氯吡格雷治療冠心病的幾個(gè)問題與對(duì)策魏盟

1、,氯吡格雷治療冠心病的幾個(gè)問題與對(duì)策,上海市第六人民醫(yī)院魏盟,,斑塊破裂血管壁受損,Von Willebrand 因子、膠原,血小板黏附,血小板聚集,凝血酶（IIa）,組織因子/ VIIa因子復(fù)合物,Xa,纖維蛋白原,纖維蛋白,,抗栓治療,,GP IIb/IIIa受體拮抗劑,,,Platelet Stimuli,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,GP IIb/IIIa integrin,ADP,Epin

2、ephrine,Collagen,Thrombin,Platelet Aggregation,,,,Serotonin,,,,Shear rate,,,AA,TxA2,COX-1,,,,,,,,,Thrombin,,,,,ADP,TXA2,,,ADP P2Y12,,ADP,Activation,COX-1,,clopidogrel bisulfate,,cAMP,Oral Anti-PAR-1 receptors,SCH 530348

3、E 5555,,adapted from Schafer AI. Am J Med. 2019;101:199-209.,,,氯吡格雷治療若干問題與對(duì)策,用藥時(shí)間、劑量、抵抗與新藥氯吡格雷與PPI國(guó)產(chǎn)氯吡格雷循證學(xué)依據(jù)及其意義,,25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with in

4、tended PCIIschemic ECG Δ (80.8%) or ↑c(diǎn)ardiac biomarker (42%),PCI 17,232(70%),Angio 24,769(99%),,,,No PCI 7,855 (30%),No Sig. CAD 3,616,CABG 1,809,CAD 2,430,,,,,,,Randomized to receive (2 X 2 factorial):CLOPIDOGREL: D

5、ouble-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d),Efficacy Outcomes:CV Death, MI or stroke at day 30Stent Thrombosis

6、at day 30Safety Outcomes:CURRENT defined Major/Severe and TIMI MajorKey Subgroup: PCI v No PCI,Clop in 1st 7d (median) 7d 7 d 2 d

7、 7d,,,,,,Complete Followup 99.8%,Compliance:,Days,Cumulative Hazard,,,,,,,,,0.0,0.004,0.008,0.012,,,,,,,,,,,,,,,,0,3,6,9,12,15,18,21,24,27,30,Clopidogrel Standard Dose,Clopidogrel Double Dose,,42% RRR

8、,HR 0.5895% CI 0.42-0.79P=0.001,Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis,,Days,Cumulative Hazard,,,,,,,0.0,0.01,0.02,0.03,0.04,,,,,,,,,,,,,,,,0,3,6,9,12,15,18,21,24,27,30,Clopidogrel: Double vs St

9、andard Dose Primary Outcome: PCI Patients,Clopidogrel Standard,Clopidogrel Double,HR 0.8595% CI 0.74-0.99P=0.036,,,15% RRR,CV Death, MI or Stroke,,Definite Stent Thrombosis in 4 Groups (Angiographically Proven),,Days

10、,Cumulative Hazard,,,,,,,,,0.0,0.004,0.008,0.012,,,,,,,,,,,,,,,,,0,3,6,9,12,15,18,21,24,27,30,C Standard, A Low,C Standard, A High,C Double, A Low,C Double, A High,Clinical Implications,For every 1,000 patients with ACS

11、receiving PCI, using double-dose clopidogrel for 7 days instead of standard dose will prevent an additional 6 MI’s and 7 stent thromboses with an excess of 3 severe bleeds and no increase in fatal, CABG-related or TIMI m

12、ajor bleeds.Patients not undergoing PCI should continue to use the standard dose regimen of clopidogrel.,,處理氯吡格雷反應(yīng)不良的三板斧,氯吡格雷治療若干問題與對(duì)策,用藥時(shí)間、抵抗與新藥氯吡格雷與PPI國(guó)產(chǎn)氯吡格雷循證學(xué)依據(jù)及其意義,,,,,,,,0.2 0.5 1 2

13、 5,,RR(95%CI)1.79(0.99-3.23)1.63(1.02-2.63)P=0.022P=0.012Multivariable analyses,RR(95%CI),4 weeks1year(n=176 vs 877),Favors PPI+Clopidogrel+ASA Favors Clopidogrel+ASA,Primary endpoints: Twenty-eight day (De

14、ath/MI/UTVR) and 1-year (Death/MI/Stroke),Fig.2. Baseline Proton Pump Inhibitor Use is Associated with Increased Cardiovascular Events With and Without the Use of Clopidogrel in the CREDO Trial,Steven PD, Tran

15、cy EM, Danielle BM, et al. Circulation. 2019;118:S-815.,雙聯(lián)抗血小板再加PPI心臟事件增加,,,,,,,0.2 0.5 1 2 5,,RR(95%CI)1.79(1.62-1.97)1.86(1.63-2.12)Multivariable analyses,RR(95%CI),Stent patients

16、with no preceding CV events Stent patients with preceding CV events(n=4521 vs 9862),Favors PPI+Clopidogrel Favors Clopidogrel,Primary endpoints: one-year incidence of major adverse CV events (hospitalization for st

17、roke, MI, angina or CABG ),Fig.4. Proton Pump Inhibitors Effect on Clopidogrel Effectiveness: The Clopidogrel Medco Outcomes Study,Ronald EA, Robert SE, Fang Xia , et al. Circulation. 2019;118:S-815.,氯吡格雷加用PPI使PCI患者M(jìn)ACE增

18、加,,,,,,,0.2 0.5 1 2 5,,AOR(95%CI)1.25(1.11-1.41)1.86(1.57-2.20)1.49(1.30-1.71)0.91(0.80-1.05)Multivariable analyses,AOR(95%CI),Primary endpointsHospitalization for recurrent ACSRe

19、vascularization proceduresAll cause mortality(n=5244 vs 2916),Favors PPI+Clopidogrel Favors Clopidogrel,Primary endpoints: Death or rehospitalization for ACS occurred,Fig.3. Risk of Adverse Outcomes Associated With

20、Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome,P. Michael H, Thomas M M,Li Wang, et al. JAMA. 2009; 301(9):937-944 .,氯吡格雷加用PPI死亡和在住院增加,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

21、,,,,,,,,,,,,,,,,N,S,O,Cl,O,CH3,,C,,,Clopidogrel,Pro-drugs,,,3,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,N,S,O,C,H,C,O,F,,,,,O,,Thienopyridines: Formation of Active Metabolite,Prasugrel,Gut,對(duì)CYP2C19的

22、抑制強(qiáng)度：蘭索拉唑>奧美拉唑>埃索美拉唑>泮托拉唑>雷貝拉唑,,Drug Safety 2019,29:769-784,Fig.3. PPI和氯吡格雷的藥代動(dòng)力學(xué)影響,Tab.2,PPI和氯吡格雷的藥代動(dòng)力學(xué)影響,Fig .5. A population-based study of the drug interaction between proton pump inhibitors and

23、clopidogrel,David NJ, Tara GM, Dennis TK, et al. CMAJ 2009; 180(7):713-738.,,,,,,,,Primary endpoints: Recurrent infarction within 90 days and 1 year following hospital discharge after treatment of acute myocardial infarc

24、tion,不同的制酸藥對(duì)氯吡格雷的影響不相同,PPI Use at Randomizationn=4529, 33% of study population,O’Donoghue ML, Braunward et al ESC，2009，Lancet，2009，online,CV death, MI or stroke,Days,CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.

25、80-1.11,PPI use at randomization (n= 4529),,,Clopidogrel,Prasugrel,PRASUGRELPPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20,Primary endpoint stratified by use of a PPI,O’Donoghue ML, Braunward et al ESC，2009，Lancet，2009

26、，online,Risk of CV events with different types of PPIs,,Rabeprazole not included due to small sample size (n=66),氯吡/普拉格雷與PPI合用對(duì)血小板抑制率的影響,Principle TIMI 44，Lancet，2009，online .n=201,,The COGENT Trial,Deepak L. Bhatt et a

27、l ESC 2009,3627 patients (above the initial target of 3200)393 sitesMedian follow-up 133 days (maximum 362 days)136 adjudicated cardiovascular events (preliminary)105 adjudicated GI events (preliminary),Adjustment th

28、rough Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori Status,HR = 1.0295% CI = 0.70; 1.51,Placebo: 67 events, 1821 at riskTreated: 69 events, 1806 at risk,HR = 0.5595% CI = 0

29、.36; 0.85p=0.007(preliminary),Placebo: 67 events, 1895 at riskTreated: 38 events, 1878 at risk,CVD－cardiovascular disease; Cere－cerebrovascular disease; ASA－aspirin; PPI－proton pump inhibitorsl; UN－unclear; M－mo

30、nth; W－week; D－day; OCLA study－Omeprazole CLopidogrel Aspirin Study,Tab.1. Characteristics of the 8 Included Studies,Fig.6. Pooled rate of recurrent upper gastrointestinal bleeding in patients receiving aspirin versus

31、 aspirin-plus-PPI..,The combined results showed no statistical heterogeneity (P=0.30, I2=6%) but lower rate of recurrent upper gastrointestinal bleeding (OR 5.96, 95%CI 1.31 to 21.70, P=0.02) in aspirin-plus-P

32、PI group. The other study reported with a significant reduction of heartburn (OR 0.48, 95% CI 0.24–0.97) but no influence on other aspirin associated symptoms in the group of aspirin-plus- PPI,Aspirin versus aspirin-plu

33、s-PPI,Meta分析結(jié)果,Kam CL,et al, (N Engl J Med 2019;346:2033-8. Francis KL, et al.. N Engl J Med 2019;344: 967-73.,Clopidogrel-plus-PPI versus aspirin-plus-PPI,There was no difference on the rate of treatment succes

34、s between two groups (P=0.34), indicating that early conversion from aspirin to clopidogrel does not appear superiority over the continuation of low-dose aspirin in the presence of PPI administration group.,End points: R

35、ecurrent ulcer complications including bleeding, perforation and obstruction,Meta分析結(jié)果,FH NG, et al. Aliment Pharmacol Ther 2019; 19: 359–365.,Clopidogrel and aspirin versus dual clopidogrel and aspirin plus PPI,Mean PRI

36、 on Days 1 and 7 in the Two Groups,Fig. 8. On Day 1, mean platelet reactivity index (PRI) was 83.2% and 83.9%,respectively, in the placebo and omeprazole groups (nonsignificant). On Day 7, mean PRI was 39.8% and 51.4%, r

37、espectively, in the placebo and omeprazole groups (p< 0.0001). VASP vasodilator -stimulated phosphoprotein.,Meta分析結(jié)果,Martine Gilard, et al. OCLA study. JACC2019; 51: 256–260.,Placebo-plus-PPI versus aspirin-plus-PPI

38、,To evaluate the effect of reintroduction of aspirin as soon as the endoscopic control of active bleeding in the condition of receiving PPI therapy. Results showed that the rate of endpoint event was similar in two grou

39、ps (18.9% in aspirin group versus 10.9% in placebo group, P=0.25). But the aspirin-plus-PPI group had lower mortality than PPI therapy alone (1 patient versus 8 patients, P=0.01). .,End points: The rate of recurrent ul

40、cer bleeding within 30 days,Meta分析結(jié)果,Sung J, et al. Gastroenterology 2019;130:A44,PPI與阿斯匹林聯(lián)用相比較阿斯匹林或氯吡格雷單用可明顯降低上消化道出血和潰瘍并發(fā)癥的再發(fā)生率,阿斯匹林、氯吡格雷分別合用PPI后的臨床結(jié)果相近，在使用PPI的基礎(chǔ)上無需將阿斯匹林更換為氯吡格雷,在阿斯匹林、氯吡格雷聯(lián)用基礎(chǔ)上服用PPI使雙重抗血小板的能力減弱,僅用PPI

41、較將PPI與ASA合用使死亡率增高，而后兩者合用并不增再出血發(fā)生?；顒?dòng)性出血停止后可安全加用ASA,小結(jié),停用氯吡格雷要緩慢減量,PCI后患者突然停用氯吡格雷在一段時(shí)期內(nèi)會(huì)導(dǎo)致死亡和再梗危險(xiǎn)的反跳性增加 (JAMA,2019)臨床上停用氯吡格雷可能需緩慢減量,,低體重是出血的重要危險(xiǎn)因素,按歐美體重標(biāo)準(zhǔn)，95%國(guó)人低于中位數(shù)體重（美國(guó)50百分位體重近似于中國(guó)95百分位體重）進(jìn)口氯吡格雷日劑量75mg加大國(guó)人出血危險(xiǎn)？prasug

42、rel也以體重標(biāo)準(zhǔn)決定給藥劑量,,氯吡格雷治療若干問題與對(duì)策,用藥時(shí)間、抵抗與新藥氯吡格雷與PPI國(guó)產(chǎn)氯吡格雷循證學(xué)依據(jù)及其意義,,國(guó)產(chǎn)氯吡格雷與進(jìn)口氯吡格雷對(duì)擇期PCI術(shù)患者療效和安全性的對(duì)比研究,目的-評(píng)價(jià)國(guó)產(chǎn)氯吡格雷與進(jìn)口氫氯吡格雷片對(duì)擇期PCI患者血小板聚集的影響觀察指標(biāo)-ADP介導(dǎo)的血小板聚集率-PCI三天內(nèi)患者急性血栓發(fā)生率-安全性和不良反應(yīng),,研究背景,較低的血小板反應(yīng)與支架置入術(shù)后的心血管事件相關(guān)ADP

43、介導(dǎo)的血小板聚集率是支架置入術(shù)后再發(fā)缺血事件的預(yù)測(cè)因子,Thromb Haemost 2019; 98: 838–843,,研究中心,,,總體設(shè)計(jì),取得受試者知情同意,測(cè)定基線ADP介導(dǎo)的血小板聚集率采集人口動(dòng)力學(xué)和基線資料,入選/排除,受試者隨機(jī)分組,試驗(yàn)組（國(guó)產(chǎn)氯吡格雷組）和對(duì)照組（進(jìn)口氯吡格雷組）各110例，共220例，給予研究藥物（國(guó)產(chǎn)氯吡格雷或進(jìn)口氯吡格雷），分別于用藥前、用藥兩小時(shí)后、用藥后第3天測(cè)血小板聚集率。記錄不良

44、事件與合并用藥。并在給藥前、后進(jìn)行安全性實(shí)驗(yàn)室檢查。,本研究為隨機(jī)、活性對(duì)照、多中心開放臨床試驗(yàn),,技術(shù)路線,用藥前測(cè)ADP聚集率、血常規(guī)、肝功能,首劑300mg國(guó)產(chǎn)氯吡格雷,首劑300mg波立維,PCI+75mg國(guó)產(chǎn)氯吡格雷,PCI+75mg波立維,30 天門診隨訪,,,華法令+培達(dá),,,ACS及穩(wěn)定心絞痛患者隨機(jī)入選,服藥2hrs ADP聚集率,,用藥3th天ADP聚集率,華法令+培達(dá),,患者出院觀察血常規(guī)、肝功能及不良反應(yīng),,

45、,,,,不合格,,,不合格,300mg國(guó)產(chǎn)氯吡格雷,300mg波立維,,服藥2hrs ADP聚集率,服藥2hrs ADP聚集率,,不合格,300mg國(guó)產(chǎn)氯吡格雷,服藥2hrs ADP聚集率,,,不合格 不入組,300mg波立維,,服藥2hrs ADP聚集率,,,不合格,不合格 不入組,,,,,合格,合格,合格,合格,合格,合格,,,,研究方法,血小板聚集率檢測(cè)所有入組患者血樣全部送至安貞醫(yī)院檢驗(yàn)科（從抽取血樣至樣本檢測(cè)不得

46、超過兩小時(shí)）采用真空采血管取血3 ml(1：9抗凝)，以800r/min低速離心10min取上層PRP10μl，加入誘導(dǎo)劑ADP（溶度為3毫摩爾/升）10μl混勻，再以3 000 r／min離心10 min，取PPP，用PPP作空白對(duì)照，用比濁法置入血小板聚集率分析儀中分析，得每份標(biāo)本的血小板聚集率，結(jié)果以聚集百分率表示。,,統(tǒng)計(jì)分析指標(biāo)及統(tǒng)計(jì)分析方法由第3方完成,入選標(biāo)準(zhǔn),所有入選患者必須符合下列要求： 1.年齡≥18歲

47、 2.擇期行PCI手術(shù)的急性冠脈綜合征患 者及穩(wěn)定性心絞痛患者 3.簽署知情同意書,,排除標(biāo)準(zhǔn),以下任意一項(xiàng)，不入選：年齡 1.5，或計(jì)劃住院期間應(yīng)用口服抗凝藥在隨機(jī)分組前10日內(nèi)使用過氯吡格雷有使用氯吡格雷和/或ASA的禁忌癥活動(dòng)性出血或有高度出血危險(xiǎn)（如接受纖溶治療及其他被證實(shí)有抗血小板聚集作用的中藥的患者，嚴(yán)重肝功能不全，消化性潰瘍，增生性糖尿病視網(wǎng)膜病變）嚴(yán)重全身性出血史(如消化道出血、肉眼血尿、肉眼出

48、血、出血性卒中、顱內(nèi)出血)，出血體質(zhì)及凝血障礙性疾病疑似或確診惡性腫瘤未控制的高血壓（DBP>120mmHg，或SBP≥180 mmHg）血小板減少（< 10萬/dl）哺乳期、妊娠期婦女之前入選其他試驗(yàn)在之前30天內(nèi)進(jìn)行過研究性（藥物或器械）治療由于醫(yī)療，地理或其他社會(huì)因素使患者不能參加本研究，或患者不能提供書面的知情同意,,觀察指標(biāo),血小板聚集率及聚集抑制率 服藥前、服藥后2小時(shí)、服藥后第3天早晨測(cè)血小

49、板聚集率（送往北京安貞醫(yī)院統(tǒng)一測(cè)定，傳統(tǒng)比濁法）ADP介導(dǎo)的血小板聚集率顯效達(dá)標(biāo)的標(biāo)準(zhǔn)： ADP介導(dǎo)的血小板聚集率較服藥前的基線水平降低≥50%。心臟標(biāo)志物 包括CK、CK-MB、TnI 服藥前、PCI術(shù)后第1天早晨血常規(guī)(血色素、白細(xì)胞計(jì)數(shù)、中性粒細(xì)胞計(jì)數(shù))、血小板計(jì)數(shù) 用藥前、出院前肝功能（ALT、AST） 用藥前、出院前超聲心動(dòng)圖 根據(jù)需要,,不良事件觀察,胃腸道疾病 如腹痛、消

50、化不良、腹瀉、惡心等血小板性出血和凝血疾病 如紫癜、鼻出血等皮膚及附屬組織疾病 如皮疹、瘙癢等中樞及周圍神經(jīng)系統(tǒng)疾病 如頭疼、眩暈等白細(xì)胞降低出血 嚴(yán)重出血的定義:危及生命：致命的、癥狀性顱內(nèi)出血，導(dǎo)致血紅蛋白降低至少 5 g/dl，導(dǎo)致靜脈使用正性肌力藥物，需要外科手術(shù)干預(yù)，或需要輸血4個(gè)單位以上非危及生命：明顯的活動(dòng)障礙，眼內(nèi)出血導(dǎo)致視力喪失，或需要輸血至少2個(gè)單位輕微出血的定義：任何其它導(dǎo)致研究用藥中斷的

51、出血,,一. 服藥后2h及服藥后3天血小板聚集抑制率考察血小板聚集率測(cè)定值、較基線變化差值和聚集抑制率a) 抑制差值=基線血小板聚集率－服藥后2h或3d血小板聚集率b) 聚集抑制率=(基線血小板聚集率－服藥后血小板聚集率)/ 基線血小板聚集率二. 療效達(dá)標(biāo)評(píng)價(jià)顯效： 血小板聚集抑制率≧50%非顯效：血小板聚集抑制率<50%三. 需多次負(fù)荷量用藥比較觀察 采用卡方檢驗(yàn)、t檢驗(yàn)、wilcoxon秩和檢驗(yàn)分析試驗(yàn)組、對(duì)

52、照組間差別 置信限水平取雙側(cè)α=0.05。,主要有效性指標(biāo),,安全性評(píng)價(jià),不良事件與不良反應(yīng)計(jì)算不良事件發(fā)生例數(shù)和發(fā)生率。列出發(fā)生各種不良事件、不良反應(yīng)的病例清單。 實(shí)驗(yàn)檢查結(jié)果在服藥前后的改變包括血液紅細(xì)胞、白細(xì)胞、血小板計(jì)數(shù)、血紅蛋白含量、中性粒細(xì)胞比例、AST、ALT、CK、CK-MB和TnI。描述給藥前后實(shí)驗(yàn)室檢查測(cè)定結(jié)果的例數(shù)、均值、標(biāo)準(zhǔn)差、最大值、最小值。,,,研究進(jìn)展及結(jié)果,本試驗(yàn)計(jì)劃入組220例受試者。20

53、19年12月9日至今已入組并完成合格病例205例其中1例不符合入選標(biāo)準(zhǔn)，被排除在外，未行治療；14例受試者未完成入組（試驗(yàn)組9例，對(duì)照組5例）。,,觀察指標(biāo) 國(guó)產(chǎn)氯吡格雷組（104 例） 對(duì)照組（101例） P年齡 60.57 ±10.51 59.43 ±11.01 0.4635性別（男） 73 (71.57 %) 62 (62.00 %)

54、 0.1487BMI 24.24 ±4.46 25.32 ±3.30 0.1705高血壓 55 (56.12 %) 52 (56.52 %) 0.9558糖尿病 21 (21.00 %) 23 (25.00 %) 0.4446血脂異常 20 (20.00 %) 22 (2

55、3.91 %) 0.7422吸煙 40 (40.00 %) 30 (32.61 %) 0.363飲酒 22 (22.00 %) 13 (14.13 %) 0.3695基線 PLA聚集率(%) 42.85 ±12.76 39.36 ±15.28 0.0780,一般臨床資料,,,,有效性分析,服藥2h

56、、服藥3日血小板聚集抑制率（意向治療分析集）━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 觀察指標(biāo) 國(guó)產(chǎn)氯吡格雷組 對(duì)照組 統(tǒng)計(jì)量 P──────────────────────────────────────────基線 PLA聚集率(%) 104 42.85 ±12.76 10

57、1 39.36 ±15.28 t'= 3.16 0.0780──────────────────────────────────────────2h PLA聚集率(%) 104 32.35 ±11.45 98 28.55 ±11.87 2h: 聚集率差值 104 10.50 ±11.35

58、 98 10.49 ±12.75 t= 0.00 0.9952 2h: 聚集抑制率 加權(quán)平均值（%） 104 13.58 ±91.29 98 16.86 ±55.18 Z=0.1758 0.8604──────────────────────────────────────────3

59、d PLA聚集率(%) 103 24.30 ±10.56 97 24.88 ±9.37 3d: 聚集率差值 103 18.46 ±14.49 97 14.20 ±14.73 t= 4.25 0.04053d: 聚集抑制率 加權(quán)平均值（%） 103 32.04 &#

60、177;77.44 97 13.27 ±112.58 Z=-2.5936 0.0095,,,國(guó)產(chǎn)氯吡格雷組,對(duì)照氯吡格雷組,42.85±12.76,32.35±11.45,24.30±10.56,39.36±15.28,28.55±11.87,24.88±9.37,兩組2h及第3天與服藥前均有差異P<0.001,兩組服藥2小時(shí)后、服藥第

61、3天較服藥前ADP介導(dǎo)的血小板聚集率明顯降低,,,,,,,,43.2%,36.7%,,,,,,服藥后2小時(shí),服藥后第3天,13.58±91.29,16.80±55.18,32.04±77.44,13.27±112.58,服藥后第3天國(guó)產(chǎn)氯吡格雷組抑制率>對(duì)照氯吡格雷組 P<0.01,兩組服藥2小時(shí)后、服藥第3天較服藥前ADP介導(dǎo)的血小板聚集抑制率加權(quán)平均值比較,P=0.68,P=

62、0.0095,血小板聚集抑制率%,國(guó)產(chǎn)氯吡格雷,對(duì)照,國(guó)產(chǎn)氯吡格雷,對(duì)照,,,有效性分析: 國(guó)產(chǎn)氯吡格雷組血小板抑制率≥50%例數(shù)更多 p＜0.01,有效性分析,,有效性分析,需服用負(fù)荷劑量2次（共計(jì)600mg)的例數(shù)及血小板聚集率情況國(guó)產(chǎn)氯吡格雷組需多次服用負(fù)荷量的例數(shù)更少,,安全性分析- 不良事件,不良事件 國(guó)產(chǎn)氯吡格雷組 對(duì)照組 肝酶升高 3

63、 3/104(2.9%) 4 4/101(4.0%)消化道出血 0 1 1/101(1.0%)婦科出血 0 1 1/101(1.0%)腹瀉 1 1/104(1.0%) 1 1/101(1.0%)左股動(dòng)脈穿刺部位出血 0

64、 1 1/101（1.0%）白細(xì)胞計(jì)數(shù)減少 0 0 合計(jì) 4 4/104(3.9%) 8 8/101(8.0%),,,結(jié)論,以ADP介導(dǎo)的血小板聚集率評(píng)價(jià)國(guó)產(chǎn)氯吡格雷與進(jìn)口氯吡格雷均有良好的抗血小板作用，兩者抗血小板聚集相似兩組用藥3天時(shí)國(guó)