Aspirin and clopidogrel resistance: an emerging clinical entity.

We read with interest the recent article which reviewed theissue of aspirin and clopidogrel resistance.¹ The authors reviewthe aspirin and clopidogrel clinical trial data and concludethat both therapies have emerged as efficacious in both theprimary and     

症状性颈动脉和椎-基底动脉狭窄患者的阿司匹林和氯吡格雷抵抗现象

目的观察症状性颈动脉和椎-基底动脉狭窄患者服用阿司匹林和氯吡格雷抵抗现象的发生情况。方法在54例症状性的颈动脉(25例)、椎动脉(19例)、颈动脉合并椎动脉(8例)以及基底动脉(2例)狭窄的患者中,有39例行择期支架置入术。采用二磷酸腺苷、肾上腺素、胶原和花生四烯酸为诱导剂,分别测定已服用阿司匹林(100mg/d)≥10d,以及随后加服氯吡格雷(75mg/d)≥5d患者的血小板聚集率。阿司匹林抵抗标准为单用阿司匹林时,以500μg/ml花生四烯酸诱导的血小板聚集率≥20%和5μmol/L二磷酸腺苷诱导的血小板聚集率≥70%。氯吡格雷抵抗标准为在阿司匹林基础上加用氯吡格雷前、后,5μmol/L二磷酸腺苷诱导血小板聚集率的差值≤10%。结果54例患者中,有9例(16.7%)存在阿司匹林抵抗,12例(22.2%)存在氯吡格雷抵抗,1例(1.8%)存在阿司匹林和氯吡格雷双抵抗。9例阿司匹林抵抗者加用氯吡格雷后有5例花生四烯酸诱导的聚集率降至<20%,有8例二磷酸腺苷诱导的聚集率降至<70%。1例支架置入术后支架内急性血栓形成为阿司匹林抵抗的患者。结论症状性颈动脉和椎-基底动脉狭窄患者中存在一定比例的阿司匹林或氯吡格雷抵抗现象,氯吡格雷与阿司匹林合用克服了部分阿司匹林抵抗现象。阿司匹林抵抗可能与支架置入术后血栓性并发症的增加有关。     

Clinical importance of aspirin and clopidogrel resistance

Aspirin and clopidogrel are important components of medical therapy for patients with acute coronary syndromes, for those who received coronary artery stents and in the secondary prevention of ischaemic stroke. Despite their use, a significant number of patients experience recurrent adverse ischaemic events. Interindividual variability of platelet aggregation in response to these antiplatelet agents may be an explanation for some of these recurrent events, and small trials have linked "aspirin and/or clopidogrel resistance", as measured by platelet function tests, to adverse events. We systematically reviewed all available evidence on the prevalence of aspirin/clopidogrel resistance, their possible risk factors and their association with clinical outcomes. We also identified articles showing possible treatments. After analyzing the data on different laboratory methods, we found that aspirin/clopidogrel resistance seems to be associated with poor clinical outcomes and there is currently no standardized or widely accepted definition of clopidogrel resistance. Therefore, we conclude that specific treatment recommendations are not established for patients who exhibit high platelet reactivity during aspirin/clopidogrel therapy or who have poor platelet inhibition by clopidogrel.     

Aspirin and clopidogrel treatment impair nitric oxide biosynthesis by platelets

Aspirin and clopidogrel are used therapeutically for their anti-platelet effects. We examined the effects of aspirin and clopidogrel on basal and β-adrenoceptor (β-AR)-mediated platelet nitric oxide (NO) synthesis in healthy subjects and patients with coronary heart disease (CHD). Healthy subjects (n = 19) were randomized in a double-blind cross-over manner to receive aspirin or clopidogrel, each at 75 mg daily, for 14 days. Patients (n = 17) of similar age with CHD, taking aspirin, were randomized double-blind to either continue on aspirin 75 mg daily or to receive clopidogrel 75 mg daily for 14 days. NO synthase (NOS) activity was measured from l-[³H]arginine to l-[³H]citrulline conversion, and cGMP was determined by radioimmunoassay, in platelets basally and following incubation with isoproterenol or albuterol (each at 10⁻⁵ mol/L). In healthy subjects, aspirin did not affect basal NOS activity or cGMP in platelets, but suppressed the normal increase in both by isoproterenol and albuterol. Clopidogrel suppressed platelet NOS activity and cGMP both basally and in response to β-AR agonists. In platelets from CHD patients, clopidogrel suppressed basal and β-AR-stimulated NOS activity and cGMP as compared with aspirin. Platelet NOS activity and cGMP were lower in CHD subjects pre-randomization compared with healthy subjects both pre-randomization and post-aspirin. We conclude that chronic aspirin treatment suppresses β-AR-stimulated but not basal platelet NO synthesis, as previously described, whereas chronic clopidogrel treatment suppresses both, with resultant functional consequences. Moreover, CHD may itself be associated with decreased platelet NO biosynthesis.     

2型糖尿病对阿司匹林和氯吡格雷双联抗血小板药物治疗效应的分析

目的:本研究通过前瞻性连续入选在我院因稳定性冠心病行经皮冠状动脉介入治疗(PCI)的患者,分析探讨糖尿病对阿司匹林和氯吡格雷双联抗血小板药物效应的影响。方法:2008年8月至2011年11月前瞻性连续入选稳定性冠心病患者。入院后服用氯吡格雷前测定花生四烯酸(AA)诱导的血小板聚集率和基线二磷酸腺苷(ADP)诱导的血小板聚集率,之后给予氯吡格雷300 mg负荷量口服,继续服用氯吡格雷75 mg/d至1 d后,再次测定服用氯吡格雷后ADP诱导的血小板聚集率。结果:入选了355例稳定性冠心病患者,其中合并2型糖尿病103例,非糖尿病252例。阿司匹林抵抗的发生率18.6%,糖尿病组与非糖尿病组阿司匹林抵抗的发生率未见明显差异(20.4%vs.17.9%,P=0.578),将患者基线特征纳入Logistic回归模型进行校正后结果显示,糖尿病并未增高阿司匹林抵抗的风险(OR=1.3,95%CI=0.7～2.7,P=0.439)。氯吡格雷抵抗的发生率为20.8%;糖尿病组氯吡格雷抵抗的发生率明显高于非糖尿病组(33.0%vs.15.9%,P<0.001);Logistic回归校正后结果显示,糖尿病是氯吡格雷抵抗的独立危险因素(OR=5.7,95%CI=2.9～11.1,P<0.001)。结论:双联抗血小板药物基础上,糖尿病未增高阿司匹林抵抗的风险;但是糖尿病明显增高了氯吡格雷抵抗的风险。     

Possible mechanisms of drug-induced aspirin and clopidogrel resistance

Aspirin (ASA) and clopidogrel have been identified as standard of care in the prevention of major cardiovascular events. Aspirin irreversibly inhibits the cyclooxygenase-1 (COX-1) enzyme, whereas non-steroidal anti-inflammatory drugs (NSAIDs) reversibly inhibit the COX-1 enzyme. An analysis of the literature revealed a statistically significant decrease in clinical benefit of ASA with concomitant administration of ibuprofen. Another NSAID, diclofenac, showed minimal effect on the inhibition of platelet aggregation when administered with ASA. Furthermore, the selective COX-2 inhibitor, rofecoxib, was not shown to influence the effect of ASA. Clopidogrel is metabolized to an active thiol metabolite by the CYP 3A4 enzyme. Some HMG CoA reductase inhibitors have the ability to inhibit the CYP 3A4 enzyme, which can result in a possible interaction if administered concomitantly with clopidogrel. Studies have demonstrated clopidogrel’s platelet inhibition being significantly attenuated by atorvastatin. However in a post-hoc analysis, it was demonstrated that there was no difference in clinical outcomes between patients taking clopidogrel and HMG-CoA reductase inhibitors metabolized by and not metabolized by CYP 3A4. Data suggest that the interaction observed involving clopidogrel and HMG-CoA reductase inhibitors appears to be significant in-vitro. Therefore, practitioners should advise patients receiving chronic aspirin therapy to limit the use of ibuprofen and may consider concomitant administration of clopidogrel with HMG-CoA reductase inhibitors without regard for the drug interaction. The intent of this paper is to review the literature discussing possible mechanisms of drug-induced aspirin and clopidogrel resistance and discuss whether the interactions translate into clinical effects.     

氯吡格雷抵抗的研究进展

氯吡格雷是临床上广泛使用的抗血小板药物,但在长期随访中发现,应用氯吡格雷治疗的患者仍有血栓性血管事件的发生,即存在抵抗现象。目前,氯吡格雷抵抗的检测方法有ADP诱导的光学法血小板聚集,血小板激活标志物检测,以及血栓弹力图等多种方法。氯吡格雷抵抗的发生机制有不恰当的用药剂量,药物间的相互作用,遗传因素等多方面的原因。     

阿司匹林抵抗

阿司匹林能有效预防缺血性脑血管病,但由于阿司匹林抵抗现象的存在,仍有部分患者在阿司匹林治疗期间发生缺血事件.文章主要对阿司匹林抵抗的机制、筛查方法 和处理措施进行了综述.     

Gender and Responses to Aspirin and Clopidogrel: Insights Using Short Thrombelastography

There is significant variability in both baseline clotting tendency and response to antiplatelet therapy. Responses are associated with outcome. We have investigated whether differences could explain the increased risk observed in women presenting with coronary artery disease. We have utilized short thrombelastography to assess (i) baseline clotting responses, (ii) response to aspirin and clopidogrel, and (iii) post‐treatment platelet reactivity in 48 young volunteers, 22 older patients and 18 patients with previous stent thrombosis. Baseline responses were significantly higher in young women than in men. While there was no difference in response to aspirin, platelet reactivity on aspirin remained higher in women (area under curve at 15 min [AUC15] of arachidonic acid channel 332 ± 122 vs. 172 ± 80, P= 0.04). Young women had less response to clopidogrel (% reduction in AUC15 with adenosine diphosphate [ADP] 36.4 ± 12.4 vs. 64.0 ± 13.2, P < 0.01) in addition to higher post‐treatment reactivity (AUC15 of ADP 714 ± 161 vs. 311 ± 146, P < 0.01) compared to men. There were no such differences between male and female patients over 50. However, young women with previous stent thrombosis had among the highest platelet reactivity observed. Compared to men, young women have greater baseline clotting tendency, reduced response to clopidogrel, and greater post‐treatment reactivity while on both aspirin and clopidogrel. Differences in clotting tendency and response to antiplatelet therapy may contribute to the excess risk observed in young women but are not observed in older female patients.     

The role of aspirin resistance on outcome in patients with acute coronary syndrome and the effect of clopidogrel therapy in the prevention of major cardiovascular events

Background: Aspirin resistance may increase up to more then threefold the risk of major cardiovascular events (MACE) in patients with stable coronary artery disease. Aim:The aim of our study was to determine; the prevalence of aspirin resistance in patients with acute coronary syndromes, the role of aspirin resistance on outcome in the follow-up and the effect of clopidogrel therapy in the prevention of MACE in aspirin resistant subjects. Material and methods: We detected the prevelance of aspirin resistance in 105 patients with acute coronary syndrome. Platelet functions were analyzed in Platelet Function Analyzer (PFA)-100 (Dade Behring, Germany) with collagen and/or epinephrine (Col/Epi) and collagen and/or ADP (Col/ADP) cartridges. Primary end points of the study were myocardial infarction, unstable angina, cardiac death. Results: 19% (n = 20) of patients were aspirin resistant by PFA-100. In the follow-up, MACE occured in 9 patients (45%) with aspirin resistance and in 10 patients (11.7%) with aspirin sensitive platelet aggregation (p = 0.001). Multivariate analysis showed that aspirin resistance was an independant predictor of MACE. The prevalence of MACE in patients who were on clopidogrel treatment for 12 months were lower compared to those who were on a clopidogrel treatment for the first six months (p = 0.040). Conclusions: We determined that the MACE risk in patients with acute coronary syndromes having detected aspirin resistance, was higher at statistically significant levels compared to patients having aspirin sensitive platelet aggregation. Our results showed that aspirin resistance, was an independant predictor of MACE in patients with acute coronary syndrome.     

Aspirin resistance: A fact or a myth?

Blood platelets play a very important role in the pathogenesis of heart attacks and stroke. Therefore, several million individuals all over the world take aspirin, an irreversible inhibitor of the cyclooxygenase enzyme, for the prevention of heart attacks and stroke. Over the past three decades, the author’s laboratory has used arachidonic acid-induced platelet aggregation as a standard to monitor aspirin sensitivity. However, there has been no detection of a significant number of nonresponders to the action of aspirin in the normal population. Recent studies from several other laboratories suggest that a significant number of patients suffering various vascular diseases are nonresponders to the action of aspirin and, therefore, are not protected from developing acute vascular events. According to some estimates, anywhere from 4% to 50% of patients taking aspirin are nonresponders. Lack of a specific diagnostic method makes it difficult to detect aspirin resistance in clinical conditions. Therefore, there is an immediate need for the development of a platelet-cyclooxygenase-specific assay to determine the prevalence of aspirin resistance in normal and patient populations. Once determined, an appropriate treatment regimen can be developed for these nonresponding individuals.     

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.     

Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel (3T/2R). Rationale for the Study and Protocol Design

PURPOSE: To assess whether glycoprotein IIb/IIIa inhibition using tirofiban in low risk patients undergoing percutaneous coronary intervention (PCI) may reduce the risk of periprocedural myocardial infarction compared to standard care in poor responders to aspirin and/or clopidogrel. METHODS: We will enroll patients at ten European sites or more to participate in the Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel (3T/2R) study with a pre-specified sample size of 240 patients out of 1,100 or more who will undergo screening. The primary outcome measure is troponin I or T elevation ratio at least three times the upper limit of normal within 48 h after completion of the PCI. CONCLUSION: The results of 3T/2R study will evaluate whether tailored intensification of anti-platelet treatment based on poor individual response to oral anti-platelet agents may modulate the risk of periprocedural myocardial infarction during PCI. Our findings attempt at unraveling a new era of individualized anti-platelet treatment through the use of point-of-care assessment.     

氯吡格雷抵抗实验室检测方法的研究进展

随着经皮冠状动脉介入治疗（PCI）的广泛开展,抗血小板治疗已成为降低心血管事件、改善患者预后的重要治疗手段[1,2].血小板功能改变与血栓形成密切相关,过多的血小板黏附、聚集和释放,可引发急性血栓等不良事件[3].氯吡格雷是目前临床常用的抗血小板药物,研究报道约有25％的患者对其反应较差.因此,明确氯吡格雷抵抗的原因及与不良心血管事件的关系具有重要的意义.     

氯吡格雷与阿司匹林或单独阿司匹林预防动脉粥样硬化血栓事件观察

目的:观察氯吡格雷联合阿司匹林对心血管病人或有动脉粥样硬化高危因素病人血栓事件的疗效。方法:选择2007年1月～2010年12月在我院治疗的心血管疾病或有多种危险因素聚集的605例患者,随机分为:联合用药组(302例,给予氯吡格雷75mg/d加阿司匹林75mg/d),阿司匹林组(303例,单用阿司匹林75mg/d),观察两组3年内主要不良心血管事件(MACE,包括心肌梗死,心性死亡,缺血性脑卒中)及次要不良心血管事件(不稳定型心绞痛,一过性脑缺血等)发生情况。结果:MACE发生率:联合用药组为6.8%,阿司匹林组为7.3%,相对风险0.93,95%CI 0.83～1.05,P=0.22,无显著差异。次要不良心血管事件:联合用药组16.7%,阿司匹林组17.9%,相对风险0.92,95%CI 0.86～0.995,P=0.04联合用药组的次要事件显著少于阿司匹林组;严重出血事件率两组分别为1.7%和1.3%,P=0.08,无显著差异;少量出血事件率两组分别为2.5%和1.3%,P<0.01。结论:氯吡格雷联合阿司匹林与单用阿司匹林比较对于心血管病人或有动脉粥样硬化高危因素病人主要不良心血管事件效果相当,次要不良心血管事件显著减少,但少量出血事件显著增加。     

Fungal empyema thoracis: an emerging clinical entity

STUDY OBJECTIVES: To analyze the clinical spectra, pathogenesis, treatment, outcome, and prognostic factors of fungal empyema thoracis. DESIGN: The medical records of patients with positive fungal cultures from pleural effusions were retrospectively analyzed. SETTING: A university-based tertiary care hospital in Taipei, Taiwan. PATIENTS AND METHODS: From January 1990 through December 1997, patients diagnosed with fungal empyema were included in this study. The criteria for diagnosis of fungal empyema thoracis were as follows: (1) isolation of a fungal species from the pleural effusion; (2) significant signs of infection, such as fever (body temperature > 38.3 degrees C) and leukocytosis (white blood cell > 10,000/microL); and (3) isolation of the same mold species from pleural effusion on more than one occasion, or from pleural effusion and other specimens such as blood, sputum, or surgical wounds that showed evidence of tissue invasion. RESULTS: Sixty-seven patients with fungal empyema thoracis were included. Their mean age was 54 years (range, 2 weeks to 93 years), and 64% (43 patients) were men. Fifty-seven patients (85%) had various underlying diseases, and 18 (27%) had more than one immunocompromising condition. A total of 73 fungal isolates were recovered from pleural effusion; the most commonly encountered were Candida species (47 isolates, 64%), Torulopsis glabrata (13 isolates, 18%), and Aspergillus species (9 isolates, 12%). Candida albicans (28 isolates) was the most common Candida species, followed by Candida tropicalis (13 isolates). Six patients (9%) had two fungal strains isolated, and 16 (24%) had concomitant bacterial empyema thoracis. Eighteen patients (27%) had concurrent fungemia. Most (56 patients, 84%) cases of fungal empyema thoracis were nosocomial, and many case (43 patients, 64%) were acquired in ICUs. Abdominal disease (20 patients, 30%), especially previous abdominal surgery and GI perforation (12% and 10%, respectively), was the most common cause of fungal empyema thoracis, followed by bronchopulmonary infection (15 patients, 22%) and chest surgery (12 patients, 18%). Forty-nine patients (73%) received systemic antifungal therapy, and 38 (57%) underwent closed drainage therapy. Eleven patients (16%) underwent pleural irrigation with normal saline solution, povidone-iodine solution, or antifungal agents. Six patients (9%) finally received decortication. All patients receiving surgery or pleural irrigation with antifungal agents survived. Despite the aforementioned management, the crude mortality was high (73%). Multivariate analysis showed a significantly increased risk of death in immunocompromised patients (relative risk, 1.58; p < 0.005) and those with respiratory failure (relative risk, 2.31; p < 0.001). Systemic antifungal therapy was associated with a significantly lower risk of death (relative risk, 0.69; p < 0.05). CONCLUSION: These data imply an increasing incidence of fungal empyema thoracis in recent years and the necessity for aggressive treatment of patients with this disease.