1、lopidogrel in nstable anginato preventecurrentventsdisclaimerthis slide kit presents new data to support the rationale for the use of adp receptor antagonists for approved and unapproved indications. the slide kit has been prepared for medical and scientific purposes. it contains information on a us

2、e that is not approved by the fda and should not be construed as an inducement to use clopidogrel for unapproved indications. neither sanofi-synthelabo inc., bristol-myers squibb nor the partnership recommends the use of clopidogrel in any manner inconsistent with that described in the full prescrib

3、ing information.curecure study investigators. eur heart j. 2000;21:2033-2041.pursuit investigators. am j cardiol. 1999;83:1147-1151.rationaleldespite treatment with aspirin and heparin, the incidence of mi and cv death during hospitalization remains high, 6-8% llong term, the incidence of these even

4、ts remain high at 6-8% per year lthe majority of patients (80%) who enter the hospital with acute coronary syndrome (acs) are already on aspirin therapylthe negative findings of the oral gp iib/iiias underscores the need for alternative strategies to treat acs curecure study investigators. eur heart

5、 j. 2000; 21:2033-2041.study objectivesprimarylevaluate the early and long-term efficacy of clopidogrel vs placebo, both given in addition to aspirin and other standard therapy in preventing ischemic complications in patients with acs without st-segment elevation (unstable angina or non-st-segment e

6、levation mi) cureclopidogrel 75mg q.d. + asa 75-325 mg q.d.* (6259 patients)placebo + asa 75-325 mg q.d.*(6303 patients)day 16 m. visit9 m. visit12 m.or final visit3 m. visitdischarge visit1 m. visitpatients withacute coronarysyndrome(unstable angina or non-st-segment elevation mi)placebo loading do

7、ser = randomization* in combination with other standard therapy. n engl j med. 2001;345:494-502.study design3 months double-blind treatment 12 monthsclopidogrel 300 mg loading dosecure1 cure study protocol (data on file, sanofi-synthelabo, inc.)2 cure study investigators. eur heart j. 2000; 21:2033-

8、2041.key inclusion criteria lage 21 years1lsuspected ua or nstemi (no st 1.0 mm)2lpresentation 24 hours after onset of symptoms2 lecg changes compatible with ischemia or elevated cardiac enzymes or troponin i or t 2 x uln2cure1 cure study investigators. eur heart j. 2000; 21:2033-2041.2 cure study p

9、rotocol (data on file, sanofi-synthelabo, inc.)key exclusion criterialnyha class iv heart failure1luncontrolled hypertension2lcurrent use of anticoagulants1, clopidogrel, ticlopidine, or nsaids2, or gp iib/iiia inhibitor within 3 days1lpci or cabg within 3 months1lhistory of severe thrombocytopenia

10、or neutropenia2lat high risk for bleeding1lcontraindications to antithrombotic or antiplatelet therapy1cureoutcome definitions mi:stroke:cv death:refractory ischemia:severe ischemia:recurrent angina:. n engl j med. 2001;345:494-502.cureefficacy analysesfirst primary end pointfirst occurrence of any

11、component of the cluster of: myocardial infarction stroke (ischemic, hemorrhagic, or of uncertain type) cardiovascular death. n engl j med. 2001;345:494-502.cureage (mean) 64.264.2mean time from pain onset to randomization (hrs)14.114.2mean heart rate (beats/min)73.073.2 mean systolic bp (mm hg)134.

12、1134.4 female (%)38.338.7diagnosis at entryunstable angina (%)74.974.9nonst-segment elevation mi (%)25.125.1ecg abnormalities (%)93.993.7placebon = 6303clopidogreln = 6259baseline characteristics. n engl j med. 2001;345:494-502.curehistory of mi32.032.4cabg surgery/ptca18.117.7stroke3.74.4heart fail

13、ure7.87.4hypertension57.859.9diabetes22.822.4current or former smoker60.960.6placebon = 6303(%)clopidogreln = 6259(%). n engl j med. 2001;345:494-502.patient historycurehistory abnormal ecg93.993.7st-segment dep 1 mm 42.042.2st-segment elevation 1 mm 3.23.2major t-wave inversion25.925.4other t-wave

14、inversion11.311.5other abnormalities10.910.7placebo(%)clopidogrel(%). n engl j med. 2001;345:494-502.ecg abnormality type cure0.000.020.040.060.080.100.120.14cumulative hazard rate* in combination with standard therapy. n engl j med. 2001;345:494-502.primary end point - mi/stroke/cv deathcure0.000.0

15、10.020.030.040.050.06cumulative hazard rate* in combination with standard therapy. n engl j med. 2001;345:494-502.mi/stroke/cv death within 30 dayscurecv death, mi, stroke (primary11.4%9.3%20% 0.001end point)mi6.7%5.2%23%stroke1.4%1.2%14%cv death5.5%5.1%7%relative risk reductionp valueoutcomeplacebo

16、 + asa*n = 6303clopidogrel + asa*n = 6259* in combination with standard therapy. n engl j med. 2001;345:494-502.main efficacy results - primary endpointcurerrrp valueend pointplacebo + asa*clopidogrel + asa*main efficacy results - second primary end point* in combination with standard therapy* not s

17、ignificant heart failure was a secondary end point18.8%16.5%14% 0.0019.3%8.7%7%ns* refractory ischemiain hospital2.0%1.4%32% 65 yr old620813.315.3st-segment deviation627511.514.3no st-segment deviation62877.08.6enzymes elevated at entry317610.713.0enzymes not elevated at entry93868.810.9diabetes2840

18、14.216.7no diabetes97227.99.9low risk41875.16.7intermediate risk41856.59.4high risk418416.318.0history of revascularization22468.414.4no history of revascularization103169.510.7revascularization after randomization457711.513.9no revascularization after randomization79858.110.0placebo + asa*character

19、isticno. ofpatientsclopidogrel + asa*percentage of patients with eventplacebo betterclopidogrel betterrelative risk (95% ci)1.21.00.80.60.4* in combination with standard therapy. n engl j med. 2001;345:494-502.beneficial outcomes with clopidogrel in various subgroupscurerelative riskreductionp value

20、placebo + asa*n = 6303clopidogrel + asa*n = 6259ci* as part of standard therapy. n engl j med. 2001;345:494-502.thrombolytic and iv gp iib/iiia inhibitor use after randomizationcure. n engl j med. 2001;345:494-502.definition of bleedingbleeding was defined as “major” and “minor”major bleeding was de

21、fined as follows:llife threatening: fatal, symptomatic intracranial hemorrhage, leading to a drop in hemoglobin of at least 5 g/dl, significant hypotention requiring iv inotropes, requiring surgical intervention, or requiring transfusion of 4 or more units of bloodlnon-life-threatening: substantiall

22、y disabling, intraocular bleeding leading to vision loss, or requiring at least 2 units of bloodcureplacebo + asa*n = 6303clopidogrel + asa*n = 6259major bleedinglife-threatening bleeding1.8%2.2% non-life-threatening bleeding0.9%1.5% minor bleedingend point* in combination with standard therapy* p =

23、 0.001; p = ns; p = 0.002; p 0.001. n engl j med. 2001;345:494-502.bleeding resultscurelife-threatening1.82.2placebo + asa*n = 6303(%)clopidogrel + asa*n = 6259(%)* in combination with standard therapy. n engl j med. 2001;345:494-502.life-threatening bleedingcureactive*difftrialnplacebo* in addition

24、 to standard therapy including aspirin and heparinprism-plus investigators. n engl j med. 1998;338:1488-97.pursuit investigators. n engl j med. 1998;339:436-43.capture investigators. lancet. 1997;349 (9063):1429-1435. n engl j med. 2001;345:494-502.major bleeding in iv gp iib/iiia antagonists acs tr

25、ials vs cure: within 30 dayscureconclusionsin the cure study of 12,562 patients with acs without st-segment elevation:lclopidogrel demonstrated a 20% relative risk reduction in mi, stroke or cardiovascular death with long-term use ( 0.001)lthe kaplan-meier curves began to diverge within hours and co

26、ntinued to diverge over the course of 12 monthslclopidogrel also demonstrated a 14% relative risk reduction in mi, stroke, cardiovascular death or refractory ischemia (0.001)clopidogrel in addition to aspirin and other standard therapy demonstrated an early effect (within hours) and sustained long-t

27、erm benefit throughout the entire study period of 12 months. n engl j med. 2001;345:494-502.cure. n engl j med. 2001;345:494-502.conclusionsminor bleeding was increased, but there was no increase in life-threatening bleeds (including intracranial bleeds) 18% relative risk reduction in heart failure

28、( = 0.03)significant reductions in the reported use of: iv gp iib/iiia inhibitor: 18% ( = 0.003) thrombolytics: 43% ( 6516.9%13.4%0.790.57-1.08male11.9%7.9%0.650.48-0.87female14.1%11.0%0.770.52-1.15diabetes16.5%12.9%0.770.48-1.22no diabetes11.7%7.9%0.660.50-0.87during initial hosp12.0%8.3%0.680.50-0

29、.92after initial hosp13.8%9.8%0.700.48-1.02rrplacebo+ asa*clopidogrel+ asa*placebo betterclopidogrel betterrelative risk (95% ci)95% ci0.11.010.0* in combination with standard therapymehta, sr. et al for the cure trial investigators. lancet. august 2001;21:2033-41.subgroup analysispci-curerrrp value

30、placebo + asa*n = 1345clopidogrel + asa*n = 1313iv gp iib/ iiia use26.6%20.9%21%0.001secondrevascularization17.1%14.2%18%0.049* in combination with standard therapymehta, sr. et al for the cure trial investigators. lancet. august 2001;21:2033-41.other outcomespci-cureplacebo + asa*clopidogrel + asa* in combination with standard