Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes and/or undergoing percutaneous coronary interventions. Clopidogrel, in combination with aspirin, is currently the antiplatelet treatment of choice for prevention of stent thrombosis, and clinical trials have shown that, in high-risk patients, prolonged dual antiplatelet treatment is more effective than aspirin alone in preventing major cardiovascular events. However, despite the use of clopidogrel, a considerable number of patients continue to have cardiovascular events. Numerous in vitro studies have shown that individual responsiveness to clopidogrel is not uniform in all patients and is subject to inter- and intraindividual variability. Notably, there is a growing degree of evidence that recurrence of ischemic complications may be attributed to poor response to clopidogrel. The mechanisms leading to poor clopidogrel effects are not fully elucidated and are likely multifactorial. Although the gold standard definition to assess antiplatelet drug response has not been fully established, there is sufficient evidence to support that persistence of enhanced platelet reactivity despite the use of clopidogrel is a clinically relevant entity. This paper reviews the impact of individual response variability to clopidogrel on clinical outcomes and current and future directions for its management.     

Modified clopidogrel loading dose according to platelet reactivity monitoring in patients carrying ABCB1 variant alleles in patients with clopidogrel resistance

Objectives

The aim of the present study was to investigate the impact of a adjusted clopidogrel loading dose (LD) according to platelet reactivity index in carriers of ABCB1 mutant allele undergoing percutaneous coronary intervention (PCI).

Methods

All patients met the inclusion criteria were recruited in the present study. Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) index. High treatment platelet reactivity (HTPR) was determined by a cut-off value of > 50%. The genetic polymorphism of ABCB1 was determined by allele-specific polymerase chain reaction (PCR). In patients carrying ABCB1 and HTPR after a first 300-mg LD of clopidogrel, dose adjustment was performed by using up to 3 additional 300-mg LDs to obtain a VASP index < 50%. The rate of major adverse cardiovascular events (MACE) and major or minor bleeding in one month were recorded.

Results

536 patients were included in the present study. One hundred seventy-two patients (32%) carried ABCB1 mutant allele (11 homozygotes [2%] and 161 heterozygotes [30%]). The VASP index in these patients was significantly higher than in homozygotic patients for the wild allele (65.5 ± 13.8% vs. 47.6 ± 21.8%; p < 0.001). Of the 172 ABCB1 mutant allele carriers, 130 were considered to have HTPR. After a second clopidogrel LD, the VASP index was significantly decreased in these patients (66.9 ± 12.8% vs.50.2 ± 18.3%; < 0.001). Finally, dose adjustment according to platelet reactivity monitoring enabled 88% of ABCB1 mutant allele carriers and 91% of wild allele carriers exhibiting HTPR to reach a VASP index < 50%. The rate of MACE and major or minor bleeding in one-month follow-up between the wild allele carriers and the mutant allele carriers didn't differentiate significantly.

Conclusions

Increased and adjusted clopidogrel loading dose according to platelet reactivity monitoring attenuated clopidogrel resistance in carriers of ABCB1 mutant allele.     

氯吡格雷对PCI患者血小板功能状态及血流变的影响

目的：比较不同剂量氯吡格雷对冠心病介入治疗患者血小板功能状态及血液流变学的影响.方法：选择2010年10月～2013年12月于本院进行介入治疗的70例冠心病患者为研究对象,均采用氯吡格雷治疗,随机分为常规剂量组（35例）和大剂量组（35例,负荷量600mg,维持量150mg/d）,比较两组介入治疗后6h、12h及24h的血小板功能状态及血液流变学指标状况.结果：与常规剂量组比较,大剂量组介入治疗后6h、12h及24h的血液流变学指标[6h：全血低切黏度（11.13±1.53） mPa·s比（8.89±1.33） mPa·s,血浆黏度（1.75±0.16） mPa·s比（1.41±0.14） mPa·s,全血还原低切黏度（24.83±2.18） mPa·s比（21.87±1.99） mPa·s],血小板活化指标-糖蛋白Ⅱb/Ⅲa[6h：（15.98±1.53）％比（13.85±1.38）％],血小板其他功能指标：P选择素[6h：（17.38±1.33） μg/L比（14.76±1.23） μg/L]、血小板聚集率[6h：（41.57±4.68）％比（35.24±3.76）％]均明显降低（P均＜0.05）.结论：大剂量氯吡格雷对冠心病介入治疗患者血流变及血小板功能状态的影响更大.     

维、汉两族经皮冠状动脉介入术后使用氯吡格雷的安全性

目的：评价氯吡格雷对维、汉两族急性冠脉综合征患者的疗效和安全性。方法：入选2004年10月至2005年4月因急性冠脉综合征而住院的维吾尔族患者40例和汉族患者40例,氯吡格雷治疗12个月,观察两组出凝血时间、血小板计数的改变,主要不良心血管事件（心血管性死亡、心肌梗死、心肌缺血复发进行靶血管再通治疗）及出血事件的发生,评价其安全性。结果：两组均未发生主要不良心血管事件,两组各发生1例出血（维吾尔族组脑出血1例,汉族组消化道出血1例）,无显著性差异（P〉0.05）,出、凝血时间均有不同程度的延长,但无显著性差异（P〉0.05）。结论：维、汉两族急性冠脉综合征患者长期（12个月）使用氯吡格雷治疗安全、有效。     

国产氯吡格雷对急性冠脉综合征经皮冠脉介入术的疗效

目的：研究国产氯吡格雷用于非ST段抬高急性冠脉综合征（NSTEACS）急诊经皮冠脉介入（PCI）治疗患者的疗效及安全性。方法：确诊NSTEACS并接受急诊PCI的患者176例,分成国产氯吡格雷组（接受泰嘉治疗,89例）和进口氯吡咯雷组（接受波立维治疗,87例）。PCI治疗前两组分别接受泰嘉、波立维每日600mg。PCI后每日分别接受75mg至1年以上。观察两组患者的疗效及不良反应的发生情况。结果：国产氯吡格雷组与进口氯吡格雷组达到的完全血运重建率（79．8％比89．3％．P=0．477）,主要不良心脑血管事件（MACCE）发生率（9．0％比6．9％,P=0．608）,不良反应的发生率（5．6％比8．0％,P=0．523）均无显著差异。结论：国产氯吡格雷（泰嘉）治疗急性非ST段抬高心肌梗死的疗效和安全性与进口氯吡格雷相当。     

急性冠脉综合征患者PCI术后应用国产硫酸氢氯吡格雷的疗效

比较急性冠脉综合征（ACS）患者择期PCI术后国产氯吡格雷（泰嘉,Talcom）和进口氯吡格雷（波立维,Plavix）应用的有效性和安全性。方法：158例行择期PCI的ACS患者随机分为：国产氯吡格雷组和进口氯吡格雷组,各79例。随访12个月以上,观察两组术后不良心血管事件及药物不良反应情况。结果：进口氯吡格雷组心源性死亡1例、非致死性心肌梗死1例、靶血管再次血运重建1例、脑卒中1例。国产氯吡格雷组心源性死亡0例、非致死性心肌梗死1例、靶血管再次血运重建2例、脑卒中1例。两组心血管不良事件发生率无显著差异（5.06%比5.06%,P〉0.05）。药物不良反应：进口氯吡格雷组胃肠道反应5例、出血1例、血小板减少1例。国产氯吡格雷组胃肠道反应7例、出血1例、血小板减少2例,两组不良反应发生率无显著差异（8.86%比12.66%,P〉0.05）。结论：与进口氯吡格雷相比,国产氯吡格雷应用于PCI术后患者是安全、有效的。     

氯吡格雷在短暂性脑缺血发作后脑卒中二级预防中的应用

目的探讨氯吡格雷在短暂性脑缺血发作(transient ischemic attack,TIA)后预防缺血性脑卒中发作的疗效。方法选择TIA患者279例,随机分为2组:氯吡格雷组158例(氯吡格雷75 mg,1次/d),长效阿司匹林组121例(拜阿司匹林100 mg,1次/d)。患者随访1.5～3.0(2.3±0.3)年,评估2组的安全性。结果氯吡格雷组患者缺血性脑卒中复发率明显低于长效阿司匹林组,差异有统计学意义(5.06% vs 12.40%,P0.05)。全部患者在TIA后缺血性脑卒中复发的危险比为0.4031,氯吡格雷组为0.1284,长效阿司匹林组为0.8129,差异有统计学意义(P0.05)。氯吡格雷组患者发生次要事件概率和胃肠道出血事件明显低于长效阿司匹林组,差异有统计学意义(1.90% vs 8.26%,1.27% vs 6.61%,P0.05)。结论氯吡格雷对TIA患者的缺血性脑卒中的预防,优于长效阿司匹林。     

阿司匹林并氯吡格雷治疗不稳定型心绞痛198例的疗效

目的：观察阿司匹林联合氯吡格雷治疗不稳定型心绞痛（UAP）的临床疗效。方法：选择我院2010年6月-2013年8月期间收治的396例UAP患者为对象,按照随机数字法均分成联合用药组（常规治疗基础上给予阿司匹林与氯吡格雷联合治疗）和阿司匹林组（在常规治疗基础上仅给予阿司匹林治疗）,观察并比较两组患者治疗前后心绞痛发作频率、持续时间的差异和临床治疗效果。结果：和治疗前相比,两组患者治疗后心绞痛发作频率[联合用药组：（4.1±1.2）次/d比（1.8±0.6）次/d,阿司匹林组：（4.0±1.4）次/d比（2.5±3.1）次/d,P＜0.05或＜0.01]和持续时间[联合用药组：（23.2±4.7）min比（3.3±2.6）min,阿司匹林组：（24.9±2.4）min比（7.3±1.6）min]均明显降低,P均＜0.01;但联合用药组患者治疗后心绞痛发作频率和持续时间较阿司匹林组降低更为明显（t＝5.36、6.03,P均＜0.05）;同时联合用药组临床治疗总有效率（98.48％）明显高于阿司匹林组（85.35％）,χ2＝22.98,P＝0.002。结论：阿司匹林联合氯吡格雷治疗不稳定型心绞痛患者临床疗效显著,而且安全,值得在临床上应用和推广。     

氯吡格雷对尼古丁诱导的血管内皮损伤的保护作用

目的探讨尼古丁对血管内皮细胞的影响及氯吡格雷的保护作用。方法将40只SD大鼠分为5组,对照组、模型组(尼古丁2 mg/kg)、尼古丁损伤+氯吡格雷低剂量组(低剂量组)、尼古丁损伤+氯吡格雷中剂量组(中剂量组)、尼古丁损伤+氯吡格雷高剂量组(高剂量组),每组8只。尼古丁造模4周后,测定大鼠血浆超氧化物歧化酶(SOD)、内皮素1、NO及内皮型一氧化氮合酶(eNOS)浓度,免疫组织化学法及Western blot法测定血管eNOS阳性细胞的表达。结果与对照组比较,模型组大鼠血浆NO、eNOS及SOD浓度明显下降,而内皮素1浓度明显上调,eNOS阳性细胞表达明显减少(P0.01);与模型组比较,低、中、高剂量组大鼠NO、eNOS及SOD浓度明显升高,eNOS阳性细胞表达明显增多,且中、高剂量组大鼠增多更显著(P0.05,P0.01)。结论氯吡格雷可能抑制氧化应激反应,调节内皮细胞中eNOS的正常表达,从而缓解尼古丁对血管内皮细胞的损害。     

质子泵抑制剂埃索美拉唑对氯吡格雷抗血小板作用的影响

目的观察质子泵抑制剂埃索美拉唑是否影响氯吡格雷的抗血小板聚集作用。方法选择不稳定性心绞痛患者118例,于入院即刻行血小板聚集率测定;患者接受100 mg/d阿司匹林和75 mg/d氯吡格雷治疗7 d后,再次测定血小板聚集率,根据结果将患者分为有效反应组87例和低反应组31例;有效反应组再随机分为2个亚组,给予埃索美拉唑20 mg/d(治疗组,44例)和安慰剂20 mg/d(安慰剂组,43例)。30 d后,再次测定全部患者的血小板聚集率,比较用药前后各组血小板聚集率的变化。结果与有效反应组比较,低反应组体重指数、糖尿病及吸烟比例明显升高(P<0.05)。治疗组和安慰剂组治疗前后的血小板聚集率无明显差异;低反应组服药前后的血小板聚集率也无明显差异(P>0.05)。结论未发现埃索美拉唑对氯吡格雷的抗血小板聚集作用产生明显影响。     

Effects of clopidogrel,prasugrel and ticagrelor on prevention of stent thrombosis in patients underwent percutaneous coronary intervention: A network meta‐analysis

BackgroundClopidogrel, prasugrel and ticagrelor, acting on platelet P2Y12 receptor, are commonly used for prevention of stent thrombosis (ST) among patients who underwent percutaneous coronary intervention (PCI). This study aimed to compare the effects of these drugs by a systematic review and network meta‐analysis.HypothesisEfficacies of clopidogrel, prasugrel and ticagrelor on preventing ST are not the same.MethodsPubMed, Embase and Cochrane Library were searched for randomized controlled trials (RCTs) that investigated the effect of clopidogrel, prasugrel, or ticagrelor on prevention of ST in patients who underwent PCI. The efficacies between groups were compared by a Bayesian network meta‐analysis, by which the pooled odds ratios (ORs) and 95% confidence intervals (CIs) was calculated.ResultsFourteen studies and 46 983 participants were included in this study. The pooled results illustrated that clopidogrel, prasugrel and ticagrelor were effective on prevention of ST. Patients treated with prasugrel (OR = 0.30, 95% CI = 0.052 ~ 0.73, P < 0.05) and ticagrelor (OR = 0.25, 95% CI = 0.035 ~ 0.65, P < 0.05) had lower incidence of ST compared to those treated with clopidogrel. Patients treated with ticagrelor showed similar frequency with those in prasugrel group (OR = 0.86, 95% CI = 0.22 ~ 2.3, P > 0.05). No significant heterogeneity was observed across included studies.ConclusionsOur findings suggest that prasugrel and ticagrelor are more effective than clopidogrel on prevention of ST among patients underwent PCI. Simultaneously, there is no significant difference in the prevention of ST between prasugrel and ticagrelor.     

阿司匹林和氯吡格雷抵抗

阿司匹林通过不可逆抑制环氧合酶（COX）-1,阻止花生四烯酸代谢产物血栓素A2（TXA2）形成,从而发挥其抑制血小板聚集作用.汇总分析表明,接受阿司匹林治疗的高危患者血管性事件（包括心肌梗死、卒中或死亡）发生率降低25%～30%,但是仍有10%～20%的患者5年内再发血管性事件.