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.     

氯吡格雷反应性的研究进展

对于急性冠状动脉综合征和经皮冠状动脉介入治疗患者,氯吡格雷联合阿司匹林的双联抗血小板治疗已成为药物治疗的核心手段。然而,越来越多的证据显示不同生物个体之间存在抗血小板治疗反应的多样性;特别是氯吡格雷低反应性,与临床上反复缺血、脑卒中、支架内血栓形成等不良事件相关;机制尚未完全阐明,涉及遗传、代谢、基因多态性、药物相互作用等方面。现就氯吡格雷反应性的研究进展做一综述。     

急性冠状动脉综合征患者对阿司匹林和氯吡格雷低反应性的研究进展

不稳定斑块破裂、血栓形成是急性冠状动脉综合征的主要病理基础。对于急性冠状动脉综合征患者,尤其是准备接受经皮冠状动脉介入术的患者,许多大规模临床试验已经证实阿司匹林和氯吡格雷联合用药,不但能降低高危心血管危险因素患者的心血管事件发生率,而且可以显著减少经皮冠状动脉介入术围手术期缺血性并发症的发生。然而,临床观察发现,接受标准化阿司匹林和氯吡格雷治疗的患者中大约有1%~45%仍发生心血管事件[1]。这一现象表明,不同个体对抗血小板药物治疗反应性不同,因此,抗血小板药物治疗"抵抗"和"低反应性"成为目前临床研究的热点。     

Poor responsiveness to antiplatelet drugs in acute coronary syndromes: clinical relevance and management

Cardiovascular diseases are the most common cause of mortality and morbidity in Western countries, accounting for more than 40% of total mortality. An optimal pharmacological management in these patients is of major importance and antiplatelet agents remain the cornerstone of acute coronary syndrome (ACS) therapy at hospital admission and during percutaneous coronary interventions (PCI). The recently described poor biological responses to aspirin and clopidogrel have been source of major concern, especially in era of drug eluting stent implantation. Indeed, insufficient platelet inhibition at the time of PCI has been consistently associated with an increased risk of complications and recurrence of ischemic events. Despite the lack of uniformly accepted definitions of aspirin and clopidogrel poor response, we sought to describe the current evidence and gaps in knowledge. While trials on the potential benefit of an increased antiplatelet maintenance dose after PCI have shown only marginal benefits, the strengthening of the initial antiplatelet regimens by additional loading doses of clopidogrel, by the administration of glycoprotein IIb/IIIa receptor inhibitors or phosphodiesterase inhibitors might further improve outcomes during ACS and PCI in patients with poor responsiveness to conventional dual antiplatelet therapy. Overall, tailoring the antiplatelet treatment on the basis of the individual biological response improves the short-term outcome after PCI. New and more potent antiplatelet drugs may overcome the clinical consequences of the poor response to antiplatelet agents.     

Antiplatelet drug response variability and the role of platelet function testing: A practical guide for interventional cardiologists

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome and is also of particular importance in those who undergo percutaneous coronary intervention with stent implantation. Dual antiplatelet therapy with aspirin and clopidogrel is associated with improvement in long‐term clinical outcomes in such patients and is presently the antiplatelet therapy of choice for secondary prevention of thrombotic events. However, a significant number of patients experience recurrent events despite antiplatelet therapy. Although poor patient compliance can account for some of these events, particularly in those patients who receive a drug‐eluting stent, increasing evidence indicates that there is variability in response to antiplatelet therapy and patients who have higher levels of platelet reactivity are at increased risk for recurrent ischemic events. However, the lack of a consistent definition of inadequate platelet response, as well as the lack of a standardized measurement technique, has made it difficult to define how to treat these patients. To translate findings associated with variability in platelet response into improved patient care, it is necessary to gain a better understanding of what variable platelet response is, how it is measured, who it should be measured in, and what its clinical relevance is. The objective of this review is to evaluate the data regarding interindividual response variability to antiplatelet therapy with the aim of providing practical considerations and where possible, recommendations, regarding this topic for interventional cardiologists. © 2008 Wiley‐Liss, Inc.     

Antiplatelet therapy for postdischarge medical management of acute coronary syndrome

Postdischarge management of patients with acute coronary syndrome is often suboptimal, despite their high risk of a subsequent event. Updated American College of Cardiology/American Heart Association guidelines emphasize the need for aggressive modification of risk factors and treatment with antiplatelet, antihypertensive, and lipid-lowering agents commenced in-hospital and continued long-term. Antiplatelet therapy involving aspirin and clopidogrel is the mainstay of secondary risk reduction. Increased adherence to medication and risk factor modification at discharge has been demonstrated with acute care quality improvement initiatives. Extension of these initiatives to postdischarge care will provide data on medication adherence post acute coronary syndrome and functional outcomes in the community setting. Successful secondary prevention of cardiovascular events requires implementation of evidence-based guidelines by physicians, and adherence to pharmacotherapy and lifestyle modifications by patients. Primary care physicians are well placed to influence adherence through their ongoing relationships with patients and can save lives by implementing secondary risk reduction measures after discharge.     

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.     

血栓弹力图检测老年冠心病患者经皮冠状动脉介入治疗后血小板反应性

目的探讨经皮冠状动脉介入治疗术后,经血栓弹力图检测的氯吡格雷药物抵抗患者,不同药物剂量治疗下血小板反应性。方法筛选120例阿司匹林抑制良好而氯吡格雷抑制不敏感的患者,随机分为试验组(60例)和对照组(60例),对照组每天服用100 mg阿司匹林及75 mg氯吡格雷,试验组服用100 mg阿司匹林及150 mg氯吡格雷,检测6个月后氯吡格雷的作用效果,观察2组间6个月内心血管事件及出血事件的发生率。结果试验组心血管死亡、支架内血栓形成、不稳定性心绞痛、心肌梗死发生率分别为0,8.3%,21.7%,8.3%;对照组分别为3.3%,18.3%,35.0%,15.0%,试验组患者氯吡格雷药物抑制率较对照组明显升高(65.6±5.1)% vs (40.9±7.3)%,差异有统计学意义(P0.01)。结论对于血小板高反应性老年患者,每天75 mg氯吡格雷不能满足血小板抑制效果,长期加倍剂量服用能够在一定程度上有效减低药物抵抗发生率,改善血小板抑制效果,从而降低心血管缺血事件的发生率。     

Recent developments in the use of antiplatelet agents to prevent cardiovascular events

Platelets are pivotal contributors to arterial thrombosis. Dual antiplatelet therapy with aspirin and clopidogrel has become the standard of care for the secondary prevention of cardiovascular events in patients with acute coronary syndromes and after percutaneous coronary intervention. Clinical evidence of the continued risk of cardiovascular events plus pharmacodynamic evidence of substantial variability in on-treatment platelet reactivity has supported the development of new therapeutic strategies, using established agents and new antiplatelet drugs. This article will highlight recent pivotal clinical trials seeking to advance the use of antiplatelet therapy in patients with cardiovascular disease.     

Platelet function monitoring in patients with coronary artery disease

Studies focused on patient responsiveness to antiplatelet therapies, particularly aspirin and clopidogrel, have increased in recent years. However, the relations of in vivo platelet function and adverse clinical events to results of ex vivo platelet function tests remain largely unknown. This article describes current methods of measuring platelet function in various clinical and research situations and their advantages and disadvantages, reviews evidence for antiplatelet response variability and resistance, discusses the potential pitfalls of monitoring platelet function, and demonstrates emerging data supporting the positive clinical and treatment implications of platelet function testing.     

Inhibition of the antithrombotic effects of clopidogrel by proton pump inhibitors: Facts or fancies?

Clopidogrel plus aspirin is considered the antiplatelet treatment of choice in patients with acute coronary syndrome, whether or not they are undergoing a percutaneous coronary intervention (PCI). The same treatment is mandatory in all patients undergoing a PCI with stent implantation. Clopidogrel is a pro-drug that needs metabolic activation through a cytochrome P450-dependent pathway, with an extensive involvement of the CYP 2C19 isoenzyme. Proton pump inhibitors (PPIs) reduce the risk of gastrointestinal bleeding in patients receiving dual antiplatelet therapy. In the past two years some scientific evidences have suggested a possible negative interference of PPIs on antiplatelet effect of clopidogrel because of the competitive inhibition of the CYP 2C19 isoenzyme. Few studies testing platelet reactivity in patients receiving both clopidogrel and a PPI have demonstrated a reduced inhibitory effect of the association on platelet aggregation. Moreover, results from retrospective observational studies have shown a higher incidence of major cardiovascular events in patients receiving both clopidogrel and PPIs. These data have not been confirmed neither by the only prospective randomized study comparing clopidogrel plus omeprazole with clopidogrel alone, nor by the retrospective analysis of the TRITON TIMI 38 trial, where PPIs did not affect the clinical outcome of patients given clopidogrel or prasugrel. Nevertheless both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have discouraged the concomitant use of clopidogrel and PPIs. Important questions concerning a true interference between the two classes of drugs still remain unanswered and need to be addressed by adequately powered studies.     

Efficacy and safety of individually tailored antiplatelet therapy in patients with acute coronary syndrome after coronary stenting: a single center, randomized, feasibility study

Background Low responsiveness to clopidogrel (LRC) is associated with increased risk of ischemic events. This study was aimed to explore the feasibility of tailored antiplatelet therapy according to the responsiveness to clopidogrel. Methods A total of 305 clopidogrel naive patients with acute coronary syndromes (ACS) undergoing coronary stenting were randomly assigned to receive standard (n = 151) or tailored (n = 154) antiplatelet therapy. The ADP-induced platelet aggregation tests by light transmission aggregometry were performed to identify LRC patients assigned to the tailored group. The standard antiplatelet regimen was dual antiplatelet therapy with aspirin and clopidogrel. The tailored antiplatelet therapy was standard regimen for non-LRC patients and an additional 6-month cilostazol treatment for LRC patients. The primary efficacy outcome was the composite of cardiovascular death, myocardial infarction or stroke at one year. Results LCR was present in 26.6% (41/154) of patients in the tailored group. The percentage platelet aggregation for LCR patients was significantly decreased at three days after adjunctive cilostazol treatment (77.5% ± 12.1% vs. 64.5% ± 12.1%, P < 0.001). At one year follow-up, a non-significant 37% relative risk reduction of primary events were observed in the tailored group as compared to the standard group (5.8% vs. 9.3%, P = 0.257). There were no differences in the rates of stent thrombosis and hemorrhagic events between the two groups. Conclusions Tailored antiplatelet therapy for ACS patients after coronary stenting according to responsiveness to clopidogrel is feasible. However, its efficacy and safety need further confirmation by clinical trials with larger sample sizes.     

Clopidogrel as adjunctive antiplatelet therapy during coronary stenting

OBJECTIVES

We examined the procedural and 30-day clinical outcomes among patients receiving aspirin and either ticlopidine or clopidogrel during coronary stenting.

BACKGROUND

Ticlopidine-plus-aspirin has become standard antiplatelet therapy for the prevention of thrombotic complications after coronary stenting. Clopidogrel has a similar mechanism of action as ticlopidine, but both its efficacy and its safety as a pharmacologic adjunct to coronary stenting have not been well described.

METHODS

This single-center, prospective analysis examined the in-hospital procedural and 30-day clinical outcomes among 875 consecutive patients undergoing coronary stenting who received adjunctive aspirin and either clopidogrel (n = 514; 58.7%) or ticlopidine (n = 361; 41.3%) therapy.

RESULTS

Procedural success rates were similar among the clopidogrel- (99.6%) and ticlopidine-treated patients (99.4%). Subacute stent thrombosis (i.e., >24 h ≤30 days) occurred in one clopidogrel-treated (0.2%) and in one ticlopidine-treated (0.3%) patient (p = 0.99). By 30 days following the index procedure, the combined rates of death, nonfatal myocardial infarction and need for target vessel revascularization were similar among patients who received either clopidogrel (2.1%) or ticlopidine (1.4%; p = 0.57) therapy.

CONCLUSIONS

In this analysis the antiplatelet combination therapy of aspirin-plus-clopidogrel was an effective regimen for preventing thrombotic complications and major adverse cardiovascular events among a broad spectrum of patients undergoing coronary artery stenting.     

大剂量氯吡格雷联合阿司匹林、尿激酶溶栓治疗急性ST段抬高型心肌梗死的疗效观察

目的:探讨大剂量氯吡格雷联合阿司匹林、尿激酶溶栓治疗急性ST段抬高型心肌梗死(STEMI)的临床疗效。方法:将70例STEMI患者随机等量分为两组,在尿激酶溶栓的基础上,试药组进行大剂量氯吡格雷联合阿司匹林治疗,对照组只进行常规阿司匹林治疗,治疗1周后观察比较两组的疗效和安全性。结果:两组复合终点事件的差异显著,试药组的近期疗效显著优于对照组(P0.05),两组的出血发生率无显著差异。结论:STEMI患者在应用阿司匹林,尿激酶治疗基础上加用大剂量氯吡格雷,可显著降低住院期间的病死率和心血管事件的发生。     

急性冠脉综合征患者介入治疗早期增加阿司匹林和氯吡格雷剂量对主要不良心血管事件的影响

目的:观察急性冠脉综合征（ACS）患者经皮冠状动脉介入治疗（PCI）早期不同剂量阿司匹林、氯吡格雷对主要不良心血管事件（MACE）的影响。方法: 选择2007年12月～2009年12月ACS行PCI术的患者102例,所有患者按入院先后随机分为两组,1组为加量组（n=54）,患者入院后阿司匹林300 mg顿服,然后300 mg,每日1次,口服1个月后改为100 mg,每日1次,长期口服;氯吡格雷150 mg ,每日1次,1周后改为75 mg,每日1次,口服1年。另1组为对照组（n=48）,患者入院后阿司匹林100 mg,每日1次,以后长期按此剂量口服。氯吡格雷75 mg,每日1次,口服1年。两组患者其他治疗低分子肝素等方法相同。分别于PCI术后1个月、6个月时比较MACE的发生情况。结果: 两组患者临床基线特征基本一致,病变血管分布情况差异无统计学意义。其MACE发生情况在第一个月时,加量组低于对照组,但差异未到达显著水平（7% vs.15%）;在第6个月时,加量组低于对照组,差异具有统计学意义（2% vs. 17%,P<0.05）。结论: ACS患者在一般治疗的基础上,介入治疗时早期增加阿司匹林、氯吡格雷的剂量可降低PCI术后MACE的发生率。     

Aspirin and clopidogrel resistance: consideration and management

The efficacy with aspirin and clopidogrel treatment has been demonstrated in various clinical trials. Laboratory evaluation of platelet response in recent studies revealed that a distinctive response variability and nonresponsiveness/resistance in selected patients were associated with these antiplatelet agents. Moreover, some studies have correlated this nonresponsiveness/resistance phenomenon to the occurrence of thrombotic events. At this time there are no uniformly established methods to quantify exvivo platelet reactivity after clopidogrel and aspirin treatment of the extent of platelet inhibition by clopidogrel and aspirin. Therefore, specific treatment recommendations for patients exhibiting high platelet reactivity or poor platelet inhibition during clopidogrel or aspirin therapy are not established. A higher aspirin dose and strict compliance to therapy may overcome the occurrence of "aspirin resistance" in selected patients. A higher clopidogrel dose may be considered in patients exhibiting clopidogrel nonresponsiveness.     

Influence of Platelet Reactivity on Clinical Outcome of Patients with Stable Coronary Artery Disease

Single antiplatelet therapy with aspirin is actually recommended for cardiovascular prevention in patients with stable coronary disease, whereas dual antiplatelet therapy (aspirin and clopidogrel) represents the established treatment in patients with acute coronary syndromes or stable angina undergoing percutaneous coronary intervention. However, recurrent ischemic events occur in patients on treatment with clopidogrel; this may be due to low responsiveness to this agent, a phenomenon influenced by environmental, clinical, and genetic factors. Different strategies have been tested to overcome this phenomenon, such as increase in clopidogrel loading and maintenance doses and use of newer P2Y12 inhibitors (prasugrel and ticagrelor), which are by now indicated for patients with acute coronary syndromes; the latter agents have been associated with stronger antiplatelet effect than clopidogrel even in patients with stable coronary disease, but further studies are needed to test their net clinical benefit in this setting (reduction of ischemic events without increase in bleeding).     

Overcoming Aspirin Resistance with Loading Clopidogrel Earlier in Elective Percutaneous Coronary Intervention

We aimed to analyze the clinical effect of clopidogrel loading time on adverse cardiovascular events among patients with aspirin resistance. Recurrent adverse events may still occur despite dual antiplatelet therapy after coronary stenting. Aspirin resistance is one of the possible reasons of this trouble. Optimal antiplatelet strategy for coronary stenting is unknown among patients with aspirin resistance. A total of 980 patients scheduled for elective coronary stenting were enrolled and allocated into two groups according to the loading time of clopidogrel more or less than 6 hours before coronary intervention (early- or late-loaded groups, respectively). Aspirin resistance was determined according to the urinary levels of 11-dehydrothromboxane B2. Overall 240 patients who were allocated to early- and late-loaded groups were identified as aspirin resistant according to the urinary levels of 11-dehydrothromboxane B2. After a follow-up period of 12 months major adverse cardiac events were observed among 16 patients (13.9%) in the early-loaded group and 30 patients (25.8%) in the late-loaded group (p = 0.02). Early loading of clopidogrel was an independent predictor of lower rate of cardiac events (hazard ratio = 0.46 [0.32–0.76, 95% confidence interval], p = 0.001). The rates of bleeding events and periprocedural myocardial infarction were similar in early- and late-loaded groups. The current study demonstrated that loading of clopidogrel earlier than 6 hours before elective coronary stenting among aspirin-resistant patients was associated with increased benefits for ischemic events with similar bleeding rates.     

High on treatment platelet reactivity

The addition of clopidogrel to aspirin for patients undergoing percutaneous coronary intervention (PCI) had significantly reduced cardiovascular events. However, despite dual antiplatelet therapy ischaemic events still occur, especially stent thrombosis, which is associated with a high mortality rate. Inter-individual response to clopidogrel is highly variable. It was shown that 4-46% could be considered as high on treatment platelet reactivity (HTPR). Recent studies had demonstrated a relationship between HTPR and ischaemic events in the setting of PCI. Actually the assessment of platelet reactivity in routine practice and its interpretation to make a decision is a debatable issue.     

Aspirin and clopidogrel response variability: review of the published literature

Antiplatelet resistance has been proposed as a possible mechanism to explain recurrent cardiovascular events in patients who have coronary artery disease and who are undergoing dual antiplatelet therapy. A comprehensive search on PubMed was conducted for literature that was printed in the English language between January 1996 and November 2007 on aspirin and clopidogrel resistance. Significant traits for aspirin hyporesponsiveness were female sex, older age, and lower levels of hemoglobin. Diabetes mellitus and elevated body mass index showed trends toward a higher incidence of resistance in some aspirin trials but did not reach statistical significance. Clopidogrel studies suggested that patients with type-2 diabetes mellitus are more likely to manifest inadequate response to the medication. Although 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors were initially suspected to decrease response to clopidogrel, later studies refuted this possibility. Patients with a suboptimal response to aspirin or clopidogrel seem to be at increased risk of recurrent cardiovascular events. Large clinical trials with standardized laboratory methods and well-defined protocols are needed to determine whether common features exist in patients with suspected hyporesponsiveness to antiplatelet therapy, and to validate the clinical relevance of response variability. A concise nonarbitrary definition of physiologic "resistance" is needed, and investigators should identify patients as having a variable response to antiplatelet therapy.