Journal of the American College of Cardiology Vol. 63, No. 21, 2014� 2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2014.02.586

Comparative Effectiveness of Clopidogrel inMedically Managed Patients With UnstableAngina and Non–ST-Segment ElevationMyocardial Infarction

Matthew D. Solomon, MD, PHD,*y Alan S. Go, MD,*yz David Shilane, PHD,yDerek B. Boothroyd, PHD,y Thomas K. Leong, MPH,* Dhruv S. Kazi, MD, MSC, MS,zxTara I. Chang, MD, MS,y Mark A. Hlatky, MDyOakland, Stanford, and San Francisco, California

From the *D

California; yof Californi

General Ho

0875162N

recipient of

they have n

Deepak L. B

Manuscri

2014, accept

Objectives T

ivision of Research, Kai

Stanford University Schoo

a, San Francisco, San F

spital, San Francisco C

from the American Hea

a research grant from Ge

o relationships relevan

hatt, MD, MPH, served

pt received September 26

ed February 5, 2014.

his study sought to examine the effectiveness of clopidogrel in real-world, medically managed patients withunstable angina (UA) or non–ST-segment elevation myocardial infarction (NSTEMI).

Background A

lthough clinical trials have demonstrated the efficacy of clopidogrel to reduce cardiovascular (CV) morbidity andmortality in medically managed patients with UA or NSTEMI, the effectiveness of clopidogrel in actual clinicalpractice is less certain.

Methods A

retrospective cohort study was conducted of Kaiser Permanente Northern California members without knowncoronary artery disease or prior clopidogrel use who presented with UA or NSTEMI between 2003 and 2008 andwere medically managed (i.e., no percutaneous coronary intervention or coronary artery bypass grafting duringthe index hospitalization or within 7 days post-discharge). Over 2 years of follow-up, we measured the associationbetween clopidogrel use and all-cause mortality, hospital stay for MI, and a composite endpoint of death or MI usingpropensity-matched multivariable Cox analyses.

Results W

e identified 16,365 patients with incident UA (35%) or NSTEMI (65%); 36% of these patients were prescribedclopidogrel within 7 days of discharge. In 8,562 propensity score–matched patients, clopidogrel users had lowerrates of all-cause mortality (8.3% vs. 13.0%; p < 0.01; adjusted hazard ratio [HR]: 0.63; 95% confidence 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 MIalone (6.7% vs. 7.2%; p ¼ 0.30; HR: 0.93, CI: 0.78 to 1.11), compared with nonusers of clopidogrel. The associationbetween clopidogrel use and the composite of death or MI was significant only among patients presenting withNSTEMI (HR: 0.67; CI: 0.59 to 0.76; pint < 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 usewas associated with a lower risk of death and MI, particularly among patients with NSTEMI. (J Am Coll Cardiol2014;63:2249–57) ª 2014 by the American College of Cardiology Foundation

In 2001, the CURE (Clopidogrel in Unstable Angina toPrevent Recurrent Events) trial showed that dual-antiplatelet therapy with aspirin and clopidogrel improvedoutcomes among patients with unstable angina (UA) or

ser Permanente Northern California, Oakland,

l of Medicine, Stanford, California; zUniversityrancisco, California; and the xSan Francisco

alifornia. This work is supported by grant

rt Association, Dallas, Texas. Dr. Go is the

nentech. All other authors have reported that

t to the contents of this paper to disclose.

as Guest Editor for this paper.

, 2013; revised manuscript received January 24,

non–ST-segment myocardial infarction (NSTEMI) (1).Patients randomly assigned to long-term treatment withaspirin in combination with clopidogrel had a lower rate ofthe combined endpoint of CV death, nonfatal MI, or strokewithin 1 year compared with patients assigned to aspirinalone. On the basis of the results of CURE, clopidogrel was

See page 2258

given a Class I recommendation in the American College ofCardiology/American Heart Association (ACC/AHA)guideline statements for patients treated medically after UAor NSTEMI for 1 month and ideally up to 9 months (2).

Abbreviationsand Acronyms

ACS = acute coronary

syndrome (s)

CABG = coronary artery

bypass grafting

CAD = coronary artery

disease

CV = cardiovascular

MI = myocardial infarction

NSTEMI = non–ST-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, 2014Clopidogrel in Unstable Angina or NSTEMI June 3, 2014:2249–57

2250

Most patients in CURE weremedically managed (only one-fifth initially underwent revascu-larization procedures), and therate of subsequent revasculariza-tion during the first 12 monthswas low (15% in the clopidogrelarm of the study and 14% inthe aspirin arm). Although clo-pidogrel therapy led to similarrisk reductions in patients whowere medically managed or whounderwent revascularization, therole of clopidogrel in percutane-ous coronary intervention (PCI)has received more attention, bothperiprocedurally (3–11) and post-PCI (12). Perhaps as a result,rates of clopidogrel use after PCIare extremely high (13). In

contrast, 50% to 60% of patients with UA or NSTEMI inclinical practice are medically managed (i.e., do not undergorevascularization during the index hospital stay) (14–16). Inaddition, clopidogrel use in medically managed patients withUA or NSTEMI remains low; less than one-half of medicallymanaged patients with UA or NSTEMI will receive clopi-dogrel on discharge (13,17–19). Further, the impact of clo-pidogrel among medically managed patients with UA orNSTEMI who are treated outside a clinical trial remainsunclear. We therefore examined the effectiveness of clopi-dogrel in a real-world, community-based cohort of patientswho were medically managed after hospital discharge for UAor NSTEMI.

Methods

This study was approved by the Institutional Review Boardsof the Kaiser Foundation Research Institute (Oakland,California) and of Stanford University (Stanford, Califor-nia). Waiver of informed consent was obtained because ofthe nature of the study.Source population. The source population was fromKaiser Permanente Northern California, a large, inte-grated healthcare delivery system that provides care to>3.2 million individuals in San Francisco and the greaterBay Area. The health plan membership is broadly repre-sentative of the local and statewide population, apart fromslightly lower representation at the extremes of age andincome.Study population. We assembled an incident diseasecohort by first identifying all adult (age >30 years) membershospitalized for an initial episode of UA or NSTEMI be-tween January 1, 2003 and December 31, 2007. UA wasdefined by a primary hospital discharge diagnosis (Interna-tional Classification of Diseases-Ninth Edition) of 411.x ora combination of a primary discharge diagnosis code of

414.0 and a secondary discharge diagnosis of 411.x for thesame hospital stay. NSTEMI was defined by a primarydiagnosis code of 410.7, 410.8, or 410.9. To ensure anincident disease cohort, we excluded any patients with earlierdiagnoses 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 defined the index date for this analysis as 7 days afterhospital discharge, to allow subjects the opportunity to fill aclopidogrel prescription after hospital stay. To identify medi-cally managed patients, we excluded patients who received anycoronary revascularization procedures (CABG or PCI) duringtheir initial hospital stay or within 7 days of hospital discharge.Patients with any clinical event, including UA, MI, or death,within the first 7 days post-discharge were also excluded. Weadopted a new-user design (20) by excluding patients whohad used clopidogrel in the 120 days before developing UA orNSTEMI. To match the eligibility criteria of the CUREstudy, we also excluded patients with an earlier history ofstroke or transient ischemic attack (TIA), as well as patientstaking warfarin or those with uncontrolled hypertension(systolic blood pressure >180 mm Hg) at baseline. We alsoexcluded patients with a history of maintenance dialysis ororgan transplantation.Covariates and exposure of interest. We defined clopi-dogrel users as patients who filled a prescription within7 days post-discharge. To mimic an intention-to-treatdesign, we defined nonusers as patients who never startedclopidogrel or who did so after the first 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 medicationuse, we restricted the analysis to patients with completedemographic data and at least 12 months of continuousmembership and continuous pharmacy benefit before theindex date.

We obtained data on age, sex, and self-reported race orethnicity from health plan databases. We identified co-morbid conditions up to 4 years before the index date byusing previously validated approaches using diagnosis andprocedure codes and current procedural terminology codesrecorded in health plan hospital stay, ambulatory, laboratory,and pharmacy databases for the following comorbidities:a history of heart failure, peripheral arterial disease, valvularheart disease, diabetes mellitus, hypertension, dyslipidemia,or bleeding during hospital stay (21–27). We used pharmacydata to identify post-discharge use of angiotensin-convertingenzyme inhibitors or angiotensin receptor blockers, beta-blockers, and statins. We also included indicator variablesfor the year of the index date to control for secular trends, anindicator for the type of presenting event (UA or NSTEMI),and an indicator for patients in the group that had notreceived clopidogrel who underwent PCI between days 7and 14 and who subsequently started taking clopidogrel.

JACC Vol. 63, No. 21, 2014 Solomon et al.June 3, 2014:2249–57 Clopidogrel in Unstable Angina or NSTEMI

2251

Outcomes. We examined a composite outcome of all-causemortality and acute myocardial infarction (MI) requiringhospital stay during the 2 years after discharge, as well as theindividual endpoints of death and MI. All-cause mortalitywas identified from health plan databases, supplemented bylinkage with Social Security Administration vital status filesand California state death certificate records. MI wasdefined as a hospital admission with a primary diagnosiscode of 410.x1.Propensity score matching. We used propensity scorematching to control selection bias and to create demo-graphically and clinically comparable cohorts (28). Thepropensity score for use of clopidogrel within 7 days wasdeveloped on the basis of the following variables: age; raceor ethnicity; sex; year of index date; type of presenting event(UA or NSTEMI); smoking status; estimated glomerularfiltration 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 withthe group that had not received clopidogrel in a 1:1 ratioby using a modified greedy matching algorithm withoutreplacement, on the basis of propensity scores within 1%.Statistical analysis. We conducted the analysis in anintention-to-treat framework (i.e., not an on-treatmentanalysis because we did not allow crossover between studyarms after 7 days post-discharge). We compared means ofbaseline characteristics by using 2-sided Student t tests. Weused Kaplan-Meier estimators to describe survival functionsfor the selected outcomes and multivariable Cox regressionanalysis to test the association of clopidogrel use with

Figure 1 Cohort Assembly

Final cohort derivation for clopidogrel users and nonusers after the application of study elig

D/C ¼ discharge; HTN ¼ hypertension; MI ¼ myocardial infarction; NSTEMI ¼ non–ST-se

SBP ¼ systolic blood pressure; STEMI ¼ ST-segment elevation myocardial infarction, TIA

outcomes, after adjustment for the covariates described earlier.We conducted analyses on unadjusted and propensity-matched models and performed sensitivity analyses, and weexamined interaction effects (pint) between outcomes and thetype of initial presentation (UA or NSTEMI) and severalpatient subgroups (history of diabetes, history of smoking, andolder age). Sensitivity analyses were performed as follows: byvarying the time window after discharge that defined clopi-dogrel use; by including patients who were excluded by oureligibility criteria (patients using warfarin at baseline, dialysisrecipients, patients with very high blood pressure, and patientswith an earlier stroke orTIA); and, to examinewhether protonpump inhibitor (PPI) use modifies the effect of clopidogrel inthis population, by restricting analyses to those patients whofilled baseline prescriptions for PPIs in both the clopidogreluser group and the nonuser group. All analyses were per-formed with the R statistical package, version 2.15.3 (RDevelopment Team, Vienna, Austria).

Results

We identified 39,455 patients 30 years of age or older withincident disease between 2003 and 2008. After applying theexclusion criteria, the analysis sample included 16,365eligible patients, 5,961 (36%) of whom filled a prescriptionfor clopidogrel with the first 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 tosmoke, but they were otherwise healthier with fewercomorbidities (Table 1). Use of CV medications before theincident event was lower among clopidogrel users (seeTable 1), but after hospital discharge, CV drug use was

ibility criteria. CABG ¼ coronary artery bypass grafting; CHD ¼ coronary heart disease;

gment elevation myocardial infarction; PCI ¼ percutaneous coronary intervention;

¼ transient ischemic attack; UA ¼ unstable angina.

Table 1 Characteristics of Study Population

Unmatched Propensity-Matched

Clopidogrel(n ¼ 5,961)

No Clopidogrel(n ¼ 10,404) p Value

Clopidogrel(n ¼ 4,281)

No Clopidogrel(n ¼ 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 60–90, % 36.7 31.8 35.9 34.7

eGFR 45–60, % 17.7 20.4 20.0 19.9

eGFR 30–45, % 9.3 14.6 11.9 12.0

eGFR 15–30, % 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 120–130, % 16.5 16.3 16.7 16.6

SBP 130–140, % 24.5 22.8 24.1 23.5

SBP 140–160, % 20.1 19.2 19.6 19.5

SBP 160–180, % 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 ¼ angiotensin converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; eGFR ¼ estimated glomerular filtration rate; HTN ¼

hypertension; NSTEMI ¼ non–ST-segment elevation myocardial infarction; PPI ¼ proton pump inhibitor; Rx ¼ treatment; SBP ¼ systolic bloodpressure; UA ¼ unstable angina.

Solomon et al. JACC Vol. 63, No. 21, 2014Clopidogrel in Unstable Angina or NSTEMI June 3, 2014:2249–57

2252

higher among clopidogrel users (Table 1). Mean length offollow-up was 976 days for clopidogrel users and 876 daysfor clopidogrel nonusers. Median and mean duration ofcontinuous clopidogrel use among users was 188 days(interquartile range: 82 to 603 days) and 206 days, respec-tively. Most (97%) clopidogrel users filled their prescriptionson the day of discharge.

Patients who did not fill a prescription for clopidogrelwithin 7 days of discharge from the index hospital stay hada low rate of subsequent initiation of clopidogrel: of the10,404 initial nonusers, 3.4% initiated clopidogrel between7 and 30 days after discharge, and another 7.4% initiatedclopidogrel after 30 days post-discharge. More than one-third (38%) of the patients who initiated clopidogrelmore than 7 days after discharge (332 of 859) did so aftersubsequent PCIs, most of which occurred well after

discharge (24% between days 7 and 30, 58% between 30and 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 was0.72. 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 balancedin the matched cohort (see Table 1), and there were nostatistically significant 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-yearsof follow-up was lower in patients receiving clopidogrel inboth the overall population and in the propensity score

JACC Vol. 63, No. 21, 2014 Solomon et al.June 3, 2014:2249–57 Clopidogrel in Unstable Angina or NSTEMI

2253

matched cohort (Fig. 2). In the propensity-matched cohort,the composite of death or MI was lower among clopidogrelusers (13.5% vs. 17.4%; p < 0.01; adjusted hazard ratio[HR]: 0.74, 95% confidence interval [CI]: 0.66 to 0.84)(Fig. 3). All-cause mortality over 2 years was also lowerfor 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 ¼ 0.30; HR: 0.93; CI:0.78 to 1.11).

There was evidence of treatment effect modification byclinical presentation (NSTEMI vs. UA) and by a history ofsmoking, but not by a history of diabetes. The impact ofolder age yielded mixed results, with a significant interactionfor 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, patientswho presented with NSTEMI had a stronger associationof clopidogrel use with the composite of death or MI (HR:0.67 vs. 1.25; pint < 0.01), as well as with the individualendpoints of mortality (HR: 0.56 vs. 1.20; pint < 0.01), andacute MI (0.84 vs. 1.38; pint ¼ 0.03).

Figure 2 Kaplan-Meier Curves for All-Cause Mortality and Acute MI

Unadjusted Kaplan-Meier estimates for all-cause mortality and acute myocardial infarctio

The association of clopidogrel with the composite ofdeath or MI was similar, however, among patients with andwithout diabetes (HR: 0.83 vs. 0.69; pint ¼0.14), but it wasstronger among patients more than 70 years of age (HR:0.70 vs. 0.88; pint ¼0.04), as well as among nonsmokers(HR: 0.69 vs. 0.86; pint ¼ 0.02). Results were similar for theindividual endpoint of all-cause mortality, although theinteraction between older age and clopidogrel use was notsignificant (Fig. 4).

Results were not materially changed in sensitivity analysesthat defined clopidogrel use as any prescription filled within30 days, that included subjects excluded by our eligibilitycriteria (i.e., patients taking warfarin, or undergoing dialysis,or with very high blood pressure, or with an earlier stroke orTIA), and that restricted the analysis to patients taking PPIsat 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

n (MI) for clopidogrel users and nonusers.

Figure 3

Multivariable Cox Regression Results AmongPropensity Score–Matched Cohort for All-CauseMortality, Acute MI, and the Composite Endpointof Death or MI

Multivariable Cox regression results among propensity score–matched 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 non–ST-segment elevation myocardial infarction (NSTEMI).

CI ¼ confidence interval; HR ¼ hazard ratio.

Figure 4

Multivariable Cox Regression Results AmongPropensity Score–Matched Cohort for All-CauseMortality and the Composite Endpoint of Deathor MI Among Patient Subgroups

Multivariable Cox regression results among propensity score–matched 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 ¼ confidence interval; HR ¼ hazard ratio.

Solomon et al. JACC Vol. 63, No. 21, 2014Clopidogrel in Unstable Angina or NSTEMI June 3, 2014:2249–57

2254

clopidogrel within the first week after hospital discharge wasassociated with a lower risk of the composite outcome ofdeath or MI over 2 years of follow-up. The association be-tween clopidogrel use and outcomes was significantly greateramong patients who presented with NSTEMI, amongnonsmokers, and among older patients.

The reduction in the composite endpoint of death and MIreplicates, in a real-world cohort, the findings of the land-mark CURE trial. Indeed, the HR for the composite pri-mary outcome in CURE (HR: 0.80) was similar to the HRfor 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 significantimprovement of in-hospital and 1-year outcomes (1,18).Our study demonstrates that long-term outcomes are alsoimproved for survivors of coronary events requiring hospitalstay and further supports the use of clopidogrel in medicallymanaged patients with acute coronary syndrome (ACS).Although significant advances in antiplatelet therapy haveoccurred, the use of these agents would not have affectedpatient selection in our study because these agents wereapproved for use after our study period.

Interestingly, clopidogrel use did not reduce the risk ofMI requiring hospital stay in this study cohort. These resultsdiffer from those of the CURE trial (1), in which clopidogreluse was associated with a reduction in the compositeendpoint of CV death, nonfatal MI, and stroke, but amongindividual endpoints, clopidogrel use reduced the risk of MI

(notably, only Q-wave MIs), but not CV mortality. Thesedifferences in individual endpoints may be chance findings,may represent secular trends in outcomes for patients withUA or NSTEMI unrelated to antiplatelet therapy, or may bethe result of important differences in study design betweenthe CURE trial and our study.

First, ours was a retrospective study of administrative andclinical data from a real-world cohort, not a prospectiverandomized controlled trial. Real-world observational datacan be analyzed reliably by applying design and analytictechniques such as new-user design, restriction of the pop-ulation to trial-eligible patients, propensity score matching,and multivariable adjustment; nevertheless, these techniquesmay not entirely eliminate selection bias. However, a keystrength of observational research is its ability to examinemore diverse populations and to generalize trial findings toreal-world patients and practice settings.

Another important distinction between our study andCURE is the definition of study endpoints. We do not havedata on the cause of death (e.g., CV mortality), and the MIendpoint in our study was a mixture of fatal and nonfatalevents. Patients who died out of hospital of an MI werecoded as a death, not an MI, in our data. Thus, a strictcomparison of the MI endpoint between CURE and ourstudy is not feasible. Patients taking clopidogrel in our studymay have been less likely to suffer fatal, out-of-hospital MIs,thus leading to fewer deaths among users while increasingthe number of patients who survived to be hospitalized for

JACC Vol. 63, No. 21, 2014 Solomon et al.June 3, 2014:2249–57 Clopidogrel in Unstable Angina or NSTEMI

2255

an MI. The CURE data support this potential explanation.In CURE, clopidogrel decreased the number of Q-waveMIs, which may be more likely to cause sudden cardiacdeath than non–Q-wave MIs. It is possible that clopidogrelreduces the “severity” of an MI, such that otherwise fatal,out-of-hospital MIs become less severe, nonfatal MIs thatallow more clopidogrel users to make it to the hospital fortreatment. Given the difficulty of identifying the cause ofdeath in observational data, the composite outcome of deathand MI requiring hospital stay is the most comparableendpoint from our study. Interestingly, in a substudy of thePLATO (Platelet Inhibition and Patient Outcomes) trial ofmore than 5,000 medically managed patients, ticagrelorreduced mortality compared with clopidogrel, but it did notreduce the rate of MI (29). Future research should examinethe mechanism driving mortality reductions that aredisproportionate to reductions in MI for patients receivingthese agents.

Although we did not examine stroke outcomes, in theCURE trial and other trials of antiplatelet and anticoagulantuse in ACS and high-risk groups (30–33), strokes wereuncommon, and stroke rates were not different amongtreatment groups. The CAPRIE (Clopidogrel VersusAspirin in Patients at Risk of Ischaemic Events) trial foundno difference in CV events among more than 12,000 pa-tients with a previous history of stroke.

Another difference between this study and CURE wasthat we analyzed a longer follow-up period (2 years vs. 1year). We excluded patients who received revascularizationeither in the hospital or within the first week post-discharge,whereas 15% of patients in the CURE trial received in-hospital revascularization. Finally, we excluded patientswith 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 CABGor PCI. The combination of these differences may possiblyaccount for the disparities seen in the individual endpoints.

An important finding from this study was that a patient’sclinical presentation affected the effectiveness of clopidogrel.Clopidogrel was associated with a significant improvementin outcomes only among patients with NSTEMI, but notamong patients presenting with UA. Patients withNSTEMI had elevated cardiac enzymes, an objective markerof myocardial damage, whereas patients with UA wereidentified by using more subjective signs and symptoms.Therefore, some patients with a discharge diagnosis of UAin our study may not have had underlying CAD and wouldhave been unlikely to benefit from clopidogrel. In addition,although both NSTEMI and UA are usually caused byatherosclerotic plaque rupture and superimposed throm-bosis, long-term antiplatelet therapy may be more effectivein patients with more severe ischemia that ultimately leads toinfarction, as occurs in NSTEMI but not UA. Patients withNSTEMI and UA may also differ in other factors that in-fluence the risk of MI or death, such as thrombogenicity,which could affect the response to clopidogrel.

Our results suggesting that patients with NSTEMI mayreceive a greater benefit from clopidogrel than patients withUA are consistent with a subanalysis of CURE thatdemonstrated a greater absolute risk reduction among high-risk subjects (Thrombolysis In Myocardial Infarction riskscore of 5 to 7) (34). Similarly, in the secondary preventionsubgroup analysis of the CHARISMA (Clopidogrel forHigh Atherothrombotic Risk and Ischemic Stabilization,Management, and Avoidance) trial (35), patients with priorMI had a larger protective effect from clopidogrel than didpatients 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 inCHARISMA). Further, in CHARISMA, there was nobenefit from clopidogrel among patients with CAD butwithout MI (HR: 1.10 [95% CI: 0.77 to 1.58]), similar toour finding for patients with UA (HR: 1.25 [95% CI: 0.94to 1.67]). In addition, the ability to discern MI in clinicaltrials is likely better than in regular clinical practice becauserigorous protocols and additional scrutiny are in place tomonitor study patients, and the coronary events identifiedthrough our claims-based algorithms may represent clinicallylarger MIs.

Unlike results from a Danish registry (36), we foundsimilar effectiveness for clopidogrel among patients with andwithout diabetes, but we did find a similar direction of theeffect (i.e., trend toward less effectiveness among patientswith diabetes) (Fig. 4). We also found a stronger associationfor clopidogrel with outcomes among nonsmokers thanamong smokers. These results differ from those of CAPRIE(37) and other trials, although this discrepancy may signifydifferences in characterization of smoking status in routinecare from those in a clinical trial. Our data suggesting thatclopidogrel may be more protective among older patients(age �70 years), at least for our composite outcome, isconsistent with findings of the CURE trial and may reflectgreater benefit of clopidogrel among higher-risk patients.This finding is important because concern over the risk ofbleeding from dual-antiplatelet therapy can often tilt theperceived benefit/risk ratio against aggressive treatment inolder populations. In TRILOGY ACS (Targeted PlateletInhibition to Clarify the Optimal Strategy to MedicallyManage Acute Coronary Syndromes), a dedicated trial ofprasugrel versus clopidogrel in medically managed patients,older patients did not receive a benefit from more potentplatelet inhibition with prasugrel (33).

Less than one-half (36%) of medically managed patientswith UA or NSTEMI were prescribed clopidogrel duringthe study period (2003 to 2008), even though it was given aClass I indication in the 2002 AHA/ACC guidelines (2).In similar patient populations, the CRUSADE (Can RapidRisk Stratification of Unstable Angina Patients SuppressAdverse Outcomes With Early Implementation of theACC/AHA Guidelines) registry reported clopidogreladherence rates of 28% in 2002 and 53% in 2005 (13), the

Solomon et al. JACC Vol. 63, No. 21, 2014Clopidogrel in Unstable Angina or NSTEMI June 3, 2014:2249–57

2256

GRACE registry (Global Registry of Acute CoronaryEvents) reported almost 50% usage of clopidogrel in Ca-nadian patients between 2003 and 2007 (17), and in theACTION 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 increasinguse of clopidogrel for UA or NSTEMI over time (18,19).Although the reported use of clopidogrel was slightly lowerin this study, given the wide availability of PCI for KaiserPermanente Northern California members, the populationof medically managed patients with ACS in our cohort maybe sicker than the U.S. average, with more clinical con-traindications to clopidogrel use. Nevertheless, this findinglends additional support to more rigorous use of clopidogreluse among medically managed patients with ACS. Indeed,the results of the medically managed arm of PLATO, inwhich ticagrelor was superior to clopidogrel on the com-posite outcome of death, MI, and stroke, suggest thatpotent platelet inhibition is indeed beneficial in this patientpopulation (29). Despite recent advances in antiplatelettherapy, clopidogrel remains a viable option; TRILOGYACS found no benefit for prasugrel over clopidogrel in asimilar patient population.Study limitations. Our analysis had limitations. It was notpossible to confirm the use of aspirin therapy because mostaspirin use is over the counter and is not captured within ourpharmacy dispensing database. We could not ascertain thecause of death, details of the coronary event, the extent andseverity of CAD (i.e., single-vessel or multivessel disease), orheart failure severity. Even though we used advanced sta-tistical methods, including propensity score matching andcovariate adjustment, we cannot rule out residual or un-measured confounding. In addition, although our studyprovides insights into clopidogrel use over the past decade,changes in guideline recommendations over this period mayhave altered selection of patients for invasive versus con-servative strategies.

Conclusions

Examining the strength and durability of clinical trialfindings is a core mission of comparative effectivenessresearch. Our results show that clopidogrel use initiatedwithin 7 days post-discharge was associated with improvedoutcomes among medically managed patients after ACS.These findings suggest that the results of antiplatelet trialsfor 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.

REFERENCES

1. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK.Effects of clopidogrel in addition to aspirin in patients with acutecoronary syndromes without ST-segment elevation. N Engl J Med2001;345:494–502.

2. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002guideline update for the management of patients with unstable anginaand non–ST-segment elevation myocardial infarctiondsummaryarticle: a report of the American College of Cardiology/AmericanHeart Association task force on practice guidelines (Committee on theManagement of Patients With Unstable Angina). J Am Coll Cardiol2002;40:1366–74.

3. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment withclopidogrel and aspirin followed by long-term therapy in patients un-dergoing percutaneous coronary intervention: the PCI-CURE study.Lancet 2001;358:527–33.

4. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dualoral antiplatelet therapy following percutaneous coronary intervention:a randomized controlled trial. JAMA 2002;288:2411–20.

5. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G.Randomized trial of high loading dose of clopidogrel for reduction ofperiprocedural myocardial infarction in patients undergoing coronaryintervention: results from the ARMYDA-2 (Antiplatelet therapy forReduction of MYocardial Damage during Angioplasty) study. Circu-lation 2005;111:2099–106.

6. von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E,Kastrati A, Schomig A. Absorption, metabolization, and antiplateleteffects of 300-, 600-, and 900-mg loading doses of clopidogrel: resultsof the ISAR-CHOICE (Intracoronary Stenting and AntithromboticRegimen: Choose Between 3 High Oral Doses for Immediate Clopi-dogrel Effect). Trial. Circulation 2005;112:2946–50.

7. Montalescot G, Sideris G, Meuleman C, et al. A randomized com-parison of high clopidogrel loading doses in patients with non–ST-segment elevation acute coronary syndromes: the ALBION(Assessment of the Best Loading Dose of Clopidogrel to Blunt PlateletActivation, Inflammation and Ongoing Necrosis) trial. J Am CollCardiol 2006;48:931–8.

8. L’Allier PL, Ducrocq G, Pranno N, et al. Clopidogrel 600-mg doubleloading dose achieves stronger platelet inhibition than conventionalregimens: results from the PREPAIR randomized study. J Am CollCardiol 2008;51:1066–72.

9. Schiele F, Meneveau N, Bassand JP. Routine pre-treatment with clo-pidogrel before diagnostic coronary angiography: the question is right,but what about the answer? Eur Heart J 2008;29:1475–7.

10. Di Sciascio G, Patti G, Pasceri V, et al. Effectiveness of in-laboratoryhigh-dose clopidogrel loading versus routine pre-load in patientsundergoing percutaneous coronary intervention: results of theARMYDA-5 PRELOAD (Antiplatelet therapy for Reduction ofMYocardial Damage during Angioplasty) randomized trial. J Am CollCardiol 2010;56:550–7.

11. Ho PM, Tsai TT, Maddox TM, et al. Delays in filling clopidogrelprescription after hospital discharge and adverse outcomes after drug-eluting stent implantation: implications for transitions of care. CircCardiovasc Qual Outcomes 2010;3:261–6.

12. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, for theCLASSICS Investigators. Double-blind study of the safety of clopi-dogrel with and without a loading dose in combination with aspirincompared with ticlopidine in combination with aspirin after coronarystenting: the Clopidogrel Aspirin Stent International CooperativeStudy (CLASSICS). Circulation 2000;102:624–9.

13. Amsterdam EA, Peterson ED, Ou FS, et al. Comparative trends inguidelines adherence among patients with non–ST-segment elevationacute coronary syndromes treated with invasive versus conservativemanagement strategies: results from the CRUSADE qualityimprovement initiative. Am Heart J 2009;158:748–54.

14. Van de Werf F, Gore JM, Avezum A, et al. Access to catheterisationfacilities in patients admitted with acute coronary syndrome: multina-tional registry study. BMJ 2005;330:441.

15. Maddox TM, Ho PM, Tsai TT, et al. Clopidogrel use and hospitalquality in medically managed patients with non–ST-segment-elevationmyocardial infarction. Circ Cardiovasc Qual Outcomes 2012;5:523–31.

JACC Vol. 63, No. 21, 2014 Solomon et al.June 3, 2014:2249–57 Clopidogrel in Unstable Angina or NSTEMI

2257

16. de Winter RJ, Windhausen F, Cornel JH, et al. Early invasive versusselectively invasive management for acute coronary syndromes. N EnglJ Med 2005;353:1095–104.

17. Banihashemi B, Goodman SG, Yan RT, et al. Underutilization ofclopidogrel and glycoprotein IIb/IIIa inhibitors in non–ST-elevationacute coronary syndrome patients: the Canadian global registry of acutecoronary events (GRACE) experience. Am Heart J 2009;158:917–24.

18. Mehta RH, Roe MT, Chen AY, et al. Recent trends in the care of pa-tients with non–ST-segment elevation acute coronary syndromes: insightsfrom the CRUSADE initiative. Arch Intern Med 2006;166:2027–34.

19. Rao RV, Goodman SG, Yan RT, et al. Temporal trends and patternsof early clopidogrel use across the spectrum of acute coronary syn-dromes. Am Heart J 2009;157:642–50.

20. Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 2003;158:915–20.

21. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronickidney disease and the risks of death, cardiovascular events, and hospitalstay. N Engl J Med 2004;351:1296–305.

22. Go AS, Lee WY, Yang J, Lo JC, Gurwitz JH. Statin therapy and risks fordeath and hospital stay in chronic heart failure. JAMA 2006;296:2105–11.

23. Selby JV, Ray GT, Zhang D, Colby CJ. Excess costs of medical care forpatients with diabetes in a managed care population. Diabetes Care1997;20:1396–402.

24. Expert Panel on Detection, Evaluation, and Treatment of High BloodCholesterol In Adults. Executive summary of the third report of theNational Cholesterol Education Program (NCEP) Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol InAdults (Adult Treatment Panel III). JAMA 2001;285:2486–97.

25. Levey AS, Coresh J, Greene T, et al. Using standardized serum creatininevalues in the modification of diet in renal disease study equation forestimating glomerular filtration rate. Ann Intern Med 2006;145:247–54.

26. National Kidney Foundation. K/DOQI clinical practice guidelines forchronic kidney disease: evaluation, classification, and stratification. AmJ Kidney Dis 2002;39 Suppl 1:S1–266.

27. Fireman BH, Fehrenbacher L, Gruskin EP, Ray GT. Cost of care forpatients in cancer clinical trials. J Natl Cancer Inst 2000;92:136–42.

28. Rosenbaum PR, Rubin DB. The central role of the propensity score inobservational studies for causal effects. Biometrika 1983;70:41–55.

29. James SK, Roe MT, Cannon CP, et al. Ticagrelor versus clopidogrel inpatients with acute coronary syndromes intended for non-invasivemanagement: substudy from prospective randomised PLATelet inhi-bition and patient Outcomes (PLATO) trial. BMJ 2011;342:d3527.

30. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clo-pidogrel in patients with acute coronary syndromes. N Engl J Med2007;357:2001–15.

31. CAPRIE Steering Committee. A randomised, blinded, trial of clopi-dogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).CAPRIE Steering Committee. Lancet 1996;348:1329–39.

32. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients witha recent acute coronary syndrome. N Engl J Med 2012;366:9–19.

33. Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrelfor acute coronary syndromes without revascularization. N Engl J Med2012;367:1297–309.

34. Budaj A, Yusuf S, Mehta SR, et al. Benefit of clopidogrel in patientswith acute coronary syndromes without ST-segment elevation invarious risk groups. Circulation 2002;106:1622–6.

35. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardialinfarction, stroke, or symptomatic peripheral arterial disease in theCHARISMA trial. J Am Coll Cardiol 2007;49:1982–8.

36. Andersson C, Lyngbaek S, Nguyen CD, et al. Association of clopi-dogrel treatment with risk of mortality and cardiovascular eventsfollowing myocardial infarction in patients with and without diabetes.JAMA 2012;308:882–9.

37. Gurbel PA, Nolin TD, Tantry US. Clopidogrel efficacy and cigarettesmoking status. JAMA 2012;307:2495–6.

Key Words: acute coronary syndrome(s) - clopidogrel - outcomes.