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DOI 10.1378/chest.11-2306 2012;141;e637S-e668SChest
Lansberg, Gordon H. Guyatt and Frederick A. SpencerFrank A. Sonnenberg, Pablo Alonso-Coello, Elie A. Akl, Maarten G. Per Olav Vandvik, A. Michael Lincoff, Joel M. Gore, David D. Gutterman, Evidence-Based Clinical Practice Guidelinesed: American College of Chest Physicians Therapy and Prevention of Thrombosis, 9thCardiovascular Disease : Antithrombotic Primary and Secondary Prevention of
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services can be found online on the World Wide Web at: The online version of this article, along with updated information and
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written permission of the copyright holder.this article or PDF may be reproduced or distributed without the priorDundee Road, Northbrook, IL 60062. All rights reserved. No part of Copyright2012by the American College of Chest Physicians, 3300Physicians. It has been published monthly since 1935.
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CHEST Supplement
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e637S
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES
Background: This guideline focuses on long-term administration of antithrombotic drugs designed for primary and secondary prevention of cardiovascular disease, including two new antiplatelet therapies. Methods: The methods of this guideline follow those described in Methodology for the Develop-ment of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. Results: We present 23 recommendations for pertinent clinical questions. For primary prevention of cardiovascular disease, we suggest low-dose aspirin (75-100 mg/d) in patients aged . 50 years over no aspirin therapy (Grade 2B). For patients with established coronary artery disease, defi ned as patients 1-year post-acute coronary syndrome, with prior revascularization, coronary stenoses . 50% by coronary angiogram, and/or evidence for cardiac ischemia on diagnostic testing, we recommend long-term low-dose aspirin or clopidogrel (75 mg/d) (Grade 1A). For patients with acute coronary syndromes who undergo percutaneous coronary intervention (PCI) with stent placement, we recommend for the fi rst year dual antiplatelet therapy with low-dose aspirin in combination with ticagrelor 90 mg bid, clopidogrel 75 mg/d, or prasugrel 10 mg/d over single antiplatelet therapy (Grade 1B). For patients undergoing elective PCI with stent place-ment, we recommend aspirin (75-325 mg/d) and clopidogrel for a minimum duration of 1 month (bare-metal stents) or 3 to 6 months (drug-eluting stents) (Grade 1A). We suggest continuing low-dose aspirin plus clopidogrel for 12 months for all stents (Grade 2C). Thereafter, we recommend single antiplatelet therapy over continuation of dual antiplatelet therapy (Grade 1B). Conclusions: Recommendations continue to favor single antiplatelet therapy for patients with established coronary artery disease. For patients with acute coronary syndromes or undergoing elective PCI with stent placement, dual antiplatelet therapy for up to 1 year is warranted. CHEST 2012; 141(2)(Suppl):e637S–e668S
Abbreviations: ACS 5 acute coronary syndrome; BMS 5 bare-metal stent; CAD 5 coronary artery disease; CAGB 5 coronary artery bypass graft; CAPRIE 5 Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events; CHARISMA 5 Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CURE 5 Clopidogrel in Unstable Angina to Prevent Recurrent Events; DES 5 drug-eluting stent; INR 5 international normalized ratio; LV 5 left ventricular; MI 5 myocardial infarction; PCI 5 percutaneous coronary intervention; PLATO 5 Platelet Inhibition and Patient Outcomes; QALY 5 quality-adjusted life year; RCT 5 randomized controlled trial; RR 5 risk ratio; TIA 5 transient ischemic attack
Primary and Secondary Prevention of Cardiovascular Disease Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Per Olav Vandvik , MD , PhD ; A. Michael Lincoff , MD ; Joel M. Gore , MD ; David D. Gutterman , MD , FCCP ; Frank A. Sonnenberg , MD ; Pablo Alonso-Coello , MD, PhD ; Elie A. Akl , MD , MPH, PhD ; Maarten G. Lansberg , MD, PhD ; Gordon H. Guyatt , MD , FCCP ; and Frederick A. Spencer , MD
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e638S Prevention of Cardiovascular Disease
period for very small benefi ts will be disinclined to use aspirin for primary prophylaxis. Individuals who value preventing an MI substantially higher than avoiding a GI bleed will be, if they are in the mod-erate or high cardiovascular risk group, more likely to choose aspirin.
3.1.1-3.1.5. For patients with established coro-nary artery disease (CAD), defi ned as patients 1-year post-acute coronary syndrome (ACS), with prior revascularization, coronary ste-noses . 50% by coronary angiogram, and/or evidence for cardiac ischemia on diagnostic testing, (including patients after the fi rst year post-ACS and/or with prior coronary artery bypass graft [CABG] surgery):
• We recommend long-term single antiplate-let therapy with aspirin 75 to 100 mg daily or clopidogrel 75 mg daily over no antiplate-let therapy (Grade 1A) .
• We suggest single over dual antiplatelet ther-apy with aspirin plus clopidogrel (Grade 2B) .
3.2.1-3.2.5. For patients in the fi rst year after an ACS who have not undergone percutaneous coronary intervention (PCI):
• We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low-dose aspirin 75-100 mg daily or clopidogrel 75 mg daily plus low-dose aspirin 75-100 mg daily) over single antiplatelet therapy (Grade 1B) .
• We suggest ticagrelor 90 mg daily plus low-dose aspirin over clopidogrel 75 mg daily plus low-dose aspirin (Grade 2B) .
For patients in the fi rst year after an ACS who have undergone PCI with stent placement:
• We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low-dose aspirin 75-100 mg daily, clopidogrel 75 mg daily plus low-dose aspirin, or prasugrel 10 mg daily plus low-dose aspirin over single antiplatelet therapy) (Grade 1B) .
Remarks: Evidence suggests that prasugrel results in no benefi t or net harm in patients with a body weight of , 60 kg, age . 75 years, or with a previous stroke/tran-sient ischemic attack.
• We suggest ticagrelor 90 mg twice daily plus low-dose aspirin over clopidogrel 75 mg daily plus low-dose aspirin (Grade 2B) .
For patients with ACS who undergo PCI with stent placement, we refer to sections 4.3.1 to
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 publica-tion of Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Recom-mendations that remain unchanged are not shaded.
2.1. For persons aged 50 years or older without symptomatic cardiovascular disease, we suggest low-dose aspirin 75 to 100 mg daily over no aspirin therapy (Grade 2B) .
Remarks: Aspirin slightly reduces total mortality regardless of cardiovascular risk profi le if taken over 10 years. In people at moderate to high risk of cardio-vascular events, the reduction in myocardial infarc-tion (MI) is closely balanced with an increase in major bleeds. Whatever their risk status, people who are averse to taking medication over a prolonged time
Revision accepted August 31, 2011. Affi liations: From the Norwegian Knowledge Centre for the Health Services and Department of Medicine (Dr Vandvik), Innlandet Hospital Trust Gjøvik, Gjøvik, Norway; Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research (C5Research) (Dr Lincoff), Cleveland Clinic, Cleveland, OH; Department of Medicine (Dr Gore), Univer-sity of Massachusetts Medical School, Worcester, MA; Department of Medicine (Dr Gutterman), Medical College of Wisconsin, Milwaukee, WI; Department of Medicine (Dr Sonnenberg), University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ; Iberoamerican Cochrane Centre (Dr Alonso-Coello), CIBERESP-IIB Sant Pau, Barcelona, Spain; Department of Medicine and Department of Clinical Epidemiology and Biostatistics (Dr Akl), State University of New York at Buffalo, Buffalo, NY; Stanford Stroke Center (Dr Lansberg), Stanford University Medical Center, Palo Alto, CA; and Department of Clinical Epidemiology and Biostatistics (Dr Guyatt) and Department of Medicine (Drs Guyatt and Spencer), McMaster University, Hamilton, ON, Canada. 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 was 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: Frederick A. Spencer, MD, Department of Medicine, McMaster University, St. Joseph’s Health Care, 50 Charlton Ave E, Hamilton, ON, L8N 4A6, Canada; 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.11-2306
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recommend discontinuation of warfarin and continuation of dual antiplatelet therapy for up to 12 months as per the ACS recom-mendations (see recommendations 3.2.1-3.2.5). After 12 months, antiplatelet therapy is recommended as per the established CAD recommendations (see recommenda-tions 3.1.1-3.1.5).
4.1.1-4.3.5. For patients who have undergone elective PCI with placement of BMS:
• For the fi rst month, we recommend dual antiplatelet therapy with aspirin 75 to 325 mg daily and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 1A) .
• For the subsequent 11 months, we suggest dual antiplatelet therapy with combination of low-dose aspirin 75 to 100 mg daily and clopidogrel 75 mg daily over single anti-platelet therapy (Grade 2C) .
• After 12 months, we recommend single anti-platelet therapy over continuation of dual antiplatelet therapy (Grade 1B) .
For patients who have undergone elective PCI with placement of DES:
• For the fi rst 3 to 6 months, we recommend dual antiplatelet therapy with aspirin 75 to 325 mg daily and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 1A) .
Remarks: Absolute minimum duration will vary based on stent type (in general, 3 months for -limus stents and 6 months for -taxel stents).
• After 3 to 6 months, we suggest continua-tion of dual antiplatelet therapy with low-dose aspirin 75 to 100 mg and clopidogrel (75 mg daily) until 12 months over single antiplatelet therapy (Grade 2C) .
• After 12 months, we recommend single antiplatelet therapy over continuation of dual antiplatelet therapy (Grade 1B) . Sin-gle antiplatelet therapy thereafter is rec-ommended as per the established CAD recommendations (see recommendations 3.1.1-3.1.5).
For patients who have undergone elective BMS or DES stent placement:
• We recommend using low-dose aspirin 75 to 100 mg daily and clopidogrel 75 mg daily alone rather than cilostazol in addition to these drugs (Grade 1B) .
4.3.5 for recommendations concerning minimum and prolonged duration of treatment.
3.2.6-3.2.7. For patients with anterior MI and left ventricular (LV) thrombus, or at high risk for LV thrombus (ejection fraction , 40%, antero-ap ical wall motion abnormality), who do not undergo stenting:
• We recommend warfarin (international nor-malized ratio [INR] 2.0-3.0) plus low-dose aspirin 75 to 100 mg daily over single anti-platelet therapy or dual antiplatelet therapy for the fi rst 3 months (Grade 1B) . Thereafter, we recommend discontinuation of warfarin and continuation of dual antiplatelet ther-apy for up to 12 months as per the ACS recommendations (see recommendations 3.2.1-3.2.5). After 12 months, single anti-platelet therapy is recommended as per the established CAD recommendations (see recommendations 3.1.1-3.1.5).
For patients with anterior MI and LV thrombus, or at high risk for LV thrombus (ejection frac-tion , 40%, anteroapical wall motion abnor-mality), who undergo bare-metal stent (BMS) placement:
• We suggest triple therapy (warfarin [INR 2.0-3.0], low-dose aspirin, clopidogrel 75 mg daily) for 1 month over dual antiplatelet therapy (Grade 2C) .
• We suggest warfarin (INR 2.0-3.0) and single antiplatelet therapy for the second and third month post-BMS over alternative regimens and alternative time frames for warfarin use (Grade 2C) . Thereafter, we recommend discontinuation of warfarin and use of dual antiplatelet therapy for up to 12 months as per the ACS recommenda-tions (see recommendations 3.2.1-3.2.5). After 12 months, antiplatelet ther apy is recommended as per the established CAD recommendations (see recommendations 3.1.1-3.1.5).
For patients with anterior MI and LV thrombus, or at high risk for LV thrombus (ejection frac-tion , 40%, anteroapical wall motion abnor-mality) who undergo drug-eluting stent (DES) placement:
• We suggest triple therapy (warfarin INR 2.0-3.0, low-dose aspirin, clopidogrel 75 mg daily) for 3 to 6 months over alternative regimens and alternative durations of war-farin therapy (Grade 2C) . Thereafter, we
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e640S Prevention of Cardiovascular Disease
by coronary angiogram, and/or evidence for cardiac ischemia on diagnostic testing); includ ing those post-ACS and post-coronary artery bypass graft (CABG) surgery; (3) patients with recent or remote percu-taneous coronary intervention (PCI) with or without stents (bare-metal stents [BMS] or drug-eluting stents [DES]); and (4) patients with systolic left ventricular (LV) dysfunction (ischemic and nonischemic).
1.0 Methods
Table 1 describes the clinical questions (ie, population, inter-vention, comparator, and outcome) for each of the recommenda-tions that follow. We defi ne only patient characteristics relevant to our questions. For example, because whether ACS occurs with or without ST-segment elevation is not relevant to long-term sec-ondary prevention, we provide a single set of recommendations for all patients following ACS. We have selected the same patient-important outcomes across all recommendations (eg, total mor-tality, nonfatal myocardial infarction [MI], nonfatal stroke, major extracranial bleed). We consider burden of treatment an impor-tant outcome for patients taking warfarin.
Stent thrombosis frequently is reported in trials evaluating antiplatelet agents in patients undergoing PCI with stent place-ment. We have not included stent thrombosis as an important outcome because stent thrombosis derives its patient impor-tance from consequent MI and deaths. Additional reporting of stent thrombosis along with MI and deaths would result in double counting of events and a distorted balance of benefi ts and harms.
Nonfatal hemorrhagic strokes and ischemic strokes are included together as nonfatal strokes. Although the former is a complica-tion and prevention of the latter is a benefi cial effect of anti-thrombotic therapy, their impact on patient morbidity is similar.
Estimation of Baseline Risks and Absolute Effects of Treatment
In order to estimate absolute benefi ts and harms associated with a given therapy, we performed the several steps. We fi rst generated relative effect estimates (relative risks) from the highest-quality published meta-analysis of randomized controlled trials (RCTs) comparing therapies for a specifi c indication. If no such meta-analyses were available, we conducted our own meta-analyses of relevant RCTs or used relative risk estimates from single RCTs in the absence of other relevant RCTs.
Ideally, in order to approximate the benefi t of a given therapy in the real world, population-based observational studies would inform estimates of baseline risk. Unfortunately, for most of our clinical questions, we were unable to identify observational studies of suffi cient quality that reported all relevant outcomes. In such cases, we estimated control group risk from the control arm of either a relevant meta-analysis or a relevant RCT and adjusted them to our specifi ed time frame. Individual sections present detailed explanations of our choices.
There are limited data to guide us with respect to the relative impact of outcomes on patient quality of life (see MacLean et al 1 in this supplement). As described in the methodology article by Guyatt et al 2 in these guidelines, we have used ratings from guide-line panelists striving to infer a patient’s valuation of the outcomes of interest. The ratings suggest that major extracranial bleeding (which is usually readily treated and with few long-lasting con-sequences) carries only slightly less weight than a nonfatal MI (which also often has minimal long-term consequences) but sub-stantially less weight than a stroke (which is often associated with
• We suggest aspirin 75 to 100 mg daily or clopidogrel 75 mg daily as part of dual anti-platelet therapy rather than the use of either drug with cilostazol (Grade 1B) .
• We suggest cilostazol 100 mg twice daily as substitute for either low-dose aspirin 75 to 100 mg daily or clopidogrel 75 mg daily as part of a dual antiplatelet regimen in patients with an allergy or intolerance of either drug class (Grade 2C) .
For patients with CAD undergoing elective PCI but no stent placement:
• We suggest for the fi rst month dual anti-platelet therapy with aspirin 75 to 325 mg daily and clopidogrel 75 mg daily over sin-gle antiplatelet therapy (Grade 2C) . Single antiplatelet therapy thereafter is rec-ommended as per the established CAD recommendations (see recommendations 3.1.1-3.1.5).
5.1-5.3. For patients with systolic LV dysfunc-tion without established CAD and no LV throm-bus, we suggest not to use antiplatelet therapy or warfarin (Grade 2C) .
Remarks: Patients who place a high value on an uncertain reduction in stroke and a low value on avoiding an increased risk of GI bleeding are likely to choose to use warfarin.
For patients with systolic LV dysfunction with-out established CAD with identifi ed acute LV thrombus (eg, Takotsubo cardiomyopathy), we suggest moderate-intensity warfarin (INR 2.0-3.0) for at least 3 months (Grade 2C) .
For patients with systolic LV dysfunction and established CAD, recommendations are as per the established CAD recommendations (see rec-ommendations 3.1.1-3.1.5).
This article is devoted to long-term administration of antithrombotic drugs designed for primary and
secondary prevention of cardiovascular disease. It does not address initial management of acute coro-nary syndromes (ACS) or periprocedural use of anti-thrombotic therapies.
We consider the desirable and undesirable conse-quences of antithrombotic treatment in the follow-ing populations and patient groups: (1) persons without established coronary artery disease (CAD); (2) patients with established CAD (established CAD is defi ned throughout as patients 1-year post ACS, with prior revascularization, coronary stenoses . 50%
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(Con
tinu
ed)
Tabl
e 1—
Qu
esti
on D
efi n
itio
n an
d E
ligi
bil
ity
Cri
teri
a fo
r A
ntit
hrom
bot
ic T
reat
men
ts i
n P
rim
ary
and
Seco
ndar
y P
reve
ntio
n of
Car
diov
ascu
lar
Dis
ease
Sect
ion
Info
rmal
Que
stio
n
PIC
O Q
uest
ion
Popu
latio
nIn
terv
entio
nsC
ompa
rato
rO
utco
me(
s)
2.0
Prim
ary
prev
entio
n of
car
diov
ascu
lar
dise
ase
2.1
Cho
ice
of a
ntith
rom
botic
ther
apy
Pers
ons
with
out s
ympt
omat
ic
card
iova
scul
ar d
isea
seA
spir
inPl
aceb
oTo
tal m
orta
lity
Non
fata
l MI
Non
fata
l str
oke
Maj
or e
xtra
cran
ial b
leed
3.0
Seco
ndar
y pr
even
tion
of c
ardi
ovas
cula
r di
seas
e (in
clud
es p
atie
nts
with
pri
or C
AB
G)
3.1.
1C
hoic
e of
long
-ter
m a
ntith
rom
botic
th
erap
y in
pat
ient
s w
ith
esta
blis
hed
CH
D
Patie
nts
with
est
ablis
hed
CH
DA
spir
inPl
aceb
oTo
tal m
orta
lity
Non
fata
l MI
Non
fata
l str
oke
Maj
or e
xtra
cran
ial b
leed
Bur
den
of tr
eatm
ent (
for
VK
A)
3.1.
2C
lopi
dogr
elA
spir
in3.
1.3
Clo
pido
grel
1 as
piri
nA
spir
in3.
1.4
VK
A m
oder
ate
inte
nsity
1 as
piri
nA
spir
in3.
1.5
Dos
e of
asp
irin
Asp
irin
75-
100
mg
Asp
irin
. 1
00 m
g 3.
2.1
Cho
ice
of a
ntith
rom
botic
ther
apy
the
fi rst
yea
r fo
llow
ing
AC
SPa
tient
s w
ith r
ecen
t AC
SA
spir
inPl
aceb
o3.
2.2
Clo
pido
grel
Asp
irin
3.2.
3A
spir
in 1
clop
idog
rel
Asp
irin
3.2.
4Ti
cagr
elor
1 as
piri
nC
lopi
dogr
el 1
aspi
rin
3.2.
5A
CS
1 u
nder
goin
g PC
IPr
asug
rel 1
aspi
rin
Clo
pido
grel
1 as
piri
n3.
2.6
Patie
nts
with
acu
te a
nter
ior
STE
MI
and
apic
al w
all m
otio
n ab
norm
ality
( � st
ent)
Asp
irin
1 V
KA
Asp
irin
� cl
opid
ogre
l3.
2.7
Asp
irin
1 cl
opid
ogre
l 1 V
KA
Asp
irin
1 cl
opid
ogre
l4.
0 A
ntith
rom
botic
ther
apy
follo
win
g el
ectiv
e PC
I4.
1.1
Cho
ice
of a
ntith
rom
botic
ther
apy
follo
win
g el
ectiv
e PC
IPa
tient
s un
derg
oing
ele
ctiv
e PC
I w
ithou
t ste
nt p
lace
men
tA
spir
in 1
clop
idog
rel
Asp
irin
alo
neTo
tal m
orta
lity
Non
fata
l MI
Stro
keM
ajor
ext
racr
ania
l ble
eds
4.1.
2Pa
tient
s un
derg
oing
ele
ctiv
e PC
I w
ith
sten
t pla
cem
ent
Thi
enop
yrid
ine
1 as
piri
nV
KA
1 as
piri
n4.
1.3
Cilo
staz
ol 1
clop
idog
rel 1
aspi
rin
Clo
pido
grel
1 as
piri
n4.
1.4
Cilo
staz
ol 1
aspi
rin
Clo
pido
grel
1 as
piri
n4.
2D
ose
of a
spir
in fo
llow
ing
PCI
Patie
nts
unde
rgoi
ng P
CI
� 1
00 m
g A
spir
in .
100
mg
Asp
irin
4.3.
1D
urat
ion
of D
AT (c
lopi
dogr
el
plus
asp
irin
) fol
low
ing
PCI
with
pl
acem
ent o
f BM
S
Patie
nts
unde
rgoi
ng P
CI
with
BM
SM
inim
um d
urat
ion
DAT
1 m
oN
o D
AT4.
3.2
Ext
ende
d du
ratio
n D
AT 6
-12
mo
DAT
1 m
o
4.3.
3D
urat
ion
of D
AT fo
llow
ing
PCI
with
pl
acem
ent o
f DE
SPa
tient
s un
derg
oing
PC
I w
ith D
ES
Min
imum
dur
atio
n D
AT 3
-6 m
oN
o D
AT4.
3.4
Ext
ende
d du
ratio
n D
AT 1
yD
AT 3
-6 m
o4.
3.5
Ext
ende
d du
ratio
n D
AT .
1 y
DAT
1 y
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e642S Prevention of Cardiovascular Disease
long-term disability). Our decisions are based on a disutility of stroke of three times the disutility, or negative weight, of a major extracranial bleed.
Trade-offs between desirable and undesirable consequences of alternative management strategies sometimes represent close-call situations. For example, in the comparison of clopidogrel and aspirin vs aspirin alone in established CAD, available evidence from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial cannot rule out a benefi t of dual antiplatelet therapy over aspirin alone, with a nonsignifi cant trend for benefi t in cardiovas-cular outcomes such as vascular mortality, MI, and stroke. 3 There is, however, suggested harm in terms of increased major bleeding events, with imprecise estimates of borderline statistical signifi -cance. In making recommendations in such situations, we have taken a primum non nocere approach, placing the burden of proof with those who would claim a benefi t of treatment. In other words, when there is uncertain benefi t and an appreciable probability of important harm (such as the aforementioned situation), we rec-ommend against such treatments.
We identifi ed the relevant evidence for our clinical questions with the assistance of a team of methodologists and medical librarians as outlined in the methodology article in this supplement. 2 Sys-tematic literature searches for systematic reviews and original studies were performed until the date of January 15, 2010. After that date, we scanned the literature regularly, although this was not performed as systematic literature searches.
2.0 Primary Prevention of Cardiovascular Disease
In this section, we address the effects of aspirin in primary prevention of cardiovascular disease. In addition, we consider recent meta-analyses dem-onstrating a reduction in cancer mortality and total mortality with long-term use of aspirin. 4-6 We do not include other antiplatelet therapies (eg, clopidogrel alone or in combination with aspirin) or oral antico-agulation (eg, warfarin) because they are not likely used in primary prevention. Whether aspirin should be prescribed in patients already receiving warfarin for atrial fi brillation (or other conditions) to enhance primary and secondary prevention of cardiovascular disease remains controversial. This topic is addressed in You et al. 7
Users of this guideline require a tool to estimate risk of a cardiovascular event in the individual patient. Figure 1 shows the Framingham risk score that predicts the 10-year risk of developing a cardiovas-cular event (composite end point of MI and coro-nary death) as low ( , 10%), moderate (10%-20%), and high ( . 20%) risk. 8
We present absolute risk estimates for people at low, moderate, and high cardiovascular risk in a 10-year time frame based on the widely used Framingham risk score ( Table 2 ). In order to derive our baseline control group risk estimates, we assumed patients with low, moderate, and high risk to have a 5%, 15%, and 25% risk of experiencing combined nonfatal and fatal MI, respectively.
Tabl
e 1—
Con
tinu
ed
Sect
ion
Info
rmal
Que
stio
n
PIC
O Q
uest
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latio
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ithro
mbo
tic th
erap
y in
pat
ient
s w
ith s
ysto
lic L
V d
ysfu
nctio
n5.
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hoic
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ant
ithro
mbo
tic th
erap
y in
pa
tient
s w
ith n
onis
chem
ic s
ysto
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LV d
ysfu
nctio
n an
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th
rom
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Patie
nts
with
non
isch
emic
sys
tolic
LV
dy
sfun
ctio
n (w
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t AF
) and
no
LV
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mbu
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l mor
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tal M
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eM
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l ble
edB
urde
n of
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tmen
t (fo
r V
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irin
No
aspi
rin
5.2
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ice
of a
ntith
rom
botic
ther
apy
in
patie
nts
with
non
isch
emic
sys
tolic
LV
dys
func
tion
and
LV th
rom
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Patie
nts
with
non
isch
emic
sys
tolic
LV
dy
sfun
ctio
n (w
ithou
t AF
) and
LV
th
rom
bus
VK
AN
o w
arfa
rin
5.3
Cho
ice
of a
ntith
rom
botic
ther
apy
in
patie
nts
with
isch
emic
LV
dy
sfun
ctio
n
Patie
nts
with
isch
emic
sys
tolic
LV
dy
sfun
ctio
nA
spir
inPl
aceb
oC
lopi
dogr
elA
spir
inC
lopi
dogr
el 1
aspi
rin
Asp
irin
VK
A m
oder
ate
inte
nsity
1 as
piri
nA
spir
in
AC
S 5
acut
e co
rona
ry sy
ndro
me;
AF
5 at
rial
fi br
illat
ion;
BM
S 5
bar
e-m
etal
sten
t; C
AB
G 5
coro
nary
art
ery
bypa
ss g
raft
surg
ery;
CH
D 5
coro
nary
hea
rt d
isea
se; D
AT 5
dua
l ant
ipla
tele
t the
rapy
; DE
S 5
dru
g-el
utin
g st
ent;
LV 5
left
ven
tric
ular
; MI 5
myo
card
ial
infa
rctio
n; P
CI 5
per
cuta
neou
s co
rona
ry i
nter
vent
ion;
PIC
O 5
pop
ulat
ion,
int
erve
ntio
n, c
ompa
rato
r, ou
tcom
e; S
TE
MI 5
ST-
segm
ent
elev
atio
n m
yoca
rdia
l inf
arct
ion;
VK
A 5
vita
min
K a
ntag
onis
t.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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stroke. The Framingham risk score does not allow separate calculation of nonfatal and fatal MI, and it does not include stroke or major extracranial bleeding.
We believe that it is important to provide estimates separately for outcomes that patients value differ-ently, as is the case for nonfatal MI, fatal MI, and
Figure 1. [Section 2.0] Framingham risk score for cardiovascular events. A, Calculator for men. B, (Continued next page) Calculator for women. Determine the number of points a patient receives for each risk factor (steps 1 through 6) and add them together (step 7). Using the point total in step 8 (using appropriate column - LDL or cholesterol depending on which was used in step 2), fi nd the corresponding 10-year CHD risk. (Reprinted with permission from Wilson et al.101) CHD 5 coronary heart disease; HDL-C 5 high-density lipoprotein cholesterol; LDL-C 5 low-density lipoprotein cholesterol.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e644S Prevention of Cardiovascular Disease
nonfatal stroke, and a 1% risk of a major nonfatal extracranial bleed. Similar calculations were made to derive control group risk estimates for moderate- and high-risk strata. 9
We made one additional modifi cation to estimates from the Framingham risk score. The Framingham risk score overestimates 10-year coronary heart dis-ease risk by 32% in men and 10% in women and is of little value in people aged . 85 years. 10,11 We have adjusted our control group risk estimates accordingly,
Therefore, to estimate the probability of each of these critical outcomes, we used the observed ratio of non fatal MI to fatal MI to nonfatal stroke to major extracranial bleeding events in an individual partic-ipant data meta-analysis assessing benefi ts and harms of aspirin in primary prevention of cardiovas-cular disease. 9 For example, a patient with a 5% (low) risk of fatal and nonfatal MI over 10 years based on the Framingham score would have a 3.3% risk of nonfatal MI, a 1.7% risk of a fatal MI, a 2.6% risk of
Figure 1. Continued.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e 2—
[Sec
tion
2.1
] A
spir
in (
75-1
00 m
g) C
ompa
red
Wit
h N
o A
spir
in i
n th
e P
rim
ary
Pre
vent
ion
of C
ardi
ovas
cula
r D
isea
se a,9
Out
com
esPa
rtic
ipan
ts (S
tudi
es),
Fol
low
-up
Qua
lity
of th
e E
vide
nce
(GR
AD
E)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
10 y
Ris
k W
ithou
t Asp
irin
Ris
k D
iffer
ence
With
Asp
irin
(95%
CI)
Tota
l mor
talit
y a 10
0,07
6 (9
), 3.
8-10
yM
oder
ate
due
to
impr
ecis
ion b
RR
0.9
4 (0
.88
to 1
.00)
60-y
-old
man
c 10
0 de
aths
per
1,0
00 c
6 fe
wer
dea
ths
per
1,00
0 (f
rom
12
few
er to
0 fe
wer
)M
I no
nfat
al e
vent
s95
,000
(6),
3.8-
10 y
Hig
hR
R 0
.77
(0.6
9-0.
86)
Low
-car
diov
ascu
lar-
risk
pop
ulat
ion d
27 M
I pe
r 1,
000 e
6 fe
wer
MI
per
1,00
0 (f
rom
8 fe
wer
to 4
few
er)
Mod
erat
e-ca
rdio
vasc
ular
ris
k po
pula
tion d
83 M
I pe
r 1,
000 e
19 fe
wer
MI
per
1,00
0 (f
rom
26
few
er to
12
few
er)
Hig
h-ca
rdio
vasc
ular
-ris
k po
pula
tion d
136
per
1,00
0 e 31
few
er p
er 1
,000
(fro
m 4
2 fe
wer
to 1
9 fe
wer
)St
roke
incl
udes
non
fata
l isc
hem
ic
and
hem
orrh
agic
str
okes
f 95
,000
(6),
3.8-
10 y
Mod
erat
e du
e to
im
prec
isio
n b R
R 0
.95
(0.8
5-1.
06)
Low
-car
diov
ascu
lar-
risk
pop
ulat
ion d
23 s
trok
es p
er 1
,000
e N
o si
gnifi
cant
diff
eren
ce; 1
few
er s
trok
e pe
r 1,
000
(fro
m 3
few
er to
1 m
ore)
Mod
erat
e-ca
rdio
vasc
ular
-ris
k po
pula
tion d
65 s
trok
es p
er 1
,000
e N
o si
gnifi
cant
diff
eren
ce; 3
few
er s
trok
es p
er 1
,000
(f
rom
10
few
er to
4 m
ore)
Hig
h-ca
rdio
vasc
ular
-ris
k po
pula
tion d
108
stro
kes
per
1,00
0 e N
o si
gnifi
cant
diff
eren
ce; 5
few
er s
trok
es p
er 1
,000
(f
rom
16
few
er to
8 m
ore)
Maj
or e
xtra
cran
ial b
leed
95,0
00 (6
), 3.
8-10
yH
igh
RR
1.5
4 (1
.30-
1.82
)L
ow-c
ardi
ovas
cula
r-ri
sk p
opul
atio
n g 8
blee
ds p
er 1
,000
e 4
mor
e bl
eeds
per
1,0
00 (f
rom
2 m
ore
to 7
mor
e)M
oder
ate-
card
iova
scul
ar r
isk
popu
latio
n g 24
ble
eds
per
1,00
0 e 16
mor
e bl
eeds
per
1,0
00 (f
rom
7 m
ore
to 2
0 m
ore)
Hig
h-ca
rdio
vasc
ular
-ris
k po
pula
tion g
40 b
leed
s pe
r 1,
000 e
22 m
ore
blee
ds p
er 1
,000
(fro
m 1
2 m
ore
to 3
3 m
ore)
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
. See
Tab
le 1
lege
nd fo
r ex
pans
ion
of o
ther
abb
revi
atio
n. a T
his
syst
emat
ic r
evie
w r
epor
ts t
otal
mor
talit
y an
d in
clud
es t
he m
ost
rece
nt t
rial
s bu
t do
es n
ot r
epor
t sp
ecifi
c ca
uses
of
mor
talit
y. O
ther
met
a-an
alys
es t
hat
use
indi
vidu
al p
atie
nt d
ata
repo
rt r
elat
ive
risk
es
timat
es fo
r vas
cula
r mor
talit
y (R
R, 0
.97;
95%
CI,
0.8
7-1.
09),
canc
er m
orta
lity
(RR
, 0.6
6; 9
5% C
I, 0
.50-
0.87
), an
d fa
tal i
ntra
cran
ial b
leed
s (R
R, 1
.73;
95%
CI,
0.9
6-3.
13).
The
risk
of a
fata
l ble
ed (i
nclu
ding
ex
trac
rani
al a
nd in
trac
rani
al) w
as lo
w (0
.3%
with
asp
irin
and
0.2
% w
ith c
ontr
ol).
b The
95%
CI
for
the
abso
lute
eff
ect i
nclu
des
no b
enefi
t of
asp
irin
. We
did
not r
ate
dow
n fo
r ri
sk o
f bia
s, b
ut th
is w
as a
bor
derl
ine
deci
sion
. Thr
ee o
f the
tria
ls d
id n
ot b
lind
patie
nts,
car
egiv
ers,
or
outc
ome
adju
dica
tors
. Sen
sitiv
ity a
naly
ses
in m
eta-
anal
ysis
by
Raj
u et
al 4 d
id n
ot s
how
evi
denc
e of
ris
k of
bia
s. c C
ontr
ol g
roup
ris
k es
timat
e fo
r 10
-y m
orta
lity
appl
y to
a 6
0-y-
old
man
and
cam
e fr
om p
opul
atio
n-ba
sed
data
from
Sta
tistic
s N
orw
ay. M
orta
lity
incr
ease
s w
ith a
ge (e
g, 5
0-y-
old
man
; 50
deat
hs p
er 1
,000
in
10 y
) and
is lo
wer
in w
omen
than
in m
en (e
g, 3
% in
wom
en a
ged
50 y
vs
5% in
men
age
d 50
y).
d Ris
k gr
oups
cor
resp
ond
to lo
w r
isk
(5%
), m
ediu
m r
isk
(15%
), hi
gh r
isk
(25%
) acc
ordi
ng to
the
Fra
min
gham
sco
re (o
r ot
her
risk
tool
) to
estim
ate
10-y
ris
k. e C
ontr
ol g
roup
ris
k es
timat
es in
low
-, m
oder
ate-
, and
hig
h-ca
rdio
vasc
ular
-ris
k gr
oups
are
bas
ed o
n th
e F
ram
ingh
am s
core
. As
expl
aine
d in
the
text
, we
have
use
d da
ta fr
om a
n in
divi
dual
pat
ient
dat
a m
eta-
anal
ysis
to p
rovi
de e
stim
ated
ris
ks fo
r pa
tient
-impo
rtan
t out
com
es n
ot c
over
ed b
y th
e F
ram
ingh
am r
isk
scor
e. W
e ha
ve a
lso
adju
sted
for
20%
ove
rest
imat
ion
asso
ciat
ed w
ith F
ram
ingh
am r
isk
scor
e. f O
f the
str
okes
in th
e tr
ials
, 89
of 6
82 (1
3%) w
ithou
t asp
irin
wer
e he
mor
rhag
ic a
nd 1
16 o
f 655
(18%
) with
asp
irin
wer
e he
mor
rhag
ic.
g In
the
indi
vidu
al p
atie
nt d
ata
met
a-an
alys
is r
isk
for
futu
re m
ajor
ble
edin
g co
rrel
ated
with
ris
k fo
r fu
ture
car
diov
ascu
lar
even
ts. T
here
fore
, we
mak
e th
e as
sum
ptio
n th
at a
pat
ient
at l
ow, m
ediu
m, o
r hi
gh
risk
of f
utur
e ca
rdio
vasc
ular
eve
nts
(det
erm
ined
by
Fra
min
gham
sco
re) w
ill b
e at
low
, med
ium
, or
high
ris
k fo
r fu
ture
maj
or b
leed
ing
even
ts, r
espe
ctiv
ely.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e646S Prevention of Cardiovascular Disease
data meta-analysis by Baigent et al 9 reported a rel-ative risk estimate for vascular mortality of 0.97 (95% CI, 0.87-1.09) associated with aspirin over a 10-year period. In another individual patient data meta-analysis, aspirin was associated with a reduction in cancer mortality (risk ratio [RR], 0.66; 95% CI, 0.50-0.87), which translated to � 20 fewer cancer deaths (30 fewer to eight fewer) per 1,000 treated for 10 years. 5 The impressive relative and anticipated absolute effect of aspirin therapy on cancer mor-tality contrast with the more-modest relative and absolute effect of aspirin on total mortality (three fewer deaths per 1,000). The difference in absolute effect is likely partly explained by the high 10-year risk of cancer mortality derived from the trials included in the individual participant data meta-analysis (60 per 1,000) compared with the low 10-year risk of total mortality derived from population-based data in a 50-year-old man (10 per 1,000). Appar-ently, patients enrolled in trials of aspirin aimed at reducing vascular risk were a population at high risk for cancer deaths.
We do not make specifi c recommendations for the use of aspirin based on patient characteristics, such as older age, sex, and diabetes mellitus. Other guide-lines that do modify recommendations according to the presence or absence of such characteristics largely ignore any differences in bleeding risks and base their recommendations on evidence from what we believe are subgroup analyses of questionable validity. 18-22 Sophisticated risk calculators used in deci-sion aids for specifi c populations may enhance indi-vidual decision-making, and when well done, we encourage their use.
Concerning diabetes, we (in contrast to some others) interpret current evidence as suggesting that the relative benefi t of aspirin is similar in patients with and without diabetes. In two systematic reviews that include recent trials of patients with diabetes, CIs for the diabetes subgroup overlap with our estimates of relative effects from the combined population. 23,24 Furthermore, analyses from the individual partici-pant data meta-analysis provide no support for a dif-ference in relative effect of aspirin in those with or without diabetes. 9
Recommendation
2.1. For persons aged 50 years or older without symptomatic cardiovascular disease, we sug-gest low-dose aspirin 75 to 100 mg daily over no aspirin therapy (Grade 2B) .
Remarks: Aspirin slightly reduces total mortality regardless of cardiovascular risk profi le if taken over 10 years. In people at moderate to high risk of cardio-vascular events, the reduction in MI is closely balanced
assuming 20% overestimation across sexes. For example, whereas Framingham estimates that 33 of 1,000 people at low cardiovascular risk will have a nonfatal MI without aspirin, our best estimate is that 27 of 1,000 people will have a nonfatal MI. Similar adjustments have been performed for vascular and bleeding outcomes because the Framingham risk estimate for nonfatal MI serves as the basis for the other risk estimates through our use of ratios from the individual participant data meta-analysis described later in this article. 9
2.1 Aspirin
Table 2 (Table S1) summarizes results from an individual participant data meta-analysis that provides the best evidence regarding the benefi ts and harms of aspirin in primary prevention of cardiovascular dis-ease. 9 The meta-analysis includes 95,000 individuals (660,000 person-years, 3,554 vascular events) from six large trials (British Doctor Study, US Physicians’ Health Study, Thrombosis Prevention Trial, Hyper-tension Optimal Treatment Trial, Primary Prevention Project, and Women’s Health Study) that compared long-term aspirin use vs control. 12-17 Doses of aspi-rin varied between 75 mg and 300 mg without an apparent difference in benefi t or harm. For total mortality, we used the relative-effect estimate derived from a high-quality systematic review and meta-analysis that included the most recent trials omitted from the individual participant data meta-analysis. 4
Based on these analyses, aspirin use in patients at low risk would be associated with six fewer MIs and four more major bleeding events per 1,000 treated, with little or no effect on nonfatal stroke over a 10-year period (Table 2, Table S1). Aspirin would be associated with six fewer total deaths, but the 95% CI includes zero fewer deaths. For moderate- to high-risk patients, aspirin again would reduce nonfatal MI (19 fewer/1,000 treated and 31 fewer/1,000 treated, respectively) and increase major bleeding (16 more/1,000 treated and 22 more/1,000 treated, respectively), with a similar impact on total mortality (six fewer total deaths) as in the low-risk group. Our baseline risk estimate of 10-year mortality is derived from population-based data in Norway (www.ssb.no) and applies to a 60-year-old man. The overall qual ity of evidence is rated as moderate given the impreci-sion in the relative effect estimates for total mortality.
Patients averse to taking therapy for an extended duration for the potential of a very small decrease in total mortality may be disinclined to use long-term aspirin therapy for primary cardiovascular preven-tion. Patients (and physicians) may be interested in the effects on cause-specifi c mortality when consid-ering aspirin prophylaxis. The individual participant
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adjusted to a 5-year time frame. 9 Because this meta-analysis does not provide data on total mortality or nonfatal major extracranial bleeds, we derived baseline risk estimates from the aspirin arm in the CHARISMA trial (total mortality) and Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial (major extracranial bleeds). 3,29 To estimate control group risks for total mortality and major bleeds in patients not taking aspirin, we used estimates from the aspirin arm in these trials as the starting point and then applied the relative risks for total mortality and major bleeds to get to the control group risk estimate without aspirin. 3,29 We used data regarding relative effects from the clopidogrel arm of the CAPRIE study, applied to baseline risks as previ-ously mentioned, to generate control group risk esti-mates of vascular events and bleeding in patients taking clopidogrel alone. 29
3.1.1 Aspirin: Table 3 (Table S2) summarizes the quality of evidence and main fi ndings from a meta-analysis of individual participant data from 16 ran-domized trials with 17,000 patients with established vascular disease (six trials of previous MI and 10 trials of previous transient ischemic attack [TIA] or stroke). 9 In this population at high risk for a serious vascular event (8.2% yearly risk), aspirin signifi cantly reduced total mortality, nonfatal MI, and nonfatal stroke at the cost of increased nonfatal extracranial bleeding events. The number of vascular events and total deaths prevented is far greater than the number of bleeding events that result from aspirin.
The benefi cial effects of aspirin are likely to also apply to patients with stable angina pectoris without prior MI. A well-performed systematic review and meta-analysis of antiplatelet therapy for prevention of vascular events in high-risk patients found that antiplatelet agents exerted similar effects on vascular events in patients with a history of MI (12 trials) and in patients with a history of stable angina and CAD (seven trials). 30
3.1.2 Clopidogrel vs Aspirin: The CAPRIE trial is the only randomized trial directly comparing clo-pidogrel and aspirin in the secondary prevention of cardiovascular events, and we consider this trial to be the most credible source of evidence. 29 More than 19,000 patients with atherosclerotic vascular disease manifested as a recent stroke, recent MI, or symp-tomatic peripheral arterial disease received clopid-ogrel or aspirin. After a mean follow-up of 1.9 years, clopidogrel was associated with a possible reduction in nonfatal MI and nonfatal extracranial bleeding and little or no effect on total mortality. Table 4 (Table S3) summarizes the quality of evidence and main fi ndings of the CAPRIE trial with anticipated
with an increase in major bleeds. Whatever their risk status, people who are averse to taking med ication over a prolonged time period for very small benefi ts will be disinclined to use aspirin for primary prophylaxis. Individuals who value preventing an MI substantially higher than avoiding a GI bleed will be, if they are in the moderate or high cardiovascular risk group, more likely to choose aspirin.
3.0 Secondary Prevention of Cardiovascular Disease
The evidence supporting the use of specifi c anti-thrombotic therapies sometimes differs between patients who have recently experienced an ACS and those with stable CAD. For purposes of these guide-lines, and based on available data, recommenda-tions for therapy following ACS will apply to the postdischarge period and extend to 1 year. There-after, patients will be considered to have established CAD. This defi nition is by necessity somewhat arbi-trary, and we acknowledge that the higher-risk period following ACS may end before 1 year.
Most studies evaluating antithrombotic therapy immediately following CABG surgery have focused on a surrogate outcome, bypass graft patency, as the primary outcome. However, in making our recommen-dations, we focus exclusively on the relevant patient-important outcomes: nonfatal MI, nonfatal stroke, major extracranial bleeding, and death. Although substudies of large RCTs of antiplatelet therapy in patients with either CAD or recent ACS have exam-ined clinical end points in patients with a history of remote CABG, these analyses do not suggest any sig-nifi cant differences in the associated relative benefi t or harm compared with the overall study population. 3,25-27 In addition, loss of bypass graft patency derives its patient importance from consequent MI and deaths. Additional reporting of graft patency along with MI and death would result in double counting of events and a distorted balance of benefi ts and harms.
Accordingly, our recommendations for antithrom-botic therapy in patients following elective CABG or CABG following ACS mirror those for patients with chronic CAD or recent ACS, respectively. For recommendations regarding continuation and dis-continuation of antithrombotic therapy and timing of reinitiation relative to CABG, see Douketis et al 28 in this supplement.
3.1 Choice of Long-term Antithrombotic Therapy in Patients With Established CAD
Control group risk estimates for nonfatal MI and stroke in patients not taking aspirin and in patients taking aspirin come from a meta-analysis of 16 RCTs
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e648S Prevention of Cardiovascular Disease
Tabl
e 3—
[Sec
tion
s 3.
1.1-
3.1.
5, 3
.2.1
] A
spir
in v
s N
o A
spir
in i
n P
atie
nts
Wit
h E
stab
lish
ed C
AD
9
Out
com
esPa
rtic
ipan
ts (S
tudi
es),
Fol
low
-up
Qua
lity
of th
e E
vide
nce
(GR
AD
E)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
5 y
Ris
k W
ithou
t Asp
irin
Ris
k D
iffer
ence
With
Asp
irin
(95%
CI)
Tota
l mor
talit
y17
,000
(16
RC
Ts),
27 m
oM
oder
ate
due
to
im
prec
isio
n a R
R 0
.90
(0.8
2-0.
99)
133
per
1,00
0 b 13
few
er p
er 1
,000
(fro
m 2
4 fe
wer
to 1
few
er)
MI
nonf
atal
eve
nts
17,0
00 (1
6 R
CTs
), 27
mo
Hig
hR
R 0
.69
(0.6
0-0.
80)
117
per
1,00
0 b 37
few
er p
er 1
,000
(fro
m 4
7 fe
wer
to 2
3 fe
wer
)St
roke
incl
udes
non
fata
l isc
hem
ic
and
hem
orrh
agic
str
okes
c 17
,000
(16
RC
Ts),
27 m
oH
igh
RR
0.8
1 (0
.71-
0.92
)13
5 pe
r 1,
000 b
26 fe
wer
per
1,0
00 (f
rom
39
few
er to
11
few
er)
Maj
or e
xtra
cran
ial b
leed
17,0
00 (1
6 R
CTs
), 27
mo
Mod
erat
e du
e to
indi
rect
ness
d R
R 2
.69
(1.2
5-5.
76)
15 p
er 1
,000
e 25
mor
e pe
r 1,
000
(fro
m 4
mor
e to
71
mor
e)
CA
D 5
coro
nary
art
ery
dise
ase;
CA
PRIE
5 C
lopi
dogr
el v
s A
spir
in i
n Pa
tient
s at
Ris
k of
Isc
hem
ic E
vent
s; C
HA
RIS
MA
5 C
lopi
dogr
el f
or H
igh
Ath
erot
hrom
botic
Ris
k an
d Is
chem
ic S
tabi
lizat
ion,
M
anag
emen
t, an
d A
void
ance
; RC
T 5
rand
omiz
ed c
ontr
olle
d tr
ial.
See
Tabl
e 1
and
2 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a Rat
ed d
own
for
impr
ecis
ion
beca
use
the
95%
CI
sugg
ests
pos
sibl
e be
nefi t
and
no
effe
ct o
n to
tal m
orta
lity.
b Con
trol
gro
up r
isk
estim
ates
(w
ithou
t as
piri
n) f
or M
I an
d st
roke
com
e fr
om o
bser
ved
year
ly e
vent
rat
es in
16
RC
Ts r
epor
ted
in t
he m
eta-
anal
ysis
, adj
uste
d to
a 5
-y t
ime
fram
e. T
he c
ontr
ol g
roup
rat
e es
timat
e fo
r to
tal m
orta
lity
with
out a
spir
in is
der
ived
from
the
even
t rat
e in
the
aspi
rin
arm
of t
he C
HA
RIS
MA
tria
l, us
ing
the
RR
of 0
.90
to g
et th
e co
ntro
l gro
up r
ate
estim
ate
with
out a
spir
in.
c Of t
he s
trok
es in
the
met
a-an
alys
is, 0
.8%
with
asp
irin
wer
e in
trac
rani
al h
emor
rhag
es, a
nd 0
.4%
of s
trok
es w
ithou
t asp
irin
wer
e in
trac
rani
al h
emor
rhag
es.
d Rat
ed d
own
for
indi
rect
ness
bec
ause
ble
edin
g ev
ents
wer
e on
ly r
epor
ted
in a
sub
set o
f tri
als
with
str
oke
and
tran
sien
t isc
hem
ic a
ttac
k po
pula
tions
. e T
o es
timat
e co
ntro
l gro
up r
isks
for
maj
or b
leed
s, w
e ha
ve u
sed
maj
or b
leed
eve
nt r
ates
from
the
aspi
rin
arm
in th
e C
APR
IE tr
ial a
djus
ted
to a
5-y
tim
e fr
ame
as th
e st
artin
g po
int (
to e
nsur
e co
nsis
tenc
y ac
ross
evi
denc
e pr
ofi le
s). W
e th
en u
sed
the
RR
of 2
.69
for
the
com
pari
son
of a
spir
in to
no
aspi
rin
obse
rved
in th
e m
eta-
anal
ysis
to d
eriv
e th
e co
ntro
l gro
up r
ate
estim
ate
with
out a
spir
in.
Tabl
e 4—
[Sec
tion
s 3.
1.1-
3.1.
5] C
lopi
dogr
el v
s A
spir
in f
or P
atie
nts
Wit
h E
stab
lish
ed C
AD
29
Out
com
esPa
rtic
ipan
ts (S
tudi
es),
Fol
low
-up
Qua
lity
of th
e E
vide
nce
(GR
AD
E)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
5 y
Ris
k W
ith A
spir
inR
isk
Diff
eren
ce W
ith C
lopi
dogr
el (9
5% C
I)
Tota
l mor
talit
y a 19
,185
(1 R
CT
), 1.
9 y
Mod
erat
e du
e to
impr
ecis
ion b
RR
0.9
8 (0
.87-
1.10
)12
0 pe
r 1,
000 c
No
sign
ifi ca
nt d
iffer
ence
; 2 fe
wer
per
1,0
00 (f
rom
16
few
er to
12
mor
e)M
I no
nfat
al e
vent
s19
,185
(1 R
CT
), 1.
9 y
Mod
erat
e du
e to
impr
ecis
ion b
RR
0.8
5 (0
.72-
1.00
)80
per
1,0
00 c
12 fe
wer
per
1,0
00 (f
rom
22
few
er to
0 m
ore)
Stro
ke in
clud
es n
onfa
tal i
sche
mic
an
d he
mor
rhag
ic s
trok
es d
19,1
85 (1
RC
T),
1.9
yM
oder
ate
due
to im
prec
isio
n b R
R 0
.94
(0.8
3-1.
06)
110
per
1,00
0 c N
o si
gnifi
cant
diff
eren
ce; 7
few
er p
er 1
,000
(fro
m 1
9 fe
wer
to 7
mor
e)
Maj
or e
xtra
cran
ial b
leed
e 19
,185
(1 R
CT
), 1.
9 y
Mod
erat
e du
e to
impr
ecis
ion b
RR
0.8
8 (0
.7-1
.12)
40 p
er 1
,000
f N
o si
gnifi
cant
diff
eren
ce; 5
few
er p
er 1
,000
(fro
m 1
2 fe
wer
to 5
mor
e)
See
Tabl
e 1-
3 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a O
f the
dea
ths
in C
APR
IE, 2
7 of
571
(4.7
%) w
ith a
spir
in w
ere
fata
l ble
edin
g ev
ents
, and
23
of 5
60 (4
.1%
) with
clo
pido
grel
wer
e fa
tal b
leed
ing
even
ts.
b Rat
ed d
own
for i
mpr
ecis
ion
due
to w
ide
CIs
for a
bsol
ute
effe
cts,
sugg
estin
g po
ssib
le h
arm
with
clo
pido
grel
for m
orta
lity,
stro
ke, a
nd b
leed
ing
and
poss
ible
no
effe
ct fo
r MI.
Not
rate
d do
wn
for i
ncon
sist
ency
, al
thou
gh s
ubgr
oup
anal
ysis
of t
he c
ompo
site
end
poi
nt r
epor
ted
a re
lativ
e ri
sk r
educ
tion
of 7
.3%
for
patie
nts
with
str
oke
and
23.8
% fo
r pa
tient
s w
ith p
erip
hera
l art
eria
l dis
ease
and
a r
elat
ive
risk
incr
ease
of
3.7
% fo
r pa
tient
s w
ith M
I (t
est f
or in
tera
ctio
n P
5 .0
43).
Bas
ed o
n cr
iteri
a fo
r cr
edib
ility
, we
did
not b
elie
ve th
e re
sults
from
the
subg
roup
ana
lysi
s; th
eref
ore,
we
did
not r
ate
dow
n fo
r in
cons
iste
ncy.
c Con
trol
gro
up ri
sk e
stim
ates
for t
otal
mor
talit
y co
me
from
the
aspi
rin
arm
of t
he C
HA
RIS
MA
tria
l. E
stim
ates
for M
I an
d st
roke
com
e fr
om o
bser
ved
even
ts in
the
aspi
rin
arm
of a
met
a-an
alys
is o
f 16
RC
Ts
in s
econ
dary
pre
vent
ion
(Bai
gent
et a
l 9 ), a
djus
ted
to a
5-y
tim
e fr
ame.
d Of t
he s
trok
es in
CA
PRIE
, 24
of 4
86 (4
.9%
) with
asp
irin
wer
e he
mor
rhag
ic a
nd 1
4 of
528
(2.6
%) w
ith c
lopi
dogr
el w
ere
hem
orrh
agic
. e O
f the
maj
or e
xtra
cran
ial b
leed
s in
CA
PRIE
, 68
of 1
49 (4
5.6%
) with
asp
irin
wer
e G
I an
d 47
of 1
32 (3
5.6%
) with
clo
pido
grel
wer
e G
I ( P
5 .0
5).
f Con
trol
gro
up r
isk
estim
ates
com
e fr
om o
bser
ved
maj
or b
leed
ing
even
ts in
the
CA
PRIE
tria
l, ad
just
ed to
a 5
-y ti
me
fram
e, a
nd n
ot fr
om th
e 16
stu
dies
incl
uded
in th
e m
eta-
anal
ysis
bec
ause
thes
e st
udie
s di
d no
t rep
ort m
ajor
ble
eds
cons
iste
ntly
.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e649S
Tabl
e 5—
[Sec
ions
3.1
.1-3
.1.5
] A
spir
in P
lus
Clo
pido
grel
vs
Asp
irin
in
the
Seco
ndar
y P
reve
ntio
n of
Car
diov
ascu
lar
Eve
nts 3
Out
com
esPa
rtic
ipan
ts (S
tudi
es),
Fol
low
-up
Qua
lity
of th
e E
vide
nce
(GR
AD
E)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
5 y
Ris
k W
ith A
spir
inR
isk
Diff
eren
ce W
ith A
spir
in 1
C
lopi
dogr
el (9
5% C
I)
Tota
l mor
talit
y a 15
,603
(1 R
CT
), 28
mo
Mod
erat
e du
e to
im
prec
isio
n b R
R 0
.99
(0.8
6-1.
14)
120
per
1,00
0 c N
o si
gnifi
cant
diff
eren
ce; 1
few
er p
er 1
,000
(f
rom
17
few
er to
17
mor
e)M
I no
nfat
al e
vent
s15
,603
(1 R
CT
), 28
mo
Mod
erat
e du
e to
im
prec
isio
n b R
R 0
.94
(0.7
5-1.
18)
80 p
er 1
,000
c N
o si
gnifi
cant
diff
eren
ce; 5
few
er p
er 1
,000
(f
rom
20
few
er to
14
mor
e)St
roke
incl
udes
non
fata
l isc
hem
ic
and
hem
orrh
agic
str
okes
d 15
,603
(1 R
CT
), 28
mo
Mod
erat
e du
e to
im
prec
isio
n b R
R 0
.81
(0.6
4-1.
02)
110
per
1,00
0 c N
o si
gnifi
cant
diff
eren
ce; 2
1 fe
wer
per
1,0
00
(fro
m 4
0 fe
wer
to 2
mor
e)M
ajor
ext
racr
ania
l ble
ed e
15,6
03 (1
RC
T),
28 m
oM
oder
ate
due
to
impr
ecis
ion b
RR
1.2
5 (0
.97-
1.61
)40
per
1,0
00 f
No
sign
ifi ca
nt d
iffer
ence
; 10
mor
e pe
r 1,
000
(fro
m 1
few
er to
24
mor
e)
See
Tabl
e 1-
3 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a O
f the
dea
ths
in th
e C
HA
RIS
MA
tria
l, 17
of 5
71 (3
%) w
ith a
spir
in w
ere
fata
l ble
edin
g ev
ents
, and
26
of 5
74 (4
.5%
) with
clo
pido
grel
and
asp
irin
wer
e fa
tal b
leed
ing
even
ts.
b Rat
ed d
own
for
impr
ecis
ion
beca
use
of w
ide
CIs
for
abs
olut
e ef
fect
s, s
ugge
stin
g im
port
ant
bene
fi t, n
o be
nefi t
, or
impo
rtan
t ha
rm w
ith c
lopi
dogr
el f
or a
ll ou
tcom
es. N
ot r
ated
dow
n fo
r in
cons
iste
ncy,
al
thou
gh s
ubgr
oup
anal
ysis
foun
d no
sig
nifi c
ant e
ffec
t of c
lopi
dogr
el o
n va
scul
ar m
orta
lity
in p
atie
nts
with
est
ablis
hed
card
iova
scul
ar d
isea
se in
con
tras
t with
incr
ease
d m
orta
lity
in a
sym
ptom
atic
pat
ient
s.
We
judg
ed c
laim
of s
ubgr
oup
effe
ct to
be
not c
redi
ble
(hig
h nu
mbe
r of
sub
grou
p hy
poth
eses
test
ed, u
ncle
ar w
heth
er a
ppro
pria
te te
st fo
r in
tera
ctio
n us
ed).
c Con
trol
gro
up r
isk
estim
ates
for
tota
l mor
talit
y co
me
from
the
aspi
rin
arm
of t
he C
HA
RIS
MA
tria
l. E
stim
ates
for
MI
and
stro
ke c
ome
from
obs
erve
d ev
ents
in a
met
a-an
alys
is o
f 16
RC
Ts in
sec
onda
ry
prev
entio
n (B
aige
nt e
t al 9 )
, adj
uste
d to
a 5
-y ti
me
fram
e. d O
f the
str
okes
in C
HA
RIS
MA
, 27
of 1
89 (1
4%) w
ith a
spir
in w
ere
intr
acra
nial
hem
orrh
ages
, and
26
of 1
50 (1
7%) w
ith c
lopi
dogr
el w
ere
intr
acra
nial
hem
orrh
ages
. e W
e ex
clud
ed fa
tal b
leed
ing
and
intr
acra
nial
hem
orrh
age
to a
void
the
doub
le c
ount
ing
of e
vent
s in
the
CH
AR
ISM
A tr
ial.
Prop
ortio
n of
seve
re G
I bl
eeds
in C
HA
RIS
MA
was
0.6
5% (n
ot re
port
ed se
para
tely
fo
r ea
ch tr
eatm
ent a
rm).
f Con
trol
gro
up r
isk
estim
ates
com
e fr
om o
bser
ved
maj
or b
leed
ing
even
ts in
the
CA
PRIE
tria
l, ad
just
ed to
a 5
-y ti
me
fram
e, a
nd n
ot fr
om th
e 16
stu
dies
incl
uded
in th
e m
eta-
anal
ysis
or
from
CH
AR
ISM
A
beca
use
thes
e st
udie
s di
d no
t rep
ort m
ajor
ble
eds
cons
iste
ntly
.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e650S Prevention of Cardiovascular Disease
thrombosis With Clopidogrel in High-Risk Patients With Recent TIA or Ischemic Stroke (MATCH) study evaluated the effi cacy and safety of clopidogrel plus aspirin compared with clopidogrel alone for 18 months in 7,599 patients with recent stroke or TIA and one other risk factor. 38 Dual antiplatelet therapy was associated with a possible reduction in nonfatal stroke and a signifi cant increase in major extracranial bleeding. Results failed to demonstrate or exclude an effect of dual antiplatelet therapy on vascular mor-tality or nonfatal MI (Table S6). We rated the overall quality of evidence from this trial as moderate given imprecision of point estimates for outcomes of MI, stroke, and total mortality. We did not rate down for indirectness because we considered the relative effects generated from this trial of patients with cere-brovascular disease to be directly applicable to patients with established CAD.
3.1.4 Moderate-Intensity Warfarin (International Normalized Ratio 2.0-3.0) Plus Aspirin vs Aspirin Alone: Prior studies evaluating low-dose warfarin (international normalized ratio [INR] , 2.0) plus aspi-rin have not shown it to be more effective than aspi-rin alone in patients with CAD. 39-41 High-intensity warfarin (INR 2.8-4.2) without aspirin has proven to be more effective than aspirin alone in two prior randomized controlled clinical trials but was associ-ated with increased bleeding risk. 42,43 As a result, low-intensity warfarin plus aspirin or high-intensity warfarin are seldom used and will not be discussed further.
Rothberg et al 44 performed a systematic review and meta-analysis of 10 randomized trials involving 5,938 patients with recent ACS who were random-ized to moderate-to-high-intensity warfarin plus low-dose aspirin vs aspirin alone. We have performed our own meta-analysis of these studies (Table S7). In brief, the meta-analysis provides evidence of a sub-stantial reduction in MI and nonfatal stroke with moderate-intensity warfarin plus aspirin at the costs of increased major extracranial bleeds.
These studies were completed in the pre-stent era, the majority started therapy immediately after ACS and had , 1-year follow-up, and we identifi ed het-erogeneity for the prevention of vascular events among patients with CAD, peripheral arterial disease, and nonembolic stroke. It is diffi cult to apply this evidence to patients with chronic CAD or ACS in the current era; therefore, we do not make recommenda-tions for warfarin in these patient populations.
3.1.5 Aspirin Doses in Established CAD: The best evidence of the effects of different aspirin doses on vascular and bleeding events comes from subgroup anal-yses in the Antithrombotic Trialists’ Collaboration 30
absolute effects in a 5-year time frame for patients with established CAD. The results indicate no effect of clopidogrel on total mortality compared with aspi-rin. These results are consistent with a meta-analysis of 10 studies examining the effects of thienopyridine derivatives (eg, clopidogrel, ticlopidine) vs aspirin in patients at high vascular risk. 31
Resource considerations— Four studies that met criteria for review examined the cost-effectiveness of clopidogrel vs aspirin for secondary prevention of cardiovascular disease (Table S4). These studies con-sidered multiple patient populations. Three studies 32-34 were based on the CAPRIE trial 29 (patients with ischemic stroke in the prior 6 months, MI in the prior 35 days, or peripheral arterial disease). The fourth study was based on patients with prior TIA or non-disabling ischemic stroke. 35 The latter study was included because patients with prior TIA or stroke are at higher risk for coronary heart disease. Coro-nary heart disease was considered as an outcome in all these studies. All these studies demonstrated that clopidogrel was cost-effective compared with aspi-rin, with incremental cost-effectiveness ratios similar after adjustment for the cost year. These results are limited in that they neglect any possible incremental benefi t of aspirin over clopidogrel after . 5 years of use on cancer incidence (see section 2.1).
3.1.3 Dual Antiplatelet Therapy With Clopidogrel and Aspirin vs Single Antiplatelet Therapy: A Cochrane systematic review evaluated short- and long-term dual antiplatelet therapy in patients with established CAD. 36 Only one large-scale RCT, the CHARISMA trial, has evaluated the long-term effi cacy of clopid-ogrel and aspirin vs aspirin alone. 3 This trial followed 15,603 patients with established vascular disease or multiple risk factors for a mean period of 28 months. Table 5 (Table S5) summarizes the quality of the evi-dence and fi ndings from this trial. Results of the study failed to demonstrate or exclude an effect of dual antiplatelet therapy relative to aspirin on total mor-tality or nonfatal MI. Dual antiplatelet therapy was associated with a possible reduction in nonfatal stroke and a possible increase in nonfatal extracranial bleeding. The quality of evidence is rated moderate because of imprecise effect estimates for all outcomes. Although this study included patients with other vas-cular diseases, we considered its fi ndings directly applicable to patients with established CAD. We did not deem subgroup analyses suggesting different effects of dual antiplatelet therapy in symptomatic vs asymptomatic patients to be credible based on cri-teria by Sun et al. 37
There are no studies comparing aspirin and clo-pidogrel to clopidogrel for secondary prevention in patients with CAD. The Management of Athero-
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e 6—
[Sec
tion
s 3.
2.1-
3.2.
5] C
lopi
dogr
el v
s A
spir
in f
or P
atie
nts
Wit
h R
ecen
t A
CS 2
9
Out
com
esPa
rtic
ipan
ts (S
tudi
es),
Fol
low
-up
Qua
lity
of th
e E
vide
nce
(GR
AD
E)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
1 y
Ris
k W
ith A
spir
inD
iffer
ence
With
Clo
pido
grel
(95%
CI)
Vasc
ular
mor
talit
y a 19
,185
(1 R
CT
), 1.
9 y
Mod
erat
e du
e to
im
prec
isio
n b R
R 0
.92
(0.8
0-1.
07)
60 p
er 1
,000
c N
o si
gnifi
cant
diff
eren
ce; 5
few
er p
er 1
,000
(fro
m 1
2 fe
wer
to 4
mor
e)M
I no
nfat
al e
vent
s19
,185
(1 R
CT
), 1.
9 y
Mod
erat
e du
e to
im
prec
isio
n b R
R 0
.85
(0.7
2-1.
00)
70 p
er 1
,000
c 10
few
er p
er 1
,000
(fro
m 2
0 fe
wer
to 0
mor
e)
Stro
ke in
clud
es n
onfa
tal i
sche
mic
an
d he
mor
rhag
ic s
trok
es d
19,1
85 (1
RC
T),
1.9
yH
igh
RR
0.9
4 (0
.83-
1.06
)20
per
1,0
00 c
No
sign
ifi ca
nt d
iffer
ence
; 1 fe
wer
per
1,0
00 (f
rom
3 fe
wer
to 1
mor
e)M
ajor
ext
racr
ania
l ble
ed e
19,1
85 (1
RC
T),
1.9
yH
igh f
RR
0.8
8 (0
.7-1
.12)
30 p
er 1
,000
c N
o si
gnifi
cant
diff
eren
ce; 3
few
er p
er 1
,000
(fro
m 9
few
er
to
3 m
ore)
See
Tabl
e 1-
3 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a O
f the
dea
ths
in C
APR
IE 2
7 of
405
(6.7
%) w
ith a
spir
in w
ere
fata
l ble
edin
g ev
ents
, and
23
of 3
72 (6
.2%
) with
clo
pido
grel
wer
e fa
tal b
leed
ing
even
ts.
b Rat
ed d
own
for
impr
ecis
ion
for
MI
beca
use
of a
wid
e C
I, in
clud
ing
impo
rtan
t ben
efi t
and
no b
enefi
t w
ith c
lopi
dogr
el.
c Con
trol
gro
up r
isk
estim
ates
for
deat
h, M
I, s
trok
e, a
nd b
leed
ing
com
e fr
om th
e C
UR
E tr
ial (
adju
sted
to 1
-y ti
me
fram
e).
d Of t
he s
trok
es in
CA
PRIE
, 24
of 4
86 (4
.9%
) with
asp
irin
wer
e he
mor
rhag
ic, a
nd 1
4 of
528
(2.6
%) w
ith c
lopi
dogr
el w
ere
hem
orrh
agic
. e O
f the
maj
or e
xtra
cran
ial b
leed
s in
CA
PRIE
, 68
of 1
49 (4
5.6%
) with
asp
irin
wer
e G
I, a
nd 4
7 of
132
(35.
6%) w
ith c
lopi
dogr
el w
ere
GI.
f Our
dec
isio
n no
t to
rate
dow
n fo
r im
prec
isio
n is
due
to th
e lo
w c
ontr
ol g
roup
ris
k fo
r st
roke
s an
d m
ajor
ble
eds
that
res
ult i
n no
impo
rtan
t har
m o
f clo
pido
grel
(as
judg
ed b
y th
e up
per
limit
of th
e 95
% C
I fo
r th
e ab
solu
te e
ffec
t).
meta-analysis of antiplatelet therapy, which included direct and indirect comparisons of different daily doses of aspirin (500-1,500 mg vs 160-325 mg vs 75-150 mg vs , 75 mg) on vascular events. In the direct comparisons of high- vs low-dose aspirin, there were no signifi cant differences (ie, lower doses of aspirin were just as effective as higher doses). How-ever, the small number of studies with aspirin , 75 mg left uncertainty about whether such low doses are as effective as daily doses of � 75 mg. The indirect com-parisons of higher daily doses of aspirin vs no aspirin provide no evidence to support that high doses of aspirin (eg, . 160 mg/d) are more effective than 75 to 160 mg. A subsequent systematic review of aspirin doses for the prevention of cardiovascular events in 2007 identifi ed eight prospective trials that included nearly 10,000 patients taking aspirin 30 to 1,300 mg/d. 45 A signifi cant benefi t of higher doses of aspirin was not identifi ed in any of these studies, and in most, the lowest event rates were seen among patients randomized to the lower-dose group.
With respect to bleeding, a number of studies have suggested a potential relationship between increased aspirin doses and bleeding. A systematic review assess-ing bleeding rates associated with different doses of aspirin included . 190,000 patients enrolled in 31 RCTs. 46 Aspirin . 200 mg was associated with an � 30% increase in major bleeding compared with doses , 200 mg ( P 5 .05). There was an increase in nonmajor bleeding in patients receiving 100 to 200 mg of aspirin per day compared with patients taking , 100 mg/d. The Antiplatelet Trialists’ Col-laboration 30 found no difference in the proportional increase in the risk of a major extracranial bleed between differing aspirin doses ( , 75, 75-150, and 160-325 mg) compared with placebo but did not comment on doses . 325 mg. Taken together, the fi ndings provide moderate-quality evidence (rated down for risk of bias because of indirect comparisons of different aspirin doses) to support the use of aspirin 75 to 100 mg/d for patients with established CAD.
Recommendations
3.1.1-3.1.5. For patients with established CAD (including patients after the fi rst year post-ACS and/or with prior CABG surgery):
• We recommend long-term single antiplate-let therapy with aspirin 75 to 100 mg daily or clopidogrel 75 mg daily over no anti-platelet therapy (Grade 1A) .
• We suggest single over dual antiplatelet ther-apy with aspirin plus clopidogrel (Grade 2B) .
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e652S Prevention of Cardiovascular Disease
3.2 Choice of Antithrombotic Therapy Following ACS
For the purposes of these guidelines, we include patients with ST-segment elevation MI, non-ST-segment elevation MI, and unstable angina in the ACS population. This refl ects our judgment that the rela-tive effi cacy and safety of specifi c therapies in the year following presentation does not differ substan-tially between these diagnostic entities. In addition, many studies evaluating antithrombotic therapy follow-ing ACS have included patients undergoing early PCI, stent placement, or both. Therefore, we use evidence from the total study cohorts, and for the most part, our recommendations apply to patients with ACS regardless of whether they undergo PCI. One exception is prasugrel, which has been studied primarily in patients with ACS with planned PCI; recommendations for this agent are restricted to this specifi c population. Recommendations for patients undergoing elective PCI/stenting (without ACS) are presented in a subsequent section.
Estimation of Baseline Risk— There have been numerous studies of antithrombotic therapy follow-ing ACS. Depending on study population, date, and use of concomitant interventions, baseline risks vary widely. Ideally, we would identify a single population receiving different antithrombotic strategies in order to derive baseline risks. Because this is not possible, we use control group risks from Clopidogrel in Unstable Angina To Prevent Recurrent Events (CURE) for comparisons where aspirin constitutes the control group (as it did in CURE) and the Platelet Inhibition and Patient Outcomes (PLATO) study for compar-isons where aspirin and clopidogrel constitute the control group. 47,48 We selected CURE and PLATO because they were designed as large, simple trials; use accepted defi nitions for both vascular and bleed-ing events; and include a large proportion of patients who underwent cardiac catheterization/PCI, which refl ects current practice in high-income countries.
3.2.1 Aspirin vs Placebo: Table 3 summarizes the evidence from a meta-analysis with individual par-ticipant data from 16 RCTs with 17,000 patients with established vascular disease treated with aspirin vs placebo (including six trials of patients with pre-vious MI). 9 We deem this meta-analysis directly appli-cable to patients with recent ACS.
3.2.2 Clopidogrel vs Aspirin: We again base our recommendation on evidence from the CAPRIE study, a randomized comparison of clopidogrel vs aspi-rin in the secondary prevention of cardiovascular events. 29 Table 6 (Table S8) summarizes the evi-dence from the CAPRIE trial as it applies to an ACS population.
Tabl
e 7—
[Sec
tion
s 3.
2.1-
3.2.
5] A
spir
in P
lus
Clo
pido
grel
vs
Asp
irin
in
Pat
ient
s W
ith
a R
ecen
t A
CS 4
7
Out
com
esPa
rtic
ipan
ts (S
tudi
es),
Fol
low
-up
Qua
lity
of th
e E
vide
nce
(GR
AD
E)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
1 y
Ris
k W
ith A
spir
inR
isk
Diff
eren
ce W
ith C
lopi
dogr
el 1
Asp
irin
(95%
CI)
Vasc
ular
mor
talit
y a 12
,562
(1 R
CT
), 9
mo
Mod
erat
e du
e to
im
prec
isio
n b R
R 0
.93
(0.7
9-1.
08)
60 p
er 1
,000
c N
o si
gnifi
cant
diff
eren
ce; 4
few
er p
er 1
,000
(f
rom
13
few
er to
5 m
ore)
MI
nonf
atal
eve
nts
12,5
62 (1
RC
T),
9 m
oH
igh
RR
0.7
7 (0
.67-
0.89
)70
per
1,0
00 c
16 fe
wer
per
100
0 (f
rom
23
few
er to
8 fe
wer
)St
roke
incl
udes
non
fata
l isc
hem
ic
and
hem
orrh
agic
str
okes
d 12
,562
(1 R
CT
), 9
mo
Mod
erat
e du
e to
im
prec
isio
n b R
R 0
.86
(0.6
3-1.
18)
20 p
er 1
,000
c N
o si
gnifi
cant
diff
eren
ce; 3
few
er p
er 1
,000
(f
rom
7 fe
wer
to 4
mor
e)M
ajor
ext
racr
ania
l ble
ed e
12,5
62 (1
RC
T),
9 m
oM
oder
ate
due
to
impr
ecis
ion b
RR
1.3
8 (1
.13-
1.67
)30
per
1,0
00 c
11 m
ore
per
1,00
0 (f
rom
4 m
ore
to 2
0 m
ore)
CU
RE
5 C
lopi
dogr
el in
Uns
tabl
e A
ngin
a to
Pre
vent
Rec
urre
nt E
vent
s. S
ee T
able
1-3
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
. a O
f the
tota
l dea
ths
in th
e C
UR
E tr
ial,
15 o
f 390
(3.8
%) w
ith a
spir
in w
ere
fata
l ble
edin
g ev
ents
, and
11
of 3
59 (3
.1%
) with
clo
pido
grel
wer
e fa
tal b
leed
ing
even
ts.
b Rat
ed d
own
for
impr
ecis
ion
beca
use
wid
e C
Is in
clud
ed b
enefi
t an
d ha
rm.
c Con
trol
gro
up r
isk
estim
ates
com
e fr
om e
vent
rat
es in
the
aspi
rin
arm
of t
he C
UR
E tr
ial (
adju
sted
to 1
-y ti
me
fram
e).
d Of t
he s
trok
es in
CU
RE
, fi v
e of
87
(5.7
%) w
ith a
spir
in w
ere
hem
orrh
agic
, and
sev
en o
f 75
(9.3
%) w
ith c
lopi
dogr
el w
ere
hem
orrh
agic
. e M
ajor
ble
ed w
as d
efi n
ed a
s a su
bsta
ntia
lly d
isab
ling
blee
d, in
trao
cula
r ble
ed le
adin
g to
the
loss
of v
isio
n, o
r ble
edin
g ne
cess
itatin
g th
e tr
ansf
usio
n of
at l
east
2 u
nits
of b
lood
. Of t
he m
ajor
ext
racr
ania
l ble
eds
in C
UR
E, 4
7 of
169
(27.
8%) w
ith a
spir
in w
ere
GI,
and
83
of 2
31 (3
5.9%
) with
clo
pido
grel
wer
e G
I.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e653S
3.2.3 Aspirin and Clopidogrel vs Aspirin: During the past decade, the use of clopidogrel in addition to aspirin during the fi rst 9 to 12 months after an ACS has become standard clinical practice. As recognized in a Cochrane systematic review, 36 the CURE trial is the only study that has addressed the effects of clo-pidogrel in addition to aspirin in patients with ACS without ST-segment elevation. 47 Table 7 (Table S9) presents the quality of the evidence and main fi nd-ings of this trial that randomized 12,562 patients with a recent ACS to clopidogrel and aspirin or aspirin alone for 3 to 12 months, included 2,658 patients who underwent PCI following ACS, and provided moderate-quality evidence that dual antiplatelet ther-apy reduces MI and increases major bleeding events. Results failed to demonstrate or exclude an effect of dual antiplatelet therapy vs aspirin alone on vascular mortality or nonfatal stroke.
Resource Considerations— Six studies 33,49-53 exam-ined the cost-effectiveness of combined antiplatelet therapy with clopidogrel plus aspirin vs aspirin alone in patients after a recent ACS. These studies are consistent in demonstrating the cost-effectiveness of combined antiplatelet therapy with clopidogrel plus aspirin compared with aspirin alone after ACS. Schleinitz et al 53 examined the effect of varying treat-ment duration and found that longer treatment duration was increasingly expensive, with incremen-tal cost-effectiveness ratios (in 2010 US dollars) of $38,252/quality-adjusted life year (QALY) for 2 years, $74,204/QALY for 3 years, and $883,665/QALY for 5 years of treatment. Not only does cost-effectiveness decrease after 1 year but also the estimates represent extrapolation from the available data (patients were followed for only 1 year). Furthermore, evidence from a comparison of aspirin and clopidogrel vs aspirin raise serious questions about the extrapolation. 3 Over-all, the benefi ts of combined antiplatelet therapy with clopidogrel plus aspirin come at acceptable cost for the fi rst year after ACS.
3.2.4 Ticagrelor and Aspirin vs Clopidogrel and Aspirin: Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has more-rapid onset and more-pronounced plate-let inhibition than clopidogrel. 54,55 Table 8 (Table S10) summarizes the quality of evidence and key fi ndings from the PLATO trial that evaluated the effects of ticagrelor vs clopidogrel in patients with a recent ACS. 56 In this study, 18,624 patients were randomized to receive, in addition to aspirin 75 mg/d, ticagrelor (180-mg loading dose, 90 mg bid thereafter) or clo-pidogrel (300-to 600-mg loading dose, 75 mg there-after) for 6 to 12 months. At 12-month follow-up, ticagrelor signifi cantly reduced vascular mortality and MI. Results failed to demonstrate or exclude an
Tabl
e 8—
[Sec
tion
s 3.
2.1-
3.2.
5] T
icag
relo
r P
lus
Asp
irin
vs
Clo
pido
grel
Plu
s A
spir
in i
n P
atie
nts
Wit
h a
Rec
ent
AC
S 56
Out
com
esPa
rtic
ipan
ts (S
tudi
es),
Fol
low
-up
Qua
lity
of th
e E
vide
nce
(GR
AD
E)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
1 y
Ris
k W
ith C
lopi
dogr
el a
nd A
spir
inR
isk
Diff
eren
ce W
ith T
icag
relo
r an
d A
spir
in (9
5% C
I)
Vasc
ular
mor
talit
y a 18
,624
(1 R
CT
), 6-
12 m
oH
igh
RR
0.7
9 (0
.69-
0.91
)50
per
1,0
00 b
10 fe
wer
per
1,0
00 (f
rom
15
few
er to
4 fe
wer
)M
I no
nfat
al e
vent
s18
,624
(1 R
CT
), 6-
12 m
oH
igh
RR
0.8
4 (0
75-0
.95)
70 p
er 1
,000
b 11
few
er p
er 1
,000
(fro
m 1
7 fe
wer
to 3
few
er)
Stro
ke in
clud
es n
onfa
tal i
sche
mic
an
d he
mor
rhag
ic s
trok
es c
18,6
24 (1
RC
T),
6-12
mo
Mod
erat
e du
e to
im
prec
isio
n d R
R 1
.17
(0.9
1-1.
52)
13 p
er 1
,000
b N
o si
gnifi
cant
diff
eren
ce; 2
mor
e pe
r 1,
000
(fro
m 1
few
er to
7 m
ore)
Maj
or e
xtra
cran
ial b
leed
18,6
24 (1
RC
T),
6-12
mo
Mod
erat
e du
e to
im
prec
isio
n d R
R 1
.25
(1.0
1-1.
53)
22 p
er 1
,000
b 6
mor
e pe
r 1,
000
(fro
m 0
mor
e to
11
mor
e)
PLAT
O 5
Pla
tele
t Inh
ibiti
on a
nd P
atie
nt O
utco
mes
. See
Tab
le 1
-3 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a Of t
he to
tal d
eath
s in
the
PLAT
O s
tudy
, 20
of 3
99 (5
.0%
) with
tica
grel
or w
ere
fata
l ble
edin
g ev
ents
, and
23
of 5
06 (4
.5%
) with
clo
pido
grel
wer
e fa
tal b
leed
ing
even
ts.
b One
-yea
r co
ntro
l gro
up r
isk
estim
ates
com
e fr
om e
vent
rat
es in
the
clop
idog
rel a
rm o
f PL
ATO
adj
uste
d to
a 1
-y ti
me
fram
e. c O
f the
tota
l str
okes
in P
LAT
O, 2
3 of
125
(18.
4%) w
ith ti
cagr
elor
wer
e he
mor
rhag
ic, a
nd 1
3 of
106
(12.
3%) w
ith c
lopi
dogr
el w
ere
hem
orrh
agic
. d R
ated
dow
n fo
r im
prec
isio
n du
e to
wid
e C
Is in
clud
ing
harm
with
tica
grel
or fo
r st
roke
and
ble
eds.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e654S Prevention of Cardiovascular Disease
effect on nonfatal stroke. The rate of death from any cause was also reduced with ticagrelor (4.5% vs 5.9% with clopidogrel, P , .001). However, ticagrelor was associated with a higher rate of major bleeding not related to CABG (2.8% vs 2.2%, P 5 .03). The quality of evidence from this study was deemed moderate because of imprecision in nonfatal stroke and major extracranial bleeding.
A separate publication reports results from the subset of patients who underwent PCI. 48 PCI was performed during the index hospitalization in 61% of patients, of whom 60% received intracoronary stents. The effects of ticagrelor compared with clopidogrel on vascular mortality, MI, stroke, and major bleeds appear to be similar in this subset of patients com-pared with the overall population.
Although the original study design was not intended to stratify observed outcomes by geographical region, patients enrolled in North America reportedly had a higher incidence of adverse cardiovascular outcomes (whereas net benefi t was observed in other areas), which initially delayed US approval of ticagrelor pend ing further data review. After further post hoc analysis, the only baseline covariate identifi ed as possibly contributing to geographic variation was use of higher doses of aspirin in the United States. To date, these data have not been published. The US Food and Drug Administration approved ticagre-lor for patients with ACS in July 2010 but recommend against this agent in patients taking . 100 mg of aspirin per day.
3.2.5 Prasugrel and Aspirin vs Clopidogrel and Aspirin: Prasugrel is a novel thienopyridine that achieves more-rapid and more-consistent platelet inhibition than standard-dose clopidogrel. Table 9 (Table S11) summarizes the quality of evidence and key fi ndings from the TRITON-TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Opti-mizing Platelet Inhibition With Prasugrel-Thrombol-ysis in Myocardial Infarction) 38, the only published randomized trial to evaluate prasugrel vs clopidogrel in patients with recent ACS who undergo PCI. 57 In this trial, 13,608 patients with moderate- to high-risk ACS and a scheduled PCI were randomized to receive, in addition to aspirin 75 mg/d, prasugrel (60-mg load-ing dose followed by 10 mg/d) or clopidogrel (300-mg loading dose followed by 75 mg/d) for 6 to 15 months. Ninety-nine percent of patients had PCI at the time of randomization, and 94% received intracoronary stents. Prasugrel signifi cantly reduced MI but increased major bleeding, including life-threatening and fatal bleeds. Prasugrel was associated with a possible reduc-tion in vascular mortality. Results failed to demonstrate or exclude an effect on nonfatal stroke. The quality of
Tabl
e 9—
[Sec
tion
s 3.
2.1-
3.2.
5] P
rasu
grel
Plu
s A
spir
in v
s C
lopi
dogr
el P
lus
Asp
irin
in
Pat
ient
s W
ith
a R
ecen
t A
CS
and
PC
I 57
Out
com
esPa
rtic
ipan
ts
(Stu
dies
), F
ollo
w-u
pQ
ualit
y of
the
Evi
denc
e (G
RA
DE
)R
elat
ive
Eff
ect
(95%
CI)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
1 y
Ris
k W
ith C
lopi
dogr
el a
nd A
spir
inR
isk
Diff
eren
ce W
ith P
rasu
grel
and
Asp
irin
(95%
CI)
Vasc
ular
mor
talit
y a 13
,608
(1 R
CT
), 14
.5 m
oL
ow d
ue to
inco
nsis
tenc
y b an
d im
prec
isio
n c R
R 0
.89
(0.7
0-1.
12)
50 p
er 1
,000
d N
o si
gnifi
cant
diff
eren
ce; 5
few
er p
er 1
,000
(f
rom
15
few
er to
6 m
ore)
MI
nonf
atal
eve
nts
13,6
08 (1
RC
T),
14.5
mo
Mod
erat
e du
e to
in
cons
iste
ncy c
RR
0.7
6 (0
.67-
0.85
)70
per
1,0
00 d
17 fe
wer
per
1,0
00 (f
rom
23
few
er to
10
few
er)
Stro
ke in
clud
es n
onfa
tal i
sche
mic
an
d he
mor
rhag
ic s
trok
es e
13,6
08 (1
RC
T),
14.5
mo
Low
due
to in
cons
iste
ncy b
and
impr
ecis
ion c
RR
1.0
2 (0
.71-
1.45
)13
per
1,0
00 d
No
sign
ifi ca
nt d
iffer
ence
; 0 m
ore
per
1,00
0 (f
rom
4 fe
wer
to 6
mor
e)M
ajor
ext
racr
ania
l ble
ed13
,608
(1 R
CT
), 14
.5 m
oL
ow d
ue to
inco
nsis
tenc
y b an
d im
prec
isio
n c R
R 1
.32
(1.0
3-1.
68)
22 p
er 1
,000
d 7
mor
e pe
r 1,
000
(fro
m 0
mor
e to
15
mor
e)
See
Tabl
e 1-
3, a
nd 8
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Fat
al b
leed
s w
ere
0.4%
with
pra
sugr
el a
nd 0
.1%
with
clo
pido
grel
. b R
ated
dow
n fo
r in
cons
iste
ncy
for
all o
utco
mes
due
to c
redi
ble
subg
roup
ana
lyse
s sh
owin
g ne
t har
m fo
r co
mpo
site
end
poi
nt in
cer
tain
sub
grou
ps.
c Rat
ed d
own
for
impr
ecis
ion
due
to w
ide
CIs
sug
gest
ing
impo
rtan
t ben
efi t
or h
arm
with
pra
sugr
el.
d Con
trol
gro
up r
isk
estim
ates
com
e fr
om th
e ev
ent r
ates
in th
e cl
opid
ogre
l arm
of t
he P
LAT
O s
tudy
, adj
uste
d to
a 1
-y ti
me
fram
e. e H
emor
rhag
ic s
trok
es c
onst
itute
d 0.
3% o
f all
stro
kes
in b
oth
grou
ps.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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evidence is rated down because of imprecision in vascular mortality, nonfatal stroke, and major extra-cranial bleeding.
Post hoc exploratory subgroup analyses spurred by these observations suggested that patients with a history of stroke or TIA before enrollment had net harm from prasugrel treatment, whereas elderly (aged . 75 years) patients and patients with a body weight , 60 kg had no net benefi t from prasugrel (composite outcome of all-cause mortality, MI, stroke, and non-CABG-related TIMI major bleeding) (tests for interaction P 5 .06 for both). We judged the claimed subgroup effects to be of moderate credibility. The Food and Drug Administration labeling includes a boxed warning that the drug should not be used in patients with a history of TIA or stroke or urgent need for surgery, including CABG. The manufacturer rec-ommends a decreased maintenance dose of 5 mg/d for patients weighing , 60 kg, although this particular recommendation is based on pharmacokinetic/phar-macodynamic modeling rather than on clinical data. Experts have expressed concern about the increased bleeding risks with intensifi ed platelet inhibition. 58
Recommendations
3.2.1-3.2.5. For patients in the fi rst year after an ACS who have not undergone PCI:
• We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low-dose aspirin 75-100 mg daily or clopidogrel 75 mg daily plus low-dose aspirin 75-100 mg daily) over single antiplatelet therapy (Grade 1B) .
• We suggest ticagrelor 90 mg daily plus low-dose aspirin over clopidogrel 75 mg daily plus low-dose aspirin (Grade 2B) .
For patients in the fi rst year after an ACS who have undergone PCI with stent placement:
• We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low-dose aspirin 75-100 mg daily, clopidogrel 75 mg daily plus low-dose aspirin, or prasugrel 10 mg daily plus low-dose aspirin over single antiplatelet therapy) (Grade 1B) .
Remarks: Evidence suggests that prasugrel results in no benefi t or net harm in patients with a body weight of less than 60 kg, age above 75 years, or with a pre-vious stroke/TIA.
• We suggest ticagrelor 90 mg twice daily plus low-dose aspirin over clopidogrel 75 mg daily plus low-dose aspirin (Grade 2B) .
For patients with ACS who undergo PCI with stent placement, we refer to sections 4.3.1 to
4.3.5 for recommendations concerning minimum and prolonged duration of treatment.
3.2.6 Antithrombotic Therapy in Patients With Acute Anterior MI and LV Thrombus (or at Risk for LV Thrombus): Patients with large anterior MI have a high risk of developing LV thrombus and sub sequent systemic embolization (eg, stroke, periph-eral embolization). Observational studies prior to the advent of thrombolysis and PCI suggested rates of LV thrombus formation as high as 20% to 50%. 59-62 More recent studies suggest LV thrombus rates of � 15% in patients with anterior MI 63,64 and up to 27% with anterior ST-segment elevation MI and LV ejection fraction , 40%. 65
Embolization rates in patients with anterior MI who develop LV thrombus and who are not treated with warfarin therapy are more diffi cult to estimate. In a natural history study of 198 consecutive patients with MI conducted from 1985 to 1987, 62 LV throm-bus occurred in 38 of 124 (31%) of patients with anterior MI. Deterioration in LV function, discharge ejection fraction � 35%, or apical aneurysm/dyskine-sis predicted development of LV thrombus by logistic regression analysis. Six of 35 patients (17%) with LV thrombus on predischarge echocardiogram experienced systemic embolization. Unfortunately, presence or absence of warfarin treatment was not included as a variable in regression analyses.
Vaitkus et al 66 performed a meta-analysis of 11 observational studies of the effects of anticoagulation on the incidence of LV thrombosis and systemic embolization in patients with Q-wave (transmural) anterior MI. Anticoagulation with vitamin K antago-nists decreased the risk of LV thrombus formation (adjusted OR, 0.32; 95% CI, 0.20-0.52) (four studies, 307 patients) and embolization (adjusted OR, 0.14; 95% CI, 0.04-0.52) (seven studies, 270 patients). Systemic embolization was � 11% in patients with LV thrombus vs 2% in those without LV thrombus (adjusted OR, 5.45; 95% CI, 3.02-9.83).
Given these data as well as prior studies suggesting that warfarin plus aspirin is more effective in patients with established CAD than aspirin alone (Table S7), the benefi ts of adding warfarin to aspirin in patients with large anterior MI (ejection fraction , 40%, antero-apical wall motion abnormality) who are not under-going stent placement, particularly those with LV thrombus, likely outweighs the bleeding risk.
3.2.7 Anterior MI, LV Thrombus, and Stent Placement: Extrapolating these data to the current era in which most patients with a large anterior MI will undergo PCI and stent placement is diffi cult. Although aspirin and clopidogrel are superior to warfarin for the pre-vention of acute stent thrombosis, their relative effect
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e656S Prevention of Cardiovascular Disease
Tabl
e 10
— [S
ecti
ons
3.2.
6-3.
2.7]
Tri
ple
The
rapy
(W
arfa
rin,
Asp
irin
, Clo
pido
grel
) vs
Du
al A
ntip
late
let
The
rapy
in
Pat
ient
s W
ith
Acu
te L
arge
Ant
erio
r M
I at
Ris
k fo
r or
Wit
h LV
Thr
omb
us
Who
Und
ergo
PC
I W
ith
Sten
t P
lace
men
t 44
Out
com
esPa
rtic
ipan
ts
(Stu
dies
), F
ollo
w-u
pQ
ualit
y of
the
Evi
denc
e (G
RA
DE
)R
elat
ive
Eff
ect (
95%
CI)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
3 m
o
Ris
k W
ith C
lopi
dogr
el a
nd A
spir
inR
isk
Diff
eren
ce W
ith W
arfa
rin
1 C
lopi
dogr
el
and
Asp
irin
(95%
CI)
Tota
l mor
talit
y10
,883
(10
RC
T),
3-60
mo
Low
due
to in
dire
ctne
ss a
and
impr
ecis
ion b
RR
1.0
0 (0
.82-
1.22
)25
per
1,0
00 c
No
sign
ifi ca
nt d
iffer
ence
; 0 fe
wer
per
1,0
00
(fro
m 4
few
er to
6 m
ore)
MI
nonf
atal
eve
nts
10,8
83 (1
0 R
CTs
), 3-
60 m
oL
ow d
ue to
ser
ious
in
dire
ctne
ss a
RR
0.6
9 (0
.54-
0.88
)35
per
1,0
00 c
11 fe
wer
per
1,0
00 (f
rom
16
few
er to
4 fe
wer
)
Stro
ke in
clud
es n
onfa
tal i
sche
mic
an
d he
mor
rhag
ic s
trok
es d
6,70
9 (1
RC
T),
1.3
yL
ow d
ue to
indi
rect
ness
d an
d im
prec
isio
n b R
R 0
.56
(0.3
9-0.
82)
Ant
eroa
pica
l MI
with
out L
V th
rom
bus
15 p
er 1
,000
e 7
few
er p
er 1
,000
(fro
m 9
few
er to
3 fe
wer
)A
nter
oapi
cal M
I w
ith L
V th
rom
bus
100
per
1,00
0 e 44
few
er p
er 1
,000
(fro
m 1
8 fe
wer
to 6
1 fe
wer
)M
ajor
ext
racr
ania
l ble
ed10
,883
(10
RC
Ts),
3-60
mo
Low
due
to in
dire
ctne
ss a
RR
2.3
7 (1
.62-
3.47
)11
per
1,0
00 c
15 m
ore
per
1,00
0 (f
rom
7 m
ore
to 2
7 m
ore)
Bur
den
of tr
eatm
ent f
Not
app
licab
leH
igh
War
fari
n .
aspi
rin
War
fari
n: d
aily
med
icat
ion,
die
tary
and
act
ivity
res
tric
tions
, fre
quen
t blo
od
test
ing/
mon
itori
ng, i
ncre
ased
hos
pita
l/clin
ic v
isits
Asp
irin
: dai
ly m
edic
atio
n on
ly
AC
TIV
E-W
5 A
tria
l Fib
rilla
tion
Clo
pido
grel
Tri
al W
ith I
rbes
arta
n fo
r Pr
even
tion
of V
ascu
lar
Eve
nts.
See
Tab
le 1
-3, a
nd 8
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
. a R
elat
ive
risk
for
war
fari
n, a
spir
in, a
nd c
lopi
dogr
el v
s du
al a
ntip
late
let t
hera
py w
as d
eriv
ed fr
om a
met
a-an
alys
is o
f stu
dies
com
pari
ng w
arfa
rin
plus
asp
irin
to a
spir
in a
lone
in p
atie
nts
follo
win
g A
CS.
b Rat
ed d
own
for
impr
ecis
ion
for
tota
l mor
talit
y du
e to
wid
e C
Is s
ugge
stin
g im
port
ant h
arm
and
ben
efi t
with
war
fari
n pl
us a
spir
in. F
or s
trok
e, w
e ra
ted
dow
n fo
r im
prec
ise
base
line
risk
est
imat
es.
c Con
trol
gro
up r
isk
estim
ates
(asp
irin
1 cl
opid
ogre
l) co
me
from
PL
ATO
tria
l, ad
just
ed to
a 3
-mo
time
fram
e as
sum
ing
that
one
-hal
f of t
he to
tal e
vent
s at
1 y
occ
urre
d in
the
fi rst
3 m
o (a
s w
as th
e ca
se in
the
PLAT
O tr
ial).
d We
assu
med
tha
t th
e re
lativ
e ri
sk f
or t
he o
utco
me
of n
onfa
tal s
trok
e (is
chem
ic a
nd h
emor
rhag
ic)
wou
ld b
e th
e sa
me
as o
bser
ved
in t
he A
CT
IVE
-W s
tudy
, whi
ch c
ompa
red
war
fari
n to
dua
l ant
ipla
tele
t th
erap
y (a
spir
in 1
clop
idog
rel).
We
calc
ulat
ed th
e R
R a
nd 9
5% C
I af
ter
extr
actin
g th
e nu
mbe
r of
non
fata
l str
okes
(is
chem
ic a
nd h
emor
rhag
ic)
in e
ach
grou
p fr
om th
e pu
blis
hed
repo
rt b
ecau
se it
did
not
di
rect
ly r
epor
t RR
in th
e ar
ticle
. e C
ontr
ol g
roup
ris
k es
timat
es f
or n
onfa
tal s
trok
e is
bas
ed o
n an
� 1.
5% r
ate/
3 m
o (s
ee t
ext)
with
clo
pido
grel
and
asp
irin
fol
low
ing
ante
rior
MI
and
10%
rat
e/3
mo
in p
atie
nts
with
ant
erio
r M
I an
d LV
th
rom
bus.
The
re is
con
side
rabl
e im
prec
isio
n in
thes
e es
timat
es.
f The
re a
re s
tudi
es e
valu
atin
g qu
ality
of l
ife in
pat
ient
s du
ring
war
fari
n tr
eatm
ent (
with
dis
para
te fi
ndin
gs),
but t
hese
are
lim
ited
by s
mal
l sam
ple
size
, lac
k of
com
para
tor,
and
othe
r de
sign
issu
es.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e657S
on the prevention of systemic embolization in patients with LV thrombus is largely unknown. Physicians must attempt to weigh the potential benefi ts and risks of adding warfarin to dual antiplatelet therapy in these patients.
Table 10 (Table S12) summarizes the evidence and anticipated absolute effects of triple therapy vs dual antiplatelet therapy in patients with large anterior MI at risk for or with LV thrombus who undergo PCI with stent placement. In the absence of direct com-parisons, we used indirect evidence to address this question. For nonstroke outcomes (death, MI, and major bleeds), we make the assumption that the rela-tive impact of triple therapy (aspirin, clopidogrel, and warfarin) vs dual therapy (aspirin plus clopidogrel) is similar to that of warfarin plus aspirin vs aspirin alone. We use data from studies included in the meta-analysis by Rothberg et al 44 that compared warfarin plus aspi-rin to aspirin alone following ACS to derive relative risk estimates for the outcomes of mortality, nonfatal MI, and major bleeding (Table S7).
We also assumed that the relative effects of triple therapy vs dual therapy on nonfatal stroke would be similar to that of warfarin alone vs aspirin plus clopidogrel. We used data from the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE-W) study to derive the rela-tive risk estimate for nonfatal stroke. 67 This assump-tion may underestimate the potential benefi t of triple therapy relative to dual antiplatelet therapy on vascu-lar outcomes.
In patients with large anterior MI but no thrombus, LV thrombus is estimated to develop in � 15%. 62,66 Given the estimated 10% associated risk of embolic stroke, there is 1.5% risk of stroke at 3 months without warfarin therapy. As shown in Table 10 (Table S12), we estimated that patients with large anterior MI but no initial thrombus who receive warfarin in addition to dual antiplatelet therapy will have seven fewer nonfatal strokes and 15 more extracranial nonfatal bleeds per 1,000 treated. For patients with large anterior MI and demonstrated LV thrombus, the addition of warfarin to antiplatelet therapy would be expected to result in 44 fewer nonfatal strokes and 15 more nonfatal extracranial bleeds. The addition of warfarin to dual antiplatelet therapy following MI may result in an absolute decrease of 11 MIs per 1,000 patients treated.
Given the increased risk of major bleeding, the duration of triple therapy, if chosen, should be mini-mized. Although the formation of LV thrombus was observed in most patients in the fi rst few weeks, addi-tional clots developed up to 3 months after anterior MI. For patients at risk for LV thrombus (but no thrombus identifi ed on initial echocardiogram) in whom warfarin therapy is withheld, repeat echocardiogram
in 1 to 2 weeks to rule out subsequent development of thrombus may be advisable.
As is discussed subsequently, we suggest that the minimal duration of dual antiplatelet therapy should be 1 month following BMS and 3 to 6 months fol-lowing DES. These time periods were considered in developing our recommendations for this section.
Recommendations
3.2.6-3.2.7. For patients with anterior MI and LV thrombus or at high risk for LV thrombus (ejection fraction , 40%, anteroapical wall mo-tion abnormality) who do not undergo stenting:
• We recommend warfarin (INR 2.0-3.0) plus low-dose aspirin 75 to 100 mg daily over single antiplatelet therapy or dual antiplate-let therapy for the fi rst 3 months (Grade 1B) . Thereafter, we recommend discontinua-tion of warfarin and continuation of dual antiplatelet therapy for up to 12 months as per the ACS recommendations (see rec-ommendations 3.2.1-3.2.5). After 12 months, single antiplatelet therapy is recommended as per the established CAD recommenda-tions (see recommendations 3.1.1-3.1.5).
For patients with anterior MI and LV thrombus, or at high risk for LV thrombus (ejection frac-tion , 40%, anteroapical wall motion abnormal-ity), who undergo BMS placement:
• We suggest triple therapy (warfarin [INR 2.0-3.0], low-dose aspirin, clopidogrel 75 mg daily) for 1 month over dual antiplatelet therapy (Grade 2C) .
• We suggest warfarin (INR 2.0-3.0) and single antiplatelet therapy for the second and third month post-BMS over alternative regimens and alternative time frames for warfarin use (Grade 2C) . Thereafter, we recommend discontinuation of warfarin and use of dual antiplatelet therapy for up to 12 months as per the ACS recommen-dations (see recommendations 3.2.1-3.2.5). After 12 months, antiplatelet therapy is recommended as per the established CAD recommendations (see recommendations 3.1.1-3.1.5).
For patients with anterior MI and LV thrombus or at high risk for LV thrombus (ejection frac-tion , 40%, anteroapical wall motion abnormal-ity) who undergo DES placement:
• We suggest triple therapy (warfarin [INR 2.0-3.0], low-dose aspirin, clopidogrel
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e658S Prevention of Cardiovascular Disease
75 mg daily) for 3 to 6 months over alter-native regimens and alternative durations of warfarin therapy (Grade 2C) . There-after, we recommend discontinuation of warfarin and continuation of dual anti-platelet therapy for up to 12 months as per the ACS recommendations (see recommen-dations 3.2.1-3.2.5). After 12 months, anti-platelet therapy is recommended as per the established CAD recommendations (see recommendations 3.1.1-3.1.5).
4.0 Antithrombotic Therapy Following Elective PCI
Choice and duration of antiplatelet therapy follow-ing PCI depends on the setting (acute vs elective), whether a stent is placed, and the type of stent (DES vs BMS) placed. We have previously discussed evi-dence for antithrombotic therapy following PCI in patients with ACS. In this section, we discuss anti-thrombotic therapy following elective PCI. As in prior sections, we address the patient-important outcomes of death, nonfatal MI, nonfatal stroke (if reported), and major bleeding.
Estimation of Baseline Risk— For the comparison of thienopyridines plus aspirin vs warfarin plus aspi-rin following elective PCI, we chose vascular and bleeding risks from the warfarin plus aspirin arm of a systematic review of four RCTs. 68 For the compari-sons involving cilostazol as part of dual or triple anti-platelet therapy vs aspirin plus clopidogrel, we chose baseline risks from the clopidogrel plus aspirin arm of a systematic review of 10 RCTs examining cil-ostazol following elective PCI. 69 For the comparison of high- vs low-dose aspirin following PCI, we chose the low-dose aspirin arm of the CURRENT-OASIS 7 (Clopidogrel Optimal Loading Dose Usage To Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions) study. 70 For duration of dual antiplate-let therapy following placement of BMS (12 months vs 1 month), we chose baseline risks from the 1-month dual antiplatelet therapy arm from a meta-analysis we performed of relevant RCTs. For duration of dual antiplatelet therapy following placement of DES ( . 1 vs , 1 year), we used the risk estimate from the , 1 year arm of the merged REAL LATE (Corre-lation of Clopidogrel Therapy Duration in Real-World Patients Treated with Drug-Eluting Stent Implanta-tion and Late Coronary Arterial Thrombotic Events) and ZEST LATE (Evaluation of the Long-Term Safety after Zotarolimus-Eluting Stent, Sirolimus-Eluting Stent, or Paclitaxel-Eluting Stent Implantation for Coronary Lesions-Late Coronary Arterial Throm-botic Events) studies. 71 These studies were merged
Tabl
e 11
— [S
ecti
ons
4.1.
1-4.
3] T
hien
opyr
idin
e P
lus
Asp
irin
vs
War
fari
n P
lus
Asp
irin
in
the
Fir
st M
onth
Fol
low
ing
PC
I 68
Out
com
esPa
rtic
ipan
ts
(Stu
dies
), F
ollo
w-u
pQ
ualit
y of
the
Evi
denc
e (G
RA
DE
)R
elat
ive
Eff
ect
(95%
CI)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
30 d
Ris
k W
ith W
arfa
rin
and
Asp
irin
Ris
k D
iffer
ence
With
Thi
enop
yrid
ine
and
Asp
irin
(9
5% C
I)
Tota
l mor
talit
y2,
436
(4 R
CTs
), 4-
6 w
kM
oder
ate
due
to im
prec
isio
n a R
R 0
.73
(0.2
5-2.
18)
7 pe
r 1,
000 b
No
sign
ifi ca
nt d
iffer
ence
; 2 fe
wer
per
1,0
00
(fro
m 5
few
er to
8 m
ore)
MI
nonf
atal
eve
nts
13,6
08 (1
RC
T),
14.5
mo
Mod
erat
e du
e to
ris
k of
bia
s c R
R 0
.50
(0.2
9-0.
83)
39 p
er 1
,000
b 19
few
er p
er 1
,000
(fro
m 2
8 fe
wer
to 7
few
er)
Stro
keT
his
criti
cal o
utco
me
was
not
rep
orte
d in
the
met
a-an
alys
isM
ajor
ext
racr
ania
l ble
ed d
2,43
6 (4
RC
Ts),
4-6
wk
Low
due
to in
cons
iste
ncy,
e im
prec
isio
n, a a
nd r
isk
of b
ias c
RR
0.3
8 (0
.14-
1.02
)64
per
1,0
00 b
No
sign
ifi ca
nt d
iffer
ence
; 40
few
er p
er 1
,000
(f
rom
55
few
er to
1 m
ore)
See
Tabl
e 1-
3 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a W
ide
CIs
incl
udin
g be
nefi t
and
har
m (t
otal
mor
talit
y) o
r no
ben
efi t
(maj
or b
leed
ing
even
ts).
b Con
trol
gro
up r
isk
estim
ates
com
e fr
om th
e m
eta-
anal
ysis
. c L
ack
of b
lindi
ng in
RC
Ts.
d Ble
edin
g de
fi niti
ons
vari
ed g
reat
ly a
cros
s st
udie
s. e H
eter
ogen
eity
was
obs
erve
d fo
r m
ajor
ble
edin
g ev
ents
( I 2 5
72%
).
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e659S
while ongoing because of slow enrollment and similar study designs.
4.1.1 Antithrombotic Therapy Following Balloon Angioplasty Without Stent Placement: All patients undergoing stent procedures undergo balloon angio-plasty, but on rare occasions, balloon angioplasty is not followed by stent placement. In many respects, balloon angioplasty can be considered a controlled rupture of a coronary plaque. Short-term antithrom-botic therapy following this iatrogenic plaque rupture is necessary to prevent initiation of subsequent throm-botic events that may lead to MI. In the prestent era, patients undergoing balloon angioplasty generally were treated with aspirin alone. Extrapolation of evi-dence from patients with ACS and undergoing stent placement suggests that dual antiplatelet therapy with low-dose aspirin plus clopidogrel may achieve additional reduction in thrombosis (see sections 3.2.3, 3.2.4, and 4.3.1).
4.1.2 Short-term Dual Antiplatelet Therapy (Thienopyridine and Aspirin) Following Elective PCI With Stenting: Stent placement following balloon angioplasty was initially limited by high rates of acute or subacute stent thrombosis (6%-24%) secondary to the thrombogenicity of metal stent struts. 72-75 Con-comitantly, a number of studies compared a new strategy, aspirin plus ticlopidine, to the previously most successful strategy of aspirin plus warfarin in patients undergoing stent placement. A Cochrane systematic review of four randomized trials including 2,436 patients found that a 30- to 42-day course of ticlopidine plus aspirin vs warfarin plus aspirin reduced the 30- to 42-day risk of nonfatal MI (RR, 0.50; 95% CI, 0.30-0.83; number needed to treat, 55) and revascularization (RR, 0.29; 95% CI, 0.16-0.56; number needed to treat, 33), with a possible reduction in major bleeding (RR, 0.36; 95% CI, 0.14-1.02). 68 Table 11 (Table S13) summarizes the quality of evi-dence and main fi ndings from the meta-analysis. Given the thrombocytopenia/neutropenia as well as rare cases of thrombotic thrombocytopenic pur-pura associated with ticlopidine, ticlopidine has been largely replaced by clopidogrel. In the current era of dual antiplatelet therapy, early stent thrombosis occurs rarely ( , 2%).
4.1.3 Cilostazol Plus Clopidogrel Plus Aspirin vs Clopidogrel Plus Aspirin: Cilostazol is a phos-phodiesterase III inhibitor that has antiplatelet and antithrombotic effects and reduces intimal hyper-plasia after endothelial injury, properties that have led to trials evaluating its effi cacy for the preven-tion of restenosis after PCI. A systematic review by Tamhane and colleagues 69 identifi ed 10 RCTs
Tabl
e 12
— [S
ecti
ons
4.1.
1-4.
3.5]
Tri
ple
The
rapy
Wit
h C
ilos
tazo
l vs
Clo
pido
grel
1 A
spir
in F
ollo
win
g E
lect
ive
PC
I W
ith
Sten
ting
69
Out
com
esPa
rtic
ipan
ts
(Stu
dies
), F
ollo
w-u
pQ
ualit
y of
the
Evi
denc
e (G
RA
DE
)R
elat
ive
Eff
ect
(95%
CI)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
6-9
mo
Ris
k W
ith C
lopi
dogr
el a
nd A
spir
inR
isk
Diff
eren
ce W
ith C
ilost
azol
1 C
lopi
dogr
el
and
Asp
irin
(95%
CI)
Tota
l mor
talit
y2,
809
(10
RC
Ts),
6-9
mo
Mod
erat
e du
e to
impr
ecis
ion a
RR
0.7
3 (0
.25-
2.12
)20
per
1,0
00 b
No
sign
ifi ca
nt d
iffer
ence
; 5 fe
wer
per
1,0
00
(fro
m 1
5 fe
wer
to 2
2 m
ore)
MI
nonf
atal
eve
nts
2,80
9 (1
0 R
CTs
), 6-
9 m
oM
oder
ate
due
to im
prec
isio
n a R
R 1
.12
(0.5
7-2.
24)
50 p
er 1
,000
b N
o si
gnifi
cant
diff
eren
ce; 6
mor
e pe
r 1,
000
(fro
m 2
1 fe
wer
to 6
2 m
ore)
Stro
ke
Thi
s cr
itica
l out
com
e w
as n
ot r
epor
ted
in th
e m
eta-
anal
ysis
Maj
or e
xtra
cran
ial b
leed
2,80
9 (1
0 R
CTs
), 6-
9 m
oM
oder
ate
due
to im
prec
isio
n a R
R 0
.87
(0.4
4-1.
74)
50 p
er 1
,000
b N
o si
gnifi
cant
diff
eren
ce; 6
few
er p
er 1
,000
(f
rom
28
few
er to
37
mor
e)
See
Tabl
e 1-
3 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a C
Is in
clud
e be
nefi t
and
har
m fo
r m
orta
lity,
MI,
and
maj
or b
leed
s. b C
ontr
ol g
roup
ris
k es
timat
es c
ome
from
the
met
a-an
alys
is p
erfo
rmed
for
dual
ant
ipla
tele
t the
rapy
follo
win
g PC
I w
ith s
tent
pla
cem
ent (
Tam
hane
et a
l 69 ).
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e660S Prevention of Cardiovascular Disease
(n 5 2,809) comparing cilostazol 1 clopidogrel 1 aspirin vs clopidogrel and aspirin following stent placement. Treatment and follow-up ranged from 6 to 9 months. Table 12 (Table S14) summarizes the quality of evi-dence and main fi ndings from the meta-analysis of triple therapy with cilostazol vs dual therapy. Results failed to demonstrate or exclude an effect of cil-ostazol on reinfarction, major bleeding, and mortality between the two groups. Triple therapy showed an increased risk of skin rash (OR, 3.67; 95% CI, 1.86-7.24) (three RCTs). Sensitivity analyses did not materially affect the results, and there was no evi-dence of publication bias or statistical heterogeneity.
The recently published randomized trial Infl uence of Cilostazol-Based Triple Antiplatelet Therapy on Ischemic Complications After Drug-Eluting Stent Implantation (CILON-T) confi rms and extends these fi ndings. 76 In this open-label study, 960 patients undergoing DES implantation were randomized to either 6 months of aspirin plus clopidogrel vs aspirin, clopidogrel, and cilostazol 100 mg bid. At 6 months, there was no signifi cant difference in the prespecifi ed primary outcome (cardiac death, nonfatal MI, clini-cally driven target vessel revascularization, ischemic stroke) (9.2% vs 8.5%, P 5 .74), any of the individual components of the primary outcome, or TIMI major bleeding (0.2% vs 0.4%, P 5 .51).
4.1.4 Cilostazol as Part of Dual Antiplatelet Therapy: A systematic review by Biondi-Zoccai and colleagues 77 identifi ed 23 randomized trials (5,428 patients; median follow-up, 6 months) comparing the effects of cilostazol to a range of control therapies (includ-ing thienopyridines) on stent thrombosis, revascular-ization, major adverse cardiac events, and bleeding. Table S15 summarizes the fi ndings from the meta-analysis of 13 studies of 3,437 patients comparing cilostazol 1 aspirin vs thienopyridine 1 aspirin. We rate the quality of evidence as very low because of risk of bias, indirectness (lacking reporting of death, MI, and stroke), publication bias, and imprecision. Cilostazol was not associated with signifi cant improve-ment in clinical outcomes but was associated with a reduction in repeat revascularization and binary angiographic restenosis. Again, we consider the latter outcomes to be of little relevance to patients.
4.2 Aspirin Dose Following PCI With Stent Placement
We do not address loading doses of aspirin or clo-pidogrel prior to PCI in this section, but we do review evidence for aspirin therapy dosing following PCI. There has been only one RCT comparing higher- vs lower-dose aspirin post-PCI. The Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent
Tabl
e 13
— [S
ecti
ons
4.1.
1-4.
3.5]
Hig
h-D
ose
Asp
irin
vs
Low
-Dos
e A
spir
in f
or 3
0 D
ays
Pos
t P
CI 7
8
Out
com
esPa
rtic
ipan
ts (s
tudi
es),
Fol
low
-up
Qua
lity
of th
e E
vide
nce
(GR
AD
E)
Rel
ativ
e E
ffec
t (9
5% C
I) a
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
30 d
Ris
k W
ith A
spir
in 7
5-10
0 m
gR
isk
Diff
eren
ce W
ith A
spir
in 3
00-3
25 m
g (9
5% C
I)
Tota
l mor
talit
y b 17
,236
(1 R
CT
), 30
dM
oder
ate
due
to im
prec
isio
n c R
R 0
.87
(0.7
4-1.
03)
25 p
er 1
,000
d N
o si
gnifi
cant
diff
eren
ce; 3
few
er p
er 1
,000
(f
rom
7 fe
wer
to 1
mor
e)M
I no
nfat
al e
vent
s17
,236
(1 R
CT
), 30
dM
oder
ate
due
to im
prec
isio
n c R
R 0
.97
(0.8
2-1.
16)
21 p
er 1
,000
d N
o si
gnifi
cant
diff
eren
ce; 1
few
er p
er 1
,000
(f
rom
4 fe
wer
to 3
mor
e)St
roke
e 17
,236
(1 R
CT
), 30
dM
oder
ate
due
to im
prec
isio
n c R
R 1
.19
(0.8
4-1.
68)
5 pe
r 1,
000 d
No
sign
ifi ca
nt d
iffer
ence
; 1 m
ore
per
1,00
0 (f
rom
1 fe
wer
to 3
mor
e)M
ajor
ext
racr
ania
l ble
ed f
17,2
36 (1
RC
T),
30 d
Mod
erat
e du
e to
impr
ecis
ion c
RR
1.0
9 (0
.89-
1.34
)14
per
1,0
00 d
No
sign
ifi ca
nt d
iffer
ence
; 1 m
ore
per
1,00
0 (f
rom
2 fe
wer
to 5
mor
e)
CU
RR
EN
T-O
ASI
S 7
5 C
lopi
dogr
el O
ptim
al L
oadi
ng D
ose
Usa
ge to
Red
uce
Rec
urre
nt E
vent
s/O
ptim
al A
ntip
late
let S
trat
egy
for
Inte
rven
tion
s; T
IMI 5
Tho
mbo
lysi
s in
Myo
card
ial I
nfar
ctio
n. S
ee
Tabl
e 1-
3 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a Stu
dy r
epor
ts h
azar
d ra
tios.
We
have
con
vert
ed to
rel
ativ
e ri
sks
(RR
) for
con
sist
ency
. b O
f the
tota
l dea
ths
in th
e C
UR
RE
NT-
OA
SIS
7 st
udy,
nin
e of
314
(2.9
%) w
ith lo
w-d
ose
aspi
rin
and
10 o
f 273
(2.7
%) w
ith h
ighe
r-do
se a
spir
in w
ere
fata
l ble
edin
g ev
ents
. c W
ide
CIs
sug
gest
ben
efi t
and
harm
with
hig
h-do
se a
spir
in.
d Con
trol
gro
up r
isk
estim
ates
com
e fr
om e
vent
rat
es in
pat
ient
s al
loca
ted
to lo
w-d
ose
aspi
rin
unde
rgoi
ng P
CI
in C
UR
RE
NT-
OA
SIS
7. e I
t is
uncl
ear
from
the
artic
le w
heth
er h
emor
rhag
ic a
nd fa
tal s
trok
es w
ere
incl
uded
in to
tal s
trok
es.
f TIM
I cr
iteri
a us
ed. I
t is
uncl
ear
from
the
artic
le w
heth
er h
emor
rhag
ic a
nd fa
tal b
leed
ing
wer
e in
clud
ed in
tota
l maj
or b
leed
ing.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e661S
Events/Optimal Antiplatelet Strategy for Interventions (CURRENT OASIS-7) trial randomized 25,086 patients with ACS referred for PCI in a two-by-two fashion to (1) clopidogrel 600 mg load followed by 150 mg for 6 days vs clopidogrel 300 mg load followed by 75 mg for 6 days and (2) aspirin 325 mg load followed by 300 to 325 mg/d for 29 days vs 75 mg/d for 29 days. 70 The investigators published a separate article reporting on the prespecifi ed analysis of a sub-set of 17,263 patients who actually underwent PCI. 78 Table 13 (Table S16) summarizes the relevant evi-dence, data, and quality of evidence for aspirin from this analysis.
The American College of Cardiology/American Heart Association Guidelines 79 recommend aspirin 162 to 325 mg for 1 month following PCI with BMS, 3 months for sirolimus stent, and 6 months for pac-litaxel stent (to be followed by aspirin 75-162 mg thereafter). This recommendation is based on aspirin doses used in prior clinical studies evaluating stent type or adjunctive therapy with stent placement. In contrast, the European Society of Cardiology recom-mends low-dose aspirin following PCI. 80 In a post hoc analysis of data from PCI-CURE, patients were stratifi ed into three groups based on aspirin dose ( � 200, 101-199, and � 100 mg). 81 All three groups had similar rates of the composite end point of cardio-vascular death, MI, or stroke at long-term follow-up (8.6%, 7.4%, 7.1%, respectively). Major bleeding was signifi cantly increased with high-dose aspirin com-pared with medium- or low-dose aspirin (3.9%, 1.5%, 1.9%, respectively).
4.3 Duration of Dual Antiplatelet Therapy Following PCI With Placement of BMS or DES
4.3.1.,4.3.3 Minimum Duration of Dual Antiplate-let Therapy Following Stent Placement: Antithrom-botic therapy following PCI with stent placement is necessary to prevent thrombosis due to exposure of blood to metal stent struts. This risk is decreased after healing of the lesion and endothelialization of the bare metal struts (in � 4-6 weeks). 82,83
In the past decade, there has been an increased use of DES. These have been shown to decrease the rate of angiographic restenosis and need for repeat revascularization, although the effect relative to BMS on more important outcomes remains less cer-tain. 84 The antiinfl ammatory/antiproliferative effects of drug-coated stents result in delayed healing char-acterized by poor endothelialization that increases the duration of stent thrombogenicity. As a result, extended dual antiplatelet therapy has been used: a minimum of 3 months for -limus stents and 6 months for -taxel stents. Initial comparative studies (DES vs BMS; sirolimus vs paclitaxel) used these or longer
Tabl
e 14
— [S
ecti
ons
4.1.
1-4.
3.5]
Six
to
Twel
ve M
onth
s vs
One
Mon
th o
f C
lopi
dogr
el P
lus
Asp
irin
Fol
low
ing
PC
I W
ith
Pla
cem
ent
of B
MS 8
9-92
Out
com
esPa
rtic
ipan
ts (S
tudi
es),
Fol
low
-up
Qua
lity
of th
e E
vide
nce
(GR
AD
E)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
6-9
mo
Ris
k W
ith 1
mo
Clo
pido
grel
1 A
spir
inR
isk
Diff
eren
ce W
ith 6
-12
mo
Clo
pido
grel
1 A
spir
in
(95%
CI)
Tota
l mor
talit
y a 3,
390
(3 R
CT
), 6-
12 m
oL
ow d
ue to
ris
k of
bia
s b and
im
prec
isio
n c R
R 0
.73
(0.4
8-1.
13)
28 p
er 1
,000
d N
o si
gnifi
cant
diff
eren
ce; 8
few
er p
er 1
,000
(f
rom
15
few
er to
4 m
ore)
MI
nonf
atal
eve
nts
4,85
2 (3
RC
Ts),
6-12
mo
Mod
erat
e du
e to
ris
k of
bia
s a R
R 0
.66
(0.5
0-86
)28
per
1,0
00 d
9 fe
wer
per
1,0
00 (f
rom
14
few
er to
4 fe
wer
)St
roke
d 2,
194
(2 R
CTs
), 6-
12 m
oL
ow d
ue to
ris
k of
bia
s a and
im
prec
isio
n c R
R 0
.46
(0.1
6-1.
32)
10 p
er 1
,000
d N
o si
gnifi
cant
diff
eren
ce; 5
few
er p
er 1
,000
(f
rom
8 fe
wer
to 3
mor
e)M
ajor
ext
racr
ania
l ble
ed e
5,05
2 (3
RC
Ts),
6-12
mo
Low
due
to r
isk
of b
ias a a
nd
impr
ecis
ion c
RR
1.1
7 (0
.86-
1.60
)50
per
1,0
00 d
No
sign
ifi ca
nt d
iffer
ence
; 8 m
ore
per
1,00
0 (f
rom
7 fe
wer
to 3
0 m
ore)
See
Tabl
e 1-
3 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a F
atal
ble
edin
g ev
ents
not
rep
orte
d. b B
erna
rdi e
t al 92
and
Pek
dem
ir e
t al 90
wer
e no
t blin
ded,
and
ther
e w
as n
o pl
aceb
o co
ntro
l; B
erna
rdi e
t al s
topp
ed e
arly
for
bene
fi t. T
he A
kbul
ut e
t al 93
des
ign
was
unc
lear
(no
men
tion
of r
ando
miz
atio
n, b
ut
the
Hea
lth T
echn
olog
y A
sses
smen
t rep
ort r
efer
red
to it
as
rand
omiz
ed).
Meh
ta e
t al 89
had
var
iabl
e fo
llow
-up.
c CIs
incl
ude
impo
rtan
t ben
efi t
and
harm
. d C
ontr
ol g
roup
ris
k es
timat
es d
eriv
ed fr
om r
ates
in s
ubje
cts
trea
ted
with
dua
l ant
ipla
tele
t the
rapy
for
1 m
o in
incl
uded
tria
ls.
e Maj
or b
leed
ing
not s
trat
ifi ed
by
type
of b
leed
; unc
lear
whe
ther
maj
or b
leed
ing
incl
uded
any
fata
litie
s.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e662S Prevention of Cardiovascular Disease
durations of dual antiplatelet therapy. 85 Discontinua-tion of clopidogrel therapy before this minimum dura-tion has been associated with stent thrombosis and clinically adverse outcomes. 86-88 In a prospective obser-vational study of 2,229 consecutive patients under-going DES implantation, 1.3% of patients had stent thrombosis at 9 months; case fatality was 45% (13/29) in these patients. 86 Premature clopidogrel therapy discontinuation ( , 3 months sirolimus, , 6 months paclitaxel) was the strongest predictor of stent throm-bosis (hazard ratio, 89.8; 95% CI, 29.9-269.6). There are no RCTs evaluating shorter duration of dual anti-platelet therapy for these different stent subtypes.
4.3.2 Extended Duration of Dual Antiplatelet Therapy Following Elective PCI and BMS Placement: As described previously, the risk of BMS thrombosis is decreased after 1 month of dual antiplatelet ther-apy. Potential benefi t of extended dual antiplatelet therapy beyond 1 month might result from a decrease in later stent thrombosis events or a decrease in coro-nary vascular events occurring at other plaque sites. Table 14 (Table S17) summarizes the quality of evi-dence and main fi ndings from our systematic review and meta-analysis of RCTs identifi ed by a systematic literature search (updated January 2010) compar-ing 1 month of dual antiplatelet therapy vs 6 to 12 months in patients undergoing PCI with place-ment of BMS. 89-93 The quality of evidence is rated as low because of risk of bias, indirectness (populations varied from PCI in ACS [PCI-CURE] to elective PCI in stable angina), and large imprecision in effect esti-mates for all outcomes. The results suggest that dual antiplatelet therapy for 6 to 12 months signifi cantly reduces MI (RR, 0.66) but does not confi rm or exclude a signifi cant effect on mortality, stroke, or major bleeds.
4.3.4 Extended Duration of Dual Antiplatelet Therapy Following Elective PCI and DES Placement:
Dual Antiplatelet Therapy for Up to One Year— No randomized trials have evaluated the effi cacy and safety of dual antiplatelet therapy in patients undergoing DES for up to 1 year (compared with the minimum of 3-6 months). A number of observa-tional studies have suggested that patients with DES are at increased risk of late-stent thrombosis and poor outcomes after discontinuation of dual antiplate-let therapy at 6 months. A consecutive series of 746 unselected patients enrolled in the Basel Stent Kosteneffektivitäts Trial (BASKET) study (a ran-domized trial of DES vs BMS) received aspirin and clopidogrel for 6 months and were followed for another 1 year. 94 The incidence of cardiac death and MI after discontinuation of clopidogrel was higher in patients undergoing DES than those undergoing BMS (4.9% vs 1.3%).
Tabl
e 15
— [S
ecti
ons
4.1.
1-4.
3.5]
Ext
ende
d D
ura
tion
of
Clo
pido
grel
Plu
s A
spir
in F
ollo
win
g P
CI
Wit
h P
lace
men
t of
DE
S 71
Out
com
esPa
rtic
ipan
ts (S
tudi
es),
Fol
low
-up
Qua
lity
of th
e E
vide
nce
(GR
AD
E)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
19 m
o
Ris
k W
ith 1
2 m
o C
lopi
dogr
el 1
Asp
irin
Ris
k D
iffer
ence
With
19
mo
Clo
pido
grel
1 A
spir
in
(95%
CI)
Tota
l mor
talit
y2,
701
(2 R
CTs
), 19
mo
Mod
erat
e du
e to
impr
ecis
ion a
RR
1.6
5 (0
.80-
3.36
)6
per
1,00
0 b N
o si
gnifi
cant
diff
eren
ce; 4
mor
e pe
r 1,
000
(fro
m 1
few
er to
14
mor
e)M
I no
nfat
al e
vent
s2,
701
(2 R
CTs
), 19
mo
Mod
erat
e du
e to
impr
ecis
ion a
RR
0.6
6 (0
.16-
1.32
)3
per
1,00
0 b N
o si
gnifi
cant
diff
eren
ce; 2
mor
e pe
r 1,
000
(fro
m 1
few
er to
13
mor
e)St
roke
2,70
1 (2
RC
Ts),
19 m
oM
oder
ate
due
to im
prec
isio
n a R
R 0
.46
(0.1
6-1.
32)
2 pe
r 1,
000 b
No
sign
ifi ca
nt d
iffer
ence
; 3 m
ore
per
1,00
0 (f
rom
1 fe
wer
to 1
6 m
ore)
Maj
or e
xtra
cran
ial b
leed
c 2,
701
(2 R
CTs
), 19
mo
Mod
erat
e du
e to
impr
ecis
ion a
RR
1.1
7 (0
.86-
1.60
)1
per
1,00
0 b N
o si
gnifi
cant
diff
eren
ce; 2
mor
e pe
r 1,
000
(fro
m 1
few
er to
19
mor
e)
See
Tabl
e 1-
3 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a R
ated
dow
n fo
r im
prec
isio
n du
e to
wid
e C
I fo
r ab
solu
te e
ffec
ts, i
nclu
ding
sub
stan
tial h
arm
with
ext
ende
d du
ratio
n of
dua
l ant
ipla
tele
t th
erap
y. W
e di
d no
t ra
te d
own
for
risk
of
bias
, alth
ough
it w
as a
n op
en-la
bel s
tudy
bec
ause
end
poi
nts
wer
e ad
judi
cate
d by
blin
ded
asse
ssor
s. b C
ontr
ol g
roup
ris
k es
timat
es c
ome
from
sub
ject
s re
ceiv
ing
dual
ant
ipla
tele
t the
rapy
for
1 y
in th
e m
erge
d tr
ials
. c M
ajor
ble
edin
g de
fi ned
by
TIM
I (T
hrom
boly
sis
in M
yoca
rdia
l Inf
arct
ion)
cri
teri
a; n
o in
form
atio
n w
as p
rovi
ded
on th
e ty
pe o
f maj
or b
leed
ing
even
t in
eith
er g
roup
. No
fata
l ble
edin
g w
as r
epor
ted.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e663S
clopidogrel 75 mg daily over single anti-platelet therapy (Grade 2C) .
• After 12 months, we recommend single anti-platelet therapy over continuation of dual antiplatelet therapy (Grade 1B) .
For patients who have undergone elective PCI with placement of DES:
• For the fi rst 3 to 6 months, we recommend dual antiplatelet therapy with aspirin 75 to 325 mg daily and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 1A) .
Remarks: Absolute minimum duration will vary based on stent type (in general 3 months for -limus stents and 6 months for -taxel stents).
• After 3 to 6 months, we suggest continua-tion of dual antiplatelet therapy with low-dose aspirin 75 to 100 mg and clopidogrel (75 mg daily) until 12 months over single antiplatelet therapy (Grade 2C) .
• After 12 months, we recommend single antiplatelet therapy over continuation of dual antiplatelet therapy (Grade 1B) . Sin-gle antiplatelet therapy thereafter is rec-ommended as per the established CAD recommendations (see recommendations 3.1.1-3.1.5).
For patients who have undergone elective BMS or DES stent placement:
• We recommend use of low-dose aspirin 75 to 100 mg daily and clopidogrel 75 mg daily alone rather than cilostazol in addi-tion to these drugs (Grade 1B).
• We suggest aspirin 75 to 100 mg daily and clopidogrel 75 mg daily as part of dual antiplatelet therapy rather than the use of either drug with cilostazol (Grade 1B).
• We suggest cilostazol 100 mg twice daily as substitute for either low-dose aspirin 75 to 100 mg daily or clopidogrel 75 mg daily as part of a dual antiplatelet reg-imen in patients with an allergy or intol-erance of either drug class (Grade 2C).
For patients with CAD undergoing elective PCI but no stent placement:
• We suggest for the fi rst month, dual anti-platelet therapy with aspirin 75 to 325 mg daily and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 2C). Single antiplatelet therapy thereafter is
In another observational study, 4,666 consecutive patients undergoing PCI with either BMS (n 5 3,165) or DES (n 5 1,501) were followed up at 6, 12, and 24 months. 95 In patients with DES who were event free at 6 months, clopidogrel use at 6 months was asso-ciated with lower rates of adjusted death (2% vs 5.3% without, P 5 .03) and death and MI (3.1% vs 7.2%, P 5 .02) at 24 months. There was a trend for decreased rates of nonfatal MI (2.6% vs 1.3%, P 5 .24). Bleeding outcomes were not reported in either study. Based on these and other observational studies, it has become standard practice to treat patients with DES with dual antiplatelet therapy for 12 months.
4.3.5 Dual Antiplatelet Therapy for More Than One Year: Table 15 (Table S18) summarizes the quality of evidence and main fi ndings from two merged RCTs (REAL LATE and ZEST LATE), examining the effects of prolonged dual antiplatelet therapy (clopidogrel 75 mg 1 aspirin 100-200 mg/d for a median of 19 months) vs 12 months in patients who had undergone implantation of DES. 71 These studies were merged by their respective executive committees because of slower-than-expected enroll-ment and similar study designs. The indication for the initial PCI with DES placement was stable angina (37%), unstable angina (41%), or ACS (21%, equally distributed between non-ST-elevation ACS and ST-elevation ACS ). Sirolimus-eluting stents were most commonly used (57%) followed by paclitaxel- (24%) and zotarolimus-eluting stents (19%).
As shown in Table 15 (Table S18), these data did not confi rm or exclude benefi t of an extended dura-tion of dual antiplatelet therapy vs 12 months of dual antiplatelet therapy for any of the outcomes. The very-low baseline risk for all outcomes results in only moderately imprecise absolute effects, although the relative risk estimates are considerably more impre-cise. The results suggest a trend favoring short-term over prolonged dual antiplatelet therapy for all out-comes. In summary, the available evidence suggests no benefi t and possible harm of continuing dual anti-platelet therapy beyond 12 months.
Recommendations
4.1.1-4.3.5. For patients who have undergone elective PCI with placement of BMS:
• For the fi rst month, we recommend dual antiplatelet therapy with aspirin 75 to 325 mg daily and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 1A) .
• For the subsequent 11 months, we suggest dual antiplatelet therapy with combination of low-dose aspirin 75 to 100 mg daily and
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e664S Prevention of Cardiovascular Disease
recommended as per the established CAD recommendations (see recommendations 3.1.1-3.1.5).
5.0 Antithrombotic Therapy in Patients With Systolic LV Dysfunction
Approximately 70% of patients with systolic LV dys-function and heart failure have ischemic heart disease. The remaining 30% of patients with systolic heart failure are considered to have a nonischemic etiology (eg, hypertensive heart disease, valvular heart disease, idiopathic). Because the majority of these latter patients are free of concomitant CAD, risk for MI is lower than that of patients with ischemic systolic LV dysfunction.
Assessment of Baseline Risk
For the comparison of warfarin vs aspirin in patients with systolic LV dysfunction (ischemic and nonisch-emic), we used risks from the aspirin-only arm of a meta-analysis we performed of three RCTs pertinent to this question.
A prior Cochrane systematic review had identifi ed only one pilot RCT. 96 We performed an updated systematic literature search and performed a meta-analysis based on four randomized trials evaluating antithrombotic therapy in patients with symptomatic heart failure and ejection fraction , 35%. 97-100 In brief, results could not demonstrate or exclude a signifi cant difference for patient-important outcomes between patients receiving warfarin or aspirin compared with those receiving no antithrombotic therapy. Table 16 presents evidence from our meta-analysis of data from the three studies comparing warfarin to aspirin (Table S19). 97-99 Warfarin was associated with a sig-nifi cant decrease in strokes. The data do not confi rm or exclude a benefi t of warfarin vs aspirin for the other end points. Quality of this evidence is low because of imprecision and risk of bias. Approximately 75% of patients were designated as having systolic LV dys-function of an ischemic etiology. Unfortunately, there were insuffi cient data for us to examine possible differences in antithrombotic effi cacy and safety in patients classifi ed by type of heart failure (ischemic vs nonischemic).
Finally, there will be patients who develop acute dilated cardiomyopathy from noncardiac causes (eg, acute viral myocarditis, Takotsubo cardiomyopathy) who may develop acute LV thrombosis. We found no studies comparing anticoagulation strategies in such patients. Based on indirect evidence from studies of patients with anterior MI and LV thrombus (see sec-tion 3.6), we assume that systemic embolization rates from acute LV thrombus in patients with nonisch-emic cardiomyopathy are similarly high ( � 10%).
Tabl
e 16
— [R
ecom
men
dati
ons
5.1-
5.3]
War
fari
n vs
Asp
irin
in
Pat
ient
s W
ith
Syst
olic
LV
Dys
func
tion
(Is
chem
ic a
nd N
onis
chem
ic) 9
7-99
Out
com
esPa
rtic
ipan
ts (S
tudi
es),
Fol
low
-up
Qua
lity
of th
e E
vide
nce
(GR
AD
E)
Rel
ativ
e E
ffec
t (95
% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts O
ver
5 y
Ris
k W
ith A
spir
inR
isk
Diff
eren
ce W
ith W
arfa
rin
(95%
CI)
Tota
l mor
talit
y1,
358
(3 R
CT
), 23
-27
mo
Low
due
to r
isk
of b
ias a a
nd im
prec
isio
n b R
R 0
.95
(0.7
6-1.
19)
193
per
1,00
0 c N
o si
gnifi
cant
diff
eren
ce; 1
0 fe
wer
per
1,0
00
(fro
m 4
6 fe
wer
to 3
6 m
ore)
MI d
1,35
8 (3
RC
T),
23-2
7 m
oL
ow d
ue to
ris
k of
bia
s a and
impr
ecis
ion b
RR
0.9
9 (0
.35-
2.84
)33
per
1,0
00 c
No
sign
ifi ca
nt d
iffer
ence
; 0 fe
wer
per
1,0
00
(fro
m 2
1 fe
wer
to 6
0 m
ore)
Stro
ke e
1,35
8 (3
RC
T),
23-2
7 m
oL
ow d
ue to
ris
k of
bia
s a and
impr
ecis
ion b
RR
0.3
4 (0
.13-
0.97
)24
per
1,0
00 c
16 fe
wer
per
100
0 (f
rom
21
few
er to
1 fe
wer
)M
ajor
ext
racr
ania
l ble
ed f
1,35
8 (3
RC
T),
23-2
7 m
oL
ow d
ue to
ris
k of
bia
s a and
impr
ecis
ion b
RR
1.9
7 (0
.89-
4.3)
30 p
er 1
,000
c N
o si
gnifi
cant
diff
eren
ce; 2
9 m
ore
per
1,00
0 (f
rom
3 fe
wer
to 9
9 m
ore)
Bur
den
of tr
eatm
ent
Not
app
licab
leH
igh
War
fari
n .
Asp
irin
War
fari
n: d
aily
med
icat
ion,
die
tary
and
act
ivity
res
tric
tions
, fre
quen
t bl
ood
test
ing/
mon
itori
ng, i
ncre
ased
hos
pita
l/clin
ic v
isits
Asp
irin
: dai
ly m
edic
atio
n on
ly
See
Tabl
e 1-
3 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a T
wo
of th
ree
tria
ls w
ere
stop
ped
earl
y (o
ne fo
r be
nefi t
, one
for
slow
enr
ollm
ent)
; pro
blem
s w
ith b
lindi
ng.
b Wid
e C
Is in
clud
e be
nefi t
and
har
m.
c Con
trol
gro
up r
isk
estim
ates
der
ived
from
eve
nt r
ates
from
asp
irin
arm
of t
he p
oole
d st
udie
s. d F
atal
and
non
fata
l MIs
not
rep
orte
d se
para
tely
in a
ll st
udie
s. e F
atal
and
non
fata
l str
okes
not
rep
orte
d se
para
tely
in a
ll st
udie
s, ty
pes
of s
trok
es (i
sche
mic
/hem
orrh
agic
) not
rep
orte
d. f D
efi n
ition
of m
ajor
hem
orrh
age
vari
ed.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e665S
Recommendations
5.1-5.3. For patients with systolic LV dysfunc-tion without established CAD and no LV throm-bus, we suggest not to use antiplatelet therapy or warfarin (Grade 2C) .
Remarks : Patients who place a high value on an uncertain reduction in stroke and a low value on avoiding an increased risk of GI bleeding are likely to choose to use warfarin.
For patients with systolic LV dysfunction with-out established CAD with identifi ed acute LV thrombus (eg, Takotsubo cardiomyopathy), we suggest moderate-intensity warfarin (INR 2.0-3.0) for at least 3 months (Grade 2C) .
For patients with systolic LV dysfunction and established CAD, recommendations are as per the established CAD recommendations (see rec-ommendations 3.1.1-3.1.5).
Acknowledgments Author contributions: As Topic Editor, Dr Vandvik oversaw the development of this article, including the data analysis and subse-quent development of the recommendations contained herein. Dr Vandvik: served as Topic Editor. Dr Lincoff: served as a panelist. Dr Gore: served as a panelist. Dr Gutterman: served as a panelist. Dr Sonnenberg: served as a resource consultant. Dr Alonso-Coello: served as a panelist. Dr Akl: served as a panelist. Dr Lansberg: served as a panelist. Dr Guyatt: served as a panelist. Dr Spencer: served as Deputy Editor. 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/e637S/suppl/DC1. In summary, the authors have reported to CHEST the following confl icts of interest: Dr Lincoff is Director of the Cleveland Clinic Coordinating Cen-ter for Clinical Research (C5Research), which has research grants from Anthera Pharmaceuticals, Inc; AstraZeneca; Bristol-Myers Squibb; Eli Lilly and Company; Kai Pharmaceuticals, Inc; Pfi zer, Inc; Hoffmann La-Roche Inc; Novartis AG; Sanofi -Aventis LLC; Merck/Schering-Plough; Scios, Inc; Takeda Pharmaceutical Com-pany Limited, and Johnson & Johnson. He has received honoraria for consultations or advisory board activities from AstraZeneca; Avanir Pharmaceuticals; Baxter; Bristol-Myers Squibb; Ikaria, Inc; Hoffmann La-Roche Inc; and Merck/Schering-Plough. Dr Gutterman has had the following relationships that are entirely unrelated to the AT9 guidelines: ACCP President, GlaxoSmithKline plc grant to study vasodilation in adipose tissue, National Insti-tutes of Health grant to study human coronary dilation, and GE Healthcare consultation on a study for ECG evaluation of chronic heart disease. Dr Guyatt is co-chair of the GRADE Working Group. Drs Vandvik, Alonso-Coello, and Akl are members of and prominent contributors to the GRADE Working Group. Drs Gore, Sonnenberg, Lansberg, and Spencer have reported that no poten-tial confl icts of interest exist with any companies/organizations whose products or services may be discussed 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. Other contributions: We thank Louis Kuritzky, MD, for pro-viding his frontline primary-care clinician perspective on the content of this article, John You, MD, for methodologic contri-butions (triple therapy in patients with acute LV thrombus), and Colin Baigent, MD, for sharing his methodologic expertise on primary prevention of cardiovascular disease with aspirin. Endorsements: This guideline is endorsed by the American Associ-ation for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis. Additional information: The supplement Tables can be found in the Online Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e637S/suppl/DC1.
References 1 . MacLean S, Mulla S, Akl EA, et al. Patient values and pref-
erences in decision making for antithrombotic therapy: a systematic review: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physi-cians evidence-based clinical practice guidelines. Chest . 2012;141(2)(suppl):e1S-e23S.
2 . Guyatt GH, Norris SL, Schulman S, et al. Methodology for the development of antithrombotic 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. Chest . 2012;141(2)(suppl):53S-70S.
3 . Bhatt DL , Fox KA , Hacke W , et al ; CHARISMA Inves-tigators . Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events . N Engl J Med . 2006 ; 354 ( 16 ): 1706 - 1717 .
4 . Raju NC , Sobieraj-Teague M , Hirsh J , O’Donnell M , Eikelboom J . Effect of aspirin on mortality in the primary prevention of cardiovascular disease . Am J Med . 2011 ;24(7):621-629.
5 . Rothwell PM , Fowkes FG , Belch JF , Ogawa H , Warlow CP , Meade TW . Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials . Lancet . 2011 ; 377 ( 9759 ): 31 - 41 .
6 . Rothwell PM , Wilson M , Elwin CE , et al . Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of fi ve randomised trials . Lancet . 2010 ; 376 ( 9754 ): 1741 - 1750 .
7 . You JJ, Singer DE, Howard PA, et al. Antithrombotic ther-apy for atrial fi brillation: antithrombotic therapy and pre-vention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest . 2012;141(2)(suppl):e531S-e575S.
8 . Wilson PW , D’Agostino RB , Levy D , Belanger AM , Silbershatz H , Kannel WB . Prediction of coronary heart disease using risk factor categories . Circulation . 1998 ; 97 ( 18 ): 1837 - 1847 .
9 . Baigent C , Blackwell L , Collins R , et al ; Antithrombotic Trialists’ (ATT) Collaboration . Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials . Lancet . 2009 ; 373 ( 9678 ): 1849 - 1860 .
10 . Collins GS , Altman DG . An independent external validation and evaluation of QRISK cardiovascular risk prediction: a prospective open cohort study . BMJ . 2009 ; 339 : b2584 .
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e666S Prevention of Cardiovascular Disease
Unstable angina to prevent Recurrent ischemic Events (CURE) Trial . Circulation . 2004 ; 110 ( 10 ): 1202 - 1208 .
27 . Patel JH , Stoner JA , Owora A , Mathew ST , Thadani U . Evidence for using clopidogrel alone or in addition to aspirin in post coronary artery bypass surgery patients . Am J Cardiol . 2009 ; 103 ( 12 ): 1687 - 1693 .
28 . Douketis JD, Spyropoulos AC, Spencer FA, et al. Periopera-tive management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest . 2012;141(2)(suppl):e326S-e350S.
29 . CAPRIE Steering Committee . A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) . Lancet . 1996 ; 348 ( 9038 ): 1329 - 1339 .
30 . Antithrombotic Trialists’ Collaboration . Collaborative meta-analysis of randomised trials of antiplatelet therapy for pre-vention of death, myocardial infarction, and stroke in high risk patients . BMJ . 2002 ; 324 ( 7329 ): 71 - 86 .
31 . Sudlow CL , Mason G , Maurice JB , Wedderburn CJ , Hankey GJ . Thienopyridine derivatives versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients . Cochrane Database Syst Rev . 2009 ;( 4 ): CD001246 .
32 . Schleinitz MD , Weiss JP , Owens DK . Clopidogrel versus aspirin for secondary prophylaxis of vascular events: a cost-effectiveness analysis . Am J Med . 2004 ; 116 ( 12 ): 797 - 806 .
33 . Karnon J , Bakhai A , Brennan A , et al . A cost-utility analysis of clopidogrel in patients with non-ST-segment-elevation acute coronary syndromes in the UK . Int J Cardiol . 2006 ; 109 ( 3 ): 307 - 316 .
34 . Durand-Zaleski I , Bertrand M . The value of clopidogrel ver sus aspirin in reducing atherothrombotic events: the CAPRIE study . Pharmacoeconomics . 2004 ; 22 ( suppl 4 ): 19 - 27 .
35 . Sarasin FP , Gaspoz JM , Bounameaux H . Cost-effectiveness of new antiplatelet regimens used as secondary prevention of stroke or transient ischemic attack . Arch Intern Med . 2000 ; 160 ( 18 ): 2773 - 2778 .
36 . Keller TT , Squizzato A , Middeldorp S . Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease . Cochrane Database Syst Rev . 2007 ; ( 3 ): CD005158 .
37 . Sun X , Briel M , Walter SD , Guyatt GH . Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses . BMJ . 2010 ; 340 : c117 .
38 . Diener HC , Bogousslavsky J , Brass LM , et al ; MATCH inves tigators . Aspirin and clopidogrel compared with clo-pidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): ran-domised, double-blind, placebo-controlled trial . Lancet . 2004 ; 364 ( 9431 ): 331 - 337 .
39 . Coumadin Aspirin Reinfarction Study (CARS) Investigators. Randomised double-blind trial of fi xed low-dose warfa-rin with aspirin after myocardial infarction. Coumadin Aspirin Reinfarction Study (CARS) . Lancet . 1997 ; 350 (9075): 389 - 396 .
40 . The Post Coronary Artery Bypass Graft Trial Investigators . The effect of aggressive lowering of low-density lipopro-tein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts . N Engl J Med . 1997 ; 336 ( 3 ): 153 - 162 .
41 . Anand SS , Yusuf S , Pogue J , Weitz JI , Flather M . Long-term oral anticoagulant therapy in patients with unstable angina or suspected non-Q-wave myocardial infarction: organi-zation to assess strategies for ischemic syndromes (OASIS) pilot study results . Circulation . 1998 ; 98 ( 11 ): 1064 - 1070 .
42 . Hurlen M , Abdelnoor M , Smith P , Erikssen J , Arnesen H . Warfarin, aspirin, or both after myocardial infarction . N Engl J Med . 2002 ; 347 ( 13 ): 969 - 974 .
11 . de Ruijter W , Westendorp RG , Assendelft WJ , et al . Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study . BMJ . 2009 ; 338 : a3083 .
12 . Peto R , Gray R , Collins R , et al . Randomised trial of prophy-lactic daily aspirin in British male doctors . Br Med J (Clin Res Ed) . 1988 ; 296 ( 6618 ): 313 - 316 .
13 . Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. Steering Committee of the Physicians’ Health Study Research Group . N Engl J Med . 1989 ; 321 ( 3 ): 129 - 135 .
14 . Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Prac tice Research Framework . Lancet . 1998 ; 351 ( 9098 ): 233 - 241 .
15 . Hansson L , Zanchetti A , Carruthers SG , et al ; HOT Study Group . Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) ran-domised trial . Lancet . 1998 ; 351 ( 9118 ): 1755 - 1762 .
16 . de Gaetano G ; Collaborative Group of the Primary Preven-tion Project . Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice . Lancet . 2001 ; 357 ( 9250 ): 89 - 95 .
17 . Ridker PM , Cook NR , Lee IM , et al . A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women . N Engl J Med . 2005 ; 352 ( 13 ): 1293 - 1304 .
18 . Bulugahapitiya U , Siyambalapitiya S , Sithole J , Fernando DJ , Idris I . Age threshold for vascular prophylaxis by aspirin in patients without diabetes . Heart . 2008 ; 94 ( 11 ): 1429 - 1432 .
19 . Buse JB , Ginsberg HN , Bakris GL , et al ; American Heart Association ; American Diabetes Association . Primary pre-vention of cardiovascular diseases in people with diabetes mellitus: a scientifi c statement from the American Heart Association and the American Diabetes Association . Diabetes Care . 2007 ; 30 ( 1 ): 162 - 172 .
20 . Colwell JA ; American Diabetes Association . Aspirin ther-apy in diabetes . Diabetes Care . 2004 ; 27 ( suppl 1 ): S72 - S73 .
21 . Elwood P , Morgan G , Brown G , Pickering J . Aspirin for every-one older than 50? For . BMJ . 2005 ; 330 ( 7505 ): 1440 - 1441 .
22 . Rydén L , Standl E , Bartnik M , et al ; Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) ; European Association for the Study of Diabetes (EASD) . Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary . Eur Heart J . 2007 ; 28 ( 1 ): 88 - 136 .
23 . De Berardis G , Sacco M , Strippoli GF , et al . Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials . BMJ . 2009 ; 339 : b4531 .
24 . Zhang C , Sun A , Zhang P , et al . Aspirin for primary pre-vention of cardiovascular events in patients with diabetes: A meta-analysis . Diabetes Res Clin Pract . 2010 ; 87 ( 2 ): 211 - 218 .
25 . Saw J , Topol EJ , Steinhubl SR , Brennan D , Berger PB , Moliterno DJ ; CREDO Investigators . Comparison of long-term usefulness of clopidogrel therapy after the fi rst per-cutaneous coronary intervention or coronary artery bypass grafting versus that after the second or repeat intervention . Am J Cardiol . 2004 ; 94 ( 5 ): 623 - 625 .
26 . Fox KA , Mehta SR , Peters R , et al ; Clopidogrel in Unstable angina to prevent Recurrent ischemic Events Trial . Benefi ts and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e667S
43 . van Es RF , Jonker JJ , Verheugt FW , Deckers JW , Grobbee DE ; Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 (ASPECT-2) Research Group . Aspi-rin and Coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial . Lancet . 2002 ; 360 ( 9327 ): 109 - 113 .
44 . Rothberg MB , Celestin C , Fiore LD , Lawler E , Cook JR . Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefi t . Ann Intern Med . 2005 ; 143 ( 4 ): 241 - 250 .
45 . Campbell CL , Smyth S , Montalescot G , Steinhubl SR . Aspirin dose for the prevention of cardiovascular disease: a systematic review . JAMA . 2007 ; 297 ( 18 ): 2018 - 2024 .
46 . Serebruany VL , Steinhubl SR , Berger PB , et al . Analysis of risk of bleeding complications after different doses of aspi-rin in 192,036 patients enrolled in 31 randomized controlled trials . Am J Cardiol . 2005 ; 95 ( 10 ): 1218 - 1222 .
47 . Yusuf S , Zhao F , Mehta SR , Chrolavicius S , Tognoni G , Fox KK ; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators . Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation . N Engl J Med . 2001 ; 345 ( 7 ): 494 - 502 .
48 . Cannon CP , Harrington RA , James S , et al ; PLATelet inhi-bition and patient Outcomes Investigators . Comparison of ticagrelor with clopidogrel in patients with a planned inva sive strategy for acute coronary syndromes (PLATO): a ran domised double-blind study . Lancet . 2010 ; 375 ( 9711 ): 283 - 293 .
49 . Lamy A , Jönsson B , Weintraub WS , et al ; CURE Economic Group . The cost-effectiveness of the use of clopidogrel in acute coronary syndromes in fi ve countries based upon the CURE study . Eur J Cardiovasc Prev Rehabil . 2004 ; 11 ( 6 ): 460 - 465 .
50 . Main C , Palmer S , Griffi n S , et al. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment-elevation acute coronary syndromes: a systematic review and economic evaluation. Health Technol Assess . 2004 ;8(40):1-141.
51 . Lindgren P , Jönsson B , Yusuf S . Cost-effectiveness of clopidogrel in acute coronary syndromes in Sweden: a long-term model based on the CURE trial . J Intern Med . 2004 ; 255 ( 5 ): 562 - 570 .
52 . Weintraub WS , Mahoney EM , Lamy A , et al ; CURE Study Investigators . Long-term cost-effectiveness of clo-pidogrel given for up to one year in patients with acute coro-nary syndromes without ST-segment elevation . J Am Coll Cardiol . 2005 ; 45 ( 6 ): 838 - 845 .
53 . Schleinitz MD , Heidenreich PA . A cost-effectiveness anal-ysis of combination antiplatelet therapy for high-risk acute coronary syndromes: clopidogrel plus aspirin versus aspirin alone . Ann Intern Med . 2005 ; 142 ( 4 ): 251 - 259 .
54 . Husted S , Emanuelsson H , Heptinstall S , Sandset PM , Wickens M , Peters G . Pharmacodynamics, pharmacoki-netics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin . Eur Heart J . 2006 ; 27 ( 9 ): 1038 - 1047 .
55 . Storey RF , Husted S , Harrington RA , et al . Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes . J Am Coll Cardiol . 2007 ; 50 ( 19 ): 1852 - 1856 .
56 . Wallentin L , Becker RC , Budaj A , et al ; PLATO Investigators . Ticagrelor versus clopidogrel in patients with acute coronary syndromes . N Engl J Med . 2009 ; 361 ( 11 ): 1045 - 1057 .
57 . Wiviott SD , Braunwald E , McCabe CH , et al ; TRITON-TIMI 38 Investigators . Prasugrel versus clopidogrel in
patients with acute coronary syndromes . N Engl J Med . 2007 ; 357 ( 20 ): 2001 - 2015 .
58 . Unger EF . Weighing benefi ts and risks—the FDA’s review of prasugrel . N Engl J Med . 2009 ; 361 ( 10 ): 942 - 945 .
59 . Asinger RW , Mikell FL , Elsperger J , Hodges M . Inci-dence of left-ventricular thrombosis after acute transmural myocardial infarction. Serial evaluation by two-dimensional echocardiography . N Engl J Med . 1981 ; 305 ( 6 ): 297 - 302 .
60 . Weinreich DJ , Burke JF , Pauletto FJ . Left ventricular mural thrombi complicating acute myocardial infarction. Long-term follow-up with serial echocardiography . Ann Intern Med . 1984 ; 100 ( 6 ): 789 - 794 .
61 . Lamas GA , Vaughan DE , Pfeffer MA . Left ventricular thrombus formation after fi rst anterior wall acute myocar-dial infarction . Am J Cardiol . 1988 ; 62 ( 1 ): 31 - 35 .
62 . Keren A , Goldberg S , Gottlieb S , et al . Natural history of left ventricular thrombi: their appearance and resolution in the posthospitalization period of acute myocardial infarc-tion . J Am Coll Cardiol . 1990 ; 15 ( 4 ): 790 - 800 .
63 . Osherov AB , Borovik-Raz M , Aronson D , et al . Incidence of early left ventricular thrombus after acute anterior wall myocardial infarction in the primary coronary intervention era . Am Heart J . 2009 ; 157 ( 6 ): 1074 - 1080 .
64 . Solheim S , Seljefl ot I , Lunde K , et al . Frequency of left ventricular thrombus in patients with anterior wall acute myocardial infarction treated with percutaneous coronary intervention and dual antiplatelet therapy . Am J Cardiol . 2010 ; 106 ( 9 ): 1197 - 1200 .
65 . Schwalm JD , Ahmad M , Salehian O , Eikelboom JW , Natarajan MK . Warfarin after anterior myocardial infarction in current era of dual antiplatelet therapy: a randomized fea-sibility trial . J Thromb Thrombolysis . 2010 ; 30 ( 2 ): 127 - 132 .
66 . Vaitkus PT , Barnathan ES . Embolic potential, prevention and management of mural thrombus complicating anterior myocardial infarction: a meta-analysis . J Am Coll Cardiol . 1993 ; 22 ( 4 ): 1004 - 1009 .
67 . Healey JS , Hart RG , Pogue J , et al . Risks and benefi ts of oral anticoagulation compared with clopidogrel plus aspirin in patients with atrial fi brillation according to stroke risk: the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE-W) . Stroke . 2008 ; 39 ( 5 ): 1482 - 1486 .
68 . Cosmi B , Rubboli A , Castelvetri C , Milandri M . Ticlopidine versus oral anticoagulation for coronary stenting . Cochrane Database Syst Rev . 2001 ;( 4 ): CD002133 .
69 . Tamhane U , Meier P , Chetcuti S , et al . Effi cacy of cilostazol in reducing restenosis in patients undergoing contemporary stent based PCI: a meta-analysis of randomised controlled trials . EuroIntervention . 2009 ; 5 ( 3 ): 384 - 393 .
70 . Mehta SR , Bassand JP , Chrolavicius S , et al ; CURRENT-OASIS 7 Investigators . Dose comparisons of clopidogrel and aspirin in acute coronary syndromes . N Engl J Med . 2010 ; 363 ( 10 ): 930 - 942 .
71 . Park SJ , Park DW , Kim YH , et al . Duration of dual anti-platelet therapy after implantation of drug-eluting stents . N Engl J Med . 2010 ; 362 ( 15 ): 1374 - 1382 .
72 . Cook S , Windecker S . Early stent thrombosis: past, present, and future . Circulation . 2009 ; 119 ( 5 ): 657 - 659 .
73 . Foley JB , Brown RI , Penn IM . Thrombosis and restenosis after stenting in failed angioplasty: comparison with elective stenting . Am Heart J . 1994 ; 128 ( 1 ): 12 - 20 .
74 . Roubin GS , Cannon AD , Agrawal SK , et al . Intracoronary stenting for acute and threatened closure complicating percu-taneous transluminal coronary angioplasty . Circulation . 1992 ; 85 ( 3 ): 916 - 927 .
75 . Serruys PW , Strauss BH , Beatt KJ , et al . Angiographic follow-up after placement of a self-expanding coronary-artery stent . N Engl J Med . 1991 ; 324 ( 1 ): 13 - 17 .
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e668S Prevention of Cardiovascular Disease
89 . Mehta SR , Yusuf S , Peters RJ , et al ; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Inves-tigators . Effects of pretreatment with clopidogrel and aspi-rin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study . Lancet . 2001 ; 358 ( 9281 ): 527 - 533 .
90 . Pekdemir H , Cin VG , Camsari A , et al . A comparison of 1-month and 6-month clopidogrel therapy on clinical and angiographic outcome after stent implantation . Heart Vessels . 2003 ; 18 ( 3 ): 123 - 129 .
91 . Steinhubl SR , Berger PB , Mann JT III , et al ; CREDO Investigators. Clopidogrel for the Reduction of Events Dur ing Observation . Early and sustained dual oral anti-platelet therapy following percutaneous coronary interven-tion: a randomized controlled trial . JAMA . 2002 ; 288 ( 19 ): 2411 - 2420 .
92 . Bernardi V , Szarfer J , Summay G , et al . Long-term versus short-term clopidogrel therapy in patients undergoing coro-nary stenting (from the Randomized Argentine Clopidogrel Stent [RACS] trial) . Am J Cardiol . 2007 ; 99 ( 3 ): 349 - 352 .
93 . Akbulut M , Ozbay Y , Karaca I , Ilkay E , Gundogdu O , Arslan N . The effect of long-term clopidogrel use on neointimal for-mation after percutaneous coronary intervention . Coron Artery Dis . 2004 ; 15 ( 6 ): 347 - 352 .
94 . Pfi sterer M , Brunner-La Rocca HP , Buser PT , et al ; BASKET-LATE Investigators . Late clinical events after clo pidogrel discontinuation may limit the benefi t of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents . J Am Coll Cardiol . 2006 ; 48 ( 12 ): 2584 - 2591 .
95 . Eisenstein EL , Anstrom KJ , Kong DF , et al . Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation . JAMA . 2007 ; 297 ( 2 ): 159 - 168 .
96 . Lip GY , G ibbs CR . Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm . Cochrane Database Syst Rev . 2010 ;(4):CD00333 3 .
97 . Cleland JG , Findlay I , Jafri S , et al . The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial com-paring antithrombotic strategies for patients with heart fail-ure . Am Heart J . 2004 ; 148 ( 1 ): 157 - 164 .
98 . Massie BM , Collins JF , Ammon SE , et al ; WATCH Trial Investigators . Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the War-farin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial . Circulation . 2009 ; 119 ( 12 ): 1616 - 1624 .
99 . Cokkinos DV , Haralabopoulos GC , Kostis JB , Toutouzas PK ; HELAS investigators . Effi cacy of antithrombotic therapy in chronic heart failure: the HELAS study . Eur J Heart Fail . 2006 ; 8 ( 4 ): 428 - 432 .
100 . Jafri SM , Mammen EF , Masura J , Goldstein S . Effects of warfarin on markers of hypercoagulability in patients with heart failure . Am Heart J . 1997 ; 134 ( 1 ): 27 - 36 .
101. Wilson PWF, D’Agostino RB, Levy D, Belanger AM, Silbershatz S, Kannel WB. Prediction of coronary artery disease using risk factor categories. Circulation. 1998;97:1837-1847.
76 . Suh JW , Lee SP , Park KW , et al . Multicenter randomized trial evaluating the effi cacy of cilostazol on ischemic vascu-lar complications after drug-eluting stent implantation for coronary heart disease: results of the CILON-T (infl uence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial . J Am Coll Cardiol . 2011 ; 57 ( 3 ): 280 - 289 .
77 . Biondi-Zoccai GG , Lotrionte M , Anselmino M , et al . Sys-tematic review and meta-analysis of randomized clinical trials appraising the impact of cilostazol after percutaneous coronary intervention . Am Heart J . 2008 ; 155 ( 6 ): 1081 - 1089 .
78 . Mehta SR , Tanguay JF , Eikelboom JW , et al ; CURRENT-OASIS 7 trial investigators . Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a ran-domised factorial trial . Lancet . 2010 ; 376 ( 9748 ): 1233 - 1243 .
79 . King SB III , Smith SC Jr , Hirshfeld JW Jr , et al ; ACC/AHA/SCAI . 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines . J Am Coll Cardiol . 2008 ; 51 ( 2 ): 172 - 209 .
80 . Silber S , Albertsson P , Avilés FF , et al ; Task Force for Per-cutaneous Coronary Interventions of the European Society of Cardiology . Guidelines for percutaneous coronary inter-ventions . Eur Heart J . 2005 ; 26 ( 8 ): 804 - 847 .
81 . Jolly SS , Pogue J , Haladyn K , et al . Effects of aspirin dose on ischaemic events and bleeding after percutaneous coronary intervention: insights from the PCI-CURE study . Eur Heart J . 2009 ; 30 ( 8 ): 900 - 907 .
82 . Bergeron P , Rudondy P , Poyen V , Pinot JJ , Alessandri C , Martelet JP . Long-term peripheral stent evaluation using angioscopy . Int Angiol . 1991 ; 10 ( 3 ): 182 - 186 .
83 . Ueda Y , Nanto S , Komamura K , Kodama K . Neointimal coverage of stents in human coronary arteries observed by angioscopy . J Am Coll Cardiol . 1994 ; 23 ( 2 ): 341 - 346 .
84 . Stettler C , Wandel S , Allemann S , et al . Outcomes asso ciated with drug-eluting and bare-metal stents: a collaborative network meta-analysis . Lancet . 2007 ; 370 ( 9591 ): 937 - 948 .
85 . Schömig A , Dibra A , Windecker S , et al . A meta-analysis of 16 randomized trials of sirolimus-eluting stents versus pacli-taxel-eluting stents in patients with coronary artery disease . J Am Coll Cardiol . 2007 ; 50 ( 14 ): 1373 - 1380 .
86 . Iakovou I , Schmidt T , Bonizzoni E , et al . Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents . JAMA . 2005 ; 293 ( 17 ): 2126 - 2130 .
87 . Spertus JA , Kettelkamp R , Vance C , et al . Prevalence, pre-dictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry . Circulation . 2006 ; 113 ( 24 ): 2803 - 2809 .
88 . Jeremias A , Sylvia B , Bridges J , et al . Stent thrombosis after successful sirolimus-eluting stent implantation . Circulation . 2004 ; 109 ( 16 ): 1930 - 1932 .
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1 Copyright © 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.11-2306
CHEST Online Data Supplement
Primary and Secondary Prevention of Cardiovascular Disease
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Per Olav Vandvik , MD, PhD ; A. Michael Lincoff , MD ; Joel M. Gore , MD ; David D. Gutterman , MD, FCCP ; Frank A. Sonnenberg , MD ; Pablo Alonso-Coello , MD ; Elie A. Akl , MD, PhD, MPH ; Maarten G. Lansberg , MD, PhD ; Gordon Guyatt , MD, FCCP ; and Frederick A. Spencer , MD
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
2 Copyright © 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.11-2306
Tabl
e S1
—[S
ecti
on 2
.1]
Asp
irin
(75
-100
mg)
Com
pare
d W
ith
No
Asp
irin
in
the
Pri
mar
y P
reve
ntio
n of
Car
diov
ascu
lar
Dis
ease
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 1
0 y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sR
elat
ive
Eff
ect
(95%
CI)
With
out
Asp
irin
With
Asp
irin
(9
5% C
I)Q
ualit
y of
E
vide
nce
Ove
rall
mor
talit
y (c
ritic
al o
utco
me)
, inc
ludi
ng c
ance
r m
orta
lity,
vas
cula
r m
orta
lity,
and
fata
l ble
eds a
100,
076
(9),
3.8-
10 y
No
seri
ous
risk
of b
ias b
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
n C
I in
clud
es n
o be
nefi t
Und
etec
ted
RR
0.9
4 (0
.88-
1.00
)60
-y-o
ld m
an c
Mod
erat
e du
e to
im
prec
isio
n 10
0 de
aths
pe
r 1,
000
6 fe
wer
de
aths
per
1,0
00
(fro
m 1
2 fe
wer
to
0 fe
wer
)
Non
fata
l MI
(cri
tical
out
com
e)
95,0
00 (6
), 3.
8-10
yN
o se
riou
s ri
sk o
f bia
s b N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
No
seri
ous
impr
ecis
ion
Und
etec
ted
RR
0.7
7 (0
.69-
0.86
)L
ow-r
isk
popu
latio
n e H
igh
27
MI
per
1,00
0 d 6
few
er
MI
per
1,00
0 (f
rom
8 fe
wer
to
4 fe
wer
)
M
oder
ate-
risk
pop
ulat
ion e
83
MI
per
1,00
0 d 19
few
er
MI
per
1,00
0 (f
rom
26
few
er
to 1
2 fe
wer
)
H
igh-
risk
pop
ulat
ion e
13
6 M
I pe
r 1,
000 d
31 fe
wer
M
I pe
r 1,
000
(fro
m 4
2 fe
wer
to
19
few
er)
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
3 Copyright © 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.11-2306
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 1
0 y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sR
elat
ive
Eff
ect
(95%
CI)
With
out
Asp
irin
With
Asp
irin
(9
5% C
I)Q
ualit
y of
E
vide
nce
Non
fata
l str
oke
(cri
tical
out
com
e), i
nclu
ding
isch
emic
, hem
orrh
agic
, and
unk
now
n ca
use f
95,0
00 (6
), 3.
8-10
y
No
seri
ous
risk
of b
ias 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
dR
R 0
.95
(0.8
5-1.
06)
Low
-ris
k po
pula
tion e
Hig
h
23
str
okes
pe
r 1,
000 d
1 fe
wer
str
oke
per
1,00
0 (f
rom
3
few
er to
1 m
ore)
M
oder
ate-
risk
pop
ulat
ion e
65 s
trok
es
per
1,00
0 d 3
few
er
stro
kes
per
1,00
0 (f
rom
10
few
er
to 4
mor
e)
H
igh-
risk
pop
ulat
ion e
10
8 st
roke
s pe
r 1,
000 d
5 fe
wer
st
roke
s pe
r 1,
000
(fro
m 1
6 fe
wer
to
6 m
ore)
Tabl
e S1
—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
4 Copyright © 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.11-2306
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 1
0 y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sR
elat
ive
Eff
ect
(95%
CI)
With
out
Asp
irin
With
Asp
irin
(9
5% C
I)Q
ualit
y of
E
vide
nce
Maj
or e
xtra
cran
ial b
leed
(im
port
ant o
utco
me)
, mai
nly
GI
and
usua
lly d
efi n
ed a
s bl
eed
requ
irin
g tr
ansf
usio
n or
res
ultin
g in
dea
th e
95,0
00 (6
), 3.
8-10
yN
o se
riou
s ri
sk o
f bia
s b N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
No
seri
ous
impr
ecis
ion
Und
etec
ted
RR
1.5
4 (1
.30-
1.82
)L
ow-r
isk
popu
latio
n g H
igh
8
blee
ds
per
1,00
0 d 4
mor
e bl
eeds
pe
r 1,
000
(fro
m 2
m
ore
to 7
mor
e)
M
oder
ate-
risk
pop
ulat
ion g
24
ble
eds
per
1,00
0 d 16
mor
e bl
eeds
per
1,0
00
(fro
m 7
mor
e to
20
mor
e)
H
igh-
risk
pop
ulat
ion g
40
ble
eds
per
1,00
0 d 22
mor
e bl
eeds
per
1,0
00
(fro
m 1
2 m
ore
to 3
3 m
ore)
Bib
liogr
aphy
: Bai
gent
C, B
lack
wel
l L, C
ollin
s R
, et a
l; A
ntith
rom
botic
Tri
alis
ts’ C
olla
bora
tion.
Asp
irin
in th
e pr
imar
y an
d se
cond
ary
prev
entio
n of
vas
cula
r di
seas
e: c
olla
bora
tive
met
a-an
alys
is o
f ind
ivid
ual
part
icip
ant d
ata
from
ran
dom
ized
tria
ls. L
ance
t . 20
09;3
73(9
678)
:184
9-18
60. R
aju
N e
t al.
Eff
ect o
f asp
irin
on
card
iova
scul
ar a
nd a
ll-ca
use
mor
talit
y in
pri
mar
y pr
even
tion
of c
ardi
ovas
cula
r di
seas
e: a
met
a-an
alys
is o
f ran
dom
ized
con
trol
led
tria
ls. A
m J
Med
. 201
1;24
(7):6
21-6
29. a M
I 5 m
yoca
rdia
l inf
arct
ion;
RR
5 ri
sk r
atio
. a T
his
syst
emat
ic r
evie
w r
epor
ts to
tal m
orta
lity
and
incl
udes
the
mos
t rec
ent t
rial
s bu
t doe
s no
t rep
ort s
peci
fi c c
ause
s of
mor
talit
y. O
ther
met
a-an
alys
es th
at u
se in
divi
dual
pat
ient
dat
a re
port
rel
ativ
e ri
sk
estim
ates
for v
ascu
lar m
orta
lity
(RR
, 0.9
7; 9
5% C
I, 0
.87-
1.09
), ca
ncer
mor
talit
y (R
R, 0
.66;
95%
CI,
0.5
0-0.
87),
and
fata
l int
racr
ania
l ble
eds (
RR
, 1.7
3; 9
5% C
I, 0
.96-
3.13
). T
he ri
sk o
f a fa
tal b
leed
(inc
ludi
ng
extr
acra
nial
and
intr
acra
nial
) was
low
(0.3
% w
ith a
spir
in a
nd 0
.2%
with
con
trol
). b B
orde
rlin
e de
cisi
on w
here
we
did
not
rate
dow
n fo
r ri
sk o
f bi
as. T
hree
of
the
tria
ls d
id n
ot b
lind
patie
nts,
car
egiv
ers,
or
outc
ome
adju
dica
tors
. Sen
sitiv
ity a
naly
ses
in m
eta-
anal
ysis
by
Raj
u et
al d
id n
ot
show
evi
denc
e of
ris
k of
bia
s.
c Con
trol
gro
up r
isk
estim
ate
for
10-y
mor
talit
y ap
plie
s to
a 6
0-y-
old
man
and
com
es f
rom
pop
ulat
ion-
base
d da
ta f
rom
Sta
tistic
s N
orw
ay. M
orta
lity
incr
ease
s w
ith a
ge (
eg, 5
0-y-
old
man
, 50
deat
hs p
er
1,00
0 in
10
y) a
nd is
low
er in
wom
en th
an in
men
(eg,
3%
in w
omen
age
d 50
y v
s 5%
in m
en a
ged
50 y
). d C
ontr
ol g
roup
ris
k es
timat
es in
low
-, m
oder
ate-
, and
hig
h-ca
rdio
vasc
ular
-ris
k gr
oups
are
bas
ed o
n th
e F
ram
ingh
am s
core
. As
expl
aine
d in
the
artic
le, w
e us
ed d
ata
from
an
indi
vidu
al p
atie
nt d
ata
met
a-an
alys
is to
pro
vide
est
imat
ed r
isks
for
patie
nt-im
port
ant o
utco
mes
not
cov
ered
by
the
Fra
min
gham
ris
k sc
ore.
We
have
als
o ad
just
ed fo
r 20
% o
vere
stim
atio
n as
soci
ated
with
Fra
min
gham
ris
k sc
ore.
e R
isk
grou
ps c
orre
spon
d to
low
ris
k (5
%),
med
ium
ris
k (1
5%),
or h
igh
risk
(25%
) acc
ordi
ng to
the
Fra
min
gham
sco
re (o
r ot
her
risk
tool
) to
estim
ate
10-y
ris
k.
f Of t
he s
trok
es in
the
tria
ls, 8
9 of
682
(13%
) with
out a
spir
in w
ere
hem
orrh
agic
, and
116
of 6
55 (1
8%) w
ith a
spir
in w
ere
hem
orrh
agic
. g I
n th
e in
divi
dual
pat
ient
dat
a m
eta-
anal
ysis
, ris
k fo
r fu
ture
maj
or b
leed
ing
corr
elat
ed w
ith r
isk
for
futu
re c
ardi
ovas
cula
r ev
ents
; the
refo
re, w
e m
ake
the
assu
mpt
ion
that
a p
atie
nt a
t low
, med
ium
, or
high
ri
sk o
f fut
ure
card
iova
scul
ar e
vent
s (d
eter
min
ed b
y F
ram
ingh
am s
core
) will
be
at lo
w, m
ediu
m, o
r hi
gh r
isk
for
futu
re m
ajor
ble
edin
g ev
ents
, res
pect
ivel
y.
Tabl
e S1
—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
5 Copyright © 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.11-2306
Tabl
e S2
—[S
ecti
ons
3.1.
1-3.
1.5,
3.2
.1]
Asp
irin
vs
No
Asp
irin
in
Pat
ient
s W
ith
Est
abli
shed
CA
D
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 5
y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sR
elat
ive
Eff
ect
(95%
CI)
Ris
k W
ithou
t A
spir
in
Ris
k D
iffer
ence
W
ith A
spir
in
(95%
CI)
Qua
lity
of
Evi
denc
e
Tota
l mor
talit
y (c
ritic
al o
utco
me)
, inc
ludi
ng s
udde
n de
ath,
pul
mon
ary
embo
lism
, hem
orrh
age,
and
unk
now
n ca
use
(pro
port
ion
not r
epor
ted)
17,0
00 (1
6 R
CTs
), 27
mo
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
Impr
ecis
e a CI
incl
udes
ben
efi t
and
no e
ffec
t
Und
etec
ted
RR
0.9
0 (0
.82-
0.99
)13
3 pe
r 1,
000 b
13 fe
wer
per
1,0
00
(fro
m 2
1 fe
wer
to
1 fe
wer
)
Mod
erat
e du
e to
im
prec
ision
a
Non
fata
l MI
(cri
tical
out
com
e)
17,0
00 (1
6 R
CTs
), 27
mo
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
Und
etec
ted
RR
0.6
9 (0
.60-
0.80
)11
7 pe
r 1,
000 b
37 fe
wer
per
1,0
00
(fro
m 4
7 fe
wer
to
23
few
er)
Hig
h
Non
fata
l str
oke
(cri
tical
out
com
e), i
nclu
ding
isch
emic
, hem
orrh
agic
, and
unk
now
n ca
use c
17 0
00 (1
6 R
CTs
), 27
mo
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
Und
etec
ted
RR
0.8
1 (0
.71-
0.92
)13
5 pe
r 1,
000 b
26 fe
wer
per
1,0
00
(fro
m 3
9 fe
wer
to
11
few
er)
Hig
h
Maj
or e
xtra
cran
ial b
leed
(im
port
ant o
utco
me)
17,0
00 (1
6 R
CTs
), 27
mo
No
seri
ous
limita
tions
No
seri
ous
limita
tions
Indi
rect
ness
on
ly r
epor
ted
in s
trok
e/T
IA
tria
ls d
No
seri
ous
limita
tions
Und
etec
ted
RR
2.6
9 (1
.25-
5.76
)15
per
1,0
00 e
25 m
ore
per
1,00
0 (f
rom
44
mor
e to
71
mor
e)
Mod
erat
e du
e to
in
dire
ctne
ss
Bib
liogr
aphy
: Bai
gent
C, B
lack
wel
l L, C
ollin
s R, e
t al;
Ant
ithro
mbo
tic T
rialis
ts’ C
olla
bora
tion.
Asp
irin
in th
e pr
imar
y an
d se
cond
ary
prev
entio
n of
vas
cula
r dise
ase:
col
llabo
rativ
e m
eta-
anal
ysis
of in
divi
dual
par
ticip
ant
data
from
rand
omiz
ed tr
ials.
Lan
cet .
2009
;373
(967
8):1
849-
1860
. CA
D 5
coro
nary
art
ery
dise
ase;
CA
PRIE
5 C
lopi
dogr
el V
ersu
s Asp
irin
in P
atie
nts a
t Risk
of I
scha
emic
Eve
nts;
CH
AR
ISM
A 5
Clo
pido
grel
for H
igh
Ath
erot
hrom
botic
Risk
and
Isch
emic
Sta
biliz
atio
n, M
anag
emen
t, an
d Av
oida
nce;
RC
T 5
rand
omiz
ed c
ontr
olle
d tr
ial;
TIA
5 tr
ansie
nt is
chem
ic a
ttack
. See
Tab
le S
1 le
gend
for e
xpan
sion
of o
ther
abb
revi
atio
n.
a Rat
ed d
own
for
impr
ecis
ion
beca
use
the
95%
CI
sugg
ests
pos
sibl
e be
nefi t
and
no
effe
ct o
n to
tal m
orta
lity.
b C
ontr
ol g
roup
ris
k es
timat
es (
with
out
aspi
rin)
for
MI
and
stro
ke c
ome
from
obs
erve
d ye
arly
eve
nt r
ates
in 1
6 R
CTs
rep
orte
d in
the
met
a-an
alys
is, a
djus
ted
to a
5-y
tim
e fr
ame.
The
con
trol
gro
up r
ate
estim
ate
for
tota
l mor
talit
y w
ithou
t asp
irin
is d
eriv
ed fr
om th
e ev
ent r
ate
in th
e as
piri
n ar
m o
f the
CH
AR
ISM
A tr
ial,
usin
g th
e R
R o
f 0.9
0 to
get
the
cont
rol g
roup
rat
e es
timat
e w
ithou
t asp
irin
. c O
f the
str
okes
in th
e m
eta-
anal
ysis
, 0.8
% w
ith a
spir
in w
ere
intr
acra
nial
hem
orrh
ages
, and
0.4
% o
f str
okes
with
out a
spir
in w
ere
intr
acra
nial
hem
orrh
ages
. d R
ated
dow
n fo
r in
dire
ctne
ss b
ecau
se b
leed
ing
even
ts w
ere
only
rep
orte
d in
a s
ubse
t of t
rial
s w
ith s
trok
e an
d T
IA p
opul
atio
ns.
e To
estim
ate
cont
rol g
roup
ris
ks fo
r m
ajor
ble
eds,
we
have
use
d m
ajor
ble
ed e
vent
rat
es fr
om th
e as
piri
n ar
m in
the
CA
PRIE
tria
l adj
uste
d to
a 5
-y ti
me
fram
e as
the
star
ting
poin
t (to
ens
ure
cons
iste
ncy
acro
ss e
vide
nce
profi
les)
. We
then
use
d th
e R
R o
f 2.6
9 fo
r th
e co
mpa
riso
n of
asp
irin
to n
o as
piri
n ob
serv
ed in
the
met
a-an
alys
is to
der
ive
the
cont
rol g
roup
rat
e es
timat
e w
ithou
t asp
irin
.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
6 Copyright © 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.11-2306
Tabl
e S3
—[S
ecti
ons
3.1.
1-3.
1.5]
Clo
pido
grel
vs
Asp
irin
for
Pat
ient
s W
ith
Est
abli
shed
CA
D
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 5
y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
A
spir
in
Ris
k D
iffer
ence
W
ith C
lopi
dogr
el
(95%
CI)
Qua
lity
of
Evi
denc
e
Tota
l mor
talit
y (c
ritic
al o
utco
me)
, inc
ludi
ng fa
tal M
I, fa
tal i
sche
mic
str
oke,
fata
l hem
orrh
agic
str
oke,
and
oth
er v
ascu
lar
deat
h a
19,1
85 (1
RC
T),
1.9
yN
o se
riou
s ri
sk o
f bia
sN
o se
riou
s in
cons
iste
ncy
subg
roup
ana
lysi
s su
gges
ted
no
bene
fi t in
pat
ient
s w
ith a
cute
MI b
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion
CI
incl
udes
har
m
with
clo
pido
grel
Und
etec
ted
RR
0.9
8 (0
.87-
1.10
)12
0 pe
r 1,
000 c
2 fe
wer
per
1,0
00
(fro
m 1
6 fe
wer
to
12
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Non
fata
l MI
(cri
tical
out
com
e)
19,1
85 (1
RC
T),
1.9
yN
o se
riou
s ri
sk o
f bia
sN
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion
CI
incl
udes
no
bene
fi t
with
clo
pido
grel
Und
etec
ted
RR
0.8
5 (0
.72-
1.0)
80 p
er 1
,000
c 12
few
er p
er 1
,000
(f
rom
22
few
er
to 0
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Non
fata
l str
oke
(cri
tical
out
com
e), i
nclu
ding
isch
emic
and
hem
orrh
agic
str
oke d
19,1
85 (1
RC
T),
1.9
yN
o se
riou
s ri
sk o
f bia
sN
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion
CI
incl
udes
har
m w
ith
clop
idog
rel
Und
etec
ted
RR
0.9
4 (0
.83-
1.06
)11
0 pe
r 1,
000 c
7 fe
wer
per
1,0
00
(fro
m 1
9 fe
wer
to
7 m
ore)
Mod
erat
e du
e to
im
prec
isio
n
Maj
or e
xtra
cran
ial b
leed
(im
port
ant o
utco
me)
, inc
ludi
ng a
ny b
leed
ing
diso
rder
, sev
ere e
19,1
85 (1
RC
T),
1.9
yN
o se
riou
s ri
sk o
f bia
sN
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion
CI
incl
udes
har
m w
ith
clop
idog
rel
Und
etec
ted
RR
0.8
8 (0
.7-1
.12)
40 p
er 1
,000
f 5
few
er p
er 1
,000
(f
rom
12
few
er
to 5
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Bib
liogr
aphy
: CA
PRIE
Ste
erin
g C
omm
ittee
. A r
ando
mis
ed, b
linde
d, tr
ial o
f clo
pido
grel
ver
sus
aspi
rin
in p
atie
nts
at r
isk
of is
chae
mic
eve
nts
(CA
PRIE
). L
ance
t . 19
96;3
48(9
038)
:132
9-13
39. S
ee T
able
S1
and
S2 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a O
f the
dea
ths
in C
APR
IE, 2
7 of
571
(4.7
%) w
ith a
spir
in w
ere
fata
l ble
edin
g ev
ents
, and
23
of 5
60 (4
.1%
) with
clo
pido
grel
wer
e fa
tal b
leed
ing
even
ts.
b Sub
grou
p an
alys
is o
f com
posi
te e
nd p
oint
rep
orte
d re
lativ
e ri
sk r
educ
tion
of 7
.3%
for
patie
nts
with
str
oke
and
23.8
% fo
r pa
tient
s w
ith p
erip
hera
l art
eria
l dis
ease
and
a r
elat
ive
risk
incr
ease
of 3
.7%
for
patie
nts
with
MI
(tes
t for
inte
ract
ion
P 5
.043
). B
ased
on
crite
ria
for
cred
ibili
ty, w
e di
d no
t bel
ieve
the
resu
lts fr
om th
e su
bgro
up a
naly
sis;
ther
efor
e, w
e di
d no
t rat
e do
wn
for
inco
nsis
tenc
y.
c Con
trol
gro
up ri
sk e
stim
ates
for t
otal
mor
talit
y co
me
from
the
aspi
rin
arm
of t
he C
HA
RIS
MA
tria
l. E
stim
ates
for M
I an
d st
roke
com
e fr
om o
bser
ved
even
ts in
the
aspi
rin
arm
of a
met
a-an
alys
is o
f 16
RC
Ts
in s
econ
dary
pre
vent
ion
(Bai
gent
et a
l 9 ), a
djus
ted
to a
5-y
tim
e fr
ame.
d O
f the
str
okes
in C
APR
IE, 2
4 of
486
(4.9
%) w
ith a
spir
in w
ere
hem
orrh
agic
and
14
of 5
28 (2
.6%
) with
clo
pido
grel
wer
e he
mor
rhag
ic.
e Of t
he m
ajor
ext
racr
ania
l ble
eds
in C
APR
IE, 6
8 of
149
(45.
6%) w
ith a
spir
in w
ere
GI
and
47 o
f 132
(35.
6%) w
ith c
lopi
dogr
el w
ere
GI
( P 5
.05)
. f C
ontr
ol g
roup
ris
k es
timat
es c
ome
from
obs
erve
d m
ajor
ble
edin
g ev
ents
in th
e C
APR
IE tr
ial,
adju
sted
to a
5-y
tim
e fr
ame,
and
not
from
the
16 s
tudi
es in
clud
ed in
the
met
a-an
alys
is b
ecau
se th
ese
stud
ies
did
not r
epor
t maj
or b
leed
s co
nsis
tent
ly.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
7 Copyright © 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.11-2306
Tabl
e S4
—[S
ecti
ons
3.1.
1-3.
1.6]
Res
ourc
e Im
plic
atio
ns: C
lopi
dogr
el v
s A
spir
in f
or S
econ
dary
Pre
vent
ion
of V
ascu
lar
Dis
ease
Aut
hor/
Year
Pa
tient
Pop
ulat
ion
Con
clus
ion
ICE
RE
ffec
tiven
ess
Uni
tYe
ar o
f Cos
t Bas
isTy
pe o
f Ana
lysi
sTy
pe o
f Mod
elTi
me
Fra
me
Sara
sin
et a
l1 /200
0A
ged
65 y
with
pri
or
stro
ke o
r T
IAC
ost-
effe
ctiv
e$
26,5
80Q
ALY
1998
Cos
t util
ityM
arko
vL
ifetim
e
Schl
eini
tz e
t al2 /2
004
Age
d 63
y in
the
CA
PRIE
tr
ial p
opul
atio
n a w
ith P
AD
Cos
t-ef
fect
ive
$ 25
,100
QA
LY20
02C
ost u
tility
Mar
kov
Life
time
Schl
eini
tz e
t al2 /2
004
Age
d 63
y in
the
CA
PRIE
tr
ial p
opul
atio
n a w
ith P
AD
with
str
oke
past
6 m
o
Cos
t-ef
fect
ive
$ 31
,200
QA
LY20
02C
ost u
tility
Mar
kov
Life
time
Schl
eini
tz e
t al2 /2
004
CA
PRIE
pop
ulat
ion
with
MI
in th
e pa
st 3
5 d
Dom
inat
edD
omin
ated
2002
Cos
t util
ityM
arko
vL
ifetim
e
Kar
non
et a
l3 /200
5M
en a
ged
60 y
in
the
CA
PRIE
tria
lC
ost-
effe
ctiv
e£
21,4
89Q
ALY
2003
Cos
t util
ityM
arko
vL
ifetim
e
Dur
and-
Zale
ski a
nd
Ber
tran
d4 /200
4C
APR
IE b
ase
case
pop
ulat
ion
Cos
t-ef
fect
ive
£ 13
,390
LYG
2003
Cos
t-ef
fect
iven
ess
Mar
kov
2 y
Dur
and-
Zale
ski a
nd
Ber
tran
d4 /200
4C
APR
IE s
ubgr
oup
with
pri
or s
trok
e or
MI
Cos
t-ef
fect
ive
£ 6,
310.
00LY
G20
03
LYG
5 li
fe y
ear
gain
ed; P
AD
5 p
erip
hera
l art
eria
l dis
ease
; QA
LY 5
qua
lity-
adju
sted
life
yea
r. Se
e Ta
ble
S1 a
nd S
2 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a LYG
.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
8 Copyright © 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.11-2306
Tabl
e S5
—[S
ecti
ons
3.1.
1-3.
1.5]
Asp
irin
Plu
s C
lopi
dogr
el v
s A
spir
in i
n th
e Se
cond
ary
Pre
vent
ion
of C
ardi
ovas
cula
r E
vent
s
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e fr
ame:
5 y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
A
spir
in
Ris
k D
iffer
ence
W
ith A
spir
in 1
C
lopi
dogr
el
(95%
CI)
Qua
lity
of
Evi
denc
e
Tota
l mor
talit
y (c
ritic
al o
utco
me)
, inc
ludi
ng d
eath
s fr
om c
ardi
ovas
cula
r ca
use
and
hem
orrh
age a
15,6
03 (1
RC
T),
28 m
oN
o se
riou
s ri
sk o
f bia
sN
o se
riou
s in
cons
iste
ncy b
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion c
Und
etec
ted
RR
0.9
9 (0
.86-
1.14
)12
0 pe
r 1,
000 d
1 fe
wer
per
1,0
00
(fro
m 1
7 fe
wer
to
17
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Non
fata
l MI
(cri
tical
out
com
e)
15,6
03 (1
RC
T),
28 m
oN
o se
riou
s ri
sk o
f bia
sN
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion c
Und
etec
ted
RR
0.9
4 (0
.75-
1.18
)80
per
1,0
00 d
5 fe
wer
per
1,0
00
(fro
m 2
0 fe
wer
to
14
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Non
fata
l str
oke
(cri
tical
out
com
e), i
nclu
ding
isch
emic
, hem
orrh
agic
, and
unk
now
n ca
use e
15,6
03 (1
RC
T),
28 m
oN
o se
riou
s ri
sk o
f bia
sN
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion c
Und
etec
ted
RR
0.8
1 (0
.64-
1.02
)11
0 pe
r 1,
000 d
21 fe
wer
per
1,0
00
(fro
m 4
0 fe
wer
to
2 m
ore)
Mod
erat
e du
e to
im
prec
isio
n
Maj
or e
xtra
cran
ial b
leed
(cri
tical
out
com
e), i
nclu
ding
sev
ere
blee
ding
as
defi n
ed b
y th
e G
UST
O c
rite
ria
but e
xclu
ding
fata
l and
intr
acra
nial
ble
eds f
15,6
03 (1
RC
T),
28 m
oN
o se
riou
s ri
sk o
f bia
sN
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion g
Und
etec
ted
RR
1.2
5 (0
.97-
1.61
)40
per
1,0
00 h
10 m
ore
per
1,00
0 (f
rom
1 fe
wer
to
24
mor
e
Mod
erat
e du
e to
im
prec
isio
n
Bib
liogr
aphy
: Bha
tt D
L, F
ox K
A, H
acke
W, e
t al
; CH
AR
ISM
A I
nves
tigat
ors.
Clo
pido
grel
and
asp
irin
ver
sus
aspi
rin
alon
e fo
r th
e pr
even
tion
of a
ther
othr
ombo
tic e
vent
s. N
Eng
l J
Med
. 200
6;35
4(16
):17
06-1
717.
Bai
gent
C, B
lack
wel
l L, C
ollin
s R, e
t al;
Ant
ithro
mbo
tic T
rialis
ts’ C
olla
bora
tion.
Asp
irin
in th
e pr
imar
y an
d se
cond
ary
prev
entio
n of
vas
cula
r dise
ase:
col
llabo
rativ
e m
eta-
anal
ysis
of in
divi
dual
par
ticip
ant
data
from
rand
omiz
ed tr
ials.
Lan
cet.
2009
;373
(967
8):1
849-
1860
. GU
STO
5 G
loba
l Use
of S
trat
egie
s To
Ope
n O
cclu
ded
Art
erie
s. Se
e Ta
ble
S1, S
2, a
nd S
4 le
gend
s for
exp
ansio
n of
oth
er a
bbre
viat
ions
. a O
f the
dea
ths
in th
e C
HA
RIS
MA
tria
l, 17
of 5
71 (3
%) w
ith a
spir
in w
ere
fata
l ble
edin
g ev
ents
, and
26
of 5
74 (4
.5%
) with
clo
pido
grel
and
asp
irin
wer
e fa
tal b
leed
ing
even
ts.
b Sub
grou
p an
alys
is fo
und
no si
gnifi
cant
eff
ect o
f clo
pido
grel
on
vasc
ular
mor
talit
y in
pat
ient
s with
est
ablis
hed
card
iova
scul
ar d
isea
se in
con
tras
t with
incr
ease
d m
orta
lity
in a
sym
ptom
atic
pat
ient
s. W
e ju
dged
th
e cl
aim
of s
ubgr
oup
effe
ct to
be
not c
redi
ble
(hig
h nu
mbe
r of
sub
grou
p hy
poth
eses
test
ed; u
ncle
ar w
heth
er a
ppro
pria
te te
st fo
r in
tera
ctio
n us
ed).
c CI
incl
udes
impo
rtan
t ben
efi t
and
harm
(for
mor
talit
y) a
nd n
o be
nefi t
(for
str
oke)
. d C
ontr
ol g
roup
ris
k es
timat
es fo
r to
tal m
orta
lity
com
es fr
om th
e as
piri
n ar
m o
f the
CH
AR
ISM
A tr
ial.
Est
imat
es fo
r M
I an
d st
roke
com
e fr
om o
bser
ved
even
ts in
a m
eta-
anal
ysis
of 1
6 R
CTs
in s
econ
dary
pr
even
tion
(Bai
gent
, Lan
cet 2
009 )
, adj
uste
d to
5-y
tim
e fr
ame.
e O
f the
str
okes
in C
HA
RIS
MA
, 27
of 1
89 (1
4%) w
ith a
spir
in w
ere
intr
acra
nial
hem
orrh
ages
, and
26
of 1
50 (1
7%) w
ith c
lopi
dogr
el w
ere
intr
acra
nial
hem
orrh
ages
. f W
e ex
clud
ed fa
tal b
leed
ing
and
intr
acra
nial
hem
orrh
age
to a
void
the
doub
le c
ount
ing
of e
vent
s in
the
CH
AR
ISM
A tr
ial.
Prop
ortio
n of
seve
re G
I bl
eeds
in C
HA
RIS
MA
was
0.6
5% (n
ot re
port
ed se
para
tely
fo
r ea
ch tr
eatm
ent a
rm).
g CI
incl
udes
no
bene
fi t a
nd im
port
ant h
arm
. h C
ontr
ol g
roup
ris
k es
timat
es c
ome
from
obs
erve
d m
ajor
ble
edin
g ev
ents
in th
e C
APR
IE tr
ial,
adju
sted
to a
5-y
tim
e fr
ame,
and
not
from
the
16 R
CTs
incl
uded
in th
e m
eta-
anal
ysis
or
from
CH
AR
ISM
A
beca
use
thes
e st
udie
s di
d no
t rep
ort m
ajor
ble
eds
cons
iste
ntly
.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
9 Copyright © 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.11-2306
Tabl
e S6
—[S
ecti
ons
3.1.
1-3.
1.6]
Asp
irin
Plu
s C
lopi
dogr
el v
s C
lopi
dogr
el i
n th
e Se
cond
ary
Pre
vent
ion
of C
ardi
ovas
cula
r E
vent
s
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e fr
ame:
1 y
Pos
t-A
CS
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)W
ith C
lopi
dogr
el
Diff
eren
ce W
ith
Asp
irin
1 C
lopi
dogr
el
(95%
CI)
Qua
lity
of
Evi
denc
e
Tota
l mor
talit
y (c
ritic
al o
utco
me)
, inc
ludi
ng fa
tal b
leed
s a
7,59
9 (1
RC
T),
18 m
oN
o se
riou
s ri
sk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
n b U
ndet
ecte
dR
R 1
.06
(0.8
4-1.
34)
119
per
1,00
0 c 7
mor
e pe
r 1,
000
(fro
m
19 fe
wer
to 4
0 m
ore)
Mod
erat
e du
e to
im
prec
isio
n
Non
fata
l MI
(cri
tical
out
com
e)
7,59
9 (1
RC
T),
18 m
oN
o se
riou
s ri
sk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
n b U
ndet
ecte
dR
R 0
.85
(0.5
7-1.
26)
68 p
er 1
,000
d 10
few
er p
er 1
,000
(fro
m
29 fe
wer
to 1
8 m
ore)
Mod
erat
e du
e to
im
prec
isio
n
Non
fata
l str
oke
(cri
tical
out
com
e), i
nclu
ding
isch
emic
, hem
orrh
agic
, and
unk
now
n ca
use e
7,59
9 (1
RC
T),
18 m
oN
o se
riou
s ri
sk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
n b U
ndet
ecte
dR
R 0
.90
(0.7
7-1.
04)
103
per
1,00
0 d 10
few
er p
er 1
,000
(fro
m
24 fe
wer
to 4
mor
e)M
oder
ate
due
to
impr
ecis
ion
Maj
or e
xtra
cran
ial b
leed
(cri
tical
out
com
e), i
nclu
ding
life
-thr
eate
ning
and
maj
or b
leed
ing f
7,59
9 (1
RC
T),
18 m
oN
o se
riou
s ri
sk
of b
ias
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
dR
R 2
.44
(1.8
3-3.
24)
35 p
er 1
,000
g 60
mor
e pe
r 1,
000
(fro
m
29 to
78
mor
e)H
igh
Bib
liogr
aphy
: Die
ner
HC
, Bog
ouss
lavs
ky J
, Bra
ss L
M, e
t al;
MAT
CH
Inv
estig
ator
s. A
spir
in a
nd c
lopi
dogr
el c
ompa
red
with
clo
pido
grel
alo
ne a
fter
rec
ent i
scha
emic
str
oke
or tr
ansi
ent i
scha
emic
att
ack
in
high
-ris
k pa
tient
s (M
ATC
H):
rand
omis
ed, d
oubl
e-bl
ind,
pla
cebo
-con
trol
led
tria
l. L
ance
t. 20
04;3
64(9
431)
:331
-337
. Bai
gent
C, B
lack
wel
l L, C
ollin
s R
, et a
l; A
ntith
rom
botic
Tri
alis
ts’ (
ATT
) C
olla
bora
tion.
A
spir
in in
the
prim
ary
and
seco
ndar
y pr
even
tion
of v
ascu
lar d
isea
se: c
olla
bora
tive
met
a-an
alys
is o
f ind
ivid
ual p
artic
ipan
t dat
a fr
om ra
ndom
ised
tria
ls. L
ance
t. 20
09;3
73(9
678)
:184
9-18
60. A
CS
5 ac
ute
coro
-na
ry s
yndr
ome.
See
Tab
le S
1, S
2, a
nd S
4 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a Ris
k of
fata
l ble
edin
g w
as 0
.43%
(16
even
ts) a
nd 0
.29
(11
even
ts) i
n th
e tr
eatm
ent a
nd c
ontr
ol g
roup
s, r
espe
ctiv
ely.
b C
Is in
clud
e po
ssib
le b
enefi
t an
d po
ssib
le h
arm
and
low
num
ber
of e
vent
s.
c Con
trol
gro
up r
isk
estim
ates
for
tota
l mor
talit
y w
ere
deri
ved
by a
pply
ing
rela
tive
risk
rat
io fo
r cl
opid
ogre
l vs
aspi
rin
to th
e to
tal m
orta
lity
rate
obs
erve
d in
the
aspi
rin
arm
of t
he C
HA
RIS
MA
tria
l. d C
ontr
ol g
roup
ris
k es
timat
es fo
r no
nfat
al M
I an
d no
nfat
al s
trok
e w
ere
deri
ved
by a
pply
ing
rela
tive
risk
rat
io fo
r cl
opid
ogre
l vs
aspi
rin
to th
e ob
serv
ed e
vent
rat
es in
the
aspi
rin
arm
of a
met
a-an
alys
is o
f 16
RC
Ts in
sec
onda
ry p
reve
ntio
n (B
aige
nt e
t al ),
adj
uste
d to
a 5
-y ti
me
fram
e.
e In
nonf
atal
isch
emic
str
oke,
the
rate
s of
pri
mar
y in
trac
rani
al h
emor
rhag
e w
ere
0.7%
(27)
and
0.4
% (1
5) in
the
trea
tmen
t and
con
trol
gro
ups,
res
pect
ivel
y.
f Con
trol
gro
up r
isk
estim
ates
for
ext
racr
ania
l ble
edin
g fr
om o
bser
ved
maj
or b
leed
ing
even
ts in
the
CA
PRIE
tri
al, a
djus
ted
to a
5-y
tim
e fr
ame,
and
not
fro
m t
he 1
6 R
CTs
incl
uded
in t
he m
eta-
anal
ysis
be
caus
e th
ese
stud
ies
did
not r
epor
t maj
or b
leed
s co
nsis
tent
ly.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
10 Copyright © 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.11-2306
Tabl
e S7
—[S
ecti
ons
3.1.
1-3.
1.6]
Mod
erat
e-In
tens
ity
War
fari
n P
lus
Asp
irin
vs
Asp
irin
Alo
ne i
n P
atie
nts
Wit
h E
stab
lish
ed C
AD
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 5
y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
A
spir
in a
Ris
k D
iffer
ence
W
ith W
arfa
rin
Plus
A
spir
in (9
5% C
I)Q
ualit
y of
E
vide
nce
Tota
l mor
talit
y
7,83
5 (1
0 R
CTs
), 3-
60 m
oN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsSe
riou
s b Im
prec
ise
CI
incl
udes
ben
efi t
and
harm
Und
etec
ted
RR
1.0
(0
.82-
1.22
)12
0 pe
r 1,
000 a
0 m
ore
per
1,00
0 (f
rom
22
few
er
to 2
6 m
ore)
Low
due
to
indi
rect
ness
and
im
prec
isio
n
Non
fata
l MI
(cri
tical
out
com
e)
7,83
5 (1
0 R
CTs
), 3-
60 m
oN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsU
ndet
ecte
dR
R 0
.69
(0.5
4-0.
88)
80 p
er 1
,000
a 25
few
er p
er 1
,000
(f
rom
37
few
er
to 1
0 fe
wer
)
Mod
erat
e du
e to
im
prec
isio
n
Non
fata
l str
oke
(cri
tical
out
com
e), i
nclu
ding
isch
emic
and
hem
orrh
agic
7,07
3 (5
RC
Ts),
3-60
mo
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
Und
etec
ted
RR
0.5
6 (0
.37-
0.86
)11
0 pe
r 1,
000 a
48 fe
wer
per
1,0
00
(fro
m 6
9 fe
wer
to
15
few
er)
Mod
erat
e du
e to
im
prec
isio
n
Maj
or e
xtra
cran
ial b
leed
(cri
tical
out
com
e) c
7,83
5 (1
0 R
CTs
), 3-
60 m
oN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsU
ndet
ecte
dR
R 2
.37
(1.6
2-3.
47)
40 p
er 1
,000
d 55
mor
e pe
r 1,
000
(fro
m 2
5 m
ore
to 9
9 m
ore)
Hig
h
Bur
den
of tr
eatm
ent (
impo
rtan
t out
com
e) e
N/A
e W
arfa
rin
.
aspi
rin
War
fari
n: d
aily
med
icat
ion,
die
tary
an
d ac
tivity
res
tric
tions
, fre
quen
t bl
ood
test
ing/
mon
itori
ng, i
ncre
ased
ho
spita
l/clin
ic v
isits
Hig
h
A
spir
in: d
aily
med
icat
ion
only
Bib
liogr
aphy
: Joh
nson
WC
, Will
iford
WO
. Ben
efi ts
, mor
bidi
ty, a
nd m
orta
lity
asso
ciat
ed w
ith lo
ng-t
erm
adm
inis
trat
ion
of o
ral a
ntic
oagu
lant
ther
apy
to p
atie
nts
with
per
iphe
ral a
rter
ial b
ypas
s pr
oced
ures
: a
pros
pect
ive
rand
omiz
ed s
tudy
. J V
asc
Surg
. 200
2;35
:413
-421
. Sar
ac T
P, H
uber
TS,
Bac
k M
R, e
t al.
War
fari
n im
prov
es th
e ou
tcom
e of
infr
aing
uina
l vei
n by
pass
gra
ftin
g at
hig
h ri
sk fo
r fa
ilure
. J V
asc
Surg
. 19
98;2
8:44
6-45
7. A
nand
S, Y
usuf
S, X
ie C
, et a
l. O
ral a
ntic
oagu
lant
and
ant
ipla
tele
t the
rapy
and
per
iphe
ral a
rter
ial d
isea
se. N
Eng
l J M
ed. 2
007;
357:
217-
227.
Rot
hber
g M
B, C
eles
tin C
, Fio
re L
D, L
awle
r E,
Coo
k JR
. War
fari
n pl
us a
spir
in a
fter
myo
card
ial i
nfar
ctio
n or
the
acut
e co
rona
ry s
yndr
ome:
met
a-an
alys
is w
ith e
stim
ates
of r
isk
and
bene
fi t. A
nn I
nter
n M
ed. 2
005;
143(
4):2
41-2
50. B
aige
nt C
, Bla
ckw
ell L
, C
ollin
s R, e
t al;
Ant
ithro
mbo
tic T
rial
ists
’ (AT
T) C
olla
bora
tion.
Asp
irin
in th
e pr
imar
y an
d se
cond
ary
prev
entio
n of
vas
cula
r dis
ease
: col
labo
rativ
e m
eta-
anal
ysis
of i
ndiv
idua
l par
ticip
ant d
ata
from
rand
omis
ed
tria
ls. L
ance
t. 20
09; 3
73(9
678)
:184
-186
0 . N
/A 5
not
app
licab
le; O
ASI
S 5
Opt
imal
Ant
ipla
tele
t Str
ateg
y fo
r In
terv
entio
ns. S
ee T
able
S1,
S2,
and
S4
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
. a C
ontr
ol g
roup
ris
k es
timat
es f
or v
ascu
lar
mor
talit
y, M
I, a
nd s
trok
es (
isch
emic
, hem
orrh
agic
, and
unk
now
n ca
use)
com
e fr
om o
bser
ved
even
ts in
a m
eta-
anal
ysis
of
16 R
CTs
in s
econ
dary
pre
vent
ion
(Bai
gent
et a
l).
b Can
not d
eter
min
e ca
rdio
vasc
ular
mor
talit
y, o
nly
tota
l mor
talit
y. I
mba
lanc
e in
one
stu
dy fo
r ca
ncer
dea
ths.
c I
n th
e O
ASI
S tr
ial,
ther
e m
ay b
e do
uble
cou
ntin
g of
hem
orrh
agic
str
okes
as
maj
or b
leed
ing
and
deat
h.
d Con
trol
gro
up r
isk
estim
ates
for
maj
or b
leed
s co
me
from
the
aspi
rin-
alon
e ar
m o
f the
CA
PRIE
tria
l. e T
here
are
stu
dies
eva
luat
ing
qual
ity o
f life
in p
atie
nts
duri
ng w
arfa
rin
trea
tmen
t (w
ith d
ispa
rate
fi nd
ings
), bu
t the
se a
re li
mite
d by
sm
all s
ampl
e si
ze, l
ack
of c
ompa
rato
r, an
d ot
her
desi
gn is
sues
.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
11 Copyright © 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.11-2306
Tabl
e S8
—[S
ecti
ons
3.2.
1-3.
2.5]
Clo
pido
grel
vs
Asp
irin
for
Pat
ient
s W
ith
Rec
ent
AC
S
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 1
y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
A
spir
in
Ris
k D
iffer
ence
W
ith C
lopi
dogr
el
(95%
CI)
Qua
lity
of
Evi
denc
e
Vasc
ular
mor
talit
y (c
ritic
al o
utco
me)
, inc
ludi
ng fa
tal M
I, fa
tal i
sche
mic
str
oke,
fata
l hem
orrh
agic
str
oke,
and
oth
er v
ascu
lar
deat
h a
19,1
85 (1
RC
T),
1.9
yN
o se
riou
s ri
sk
of b
ias
No
seri
ous
inco
nsis
tenc
y Su
bgro
up a
naly
sis
sugg
este
d no
ben
efi t
in p
atie
nts
with
ac
ute
MI b
No
seri
ous
indi
rect
ness
No
seri
ous
impr
ecis
ion
Und
etec
ted
RR
0.9
2 (0
.80-
1.07
)60
per
1,0
00 c
5 fe
wer
per
1,0
00
(fro
m 1
2 fe
wer
to
5 m
ore)
Hig
h
Non
fata
l MI
(cri
tical
out
com
e)
19,1
85 (1
RC
T),
1.9
yN
o se
riou
s ri
sk
of b
ias
No
seri
ous
inco
nsis
tenc
y b N
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
n C
I in
clud
es n
o be
nefi t
w
ith c
lopi
dogr
el
Und
etec
ted
RR
0.8
5 (0
.72-
1.0)
70 p
er 1
,000
c 10
few
er p
er 1
,000
(f
rom
22
few
er
to 0
mor
e)
Mod
erat
e du
e to
impr
ecis
ion
Non
fata
l str
oke
(cri
tical
out
com
e), i
nclu
ding
isch
emic
and
hem
orrh
agic
str
oke d
19,1
85 (1
RC
T),
1.9
yN
o se
riou
s ri
sk
of b
ias
No
seri
ous
inco
nsis
tenc
y b N
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
n e U
ndet
ecte
dR
R 0
.94
(0.8
3-1.
06)
20 p
er 1
,000
c 1
few
er p
er 1
,000
(f
rom
3 fe
wer
to
1 m
ore)
Hig
h
Maj
or e
xtra
cran
ial b
leed
(im
port
ant o
utco
me)
, inc
ludi
ng a
ny b
leed
ing
diso
rder
, sev
ere f
19,1
85 (1
RC
T),
1.9
yN
o se
riou
s ri
sk
of b
ias
No
seri
ous
inco
nsis
tenc
y b N
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
n e U
ndet
ecte
dR
R 0
.88
(0.7
0-1.
12)
30 p
er 1
,000
c 3
few
er p
er 1
,000
(f
rom
9 fe
wer
to
3 m
ore)
Hig
h
Bib
liogr
aphy
: CA
PRIE
Ste
erin
g C
omm
ittee
. A ra
ndom
ised
, blin
ded,
tria
l of c
lopi
dogr
el v
ersu
s asp
irin
in p
atie
nts a
t ris
k of
isch
aem
ic e
vent
s (C
APR
IE).
Lan
cet .
1996
;348
(903
8):1
329-
1339
. CU
RE
5 C
lopi
dogr
el
in U
nsta
ble
Ang
ina
To P
reve
nt R
ecur
rent
Eve
nts.
See
Tab
le S
1, S
2, S
4, a
nd S
6 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a Of t
he d
eath
s in
CA
PRIE
, 27
of 4
05 (6
.7%
) with
asp
irin
wer
e fa
tal b
leed
ing
even
ts, a
nd 2
3 of
372
(6.2
%) w
ith c
lopi
dogr
el w
ere
fata
l ble
edin
g ev
ents
. b S
ubgr
oup
anal
ysis
of c
ompo
site
end
poi
nt r
epor
ted
rela
tive
risk
red
uctio
n of
7.3
% fo
r pa
tient
s w
ith s
trok
e an
d 23
.8%
for
patie
nts
with
per
iphe
ral a
rter
ial d
isea
se p
atie
nts
and
rela
tive
risk
incr
ease
of 3
.7%
fo
r pa
tient
s w
ith M
I (t
est f
or in
tera
ctio
n P
5 .0
43).
Bas
ed o
n cr
iteri
a fo
r cr
edib
ility
, we
did
not b
elie
ve th
e re
sults
from
sub
grou
p an
alys
is; t
here
fore
, we
did
not r
ate
dow
n fo
r in
cons
iste
ncy.
c C
ontr
ol g
roup
ris
k es
timat
es fo
r de
ath,
MI,
str
oke,
and
ble
eds
com
e fr
om th
e C
UR
E tr
ial (
9-m
o fo
llow
-up
slig
htly
adj
uste
d to
fi t 1
-y ti
me
fram
e).
d Of t
he s
trok
es in
CA
PRIE
, 24
of 4
86 (4
.9%
) with
asp
irin
wer
e he
mor
rhag
ic, a
nd 1
4 of
528
(2.6
%) w
ith c
lopi
dogr
el w
ere
hem
orrh
agic
. e O
ur d
ecis
ion
not t
o ra
te d
own
for
impr
ecis
ion
is d
ue to
the
low
con
trol
gro
up r
isk
for
stro
kes
and
maj
or b
leed
s th
at r
esul
t in
no im
port
ant h
arm
of c
lopi
dogr
el (a
s ju
dged
by
the
uppe
r lim
it of
the
95%
CI
for
the
abso
lute
eff
ect)
. f O
f the
maj
or e
xtra
cran
ial b
leed
s in
CA
PRIE
, 68
of 1
49 (4
5.6%
) with
asp
irin
wer
e G
I, a
nd 4
7 of
132
(35.
6%) w
ith c
lopi
dogr
el w
ere
GI.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
12 Copyright © 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.11-2306
Tabl
e S9
—[S
ecti
ons
3.2.
1-3.
2.5]
Asp
irin
Plu
s C
lopi
dogr
el v
s A
spir
in i
n P
atie
nts
Wit
h a
Rec
ent
AC
S
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 1
y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
A
spir
in
Ris
k D
iffer
ence
W
ith A
spir
in 1
C
lopi
dogr
el (9
5% C
I)Q
ualit
y of
E
vide
nce
Vasc
ular
mor
talit
y (c
ritic
al o
utco
me)
a
12,5
62 (1
RC
T),
9 m
oN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsIm
prec
ise
CI
incl
udes
ben
efi t
and
harm
Und
etec
ted
RR
0.9
3 (0
.79-
1.08
)60
per
1,0
00 b
4 fe
wer
per
1,0
00 (f
rom
13
few
er to
5 m
ore)
Mod
erat
e du
e to
im
prec
isio
n
Non
fata
l MI
(impo
rtan
t out
com
e)
12,5
62 (1
RC
T),
9 m
oN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsU
ndet
ecte
dR
R 0
.77
(0.6
7-0.
89)
70 p
er 1
,000
b 16
few
er p
er 1
,000
(fro
m
23 fe
wer
to 8
few
er)
Hig
h
Non
fata
l str
oke
(impo
rtan
t out
com
e) c
12,5
62 (1
RC
T),
9 m
oN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsIm
prec
ise
CI
incl
udes
ben
efi t
and
harm
Und
etec
ted
RR
0.8
6 (0
.63-
1.18
)20
per
1,0
00 b
3 fe
wer
per
1,0
00 (f
rom
7
few
er to
4 m
ore)
Mod
erat
e du
e to
im
prec
isio
n
Maj
or b
leed
(im
port
ant o
utco
me)
d,e
12,5
62 (1
RC
T),
9 m
oN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsIm
prec
ise
CI
incl
udes
no
subs
tant
ial h
arm
Und
etec
ted
RR
1.3
8 (1
.13-
1.67
)30
per
1,0
00 b
11 m
ore
per
1,00
0 (f
rom
4
mor
e to
20
mor
e)M
oder
ate
due
to
impr
ecis
ion
Bib
liogr
aphy
: Yus
uf S
, Zha
o F,
Meh
ta S
R, C
hrol
avic
ius
S, T
ogno
ni G
, Fox
KK
; Clo
pido
grel
in U
nsta
ble
Ang
ina
to P
reve
nt R
ecur
rent
Eve
nts
Tria
l Inv
estig
ator
s. E
ffec
ts o
f clo
pido
grel
in a
dditi
on to
asp
irin
in
pat
ient
s w
ith a
cute
cor
onar
y sy
ndro
mes
with
out S
T-se
gmen
t ele
vatio
n. N
Eng
l J M
ed . 2
001;
345(
7):4
94-5
02. S
ee T
able
S1,
S2,
and
S6
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Of t
he to
tal d
eath
s in
the
CU
RE
(Clo
pido
grel
in U
nsta
ble
Ang
ina
To P
reve
nt R
ecur
rent
Eve
nts)
tria
l, 15
of 3
90 (3
.8%
) with
asp
irin
wer
e fa
tal b
leed
ing
even
ts, a
nd 1
1 of
359
(3.1
%) w
ith c
lopi
dogr
el w
ere
fata
l ble
edin
g ev
ents
. b C
ontr
ol g
roup
ris
k es
timat
es c
ome
from
the
CU
RE
tria
l (9-
mo
follo
w-u
p ad
just
ed to
fi t 1
-y ti
me
fram
e).
c Of t
he s
trok
es in
CU
RE
, fi v
e of
87
(5.7
%) w
ith a
spir
in w
ere
hem
orrh
agic
, and
sev
en o
f 75
(9.3
%) w
ith c
lopi
dogr
el w
ere
hem
orrh
agic
. d M
ajor
ble
ed d
efi n
ed a
s su
bsta
ntia
lly d
isab
ling
blee
d, in
trao
cula
r bl
eed
lead
ing
to th
e lo
ss o
f vis
ion,
or
blee
ding
nec
essi
tatin
g th
e tr
ansf
usio
n of
at l
east
2 u
nits
of b
lood
. e O
f the
maj
or e
xtra
cran
ial b
leed
s in
CU
RE
, 47
of 1
69 (2
7.8%
) with
asp
irin
wer
e G
I an
d 83
of 2
31 (3
5.9%
) with
clo
pido
grel
wer
e G
I.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
13 Copyright © 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.11-2306
Tabl
e S1
0 —[S
ecti
ons
3.2.
1-3.
2.5]
Tic
agre
lor
Plu
s A
spir
in v
s C
lopi
dogr
el P
lus
Asp
irin
in
Pat
ient
s W
ith
a R
ecen
t A
CS
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts,
Tim
e F
ram
e: 1
y a
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
Clo
pido
grel
an
d A
spir
in
Ris
k D
iffer
ence
W
ith T
icag
relo
r an
d A
spir
in (9
5% C
I)Q
ualit
y of
E
vide
nce
Vasc
ular
mor
talit
y (c
ritic
al o
utco
me)
a
18,6
24 (1
RC
T),
6-12
mo
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
Und
etec
ted
RR
0.7
9 (0
.69-
0.91
)50
per
1,0
00 b
10 fe
wer
per
1,0
00
(fro
m 1
5 fe
wer
to
4 fe
wer
)
Hig
h
Non
fata
l MI
(cri
tical
out
com
e)
18,6
24 (1
RC
T),
6-12
mo
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
Und
etec
ted
RR
0.8
4 (0
.75-
0.95
)70
per
1,0
00 b
11 fe
wer
per
1,0
00
(fro
m 1
7 fe
wer
to
3 fe
wer
)
Hig
h
Non
fata
l str
oke
(cri
tical
out
com
e) c
18,6
24 (1
RC
T),
6-12
mo
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
Impr
ecis
e C
I in
clud
es im
port
ant
harm
Und
etec
ted
RR
1.1
7 (0
.91-
1.52
)13
per
1,0
00 b
2 m
ore
per
1,00
0 (f
rom
1 fe
wer
to
7 m
ore)
Mod
erat
e du
e to
im
prec
isio
n
Maj
or b
leed
(cri
tical
out
com
e), i
nclu
ding
maj
or n
on-C
AB
G-r
elat
ed b
leed
ing
TIM
I cr
iteri
a
18,6
24 (1
RC
T),
6-12
mo
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
Impr
ecis
e C
I in
clud
es
impo
rtan
t har
mU
ndet
ecte
dR
R 1
.25
(1.0
1-1.
53)
22 p
er 1
,000
b 6
mor
e pe
r 1,
000
(fro
m 0
mor
e to
11
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Bib
liogr
aphy
: W
alle
ntin
L,
Bec
ker
RC
, B
udaj
A,
et a
l; PL
ATO
Inv
estig
ator
s. T
icag
relo
r ve
rsus
clo
pido
grel
in
patie
nts
with
acu
te c
oron
ary
synd
rom
es.
N E
ngl
J M
ed .
2009
;361
(11)
:104
5-10
57.
CA
BG
5 co
rona
ry a
rter
y by
pass
gra
ft; T
IMI 5
Thr
ombo
lysi
s in
Myo
card
ial I
nfar
ctio
n. S
ee T
able
S1,
S2,
and
S6
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
. a O
f the
tota
l dea
ths
in P
LAT
O (P
late
let I
nhib
ition
and
Pat
ient
Out
com
es),
20 o
f 399
(5.0
%) w
ith ti
cagr
elor
wer
e fa
tal b
leed
ing
even
ts, a
nd 2
3 of
506
(4.5
%) w
ith c
lopi
dogr
el w
ere
fata
l ble
edin
g ev
ents
. b O
ne-y
ear
cont
rol g
roup
ris
k es
timat
es c
ome
from
PL
ATO
, with
eve
nts
repo
rted
at 1
2 m
o.
c Of t
he to
tal s
trok
es in
PL
ATO
, 23
of 1
25 (1
8.4%
) with
tica
grel
or w
ere
hem
orrh
agic
, and
13
of 1
06 (1
2.3%
) with
clo
pido
grel
wer
e he
mor
rhag
ic.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
14 Copyright © 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.11-2306
Tabl
e S1
1 —[S
ecti
ons
3.2.
1-3.
2.5]
Pra
sugr
el P
lus
Asp
irin
vs
Clo
pido
grel
Plu
s A
spir
in i
n P
atie
nts
Wit
h a
Rec
ent
AC
S an
d P
CI
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts,
Tim
e F
ram
e: 1
y a
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
Clo
pido
grel
an
d A
spir
in
Ris
k D
iffer
ence
W
ith P
rasu
grel
and
A
spir
in (9
5% C
I)Q
ualit
y of
E
vide
nce
Vasc
ular
mor
talit
y (c
ritic
al o
utco
me)
, inc
ludi
ng fa
tal b
leed
s 0.
4% w
ith p
rasu
grel
and
0.1
% w
ith c
lopi
dogr
el
13,6
08 (1
RC
T),
14.5
mo
No
seri
ous
limita
tions
Seri
ous
limita
tions
b N
o se
riou
s lim
itatio
nsIm
prec
ise
CI
incl
udes
ben
efi t
and
harm
Und
etec
ted
RR
0.8
9 (0
.70-
1.12
)50
per
1,0
00 a
5 fe
wer
per
1,0
00
(fro
m 1
5 fe
wer
to
6 m
ore)
Low
due
to
inco
nsis
tenc
y an
d im
prec
isio
n
Non
fata
l MI
(cri
tical
out
com
e)
13,6
08 (1
RC
T),
14.5
mo
No
seri
ous
limita
tions
Seri
ous
limita
tions
b N
o se
riou
s lim
itatio
nsN
o se
riou
s im
prec
isio
nU
ndet
ecte
dR
R 0
.76
(0.6
7-0.
85)
70 p
er 1
,000
a 17
few
er p
er 1
,000
(f
rom
23
few
er
to 1
0 fe
wer
)
Mod
erat
e du
e to
in
cons
iste
ncy
Non
fata
l str
oke
(cri
tical
out
com
e), i
nclu
ding
hem
orrh
agic
(0.3
%) i
n bo
th g
roup
s
13,6
08 (1
RC
T),
14.5
mo
No
seri
ous
limita
tions
Seri
ous
limita
tions
b N
o se
riou
s lim
itatio
nsIm
prec
ise
CI
incl
udes
ben
efi t
and
harm
Und
etec
ted
RR
1.0
2 (0
.71-
1.45
)13
per
1,0
00 a
0 fe
wer
per
1,0
00
(fro
m 2
few
er
to 6
mor
e)
Low
due
to
inco
nsis
tenc
y an
d im
prec
isio
n
Maj
or b
leed
(cri
tical
out
com
e), i
nclu
ding
maj
or n
on-C
AB
G-r
elat
ed b
leed
ing
TIM
I cr
iteri
a
13,6
08 (1
RC
T),
14.5
mo
No
seri
ous
limita
tions
Seri
ous
limita
tions
b N
o se
riou
s lim
itatio
nsIm
prec
ise
CI
incl
udes
neg
ligib
le
and
subs
tant
ial h
arm
Und
etec
ted
RR
1.3
2 (1
.03-
1.68
)22
per
1,0
00 a
7 m
ore
per
1,00
0 (f
rom
0 m
ore
to 1
8 m
ore)
Low
due
to
inco
nsis
tenc
y an
d im
prec
isio
n
Bib
liogr
aphy
: W
ivio
tt S
D,
Bra
unw
ald
E,
McC
abe
CH
, et
al;
TR
ITO
N-T
IMI
38 I
nves
tigat
ors.
Pra
sugr
el v
ersu
s cl
opid
ogre
l in
pat
ient
s w
ith a
cute
cor
onar
y sy
ndro
mes
. N
Eng
l J
Med
. 20
07;3
57(2
0):
2001
-201
5. P
CI 5
per
cuta
neou
s co
rona
ry in
terv
entio
n. P
LAT
O 5
Pla
tele
t Inh
ibiti
on a
nd P
atie
nt O
utco
mes
. See
Tab
le S
1, S
2, S
6, a
nd S
10 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a Con
trol
gro
up r
isk
estim
ates
com
e fr
om th
e PL
ATO
stu
dy, a
djus
ted
to a
1-y
tim
e fr
ame.
b R
ated
dow
n fo
r in
cons
iste
ncy
for
all o
utco
mes
bec
ause
of c
redi
ble
subg
roup
ana
lyse
s sh
owin
g ne
t har
m fo
r co
mpo
site
end
poi
nt in
cer
tain
sub
grou
ps.
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15 Copyright © 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.11-2306
Tabl
e S1
2 —[S
ecti
ons
3.2.
6-3.
2.7]
Tri
ple
The
rapy
(W
arfa
rin,
Asp
irin
, Clo
pido
grel
) vs
Du
al A
ntip
late
let
The
rapy
in
Pat
ient
s W
ith
Acu
te L
arge
Ant
erio
r M
I at
Ris
k fo
r or
Wit
h LV
Thr
omb
us
Who
Und
ergo
PC
I W
ith
Sten
t P
lace
men
t
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 3
mo
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
C
lopi
dogr
el 1
Asp
irin
Ris
k D
iffer
ence
W
ith W
arfa
rin
1
Clo
pido
grel
and
A
spir
in (9
5% C
I)Q
ualit
y of
E
vide
nce
Tota
l mor
talit
y (c
ritic
al o
utco
me)
10,8
83 (1
0 R
CT
), 3-
60 m
o N
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsVe
ry s
erio
us
indi
rect
ness
a Im
prec
ise
confi
den
ce
inte
rval
incl
udes
be
nefi t
and
har
m
Und
etec
ted
RR
1.0
0 (0
.82-
1.22
)25
per
1,0
00 b
0 m
ore
per
1,00
0 (f
rom
4 fe
wer
to
6 m
ore)
Low
due
to
indi
rect
ness
and
im
prec
isio
n
Non
fata
l MI
(cri
tical
out
com
e)
10,8
83 (1
0 R
CTs
), 3-
60 m
oN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsVe
ry s
erio
us
indi
rect
ness
a N
o se
riou
s im
prec
isio
nU
ndet
ecte
dR
R 0
.69
(0.5
4-0.
88)
35 p
er 1
,000
b 11
few
er p
er 1
,000
(f
rom
16
few
er
to 4
few
er)
Low
due
to
indi
rect
ness
Non
fata
l str
oke
(cri
tical
out
com
e), i
nclu
ding
isch
emic
and
hem
orrh
agic
6,70
9 (1
RC
T),
1.3
yN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsVe
ry s
erio
us
indi
rect
ness
c Se
riou
s im
prec
isio
n B
asel
ine
risk
es
timat
es im
prec
ise d
Und
etec
ted
RR
0.5
6 (0
.39-
0.82
)A
nter
oapi
cal M
I w
ithou
t LV
thro
mbu
sL
ow d
ue to
in
dire
ctne
ss a
nd
impr
ecis
ion
15 p
er 1
,000
d 7
few
er p
er 1
,000
(f
rom
9 fe
wer
to
3 fe
wer
)
A
nter
oapi
cal M
I w
ith L
V th
rom
bus
10
0 pe
r 1,
000 d
44 fe
wer
per
1,0
00
(fro
m 1
8 fe
wer
to
61
few
er)
Maj
or e
xtra
cran
ial b
leed
(cri
tical
out
com
e)
10,8
83 (1
0 R
CTs
), 3-
60 m
oN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsVe
ry s
erio
us
indi
rect
ness
a N
o se
riou
s lim
itatio
nsU
ndet
ecte
dR
R 2
.37
(1.6
2-3.
47)
11 p
er 1
,000
c 15
mor
e pe
r 1,
000
(fro
m 7
mor
e to
27
mor
e)
Low
due
to
indi
rect
ness
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
16 Copyright © 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.11-2306
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 3
mo
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
C
lopi
dogr
el 1
Asp
irin
Ris
k D
iffer
ence
W
ith W
arfa
rin
1
Clo
pido
grel
and
A
spir
in (9
5% C
I)Q
ualit
y of
E
vide
nce
Bur
den
of tr
eatm
ent (
impo
rtan
t out
com
e) e
N/A
e W
arfa
rin
.
aspi
rin
War
fari
n: d
aily
med
icat
ion,
die
tary
and
act
ivity
re
stri
ctio
ns, f
requ
ent b
lood
test
ing/
mon
itori
ng, i
ncre
ased
hos
pita
l/clin
ic v
isits
Hig
h
A
spir
in: d
aily
med
icat
ion
only
Bib
liogr
aphy
: Rot
hber
g M
B, C
eles
tin C
, Fio
re L
D, L
awle
r E
, Coo
k JR
. War
fari
n pl
us a
spir
in a
fter
myo
card
ial i
nfar
ctio
n or
the
acut
e co
rona
ry s
yndr
ome:
met
a-an
alys
is w
ith e
stim
ates
of r
isk
and
bene
fi t.
Ann
Int
ern
Med
. 200
5;14
3(4)
:241
-250
. AC
TIV
E-W
5 A
tria
l Fib
rilla
tion
Clo
pido
grel
Tri
al W
ith I
rbes
arta
n fo
r Pr
even
tion
of V
ascu
lar
Eve
nts;
LV
5 le
ft v
entr
icul
ar. S
ee T
able
S1,
S2,
S6,
and
S11
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
. a R
elat
ive
risk
for
war
fari
n, a
spir
in, a
nd c
lopi
dogr
el v
s du
al a
ntip
late
let t
hera
py d
eriv
ed fr
om m
eta-
anal
ysis
of s
tudi
es c
ompa
ring
war
fari
n pl
us a
spir
in to
asp
irin
alo
ne in
pat
ient
s fo
llow
ing
AC
S.
b Thr
ee-m
onth
ris
k es
timat
es fo
r co
ntro
l (as
piri
n 1
clo
pido
grel
) eve
nt r
ates
com
e fr
om P
LAT
O s
tudy
. Ass
umed
that
one
hal
f of t
otal
eve
nts
at 1
y o
ccur
red
in fi
rst 3
mo
base
d on
the
PLAT
O s
tudy
. c W
e as
sum
ed t
hat
the
rela
tive
risk
for
the
out
com
e of
non
fata
l str
oke
(isch
emic
and
hem
orrh
agic
) w
ould
be
the
sam
e as
obs
erve
d in
AC
TIV
E-W
, whi
ch c
ompa
red
war
fari
n to
dua
l ant
ipla
tele
t th
erap
y (a
spir
in 1
clo
pido
grel
). W
e ca
lcul
ated
the
RR
and
95%
CI
afte
r ex
trac
ting
the
num
ber
of n
onfa
tal s
trok
es (i
sche
mic
and
hem
orrh
agic
) in
each
gro
up fr
om th
e pu
blis
hed
repo
rt b
ecau
se it
did
not
dir
ectly
re
port
RR
in th
e ar
ticle
. d C
ontr
ol g
roup
risk
est
imat
es fo
r non
fata
l str
oke
is b
ased
on
� 1
.5%
rate
/3 m
o (s
ee te
xt) w
ith c
lopi
dogr
el a
nd a
spir
in fo
llow
ing
ante
rior
MI
and
10%
rate
/3 m
o in
pat
ient
s with
ant
erio
r MI
and
LV th
rom
bus.
T
here
is c
onsi
dera
ble
impr
ecis
ion
in th
ese
estim
ates
. e T
here
are
stu
dies
eva
luat
ing
qual
ity o
f life
in p
atie
nts
duri
ng w
arfa
rin
trea
tmen
t (w
ith d
ispa
rate
fi nd
ings
), bu
t the
se a
re li
mite
d by
sm
all s
ampl
e si
ze, l
ack
of c
ompa
rato
r, an
d ot
her
desi
gn is
sues
.
Tabl
e S1
2—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
17 Copyright © 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.11-2306
Tabl
e S1
3 —[S
ecti
ons
4.1.
1-4.
3.5]
Thi
enop
yidi
ne P
lus
Asp
irin
vs
War
fari
n P
lus
Asp
irin
in
the
Fir
st M
onth
Fol
low
ing
PC
I
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts,
Tim
e F
ram
e: 3
0 d
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
War
fari
n an
d A
spir
in
Ris
k D
iffer
ence
W
ith T
hien
opyi
dine
an
d A
spir
in
(95%
CI)
Qua
lity
of
Evi
denc
e
Tota
l mor
talit
y (c
ritic
al o
utco
me)
2,43
6 (4
RC
Ts),
4-6
wk
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
limita
tions
Impr
ecis
e C
I in
clud
es
bene
fi t a
nd h
arm
Und
etec
ted
RR
0.7
3 (0
.25-
2.18
)7
per
1,00
0 a 2
few
er p
er 1
,000
(f
rom
5 fe
wer
to
8 m
ore)
Mod
erat
e du
e to
im
prec
isio
n
Non
fata
l MI
(cri
tical
out
com
e)
2,43
6 (4
RC
Ts),
4-6
wk
Seri
ous
risk
of
bia
sL
ack
of b
lindi
ng
No
seri
ous
limita
tions
No
seri
ous
limita
tions
No
seri
ous
impr
ecis
ion
Und
etec
ted
RR
0.5
0 (0
.29-
0.83
)39
per
1,0
00 a
19 fe
wer
per
1,0
00
(fro
m 2
8 fe
wer
to
7 fe
wer
)
Mod
erat
e du
e to
ri
sk o
f bia
s
Stro
ke (c
ritic
al o
utco
me)
; not
rep
orte
d in
met
a-an
alys
is
Maj
or b
leed
b (cr
itica
l out
com
e)
2,43
6 (4
RC
Ts),
4-6
wk
Seri
ous
risk
of
bia
sL
ack
of b
lindi
ng
Seri
ous
inco
nsis
tenc
y I 2 5
72%
No
seri
ous
limita
tions
Seri
ous
impr
ecis
ion
CI
incl
udes
no
bene
fi tU
ndet
ecte
dR
R 0
.38
(0.1
4-1.
02)
64 p
er 1
,000
a 40
few
er p
er 1
,000
(f
rom
55
few
er
to 1
mor
e)
Low
due
to
impr
ecis
ion,
he
tero
gene
ity,
and
stud
y lim
itatio
ns
Bib
liogr
aphy
: Cos
mi B
, Rub
boli
A, C
aste
lvet
ri C
, Mila
ndri
M. T
iclo
pidi
ne v
ersu
s or
al a
ntic
oagu
latio
n fo
r co
rona
ry s
tent
ing.
Coc
hran
e D
atab
ase
Syst
Rev
. 200
1;(4
): CD
0021
33 . S
ee T
able
S1,
S2,
and
S11
le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a C
ontr
ol g
roup
ris
k es
timat
es c
ome
from
the
met
a-an
alys
is.
b Ble
edin
g de
fi niti
ons
vari
ed g
reat
ly a
cros
s st
udie
s.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
18 Copyright © 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.11-2306
Tabl
e S1
4 —[S
ecti
ons
4.1.
1-4.
3.5]
Tri
ple
The
rapy
Wit
h C
ilos
tazo
l vs
Clo
pido
grel
Plu
s A
spir
in F
ollo
win
g E
lect
ive
PC
I W
ith
Sten
ting
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 6
-9 m
o
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
Clo
pido
grel
1
Asp
irin
Ris
k D
iffer
ence
with
C
ilost
azol
1 C
lopi
dogr
el 1
A
spir
in (9
5% C
I)Q
ualit
y of
E
vide
nce
Tota
l mor
talit
y (c
ritic
al o
utco
me)
; vas
cula
r m
orta
lity
not r
epor
ted
2,80
9 (1
0 R
CTs
), 6-
9 m
oN
o se
riou
s ri
sk o
f bia
sN
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion
Und
etec
ted
RR
0.7
3 (0
.25-
2.12
)20
per
1,0
00 a
5 fe
wer
per
1,0
00 (f
rom
15
few
er to
22
mor
e)M
oder
ate
due
to
impr
ecis
ion
Non
fata
l MI
(cri
tical
out
com
e)
2,68
9 (9
RC
Ts),
6-9
mo
No
seri
ous
risk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
n C
I in
clud
es b
enefi
t an
d ha
rm
Und
etec
ted
RR
1.1
2 (0
.57-
2.24
)50
per
1,0
00 a
6 m
ore
per
1,00
0 (f
rom
21
few
er to
62
mor
e)M
oder
ate
due
to
impr
ecis
ion
Non
fata
l str
oke
(cri
tical
out
com
e); n
ot r
epor
ted
in m
eta-
anal
ysis
Maj
or e
xtra
cran
ial b
leed
(im
port
ant o
utco
me)
; not
cle
arly
defi
ned
19,1
85 (1
RC
Ts),
6-9
mo
No
seri
ous
risk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
n C
I in
clud
es b
enefi
t an
d ha
rm
Und
etec
ted
RR
0.8
7 (0
.44-
1.74
)50
per
1,0
00 a
6 fe
wer
per
1,0
00 (f
rom
28
few
er to
37
mor
e)M
oder
ate
due
to
impr
ecis
ion
Bib
liogr
aphy
: Tam
hane
U, M
eier
P, C
hetc
uti S
, et
al. E
ffi ca
cy o
f ci
lost
azol
in r
educ
ing
rest
enos
is in
pat
ient
s un
derg
oing
con
tem
pora
ry s
tent
bas
ed P
CI:
a m
eta-
anal
ysis
of
rand
omis
ed c
ontr
olle
d tr
ials
. E
uroI
nter
vent
ion .
200
9;5(
3):3
84-3
93. S
ee T
able
S1,
S2,
and
S11
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Con
trol
gro
up r
isk
estim
ates
com
e fr
om th
e m
eta-
anal
ysis
per
form
ed fo
r du
al a
ntip
late
let t
hera
py fo
llow
ing
PCI
with
ste
nt p
lace
men
t (Ta
mha
ne e
t al).
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
19 Copyright © 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.11-2306
Tabl
e S1
5 — [ S
ecti
ons
4.1.
1-4.
3.5 ]
Cil
osta
zol
Plu
s A
spir
in v
s C
lopi
dogr
el P
lus
Asp
irin
Fol
low
ing
Ele
ctiv
e P
CI
Wit
h St
enti
ng
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Est
imat
ion
of A
bsol
ute
Eve
nt R
ates
and
R
isk
Diff
eren
ces
Tim
e F
ram
e: 6
-9 m
o
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sR
elat
ive
Eff
ect
(95%
CI)
Eve
nt R
ate
With
C
lopi
dogr
el 1
A
spir
in
Ris
k D
iffer
ence
W
ith C
ilost
azol
1
Asp
irin
(95%
CI)
Qua
lity
of
Evi
denc
e
Tota
l mor
talit
y (c
ritic
al o
utco
me)
; not
rep
orte
d
Non
fata
l MI
(cri
tical
out
com
e); n
ot r
epor
ted
Non
fata
l str
oke
(cri
tical
out
com
e); n
ot r
epor
ted
Maj
or a
dver
se c
ardi
ac e
vent
s (im
port
ant o
utco
me)
; the
onl
y va
scul
ar e
vent
out
com
e re
port
ed in
met
a-an
alys
is, b
ut n
ot s
peci
fi ed
furt
her
3,43
7 (1
3 R
CTs
), 6
mo
Seri
ous
risk
of b
ias
vari
able
blin
ding
, lo
ss to
follo
w-u
p
No
seri
ous
inco
nsis
tenc
ySe
riou
s in
dire
ctne
ss
Com
posi
te
outc
ome
Seri
ous
impr
ecis
ion
CI
incl
udes
ben
efi t
and
harm
Publ
icat
ion
bias
de
tect
edR
R 0
.56
(0.2
5-1.
27)
75 p
er 1
,000
a 33
few
er p
er 1
,000
(f
rom
56
few
er
to 2
0 m
ore)
Low
due
to r
isk
of
bias
, ind
irec
tnes
s,
impr
ecis
ion,
and
pu
blic
atio
n bi
as
Maj
or e
xtra
cran
ial b
leed
(im
port
ant o
utco
me)
Not
cle
arly
defi
ned
3,43
7 (1
3 R
CTs
), 6
mo
Seri
ous
risk
of b
ias
vari
able
blin
ding
, lo
ss to
follo
w-u
p
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
n C
I in
clud
es
bene
fi t a
nd h
arm
Publ
icat
ion
bias
de
tect
edR
R 0
.66
(0.3
2-1.
39)
50 p
er 1
,000
a 17
few
er p
er 1
,000
(f
rom
34
few
er
to 2
0 m
ore)
Low
due
to r
isk
of b
ias,
impr
ecis
ion,
an
d pu
blic
atio
n bi
as
Bib
liogr
aphy
: Bio
ndi-Z
occa
i GG
, Lot
rion
te M
, Ans
elm
ino
M, e
t al.
Syst
emat
ic r
evie
w a
nd m
eta-
anal
ysis
of r
ando
miz
ed c
linic
al tr
ials
app
rais
ing
the
impa
ct o
f cilo
staz
ol a
fter
per
cuta
neou
s co
rona
ry in
ter-
vent
ion.
Am
Hea
rt J
. 200
8;15
5(6)
:108
1-10
89. S
ee T
able
S1,
S2,
and
S11
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Con
trol
gro
up r
isk
estim
ates
com
e fr
om th
e m
eta-
anal
ysis
(Bio
ndi-Z
occa
i et a
l).
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
20 Copyright © 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.11-2306
Tabl
e S1
6 —[S
ecti
ons
4.1.
1-4.
3.5]
Hig
h-D
ose
Asp
irin
vs
Low
-Dos
e A
spir
in f
or 3
0 d
Pos
t-P
CI
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 3
0 d
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
HR
(95%
CI)
Ris
k W
ith A
spir
in
75-1
00 m
g
Ris
k D
iffer
ence
With
A
spir
in 3
00-3
25 m
g (9
5% C
I)Q
ualit
y of
E
vide
nce
Tota
l mor
talit
y (c
ritic
al o
utco
me)
a
17,2
36 (1
RC
T),
30 d
No
seri
ous
risk
of
bia
s b N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion
CI
incl
uded
im
port
ant b
enefi
t an
d no
ben
efi t c
Und
etec
ted
HR
0.8
7 (0
.74-
1.03
)25
per
1,0
00 d
3 fe
wer
per
1,0
00
(fro
m 7
few
er
to 1
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Non
fata
l MI
(cri
tical
out
com
e)
17,2
36 (1
RC
T),
30 d
No
seri
ous
risk
of
bia
s b N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion
CI
incl
uded
be
nefi t
and
har
m c
Und
etec
ted
HR
0.9
7 (0
.82-
1.16
)21
per
1,0
00 d
1 fe
wer
per
1,0
00
(fro
m 4
few
er
to 3
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Stro
ke (c
ritic
al o
utco
me)
e
17,2
36 (1
RC
T),
30 d
No
seri
ous
risk
of
bia
s b N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion
CI
incl
uded
be
nefi t
and
har
m c
Und
etec
ted
HR
1.1
9 (0
.84-
1.68
)5
per
1,00
0 d 1
mor
e pe
r 1,
000
(fro
m 1
few
er
to 3
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Maj
or b
leed
(im
port
ant o
utco
me)
f
17,2
36 (1
RC
T),
30 d
No
seri
ous
risk
of
bia
s b N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion
CI
incl
uded
be
nefi t
and
har
m c
Und
etec
ted
HR
1.0
9 (0
.89-
1.34
)14
per
1,0
00 d
1 m
ore
per
1,00
0 (f
rom
2 fe
wer
to
5 m
ore)
Mod
erat
e du
e to
im
prec
isio
n
Bib
liogr
aphy
: Meh
ta S
R, T
angu
ay JF
, Eik
elbo
om JW
, et a
l; C
UR
RE
NT-
OA
SIS
7 tr
ial i
nves
tigat
ors.
Dou
ble-
dose
ver
sus s
tand
ard-
dose
clo
pido
grel
and
hig
h-do
se v
ersu
s low
-dos
e as
piri
n in
indi
vidu
als u
nder
-go
ing
perc
utan
eous
cor
onar
y in
terv
entio
n fo
r acu
te c
oron
ary
synd
rom
es (C
UR
RE
NT-
OA
SIS
7): a
rand
omis
ed fa
ctor
ial t
rial
. Lan
cet .
2010
;376
(974
8):1
233-
1243
. CU
RR
EN
T-O
ASI
S 5
Clo
pido
grel
Opt
imal
L
oadi
ng D
ose
Usa
ge T
o R
educ
e R
ecur
rent
Eve
nts/
Opt
imal
Ant
ipla
tele
t Str
ateg
y fo
r In
terv
entio
ns; H
R 5
haz
ard
ratio
. See
Tab
le S
1, S
10, a
nd S
11 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a Of t
he to
tal d
eath
s in
CU
RR
EN
T-O
ASI
S 7,
15
of 3
14 (4
.8%
) occ
urre
d w
ith lo
w-d
ose
aspi
rin,
and
16
of 2
73 (5
.9%
) wer
e fa
tal b
leed
ing
even
ts.
b OA
SIS
aspi
rin
dose
was
not
blin
ded.
c B
orde
rlin
e de
cisi
on to
rat
e do
wn
for
impr
ecis
ion.
Alth
ough
CIs
for
abso
lute
eff
ects
are
fair
ly n
arro
w, t
he 3
0-d
time
fram
e su
gges
ts im
prec
ise
effe
ct e
stim
ates
(eg,
thre
e m
ore
stro
kes
and
blee
ds p
er 1
,000
tr
eate
d fo
r 30
d).
d Con
trol
gro
up r
isk
estim
ates
com
e fr
om e
vent
rat
es in
pat
ient
s al
loca
ted
to lo
w-d
ose
aspi
rin
unde
rgoi
ng P
CI
in C
UR
RE
NT-
OA
SIS
7.
e Unc
lear
from
the
artic
le w
heth
er h
emor
rhag
ic a
nd fa
tal s
trok
es w
ere
incl
uded
in to
tal s
trok
es.
f TIM
I cr
iteri
a us
ed. I
t is
uncl
ear
from
the
artic
le w
heth
er h
emor
rhag
ic a
nd fa
tal b
leed
ing
wer
e in
clud
ed in
tota
l maj
or b
leed
ing.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
21 Copyright © 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.11-2306
Tabl
e S1
7 —[S
ecti
ons
4.1.
1-4.
3.5]
Six
to
Twel
ve M
onth
s vs
One
Mon
th o
f C
lopi
dogr
el P
lus
Asp
irin
Fol
low
ing
PC
I W
ith
Pla
cem
ent
of B
are
Met
al S
tent
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts T
ime
Fra
me:
6-9
mo
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
1 m
o C
lopi
dogr
el 1
Asp
irin
Risk
Diff
eren
ce W
ith 6
-12
mo
Clo
pido
grel
1 A
spir
in
(95%
CI)
Qua
lity
of
Evi
denc
e
Tota
l mor
talit
y (c
ritic
al o
utco
me)
3,39
0 (3
RC
Ts),
6-12
mo
Seri
ous
risk
of
bia
s a N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion
CI
incl
uded
impo
rtan
t be
nefi t
and
har
m
Und
etec
ted
RR
0.7
3 (0
.48-
1.13
)28
per
1,0
00 b
8 fe
wer
per
1,0
00 (f
rom
15
few
er to
4 m
ore)
Low
due
to r
isk
of b
ias
and
impr
ecis
ion
Non
fata
l MI
(cri
tical
out
com
e)
4,85
2 (3
RC
Ts),
6-12
mo
Seri
ous
risk
of
bia
s a N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
No
seri
ous
impr
ecis
ion
Und
etec
ted
RR
0.6
6 (0
.50-
0.86
)28
per
1,0
00 b
9 fe
wer
per
1,0
00 (f
rom
14
few
er to
4 fe
wer
)M
oder
ate
due
to ri
sk o
f bia
s
Non
fata
l str
oke
(cri
tical
out
com
e)
2,19
4 (2
RC
Ts),
6-12
mo
Seri
ous
risk
of
bia
s a N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion
CI
incl
uded
impo
rtan
t be
nefi t
and
har
m
Und
etec
ted
RR
0.4
6 (0
.16-
1.32
)10
per
1,0
00 b
5 fe
wer
per
1,0
00 (f
rom
8
few
er to
3 m
ore)
Low
due
to r
isk
of b
ias
and
impr
ecis
ion
Maj
or e
xtra
cran
ial b
leed
(im
port
ant o
utco
me)
; not
cle
arly
defi
ned
c
5,05
2 (3
RC
Ts),
6-12
mo
Seri
ous
risk
of
bia
s a N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous
impr
ecis
ion
CI
incl
udes
impo
rtan
t be
nefi t
and
har
m
Und
etec
ted
RR
1.1
7 (0
.86-
1.6)
50 p
er 1
,000
b 8
mor
e pe
r 1,
000
(fro
m
7 fe
wer
to 3
0 m
ore)
Low
due
to r
isk
of b
ias
and
impr
ecis
ion
Bib
liogr
aphy
: Dat
a fo
r m
eta-
anal
ysis
ext
ract
ed fr
om fo
llow
ing
stud
ies:
Meh
ta S
R, Y
usuf
S, P
eter
s R
J, e
t al.
Eff
ects
of p
retr
eatm
ent w
ith c
lopi
dogr
el a
nd a
spir
in fo
llow
ed b
y lo
ng-t
erm
ther
apy
in p
atie
nts
unde
rgoi
ng p
ercu
tane
ous
coro
nary
inte
rven
tion:
the
PC
I-C
UR
E s
tudy
. Lan
cet .
2001
;358
(928
1):5
27-5
33. P
ekde
mir
H, C
in V
G, C
amsa
ri A
, et
al. A
com
pari
son
of 1
-mo
and
6-m
o cl
opid
ogre
l the
rapy
on
clin
ical
and
ang
iogr
aphi
c ou
tcom
e af
ter
sten
t im
plan
tatio
n. H
eart
Ves
sels
. 200
3;18
(3):1
23-1
29. S
tein
hubl
SR
, Ber
ger
PB, M
ann
JT I
II, e
t al
. Ear
ly a
nd s
usta
ined
dua
l ora
l ant
ipla
tele
t th
erap
y fo
llow
ing
perc
utan
eous
cor
onar
y in
terv
entio
n: a
ran
dom
ized
con
trol
led
tria
l. JA
MA
. 200
2;28
8(19
):241
1-24
20. B
erna
rdi V
, Sza
rfer
J, S
umm
ay G
, et a
l. L
ong-
term
vs
shor
t-te
rm c
lopi
dogr
el th
erap
y in
pat
ient
s un
der-
goin
g co
rona
ry s
tent
ing
(fro
m th
e R
ando
miz
ed A
rgen
tine
Clo
pido
grel
Ste
nt [R
AC
S] tr
ial).
Am
J C
ardi
ol . 2
007;
99(3
):349
-352
. Akb
ulut
M, O
zbay
Y, K
arac
a I,
Ilk
ay E
, Gun
dogd
u O
, Ars
lan
N. T
he e
ffec
t of
long
-ter
m c
lopi
dogr
el u
se o
n ne
oint
imal
form
atio
n af
ter
perc
utan
eous
cor
onar
y in
terv
entio
n. C
oron
Art
ery
Dis
. 200
4;15
(6):3
47-3
52. S
ee T
able
S1,
S2,
and
S11
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Ber
nard
i et a
l and
Pek
dem
ir e
t al w
ere
not b
linde
d, a
nd th
ere
was
no
plac
ebo
cont
rol;
Ber
nard
i et a
l sto
pped
ear
ly fo
r ben
efi t.
Akb
ulut
et a
l des
ign
was
unc
lear
(no
men
tion
of ra
ndom
izat
ion,
but
the
Hea
lth
Tech
nolo
gy A
sses
smen
t rep
ort r
efer
s to
it a
s ra
ndom
ized
); M
ehta
et a
l had
var
iabl
e fo
llow
-up.
b C
ontr
ol g
roup
ris
k es
timat
es w
ere
deri
ved
from
rat
es in
sub
ject
s tr
eate
d w
ith d
ual a
ntip
late
let t
hera
py fo
r 1
mo
in in
clud
ed tr
ials
. c M
ajor
ble
edin
g no
t str
atifi
ed b
y ty
pe o
f ble
ed; u
ncle
ar w
heth
er m
ajor
ble
edin
g in
clud
ed a
ny fa
talit
ies.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
22 Copyright © 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.11-2306
Tabl
e S1
8 —[S
ecti
ons
4.1.
1-4.
3.5]
Ext
ende
d D
ura
tion
of
Clo
pido
grel
Plu
s A
spir
in F
ollo
win
g P
CI
Wit
h P
lace
men
t of
Dru
g-E
luti
ng S
tent
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e fr
ame:
19
mo
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sR
elat
ive
Eff
ect
(95%
CI)
Ris
k W
ith 1
2 m
o C
lopi
dogr
el 1
A
spir
in
Ris
k D
iffer
ence
With
19
mo
Clo
pido
grel
1
Asp
irin
(95%
CI)
Qua
lity
of
Evi
denc
e
Tota
l mor
talit
y (c
ritic
al o
utco
me)
2,70
1 (2
RC
Ts),
19 m
oN
o se
riou
s ri
sk
of b
ias a
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
n C
I in
clud
ed
no b
enefi
t an
d im
port
ant h
arm
Und
etec
ted
RR
1.6
5 (0
.80-
3.36
)6
per
1,00
0 b 4
mor
e pe
r 1,
000
(fro
m 1
few
er to
14
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Non
fata
l MI
(cri
tical
out
com
e)
2,70
1 (2
RC
Ts),
19 m
oN
o se
riou
s ri
sk
of b
ias a
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
n C
I in
clud
es n
o be
nefi t
and
im
port
ant h
arm
Und
etec
ted
RR
1.7
3 (0
.54-
5.53
)3
per
1,00
0 b 2
mor
e pe
r 1,
000
(fro
m 1
few
er to
13
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Non
fata
l str
oke
(cri
tical
out
com
e)
2,70
1 (2
RC
Ts),
19 m
oN
o se
riou
s ri
sk
of b
ias a
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
n C
I in
clud
es n
o be
nefi t
an
d im
port
ant h
arm
Und
etec
ted
RR
2.6
4 (0
.76-
9.16
)2
per
1,00
0 b 3
mor
e pe
r 1,
000
(fro
m 1
few
er to
16
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Maj
or e
xtra
cran
ial b
leed
(im
port
ant o
utco
me)
Not
cle
arly
defi
ned
c
2,70
1 (2
RC
Ts),
19 m
oN
o se
riou
s ri
sk
of b
ias a
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
n C
I in
clud
es n
o be
nefi t
an
d im
port
ant h
arm
Und
etec
ted
RR
2.9
7 (0
.43-
20.7
2)1
per
1,00
0 b 2
mor
e pe
r 1,
000
(fro
m 1
few
er to
19
mor
e)
Mod
erat
e du
e to
im
prec
isio
n
Bib
liogr
aphy
: Par
k SJ
, Par
k D
W, K
im Y
H, e
t al.
Dur
atio
n of
dua
l ant
ipla
tele
t the
rapy
aft
er im
plan
tatio
n of
dru
g-el
utin
g st
ents
. N E
ngl J
Med
. 201
0;36
2(15
):137
4-13
82. S
ee T
able
S1,
S2,
S10
, and
S11
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Ope
n-la
bel s
tudy
, alth
ough
stu
dy e
nd p
oint
s w
ere
adju
dica
ted
by b
linde
d as
sess
ors.
b C
ontr
ol g
roup
ris
k es
timat
es c
ome
from
sub
ject
s re
ceiv
ing
dual
ant
ipla
tele
t the
rapy
for
1 y
in th
e m
erge
d tr
ials
. c M
ajor
ble
edin
g de
fi ned
by
TIM
I cr
iteri
a; n
o in
form
atio
n w
as p
rovi
ded
on th
e ty
pe o
f maj
or b
leed
ing
even
ts in
eith
er g
roup
. No
fata
l ble
edin
g w
as r
epor
ted.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
23 Copyright © 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.11-2306
Tabl
e S1
9 —[S
ecti
ons
5.1-
5.3]
War
fari
n vs
Asp
irin
in
Pat
ient
s W
ith
Syst
olic
LV
Dys
func
tion
(Is
chem
ic a
nd N
onis
chem
ic)
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Ant
icip
ated
Abs
olut
e E
ffec
ts
Tim
e F
ram
e: 5
y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
A
spir
in a
Ris
k D
iffer
ence
With
W
arfa
rin
(95%
CI)
Qua
lity
of
Evi
denc
e
Tota
l mor
talit
y (c
ritic
al o
utco
me)
1,35
7 (3
RC
Ts),
23-2
7 m
oSe
riou
s b lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsIm
prec
ise
CI
incl
udes
ben
efi t
and
harm
Und
etec
ted
RR
0.9
5 (0
.76-
1.19
)19
3 pe
r 1,
000 a
10 fe
wer
per
1,0
00
(fro
m 4
6 fe
wer
to
36 m
ore)
Low
due
to r
isk
of b
ias
and
impr
ecis
ion
MI
(cri
tical
out
com
e) c
1,35
8 (3
RC
Ts),
23-2
7 m
oSe
riou
s b lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsIm
prec
ise
CI
incl
udes
ben
efi t
and
harm
Und
etec
ted
RR
0.9
9 (0
.35-
2.84
)33
per
1,0
00 a
0 fe
wer
per
1,0
00
(fro
m 2
1 fe
wer
to
60 m
ore)
Low
due
to r
isk
of b
ias
and
impr
ecis
ion
Stro
ke (c
ritic
al o
utco
me)
d
1,35
8 (3
RC
Ts),
23-2
7 m
oSe
riou
s b lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsIm
prec
ise
CI
incl
udes
no
bene
fi t
Und
etec
ted
RR
0.3
4 (0
.13-
0.97
)24
per
1,0
00 a
16 fe
wer
per
1,0
00
(fro
m 2
1 fe
wer
to
1 fe
wer
)
Low
due
to r
isk
of b
ias
and
impr
ecis
ion
Maj
or b
leed
(cri
tical
out
com
e) e
1,35
8 (3
RC
Ts),
23-2
7 m
oSe
riou
s b lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsIm
prec
ise
CI
incl
udes
im
port
ant h
arm
Und
etec
ted
RR
1.9
7 (0
.89-
4.3)
30 p
er 1
,000
a 29
mor
e pe
r 1,
000
(fro
m 3
few
er to
99
mor
e)
Low
due
to r
isk
of b
ias
and
impr
ecis
ion
Bur
den
of tr
eatm
ent (
impo
rtan
t out
com
e)
W
arfa
rin
.
aspi
rin
War
fari
n: d
aily
med
icat
ion,
die
tary
an
d ac
tivity
res
tric
tions
, fre
quen
t bl
ood
test
ing/
mon
itori
ng, i
ncre
ased
ho
spita
l/clin
ic v
isits
Hig
h
A
spir
in: d
aily
med
icat
ion
only
Bib
liogr
aphy
: Dat
a fo
r m
eta-
anal
ysis
ext
ract
ed fr
om th
ree
stud
ies.
Cle
land
JG
, Fin
dlay
I, J
afri
S, e
t al.
The
War
fari
n/A
spir
in S
tudy
in H
eart
failu
re (
WA
SH):
a ra
ndom
ized
tria
l com
pari
ng a
ntith
rom
botic
st
rate
gies
for
patie
nts
with
hea
rt fa
ilure
. Am
Hea
rt J
. 200
4;14
8(1)
:157
-164
. Mas
sie
BM
, Col
lins
JF, A
mm
on S
E, e
t al.
Ran
dom
ized
tria
l of w
arfa
rin,
asp
irin
, and
clo
pido
grel
in p
atie
nts
with
chr
onic
hea
rt
failu
re: t
he W
arfa
rin
and
Ant
ipla
tele
t The
rapy
in C
hron
ic H
eart
Fai
lure
(WAT
CH
) tri
al. C
ircu
lati
on . 2
009;
119(
12):1
616-
1624
. Cok
kino
s D
V, H
aral
abop
oulo
s G
C, K
ostis
JB
, Tou
touz
as P
K. E
ffi ca
cy o
f ant
i-th
rom
botic
ther
apy
in c
hron
ic h
eart
failu
re: t
he H
EL
AS
stud
y. E
ur J
Hea
rt F
ail.
2006
;8(4
):428
-432
. See
Tab
le S
1, S
2, a
nd S
12 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a C
ontr
ol g
roup
ris
k es
timat
es w
ere
deri
ved
from
eve
nt r
ates
from
the
aspi
rin
arm
of t
he p
oole
d st
udie
s.
b Tw
o of
thre
e tr
ials
wer
e st
oppe
d ea
rly
(one
for
bene
fi t, o
ne fo
r sl
ow e
nrol
lmen
t); p
robl
ems
with
blin
ding
. c F
atal
and
non
fata
l MIs
not
rep
orte
d se
para
tely
in a
ll st
udie
s.
d Fat
al a
nd n
onfa
tal s
trok
es n
ot r
epor
ted
sepa
rate
ly in
all
stud
ies;
type
s of
str
okes
(isc
hem
ic/h
emor
rhag
ic) n
ot r
epor
ted.
e D
efi n
ition
of m
ajor
hem
orrh
age
vari
ed.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
24 Copyright © 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.11-2306
References 1 . Sarasin FP , Gaspoz JM , Bounameaux H . Cost-effectiveness
of new antiplatelet regimens used as secondary prevention of stroke or transient ischemic attack . Arch Intern Med . 2000 ; 160 ( 18 ): 2773 - 2778 .
2 . Schleinitz MD , Weiss JP , Owens DK . Clopidogrel ver-sus aspirin for secondary prophylaxis of vascular events:
a cost-effectiveness analysis . Am J Med . 2004 ; 116 ( 12 ): 797 - 806 .
3 . Karnon J , Bakhai A , Brennan A , et al . A cost-utility analysis of clopidogrel in patients with non-ST-segment-elevation acute coro-nary syndromes in the UK . Int J Cardiol . 2006 ; 109 ( 3 ): 307 - 316 .
4 . Durand-Zaleski I , Bertrand M . The value of clopidogrel ver-sus aspirin in reducing atherothrombotic events: the CAPRIE study . Pharmacoeconomics . 2004 ; 22 ( suppl 4 ): 19 - 27 .
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DOI 10.1378/chest.11-2306 2012;141; e637S-e668SChest
Lansberg, Gordon H. Guyatt and Frederick A. SpencerFrank A. Sonnenberg, Pablo Alonso-Coello, Elie A. Akl, Maarten G.
Per Olav Vandvik, A. Michael Lincoff, Joel M. Gore, David D. Gutterman,Practice Guidelines
American College of Chest Physicians Evidence-Based ClinicalAntithrombotic Therapy and Prevention of Thrombosis, 9th ed: Primary and Secondary Prevention of Cardiovascular Disease :
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