Comparative Effectiveness of Clopidogrel in

Medically Managed Patients With Unstable

Angina and NonST-Segment Elevation
Myocardial Infarction
Matthew D. Solomon, MD, PHD,*y Alan S. Go, MD,*yz David Shilane, PHD,y
Derek B. Boothroyd, PHD,y Thomas K. Leong, MPH,* Dhruv S. Kazi, MD, MSC, MS,zx
Tara I. Chang, MD, MS,y Mark A. Hlatky, MDy
Oakland, Stanford, and San Francisco, California
Objectives This study sought to examine the effectiveness of clopidogrel in real-world, medically managed patients with
unstable angina (UA) or nonST-segment elevation myocardial infarction (NSTEMI).
Background Although clinical trials have demonstrated the efcacy of clopidogrel to reduce cardiovascular (CV) morbidity and
mortality in medically managed patients with UA or NSTEMI, the effectiveness of clopidogrel in actual clinical
practice is less certain.
Methods A retrospective cohort study was conducted of Kaiser Permanente Northern California members without known
coronary artery disease or prior clopidogrel use who presented with UA or NSTEMI between 2003 and 2008 and
were medically managed (i.e., no percutaneous coronary intervention or coronary artery bypass grafting during
the index hospitalization or within 7 days post-discharge). Over 2 years of follow-up, we measured the association
between clopidogrel use and all-cause mortality, hospital stay for MI, and a composite endpoint of death or MI using
propensity-matched multivariable Cox analyses.
Results We identied 16,365 patients with incident UA (35%) or NSTEMI (65%); 36% of these patients were prescribed
clopidogrel within 7 days of discharge. In 8,562 propensity scorematched patients, clopidogrel users had lower
rates of all-cause mortality (8.3% vs. 13.0%; p < 0.01; adjusted hazard ratio [HR]: 0.63; 95% condence interval [CI]:
0.54 to 0.72) and the composite of death or MI (13.5% vs. 17.4%; p < 0.01; HR: 0.74, CI: 0.66 to 0.84), but not MI
alone (6.7% vs. 7.2%; p 0.30; HR: 0.93, CI: 0.78 to 1.11), compared with nonusers of clopidogrel. The association
between clopidogrel use and the composite of death or MI was signicant only among patients presenting with
NSTEMI (HR: 0.67; CI: 0.59 to 0.76; p
int
< 0.01), not among those presenting with UA (HR: 1.25; CI: 0.94 to 1.67).
Conclusions In a large, community-based cohort of patients who were medically managed after UA/NSTEMI, clopidogrel use
was associated with a lower risk of death and MI, particularly among patients with NSTEMI. (J Am Coll Cardiol
2014;63:224957) 2014 by the American College of Cardiology Foundation
In 2001, the CURE (Clopidogrel in Unstable Angina to
Prevent Recurrent Events) trial showed that dual-
antiplatelet therapy with aspirin and clopidogrel improved
outcomes among patients with unstable angina (UA) or
nonST-segment myocardial infarction (NSTEMI) (1).
Patients randomly assigned to long-term treatment with
aspirin in combination with clopidogrel had a lower rate of
the combined endpoint of CV death, nonfatal MI, or stroke
within 1 year compared with patients assigned to aspirin
alone. On the basis of the results of CURE, clopidogrel was
given a Class I recommendation in the American College of
Cardiology/American Heart Association (ACC/AHA)
guideline statements for patients treated medically after UA
or NSTEMI for 1 month and ideally up to 9 months (2).
See page 2258
From the *Division of Research, Kaiser Permanente Northern California, Oakland,
California; yStanford University School of Medicine, Stanford, California; zUniversity
of California, San Francisco, San Francisco, California; and the xSan Francisco
General Hospital, San Francisco California. This work is supported by grant
0875162N from the American Heart Association, Dallas, Texas. Dr. Go is the
recipient of a research grant from Genentech. All other authors have reported that
they have no relationships relevant to the contents of this paper to disclose.
Deepak L. Bhatt, MD, MPH, served as Guest Editor for this paper.
Manuscript received September 26, 2013; revised manuscript received January 24,
2014, accepted February 5, 2014.
Journal of the American College of Cardiology Vol. 63, No. 21, 2014
2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2014.02.586
Most patients in CURE were
medically managed (only one-
fth initially underwent revascu-
larization procedures), and the
rate of subsequent revasculariza-
tion during the rst 12 months
was low (15% in the clopidogrel
arm of the study and 14% in
the aspirin arm). Although clo-
pidogrel therapy led to similar
risk reductions in patients who
were medically managed or who
underwent revascularization, the
role of clopidogrel in percutane-
ous coronary intervention (PCI)
has received more attention, both
periprocedurally (311) and post-
PCI (12). Perhaps as a result,
rates of clopidogrel use after PCI
are extremely high (13). In
contrast, 50% to 60% of patients with UA or NSTEMI in
clinical practice are medically managed (i.e., do not undergo
revascularization during the index hospital stay) (1416). In
addition, clopidogrel use in medically managed patients with
UA or NSTEMI remains low; less than one-half of medically
managed patients with UA or NSTEMI will receive clopi-
dogrel on discharge (13,1719). Further, the impact of clo-
pidogrel among medically managed patients with UA or
NSTEMI who are treated outside a clinical trial remains
unclear. We therefore examined the effectiveness of clopi-
dogrel in a real-world, community-based cohort of patients
who were medically managed after hospital discharge for UA
or NSTEMI.
Methods
This study was approved by the Institutional Review Boards
of the Kaiser Foundation Research Institute (Oakland,
California) and of Stanford University (Stanford, Califor-
nia). Waiver of informed consent was obtained because of
the nature of the study.
Source population. The source population was from
Kaiser Permanente Northern California, a large, inte-
grated healthcare delivery system that provides care to
>3.2 million individuals in San Francisco and the greater
Bay Area. The health plan membership is broadly repre-
sentative of the local and statewide population, apart from
slightly lower representation at the extremes of age and
income.
Study population. We assembled an incident disease
cohort by rst identifying all adult (age >30 years) members
hospitalized for an initial episode of UA or NSTEMI be-
tween January 1, 2003 and December 31, 2007. UA was
dened by a primary hospital discharge diagnosis (Interna-
tional Classication of Diseases-Ninth Edition) of 411.x or
a combination of a primary discharge diagnosis code of
414.0 and a secondary discharge diagnosis of 411.x for the
same hospital stay. NSTEMI was dened by a primary
diagnosis code of 410.7, 410.8, or 410.9. To ensure an
incident disease cohort, we excluded any patients with earlier
diagnoses of UA, NSTEMI, ST-segment elevation myo-
cardial infarction (STEMI), coronary artery bypass grafting
(CABG), or PCI for at least the previous 12 months,
although most patients had a much longer (>12 months)
lookback period for these diagnoses and procedures.
We dened the index date for this analysis as 7 days after
hospital discharge, to allow subjects the opportunity to ll a
clopidogrel prescription after hospital stay. To identify medi-
cally managed patients, we excluded patients who received any
coronary revascularization procedures (CABG or PCI) during
their initial hospital stay or within 7 days of hospital discharge.
Patients with any clinical event, including UA, MI, or death,
within the rst 7 days post-discharge were also excluded. We
adopted a new-user design (20) by excluding patients who
had used clopidogrel in the 120 days before developing UA or
NSTEMI. To match the eligibility criteria of the CURE
study, we also excluded patients with an earlier history of
stroke or transient ischemic attack (TIA), as well as patients
taking warfarin or those with uncontrolled hypertension
(systolic blood pressure >180 mm Hg) at baseline. We also
excluded patients with a history of maintenance dialysis or
organ transplantation.
Covariates and exposure of interest. We dened clopi-
dogrel users as patients who lled a prescription within
7 days post-discharge. To mimic an intention-to-treat
design, we dened nonusers as patients who never started
clopidogrel or who did so after the rst 7 days of follow-up,
and we did not allow patients to cross over into the clopi-
dogrel arm of the study. To capture complete data on de-
mographic characteristics, comorbidities, and medication
use, we restricted the analysis to patients with complete
demographic data and at least 12 months of continuous
membership and continuous pharmacy benet before the
index date.
We obtained data on age, sex, and self-reported race or
ethnicity from health plan databases. We identied co-
morbid conditions up to 4 years before the index date by
using previously validated approaches using diagnosis and
procedure codes and current procedural terminology codes
recorded in health plan hospital stay, ambulatory, laboratory,
and pharmacy databases for the following comorbidities:
a history of heart failure, peripheral arterial disease, valvular
heart disease, diabetes mellitus, hypertension, dyslipidemia,
or bleeding during hospital stay (2127). We used pharmacy
data to identify post-discharge use of angiotensin-converting
enzyme inhibitors or angiotensin receptor blockers, beta-
blockers, and statins. We also included indicator variables
for the year of the index date to control for secular trends, an
indicator for the type of presenting event (UA or NSTEMI),
and an indicator for patients in the group that had not
received clopidogrel who underwent PCI between days 7
and 14 and who subsequently started taking clopidogrel.
Abbreviations
and Acronyms
ACS = acute coronary
syndrome (s)
CABG = coronary artery
bypass grafting
CAD = coronary artery
disease
CV = cardiovascular
MI = myocardial infarction
NSTEMI = nonST-segment
elevation myocardial
infarction
PCI = percutaneous coronary
intervention
PPI = proton pump inhibitor
TIA = transient ischemic
attack
UA = unstable angina
Solomon et al. JACC Vol. 63, No. 21, 2014
Clopidogrel in Unstable Angina or NSTEMI June 3, 2014:224957
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Outcomes. We examined a composite outcome of all-cause
mortality and acute myocardial infarction (MI) requiring
hospital stay during the 2 years after discharge, as well as the
individual endpoints of death and MI. All-cause mortality
was identied from health plan databases, supplemented by
linkage with Social Security Administration vital status les
and California state death certicate records. MI was
dened as a hospital admission with a primary diagnosis
code of 410.x1.
Propensity score matching. We used propensity score
matching to control selection bias and to create demo-
graphically and clinically comparable cohorts (28). The
propensity score for use of clopidogrel within 7 days was
developed on the basis of the following variables: age; race
or ethnicity; sex; year of index date; type of presenting event
(UA or NSTEMI); smoking status; estimated glomerular
ltration rate; systolic blood pressure; a history of bleeding,
heart failure, hypertension, hyperlipidemia, or diabetes;
and the use of angiotensin-converting enzyme inhibitors,
angiotensin receptor blockers, beta-blockers, or statins. Pa-
tients in the clopidogrel-treated cohort were matched with
the group that had not received clopidogrel in a 1:1 ratio
by using a modied greedy matching algorithm without
replacement, on the basis of propensity scores within 1%.
Statistical analysis. We conducted the analysis in an
intention-to-treat framework (i.e., not an on-treatment
analysis because we did not allow crossover between study
arms after 7 days post-discharge). We compared means of
baseline characteristics by using 2-sided Student t tests. We
used Kaplan-Meier estimators to describe survival functions
for the selected outcomes and multivariable Cox regression
analysis to test the association of clopidogrel use with
outcomes, after adjustment for the covariates described earlier.
We conducted analyses on unadjusted and propensity-
matched models and performed sensitivity analyses, and we
examined interaction effects (p
int
) between outcomes and the
type of initial presentation (UA or NSTEMI) and several
patient subgroups (history of diabetes, history of smoking, and
older age). Sensitivity analyses were performed as follows: by
varying the time window after discharge that dened clopi-
dogrel use; by including patients who were excluded by our
eligibility criteria (patients using warfarin at baseline, dialysis
recipients, patients with very high blood pressure, and patients
withanearlier stroke or TIA); and, to examine whether proton
pump inhibitor (PPI) use modies the effect of clopidogrel in
this population, by restricting analyses to those patients who
lled baseline prescriptions for PPIs in both the clopidogrel
user group and the nonuser group. All analyses were per-
formed with the R statistical package, version 2.15.3 (R
Development Team, Vienna, Austria).
Results
We identied 39,455 patients 30 years of age or older with
incident disease between 2003 and 2008. After applying the
exclusion criteria, the analysis sample included 16,365
eligible patients, 5,961 (36%) of whom lled a prescription
for clopidogrel with the rst 7 days after discharge (Fig. 1).
In the overall study population, patients who used clopi-
dogrel were younger and more likely to be male and to
smoke, but they were otherwise healthier with fewer
comorbidities (Table 1). Use of CV medications before the
incident event was lower among clopidogrel users (see
Table 1), but after hospital discharge, CV drug use was
Figure 1 Cohort Assembly
Final cohort derivation for clopidogrel users and nonusers after the application of study eligibility criteria. CABG coronary artery bypass grafting; CHD coronary heart disease;
D/C discharge; HTN hypertension; MI myocardial infarction; NSTEMI nonST-segment elevation myocardial infarction; PCI percutaneous coronary intervention;
SBP systolic blood pressure; STEMI ST-segment elevation myocardial infarction, TIA transient ischemic attack; UA unstable angina.
JACC Vol. 63, No. 21, 2014 Solomon et al.
June 3, 2014:224957 Clopidogrel in Unstable Angina or NSTEMI
2251
higher among clopidogrel users (Table 1). Mean length of
follow-up was 976 days for clopidogrel users and 876 days
for clopidogrel nonusers. Median and mean duration of
continuous clopidogrel use among users was 188 days
(interquartile range: 82 to 603 days) and 206 days, respec-
tively. Most (97%) clopidogrel users lled their prescriptions
on the day of discharge.
Patients who did not ll a prescription for clopidogrel
within 7 days of discharge from the index hospital stay had
a low rate of subsequent initiation of clopidogrel: of the
10,404 initial nonusers, 3.4% initiated clopidogrel between
7 and 30 days after discharge, and another 7.4% initiated
clopidogrel after 30 days post-discharge. More than one-
third (38%) of the patients who initiated clopidogrel
more than 7 days after discharge (332 of 859) did so after
subsequent PCIs, most of which occurred well after
discharge (24% between days 7 and 30, 58% between 30
and 365 days, and 18% between 1 and 2 years post-
discharge).
The c-statistic for the propensity score model for pre-
dicting clopidogrel use within 7 days after discharge was
0.72. We matched 72% of clopidogrel users (4,281 of 5,961)
with nonusers (1:1 match) within 1% (2 decimal places)
of propensity score; 97% of pairs were matched within 0.1%
(3 decimal places). Baseline covariates were well balanced
in the matched cohort (see Table 1), and there were no
statistically signicant differences among measured cova-
riates for clopidogrel users and nonusers.
In unadjusted analyses, the composite endpoint of all-
cause mortality and MI requiring hospital stay over 2-years
of follow-up was lower in patients receiving clopidogrel in
both the overall population and in the propensity score
Table 1 Characteristics of Study Population
Unmatched Propensity-Matched
Clopidogrel
(n 5,961)
No Clopidogrel
(n 10,404) p Value
Clopidogrel
(n 4,281)
No Clopidogrel
(n 4,281) p Value
Presentation
UA, % 31.7 36.8 d 36.0 36.2 d
NSTEMI, % 68.3 63.2 <0.01 64.0 63.8 0.84
Demographics
Age (mean), yrs 65.8 70.5 <0.01 68.1 68.0 0.64
Male, % 66.3 53.1 <0.01 60.1 61.0 0.36
White race, % 73.0 73.4 0.56 73.1 73.3 0.83
Comorbidities
Smoker, % 33.1 30.7 <0.01 31.6 31.9 0.75
Heart failure, % 4.9 11.6 <0.01 6.7 7.6 0.12
Bleeding, % 1.7 3.6 <0.01 2.2 2.1 0.83
HTN, % 58.9 65.2 <0.01 64.1 64.4 0.80
Diabetes, % 28.4 32.1 <0.01 32.1 31.7 0.69
Hyperlipidemia,% 84.3 80.0 <0.01 84.6 84.7 0.93
Patient characteristics
eGFR >90, % 7.2 6.1
<0.01
6.9 6.0
0.29
eGFR 6090, % 36.7 31.8 35.9 34.7
eGFR 4560, % 17.7 20.4 20.0 19.9
eGFR 3045, % 9.3 14.6 11.9 12.0
eGFR 1530, % 3.0 6.0 3.9 4.1
eGFR <15, % 0.4 1.0 0.5 0.7
eGFR, unknown, % 25.7 20.1 20.9 22.6
SBP <120, % 20.1 23.9
<0.01
22.0 22.8
0.75
SBP 120130, % 16.5 16.3 16.7 16.6
SBP 130140, % 24.5 22.8 24.1 23.5
SBP 140160, % 20.1 19.2 19.6 19.5
SBP 160180, % 6.1 6.6 6.7 6.1
SBP 180, % 0.0 0.0 0.0 0.0
SBP, unknown, % 12.7 11.2 11.0 11.5
Rx use after event*
Statin, % 90.8 70.4 <0.01 87.2 86.9 0.68
ACEI/ARB, % 74.7 58.0 <0.01 68.9 69.6 0.47
Beta-blocker, % 91.6 74.8 <0.01 88.7 88.3 0.57
PPI, % 20.3 23.1 <0.01 21.7 22.9 0.19
*Prior Rx or started within 7 days of discharge.
ACEI angiotensin converting enzyme inhibitor; ARB angiotensin receptor blocker; eGFR estimated glomerular ltration rate; HTN
hypertension; NSTEMI nonST-segment elevation myocardial infarction; PPI proton pump inhibitor; Rx treatment; SBP systolic blood
pressure; UA unstable angina.
Solomon et al. JACC Vol. 63, No. 21, 2014
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matched cohort (Fig. 2). In the propensity-matched cohort,
the composite of death or MI was lower among clopidogrel
users (13.5% vs. 17.4%; p < 0.01; adjusted hazard ratio
[HR]: 0.74, 95% condence interval [CI]: 0.66 to 0.84)
(Fig. 3). All-cause mortality over 2 years was also lower
for clopidogrel users (8.3% vs. 13.0%; p<0.01; HR: 0.63,
CI: 0.54 to 0.72), but the rate of acute MI was not signif-
icantly different (6.7% vs. 7.2%; p 0.30; HR: 0.93; CI:
0.78 to 1.11).
There was evidence of treatment effect modication by
clinical presentation (NSTEMI vs. UA) and by a history of
smoking, but not by a history of diabetes. The impact of
older age yielded mixed results, with a signicant interaction
for the composite of death and MI, but not for the indi-
vidual endpoint of all-cause mortality (Figs. 3 and 4).
Compared with patients who presented with UA, patients
who presented with NSTEMI had a stronger association
of clopidogrel use with the composite of death or MI (HR:
0.67 vs. 1.25; p
int
< 0.01), as well as with the individual
endpoints of mortality (HR: 0.56 vs. 1.20; p
int
< 0.01), and
acute MI (0.84 vs. 1.38; p
int
0.03).
The association of clopidogrel with the composite of
death or MI was similar, however, among patients with and
without diabetes (HR: 0.83 vs. 0.69; p
int
0.14), but it was
stronger among patients more than 70 years of age (HR:
0.70 vs. 0.88; p
int
0.04), as well as among nonsmokers
(HR: 0.69 vs. 0.86; p
int
0.02). Results were similar for the
individual endpoint of all-cause mortality, although the
interaction between older age and clopidogrel use was not
signicant (Fig. 4).
Results were not materially changed in sensitivity analyses
that dened clopidogrel use as any prescription lled within
30 days, that included subjects excluded by our eligibility
criteria (i.e., patients taking warfarin, or undergoing dialysis,
or with very high blood pressure, or with an earlier stroke or
TIA), and that restricted the analysis to patients taking PPIs
at baseline (data not shown).
Discussion
In our analysis of a large, community-based cohort of medi-
cally managed patients with UA or NSTEMI, initiation of
Figure 2 Kaplan-Meier Curves for All-Cause Mortality and Acute MI
Unadjusted Kaplan-Meier estimates for all-cause mortality and acute myocardial infarction (MI) for clopidogrel users and nonusers.
JACC Vol. 63, No. 21, 2014 Solomon et al.
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2253
clopidogrel within the rst week after hospital discharge was
associated with a lower risk of the composite outcome of
death or MI over 2 years of follow-up. The association be-
tween clopidogrel use and outcomes was signicantly greater
among patients who presented with NSTEMI, among
nonsmokers, and among older patients.
The reduction in the composite endpoint of death and MI
replicates, in a real-world cohort, the ndings of the land-
mark CURE trial. Indeed, the HR for the composite pri-
mary outcome in CURE (HR: 0.80) was similar to the HR
for the composite outcome of death or MI in our study (HR:
0.74). In CURE, as well as in CRUSADE, early adminis-
tration of clopidogrel was associated with a signicant
improvement of in-hospital and 1-year outcomes (1,18).
Our study demonstrates that long-term outcomes are also
improved for survivors of coronary events requiring hospital
stay and further supports the use of clopidogrel in medically
managed patients with acute coronary syndrome (ACS).
Although signicant advances in antiplatelet therapy have
occurred, the use of these agents would not have affected
patient selection in our study because these agents were
approved for use after our study period.
Interestingly, clopidogrel use did not reduce the risk of
MI requiring hospital stay in this study cohort. These results
differ from those of the CURE trial (1), in which clopidogrel
use was associated with a reduction in the composite
endpoint of CV death, nonfatal MI, and stroke, but among
individual endpoints, clopidogrel use reduced the risk of MI
(notably, only Q-wave MIs), but not CV mortality. These
differences in individual endpoints may be chance ndings,
may represent secular trends in outcomes for patients with
UA or NSTEMI unrelated to antiplatelet therapy, or may be
the result of important differences in study design between
the CURE trial and our study.
First, ours was a retrospective study of administrative and
clinical data from a real-world cohort, not a prospective
randomized controlled trial. Real-world observational data
can be analyzed reliably by applying design and analytic
techniques such as new-user design, restriction of the pop-
ulation to trial-eligible patients, propensity score matching,
and multivariable adjustment; nevertheless, these techniques
may not entirely eliminate selection bias. However, a key
strength of observational research is its ability to examine
more diverse populations and to generalize trial ndings to
real-world patients and practice settings.
Another important distinction between our study and
CURE is the denition of study endpoints. We do not have
data on the cause of death (e.g., CV mortality), and the MI
endpoint in our study was a mixture of fatal and nonfatal
events. Patients who died out of hospital of an MI were
coded as a death, not an MI, in our data. Thus, a strict
comparison of the MI endpoint between CURE and our
study is not feasible. Patients taking clopidogrel in our study
may have been less likely to suffer fatal, out-of-hospital MIs,
thus leading to fewer deaths among users while increasing
the number of patients who survived to be hospitalized for
Figure 3
Multivariable Cox Regression Results Among
Propensity ScoreMatched Cohort for All-Cause
Mortality, Acute MI, and the Composite Endpoint
of Death or MI
Multivariable Cox regression results among propensity scorematched cohort for
all-cause mortality, acute myocardial infarction (MI), and the composite endpoint
of death or MI among all patients and among patients presenting with either un-
stable angina (UA) or nonST-segment elevation myocardial infarction (NSTEMI).
CI condence interval; HR hazard ratio.
Figure 4
Multivariable Cox Regression Results Among
Propensity ScoreMatched Cohort for All-Cause
Mortality and the Composite Endpoint of Death
or MI Among Patient Subgroups
Multivariable Cox regression results among propensity scorematched cohort for
all-cause mortality and the composite endpoint of death or myocardial infarction
(MI) among patient subgroups including diabetic patients, older adults (age >70
years), and smokers. CI condence interval; HR hazard ratio.
Solomon et al. JACC Vol. 63, No. 21, 2014
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an MI. The CURE data support this potential explanation.
In CURE, clopidogrel decreased the number of Q-wave
MIs, which may be more likely to cause sudden cardiac
death than nonQ-wave MIs. It is possible that clopidogrel
reduces the severity of an MI, such that otherwise fatal,
out-of-hospital MIs become less severe, nonfatal MIs that
allow more clopidogrel users to make it to the hospital for
treatment. Given the difculty of identifying the cause of
death in observational data, the composite outcome of death
and MI requiring hospital stay is the most comparable
endpoint from our study. Interestingly, in a substudy of the
PLATO (Platelet Inhibition and Patient Outcomes) trial of
more than 5,000 medically managed patients, ticagrelor
reduced mortality compared with clopidogrel, but it did not
reduce the rate of MI (29). Future research should examine
the mechanism driving mortality reductions that are
disproportionate to reductions in MI for patients receiving
these agents.
Although we did not examine stroke outcomes, in the
CURE trial and other trials of antiplatelet and anticoagulant
use in ACS and high-risk groups (3033), strokes were
uncommon, and stroke rates were not different among
treatment groups. The CAPRIE (Clopidogrel Versus
Aspirin in Patients at Risk of Ischaemic Events) trial found
no difference in CV events among more than 12,000 pa-
tients with a previous history of stroke.
Another difference between this study and CURE was
that we analyzed a longer follow-up period (2 years vs. 1
year). We excluded patients who received revascularization
either in the hospital or within the rst week post-discharge,
whereas 15% of patients in the CURE trial received in-
hospital revascularization. Finally, we excluded patients
with a previous history of coronary artery disease (CAD),
whereas one-third of patients in the CURE trial had a pre-
vious MI, and nearly 20% had previously undergone CABG
or PCI. The combination of these differences may possibly
account for the disparities seen in the individual endpoints.
An important nding from this study was that a patients
clinical presentation affected the effectiveness of clopidogrel.
Clopidogrel was associated with a signicant improvement
in outcomes only among patients with NSTEMI, but not
among patients presenting with UA. Patients with
NSTEMI had elevated cardiac enzymes, an objective marker
of myocardial damage, whereas patients with UA were
identied by using more subjective signs and symptoms.
Therefore, some patients with a discharge diagnosis of UA
in our study may not have had underlying CAD and would
have been unlikely to benet from clopidogrel. In addition,
although both NSTEMI and UA are usually caused by
atherosclerotic plaque rupture and superimposed throm-
bosis, long-term antiplatelet therapy may be more effective
in patients with more severe ischemia that ultimately leads to
infarction, as occurs in NSTEMI but not UA. Patients with
NSTEMI and UA may also differ in other factors that in-
uence the risk of MI or death, such as thrombogenicity,
which could affect the response to clopidogrel.
Our results suggesting that patients with NSTEMI may
receive a greater benet from clopidogrel than patients with
UA are consistent with a subanalysis of CURE that
demonstrated a greater absolute risk reduction among high-
risk subjects (Thrombolysis In Myocardial Infarction risk
score of 5 to 7) (34). Similarly, in the secondary prevention
subgroup analysis of the CHARISMA (Clopidogrel for
High Atherothrombotic Risk and Ischemic Stabilization,
Management, and Avoidance) trial (35), patients with prior
MI had a larger protective effect from clopidogrel than did
patients with ischemic stroke or peripheral vascular disease,
with effect sizes similar to those in our study (HR: 0.74
[95% CI: 0.66 to 0.84] for death and MI in our study; HR:
0.83 [95% CI: 0.72 to 0.96] for CV death, MI, or stroke in
CHARISMA). Further, in CHARISMA, there was no
benet from clopidogrel among patients with CAD but
without MI (HR: 1.10 [95% CI: 0.77 to 1.58]), similar to
our nding for patients with UA (HR: 1.25 [95% CI: 0.94
to 1.67]). In addition, the ability to discern MI in clinical
trials is likely better than in regular clinical practice because
rigorous protocols and additional scrutiny are in place to
monitor study patients, and the coronary events identied
through our claims-based algorithms may represent clinically
larger MIs.
Unlike results from a Danish registry (36), we found
similar effectiveness for clopidogrel among patients with and
without diabetes, but we did nd a similar direction of the
effect (i.e., trend toward less effectiveness among patients
with diabetes) (Fig. 4). We also found a stronger association
for clopidogrel with outcomes among nonsmokers than
among smokers. These results differ from those of CAPRIE
(37) and other trials, although this discrepancy may signify
differences in characterization of smoking status in routine
care from those in a clinical trial. Our data suggesting that
clopidogrel may be more protective among older patients
(age 70 years), at least for our composite outcome, is
consistent with ndings of the CURE trial and may reect
greater benet of clopidogrel among higher-risk patients.
This nding is important because concern over the risk of
bleeding from dual-antiplatelet therapy can often tilt the
perceived benet/risk ratio against aggressive treatment in
older populations. In TRILOGY ACS (Targeted Platelet
Inhibition to Clarify the Optimal Strategy to Medically
Manage Acute Coronary Syndromes), a dedicated trial of
prasugrel versus clopidogrel in medically managed patients,
older patients did not receive a benet from more potent
platelet inhibition with prasugrel (33).
Less than one-half (36%) of medically managed patients
with UA or NSTEMI were prescribed clopidogrel during
the study period (2003 to 2008), even though it was given a
Class I indication in the 2002 AHA/ACC guidelines (2).
In similar patient populations, the CRUSADE (Can Rapid
Risk Stratication of Unstable Angina Patients Suppress
Adverse Outcomes With Early Implementation of the
ACC/AHA Guidelines) registry reported clopidogrel
adherence rates of 28% in 2002 and 53% in 2005 (13), the
JACC Vol. 63, No. 21, 2014 Solomon et al.
June 3, 2014:224957 Clopidogrel in Unstable Angina or NSTEMI
2255
GRACE registry (Global Registry of Acute Coronary
Events) reported almost 50% usage of clopidogrel in Ca-
nadian patients between 2003 and 2007 (17), and in the
ACTION Registry-GWTG (Get With the Guidelines),
55% of medically managed patients with NSTEMI be-
tween 2009 and 2011 were discharged on clopidogrel (15).
Both GRACE and CRUSADE demonstrated increasing
use of clopidogrel for UA or NSTEMI over time (18,19).
Although the reported use of clopidogrel was slightly lower
in this study, given the wide availability of PCI for Kaiser
Permanente Northern California members, the population
of medically managed patients with ACS in our cohort may
be sicker than the U.S. average, with more clinical con-
traindications to clopidogrel use. Nevertheless, this nding
lends additional support to more rigorous use of clopidogrel
use among medically managed patients with ACS. Indeed,
the results of the medically managed arm of PLATO, in
which ticagrelor was superior to clopidogrel on the com-
posite outcome of death, MI, and stroke, suggest that
potent platelet inhibition is indeed benecial in this patient
population (29). Despite recent advances in antiplatelet
therapy, clopidogrel remains a viable option; TRILOGY
ACS found no benet for prasugrel over clopidogrel in a
similar patient population.
Study limitations. Our analysis had limitations. It was not
possible to conrm the use of aspirin therapy because most
aspirin use is over the counter and is not captured within our
pharmacy dispensing database. We could not ascertain the
cause of death, details of the coronary event, the extent and
severity of CAD (i.e., single-vessel or multivessel disease), or
heart failure severity. Even though we used advanced sta-
tistical methods, including propensity score matching and
covariate adjustment, we cannot rule out residual or un-
measured confounding. In addition, although our study
provides insights into clopidogrel use over the past decade,
changes in guideline recommendations over this period may
have altered selection of patients for invasive versus con-
servative strategies.
Conclusions
Examining the strength and durability of clinical trial
ndings is a core mission of comparative effectiveness
research. Our results show that clopidogrel use initiated
within 7 days post-discharge was associated with improved
outcomes among medically managed patients after ACS.
These ndings suggest that the results of antiplatelet trials
for this patient population translate well to real world
practice.
Reprint requests and correspondence: Dr. Matthew D. Solomon,
Kaiser Permanente Oakland Medical Center, 3600 Broadway,
Oakland, California 94611. E-mail: Matthew.D.Solomon@kp.
org.
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Key Words: acute coronary syndrome(s)
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clopidogrel
-
outcomes.
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