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  Antithrombotic Therapy Impact of Smoking on Long-Term Outcomes inPatients With Atherosclerotic Vascular Disease Treated With Aspirin or Clopidogrel Insights From the CAPRIE Trial (Clopidogrel Versus Aspirinin Patients at Risk of Ischemic Events)  José L. Ferreiro, MD,* y  Deepak L. Bhatt, MD, MPH, z  Masafumi Ueno, MD, P H D,*Deborah Bauer, MS, x  Dominick J. Angiolillo, MD, P H D*  Jacksonville, Florida; Barcelona, Spain; Boston, Massachusetts; and Bridgewater, New Jersey  Objectives  The goal of this study was to investigate the differential ef 󿬁 cacy of clopidogrel or aspirin monotherapy according tosmoking status in patients with atherosclerotic vascular disease. Background  Smoking enhances clopidogrel-induced platelet inhibition, which may explain the higher relative bene 󿬁 t among smokers observed in trials evaluating dual antiplatelet therapy. Whether smoking has an impact on clinicaloutcomes in patients requiring a single antiplatelet agent remains unknown. Methods  This was a post-hoc analysis of the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trialthat compared clopidogrel and aspirin monotherapy in patients (N  ¼  19,184) with atherosclerotic vascular disease. Results  Current smokers (n  ¼  5,688) had an increased risk of ischemic events compared with never smokers (n  ¼  4,135;hazardratio[HR]:1.24[95%con 󿬁 denceinterval(CI):1.08to1.42])andex-smokers(n ¼ 9,381;HR:1.32[95%CI:1.18to1.47])(p < 0.001).Clopidogrelwasassociatedwithareductioninischemiceventsamongcurrentsmokers(8.3%vs.10.8%; HR: 0.76 [95% CI: 0.64 to 0.90]), whereas no bene 󿬁 t over aspirin was seen in the combined group ofex-smokers/never-smoked patients (10.4% vs. 10.6%; HR: 0.99 [95% CI: 0.89 to 1.10]; p  ¼  0.01 for interaction).Among current smokers, clopidogrel also reduced myocardial infarction, vascular death, and death from any causecomparedwithaspirin.Nointeractionbetweensmokingstatusandstudytreatmentwasobservedforbleedingevents. Conclusions  In a post-hoc analysis of the CAPRIE population, current smokers appeared to have enhanced bene 󿬁 t withclopidogrel therapy for secondary prevention compared with aspirin. These results should be considered hypothesisgenerating for future prospective studies assessing the impact of speci 󿬁 c platelet-inhibiting strategies according tosmoking status. (J Am Coll Cardiol 2014;63:769 – 77) ª 2014 by the American College of Cardiology Foundation Cigarette smoking is a potent inducer of the hepaticcytochrome P450 (CYP) 1A2 and 2B6 isoenzymes andcan have an impact on the pharmacokinetic andpharmacodynamic pro 󿬁 les of drugs sharing this metabolicpathway, including clopidogrel (1 – 4). In particular, CYP1A2is the predominant isoenzyme responsible for the  󿬁 rst  From the *University of Florida College of Medicine-Jacksonville, Jacksonville,Florida;  y Heart Diseases Institute, Hospital Universitari de Bellvitge-IDIBELL,University of Barcelona, L ’ Hospitalet de Llobregat, Barcelona, Spain;  z VA BostonHealthcare System, Brigham and Women ’ s Hospital, and Harvard Medical School,Boston, Massachusetts; and the  x Department of Biostatistics, Sano 󿬁 , Bridgewater,New Jersey. The CAPRIE trial was funded by Sano 󿬁  and Bristol-Myers Squibb. Thestudy sponsor had no role in the design of the present analysis. Dr. Ferreiro has receivedhonoraria for lectures from Eli Lilly and Company, Daiichi Sankyo, and AstraZeneca.Dr. Bhatt has been on the advisory boards of Elsevier Practice Update Cardiology,Medscape Cardiology, and Regado Biosciences; has been on the board of directors of Boston VA Research Institute and the Society of Chest Pain Centers; has chaired the American Heart Association Get With the Guidelines Science Subcommittee; hasreceived honoraria from the American College of Cardiology, Duke Clinical ResearchInstitute, Slack Publications, and WebMD; has been a senior associate editor of the  Journal of Invasive Cardiology  ;hasbeenondatamonitoringcommitteesofDukeClinicalResearchInstitute,MayoClinic,andPopulationHealthResearchInstitute;hasreceivedresearch grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon,Medtronic, sano 󿬁 -aventis, and The Medicines Company; has performed unfundedresearch for FlowCo, PLx Pharma, and Takeda; has been a principal investigator on theCHARISMA trial; has been on the steering committee of the TRILOGY-ACS trial;and has been on the executive committee of the PEGASUS trial(s). Ms. Bauer is anemployeeofsano 󿬁 -aventis.Dr.AngiolillohasreceivedconsultingfeesorhonorariafromBristol-Myers Squibb, sano 󿬁 -aventis, Eli Lilly and Company, Daiichi Sankyo, TheMedicines Company, AstraZeneca, Merck & Co., Evolva, Abbott Vascular, and PLxPharma;has been a consultant for Johnson & Johnson, St. Jude Medical,and Sunovion;has received research grants (paid to his institution) from Bristol-Myers Squibb, sano 󿬁 -aventis, GlaxoSmithKline, Otsuka, Eli Lilly and Company, Daiichi Sankyo, TheMedicines Company, AstraZeneca, and Evolva; and has received an Esther and King BiomedicalResearchGrant.Dr.Uenohas reportedthat hehas norelationshipsrelevant to the contents of this paper to disclose.Manuscript received July 9, 2013; revised manuscript received October 7, 2013,accepted October 15, 2013. Journal of the American College of Cardiology Vol. 63, No. 8, 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.2013.10.043  oxidative step in the conversion of clopidogrel into its active metab-olite and may therefore increaseclopidogrelbiotransformation(5). This is supported by pharma-codynamic studies, which haveshown, with some exception (6),that cigarette smoking enhancesclopidogrel-induced platelet in-hibitory effects (7 – 12). Thesepharmacodynamic  󿬁 ndings may explain the observations fromlarge-scale clinical trials demon-strating that, among clopidogrel-treated patients, smokers havea higher relative clinical bene 󿬁 t compared with nonsmokers(13 – 19). However, to date, such a   “ smoker  ’ s paradox ”  hasbeen assessed only in patients requiring dual antiplatelet therapy (DAPT) with aspirin and clopidogrel, and whether smoking impacts clinical outcomes in patients with athero-sclerotic disease manifestations requiring a single antiplatelet agent for secondary prevention of ischemic events remainsunknown. The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial is the only large-scale head-to-head clinical investigation comparing clopidogrel versusaspirin for secondary prevention in patients with variousatherosclerotic disease manifestations (20). The trial showedclopidogrel to be modestly, and statistically signi 󿬁 cantly,more effective in reducing ischemic outcomes than aspirin, with a favorable safety pro 󿬁 le. The objectives of the present analysis were 2-fold:  󿬁 rst, to evaluate the relationshipbetween smoking status and clinical outcomes in the ove-rall CAPRIE study population; and second, to investigatethe differential effects of clopidogrel or aspirin therapy according to smoking status. Methods  The design, methods, and primary results of the CAPRIEtrial have been reported previously  (20). In brief, CAPRIE was a randomized, multicenter, blinded trial that comparedthe ef  󿬁 cacy of clopidogrel (75 mg once daily) and aspirin(325 mg once daily) in reducing the risk of the outcomeevent cluster of ischemic stroke, myocardial infarction (MI),or vascular death in a population of patients with athero-sclerotic vascular disease. The study population comprisedsubgroups of patients with either recent ischemic stroke,recent MI, or symptomatic peripheral artery disease. After a mean follow-up of 1.91 years, clopidogrel was moreeffective in reducing ischemic outcomes than aspirin (5.32% vs. 5.83%; p  ¼  0.043). For the purpose of the present analysis, the impact of smoking status on outcomes wasevaluated in the overall study population. In addition, thedifferential treatment effect (interaction) of clopidogrel versus aspirin according to smoking status was alsoevaluated. Ischemic events were de 󿬁 ned consistent with theprimary ef  󿬁 cacy endpoint of the CAPRIE trial and includedthe outcome event cluster of ischemic stroke, MI, or vascular death, whichever occurred  󿬁 rst. In addition to the compo-nents of the primary endpoint, a secondary ef  󿬁 cacy endpoint assessed was death from any cause. Smoking status wasascertained only at a single time at the moment of enroll-ment, and was evaluated both as collected (neversmokers, ex-smokers, and current smokers) and by combining never smokers/ex-smokers versus current smokers. A safety endpoint was also considered, and CAPRIE bleeding events were de 󿬁 ned as any bleeding disorder, as previously described(20,21). Outcomes reported were validated by the central validation committee of the trial. Statistical analysis.  Data are presented as numbers andfrequencies for categorical variables and as means    SD for continuous variables. All data analyses were performed onthe intention-to-treat population including all patients who were randomized. Baseline characteristics were compared with the chi-square test for categorical variables and analysisof variance for continuous variables. The effect of smoking status on ischemic events was evaluated using a Cox pro-portional hazards model, and p values were calculated using a log-rank test. For the overall population, the model wasstrati 󿬁 ed by qualifying condition. Tests of interactionbetween smoking status and study treatment were calculatedusing the Cox proportional hazards model including treat-ment, smoking status (as a categorical variable), and theinteraction; also included in the adjusted model are thecovariates detailed in the following text. To take into account any imbalances in baseline variables, analyses were repeatedusing multivariable Cox proportional hazards model, adjust-ing for treatment, race, diabetes, hypercholesterolemia,congestiveheartfailure,cardiomegaly,atrial 󿬁 brillation,stableangina, unstable angina, previous MI, transient ischemicattack, reversible ischemic neurological de 󿬁 cit, previousischemic stroke, intermittent claudication, and leg amputa-tion (these variables were selected on the basis of a previousmultivariable analysis) (22), and also for age, sex, and body mass index. The effect of smoking status and treatment onbleeding disorders was evaluated using a logistic regressionmodel, and groups were compared using a chi-square test. A 2-tailed p value of   < 0.05 was considered to indicatea statistically signi 󿬁 cant difference for all of the analyses per-formed. Statistical analysis was performed using SAS version9.2 software (SAS Institute, Cary, North Carolina). Results Study population.  A total of 19,185 patients wererandomized in the CAPRIE trial. Smoking status wasascertained only at the moment of enrollment and recordedin all except 1 patient who was excluded from the present analysis. Of the 19,184 patients evaluated, 5,668 (29.5%) were current smokers, 9,381 (48.9%) were ex-smokers,and 4,135 (21.6%) never smokers. Compared with Abbreviationsand Acronyms ACS = acute coronarysyndromeCI = con 󿬁 dence intervalCYP = cytochrome P450HR = hazard ratioDAPT = dual antiplatelettherapyMI = myocardial infarctionOR = odds ratioPCI= percutaneous coronaryintervention Ferreiro  et al  .  JACC Vol. 63, No. 8, 2014  Smoking Effects on Clopidogrel or Aspirin Monotherapy   March 4, 2014:769 – 77 770  never-smokers, current smokers were younger, morefrequently male, and more likely to have peripheral artery disease, but less likely to have recent ischemic stroke asqualifying conditions. Current smokers were also less likely to have a history of hypertension, diabetes mellitus, atrial 󿬁 brillation, stable angina, cardiomegaly, and congestive heart failure. Baseline demographics and clinical characteristicsstrati 󿬁 ed according to smoking status (current smokers vs.the combined group of ex-smokers and never smokers) andtreatment are shown in Table 1. Effect of smoking status in the overall study population. In the overall population, current and ex-smokers hada numerically lower rate of ischemic events (primary ef  󿬁 -cacy endpoint) compared with patients who never smoked:9.5%, 9.8%, and 12.0%, respectively (p  ¼  0.30). However,after adjustment for baseline characteristics, current smokers had an increased risk of ischemic events compared with patients who never smoked (hazard ratio [HR]: 1.24[95% con 󿬁 dence interval (CI): 1.08 to 1.42]) and to ex-smokers (HR: 1.32 [95% CI: 1.18 to 1.47]), achieving statistical signi 󿬁 cance (p  <  0.001). Both unadjusted andadjusted HRs for the overall population and the study subgroups (patients with recent ischemic stroke, recent MI,or symptomatic peripheral artery disease) are reportedin Table 2.Similar results were obtained when analyzing smoking status as a dichotomous variable. Current smokers hada numerically lower rate of the primary ef  󿬁 cacy endpoint compared with ex-smokers/never-smoked patients, whichdid not reach statistical signi 󿬁 cance (9.5% vs. 10.5%, HR:0.99 [95% CI: 0.89 to 1.09]; p  ¼  0.82). However, in theadjusted model, current smokers had an enhanced risk of ischemic outcomes compared with the combined group of ex-smokers/never-smoked subjects (HR: 1.30 [95% CI: 1.17to 1.44]; p  <  0.001).Bleeding disorders occurred in 8.6% of current smokers,9.7% of ex-smokers, and 9.1% of never-smoked patients(p  ¼  0.07). When evaluating smoking status as a dichoto-mous variable, current smokers had a lower rate of bleeding events compared with ex-smokers/never-smoked subjects(8.6% vs. 9.6%; odds ratio [OR]: 0.89 [95% CI: 0.80 to0.99]; p  ¼  0.04). In the adjusted model, the ratio wasinverted, indicating that current smokers had a signi 󿬁 cantly increased risk of bleeding events compared with patients who had never smoked (OR: 1.23 [95% CI: 1.04 to 1.46];p  ¼  0.02) and similar when compared with ex-smokers(OR: 0.93 [95% CI: 0.83 to 1.05]; p  ¼  0.25). No differ-ence was seen between current smokers and the combinedgroup of ex-smokers/never-smoked patients (OR: 1.01[95% CI: 0.90 to 1.13]; p  ¼  0.93). Table 1 Baseline Demographic Data and Clinical Characteristics Strati 󿬁 ed According to Smoking Status and Treatment AspirinCurrent Smokers(n  ¼  2,860)ClopidogrelCurrent Smokers(n  ¼  2,808) p ValueAspirinEx/Never Smokers(n  ¼  6,726)ClopidogrelEx/Never Smokers(n  ¼  6,726) p Value Age, yrs 58.6    10.9 58.3    10.8 0.3933 64.2    10.7 64.1    10.8 0.8294Male 2,174 (76.0) 2,145 (76.4) 0.7404 4,731 (70.3) 4,804 (70.8) 0.5992BMI, kg/m 2 25.9    4.4 25.9    4.3 0.8158 26.7    4.4 26.7    4.4 0.7273Race 0.5564 0.0025Caucasian 2,718 (95.0) 2,665 (94.9) 6,378 (94.8) 6,415 (94.5)Black 92 (3.2) 81 (2.9) 169 (2.5) 210 (3.1)Asian 13 (0.5) 15 (0.5) 65 (1.0) 35 (0.5)Other 37 (1.3) 47 (1.7) 114 (1.7) 130 (1.9)Risk factorsHypertension 1,225 (42.8) 1,187 (42.3) 0.6698 3,679 (54.7) 3,793 (55.9) 0.1738Diabetes mellitus 451 (15.8) 425 (15.1) 0.5092 1,510 (22.5) 1,494 (22.0) 0.5318Dyslipidemia 1,132 (39.6) 1,156 (41.2) 0.2232 2,845 (42.3) 2,770 (40.8) 0.0762Medical historyStable angina 510 (17.8) 525 (18.7) 0.3997 1,561 (23.2) 1,575 (23.2) 0.9862Unstable angina 207 (7.2) 208 (7.4) 0.8063 617 (9.2) 629 (9.3) 0.8561Atrial  󿬁 brillation 56 (2.0) 87 (3.1) 0.0062 337 (5.0) 331 (4.9) 0.7161Cardiac surgery 142 (5.0) 157 (5.6) 0.2917 566 (8.4) 623 (9.2) 0.1188Other cardiac arrhythmia 242 (8.5) 246 (8.8) 0.6881 734 (10.9) 821 (12.1) 0.0318Cardiac valve disease 79 (2.8) 81 (2.9) 0.7809 282 (4.2) 305 (4.5) 0.3935Cardiomegaly 83 (2.9) 108 (3.8) 0.0489 333 (5.0) 361 (5.3) 0.3355Congestive heart failure 110 (3.8) 116 (4.1) 0.5836 414 (6.2) 433 (6.4) 0.5947Qualifying condition 0.8084 0.8961Ischemic stroke 719 (25.1) 708 (25.2) 2,479 (36.9) 2,525 (37.2)Peripheral artery disease 1,235 (43.2) 1,232 (43.9) 1,994 (29.6) 1,991 (29.3)Myocardial infarction 906 (31.7) 868 (30.9) 2,253 (33.5) 2,274 (33.5) Values are mean    SD or n (%).BMI  ¼  body mass index. JACC Vol. 63, No. 8, 2014  Ferreiro  et al  . March 4, 2014:769 – 77  Smoking Effects on Clopidogrel or Aspirin Monotherapy 771  Effect of smoking status on study treatment: clopidogrel versus aspirin.  In aspirin-treated patients, the unadjustedanalysis showed no signi 󿬁 cant difference according tosmoking status (current smokers vs. ex-smokers/never-smoked subjects) in the overall population (10.8% vs.10.6%, HR: 1.11 [95% CI: 0.97 to 1.27]; p  ¼  0.14).However, in the adjusted model, current smokers hada higher risk of ischemic outcomes (HR: 1.39 [95% CI: 1.20to 1.60]; p < 0.001), an effect that was consistent among allqualifying conditions. Similarly, the impact on ischemicoutcomes in clopidogrel-treated patients was not observedin the unadjusted model (8.3% vs. 10.4%, HR: 0.87 [95%CI: 0.75 to 1.01]; p  ¼  0.07), but it reached signi 󿬁 cancein the adjusted analysis (HR: 1.19 [95% CI: 1.02 to 1.39];p  ¼  0.03). A signi 󿬁 cant interaction between study treatment andsmoking status was found (p  ¼  0.01 for interaction) whenevaluated as a dichotomous variable (current smokers vs.ex-smokers/never-smoked patients). In particular, clopidogrel-treated patients had no reduction in the incidence of theprimary ef  󿬁 cacy outcome compared with aspirin-treatedpatients in the combined group of ex-smokers/never-smoked patients (10.4% vs. 10.6%; HR: 0.99 [95% CI:0.89 to 1.10]; p  ¼  0.73), whereas patients treated withclopidogrel in the current smoker group had a signi 󿬁 cantly lower rate of ischemic events (8.3% vs. 10.8%; HR: 0.76[95% CI: 0.64 to 0.90]; p  ¼  0.001) than aspirin-treatedpatients (Fig. 1). This trend toward a lower risk of ischemic events among clopidogrel-treated subjects wasobserved in all qualifying conditions (recent ischemic stroke:14.0% vs. 16.1%, HR: 0.88 [95% CI: 0.67 to 1.16]; recent MI: 7.4% vs. 8.7%, HR: 0.88 [95% CI: 0.63 to 1.22];and peripheral artery disease: 5.7% vs. 9.1%, HR: 0.60[95% CI: 0.44 to 0.81]). The bene 󿬁 t of the clopidogrel-treated current smokers subgroup compared with theother 3 subgroups (clopidogrel-treated ex-smokers/never smoked, aspirin-treated current smokers, and aspirin-treated ex-smokers/never smoked) was observed during theentire study follow-up (Fig. 2 A). Among current smokers,in addition to the bene 󿬁 t observed in the combined primary ef  󿬁 cacy endpoint, clopidogrel was associated with a reduc-tion in MI, vascular death, or death from any causecompared with aspirin, with the interaction mainly due tothe difference in the rates of vascular death (Fig. 3). When evaluating smoking status as a variable with3 categories (current smokers, ex-smokers, and never smokers), a signi 󿬁 cant interaction (p  <  0.01) with study treatment for the primary ef  󿬁 cacy endpoint was observedin the overall population due to no observed ef  󿬁 cacy inex-smokers (clopidogrel vs. aspirin: 8.3% vs. 10.8% in current smokers, HR: 0.76 [95% CI: 0.64 to 0.90], p  ¼  0.002;10.1% vs. 9.5% in ex-smokers, HR: 1.10 [95% CI: 0.97 to1.26], p  ¼  0.14; 10.9% vs. 13.1% in patients who never smoked, HR: 0.79 [95% CI: 0.66 to 0.94]; p < 0.01).No interaction between smoking status and study treat-ment was observed for bleeding events when considering the variable smoking status with 3 categories (current smokers, ex-smokers, and never smokers) or dichotomous(current smokers vs. ex-smokers/never-smoked patients):p  ¼  0.35 and p  ¼  0.73 for interaction, respectively. Theincidence of bleeding events in the 4 subgroups of subjectsevaluated according to smoking status and treatment (clopidogrel-treated current smokers, clopidogrel-treatedex-smokers/never smokers, aspirin-treated current smokers,and aspirin-treated ex-smokers/never smokers) was similar,as illustrated in Figure 2B. Discussion  The present analysis of the CAPRIE trial showed that: 1)current smokers, despite being younger and with fewer comorbidities, presented in the adjusted model with an Table 2 Summary of Patients With Ischemic Events and Unadjusted and Adjusted HRs for the Primary Ef  󿬁 cacy EndpointAccording to Smoking Status Never Smokers(n  ¼  4,135)Ex-Smokers(n  ¼  9,381)Current Smokers(n  ¼  5,668)Unadjusted HR(95% CI)Adjusted HR*(95% CI) Overall (N  ¼  19,184) 496 (12.0) 921 (9.8) 541 (9.5) 0.92 (0.82 – 1.03) 0.94 (0.83 – 1.06)0.93 (0.82 – 1.06) 1.24 (1.08 – 1.42)1.02 (0.91 – 1.13) 1.32 (1.18 – 1.47)Ischemic stroke (n  ¼  6,431) 296 (13.4) 383 (13.7) 215 (15.1) 1.01 (0.87 – 1.18) 0.98 (0.83 – 1.15)1.11 (0.93 – 1.32) 1.34 (1.10 – 1.62)1.09 (0.93 – 1.29) 1.37 (1.15 – 1.63)Myocardial infarction (n  ¼  6,301) 139 (10.3) 290 (9.1) 143 (8.1) 0.87 (0.71 – 1.07) 1.00 (0.81 – 1.24)0.78 (0.62 – 0.98) 1.18 (0.91 – 1.52)0.89 (0.73 – 1.09) 1.18 (0.96 – 1.45)Peripheral artery disease (n  ¼  6,452) 61 (10.6) 248 (7.3) 183 (7.4) 0.65 (0.49 – 0.86) 0.71 (0.53 – 0.96)0.68 (0.51 – 0.91) 1.02 (0.74 – 1.41)1.05 (0.87 – 1.28) 1.43 (1.18 – 1.75) Values are n (%). In the Unadjusted and Adjusted HR columns, the  󿬁 rst hazard ratio (HR) is for ex-smokers versus never smokers, the second hazard ratio is for current smokers versus never smokers, and thethird hazard ratio is for current smokers versus ex-smokers. *Model adjusted for treatment, age, sex, body mass index, race, diabetes, hypercholesterolemia, congestive heart failure, cardiomegaly, atrial 󿬁 brillation, stable angina, unstable angina, previous myocardial infarction, transient ischemic attack, reversible ischemic neurological de 󿬁 cit, previous ischemic stroke, intermittent claudication, and leg amputation.CI  ¼  con 󿬁 dence interval. Ferreiro  et al  .  JACC Vol. 63, No. 8, 2014  Smoking Effects on Clopidogrel or Aspirin Monotherapy   March 4, 2014:769 – 77 772
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