©2008 Schattauer GmbH,Stuttgart
CardiovascularBiology andCell Signalling
Clopidogrel in addition to aspirin reduces in-hospital major cardiac andcerebrovascular events in unselected patients withacuteST segment elevationmyocardial
UweZeymer1,2,Anselm K. Gitt1,2,Claus Jünger2,Timm Bauer1,Oliver Koeth1,Tobias Heer1,Bernd Mark1, Ralf Zahn1,Martin Gottwik3,Jochen Senges1,2 1Herzzentrum Ludwigshafen, MedizinscheKlinik B, Ludwigshafen, Germany; 2Institutfür Herzinfarktforschung Ludwigshafen an derUniversität Heidelberg; 3Klinikum Nürnberg-Süd, Medizinische Klinik8,Nürnberg, Germany
Summary We soughttoassess theeffectofclopidogrelonin-hospital theaspirin plus clopidogrelgroup,compared to the aspirin alone events in unselectedpatientswith acute ST elevation myocardial group in the entirecohortand allthree reperfusionstrategy infarction (STEMI).In aretrospectiveanalysis of consecutivepa- groups (entiregroup odds ratio 0.60,95% CI 0.49–0.72 ,norep- tientsenrolled in the Acute CoronarySyndromes (ACOS) reg- erfusionOR0.69,95% CI 0.51–0.94,fibrinolysis OR 0.62,95% CI istrywith acute STEMI we compared outcomesofeitherad- 0.44–0.88, primaryPCI OR 0.54,95% CI 0.39–0.74).Therewas junctivetherapy with aspirin alone or aspirin plus clopidogrel asignificant increase in major bleeding complications with clopi- within 24 hours after admission.A total of 7,559 patients were dogrel(7.1% vs.3.4%, p<0.001).Inclinical practice earlyadjunc- included in this analysis,ofwhom 3,541 were treatedwith as- tivetherapy with clopidogrelinaddition to aspirin in patients pirin alone,and 4,018 withdual antiplatelettherapy.The multi- with STEMI is associated with asignificant reduction of in-hospi- variable analysis with adjustment forbaseline characteristics and tal MACCE regardless of theinitial reperfusionstrategy.This ad- treatments showedthat the rate of in-hospital MACCE (death, vantage was associated with an increase in major bleeding com- non-fatal reinfarction,non-fatalstroke) was significantlylower in plications.
Keywords Clopidogrel, reperfusiontherapy,primary percutaneous coron- aryintervention, ST elevation myocardial infarction, prognosis, clinical practice ThrombHaemost 2008; 99: 155–160
Introduction ducedplateletactivation and thrombotic and ischemic compli- cations after oneyear.Recently,the beneficial effect of clopido- Platelets play an important roleinthe pathogenesis of acute cor- grel in patients with STEMItreated with fibrinolysis has been onarysyndromes. It has beenwellestablished thatantiplatelet shown in the CLopidogrel as Adjunctive Reperfusion TherapY therapywith aspirinimproves the prognosis in patients with (CLARITY-TIMI28) study (6).Furthermore alarge clinical acute ST-segment elevation myocardialinfarction (STEMI) and study performed in patients with and withoutreperfusion ther- is therefore astandard treatment in these patients (1, 2). Aspirin apyinChina, the ClOpidogrel and Metoprolol in Myoycardial only blocks the arachnidon-acid pathway of plateletaggregation, Infarction Trial(COMMIT) trialshowedareduction in four- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. while clopidogrel blocks the P2Y12 adenosine diphosphate re- week mortality with clopidogrel (7). In addition, clopidogrel ceptor and acts synergisticallywith aspirin(3). In patients with pretreatment reduced ischemic complications before and after acute coronarysyndromeswithoutSTelevations (4), and pa- percutaneouscoronary intervention (PCI)inthe PCI-CLARITY tients with electivepercutaneous coronaryintervention (PCI) substudy (8).However,little is known about the efficacyand (5),the therapywith clopidogrel in addition to aspirinfurther re- safety of clopidogrel after STEMI in clinicalpractice. We there-
Correspondence to: Financial Support Priv.Doz. Dr.Uwe Zeymer Supportedbyanunrestrictedgrant of Sanofi-Aventis AG,Berlin, Germany Herzzentrum Ludwigshafen Department of Cardiology, MedizinischeKlinik B Received September 10, 2007 Bremserstrasse 79 Accepted after major revision October 19,2007 67063 Ludwigshafen, Germany Te l.: +49621 503 4045, Fax: +49 621 503 4002 Prepublished onlineDecember 5, 2007 E-mail: [email protected] doi:10.1160/TH07-09-0556
155 Zeymer et al. ClopidogrelinSTEMI fore analyzed datafrom the Acute COronary Syndromes demonstration of occlusion of the infarct vessel. Strokewas de- (ACOS) registry to determine the impact of clopidogrel on in- fined as the occurrence of persistent specific neurologic deficits. hospitalevents in patients with STEMI treatedwith or without Major adverse cardiacand cerebrovascularevents (MACCE) earlyreperfusion therapy. were classified as death, non-fatalreinfarction and non-fatal stroke. Major bleeding wasdefinedasbleeding needing blood Methods transfusion, intracranial bleeding,bleeding needing surgical in- tervention or clinically relevant bleeding as judged by the treat- The ACOS registry ing physician. The Acute CoronarySyndromesRegistry(ACOS)isaprospec- tive,multi-center, observationalstudy on currenttreatment of Statisticalmethods acutecoronary syndromes(STEMI, NSTEMI, and unstable an- Data are presented as absolute numbers, percentage or medians ginapectoris) (9, 10). Consecutivepatients were recruitedwith- with25th and 75th percentiles as appropriate. Wheneverpossible, in the period from June 2000 to December 2002.The 154 partici- percentageswere used to describe patient populations.The fre- pating hospitals were located throughoutGermany and included quencies of categorialvariablesintwo populations were com- university hospitals, community hospitals and tertiary care pared by χ2 test and by calculating odds-ratios (OR)and 95% centers allproviding intensive care units and earlyreperfusion confidenceintervals (CI). Continuous variableswere compared therapy.Two thirds (n=102)ofthe hospitals had interventional by two-tailedWilcoxon rank sum test. The effect of clopidogrel facilities. During the entirestudy period patients with acutecor- on in-hospitaldeathand MACCEwas evaluatedbyamutivari- onarysyndromeswere registered prospectivelyover12months able regression modelcalculating the oddsratio and the 95% and followedduring their clinicalcourse to document patient confidenceinterval. Thefollowing variableswere includedin characteristics, acute therapyand hospital course. The present the multivariable regression model: age, sex, diabetes mellitus, study is an analysis of consecutivepatients with STEMItreated hypertension, hyperlipidemia, prior stroke, 3-vesseldisease, with eitheraspirin monotherapy or dual plateletinhibition with renal insufficiency, anterior infarct location, cardiogenic shock, aspirin and clopidogrel within 24 hours of admission. reduced left ventricularfunction, elective revascularization, acutetreatment with GP IIb/IIIa inhibitors, beta-blockers, sta- Data collection tins,ACE-inhibitors, fibrinolysis, primaryPCI and stentimplan- Data on patient characteristics on admissionwere recorded,in- tation. In the subgroup of patients treatedwith primary PCI stent cluding age,gender,cardiovascularrisk factors, concomitant implantation and succesfulPCI were includedinthe multivariate diseases,prior myocardialinfarction, prior stroke, prior cardio- analysis. P-values <0.05were consideredsignificant.All p-valu- vascularinterventions and chronic medicaltreatment,aswellas es are the results of two-tailedtests. Theanalysis wasperformed data on symptoms and prehospital delay. Data on electrocardio- with the SAS systemrelease8.2 on apersonal computer(SAS grafic findings, biochemical markers, reperfusion therapy, and Institute,Inc., Cary, NC,USA). adjunctivetherapywere documented. Major cardiovascularand cerebrovascularadverse eventsuntil hospital dischargewere rec- Results orded. Everyparticipating center wascommitted by written consent Baseline characteristics to includeevery consecutivepatient with acutecoronary syn- From 2000 and 2002, atotal of 16,814 consecutive patients from drome.All patients gave informedconsent for processing their 154 hospitals with acute coronarysyndromeswere enrolledin anonymous data.Datawere collected on three record formsby the ACOS registry.Ofthese,8,305 had STEMI. Sevenhundred the treating physicians. Completeddatasheets were senttothe forty-six (0.8%)patients were excluded whohad notbeen centraldataprocessing center Institut für Herzinfarktforschung treated with aspirinwithin 24 hours after admission.Therefore, Ludwigshafen for uniformmonitoring and registration. Source this analysis contains 7,559 patients; 3,541 (46.8%) were treated data verification wasperformed by comparison of the registry with aspirinalone and 4,018(53.2 %) with aspirin and clopido- data with hospital records in randomlyselected 800patients in grel.Ofthese,2,141 (28.3%)receivednoreperfusion therapy, This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. randomly chosenparticipating centers.The entire data were 2,186 (28.9 %) fibrinolysis and 3,232 primaryPCI (42.8%). The double keyedand regularly checked forinconsistencies and out baseline characteristicsofthe patients of the entire cohortand in of range errors.The study wasapprovedbythe ethicalcommittee the threereperfusion strategy groups areshown in Table1. of Landesärztekammer Mainz. In-hospitalevents Definitions The total in-hospital mortality waslower in the patients treated STEMI wasdiagnosedinthe presenceofthe following twocrite- with clopidogrel and aspirincompared to the group treatedwith ria: persistent angina pectoris for ≥ 20 min and ST-segment elev- aspirinalone (12.4%versus 5.1%,p<0.001) (Table 2). However, ation of >1mm in ≥ 2standard leads or ≥ 2mmin≥2contigu- in the multivariable analysis asignificant reduction in mortality ous precordial leads, or the presenceofaleft bundle branch with clopidogrel wasnolonger observed, onlyatrend towards re- block and elevations of cardiacenzymesCK-MB or troponin. duced mortality in the entiregroupand patients treatedwith pri- SuccessfulPCI wasdefinedasTIMI 3patencyand residual ste- mary PCI (Table 3).MACCE were observedsignificantly less nosis of <50% after PCI. Reinfarction wasdiagnosedincaseof ofteninthe clopidogrel groups (Fig. 1). The absolute reduction recurrent angina with re-elevation of CK-MB or angiographic in MACCEwas higher in patients with higher baseline risk as-
156 Zeymer et al. ClopidogrelinSTEMI
Ta ble1:Baseline characteristics and treatments during the index hospitalisation in theentiregroup and subgroups according to theinitialreperfusionstrategy.
Patients Entiregroup Without early reperfusiontherapy Treated withfibrinolysis Treated withprimaryPCI (n=7559) (n=2141) (n=2186) (n=3232) Aspirin Aspirin+ p- value Aspirin Aspirin + p- value Aspirin Aspirin + p-value Aspirin Aspirin + p-Value N=3541 clopidogrel n=1604 clopidogrel n=1448 clopidogrel n=489 clopidogrel n=4018 n=537 n=738 n=2743 Baseline characteristics Age (years), 68.2 63.8 <0.001 73.5 70.3 0.001 64.3 60.9 <0.001 63.8 63.5 0.2 median (58.3–77.0) (53.8–72.4) (63.4–80.6) (61.6–78.7) (54.2–72.7) (51.1–68.0) (54.8–72.5) (53.4–71.8) Women 1196 1098 <0.001 678 193 0.01 376 170 0.1 142 726 0.2 (33.8 %) (27.1 %) (42.3 %) (35.9%) (26.0 %) (23.0 %) (29.0 %) (26.5 %) Medicalhistory Prior 633 565 <0.001 347 129 0.2 202 93 0.4 84 342 0.005 myocardial (17.9 %) (14.1 %) (21.6 %) (24.0 %) (14.0 %) (12.6 %) (17.2 %) (12.5 %) infarction Prior PCIor 295 439 <0.001 132 84 <0.001 102 69 0.06 61 286 0.2 CABG (8.3 %) (10.9 %) (8.2 %) (15.6 %) (7.0 %) (9.3 %) (12.5 %) (10.4 %) PriorStroke/ 241 193 <0.001 155 45 0.4 61 23 0.2 25 125 0.6 TIA (6.8 %) (4.8 %) (9.7 %) (8.4 %) (4.2 %) (3.1 %) (5.1 %) (4.6 %) Risk factors Hypertension 2129 2326 0.05 1037 362 0.2 780 401 0.8 312 1562 0.005 (60.1 %) (57.9 %) (64.7 %) (67.4 %) (53.9 %) (54.3 %) (63.8 %) (56.9 %) Diabetes 1038 953 <0.001 588 186 0.4 314 157 0.8 136 610 0.007 mellitus (29.3 %) (23.7 %) (36.7 %) (34.6 %) (21.7 %) (21.3 %) (27.8 %) (22.2 %) Hypercholes- 2166 2538 0.08 929 313 0.9 917 482 0.4 320 1742 0.4 terolemia* (61.2 %) (63.2 %) (57.9 %) (58.3 %) (63.3 %) (65.3 %) (65.4 %) (63.5 %) Smoker 1142 1604 <0.001 370 150 0.02 604 331 0.2 168 1123 0.006 (32.3 %) (39.3 %) (23.1 %) (27.9 %) (41.7 %) (44.9 %) (34.4 %) (40.9 %) Renal impair- 143 81 <0.001 86 23 0.4 34 7 0.02 23 51 <0.001 ment‡ (%) (4.0 %) (2.0 %) (5.4 %) (4.3 %) (2.3 %) (0.9 %) (4.7 %) (1.9 %) Findingsonadmission Prehospital 1835 1941 <0.001 1117 340 0.01 429 248 0.09 289 1353 <0.001 delay>3h (54.8 %) (50.3 %) (74.9 %) (69.1 %) (30.8 %) (34.4 %) (62.0 %) (51.2 %) Cardiogenic 410 318 <0.001 202 40 0.001 158 72 0.4 50 206 0.04 shock (11.6 %) (7.9 %) (12.6 %) (7.4 %) (10.9 %) (9.8 %) (10.2 %) (7.5 %) Heart rate 748 546 <0.001 460 122 0.007 207 93/737 0.3 81 330 0.005 >100 bpm (21.1 %) (13.6 %) (28.7 %) (22.7 %) (14.3 %) (12.6 %) (16.6 %) (12.0 %) Anterior in- 648/1278 1187/2465 0.1 293/549 207/361 0.2 273/549 214/442 0.7 82/180 765/1661 0.9 farct location (50.7 %) (48.2 %) (53.4 %) (57.3 %) (49.7 %) (48.4 %) (45.6 %) (46.1 %) Revascularization procedures during administration PCI 542/2966 239/3901 <0.001 215/1308 112/482 0.00096 504 597 <0.001 14/470 41/2710 0.02 >48hours (18.3 %) (6.1 %) (16.4 %) (23.2 %) (34.8 %) (80.9%) (3.0 %) (1.5 %) To talstent 499 2994 <0.001 67 68 <0.001 202 497 <0.001 83 2144 <0.001 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. rate (
157 Zeymer et al. ClopidogrelinSTEMI
Ta ble2:In-hospital mortalityand non- Aspirin Aspirin+ P-value Odds ratio fatal events in patients withdual antipla- Clopidogrel (95% CI) telet therapy compared to aspirinalone Entiregroup n=3541 n=4018 in theunivariateanalysis. Death 438 206 <0.001 0.38 (0.32–0.45) (12.4 %) (5.1 %) Non-fatal reinfarction 110 206 <0.001 0.42 (0.33–0.53) (6.6 %) (2.9 %) Non-fatal stroke 32 18 0.006 0.46 (0.26–0.81) (1.0 %) 0.5 % No reperfusion n=1604 n=559 Death 15.6 %9.3 %0.00020.55 (0.40–0.76) Non-fatal reinfarction 7.8 %3.9 %0.003 0.48 (0.29–0.79) Non-fatal stroke 1.0 %0.8 %0.8 0.85 (0.28–2.63) Fibrinolysis n=1448n=738 Death 9.7 %5.6 %0.00080.55 (0.38–0.78) Non-fatal reinfarction 5.7 %3.0 %0.006 0.51 (0.31–0.84) Non-fatal stroke 1.0 %0.4 %0.17 0.43 (0.12–1.52) PrimaryPCI n=489 n=2743 Death 45 115 <0.00010.42 (0.30–0.60) (9.4 %) (4.2 %) Non-fatal reinfarction 25 70 0.008 0.46 (0.29–0.73) (5.6 %) (2.7 %) Non-fatal stroke 6 11 0.01 0.31 (0.11–0.83) (1.4 %) (0.4 %)
Ta ble3:Oddsratios forin-hospital mortalityand MACCE TIMI 3flowand less than 50% stenosis after PCIwas includedin (death, non-fatal reinfarction and non-fatal stroke)inthe multi- the mutivariable analysis in the PCI group. variable analysis in theentiregroup and in-patients treated withand withoutearlyreperfusiontherapy treated withdual antiplatelet therapycompared to aspirinalone. Bleedingcomplications There wasasignificant increaseinmajor bleeding complications Odds ratio 95 %Confidence with clopidogrel (7.1%versus 3.4%,odds ratio 2.2, 95% CI interval 1.5–3.1,p <0.0001). The rate of in-hospital major bleeding com- Mortality plications in the subgroups is shown in Table4and showedasig- nificant increase in major bleeding complications in the patients Entiregroup 0.65 0.42–1.00 without earlyreperfusion and fibrinolysis. The rate of intracran- No reperfusion 0.84 0.58–1.23 ial hemmorrhage was0.2% versus0.4% with and without clopi- Fibrinolysis 0.83 0.52–1.33 dogrel,while the rate of tranfusions was3.2% versus1.8%, re-
PrimaryPCI 0.65 0.42–1.00 spectively.The rate of patients with MACCEand major bleeding This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. MACCE in patients with and withoutclopidogrel was0.6% versus1.0% in the total population ((p=0.2), 1.0% versus0.7% in the group Entiregroup 0.61 0.51–0.73 without reperfusion therapy(p=0.6), 0.9% versus0.9% in the No reperfusion 0.69 0.51–0.94 group with fibrinolysis (p=0.9) and 0.5% versus2.2% in the Fibrinolysis 0.62 0.44–0.89 group with primaryPCI (p< 0.01), respectively PrimaryPCI 0.50 0.35–0.72 Netclinical benefit The incidenceofthe combined endpoint MACCEormajor bleeding in patients with and withoutclopidogrel was12.5 % sesedwith the TIMI risk score (11)(Fig. 2). The multivariable versus21.0% in the total population (p <0.001), 15.6 %versus analysis of MACCE after adjustment for baseline characteristics 24.9%inthe group without reperfusion therapy(p<0.001), 13.9 and adjunctivetherapiesshowedthat the rate of MACCEwere %versus 17.1 %inthe group with fibrinolysis (p=0.1) and significantlylower with dualantiplatelet therapy(Table3). This 11.4% versus19.4 %inthe group with primaryPCI (p <0.01), significant advantage persisted when successfulPCI defined as respectively.
158 Zeymer et al. ClopidogrelinSTEMI
Figure1:In-hospital MACCEinthe en- tire groupand subgroups according to theinitialreperfusionstrategy.
Figure2:Rate of of in-hospital MACCE according to thebaseline risk of the pa- tients as assessedbytheTIMI risk score.
Ta ble4:In-hospital major bleeding com- Reperfusion strategy Aspirin Aspirin + P-value Odds ratio plications. Clopidogrel (95 %CI) Entiregroup 3.4 %7.1 %<0.001 2.2 (1.5–3.1) No reperfusion 2.0 %5.1 %0.01 2.6 (1.2–5.8) Fibrinolysis 4.1 %9.4 %0.002 2.4 (1.3–4.4) PrimaryPCI 6.3 %7.1 %0.7 1.1 (0.6–2.3) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Discussion fibrinolysis in patients <75years (6). Patents with STEMIre- ceiving astandard fibrinolytic regimen including aspirin were In ouranalysis clopidogrel,when giveninaddition to aspirin, randomisedtoreceive aloading dose of 300 mg clopidogrel and significantly reduced the oddsfor mortality,recurrentmyo- 75 mg dailythereafterorplacebo.The primaryendpoint of an oc- cardialinfarction and strokeinunslected patients with STEMI in cludedinfarct vesselafter 2–8days, deathand reinfaction was clinicalpractice, regardless of the initialreperfusion strategy. significantlyreduced with clopidogrel.Inaddition, the compos- Our analysis is the first evaluation of alarge prospectiveregistry ite endpoint of death, reinfarction and urgent revascularization with STEMIpatients, whichinvestigates the effect of earlyad- until day30occurred significantlymore ofteninthe placebo ministration of clopidogrel in patients with STEMI. Tworecent group. There wasnoincrease in major bleeding complications randomisedtrials have evaluatedthe role of clopidogrel in addi- with clopidogrel,especially the rate of intracranialbleedingswas tion to aspirininpatients with STEMI: the CLARITY- TIMI 28 similar.Inaddition, clopidogrel reduced cardiovasculardeath trial showedthe safety and efficacyofclopidogrel in addition to and reinfarction in patients in CLARITYtreated with PCI during
159 Zeymer et al. ClopidogrelinSTEMI the indexhospitalisation (8).The beneficial effect of ashort- more bleedings. However, the netclinical benefit incorporationg termtherapyuptofour weeks with clopidogrel has been demon- bleeding complications into outcome wasinfavour of clopido- strated in the COMMITstudy (7), whichincludedalarge grel in the totalpatient population and patients without reperfu- numberofpatients with STEMItreated with fibrinolysis or with- sion therapyand with primaryPCI. out earlyreperfusion therapy.Here, clopidogrel giveninaddition to aspirin leadtoa0.7% reduction in all causes of mortality. Limitations Again therewas no increase in the rate of major bleeding compli- The present reportisnot arandomized,controlled study evalu- cations. ating the effect of clopidogrel in addition to aspirininpatients In the ACOS registry consecutivepatients were enrolled, in- with STEMI. In the ACOS registry,treatment with clopidogrel cluding high risk patients with advanced age, renal insufficiency, wasleft to the discretion of the physician. This could result in se- cardiogenic shock and resuscitatedpatients. In these unselected lection bias, whichcan notbefullyeliminatedbyamultivariable patients we observedareduction in MACCE with clopidogrel. analysis. In the PCI group, stenting waslessoften used in the as- As shown in Figure 2the absolute reduction in MACCEwas pirinalone group. This might explain that clopidogrel wasnot morepronounced in patients with higher baseline risk as indi- givenduring the earlyphase after STEMI. Another reason might cated by ahigherTIMI risk score.That might indicatethat an im- be the needfor oralanticoagulation. In addition we have no infor- provedantiplatelet therapyisespecially beneficial in high risk mation about the initial loading dose of clopidogrel and can groups. The reduction in mortality seeninthe univariate analysis therefore notevaluate the effect of differentdosing strategies. wasnolonger significant in the multivariable analysis. However, Our definition of bleeding didnot exactly correspond to one the MACCE rate wassignificantly lower, even after adjustment of the establisheddefinitions. However, the definition wasvery for baseline variablesand concomitant therapies. This is consist- closetothe GUSTOsevere and moderate bleeding,which has ent with the findings of the CLARITY-TIMI 28 and the COM- beenshown to correlate closely withclinical outcome (12). MIT trials. In contrast to the resultsinthe randomized clinical trials we observedasignificant increase in bleeding compli- Conclusion cations with dualantiplatelet therapy. This is certainlydue to the In conclusion,our data suggest that clopidogrel improves the inclusion of unselectedpatients with higher risk forbleeding clinical courseofpatients with STEMI. This benefitisobserved complications compared to randomisedtrials and therefore not regardless of the initialreperfusion strategy.This advantage was unexpected. On the other hand it assures that amore effective associatedwith asignificant increase in major bleeding compli- plateletinhibition wasachieved with dualantiplatelet therapy, cations. whichwas notonlyassociatedwith less ischemic eventsbut with
References 1. VandeWerfF,Ardissino D, BetriuA, etal. Manage- cutaneous coronary intervention: arandomized con- 10. Zeymer U, GittAK, JungerC,etal. and theAcute ment of acute myocardialinfarction in patients pres- trolled trial. JAMA 2002;288: 2411–2420. COronary Syndromes (ACOS) registry investigators. enting withST- segment elevation. The Task Force on 6. Sabatine MS, CannonCP, Gibson CM,etal. Addi- Effect of clopidogrel on 1-year mortality in hospital theManagement of Acute Myocardial Infarctionofthe tionofclopidogrel to aspirin and fibrinolytictherapy survivors of acute ST-segment elevationmyocardial in- European Society of Cardiology. EurHeartJ2003; 24: formyocardial infarctionwith ST-segment elevation. N farctioninclinical practice. Eur HeartJ2006; 27: 28–66. Engl JMed 2005; 352:1179–1189. 2661–2666. 2. ISIS 2Collaborative Group:Randomised trialof 7. COMMIT collobarative group.Additionofclopi- 11. MorrowDA, AntmanEM, CharlesworthA,etal. intravenous streptokinase, oral aspirin, both, or neither dogrel to aspirin in 45 852 patients withacute myo- TIMI risk score for St-elevationmyocardial infarction: among 17187 cases of suspectedmyocardial infarction. cardial infarction: randomised placebo-controlledtrial. aconvenient,bedside, clinical scorefor risk assessment Lancet1988;2:349–360. Lancet2005;366: 1607–1621. at presentation: an InTIMEIItrial substudy.Circu- 3. HerbertJM, Frechel D, VallerE,etal. Clopidogrel, 8. Sabatine MS, CannonCP, Gibson CM,etal. Effect lation2000;102: 2031–2037. anovel antiplatelet and antithrombotic drug. Cardiov- of clopidogrel pretreatment beforepercutaneous cor- 12. Steinhubl SR, KastratiA,Berger P. Variationinthe ascDrugRev 1993; 11: 180–198. onary intervention in patients withSt-elevationmyo- definitions of bleedinginclinical trials of patients with 4. The CURE Investigators.Effects of clopidogrel in cardial infarction. The PCI-CLARITY Study.JAMA acute coronary syndromes and undergoing percut- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. additiontoaspirininpatients withacue coronary syn- 2005; 294:1224–1232. aneous coronary intervention and its impact on theap- dromes withoutST- segment elevation. NEngl JMed 9. Zeymer U, Senges J. Qualitätsregister in der Kar- parent safety of antithrombotic drugs.AmHeartJ 2001; 345:494–502. diologie.Bundesgesundheitsbl-Gesundheitsforsch- 2007; 154:3–11. 5. Steinhubl SR, Berger PB,Mann JT, et al. Early and Gesundheitsschutz2004;47: 533–539. sustained dualoral antiplatelettherapyfollowingper-
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