Bleeding risk with AZD6140, a reversible P2Y12 receptor antagonist,vs. clopidogrel in patients undergoing coronary artery bypass grafting in the DISPERSE2 trial

AZD6140, the first reversible oral P2Y₁₂ receptor antagonist, exhibits greater and more consistent inhibition of platelet aggregation than the irreversible thienopyridine clopidogrel. As a result of its reversible effect, AZD6140 may pose less risk for bleeding when antiplatelet treatment cannot be stopped at least 5 days before coronary artery bypass graft (CABG) surgery or other invasive procedures. The Dose conflrmation Study assessing anti‐Platelet Effects of AZD6140 vs. clopidogRel in NSTEMI (DISPERSE2) trial showed overall comparable bleeding rates with antiplatelet treatment with AZD6140 90 mg twice daily or 180 mg twice daily vs. clopidogrel 75 mg once daily in 984 patients with non‐ST‐elevation acute coronary syndromes. A post hoc exploratory analysis of bleeding outcomes in the subset of 84 patients undergoing CABG in DISPERSE2 suggests reduced risk for total bleeding (41% and 58% vs. 62%), all major bleeding (38% and 50% vs. 62%), and life‐threatening bleeding (22% and 38% vs. 54%) with AZD6140 90 mg (n = 32) and 180 mg (n = 26) vs. clopidogrel (n = 26) respectively. Trends suggested that major bleeding rates were reduced with AZD6140 (combined groups) vs. clopidogrel when treatment was stopped ≤ 5 days prior to surgery (39% vs. 63%, p = 0.15) but not when treatment was stopped > 5 days before surgery (50% vs. 60%). This observation is consistent with the reversible binding of AZD6140 to the P2Y₁₂ receptor. Further prospective studies are planned to assess the relationship between this potential clinical benefit of AZD6140 and the reversibility of its antiplatelet effects.     

Prasugrel in acute coronary syndrome patients undergoing percutaneous coronary intervention

Currently, dual antiplatelet therapy with aspirin and clopidogrel represents the key treatment strategy for the prevention of ischemic events in patients with acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI). However, there is a broad inter-individual response variability to such treatment strategy, and a considerable number of patients persist with inadequate platelet inhibition, which has been associated with an increased risk of ischemic events. Overall, these findings underscore the need for novel antiplatelet agents able to achieve greater platelet inhibition; this can potentially reduce ischemic event rates. Prasugrel (CS-747; LY 640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet adenosine diphosphate P2Y₁₂ receptor. Laboratory studies have shown prasugrel to be associated with more prompt, potent and predictable degrees of platelet inhibition compared with clopidogrel. In a large-scale clinical study, which was comprised of high-risk ACS patients undergoing PCI, prasugrel was shown to significantly reduce the short- and long-term risk of ischemic events, including stent thrombosis. However, such significant reduction in ischemic events occurred at the expense of a higher risk of bleeding. Recent clinical trial data analyses have led to a better understanding of the efficacy and safety of prasugrel. This article reviews the currently available data regarding the efficacy and safety of prasugrel in ACS patients.     

Antiplatelet therapy - ticagrelor

Ticagrelor, a cyclopentyltriazolopyrimidine (CPTP), is the representative of a new chemical class of P2Y(12) receptor inhibitors that differ from thienopyridines (ticlopidin, clopidogrel, prasugrel) as ticagrelor is not a prodrug requiring active biotransformation by cytochromes in the liver and thus is characterized by a more rapid, more effective and more consistent platelet inhibition than ticlopidin or clopidogrel. An extensive study program for dose finding and safety for AZD6140 (DISPERSE studies) and a large-scaled phase III trial (PLATO) were undertaken on more than 18,000 patients for validation of efficacy and safety. In the PLATO trial, patients presenting with the broad spectrum of ACS, i.e. unstable angina, non-STEMI or STEMI, were randomized to ticagrelor (Brilique, Brilinta) or clopidogrel within 24 hours after onset of symptoms, regardless whether they were allocated to a planned invasive or conservative treatment. Compared to clopidogrel, ticagrelor reduced rates of the primary endpoint consisting of cardiovascular death, non-fatal MI, or stroke, without an excess of the primary safety endpoint that was PLATO-defined major bleedings. Results from the pre-specified confirmatory subgroup of patients undergoing planned invasive treatment was consistent with PLATO main trial. In addition, the primary endpoint, as well as CV death and all cause death were consistently reduced with ticagrelor in numerous exploratory subgroups including STEMI patients, those planned for non-invasive treatment, patients undergoing CABG, patients with renal failure, and those with diabetes mellitus, although patients were pretreated before coronary angiography and patients with clopidogrel pretreatment were not excluded. CONCLUSIONS: The pharmacological properties and convincing study results of the PLATO trial have stimulated a paradigm change for dual antiplatelet therapy. The new ESC guidelines on the management of ACS without ST segment elevation recommend the use of clopidogrel only when a new antiplatelet drug, e.g. ticagrelor or prasugrel is not available or contraindicated.     

New P2Y12 blockers

Summary.  A number of new antiplatelet agents currently in development are anticipated to improve clinical outcomes and safety benefits in patients with acute coronary syndrome (ACS). This article reviews the pharmacology and clinical development of three of these agents: prasugrel, cangrelor, and ticagrelor. Prasugrel, a third-generation, oral thienopyridine, has been shown to be superior to clopidogrel, the current gold standard, in preventing ischemic events in patients with ACS undergoing percutaneous coronary intervention (PCI), although the bleeding rate was higher. Cangrelor, a chemical analog of adenosine triphosphate, is a potent direct platelet P2Y₁₂ antagonist. In development as an intravenous agent, cangrelor is currently being evaluated in two phase III studies in patients requiring PCI. Ticagrelor is the first of a new class of orally available antiplatelet agents antagonizing the effects of ADP mediated by P2Y₁₂; it is currently being studied in a phase III trial in patients with ACS.     

Prasugrel hydrochloride for the treatment of acute coronary syndrome patients

Introduction: Dual antiplatelet therapy (DAPT) with aspirin combined with either a thienopyridine (clopidogrel or prasugrel) or acyclopentyl-triazolo-pyrimidine (ticagrelor) plays a vital role in the management of acute coronary syndrome (ACS) especially in those undergoing percutaneous coronary intervention (PCI) but even those being managed medically. Observational studies and some formal studies have shown patients on the standard dual antiplatelet regimen (clopidogrel and aspirin) continue to have further ischemic events and can suffer stent thrombosis. It has been demonstrated that clopidogrel is associated with a delayed onset of action with a considerable inter-individual variation to treatment thus making it difficult to achieve an optimal level of platelet inhibition.

Areas covered: This article will review the current evidence that is available regarding the effectiveness and safety of prasugrel in ACS patients undergoing percutaneous coronary intervention (PCI).

Expert commentary: Prasugrel is an oral third-generation inhibitor of platelet activation and aggregation. Laboratory studies and early phase clinical trials show prasugrel has a faster onset of action, is more potent and has reduced inter-patient response variability compared to clopidogrel. The published studies so far demonstrated that prasugrel when compared to clopidogrel also shows a higher degree of effectiveness in the prevention of platelet-initiated thrombotic events in patients with ACS undergoing PCI, however these benefits are offset somewhat by an increased bleeding risk.     

The role of clopidogrel in the management of acute coronary syndromes

BACKGROUND: Despite significant advances in the management of coronary heart disease, myocardial infarction (MI) is still associated with a mortality rate of 45%. Acetylsalicylic acid (ASA) has been the oral antiplatelet drug of choice until recently. Thienopyridines such as clopidogrel have been shown to provide significant benefits in the management of acute coronary syndromes (ACS), either as an alternative to or in combination with ASA therapy. OBJECTIVE: The purpose of this article was to review the available scientific literature evaluating the use of clopidogrel in the management of ACS. METHODS: Relevant published data were identified through searches of the English-language literature indexed on MEDLINE and International Pharmaceutical Abstracts through April 2003. Search terms included thienopyridines, platelet aggregation inhibitors, clopidogrel, ticlopidine, acute coronary syndrome, myocardial infarction, and percutaneous coronary intervention. Pertinent conference abstracts were also included. RESULTS: The results of 3 large clinical trials-Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), Effect of Pretreatment with Clopidogrel and Aspirin Followed by Long-Term Therapy in Patients Undergoing Percutaneous Coronary Intervention (PCI-CURE), and Clopidogrel for the Reduction of Events During Observation (CREDO)-support prolonged use of clopidogrel (up to 12 months) in combination with ASA in patients with non-ST-segment elevation MI and patients undergoing a percutaneous coronary intervention (PCI). A significant increase in bleeding events was observed in the group that received clopidogrel plus ASA compared with ASA alone in the CURE (major bleeding, P = 0.001; minor bleeding, P < 0.001) and PCI-CURE (minor bleeding, P = 0.03) trials. Use of the combination of clopidogrel and ASA with other antiplatelet and/or anticoagulant agents has not been studied extensively. CONCLUSIONS: Use of the combination of clopidogrel and ASA for up to 9 months is recommended for the medical management of non-ST-segment elevation MI and after a PCI. The increased risk of bleeding must be taken into account, and use of this combination with other agents that affect bleeding risk should be considered carefully.     

Antiplatelet options for secondary prevention in acute coronary syndromes

Current guidelines recommend dual antiplatelet therapy, a combination of aspirin and a P2Y₁₂ inhibitor, for 6–12 months after percutaneous coronary intervention with drug-eluting stent implantation in all patients and for 1 year in all patients after an acute coronary syndrome (ACS), irrespective of revascularization strategy. Clopidogrel has a pharmacokinetic and pharmacodynamic profile that results in a delayed and/or subtherapeutic antiplatelet effect, and wide variability in antiplatelet response. New P2Y₁₂ inhibitors, such as prasugrel and ticagrelor, have favorable pharmacodynamics and clinical efficacy over clopidogrel and offer an alternative antiplatelet treatment strategy in specific patients. Prasugrel has more potent, rapid, and consistent effects on inhibiting ADP-induced platelet aggregation than clopidogrel. Ticagrelor also appears to have more rapid and consistent antiplatelet effects than clopidogrel. The higher levels of antiplatelet inhibition provided by prasugrel and ticagrelor compared with standard-dose clopidogrel result in improved ischemic outcomes in patients with ACS. Despite an increase in bleeding risk, prasugrel and ticagrelor appear to have a better net clinical benefit, especially in higher-risk patients with ACS.     

Antiplatelet options for secondary prevention in acute coronary syndromes

Current guidelines recommend dual antiplatelet therapy, a combination of aspirin and a P2Y(12) inhibitor, for 6?12 months after percutaneous coronary intervention with drug-eluting stent implantation in all patients and for 1 year in all patients after an acute coronary syndrome (ACS), irrespective of revascularization strategy. Clopidogrel has a pharmacokinetic and pharmacodynamic profile that results in a delayed and/or subtherapeutic antiplatelet effect, and wide variability in antiplatelet response. New P2Y(12) inhibitors, such as prasugrel and ticagrelor, have favorable pharmacodynamics and clinical efficacy over clopidogrel and offer an alternative antiplatelet treatment strategy in specific patients. Prasugrel has more potent, rapid, and consistent effects on inhibiting ADP-induced platelet aggregation than clopidogrel. Ticagrelor also appears to have more rapid and consistent antiplatelet effects than clopidogrel. The higher levels of antiplatelet inhibition provided by prasugrel and ticagrelor compared with standard-dose clopidogrel result in improved ischemic outcomes in patients with ACS. Despite an increase in bleeding risk, prasugrel and ticagrelor appear to have a better net clinical benefit, especially in higher-risk patients with ACS.     

New antiplatelet drugs: beyond aspirin and clopidogrel

Antiplatelet therapy remains a cornerstone of modern management of atherothrombotic vascular disease. For many years, aspirin has been the mainstay of initial antiplatelet drug management in coronary heart disease, while the need for inhibition of other platelet activation pathways has led to the development of various other antiplatelet drugs, such as clopidogrel. An improved understanding of the underlying mechanisms involved in thrombogenesis has paved the way for further development of newer antiplatelet drug therapies. Various clinical studies have probed the effectiveness and risk profile of the newer antiplatelet drugs, such as prasugrel, in comparison with currently available drugs. Some newer agents such as prasugrel are close to being approved for clinical use, whereas other agents such as cangrelor and AZD6140 are in phase 3 clinical trials. New drug classes, such as the thromboxane receptor antagonists (such as NCX‐4016 and S18886), as well as platelet adhesion antagonists and thrombin receptor antagonists are similarly being evaluated for their efficacy and risk profile in phase I and II trials.     

High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome

Summary.  Background and objectives: Low response to antiplatelet therapy may be a risk factor for the development of ischemic complications in patients with non-ST segment elevation acute coronary syndrome (NSTE ACS) undergoing coronary stenting. Methods: We prospectively studied the platelet response to both clopidogrel and aspirin in 106 NSTE ACS consecutive patients undergoing percutaneous coronary intervention (PCI) with stenting. A single post-treatment blood sample was obtained just before PCI and analyzed by platelet aggregometry using both ADP and arachidonic acid (AA) as agonists to explore the responses to clopidogrel and aspirin, respectively. Patients were divided into quartiles according to the ADP or AA induced maximal intensity of platelet aggregation. Patients of the highest quartile (quartile 4) were defined as the 'low-responders'. Results: Twelve recurrent cardiovascular (CV) events occurred during the 1-month follow-up. Clinical outcome was significantly associated with platelet response to clopidogrel [Quartile 4 vs. 1, 2, 3: OR (95% CI) 22.4 (4.6–109)]. Low platelet response to aspirin was significantly correlated with clopidogrel low response ( P  = 0.003) but contributed less to CV events [OR (95%CI): 5.76 (1.54–35.61)]. Conclusions: A post-treatment ADP-induced platelet aggregation performed just before PCI identifies low responders to dual antiplatelet therapy with an increased risk of recurrent CV events.     

Oral antiplatelet agents in ACS: from pharmacology to clinical differences

Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS). Numerous clinical trials have established the value of antiplatelet therapies for ACS. Aspirin (ASA), thienopyridines and GP IIb/IIIa antagonists comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS. Thienopyridines are a class of drugs that function via inhibition of the adenosine diphosphate (ADP) P2Y12 platelet receptors. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Recently, a third generation of thienopyridines has been introduced represented by prasugrel that has demonstrated promising results in ACS patients treated with percutaneous coronary intervention (PCI). A number of nonthienopyridine oral antiplatelet drugs are under development, and one of them, ticagrelor has already been tested in a major phase III clinical trial, PLATO, with the inclusion of a broad spectrum of patients with ACS. The present review aims to discuss the present knowledge about the safety and efficacy of oral antiplatelet treatment of patients with ACS.     

New Antiplatelet Agents and the Role of Platelet Function Testing in Acute Coronary Syndromes

Background

Dual antiplatelet therapy is a guideline mandated for patients with acute coronary syndromes (ACS). Despite its use, thrombotic events continue to occur both early and late. Platelet function testing has been used to define the in vitro effects of new antiplatelet agents, and it has been suggested that it be used to choose therapy. The role of platelet function testing, particularly with newer antiplatelet agents, remains unclear.

Objective

We review the rationale for platelet function testing and its application in monitoring patients on antiplatelet therapy. We also review recent clinical trials of newer antiplatelet agents. On the basis of this review, we reach conclusions on the current role of antiplatelet function testing in monitoring modern antiplatelet therapy and the role of the new antiplatelet agents in the treatment of ACS.

Methods

We reviewed recent publications on platelet function testing and clinical trials of newer antiplatelet therapies compared with clopidogrel.

Results

Platelet function testing is complex, but there is now a bedside test, VerifyNow. High platelet reactivity has been associated with worse cardiovascular outcomes in patients undergoing percutaneous coronary intervention. Recent clinical trials have not found any advantage in outcomes in patients who have their therapy adjusted by monitoring their platelet function. Newer agents, prasugrel, ticagrelor, and cangrelor, produce more rapid, complete, less variable effects on platelet function than clopidogrel. Prasugrel was found to improve outcomes compared with clopidogrel in patients with ACS undergoing percutaneous intervention. Ticagrelor is beneficial in all patients with ACS and reduces cardiovascular mortality compared with clopidogrel. Cangrelor improves outcomes in patients undergoing stenting. Recent studies to assess the role of platelet function monitoring of the effects of clopidogrel and modifying treatments have not been successful.

Conclusion

Recent clinical trials have indicated that newer antiplatelet agents have advantages over clopidogrel in the treatment of ACS. Platelet function testing gives us a guide to the timing, efficacy, and variability of therapy and can correlate with poor patient outcomes; however, the use of antiplatelet function testing to tailor therapy does not seem appropriate.     

Clinical effects and outcomes with new P2Y12 inhibitors in ACS

Thienopyridines have become the cornerstone of treatment for percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses. Newly developed P2Y12 inhibitors are more potent, more predictable, and have a faster onset of action than clopidogrel, characteristics that make them particularly attractive for high-risk percutaneous coronary intervention (PCI). Four new P2Y12 inhibitors have been tested each of them having particular individual properties. Prasugrel is an oral pro-drug leading to irreversible blockade of the P2Y12 receptor and is approved worldwide for ACS PCI. Ticagrelor is a direct-acting and reversible inhibitor of the P2Y12 receptor with potentially more pleiotropic effects. Cangrelor is an intravenous direct and reversible inhibitor of the P2Y12 receptor providing the highest level of inhibition, and elinogrel is an intravenous and oral P2Y12 antagonist with a direct and reversible action. Both prasugrel and ticagrelor, opposed to clopidogrel, have shown that stronger P2Y12 inhibition led respectively to significant 19 and 16% relative risk reduction of a similar primary end point combining cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Both drugs showed a significant 0.6% absolute excess of TIMI major bleeding not related to CABG surgery. Because in clinical trials, patients perceived to be at higher risk of bleeding usually are excluded, the risk of major and even fatal bleeding might even be higher in a 'real-world' setting, i.e. in the elderly patient with comorbidities. On the other hand, these newly developed P2Y12 inhibitors decrease mortality after PCI compared with clopidogrel. The risk/benefit ratio is particularly favorable in PCI for patients with STEMI.     

替格瑞洛治疗氯吡格雷低反应患者的有效性及安全性分析

目的 观察替格瑞洛对氯吡格雷低反应急性冠状动脉综合征(acute coronary syndromes,ACS)患者治疗的有效性及安全性。方法 选择2013年1月至2014年6月应用氯吡格雷75 mg/d治疗的ACS经皮冠状动脉介入治疗(PCI)术后患者493例,用血栓弹力图测定血小板聚集率,根据血小板聚集率筛选出氯吡格雷低反应患者173例,采用数字随机法分为氯吡格雷组(n=87)和替格瑞洛组(n=86)。氯吡格雷组继续服用氯吡格雷(75 mg/d),替格瑞洛组将氯吡格雷替换为替格瑞洛(90 mg,2次/d)。主要终点事件为治疗3天、7天、30天二磷酸腺苷(ADP)诱导的血小板聚集率变化情况,次要终点事件为主要不良心脑血管事件(MACCE)及出血的发生率。结果 替格瑞洛组3天、7天、30天血小板聚集率分别为(56.7±12.5)%、(54.1±12.3)%、(53.2±15.3)%显著低于氯吡格雷组(87.7±14.3)%、(85.4±12.7)、(84.9±10.7)%,差异有统计学意义(P<0.01)。对所有患者随访12个月,替格瑞洛组MACCE及出血的发生率显著低于氯吡格雷组(P<0.05)。而两组出血发生率差异无统计学意义(P＞0.05)。结论 对于经皮冠状动脉介入治疗的氯吡格雷低反应患者接受替格瑞洛治疗后能获得理想的抗血小板效果,且替格瑞洛是有效、安全可信赖的药物。     

Elinogrel, an orally and intravenously available ADP-receptor antagonist. How does elinogrel affect a personalized antiplatelet therapy?

The antiplatelet therapy with aspirin and the ADP-receptor blocker clopidogrel is currently the standard medication after coronary intervention or after acute coronary syndrome to prevent recurrent ischemic events and reduce mortality. However, high interindividual response variability to antiplatelet treatment is described in up to 44% of treated patients. A poor response to clopidogrel is caused by multifactorial mechanisms. Individual risk assessment including platelet function testing (PFT) can help to identify high risk patients, although recent randomized trials to investigate effects of PFT-guided therapy have failed to detect an impact on prognostic outcome. Poor response to standard antiplatelet agents can be overcome by switching to alternate substances. Elinogrel is a novel competitive, reversible ADP-receptor antagonist available in oral and intravenous formulation. Additional treatment with elinogrel showed advantages over clopidogrel, including more rapid, less variable, and more complete inhibition of platelet function without significantly increased bleeding complications. This review gives an overview over the investigational drug elinogrel for use in a personalized antiplatelet approach.     

Long-term care after percutaneous coronary intervention: focus on the role of antiplatelet therapy

Arterial wall injury caused by percutaneous coronary intervention (PCI) triggers transient platelet activation and mural thrombosis; these effects are superimposed on the preexisting platelet hyperreactivity associated with underlying atherothrombosis. Platelet activation has been implicated in the major complications of PCI: acute and subacute thrombosis and restenosis. Antithrombotic and anticoagulant therapy minimizes thrombotic complications after PCI. Aspirin plus a thienopyridine (ticlopidine or clopidogrel) is more effective than aspirin plus heparin and extended warfarin therapy in preventing periprocedural ischemic events and subsequent stent thrombosis and results in less major and minor bleeding. Dual antiplatelet therapy with aspirin and clopidogrel (the preferred thienopyridine because of its superior hematologic safety) is recommended for at least 4 weeks to prevent subacute stent thrombosis with bare-metal stents and 3 to 6 months to prevent late-stent thrombosis with drug-eluting stents. Coronary atherothrombosis is a diffuse vascular disease, and reduction of the risk of future ischemic events requires strategies that extend beyond the focal treatment of stenotic lesions. Optimal long-term care after PCI requires aggressive systemic pharmacotherapy (antiplatelet agents, statins, beta-blockers, and angiotensin-converting enzyme Inhibitors) in conjunction with therapeutic lifestyle changes (smoking cessation, weight reduction, dietary measures, and exercise). In this context, dual antiplatelet therapy (aspirin plus clopidogrel) is recommended for at least 12 months after PCI for prophylaxis of future atherothrombotic events.     

Dyspnoea after antiplatelet agents: the AZD6140 controversy

Recent randomised studies suggest that experimental oral reversible platelet P2Y12 receptor inhibitor, AZD6140, causes dyspnoea. This also raises similar concerns about the parent compound, and another adenosine triphosphate (ATP) analogue (AR-69931MX or cangrelor), which is currently in Phase 3 trial in patients undergoing coronary interventions. We analysed package inserts, and available clinical trials safety data for antiplatelet agents with regard to the incidence of dyspnoea. We found that dyspnoea is a very rare complication of the presently approved platelet inhibitors, mostly caused by underlying disease, rather than antiplatelet therapy per se. The main reasons for respiratory distress after oral (AZD6140), and intravenous (cangrelor) agents may be the development of mild asymptomatic thrombotic thrombocytopenic purpura, fluid retention and dyspnoea because of the reversible nature of these drugs. Also, these agents are ATP analogues, which rapidly metabolise to adenosine, a well-known bronchoprovocator causing dyspnoea as well. In summary, dyspnoea is seldom considered, there are no treatment algorithms when it does occur, plausible mechanisms exist and despite these plausible mechanisms, the true cause of dyspnoea in these exposed individuals is unknown. Additional pulmonary function testing, immunological investigations and platelet receptor studies are urgently needed to determine the cause of dyspnoea after AZD6140, and to point out how such serious adverse reactions can be prevented, or at least minimised, raising potential concerns about this drug.     

急性冠状动脉综合征患者介入术后抗血小板药物抵抗的临床研究

目的 探讨急性冠状动脉综合征(ACS)患者经皮冠状动脉介入术(PCI)后阿司匹林和氯吡格雷抵抗的发生率及相关影响因素;根据血栓弹力图(TEG)结果指导ACS患者抗血小板药物的使用.方法 用TEG方法检测ACS患者服用阿司匹林和氯吡格雷的血小板抑制率.比较性别、年龄、吸烟、家族史、使用质子泵抑制剂(PPI)、高血压病、高脂血症、糖尿病等对PCI术后阿司匹林和氯吡格雷抵抗的影响,以及对阿司匹林和氯吡格雷抵抗的预测意义.结果 67例ACS患者中13例(19.4％)存在阿司匹林反应低下,9例(13.4％)患者存在氯吡格雷反应低下,3例(4.5％)同时存在阿司匹林反应低下和氯吡格雷反应低下.血小板药物反应低下者44.0％(11/25)合并糖尿病,血小板药物反应正常者11.9％(5/42)合并糖尿病,两者比较差异有统计学意义(P＜0.05);血小板药物反应正常者女性比例(60.0％)明显高于血小板药物反应低下者(19.1％),两者比较差异有统计学意义(P＜0.05).随着年龄的增长抗血小板药物的反应性会降低(P＜0.05).而两者在吸烟、家族史、使用PPI、合并高血压病、高脂血症比例等方面比较差异无统计学意义(P＞0.05).二分变量线性回归分析结果表明,PCI术后阿司匹林和氯吡格雷抵抗的影响因素包括性别、年龄、糖尿病.结论 对不同性别、年龄的ACS合并糖尿病的患者采用个性化抗血小板治疗,可以减少临床缺血事件的发生.     

Clinical use of clopidogrel in acute coronary syndrome

Several therapeutic approaches have been developed to improve the outcome among patients with acute coronary syndrome (ACS). However, treatment with antithrombotic therapies such as oral glycoprotein IIb/IIIa inhibitors has been limited by the lack of efficacy and excess bleeding complications. As the publication of the landmark study Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), the clinical benefit of early and intermediate-term use of combined antiplatelet agents--clopidogrel plus aspirin--in non-ST-segment elevation myocardial infarction (NSTEMI) patients became evident. Pretreatment and intermediate-term therapy with clopidogrel in NSTEMI ACS patients undergoing percutaneous coronary intervention (PCI) was further supported by the PCI-CURE trial. Recently, the results of two major trials Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction 28, Clopidogrel and Metoprolol in Myocardial Infarction Trial established the pivotal role of clopidogrel in the other spectrum of ACS-STEMI. Coupled with the results from previous multicentre trials, these two studies provide a guide for the early and long-term use of clopidogrel in the whole spectrum of ACS. A review summarising the results of the recent clinical trials and a discussion on its implications for the clinical management of ACS is presented.     

Antiplatelet therapy in acute coronary syndromes: the emergency physician's perspective

The platelet plays a central role in the pathogenesis of coronary thrombosis after atherosclerotic plaque rupture, and its active inhibition forms a cornerstone of the management of acute coronary syndromes (ACS). Early treatment with clopidogrel in addition to aspirin is more effective than aspirin alone in reducing recurrent ischemic events in patients presenting with ACS, and is a useful adjunct to percutaneous coronary intervention, especially with stenting. There is a potential for increased bleeding complications in patients on clopidogrel therapy who subsequently undergo urgent coronary artery bypass graft surgery. Consequently, many emergency physicians withhold clopidogrel treatment until it is clear that urgent coronary artery bypass graft surgery will not be required. The potential untoward effects seem to be minimized by withholding antiplatelet therapy 3-5 days before surgery. Intravenous glycoprotein (GP) IIb/IIIa receptors inhibitors are also particularly useful in patients who undergo percutaneous coronary intervention, and may have some utility in the medical management of patients with high-risk non-ST-segment elevation ACS, starting in the emergency department. For patients presenting to the emergency department with ACS, the benefits and risks of initiating clopidogrel or GP IIb/IIIa inhibitor therapy need to be considered on an individual basis.