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  Comparative Effectiveness of Clopidogrel inMedically Managed Patients With Unstable Angina and Non –  ST-Segment ElevationMyocardial Infarction Matthew D. Solomon, MD, P H D,*  y  Alan S. Go, MD,*  yz  David Shilane, P H D, y Derek B. Boothroyd, P H D, y  Thomas K. Leong, MPH,*  Dhruv S. Kazi, MD, MS C , MS, zx  Tara I. Chang, MD, MS, y  Mark A. Hlatky, MD y Oakland, Stanford, and San Francisco, California  Objectives  This 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  Although clinical trials have demonstrated the ef 󿬁 cacy 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 during the 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 using propensity-matched multivariable Cox analyses. Results  We identi 󿬁 ed 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% con 󿬁 dence 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 signi 󿬁 cant only among patients presenting withNSTEMI (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 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 non – ST-segment myocardial infarction (NSTEMI) (1).Patients randomly assigned to long-term treatment withaspirin 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 aspirinalone. On the basis of the results of CURE, clopidogrel wasgiven a Class I recommendation in the American College of Cardiology/American Heart Association (ACC/AHA)guideline statements for patients treated medically after UAor 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;  y Stanford University School of Medicine, Stanford, California;  z University of California, San Francisco, San Francisco, California; and the  x San FranciscoGeneral Hospital, San Francisco California. This work is supported by grant 0875162N from the American Heart Association, Dallas, Texas. Dr. Go is therecipient 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/$36.00Published by Elsevier Inc.  Most patients in CURE weremedically managed (only one- 󿬁 fth initially underwent revascu-larization procedures), and therate of subsequent revasculariza-tion during the  󿬁 rst 12 months was low (15% in the clopidogrelarm of the study and 14% inthe aspirin arm). Although clo-pidogrel therapy led to similar risk reductions in patients who were 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). Incontrast, 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 medically managed 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 or NSTEMI who are treated outside a clinical trial remainsunclear. 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 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 of the 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 greater Bay 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   󿬁 rst 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 wasde 󿬁 ned by a primary hospital discharge diagnosis (Interna-tional Classi 󿬁 cation 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 thesame hospital stay. NSTEMI was de 󿬁 ned by a primary diagnosis code of 410.7, 410.8, or 410.9. To ensure anincident 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 de 󿬁 ned 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, withinthe 󿬁 rst7dayspost-discharge were also excluded. Weadopted a new-user design (20) by excluding patients whohad used clopidogrelinthe120 days before developing UA or NSTEMI. To match the eligibility criteria of the CUREstudy, we also excluded patients with an earlier history of stroke 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 or organ transplantation. Covariates and exposure of interest.  We de 󿬁 ned clopi-dogrel users as patients who  󿬁 lled a prescription within7 days post-discharge. To mimic an intention-to-treat design, we de 󿬁 ned nonusers as patients who never startedclopidogrel 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 medicationuse, we restricted the analysis to patients with completedemographic data and at least 12 months of continuousmembership and continuous pharmacy bene 󿬁 t before theindex date. We obtained data on age, sex, and self-reported race or ethnicity from health plan databases. We identi 󿬁 ed co-morbid conditions up to 4 years before the index date by using 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, valvular heart disease, diabetes mellitus, hypertension, dyslipidemia,or bleeding during hospital stay  (21 – 27). 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 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 not received clopidogrel who underwent PCI between days 7and 14 and who subsequently started taking clopidogrel. Abbreviationsand Acronyms ACS = acute coronarysyndrome (s)CABG = coronary arterybypass grafting CAD = coronary arterydiseaseCV = cardiovascularMI = myocardial infarctionNSTEMI = non – ST-segmentelevation myocardialinfarctionPCI = percutaneous coronaryinterventionPPI = proton pump inhibitorTIA = transient ischemicattack UA = unstable angina  Solomon  et al  .  JACC Vol. 63, No. 21, 2014 Clopidogrel in Unstable Angina or NSTEMI  June 3, 2014:2249 – 57 2250  Outcomes.  We examined a composite outcome of all-causemortality and acute myocardial infarction (MI) requiring hospital stay during the 2 years after discharge, as well as theindividual endpoints of death and MI. All-cause mortality  was identi 󿬁 ed from health plan databases, supplemented by linkage with Social Security Administration vital status  󿬁 lesand California state death certi 󿬁 cate records. MI wasde 󿬁 ned 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 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 withthe group that had not received clopidogrel in a 1:1 ratioby using a modi 󿬁 ed greedy matching algorithm without replacement, on the basis of propensity scores within 1%. Statistical analysis.  We conducted the analysis in anintention-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. Weused Kaplan-Meier estimators to describe survival functionsfor the selected outcomes and multivariable Cox regressionanalysis to test the association of clopidogrel use withoutcomes,afteradjustmentforthecovariatesdescribedearlier. We conducted analyses on unadjusted and propensity-matched models and performed sensitivity analyses, and weexamined interaction effects (p int  ) between outcomes and thetype of initial presentation (UA or NSTEMI) and severalpatientsubgroups(historyofdiabetes,historyofsmoking,andolder age). Sensitivity analyses were performed as follows: by  varying the time window after discharge that de 󿬁 ned clopi-dogrel use; by including patients who were excluded by our eligibility criteria (patients using warfarin at baseline, dialysisrecipients,patientswithveryhighbloodpressure,andpatients withanearlierstrokeorTIA);and,toexaminewhetherprotonpump inhibitor (PPI) use modi 󿬁 es the effect of clopidogrel inthis population, by restricting analyses to those patients who 󿬁 lled 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 (R Development Team, Vienna, Austria). Results   We identi 󿬁 ed 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  󿬁 lled a prescriptionfor 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 tosmoke, but they were otherwise healthier with fewer comorbidities ( Table 1). Use of CV medications before theincident 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  ¼  coronary artery bypass grafting; CHD  ¼  coronary heart disease;D/C  ¼  discharge; HTN  ¼  hypertension; MI  ¼  myocardial infarction; NSTEMI  ¼  non – ST-segment elevation myocardial infarction; PCI  ¼  percutaneous coronary intervention;SBP  ¼  systolic blood pressure; STEMI  ¼  ST-segment elevation myocardial infarction, TIA  ¼  transient ischemic attack; UA  ¼  unstable angina. JACC Vol. 63, No. 21, 2014  Solomon  et al  . June 3, 2014:2249 – 57  Clopidogrel in Unstable Angina or NSTEMI2251  higher among clopidogrel users ( Table 1). Mean length of follow-up was 976 days for clopidogrel users and 876 daysfor 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 prescriptionson the day of discharge.Patients who did not   󿬁 ll a prescription for clopidogrel within 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 after subsequent 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 signi 󿬁 cant 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 Table 1 Characteristics of Study Population Unmatched Propensity-MatchedClopidogrel(n  ¼  5,961)No Clopidogrel(n  ¼  10,404) p ValueClopidogrel(n  ¼  4,281)No Clopidogrel(n  ¼  4,281) p Value PresentationUA, % 31.7 36.8  d  36.0 36.2  d NSTEMI, % 68.3 63.2  < 0.01 64.0 63.8 0.84DemographicsAge (mean), yrs 65.8 70.5  < 0.01 68.1 68.0 0.64Male, % 66.3 53.1  < 0.01 60.1 61.0 0.36White race, % 73.0 73.4 0.56 73.1 73.3 0.83ComorbiditiesSmoker, % 33.1 30.7  < 0.01 31.6 31.9 0.75Heart failure, % 4.9 11.6  < 0.01 6.7 7.6 0.12Bleeding, % 1.7 3.6  < 0.01 2.2 2.1 0.83HTN, % 58.9 65.2  < 0.01 64.1 64.4 0.80Diabetes, % 28.4 32.1  < 0.01 32.1 31.7 0.69Hyperlipidemia,% 84.3 80.0  < 0.01 84.6 84.7 0.93Patient characteristicseGFR  > 90, % 7.2 6.1 < 0.016.9 6.00.29eGFR 60 – 90, % 36.7 31.8 35.9 34.7eGFR 45 – 60, % 17.7 20.4 20.0 19.9eGFR 30 – 45, % 9.3 14.6 11.9 12.0eGFR 15 – 30, % 3.0 6.0 3.9 4.1eGFR  < 15, % 0.4 1.0 0.5 0.7eGFR, unknown, % 25.7 20.1 20.9 22.6SBP  < 120, % 20.1 23.9 < 0.0122.0 22.80.75SBP 120 – 130, % 16.5 16.3 16.7 16.6SBP 130 – 140, % 24.5 22.8 24.1 23.5SBP 140 – 160, % 20.1 19.2 19.6 19.5SBP 160 – 180, % 6.1 6.6 6.7 6.1SBP   180, % 0.0 0.0 0.0 0.0SBP, unknown, % 12.7 11.2 11.0 11.5Rx use after event*Statin, % 90.8 70.4  < 0.01 87.2 86.9 0.68ACEI/ARB, % 74.7 58.0  < 0.01 68.9 69.6 0.47Beta-blocker, % 91.6 74.8  < 0.01 88.7 88.3 0.57PPI, % 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  󿬁 ltration 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, 2014 Clopidogrel in Unstable Angina or NSTEMI  June 3, 2014:2249 – 57 2252
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