H

ealth

Im

prov

emen

t Net

wor

k . S

ee T

able

S1

and

S3 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a E

vent

s pe

r 1,

000

patie

nt-y

ear

follo

w-u

p.

b Per

form

ed o

n th

e ba

sis

of 9

4 ca

ses

iden

tifi e

d be

fore

Mar

ch 2

0, 2

008,

whe

n tr

ial s

topp

ed e

arly

for

effi c

acy.

c P

erfo

rmed

on

the

basi

s of

99

case

s th

at w

ere

iden

tifi e

d be

fore

the

stud

y w

as u

nble

nded

. Tabl

e S3

1—C

onti

nued




Tabl

e S3

2 —St

udi

es E

xam

inin

g th

e E

ffec

t of

Exp

osu

re t

o St

atin

s on

DV

T, P

E, a

nd D

eath

: Cli

nica

l D

escr

ipti

on a

nd R

esu

lts:

Cas

e-C

ontr

ol S

tudi

es

Stud

y/Ye

ar; T

rial

N

ame;

Cou

ntry

Inte

rven

tion

and

Com

para

tor

Sam

ple

Size

Popu

latio

n C

hara

cter

istic

sL

engt

h of

F

ollo

w-u

p, M

ean

Res

ults

Com

men

ts

Bro

phy

et a

l 72 /2

009;

U

nite

d St

ates

Stat

in u

se

vs n

o st

atin

use

Cas

es: 6

0A

ge:

NA

: cur

rent

st

atin

use

ass

esse

d by

sel

f-re

port

Stat

in u

se a

nd c

ases

of v

ascu

lar

acce

ss

thro

mbo

sis:

Con

trol

s: 4

1

Cas

es: p

atie

nts

who

(1) e

xper

ienc

ed

two

or m

ore

epis

odes

of

vas

cula

r ac

cess

th

rom

bosi

s in

12

mo

diag

nose

d by

ultr

asou

nd,

fi stu

logr

am, o

r ph

ysic

al

exam

inat

ion;

and

(2

) req

uire

d tw

o or

m

ore

new

dia

lysi

s ac

cess

pla

cem

ents

not

re

late

d to

infe

ctio

n in

2

y; o

r (3

) pat

ient

s w

ho

coul

d no

t mai

ntai

n a

pate

nt A

VG

or

AVF

w

ithin

2 m

o th

at

nece

ssita

ted

plac

emen

t of

a p

erm

anen

t cat

hete

r or

the

perm

anen

t co

nver

sion

to

peri

tone

al d

ialy

sis.

I:

53.

8 y

(S

D, 1

4.2

y)

Cas

es: 1

8

of 6

0 (3

1%)

C

ontr

ols:

8

of

41

(20.

5%)

P

5 .3

5

C

: 54.

8 y

(S

D, 1

0.2

y)M

ultiv

aria

ble

logi

stic

regr

essi

on fo

r va

scul

ar a

cces

s th

rom

bosi

s: O

R,

5.12

(95%

CI,

1.

25-2

0.90

); P

5 .0

2

P

5 .6

9

Sex,

fem

ale:

I:

27

(45%

)

C

: 16

(39%

)

P

5 .5

5

Rac

e, b

lack

:

I:

55

(92%

)

Con

trol

s: p

atie

nts

who

had

not

ex

peri

ence

d va

scul

ar

acce

ss th

rom

bosi

s in

at l

east

3 y

C

: 39

(95%

)

P

5 .4

9

All

patie

nts

had

st

age

5 ch

roni

c ki

dney

dis

ease

an

d re

ceiv

ed

mai

nten

ance

he

mod

ialy

sis

for .

3 y

(C

onti

nued

)




Stud

y/Ye

ar; T

rial

N

ame;

Cou

ntry

Inte

rven

tion

and

Com

para

tor

Sam

ple

Size

Popu

latio

n C

hara

cter

istic

sL

engt

h of

F

ollo

w-u

p, M

ean

Res

ults

Com

men

ts

Dog

gen

et a

l 73 /2

004;

U

nite

d St

ates

All

case

s ha

d a

fi rst

ve

nous

thro

mbo

sis

betw

een

Janu

ary

1,

1995

and

Dec

embe

r 31

, 20

00 a

nd w

ere

taki

ng:

Cas

es: 4

65 (D

VT

in

the

leg,

348

; PE

, 42

; bot

h, 7

5)

Age

: 30-

89 y

NR

; dur

atio

n of

us

e ca

lcul

ated

from

ph

arm

acy

reco

rds

Veno

us th

rom

bosi

s

(DV

T a

nd/o

r PE

) (fi

rst O

R a

djus

ted

for

mat

chin

g fa

ctor

s,

seco

nd O

R a

lso

adju

sted

for

vasc

ular

di

seas

e hi

stor

y):

Cur

rent

use

defi

ned

as:

th

e re

ceip

t of a

t lea

st

one

lipid

-low

erin

g pr

escr

iptio

n pr

ior

to

the

inde

x da

te w

ith

enou

gh m

edic

atio

ns

to la

st u

ntil

the

inde

x da

te, a

ssum

ing

80%

co

mpl

ianc

e

Sex:

100

% w

omen

Incl

usio

n cr

iteri

a:

al

l pat

ient

s w

ere

post

men

opau

sal

Con

trol

s: 1

,962

Cas

es:

I1

: No

lipid

-low

erin

g

med

icat

ion

Any

sta

tin u

se

vs

no

use:

I2

: Sta

tin u

sers

(sim

vast

atin

, low

dose

and

hig

h do

se;

an

d pr

avas

tatin

)

O

R, 0

.84

(9

5% C

I, 0

.51-

1.37

)

O

R, 0

.64

(9

5% C

I, 0

.39

to 1

.07)

I3: U

sers

of n

on-s

tatin

lipid

-low

erin

g

med

icat

ions

, inc

ludi

ng

bi

le-a

cid

sequ

estr

ants

,

fi bra

tes,

and

nia

cins

Use

of s

imva

stat

in:

O

R, 0

.69

(9

5% C

I, 0

.40-

1.20

)

O

R, 0

.51

(95%

CI,

0.2

9 -0

.91)

Con

trol

s: fr

eque

ncy

mat

ched

on

age,

ca

lend

ar y

ear

of

iden

tifi c

atio

n, a

nd

trea

ted

hype

rten

sion

st

atus

to d

istr

ibut

ions

of

MI

case

s

Dat

a al

so p

rese

nted

on lo

w a

nd h

igh

dose

sim

vast

atin

Use

of p

rava

stat

in:

O

R, 2

.30

(9

5% C

I, 0

.81-

6.49

)

O

R, 1

.85

(9

5% C

I, 0

.65-

5.26

)

Use

of o

ther

lipid

-low

erin

g ag

ents

:

O

R, 1

.68

(9

5% C

I, 0

.75-

3.79

)

O

R, 1

.43

(9

5% C

I, 0

.62-

3.25

)

Tabl

e S3

2—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

ar; T

rial

N

ame;

Cou

ntry

Inte

rven

tion

and

Com

para

tor

Sam

ple

Size

Popu

latio

n C

hara

cter

istic

sL

engt

h of

F

ollo

w-u

p, M

ean

Res

ults

Com

men

ts

Lac

ut e

t al 74

/200

4;

Fra

nce;

ED

ITH

Cas

es: p

atie

nts

with

doc

umen

ted

sym

ptom

atic

DV

T

of th

e lo

wer

lim

bs

(eith

er d

ista

l or

prox

imal

con

fi rm

ed b

y du

plex

ultr

ason

ogra

phy)

or

/and

an

obje

ctiv

ely

docu

men

ted

PE, n

ot

rela

ted

to a

maj

or

acqu

ired

ris

k fa

ctor

fo

r V

TE

Cas

es: 3

77 (D

VT,

252

; PE

, 46;

bot

h, 7

9)A

ge:

Con

trol

s fo

llow

ed fo

r up

to 3

mo

for

VT

ESt

atin

use

, cas

es o

f VT

E:

Popu

latio

ns in

L

acut

200

474 a

nd

2008

75 o

verl

ap. T

he

2008

pub

licat

ion

incl

uded

long

er

recr

uitm

ent p

erio

d bu

t on

ly in

clud

ed c

ases

w

ithou

t maj

or r

isk

fact

ors

for

VT

E,

whe

reas

Lac

ut 2

004

incl

uded

69

of

377

patie

nts

in e

ach

grou

p w

ith m

ajor

ac

quir

ed r

isk

fact

ors

for

VT

E

I:

20

of 3

77

C

: 44

of 3

77

O

R, 0

.42

(9

5% C

I, 0

.23-

0.76

); P

5 .0

02

Con

trol

s: 3

77

Cas

es: 6

8.0

y

(SD

, 16.

4 y)

C

urre

nt s

tatin

us

e w

as c

onsi

dere

d (w

ithin

pri

or 3

mo)

Stat

ins

incl

uded

pra

vast

atin

,

sim

vast

atin

, ato

rvas

tatin

; re

sults

not

str

atifi

ed b

y sp

ecifi

c st

atin

C: 6

8.1

y

(SD

, 16.

2 y)

Con

trol

s: h

ospi

taliz

ed

patie

nts

mat

ched

fo

r ag

e ( �

2 y

), se

x,

geog

raph

ical

ori

gin,

an

d m

ajor

acq

uire

d ri

sk fa

ctor

s of

VT

E,

and

no p

rior

VT

E

P 5

.90

Sex,

fem

ale:

St

ratifi

ed

anal

yses

of

vari

ous

leve

ls o

f ASA

us

e, C

AD

, sec

onda

ry

vs id

iopa

thic

VT

E,

age,

sex

did

not

si

gnifi

cant

ly in

tera

ct

with

odd

s of

VT

E

C

ases

: 211

(55.

9%)

C

: 211

(55.

9%)

Incl

usio

n cr

iteri

a:

Pa

tient

s . 1

8 y

of a

ge h

ospi

taliz

ed

betw

een

May

200

0 an

d M

ay 2

002

Tabl

e S3

2—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

ar; T

rial

N

ame;

Cou

ntry

Inte

rven

tion

and

Com

para

tor

Sam

ple

Size

Popu

latio

n C

hara

cter

istic

sL

engt

h of

F

ollo

w-u

p, M

ean

Res

ults

Com

men

ts

Lac

ut e

t al 75

/200

8;

Fra

nce;

ED

ITH

Cas

es: p

atie

nts

with

an

obje

ctiv

ely

confi

rm

ed

sym

ptom

atic

VT

E a

nd

no m

ajor

acq

uire

d ri

sk fa

ctor

for

VT

E

Cas

es: 6

77 (D

VT,

303

; PE

, 121

; bot

h, 2

56)

Age

:C

urre

nt s

tatin

use

(t

aken

with

in 1

wk)

Cur

rent

sta

tin u

se:

Con

trol

s: 6

77

Con

trol

s: p

atie

nts

mat

ched

by

age

( � 5

y)

and

sex

and

with

out

a pr

evio

us e

piso

de o

f ob

ject

ivel

y do

cum

ente

d V

TE

or

lifel

ong

antic

oagu

lant

ther

apy

I:

67.

9 y

(S

D, 1

7.0

y)

Cas

es: 5

5 (8

.1%

)

C

: 68.

0 y

(S

D, 1

7.0

y)

C: 9

1 (1

3.4%

)

Sex,

fem

ale:

OR

VT

E in

sta

tin

vs

non

use

r, 0.

53

(95%

CI,

0.3

7-0.

78)

I:

56.

7%A

djus

ted

OR

, 0.6

0

(0.3

9-0.

93)

C

: 56.

7%A

djus

ted

for

at

hero

thro

mbo

sis,

as

piri

n us

e, s

uspe

cted

as

the

mai

n co

nfou

ndin

g fa

ctor

s, a

nd c

hron

ic

pulm

onar

y di

seas

e,

BM

I, a

nd fa

mily

his

tory

of

VT

E

BM

I:

I:

26.

1 (S

D, 4

.7)

C

: 24.

7 (S

D, 5

.6)

P

, .0

001

Incl

usio

n cr

iteri

a,

case

s an

d co

ntro

ls:

patie

nts .

18

y of

age

hos

pita

lized

be

twee

n M

ay 2

000

and

Dec

embe

r 20

04,

with

out m

ajor

ac

quir

ed r

isk

fact

or o

f VT

E

(no

surg

ery

or p

last

er

cast

imm

obili

zatio

n in

the

past

3 m

o,

preg

nanc

y or

del

iver

y in

the

past

3 m

o,

or a

ctiv

e ca

ncer

)

Tabl

e S3

2—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

ar; T

rial

N

ame;

Cou

ntry

Inte

rven

tion

and

Com

para

tor

Sam

ple

Size

Popu

latio

n C

hara

cter

istic

sL

engt

h of

F

ollo

w-u

p, M

ean

Res

ults

Com

men

ts

Ram

char

an e

t al 76

/200

9;

Net

herl

ands

Stat

in u

se, c

urre

nt

(use

d m

edic

atio

n at

tim

e of

the

VT

E

or w

hen

ques

tionn

aire

fi l

led

out [

cont

rols

])

Ent

ire

stud

y: 4

,538

cas

es

of V

TE

, 154

us

ed s

tatin

s

Age

: 18-

70 y

, m

edia

n 49

.6 y

(2

5.7-

67.8

y)

for

case

s; 4

8.3

y (2

5.7-

66.8

y)

for

cont

rols

(5

4.2%

fem

ale

for

case

s, 5

3.8%

fo

r co

ntro

ls)

12 m

o pr

ior

to

inde

x ca

se/d

ate

“Ven

ous

thro

mbo

sis”

:

stat

in c

urre

nt u

se

vs n

o st

atin

use

: OR

, 0.

55 (9

5% C

I, 0

.46-

0.67

) (u

nadj

uste

d)

“Ven

ous

thro

mbo

sis”

w

as th

e re

port

ed

outc

ome

and

appe

ars

to

incl

ude

DV

T

and/

or P

E

5,91

4 co

ntro

l su

bjec

ts, m

atch

ed

on a

ge a

nd s

ex,

354

used

sta

tins

Cas

es o

f fi r

st

epis

ode

DV

T a

nd/o

r PE

(pro

babl

e or

defi

nite

) wer

e ob

tain

ed fr

om a

la

rge

popu

latio

n-ba

sed

stud

y (M

EG

A s

tudy

)

OR

adj

uste

d

for

age,

sex

, BM

I,

athe

rosc

lero

tic

dise

ase,

and

the

othe

r m

edic

atio

ns, 0

.45

(95%

CI,

0.3

6-0.

56)

Con

trol

s w

ere

part

ners

of p

atie

nts

or w

ere

recr

uite

d vi

a ra

ndom

-dig

it di

alin

g

DV

T p

rava

stat

in

vs

sim

vast

atin

ad

just

ed O

R, 0

.59

(95%

CI,

0.3

1-1.

11)

Cas

es h

ad h

ighe

r B

MI

and

mor

e of

ten

had

athe

rosc

lero

tic d

isea

se

and

mal

igna

ncy,

dia

bete

s,

or s

urge

ry, a

s co

mpa

red

with

con

trol

sub

ject

s (T

able

1, s

tatis

tics

not r

epor

ted)

PE: a

djus

ted

OR

,

0.56

(95%

CI

0.43

-0.7

5)

DV

T: a

djus

ted

OR

, 0.3

1

(95%

CI

0.23

-0.4

2)

Tabl

e S3

2—C

onti

nued

(Con

tinu

ed)




Stud

y/Ye

ar; T

rial

N

ame;

Cou

ntry

Inte

rven

tion

and

Com

para

tor

Sam

ple

Size

Popu

latio

n C

hara

cter

istic

sL

engt

h of

F

ollo

w-u

p, M

ean

Res

ults

Com

men

ts

Sore

nsen

et a

l 77 /2

009;

D

enm

ark

Stat

in u

se in

last

1 y

5,82

4 Pa

tient

s w

ith

VT

E a

nd 5

8,24

0 co

ntro

ls m

atch

ed

on a

ge, s

ex, c

ount

y

Age

. 7

1 y:

47.

8%;

rang

e, 1

8-89

yN

APr

eval

ence

of s

tatin

use

in V

TE

pat

ient

s 4%

, co

ntro

ls 4

%

C

urre

nt u

se: �

90

d

F

orm

er u

se: 9

1-36

5 d

Fem

ale:

54.

7%

Cur

rent

sta

tin u

se:

3,36

6 W

ere

unpr

ovok

ed

(no

risk

fact

ors)

: 2,3

10

with

DV

T a

nd 1

,056

w

ith P

E

V

TE

: OR

, 0.7

4

(95%

CI,

0.6

3-0.

85

U

npro

voke

d V

TE

: OR

,

0.79

(95%

CI,

0.6

5-0.

96)

D

VT:

OR

, 0.8

1

(95%

CI,

0.6

8-0.

97)

PE

: OR

, 0.6

1

(95%

CI,

0.4

8-0.

78)

For

mer

sta

tin u

se:

V

TE

: OR

, 0.7

0 (0

.53-

0.92

)

U

npro

voke

d V

TE

: OR

,

0.97

(95%

CI,

0.69

-1.3

6)

All

OR

are

adj

uste

d

for

mul

tiple

pot

entia

l co

nfou

nder

s

Yang

et a

l 78 /2

002;

U

nite

d K

ingd

omC

urre

nt/r

ecen

t ( �

90

d)

and

past

. 9

0 d

stat

in u

se

Tota

l N 5

84,

093

(coh

ort s

tudy

)G

ener

al P

ract

ice

Res

earc

h D

atab

ase

was

use

d.

Coh

ort s

tudy

: 393

,756

pe

rson

-yea

rsC

ohor

t stu

dy

Ref

eren

ce g

roup

was

the

non-

hype

rlip

idem

ic

non-

stat

in u

sers

Cas

e-co

ntro

l stu

dyF

irst

idio

path

ic V

TE

, co

nfi r

med

or

prob

able

Cas

es: 7

2

C

ontr

ols:

432

C

ontr

ols:

6 m

atch

ed

cont

rols

: age

, sex

, ca

lend

ar ti

me,

tim

e in

dat

abas

e

Cas

e-co

ntro

l stu

dy:

NR

(tim

e of

po

tent

ial e

xpos

ure)

V

TE

and

cur

rent

stat

in u

se: A

djus

ted

rate

ra

tio, 0

.8 (9

5% C

I, 0.

3-2.

7)

A

djus

ted

RR

with

pas

t

stat

in u

se, 2

.4 (0

.6-1

0)

Cas

e-co

ntro

l stu

dy

V

TE

, cur

rent

/rec

ent s

tatin

use:

OR

adj

uste

d fo

r

smok

ing,

BM

I, an

d es

trog

en

us

e, 1

.1 (9

5% C

I, 0

.3-4

.3)

V

TE

: pas

t sta

tin u

se:

O

R a

djus

ted

for s

mok

ing,

B

MI,

and

estr

ogen

use

, 3.

7 (9

5% C

I, 0

.6-2

4)

AVF

5 ar

teri

oven

ous fi

stu

la; C

5 co

ntro

l; C

AD

5 co

rona

ry a

rter

y di

seas

e; E

DIT

H 5

Etu

des d

es D

éter

min

ants

et I

nter

actio

ns d

e la

Thr

ombo

se V

eine

use;

I 5

inte

rven

tion;

ME

GA

5 M

ultip

le E

nvir

onm

enta

l and

G

enet

ic A

sses

smen

t of R

isk

Fac

tors

for

Veno

us T

hrom

bosi

s. S

ee T

able

S1,

S3,

and

S7

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

.

Tabl

e S3

2—C

onti

nued




Tabl

e S3

3 —[S

ecti

on 8

.1]

Eff

ect

of S

tati

ns o

n R

isk

of V

TE

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Impo

rtan

ce

N

o. o

f Pat

ient

sE

ffec

t

Qua

lity

No.

of S

tudi

esD

esig

nL

imita

tions

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

C

onsi

dera

tions

Stat

ins

No

Stat

in U

seR

elat

ive

(95%

CI)

Abs

olut

e

DV

T (f

ollo

w-u

p m

edia

n, 1

.9 y

; ultr

asou

nd o

r ve

nogr

am)

1R

ando

miz

ed

tria

ls a

No

seri

ous

limita

tions

No

seri

ous

inco

nsis

tenc

y b N

o se

riou

s in

dire

ctne

ss c

No

seri

ous

impr

ecis

ion d

Non

e17

of 8

,901

(0

.2%

)38

of 8

,901

(0

.4%

)H

R, 0

.45

(0.2

5-0.

79)

2 fe

wer

pe

r 1,

000

(fro

m 1

few

er

to 3

few

er)

Hig

hYe

s, c

linic

ally

di

agno

sed

DV

T

PE (f

ollo

w-u

p m

edia

n, 1

.9 y

; ang

iogr

am,

/ s

can,

or

CT

sca

n)

1R

ando

miz

ed

tria

lsN

o se

riou

s lim

itatio

nsN

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

No

seri

ous

impr

ecis

ion

Non

e17

of 8

,901

(0

.2%

)22

of 8

,901

(0

.2%

)H

R, 0

.77

(0.4

1-1.

45)

0 fe

wer

pe

r 10

0 (f

rom

0 fe

wer

to

0 m

ore)

Hig

hYe

s, c

linic

ally

di

agno

sed

PE

See

Tabl

e S1

and

S3

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Bod

y of

evi

denc

e co

nsis

ts o

f one

RC

T. S

ix c

ase-

cont

rol s

tudi

es a

nd th

ree

obse

rvat

iona

l stu

dies

are

des

crib

ed in

the

text

. b I

ncon

sist

ency

is n

ot a

pplic

able

as

ther

e is

onl

y on

e st

udy.

Obs

erva

tiona

l dat

a w

ere,

how

ever

, con

sist

ent w

ith th

e tr

ial d

ata.

c T

he s

ingl

e R

CT

(JU

PIT

ER

, Gly

nn e

t al

69 )

was

a la

rge

inte

rnat

iona

l stu

dy in

clud

ing

heal

thy

subj

ects

with

out

diab

etes

, car

diov

ascu

lar

dise

ase,

or

kidn

ey d

isea

se, w

ith L

DL

cho

lest

erol

, 1

30 m

g/dL

and

C

-rea

ctiv

e pr

otei

n .

2 m

g/L

. Res

ults

may

then

be

appl

icab

le o

nly

to s

imila

r pe

rson

s.

d The

num

ber

of e

vent

s w

as lo

w f

or V

TE

(D

VT

1 P

E):

inte

rven

tion

34, c

ontr

ol 6

0, w

hich

is m

uch

less

tha

n th

e op

timal

info

rmat

ion

size

. How

ever

, the

tot

al s

ampl

e si

ze w

as la

rge

(8,9

01 e

ach

grou

p), s

o im

prec

isio

n no

t lik

ely.




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DOI 10.1378/chest.11-2296 2012;141; e195S-e226SChest

Hoang Le, Sam Schulman and M. Hassan MuradDentali, Elie A. Akl, Deborah J. Cook, Alex A. Balekian, Russell C. Klein,

Susan R. Kahn, Wendy Lim, Andrew S. Dunn, Mary Cushman, FrancescoPhysicians Evidence-Based Clinical Practice Guidelines

and Prevention of Thrombosis, 9th ed: American College of Chest Prevention of VTE in Nonsurgical Patients : Antithrombotic Therapy

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