Inter-individual variability in response to clopidogrel in patients with coronary artery disease

BACKGROUND: Clopidogrel, especially when combined with aspirin, reduces the rate of ischaemic events in patients with coronary artery disease (CAD). There are scare data in literature on the inter-individual variability in response to clopidogrel. AIM: To assess the incidence of clopidogrel resistance using rapid whole blood platelet function assessment, and to examine the possibility of early identification of non-responders. METHODS: In 31 consecutive patients with stable angina treated with aspirin, the degree of platelet aggregation inhibition (DPAI) in the whole blood was assessed at baseline and 3, 6, 12 as well as 24 hours after administration of loading dose of clopidogrel (300 mg). Response to clopidogrel was measured by calculating the absolute difference between the baseline DPAI and DPAI obtained at the investigated time-points (DPAI). RESULTS: After 24 hours from clopidogrel administration, seven (22.6%) patients were identified as non-responders (DPAI < or =10%). Demographic and clinical variables as well as baseline DPAI were similar in responders and non-responders (DPAI: 5.8+/-3.7% vs 7.1+/-5.3%, p=NS). Out of the patients who were found to be resistant to clopidogrel at the six-hour time-point, 87.5% remained resistant to this agent 24 hours after drug administration. DPAI calculated at the 24-hour time-point highly correlated with the six-hour DPAI (r=0.74). No differences in the rate of ischaemic or bleeding complications between responders and non-responders were noted. CONCLUSIONS: The assessment of the degree of platelet aggregation inhibition allows early (six hours from the initiation of treatment) identification of patients who are resistant to clopidogrel. The method of the rapid whole blood platelet function assessment is feasible in every-day clinical practice.     

Contemporary use of clopidogrel in patients with coronary artery disease

Antiplatelet agents have long served as the cornerstone of pharmacologic therapy to prevent atherothrombotic events. The thienopyridines have risen to prominence as both an alternative and adjunctive treatment to aspirin monotherapy. These agents prevent platelet aggregation by selectively and irreversibly blocking the platelet ADP P2Y12 receptor. In this article we focus on the use of clopidogrel in the contemporary management of coronary artery disease. We assess the use of clopidogrel following revascularization for coronary artery disease with percutaneous coronary intervention, particularly after deployment of drug-eluting stents. Finally, we address some aspects of clopidogrel resistance.     

氯吡格雷对稳定性冠心病患者甲襞微循环的影响

目的 观察氯吡格雷对稳定型冠心病（SCAD）患者甲襞微循环的影响。 方法 采用回顾性队列研究的方法,将135例SCAD患者依据过去3个月内是否服用氯吡格雷分为两组,其中服用氯吡格雷的患者（氯吡格雷组）61例,未服用氯吡格雷的患者（对照组）74例。进行甲襞微循环检测,观察两组患者甲襞微循环异常程度分布情况,并进一步分析形态、流态和袢周状态等11项指标变化。 结果 ①氯吡格雷组患者的甲襞微循环总积分显著低于对照组（P<0.01）,主要体现在流态积分的下降（P<0.01）,袢周积分下降（P<0.05）,形态积分组间无显著差异。②氯吡格雷组患者甲襞微循环中、重度异常的比例均显著低于对照组,甲襞微循环异常程度的组间总体差异显著（P<0.01）。③氯吡格雷组患者的甲襞微循环11项指标中只有红细胞聚集程度低于对照组患者（P<0.05）,其余指标组间均无显著差异。 结论 SCAD患者服用氯吡格雷可以改善甲襞微循环障碍。     

药物洗脱支架植入术联合氯吡格雷治疗冠心病的临床疗效

目的探讨药物洗脱支架(DES)植入术联合氯吡格雷治疗冠心病的临床疗效。方法回顾性分析2007年1月至2011年12月,该院收治的73例接受经皮冠状动脉介入治疗(PCI)的患者,对照组(DES治疗术后,除了常规二级预防以外,服用氯吡格雷12个月)28例,观察组(DES治疗术后,除了常规二级预防外,服用氯吡格雷18个月)45例。比较两组治疗2年后急性心血管事件的再发生率、再次住院率、死亡率的差别。结果对照组与观察急性心血管事件发生率(10.7%vs 4.4%,P=0.001)、再次住院率(14.3%vs 4.4%,P=0.001)、晚期血栓发生率(14.3%vs 6.3%,P=0.001)比较差异显著,有统计学意义;死亡率(0%vs 0%,P=0.95)比较差异无统计学意义(P>0.05)。两组患者治疗后血液流变学指标显著优于治疗前,差异有统计学意义(P<0.05);观察组治疗后血液流变学指标明显优于对照组,差异有统计学意义(P<0.05)。远期观察疗效良好。结论 DES植入联合氯吡格雷对冠心病治疗效果良好,值得推广。     

Description of response to aspirin and clopidogrel in outpatients with coronary artery disease using multiple electrode impedance aggregometry

Identification of outpatients with high platelet reactivity (HPR) on antiplatelet treatment is an unmet need. The present study was conducted in healthy individuals (n = 50) and in outpatients with coronary artery disease (CAD) at a distance from the acute ischemic episode (aspirin group, n = 71; aspirin/clopidogrel group, n = 106). We studied the feasibility and the precision of whole blood multiple electrode aggregometry (MEA) after triggering platelet aggregation by arachidonic acid or adenosine diphospate (ADP). The MEA can be performed on whole blood within 2 hours after sample venipuncture. The threshold for the diagnosis of HPR is situated at 55 and 50 U for the arachidonic acid and ADP test, respectively. Frequency of HPR was 7% and 20% in aspirin and aspirin/clopidogrel groups, respectively. In 3.8% of patients in aspirin/clopidogrel group, combined HPR on aspirin and clopidogrel was found. In outpatients with CAD, use of MEA is feasible for the diagnosis of HPR.     

精神应激时冠心病患者冠状动脉的舒缩反应

目的　观察精神应激时冠心病患者冠状动脉的舒缩反应。方法　用定量冠状动脉造影观察 2 1例冠心病患者精神应激 (心算 10min)前后冠状动脉内径。结果　精神应激时心率由 ( 78± 16 )增加到 ( 91± 2 2 )次 /min(P <0 0 0 1) ;收缩压由 ( 14 4± 2 2 )上升到 ( 16 6± 2 9)mmHg( 1mmHg =0 133kPa) (P <0 0 0 1) ;舒张压由 ( 93± 8)上升到 ( 10 1± 11)mmHg(P <0 0 5 ) ;心率收缩压乘积由 ( 11 4±3 3)增加到 ( 15 6± 5 7)次 /min·mmHg·10 3 (P <0 0 0 1)。精神应激时冠状动脉病变 ( 2 2处 )段内径由应激前的 ( 1 97± 0 5 7)mm降至 ( 1 6 6± 0 5 2 )mm (P <0 0 1) ,休息 10min后为 ( 1 75± 0 6 2 )mm ,仍明显小于应激前的 ( 1 97± 0 5 7)mm(P <0 0 5 )。结论　精神应激使冠心病患者心率血压明显增高 ,病变段冠状动脉内径明显降低     

血栓弹力图在冠心病介入术后氯吡格雷低反应性研究

目的 应用血栓弹力图（TEG）监测冠心病患者双联抗血小板治疗效果,主要观察氯吡格雷对二磷酸腺苷（ADP）诱导的血小板抑制率,同时观察患者临床缺血及出血事件的发生情况.在应用TEG监测同时,用流式细胞术监测患者抗血小板效果,探讨更适用临床的检测模式.方法 同时应用TEG及流式细胞仪分别检测血小板活化标志物CD62p和PAC-1,观察临床终点事件的发生.结果 TEG中ADP抑制率与血小板-纤维蛋白凝块强度（MAADP）检测血小板功能,有较好的敏感性和特异性,ADP抑制率为32.70％时受试者工作特征曲线（ROC曲线）下的面积最大0.715（95％ CI：0.609 ～0.822,P=0.001）,MAADP为42.05 mm时ROC曲线下的面积最大0.869（95％ CI：0.794 ～0.944,P=0.000）,MAADP较ADP能更准确地反映患者抗血小板效果.结论 TEG检测的ADP抑制率在＜32.70％与MAADP＞ 42.05 mm时可能反映患者对氯吡格雷反应性低下,具有较好的缺血事件预测价值.     

Evidence of platelet sensitization to ADP following discontinuation of clopidogrel therapy in patients with stable coronary artery disease

Epidemiological studies have linked clopidogrel discontinuation with an increased incidence of ischemic events. This has led to the hypothesis that clopidogrel discontinuation may result in a pharmacological rebound. We evaluated the impact of clopidogrel discontinuation on platelet function. Platelet aggregation was measured by light transmission aggregometry (LTA) in response to adenosine diphosphate (ADP) 0.5, 1, 1.5, 2.5, 5 and 10?µM and by VerifyNow® P2Y₁₂, in 37 clinically stable coronary artery disease (CAD) patients scheduled to discontinue clopidogrel treatment, and 37 clinically stable CAD patients not taking clopidogrel. Platelet function was assessed the day before clopidogrel cessation and 1, 3, 7, 14, 21 and 28 days after. Clopidogrel had been initiated a median of 555 days (ranging from 200 to 2280 days) before the treating cardiologist recommended its discontinuation. All participants were taking aspirin, most commonly 80?mg daily although a minority was prescribed 325?mg daily. Following clopidogrel discontinuation, VerifyNow® P2Y₁₂ did not detect any rebound platelet activity, but ADP-induced LTA showed platelet sensitization to ADP, particularly at low ADP levels. Increased platelet activity was detectable seven days after clopidogrel cessation and remained higher than in controls 28 days after discontinuation. No clinical event occurred in any of the participants during the 28 days following clopidogrel cessation. In conclusion, platelet sensitization to ADP as a consequence of chronic clopidogrel administration may partially explain the recrudescence of ischemic events following clopidogrel discontinuation in otherwise stable coronary artery patients.     

Cerebral cortical hyperactivation in response to mental stress in patients with coronary artery disease

The central nervous system (CNS) effects of mental stress in patients with coronary artery disease (CAD) are unexplored. The present study used positron emission tomography (PET) to measure brain correlates of mental stress induced by an arithmetic serial subtraction task in CAD and healthy subjects. Mental stress resulted in hyperactivation in CAD patients compared with healthy subjects in several brain areas including the left parietal cortex [angular gyrus/parallel sulcus (area 39)], left anterior cingulate (area 32), right visual association cortex (area 18), left fusiform gyrus, and cerebellum. These same regions were activated within the CAD patient group during mental stress versus control conditions. In the group of healthy subjects, activation was significant only in the left inferior frontal gyrus during mental stress compared with counting control. Decreases in blood flow also were produced by mental stress in CAD versus healthy subjects in right thalamus (lateral dorsal, lateral posterior), right superior frontal gyrus (areas 32, 24, and 10), and right middle temporal gyrus (area 21) (in the region of the auditory association cortex). Of particular interest, a subgroup of CAD patients that developed painless myocardial ischemia during mental stress had hyperactivation in the left hippocampus and inferior parietal lobule (area 40), left middle (area 10) and superior frontal gyrus (area 8), temporal pole, and visual association cortex (area 18), and a concomitant decrease in activation observed in the anterior cingulate bilaterally, right middle and superior frontal gyri, and right visual association cortex (area 18) compared with CAD patients without myocardial ischemia. These findings demonstrate an exaggerated cerebral cortical response and exaggerated asymmetry to mental stress in individuals with CAD.     

氯吡格雷抵抗和冠心病患者PCI术后心血管事件的关系

目的：前瞻性研究氯吡格雷抵抗对冠心病患者发生近、中期心血管事件的影响。方法：102例冠心病患者在服用氯吡格雷前及服药后4天取血，利用比浊法测定血小板聚集率（PAR），计算PAR基线值与服药后最大血小板聚集率（MPAR）差值，其差值≤10％为发生氯吡格雷抵抗，氯吡格雷抵抗组24例，非氯吡格雷抵抗组78例。患者住院期间及出院后随访2～12，平均（7．57士2．91）个月，COX回归分析氯吡格雷抵抗对103例冠心病介入治疗后患者近、中期心血管事件的影响。结果：氯吡格雷抵抗组心血管事件的发生率为58．3％，显著高于非抵抗组（16．7％），P〈0．001。COX回归分析发现，氯吡格雷抵抗（RR=70．262，95％CI=0．123～0．558，P=0．001）和冠脉病变程度（RR=1．052，95％CI=1．030～1．075，P〈0．001）是冠心病患者PCI术后近、中期发生心血管事件的独立危险因素。结论：氯吡格雷抵抗、冠脉病变程度重的患者容易于PCI术后近、中期发生心血管事件。     

Intra-individual variability in clopidogrel responsiveness in coronary artery disease patients under long term therapy

Clopidogrel responsiveness (CR) following a loading dose (LD) predicts thrombotic events after percutaneous coronary interventions (PCI). Some of the mechanisms involved in large inter-individual variability in CR may be varied. We therefore postulated that there may be an intra-individual variability in CR. Two hundred and one patients receiving long-term therapy with aspirin and clopidogrel after drug-eluting stents PCI were prospectively included in this monocentre study along with any patient re-admitted within 12 months post-PCI. Platelet reactivity (PR) inhibition was assessed by the vasodilator phosphoprotein (VASP) index following a 600 mg loading dose of clopidogrel on each admission to determine CR (VASP 1 during the first admission and VASP 2 during re-admission). DeltaVASP = VASP 2 –VASP 1 was used to study intra-individual variability in CR. We observed that the response to a 600 mg LD of clopidogrel was poorly correlated within an individual (kappa = 0.33; p < 0.001 (n = 201)). Although most patients had increased platelet inhibition at the time of readmission, 35.3% of patients exhibited a decreased platelet inhibition despite chronic clopidogrel therapy and a 600 mg reload. Quartiles analysis of DeltaVASP demonstrated that insulin-treated diabetes was associated with decreased CR over time (p = 0.03). In addition to the large inter-individual variability in clopidogrel responsiveness, there is large intra-individual variability. Decreased clopidogrel responsiveness despite long-term clopidogrel therapy could be a trigger for recurrent thrombotic events.     

Relation of vasodilator response of the brachial artery to inflammatory markers in patients with coronary artery disease

Endothelial dysfunction of the coronary artery is closely related to elevated levels of systemic inflammatory markers and cardiovascular events in patients with coronary artery disease (CAD). We hypothesized that patients with CAD may have a higher risk of endothelial dysfunction of the peripheral artery than patients without evidence of CAD, and that endothelial dysfunction of the peripheral artery also may be related to elevated levels of inflammatory markers. Using high resolution ultrasound, we assessed the brachial vasodilator response to reactive hyperemia (endothelium-dependent) and sublingual nitroglycerin (endothelium-independent). As inflammatory markers, serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) levels, and lipid profiles were measured in patients with CAD (n = 30, 16 male and 14 female) and normal subjects without evidence of CAD (n = 45, 23 male and 22 female). Patients with CAD (Group II) showed a significantly reduced endothelium-dependent vasodilation as compared with normal subjects (Group I) (4.4 +/- 3.6 vs 7.4 +/- 6.1%, P < 0.05). However, endothelium-independent vasodilation was not significantly different between the two groups (7.7 +/- 7.1 vs 9.7 +/- 8.0%, P > 0.05). In Group II, CRP level was inversely related to endothelium-dependent vasodilation (r = -0.398, P = 0.029). In contrast, ESR level was not significantly associated to endothelium-dependent vasodilation (r = -0.113, P = 0.552). On multivariate analysis, CRP and low density lipoprotein cholesterol levels were significant independent predictors of a blunted endothelium-dependent vasodilation in Group II. Our study showed that elevated CRP level was associated with blunted endothelium-dependent vasodilation of the brachial artery in patients with CAD. Thus, identification of elevated CRP levels combined with demonstration of endothelial dysfunction of the brachial artery may have a possible clinical application for the detection of high risk CAD patients.     

Myocardial blood-flow response during mental stress in patients with coronary artery disease

Positron emission tomography was used to quantify changes in myocardial blood flow during mental stress in patients with and without coronary artery disease. Blunted augmentation of myocardial blood flow during mental stress was observed in regions without significant epicardial stenosis.