CLINICAL RESEARCH STUDY

Impact of Aspirin According to Type of Stable

Coronary Artery Disease: Insights from a Large
International Cohort
Anthony A. Bavry, MD, MPH,a,b Yan Gong, PhD,c Eileen M. Handberg, PhD,b Rhonda M. Cooper-DeHoff, PharmD, MS,b,c
Carl J. Pepine, MDb
a
North Florida/South Georgia Veterans Health System, Gainesville, Fla; bCollege of Medicine and cCollege of Pharmacy, University of
Florida, Gainesville.

ABSTRACT

BACKGROUND: Aspirin is recommended in stable coronary artery disease based on myocardial infarction
and stroke studies. However, benefit among stable coronary artery disease patients who have not suffered an
acute ischemic event is uncertain. The objective of this study was to evaluate the impact of aspirin in stable
coronary artery disease. We hypothesized that aspirin’s benefit would be attenuated among individuals with
stable coronary artery disease but no prior ischemic event.
METHODS: An observational study was conducted from the INternational VErapamil-SR/Trandolapril
STudy cohort. Ambulatory patients
50 years of age with clinically stable coronary artery disease
requiring antihypertensive drug therapy (n ¼ 22,576) were classified “ischemic” if they had a history of
unstable angina, myocardial infarction, transient ischemic attack, or stroke at the baseline visit. All others
were classified “non-ischemic.” Aspirin use was updated at each clinic visit and considered as a time-
varying covariate in a Cox regression model. The primary outcome was first occurrence of all-cause
mortality, myocardial infarction, or stroke.
RESULTS: At baseline, 56.7% of all participants used aspirin, which increased to 69.3% at study close
out. Among the “non-ischemic” group (n ¼ 13,091), aspirin was not associated with a reduction in risk
(hazard ratio [HR] 1.11; 95% confidence interval [CI], 0.97-1.28; P ¼ .13); however, among the
“ischemic” group (n ¼ 9485), aspirin was associated with a reduction in risk (HR 0.87; 95% CI,
0.77-0.99; P ¼ .033).
CONCLUSIONS: In patients with stable coronary artery disease and hypertension, aspirin use was associated
with reduced risk for adverse cardiovascular outcomes among those with prior ischemic events. Among
patients with no prior ischemic events, aspirin use was not associated with a reduction in risk.
Published by Elsevier Inc.  The American Journal of Medicine (2015) 128, 137-143

KEYWORDS: Adverse cardiovascular events; Aspirin; Coronary artery disease; Ischemic heart disease

Aspirin is used by approximately one-third of the United
States population (over 50 million individuals), including
over 80% of those with known cardiovascular disease,
which makes this a medication of significant public health
importance.1 Aspirin is widely recommended for patients
Funding: See last page of article.
Conflict of Interest: See last page of article.
Authorship: See last page of article.
Requests for reprints should be addressed to Anthony A. Bavry, MD,
MPH, North Florida/South Georgia Veterans Health System, 1600 SW
Archer Rd., PO Box 100277, Gainesville, FL 32610-0277.
E-mail address: Anthony.bavry@va.gov
with stable coronary artery disease.2-5 This recommendation
includes patients with hypertension and previous cardio-
vascular events.6
Aspirin has been documented to be beneficial in red-
uction of cardiovascular outcomes after coronary ischemic
events (unstable angina/myocardial infarction) and cere-
brovascular ischemic events (transient ischemic attack/
stroke).7-9 Moreover, a large meta-analysis of secondary
prevention studies documented the absolute reduction
in cardiovascular outcomes to be greater than the absolute
excess in major bleeds.10 However, it is important to
note that stable coronary artery disease is a broad spectrum

0002-9343/$ -see front matter Published by Elsevier Inc.

http://dx.doi.org/10.1016/j.amjmed.2014.09.028
138 The American Journal of Medicine, Vol 128, No 2, February 2015

of disease that also includes patients with no prior ischemic difference in hypertension control or outcomes between
events. Such a patient might have stable angina symp- treatment strategies.15
toms with or without percutaneous or surgical Coronary artery disease was defined as prior documented
revascularization. myocardial infarction, abnormal coronary angiogram
With the frequent use of coronary angiogram (and (
50% stenosis in at least one major coronary artery),
cardiac computed tomography), many patients with signs concordant abnormalities on 2 different types of cardiac
and symptoms of ischemia are tests (electrocardiogram, echocar-
diagnosed with nonobstructive diogram, or myocardial perfusion
coronary artery disease that does CLINICAL SIGNIFICANCE study), or classic angina pectoris.
not require revascularization.11  In a large observational study, we found Patients were excluded for current
For such patients, aspirin is still that some individuals with stable coro- unstable angina; coronary revas-
recommended, although there is a cularization, or stroke within the
nary artery disease do not derive appre-
relative paucity of data to guide last month; myocardial infarction
ciable benefit from aspirin.
this recommendation.2,3 There- within the last 3 months; beta-
fore, the aim of this study was to  Among those with no prior ischemic blocker use within the last 2
investigate the association be- event, aspirin use was not associated weeks or within 12 months of a
tween aspirin and adverse cardio- with a reduction in adverse cardiovas- myocardial infarction; sinus bra-
vascular events among 2 groups cular events, but was associated with an dycardia, sick sinus syndrome or
of hypertensive patients with sta- increase in strokes. type 2 or 3 heart block without
ble coronary artery diseaseeprior permanent pacemaker, Wolff-
ischemic events vs no prior  Among those with prior ischemic events, Parkinson-White syndrome, ven-
ischemic events. We utilized aspirin was associated with a reduction tricular tachycardia, or other
the INternational VErapamil-SR/ in adverse cardiovascular events and all- serious arrhythmias; decompen-
Trandolapril STudy (INVEST) cause mortality. sated heart failure (New York
cohort where aspirin use was left Heart Association class IV); renal
to provider discretion to test our or hepatic dysfunction; contrain-
hypothesis that the magnitude of benefit for aspirin would dication to study medication; or limited life expectancy.
be attenuated among stable coronary artery disease patients Participants were classified into “ischemic”/“non-ischemic”
with no prior ischemic event. sub-groups at the baseline visit according to history of
unstable angina, myocardial infarction, transient ischemic
METHODS attack, or stroke.

Study Cohort
Details about the INVEST protocol and outcomes
have been published elsewhere (clinicaltrials.gov
NCT00133692).12,13 Briefly, INVEST was an inter-
national randomized trial that compared the effects of a
calcium antagonist (verapamil SR)-based strategy with
a beta-blocker (atenolol)-based strategy for treatment of
hypertension among 22,576 patients at least 50 years
of age with clinically stable coronary artery disease.
Enrollment began September 1997, and follow-up was
completed in February 2003. The study was conducted
according to the principles of the Declaration of Helsinki.
Local institutional review boards and ethics committees
approved the protocol, and written informed consent was
obtained from all subjects. Target blood pressure
was <140/90 mm Hg (<130/85 mm Hg in the presence
of diabetes or chronic kidney disease).14 Trandolapril
or hydrochlorothiazide, or both, could be added as
necessary to achieve target blood pressure. Because
INVEST was a large, international, contemporary trial
with good blood pressure control, this was considered
an excellent database to study the effectiveness of aspirin
among individuals with hypertension and stable co-
ronary artery disease. The entire INVEST cohort was
considered for this analysis because there was no
Exposure/Outcomes
Protocol-scheduled follow-up visits occurred every
6 weeks for the first 6 months (visits 2 to 5), then twice
per year until 2 years after the last patient was enrolled.
At the baseline visit and each postbaseline visit, a medi-
cation inventory was obtained. The use of aspirin was
queried separately from nonaspirin nonsteroidal anti-
inflammatory drugs. The primary study outcome was the
first occurrence of all-cause mortality, nonfatal myocardial
infarction, or nonfatal stroke. Secondary outcomes were
the composite of cardiovascular death, nonfatal myocar-
dial infarction, or nonfatal stroke, and individual com-
ponents of all-cause mortality, cardiovascular mortality,
nonfatal myocardial infarction, nonfatal stroke, or
bleeding. Outcomes were adjudicated by an events com-
mittee by review of pertinent patient and hospital records.
Nonfatal myocardial infarction was defined as an elevation
in cardiac enzymes (troponin I or T, or creatine-kinase
myocardial band isoenzyme) greater than the upper limit
of normal with ischemic symptoms or ischemic electro-
cardiographic changes. Nonfatal stroke was defined as a
sudden onset of a neurological deficit that persisted for at
least 24 hours and was confirmed by neurological imaging
or neurology consult.
Bavry et al Aspirin and Stable Coronary Artery Disease 139

including statistically significant covariates as suggested by

a cut-off P value of .05. The association of aspirin and
adverse cardiovascular events was reported as hazard ratio
(HR) and 95% confidence interval (CI) (SAS software,
version 9.3; SAS Institute, Inc., Cary, NC).
Baseline characteristics were reported as mean and
standard deviation or frequencies as appropriate, and
continuous and categorical variables were compared with
Student’s t test and the chi-squared test, respectively. A P
value <.05 was considered significant. No funding was
obtained for the conduct of this study.

Figure 1 Proportion of aspirin use over time among INVEST
participants. The use of aspirin increased during the course of
the study, especially among participants with no prior ischemic
event.
Statistical Methods
We performed Cox regression analyses by adjusting for
time-varying use of aspirin. Confounding was controlled by
RESULTS
At baseline, slightly more than half of all participants re-
ported use of aspirin, which increased during the course of
the study (from 56.7% at baseline to 69.3% at study close
out). Use of aspirin was less frequent among the group with
no prior ischemic event (n ¼ 5923/13,091; 45.2%)
compared with those with a prior ischemic event (n ¼ 6872/
9485; 72.5%) (Figure 1). There were many differences in
baseline characteristics between aspirin use and no aspirin
use within each group of participants. For example,
participants with no prior ischemic event and baseline use
of aspirin were older, less frequently women, less

Table 1 Baseline Patient Characteristics

No Prior Ischemic Event (n ¼ 13,091) Prior Ischemic Event (n ¼ 9485)

Aspirin at No Aspirin Aspirin at No Aspirin

Baseline at Baseline Baseline at Baseline
Characteristic (n ¼ 5923) (n ¼ 7168) P Value (n ¼ 6872) (n ¼ 2613) P Value
Age, years, mean (SD) 66.1 (9.5) 64.7 (10.0) <.0001 66.9 (9.4) 67.4 (10.1) .044
Women, % 51.4 66.8 <.0001 37.8 51.2 <.0001
Black race, % 11.5 14.9 <.0001 10.8 20.5 <.0001
BMI, kg/m2, mean (SD) 29.3 (7.2) 29.5 (5.8) .25 28.8 (8.5) 29.0 (6.1) .39
SBP, mm Hg, mean (SD) 151.3 (19.4) 150.9 (19.3) .25 150.4 (19.5) 151.0 (20.5) .24
History of, %
Myocardial infarction* 0 0 76.7 74.5 .025
Stroke/transient ischemic attack 0 0 17.0 17.7 .42
Classic angina pectoris 66.2 89.6 <.0001 48.1 53.4 <.0001
Coronary revascularization† 30.3 5.2 <.0001 49.3 23.3 <.0001
Congestive heart failure 4.6 3.0 <.0001 7.8 8.9 .099
Smoking‡ 47.5 32.2 <.0001 60.0 46.2 <.0001
Diabetes mellitus§ 28.1 25.7 .0018 31.1 29.0 .053
Hyperlipidemiak 62.8 38.6 <.0001 69.4 51.2 <.0001
Peripheral arterial disease 13.0 9.3 <.0001 14.1 11.1 .00016
Chronic kidney disease 1.8 0.7 <.0001 2.9 2.5 .31
Medications, %
NSAID 20.1 20.5 .55 13.4 16.3 .0003
Lipid-lowering agent 43.3 18.2 <.0001 53.2 29.4 <.0001
Nitrate 40.7 26.3 <.0001 44.4 29.9 <.0001
BMI ¼ body mass index; NSAID ¼ nonsteroidal anti-inflammatory drug; SBP ¼ systolic blood pressure; SD ¼ standard deviation.
*Includes unstable angina.
†Defined as coronary artery bypass grafting or percutaneous coronary intervention.
‡Defined as current or prior smoking.
§Defined as diagnosis of diabetes or use of oral hypoglycemic medications or insulin, or both.
kDefined as diagnosis of hypercholesterolemia or use of lipid-lowering medications.
140 The American Journal of Medicine, Vol 128, No 2, February 2015

Table 2 Aspirin Status during the Course of the Study

No Aspirin at Infrequent Frequent Aspirin At
Aspirin Status at Any Follow- Aspirin: >0 Aspirin:
50% Each Follow- Aspirin:
1
Ischemic Subgroup Baseline up Visit to <50% Visits to <100% Visits up Visit Visit
No prior ischemic Aspirin (n ¼ 5923) 310 (5.5%) 434 (7.7%) 1547 (27.4%) 3355 (59.4%) 5336 (90.1%)
event (n ¼ 13,091) No aspirin (n ¼ 7168) 4332 (63.5%) 1209 (17.7%) 834 (12.2%) 444 (6.5%) 2487 (34.7%)
Prior ischemic Aspirin (n ¼ 6872) 163 (2.5%) 334 (5.1%) 1766 (27.0%) 4272 (65.4%) 6372 (92.7%)
event (n ¼ 9485) No aspirin (n ¼ 2613) 999 (41.1%) 556 (22.9%) 560 (23.0%) 317 (13.0%) 1433 (54.8%)

frequently of black race, and more frequently had coronary
revascularization, congestive heart failure, smoking,
diabetes, hyperlipidemia, peripheral arterial disease, and
chronic kidney disease than nonaspirin users (Table 1).
Among those with no prior ischemic event, over 90%
reported use of aspirin during at least one clinic visit.
Aspirin classification changed over time, based on reported
use of aspirin at follow-up visits. For example, among
participants with no prior ischemic event and baseline use of
aspirin, 5.5% reported no aspirin at any follow-up visit,
7.7% reported infrequent aspirin use, 27.4% reported
frequent aspirin use, and 59.4% reported aspirin use at each
follow-up visit (Table 2).
In the “non-ischemic” group, aspirin was not associated
with reduction in risk for the primary outcome during a
mean follow-up of 2.7 years (HR 1.11; 95% CI, 0.97-1.28;
P ¼ .13) (Table 3). In the “ischemic” group, aspirin was
associated with a 13% reduction in risk for the primary
outcome (HR 0.87; 95% CI, 0.77-0.99; P ¼ .033)
(Table 4). Figure 2 explored for effect modification
among various sub-groups (mean blood pressure, treat-
ment assignment, diabetic status, and sex) on the aspirin and
adverse cardiovascular event association. Among partici-
pants with no prior ischemic event, there was no evidence
for effect modification; however, among those with a prior
ischemic event, the use of aspirin was associated with fewer
adverse cardiovascular events when coupled with a beta-
blocker, but not a calcium antagonist, strategy. The associ-
ation of aspirin and secondary outcomes is displayed in
Table 5. Among the “non-ischemic” group, the use of
aspirin was associated with an increase in incident
nonfatal stroke. Among the “ischemic” group, the use of
aspirin was associated with a reduction in all-cause
mortality.
DISCUSSION
We found that the impact of aspirin among hypertensive
individuals with stable coronary artery disease is variable
depending upon presence or absence of prior ischemic
events. Among those with no prior ischemic event, aspirin
use was not associated with a reduction in adverse cardio-
vascular events, but was associated with an increase in
strokes. Conversely, aspirin was associated with a reduction
in adverse cardiovascular events and all-cause mortality
among those with a prior coronary or cerebrovascular
ischemic event. Among ischemic participants assigned to a
beta-blocker strategy, aspirin was associated with fewer

Table 3 Cox Regression Model for Participants with No Prior Ischemic Event: Association of Aspirin Use and Adverse Cardiovascular
Outcomes
Characteristic Parameter Estimate Standard Error Chi-squared HR 95% CI P Value
Time varying aspirin use 0.11 0.07 2.25 1.11 0.97-1.28 0.13
Age 0.06 0.003 259.21 1.06 1.06-1.05 <.0001
Male sex 0.24 0.073 11.15 1.28 1.11-1.48 .0008
BMI 0.03 0.007 22.78 0.97 0.95-0.98 <.0001
SBP 0.01 0.002 38.68 1.01 1.01-1.02 <.0001
Heart rate 0.03 0.004 42.79 1.03 1.02-1.04 <.0001
CHF 0.56 0.119 22.36 1.76 1.39-2.23 <.0001
Smoking 0.46 0.073 39.18 1.58 1.37-1.83 <.0001
Diabetes 0.51 0.072 51.50 1.67 1.45-1.93 <.0001
Hyperlipidemia 0.15 0.070 4.97 0.85 0.74-0.98 .0257
PAD 0.23 0.091 6.75 1.26 1.06-1.51 .0094
CKD 0.79 0.176 20.36 2.21 1.56-3.13 <.0001
Variables not included in the final model: race, history of left ventricular hypertrophy, treatment strategy, nonsteroidal anti-inflammatory drug use, and
history of arrhythmia.
BMI ¼ body mass index; CHF ¼ congestive heart failure; CI ¼ confidence interval; CKD ¼ chronic kidney disease; HR ¼ hazard ratio; PAD ¼ peripheral
arterial disease; SBP ¼ systolic blood pressure.
Bavry et al Aspirin and Stable Coronary Artery Disease 141

Table 4 Cox Regression Model for Participants with Prior Ischemic Events: Association of Aspirin Use and Adverse Cardiovascular
Outcomes
Characteristic Parameter Estimate Standard Error Chi-squared HR 95% CI P Value
Time varying aspirin use 0.13 0.06 4.53 0.87 0.77-0.99 .033
Age 0.04 0.003 181.68 1.04 1.04-1.05 <.0001
BMI 0.01 0.006 9.73 0.98 0.97-0.99 .0018
SBP 0.00 0.002 5.32 1.01 1.00-1.01 .0210
Heart rate 0.02 0.004 34.10 1.02 1.01-1.03 <.0001
MI 0.25 0.077 10.68 1.29 1.10-1.50 .0011
Stroke/TIA 0.37 0.075 23.92 1.44 1.24-1.68 <.0001
CHF 0.65 0.084 59.93 1.92 1.62-2.26 <.0001
Smoking 0.31 0.062 24.37 1.36 1.20-1.54 <.0001
Diabetes 0.58 0.063 85.54 1.79 1.58-2.02 <.0001
Hyperlipidemia 0.17 0.062 8.19 0.83 0.74-0.94 .0042
PAD 0.23 0.077 9.50 1.26 1.09-1.47 .0020
CKD 0.38 0.126 9.13 1.46 1.14-1.87 .0025
Treatment strategy* 0.16 0.062 7.39 0.84 0.74-0.95 .0065
NSAID use 0.15 0.079 4.05 1.17 1.00-1.37 .0441
Variables not included in the final model: sex, race, history of left ventricular hypertrophy, history of arrhythmia.
BMI ¼ body mass index; CHF ¼ congestive heart failure; CI ¼ confidence interval; CKD ¼ chronic kidney disease; HR ¼ hazard ratio; MI ¼ myocardial
infarction; NSAID ¼ nonsteroidal anti-inflammatory drug; PAD ¼ peripheral arterial disease; SBP ¼ systolic blood pressure; TIA ¼ transient ischemic attack.
*Treatment strategy refers to initial assignment to beta-blocker or calcium antagonist based strategy.

adverse cardiovascular events compared with a calcium
antagonist strategy.
Among the “non-ischemic” group, aspirin was associ-
ated with a nonsignificant increase in composite adverse
events, including an 86% increase in the risk of stroke. In
part, this stroke hazard could be due to an increased risk of
hemorrhagic stroke from the use of aspirin.16 Also, the
Antithrombotic Trialists’ Collaboration documented a
harmful association between the use of aspirin and
ischemic stroke in the setting of primary prevention. This
harmful association was not apparent among low-risk in-
dividuals (ie, estimated 5-year risk of a coronary heart
disease event <2.5%), but it was among high-risk in-
dividuals (ie, estimated 5-year risk of a coronary heart
disease event >10%; P for trend ¼ .05).17 This high-risk
group may resemble the INVEST cohort that had no prior
ischemic event, because their 5-year risk of a coronary
event was approximately 13%.
Among the “ischemic” group, aspirin was associated
with a 13% relative reduction in risk for adverse cardio-
vascular events. The association between aspirin use and
reduced risk was driven by a reduction in all-cause mor-
tality, but not cardiovascular mortality. This finding is
consistent with an updated meta-analysis (included 12 pri-
mary prevention trials and 39 secondary prevention trials)
that documented a reduction in nonvascular deaths with the
use of aspirin, possibly by decreasing cancer-related
deaths.18 The beneficial effect of aspirin was not apparent
among participants assigned to a calcium antagonist strategy
compared with a beta-blocker strategy. This could be
explained by the known antiplatelet effects of calcium
antagonists.19

Figure 2 Interaction of aspirin and adverse cardiovascular events (all-cause death,

myocardial infarction, or stroke) among participant subgroups. The hazard ratio is the risk
for adverse cardiovascular events for aspirin vs no aspirin use. SBP ¼ systolic blood
pressure.
142 The American Journal of Medicine, Vol 128, No 2, February 2015

Table 5 Association of Time-varying Aspirin and Secondary Outcomes

Rate per 1000
Outcome Events (%) Patient-years HR 95% CI P Value
No prior ischemic event (n ¼ 13,091)
All-cause death, MI or stroke 980 (7.5%) 28.1 1.11 0.97-1.28 .13
All-cause death, MI, stroke, or bleeding 1040 (7.9%) 29.9 1.12 0.98-1.28 .10
CV death, MI, or stroke 597 (4.6%) 17.1 1.18 0.99-1.43 .06
All-cause mortality 775 (5.9%) 22.0 0.97 0.83-1.14 .74
CV mortality 382 (2.9%) 10.9 0.97 0.77-1.21 .76
Nonfatal MI 125 (1.0%) 3.6 1.23 0.81-1.86 .34
Nonfatal stroke 102 (0.8%) 2.9 1.86 1.22-2.83 .0039
Prior ischemic event (n ¼ 9485)
All-cause death, MI or stroke 1289 (13.6%) 49.3 0.87 0.77-0.99 .03
All-cause death, MI, stroke, or bleeding 1377 (14.5%) 53.0 0.88 0.78-0.99 .039
CV death, MI, or stroke 808 (8.5%) 30.9 1.04 0.88-1.23 .65
All-cause mortality 991 (10.5%) 37.1 0.79 0.68-0.91 .0011
CV mortality 480 (5.1%) 18.0 0.96 0.78-1.19 .74
Nonfatal MI 179 (1.9%) 6.8 1.26 0.88-1.81 .21
Nonfatal stroke 177 (1.9%) 6.7 1.05 0.75-1.48 .77
CI ¼ confidence interval; CV ¼ cardiovascular; HR ¼ hazard ratio; MI ¼ myocardial infarction.

There are multiple strengths of the current analysis. One
is the use of a large international cohort of patients with
documented coronary artery disease and multiple follow-up
visits with repeated ascertainment of aspirin use. The latter
is important because patients might temporarily stop aspirin
therapy due to intolerance or an adverse event such as a
gastrointestinal hemorrhage. In fact, there was some change
in aspirin classification, from use to disuse and vice versa,
over the course of the study. Another strength is the
excellent blood pressure control achieved in INVEST.
It is plausible that aspirin may not be helpful or may even
be harmful among stable coronary artery disease patients
with no prior ischemic events. In the Clopidogrel for High
Atherothrombotic Risk and Ischemic Stabilization, Man-
agement, and Avoidance (CHARISMA) trial, participants at
high risk for atherothrombotic events were randomized to
dual antiplatelet therapy (aspirin and clopidogrel), compared
with mono antiplatelet therapy (aspirin and placebo).20
Among asymptomatic participants, aspirin and clopidogrel
was associated with an increase in all-cause mortality
(P ¼ .04) and cardiovascular mortality (P ¼ .01).20 While
the INVEST analysis only explored aspirin monotherapy,
the CHARISMA trial supports that there are certain
subgroups of patients in whom potent antiplatelet therapy
may be harmful. It is possible that antiplatelet therapy could
result in hemorrhage into atherosclerotic plaques, and thus
result in plaque instability.
Limitations
Unfortunately, INVEST did not record stroke type (hem-
orrhagic vs ischemic) separately; however, based on
epidemiological data, the proportion of ischemic strokes is
approximately 90%.21 We attempted to examine gastroin-
testinal hemorrhage as an adverse event and a possible
reason for termination in aspirin therapy; however, there
were only 176 such events, which precluded meaningful
analysis of this outcome. The period of enrollment predates
drug-eluting stents, which are known to have a unique side-
effect profile.22 Although the use of aspirin was carefully
recorded during the study, the dose of aspirin therapy was
not captured. This is likely of minimal significance because
300 to 325 mg of aspirin has not been shown to be superior
to 75 to 100 mg of aspirin.23 Although we performed a
rigorous Cox regression analysis to account for known
confounders and controlled for the use of aspirin as a time-
varying covariate, issues of residual confounding within an
observational study remain.
CONCLUSIONS
In conclusion, among patients with stable coronary disease
and no prior ischemic event, the benefit of aspirin appears
limited. The contemporary use of aspirin in stable coronary
artery disease patients deserves further study.
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Funding: No funding was obtained for this study. The original
INVEST study was funded by a grant from BASF Pharma, Ludwigshafen,
Germany; Abbott Laboratories, Abbott Park, IL, USA, and the University
of Florida Research Foundation and Opportunity Fund. BASF Pharma and
Abbott Laboratories had no role in the design or conduct of the study,
collection or analysis of data, or preparation or approval of the manuscript.
Conflict of Interest: AAB currently receives research support from
Novartis Pharmaceuticals, Gilead, and Eli Lilly and serves as a contractor
for the American College of Cardiology’s CardioSource, and previously
served on an advisory board for Gilead and as a contractor for Boehringer
Ingelheim. RMC currently receives funding from the National Institutes of
Health (NIH), National Human Genome Research Institute (U01
HG007269); NIH, National Institute of General Medical Sciences (PEAR,
2U01 GM074492); NIH, National Heart, Lung and Blood Institute
(NHLBI) through a contract with Wake Forest University (WHI,
HHSN268201100004C); University of Florida Clinical and Translational
Science Institute (UF CTSI, Clinical Research Pilot Award); and Southeast
Center for Integrative Metabolomics, UF CTSI (Pilot and Feasibility Project
Award). EMH reported receiving grant support from NHLBI, Gilead, and
educational grants from AstraZeneca, Daiichi Sankyo, Amarin, Mesoblast,
ISIS Pharmaceuticals, Esperion Therapeutics, Vessex, Genentech, Cytori,
Daiichi-Sankyo, Medtronic, Baxter, United Therapeutics, Sanofi/Aventis,
Amgen, and Catabasis. CJP reported receiving research grants from Abbott,
Actelion Pharmaceuticals, Amarin, Amgen, Amorcyte, Angioblast/Meso-
blast, AstraZeneca, Baxter Healthcare, Brigham and Women’s Hospital,
Capricor, Inc., Catabasis Pharmaceuticals, Cytori, Daiichi Sankyo, Esperion
Therapeutics, Genentech, Gilead, GlaxoSmithKline, InfraReDx Inc., Isis
Pharmaceuticals, Lilly, Medtronic, NeoStem Inc., NIH/NHLBI, Regeneron
Pharmaceuticals, Sanofi, United Therapeutics Corp; consulting for Lilly/
Cleveland Clinic-Data Safety Monitoring Board (DSMB) member for a
Phase 2 Efficacy and safety study of Ly2484595, Mesoblast DSMB,
Servier, and SLACK Inc. CJP receives support in part from the NIH/NCRR
Clinical and Translational Science Award to the University of Florida UL1
TR000064. YG reports that she has no financial disclosures.
Authorship: All authors had access to the data and a substantive role in
writing the manuscript. AAB drafted the manuscript, performed research,
and analyzed data. All co-authors assisted in writing the manuscript, revised
it critically for important intellectual content, and approved the final version
of the manuscript and the decision to submit for publication. Additionally,
YG analyzed data; RNC designed research and analyzed data; and EMH
and CJP designed and performed research.