JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER INC.

VOL. 64, NO. 14, 2014

ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2014.08.001

EDITORIAL COMMENT

Reconsidering the Necessity of Aspirin

in Stable Coronary Artery Disease*
Harold L. Dauerman, MD

spirin has been a cornerstone of secondary

of coronary revascularization or acute myocardial

prevention in patients with stable coronary

infarction in the previous 12 months. This observa-

artery disease (CAD) for more than 4 de-

tional registry provides 2 major insights into a

cades. Aspirin targets a specic pathophysiological

generally low-risk population. (1) Bleeding Academic

process that is considered fundamental to the

Research Consortium (BARC) bleeds type $3 during 2

progression from stable to unstable coronary syn-

years of follow-up is mostly gastrointestinal and oc-

dromesplatelet activation (1). Aspirin is inexpensive

curs in <1% of patients per year. The investigators

and easy to use, but it does increase the risk of

called BARC bleeds of types 3, 4, and 5 major

bleeding compared with not using antiplatelet ther-

bleeding, which only makes sense if BARC 2 is de-

apy (2). Use of aspirin in secondary prevention is

nitively proven not to be associated with death (9).

strongly supported by several guidelines, because

Of note, BARC bleed scales have only been utilized in

the bleeding risk is balanced by prevention of throm-

the inpatient setting; therefore, the CORONOR study

botic events (3,4).

provides the rst point estimates of BARC bleeds in

Thus, it is not surprising that when faced with an

the outpatient setting. (2) BARC major bleeds among

elderly patient with stable CAD, new-onset atrial

outpatients are similar to major bleeding among in-

brillation, and additional oral anticoagulation, we

patients with CAD in unstable condition; these major

adhere to a simple mantra: never stop the aspirin.

bleeds are associated with more death (10).

Recently, investigators have suggested that this

The most challenging aspect of this outpatient

practice puts patients at undue risk of bleeding with

observational registry is the question of aspirin in

no ischemic benets (57). Thus, is it time to abandon

patients who require oral anticoagulation. The 4

inhibition of platelet activation in patients with stable

predictors of major bleeding in this study were not

CAD who are on oral anticoagulation?

surprising; older age, diabetes, renal failure, and

SEE PAGE 1430

BLEEDING IN THE CLINIC: INSIGHTS INTO INCIDENCE,

PROGNOSIS, AND PREDICTORS. In this issue of the

Journal, Hamon et al. (8) present CORONOR (Suivi

dune cohorte de patients COROnariens stables en
region NORd-Pas-de-Calais), a large, multicenter sitebased registry of patients in stable condition with
documented CAD. Stability is dened as the absence

warfarin were associated with more bleeding (8).

Although some predictors of bleeding common to
inpatients did not show up in this analysis (i.e., female sex) (11), in general, these ndings are consistent with previous inpatient studies of acute coronary
syndromes. The most powerful predictor of major
bleeding in CAD patients in stable condition is use
of vitamin K antagonists (hazard ratio of 4.7 compared with patients who do not require oral anticoagulation). The CORONOR registry suggests that
warfarin does not confer a bleeding risk; rather, the

*Editorials published in the Journal of the American College of Cardiology

combination of antiplatelet therapy with warfarin is

reect the views of the authors and do not necessarily represent the

the only antithrombotic regimen that independently

views of JACC or the American College of Cardiology.

From the Division of Cardiology, University of Vermont College of Medicine, Burlington, Vermont. Dr. Dauerman is a consultant for Medtronic

predicts bleeding (8). Importantly, continuing aspirin

with warfarin does not demonstrate ischemic benet

Inc. and The Medicines Company; and has received research grants from

(8). As shown in Table 1, at least 4 studies seem to

Abbott Vascular and Medtronic Inc.

provide a clear message (57,12): stop worrying

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Dauerman

JACC VOL. 64, NO. 14, 2014

OCTOBER 7, 2014:143740

Aspirin in Stable Coronary Disease

T A B L E 1 Addressing the Risk of Aspirin Combined With Oral Anticoagulation

Study
Sample Size
Enrollment Dates

Aspirin Impact on
Ischemic Outcomes

Study Design

Primary Patient Population

CORONOR Registry
(N 4,184)
20102011

Broadly inclusive
European multicenter
site-based registry

Stable CAD: at least 12 months

post-MI or postrevascularization;
11% on VKA

None
VKA APT vs. VKA alone:
Adjusted HR: 1.15
(95% CI: 0.582.27)

High risk
Adjusted HR: 7.9 (95% CI: 3.913.6)
compared with aspirin without VKA

Aspirin Impact on Bleeding

Danish National Registry

(N 8,700)
20022011

National European
multicenter sitebased registry

Stable CAD with AF

At least 12 months posthospitalization for PCI,
MI, or ACS
37% on VKA
Drug-eluting stents: undened

None
VKA APT vs. VKA alone:
HR: 1.12 (95% CI: 0.941.34)

High risk
HR: 1.50 (95% CI: 1.231.82) comparing
aspirin VKA vs. VKA alone

ORBIT AF Registry
(N 7,347)
20102011

Broadly inclusive U.S.

multicenter sitebased registry

AF on OAC;
<10% drug-eluting stents;
<50% with CAD

None
MI: w0.4% in both groups

High risk
Adjusted HR: 1.53 (95% CI: 1.201.96)
compared with OAC alone

WOEST Trial
(N 573)
20082011

Randomized European
multicenter
clinical trial

Elective and urgent coronary

intervention: randomized
to aspirin, clopidogrel, VKA
vs. clopidogrel and VKA

None
Stent thrombosis
1.4 vs. 3.2%; p 0.17

High risk
19% for clopidogrel and VKA vs. 44% for
aspirin, clopidogrel and VKA (HR 0.36;
95% CI: 0.260.50; p < 0.0001)

ACS acute coronary syndrome(s); AF atrial brillation; APT antiplatelet therapy; CAD coronary artery disease; CI condence interval; HR hazard ratio; MI myocardial infarction;
OAC oral anticoagulant therapy; PCI percutaneous coronary intervention; VKA vitamin K antagonist.

about platelet inhibition in patients with CAD who

to form rm conclusions. Some studies focus on

are taking oral anticoagulant agents.

the early pathophysiological response after coronary

THE ASSAULT ON ASPIRIN IN CONJUNCTION WITH

revascularization or

ORAL ANTICOAGULANT AGENTS. The indications

(12,15). Can the WOEST trial really show that one

for and benet of oral anticoagulation are clear and

antithrombotic regimen is noninferior to another

consistent across a broad spectrum of patients with

regimen with respect to stent thrombosis in 536 ran-

atrial brillation who are at moderate to high risk of

domized patients (12)? If so, then why did the DAPT

embolic events (13,14). Recent guideline statements

(Dual Antiplatelet Therapy) trial require >20,000 pa-

support the conclusions of the CORONOR registry: the

tients to demonstrate the risk associated with

coexistence of atrial brillation with CAD is neither

different durations of oral antiplatelet therapy after

an excuse for stopping oral anticoagulation, nor an

stenting (16)? It seems implausible that the WOEST

indication for continuing antiplatelet therapy. An

trial can claim it is safe to halt aspirin therapy early

example from the 2006 American College of Cardio-

after a revascularization procedure.

acute myocardial infarction

logy/American Heart Association Atrial Fibrillation

The CORONOR registry provides valuable insight

management guidelines states, For most patients

into the bleeding risk of patients who continue

with atrial brillation who have stable CAD, warfarin

aspirin with vitamin K antagonists; like WOEST, the

alone (target INR 2.0-3.0) should provide satisfactory

power to analyze infrequent events (i.e., stent

antithrombotic prophylaxis against both cerebral and

thrombosis) may be limited. In CORONOR, <500 pa-

myocardial ischemic events (14). More recently, the

tients who had an indication for oral anticoagulation

WOEST (What is the Optimal Antiplatelet and Anti-

were studied. The 95% condence intervals for pre-

coagulant Therapy in Patients with Oral Anti-

dicting the excess hazard ratio of ischemic events

coagulation and Coronary Stenting) trial suggested

associated with aspirin cessation in this relatively

that even the foundational principle of dual anti-

small group of patients was necessarily wide (0.58 to

platelet therapy after implanting a drug-eluting stent

2.27). Thus, even if it could be argued that multivar-

is wrong; the combination of clopidogrel and warfarin

iable analysis controls for the differences between

does not increase the risk of ischemic events and

patients getting aspirin and those who are not, the

lessens the risk of major bleeding dramatically (12).

strong conclusions applied to clinical practice should

Although there is a broad chorus of guidelines,

be cautioned by the small sample size. A Danish reg-

registries, and trial data that all say the same thing,

istry also concluded that aspirin should be dis-

this entire area may be less clear than these strong

continued in patients with stable CAD on oral

concluding statements. Table 1 looks uniformly con-

anticoagulant agents (5); like CORONER, this registry

clusive, but closer inspection highlights two striking

was a large (N 8,700) multicenter trial, and appro-

limitations: heterogeneity of focus and lack of power

priate multivariable analyses were performed to try to

Dauerman

JACC VOL. 64, NO. 14, 2014

OCTOBER 7, 2014:143740

Aspirin in Stable Coronary Disease

control for differences in patients on aspirin versus

may seem obvious, but ORBIT AF demonstrated

patients off aspirin. However, the strong conclusion

that nearly 40% of patients who received a com-

was at odds with the clinical practice of the majority

bination of aspirin and oral anticoagulant agents

of the Danish population sampled; of the 8,700 pa-

had no evidence of CAD. Stop the aspirin in these

tients with stable CAD and atrial brillation, only

patients.

11% received the recommended regimen of warfarin

2. CORONOR showed that the risk of major bleeding

alone. Perhaps 90% of clinicians are practicing in-

in patients with stable CAD was lower than that

correctly; perhaps, there are uncontrolled for con-

seen in the inpatient setting, and that the bleeding

founders (i.e., clinicians continue aspirin in patients

was primarily gastrointestinal in nature. In pa-

with drug-eluting stents or more extensive CAD) that

tients with a history of gastrointestinal bleeding

might explain this variance in practice and its asso-

and CAD, increased vigilance and prophylactic

ciated risks.

measures are warranted. If a patient with atrial

Other atrial brillation registries also provide

brillation and stable CAD is at high risk for

similar conclusions: aspirin cessation is not an

gastrointestinal bleeding, aspirin cessation, rather

ischemic risk, but it can cause major bleeding in the

than warfarin cessation, may be recommended.

setting of oral anticoagulation. As shown in Table 1,

3. In patients with acute and stable CAD who have

the ORBIT AF (Outcomes Registry for Better Infor-

undergone revascularization with coronary stents,

med Treatment of Atrial Fibrillation) study was a

it is certain that continuing aspirin increases the

large registry of outpatients in stable condition with

bleeding risk in patients who require oral anti-

chronic atrial brillation that suggested that myo-

coagulation. However, there are no adequately

cardial infarction is rare and similar (0.4% per year) in

powered trials or large dedicated registries to

patients treated with aspirin or in patients who

answer the question of whether aspirin cessation is

stopped aspirin and are now on oral anticoagulant

safe in this particular group.

agents (7). However, the focus was not on CAD

patients

in

stable

conditionrather,

the

focus

was atrial brillation patientsthe stable CAD population was a subgroup analysis of the study. Importantly, <10% of patients in this study had previous
drug-eluting stents. The total population of patients
with previous drug-eluting stents who received oral
anticoagulation in ORBIT AF was 115 patients. Unfortunately, it was hard to provide rm guidance for
clinical decision-making from an underpowered subgroup analyses of observational studies.

Thus, tomorrow in clinic, I will continue to give a

platelet activation inhibitor, aspirin 81 mg/day, to
many of my patients in stable condition with CAD
and atrial brillation; this will be especially true for
those patients who have rst-generation drug-eluting
stents, who had platelet activation leading to very
late stent thrombosis which is a rare, but devastating
risk (17). In selected CAD patients in stable condition
with atrial brillation identied by CORONOR as at
high risk for bleeding, these registry observations will
be heeded: stop the aspirin, continue the warfarin,

ASPIRIN AND THE ART OF STABLE CAD MAIN-

and use the art of clinical medicine to guide decisions

TENANCE. The absence of clear data does not pro-

where clear information remains wanting.

vide

any

relief

from

clinical

decision-making.

CORONOR, ORBIT AF, and other registry studies have

provided some actionable messages:

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

Harold L. Dauerman, Division of Cardiology, McClure

1. There is no evidence that inhibition of platelet

1, Fletcher Allen Health Care, University of Vermont,

activation provides anything but harm in patients

111 Colchester Avenue, Burlington, Vermont 05401.

with atrial brillation who do not have CAD. This

E-mail: harold.dauerman@vtmednet.org.

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KEY WORDS aspirin, bleeding,

coronary artery disease