Antiplatelet therapy in patients with diabetes mellitus

Platelets are key players in arterial thrombosis, and oral antiplatelet therapy is a cornerstone in the treatment and prevention of cardiovascular events. However, although currently approved antiplatelet drugs have proved successful in reducing cardiovascular events, platelet-dependent thrombosis remains an important cause of morbidity and mortality in patients with coronary artery disease. It is well-known that patients with diabetes mellitus (DM) have an increased risk of cardiovascular events and, therefore, understanding the mechanism of action and safety profile of antiplatelet drugs in this high-risk population is of particular interest. There is considerable inter-individual variation in the efficacy of established antiplatelet drugs, and high on-treatment platelet reactivity is associated with an increased risk of cardiovascular events, thus prompting the search for novel drugs against platelet-dependent thrombosis. New antiplatelet treatment strategies include drugs with more efficient and reversible platelet inhibition. This review discusses selective inhibitors of the platelet cyclooxygenase enzyme, thienopyridine and non-thienopyridine inhibitors of the platelet adenosine diphosphate receptor, phosphodiesterase inhibitors, and protease-activated receptor antagonists. An overview of currently available antiplatelet drugs is provided, focusing on benefits and limitations in patients with DM. Furthermore, the rationale for new oral antiplatelet drugs under development is discussed with particular focus on the potential role of these drugs to improve cardiovascular outcomes in patients with DM.     

临床药师参与１例冠心病伴假性血小板减少症诊治病例分析

摘 要抗血小板药物在冠心病患者的治疗中十分重要,但伴血小板重度减少往往限制了抗血小板药物的应用。因此,临床中应及时准确辨别血小板减少的原因以指导临床抗血小板药物的应用。本案例中临床药师通过分析１例老年冠心病患者出现血小板减少的原因,排除药源性血小板减少,明确为ＥＤＴＡ依赖性假性血小板减少症,及时恢复抗血小板治疗,避免误停抗血小板药物而导致心血管不良事件的发生。     

延长双重抗血小板治疗对心肌梗死后高危稳定性冠心病患者预后的影响

目的 探讨延长双重抗血小板治疗对心肌梗死后高危稳定性冠心病患者预后的影响.方法 选取2013年6月至2014年8月本院收治的心肌梗死后高危稳定性冠心病患者84例为研究对象,采用随机数表法分为观察组和对照组,各42例,对照组实施短期(12个月)双重抗血小板治疗,观察组采用长期(24个月)双重抗血小板治疗.比较两组治疗结束时血脂复常率、左室射血分数正常率、血小板聚集率,评价疗效;同时记录两组复合终点事件(心血管死亡、心肌梗死、脑卒中)发生率及消化道出血发生率.结果 观察组血脂复常率为90.5％、左室射血分数正常率为88.1％,显著高于对照组的71.4％、69.0％(P＜0.05),观察组血小板聚集率为4.8％,明显低于对照组的23.8％(P＜0.05);观察组消化道出血率为19.0％,与对照组的14.3％比较,差异无统计学意义(P＞0.05);观察组复合终点事件发生率为21.4％,与对照组的7.1％比较,差异无统计学意义(P＞0.05).结论 在心肌梗死后高危稳定性冠心病患者抗血小板治疗中,长期双重抗血小板治疗可有效改善血脂水平、左室射血分数及血小板聚集率,且长期治疗后消化道出血、复合终点事件发生率与短期双重抗血小板治疗无显著差异,因此延长双重抗血小板治疗的方案值得临床应用.     

Antiplatelet Drug Resistance and Drug-Drug Interactions: Role of Cytochrome P450 3A4

Antiplatelet therapy provided pivotal advances in the treatment of cardiovascular disease. Aspirin and thienopyridine, clopidogrel, is currently the treatment of choice in acute coronary syndromes and the prevention of thrombosis after coronary stent implantation. Despite the efficacy of this dual antiplatelet therapy in reduction of adverse coronary events in patients with acute coronary syndromes, complications persist in a subgroup of these patients. Emerging causes of aspirin and clopidogrel resistance may translate to increase risk for recurrent myocardial infarction, stroke, or cardiac related mortality. However, the mechanism of antiplatelet drug resistance remains incompletely characterized, and a sensitive and specific assay of aspirin and clopidogrel effect that reliably predicts treatment failure has not emerged. To date, evidence supporting antiplatelet drug resistance are pharmacokinetic response variability, drug-drug interaction through competitive inhibition a specific enzymatic pathway, genetic variability, and variability in the induction of enzymatic pathway in metabolic activation of prodrugs, like clopidogrel. Further investigation or guidelines are needed to optimize antiplatelet treatment strategies to identify and treat patients resistant to aspirin and/or clopidogrel.     

西洛他唑治疗经皮冠脉内介入术后对阿司匹林致上消化道出血患者的随访研究

目的观察经皮冠脉内介入术(percutaneous coronary intervention,PCI)后使用西洛他唑对阿司匹林致上消化道出血患者的外周血血小板聚集率、PGE2及心血管事件发生率的影响。方法 64例确诊冠心病并行PCI术后的患者,服用阿司匹林和氯吡格雷双重抗血小板治疗出现阿司匹林相关上消化道出血,其中32例患者改用西洛他唑加氯吡格雷,而另外32例患者出血治疗后继续原抗血小板治疗方案,随访比较两组患者血小板聚集率、PGE2及心血管事件发生率。结果平均随访(0.9±0.1)年,两组患者血小板聚集率均明显下降,西洛他唑组的血小板聚集率显著低于阿司匹林组(P<0.05),外周血PGE2的浓度高于阿司匹林组(P<0.05),但两组患者临床不良事件发生率差异无统计意义。结论对PCI术后上消化道出血患者,应用西洛他唑替代阿司匹林,联用氯吡格雷进行抗血小板治疗,经过短期的临床观察,其血小板聚集率优于阿司匹林,升高外周血PGE2的浓度,且安全性与阿司匹林相当,可用于预防上消化道出血的复发。     

The pharmacogenetics of antiplatelet drugs

Platelets play a pivotal role in coronary heart disease and atherothrombotic events, and thus antiplatelet therapy is commonly used to treat cardiovascular disease. Unfortunately, the benefits of this approach are limited, and a large proportion of treated patients will suffer a new thrombotic event, either within the first few weeks following stent implantation or in the follow-up period after myocardial infarction. This lack of clinical benefit may be related to a heterogeneous response to antiplatelet drugs among individuals. Recently, the field of pharmacogenetics has tried to identify gene variants in order to explain tile observed heterogeneity in patient responses to drugs. This review explores the genetic influences on antiplatelet drug efficacy by analyzing the modulating role of different genetic polymorphisms on individual responses to antiplatelet therapy.     

Heterogeneity of Efficacy and Safety of Antiplatelet Therapy in Cardiovascular and Cerebrovascular Disease

The beneficial effects of antiplatelet therapy for secondary prevention in patients with prior cardiovascular or cerebrovascular events, including stroke, transient ischemic attack, and myocardial infarction, have been demonstrated repeatedly over the past decade. It is increasingly apparent that pathophysiologic differences between patients with different types of prior vascular events have an important effect on treatment outcomes. Several large, important trials of antiplatelet therapies, including MATCH, CHARISMA, ESPRIT, and TRITON-TIMI 38, underscore the heterogeneity of the efficacy and safety of antiplatelet agents in patients with recent cerebrovascular disease, compared with patients with recent acute coronary syndromes. Trial data therefore support an individualized approach to antithrombotic therapy for secondary vascular-event prevention that is appropriate for any probable future vascular events and actively reduces the impact of modifiable risk factors common to all vascular events. The potential for benefit in reducing recurrent vascular events must be weighed against the increased risk of bleeding and of patient non-responsiveness to treatment. A number of other factors also need to be considered, including drug interactions, patient compliance, and adverse-effect profiles. Overall, there is now a substantial body of clinical trial evidence that supports the need to carefully individualize antiplatelet therapy and other risk-reducing strategies on the basis of each patient’s pathology and specific needs.     

加用泮托拉唑对行双抗血小板治疗冠心病患者血小板抑制率的影响

目的 研究加用泮托拉唑对行双抗血小板治疗冠心病患者血小板抑制率的影响.方法 选取2015年7月至2016年11月本院收治的76例行双抗血小板治疗冠心病患者为研究对象,依据用药差异,分为观察组(n=38)与对照组(n=38),观察组加用泮托拉唑,对照组不加用其他药物,对比两组血小板聚集率、血小板反应指数与不良心血管事件出现率、消化道不良反应情况.结果 观察组ADP-Ag(19.08±18.36)％、不良心血管事件出现率0.00％、消化道不良反应总发生率2.63％,明显小于对照组的(28.26±20.84)％、10.53％、18.42％,且PRI为(67.43±21.13)％,明显高于对照组的(48.48±19.32)％,均P＜ 0.05.结论 对氯吡格雷条件下抗血小板治疗患者加用泮托拉唑,可产生良好血小板抑制效果,并且不会诱发心血管事件,降低消化道不良反应出现率,具有积极应用意义.     

Oral Antiplatelet Therapy in the Secondary Prevention of Atherothrombotic Events

Atherothrombosis is the leading cause of death worldwide and has a large economic impact. It is a pathologic process related to atherosclerosis, which leads to adverse clinical manifestations, including acute coronary syndrome, cerebrovascular disease, and peripheral arterial disease. Patients with atherothrombosis are at heightened risk for recurrent ischemic events or death, and therefore, secondary prevention is an important goal in the treatment of these patients. Antiplatelet therapies available for long-term secondary prevention include aspirin (acetylsalicylic acid), extended-release dipyridamole plus aspirin, and clopidogrel. A number of clinical trials have demonstrated the benefit of combined antiplatelet therapy in secondary prevention, supporting the recommendations made in current published guidelines. Although the efficacy and safety of antiplatelet agents is well established and supported by clinical trials, their utilization rate in patients with atherothrombosis remains suboptimal. Quality improvement initiatives have demonstrated effectiveness in promoting the awareness and implementation of treatment guidelines. This article reviews the benefits and risks of antiplatelet therapy in patients with cardiovascular disease with the aim of spurring greater adherence to treatment recommendations and, thereby, better patient outcomes.     

Prevention of coronary heart disease with aspirin and clopidogrel: efficacy, safety, costs and cost-effectiveness

Atherothrombotic coronary artery disease is the single most common cause of death worldwide and a growing public health problem. Platelets play a central role in the pathogenesis of atherothrombosis and are therefore commonly targeted by one or more antiplatelet drugs as part of primary and secondary atherothrombosis prevention strategies. Aspirin reduces the risk of serious vascular events (myocardial infarction, stroke or cardiovascular death) by approximately 20% in a broad range of high-risk patients and remains the first-line antiplatelet drug because of its relative safety, low cost and cost-effectiveness. Compared with aspirin alone, clopidogrel reduces the risk of serious vascular events by approximately 10% and the combination of aspirin and clopidogrel reduces the risk by approximately 20% in patients with non-ST-segment elevation acute coronary syndrome. Clopidogrel has a similar safety profile to aspirin but clopidogrel tablets are substantially more expensive. However, the incremental cost-effectiveness ratio of clopidogrel compared with aspirin is favourable, particularly in high-risk patients and is intermediate compared with a range of other effective therapeutic strategies for the treatment of coronary heart disease. Clopidogrel should be considered as a replacement for aspirin in patients who are allergic to aspirin, cannot tolerate aspirin, have experienced a recurrent atherothrombotic vascular event whilst taking aspirin and are at very high absolute risk of a serious vascular event (e.g., > 20%/year). The combination of clopidogrel and aspirin should be considered in patients with non-ST-segment elevation acute coronary syndrome or undergoing percutaneous coronary intervention.     

Clopidogrel: a review of its use in the prevention of thrombosis

Clopidogrel (Plavix), Iscover) selectively and irreversibly inhibits adenosine diphosphate (ADP)-induced platelet aggregation. Long-term administration of clopidogrel was associated with a modest but statistically significant advantage over aspirin in reducing adverse cardiovascular outcomes in patients with established cardiovascular disease in the CAPRIE trial. In other large well designed multicentre trials, such as CURE, COMMIT and CLARITY-TIMI 28, the addition of clopidogrel to aspirin therapy improved outcomes in patients with acute coronary syndromes. However, some issues regarding the use of clopidogrel remain unresolved, such as the optimal loading dose in patients undergoing percutaneous coronary interventions (PCI) and the optimal treatment duration following drug-eluting intracoronary stent placement. Results of several large randomised trials, therefore, have established clopidogrel as an effective and well tolerated antiplatelet agent for the secondary prevention of ischaemic events in patients with various cardiovascular conditions, including those with ischaemic stroke or acute coronary syndromes. In addition, treatment guidelines from the US and Europe acknowledge the importance of clopidogrel in contemporary cardiovascular medicine.     

双抗血小板联合阿托伐他汀治疗对高龄冠心病PCI术患者颈动脉硬化斑块及心肌功能的影响

目的 观察双抗血小板联合阿托伐他汀治疗对高龄冠心病经皮冠状动脉介入治疗(PCI)术患者颈动脉硬化斑块及心肌功能的影响.方法 将2014年1月至2016年2月本院收治的66例高龄冠心病PCI术患者随机数字表法均分为研究组和对照组,两组均实施双抗血小板治疗,研究组另给予阿托伐他汀治疗,观察两组治疗前后颈动脉硬化斑块[颈动脉内中膜厚度(IMT)、斑块面积(PA)]、心肌功能指标[肌酸激酶同工酶(CKMB)、肌钙蛋白Ⅰ(cTNⅠ)]及治疗期间不良心血管事件发生率.结果 两组治疗结束后IMT、PA均较治疗前显著减小,且治疗结束后研究组IMT、PA较对照组显著减小,差异均有统计学意义(均P＜ 0.05);治疗结束后仅对照组CKMB、cTNⅠ较治疗前显著升高,且治疗结束后研究组CKMB、cTNⅠ显著低于对照组(P＜0.05);治疗期间研究组不良心血管事件总发生率较对照组显著低(P＜0.05).结论 双抗血小板联合阿托伐他汀治疗可显著减小高龄冠心病PCI术患者的颈动脉硬化斑块,且有效减轻对心肌功能损害程度.     

Monitoring of the antiplatelet drugs effect in patients with coronary artery disease: what is the real clinical impact?

Antiplatelet therapy is used to reduce the risk of ischemic events in patients with cardiovascular disease. The balance of benefits and risks of antiplatelet drugs in coronary artery disease has been evaluated in large-scale randomised trials, however the absolute benefit for an individual patient and a specific platelet-active drug need further evaluation. Several well-conducted studies have demonstrated a substantial inter-individual variability in the platelet responsiveness to drugs. The historical "gold standard" test of platelet function (optical aggregation) has well established limitations for measuring the effect of antiplatelet drugs. Other new tests developed (i.e. PFA-100, VerifyNow) may overcome some of these limitations but they do not correlate well with each other. Despite these unresolved methodological questions, several recent clinical studies, but not all, suggest a significant correlation between antiplatelet resistance status and serious vascular events. In these conditions, laboratory monitoring for antiplatelet therapies raises several questions: (i) the necessity for a consensus on the definition of resistance and on the best test for evaluation of the condition, (ii) the demonstration that biological resistance has clinical significance, and (iii) the clinical impact of adapting the antiplatelet therapy. Therefore, it is not currently appropriate to test patients or to change therapy on the basis of such tests, other than in prospective and adequately powered clinical trials.     

The risk of bleeding with the use of antiplatelet agents for the treatment of cardiovascular disease

Introduction: In the presence of injured coronary vascular endothelium, platelets become activated to form hemostatic plugs. While this represents a normal healing response to disrupted vascular endothelium, occlusive cardiovascular disease, as a result of maladaptive thrombus formation, is a major cause of morbidity and mortality. Due to the platelet predominance of arterial thrombi, antiplatelet agents are the mainstay of therapy for arterial cardiovascular disease, though come with a significantly increased risk of bleeding.

Areas covered: This review will provide a comprehensive overview of available antiplatelet agents used to treat coronary artery cardiovascular disease. The risks of bleeding with each agent will be considered.

Expert opinion: Available antiplatelet therapies are effective in treating acute thrombotic events and preventing recurrent events, however, they also carry significant bleeding risks. The decision to use or continue antiplatelet agents remains challenging for physicians and necessitates a thorough understanding of the future risk of thrombotic risks of thrombotic or bleeding events in a patient. Clinical prediction rules and risk scores may be useful to support physician decision-making.     

新型P2Y12受体抑制剂替格瑞洛临床研究进展

抗血小板药物是急性冠脉综合征（Acute Coronary Syndrome,ACS）治疗的基石,对防治心肌缺血和介入并发症是有益的。目前治疗ACS和经皮冠状动脉介入治疗（percutaneous coronary intervention,PCI）指南推荐使用的口服抗血小板药物包括氯吡格雷、替格瑞洛、普拉格雷联合阿司匹林双重抗血小板治疗预防复发性缺血事件。本文对新型P2Y12受体抑制剂替格瑞洛的药代动力学和药效学特点以及在ACS患者中的循证医学证据作一介绍。     

Safety of clopidogrel and aspirin for stroke prevention: implications of the CHARISMA trial.

Antiplatelet therapy is universally recommended for the prevention of recurrent events in patients with noncardioembolic ischaemic stroke or transient ischaemic attack (TIA), acute and chronic coronary artery disease, or peripheral arterial disease. However, choosing which antiplatelet agents to use in these situations remains controversial. The use of aspirin, aspirin plus extended-release dipyridamole, or clopidogrel is recommended as initial therapy in patients with noncardioembolic ischaemic stroke or TIA to reduce the risk of recurrent stroke and other cardiovascular events. Based on the results of the MATCH trial, combination therapy with aspirin plus clopidogrel is not recommended for patients with ischaemic stroke or TIA due to the increased risk of haemorrhage.The results of the CHARISMA trial support this recommendation; despite previous data demonstrating a favourable benefit-risk profile of aspirin plus clopidogrel in patients with acute coronary syndrome, this combination should not be used in patients at high risk for atherothrombosis and those with previous stroke or TIA. In these patients, the CHARISMA trial demonstrated a lack of significant clinical efficacy and an increased risk of bleeding with clopidogrel plus aspirin compared with aspirin alone.Further research is needed to assess the benefit-risk ratio of clopidogrel plus aspirin in specific subpopulations of patients at high risk for atherothrombotic events, and to determine the role of clopidogrel plus aspirin in preventing cardioembolic stroke or early recurrent stroke after symptomatic large-vessel atherostenosis. Recent and ongoing studies are seeking to better define the roles of different antiplatelet regimens in preventing recurrent stroke.     

CYP2C19基因导向的抗血小板药物治疗方案在急性冠状动脉综合征患者中的经济学评价

目的： 从药物经济学角度评价拟行介入手术的急性冠脉综合征患者依据CYP2C19基因指导抗血小板药物应用的可行性。方法： 采用回顾性分析,选取皖南医学院弋矶山医院2018年4月至2020年4月收治的513例采用氯吡格雷联合阿司匹林或替格瑞洛联合阿司匹林进行抗血小板治疗的急性冠脉综合征住院患者,根据是否进行CYP2C19基因检测及个体化用药指导,非随机分为个体化治疗组和采用氯吡格雷标准剂量的常规治疗组。成本仅包括直接医疗成本,效果指标采用患者1年内发生主要心血管不良事件次数,进行增量成本效果分析和敏感性分析。结果： 个体化治疗组（n=312）的人均总治疗费用为49 319元,常规治疗组（n=201）为51 820元;1年内再入院率个体化治疗组为12.18%,常规治疗组为21.89%,具有统计学差异（P<0.05）。增量成本效果比为257.5元/%,相比常规治疗组,个体化治疗组每使100个患者中减少1例因发生主要心血管不良事件再入院,可少花费25 750元,表明个体化治疗策略具有明显的成本-效果优势。敏感性分析表明,提高用药效果对增量成本效果比的改变并不十分显著,提示医疗费用才是影响基因检测经济性的关键因素。结论： 通过CYP2C19基因检测指导的抗血小板治疗方案对急性冠脉综合征患者经皮冠状动脉介入术后预防主要心血管不良事件具有良好效果,并具有明显成本-效果收益,更具有药物经济学优势。     

Antiplatelet drug resistance: not ready for prime time

Antiplatelet drug therapy reduces vascular events in a wide range of patients. Although antiplatelet drug resistance is becoming well documented, a universal definition has not been established. This lack and the lack of standardized measures of platelet function make estimation of the prevalence of antiplatelet drug resistance difficult. Mounting evidence suggests that antiplatelet drug resistance is associated with adverse clinical outcomes, which have been assessed in patients with coronary artery disease, myocardial infarction, cerebrovascular disease, and peripheral vascular disease. Patients with antiplatelet drug resistance have significantly more vascular events than patients without such resistance. However, there are no guidelines for the treatment of antiplatelet drug resistance. Although point-of-care platelet-function testing makes screening for resistance feasible, routine screening should not be standard practice until data regarding the management of antiplatelet drug resistance are available.     

PHARMAC and lack of funding for clopidogrel

Clopidogrel is an antiplatelet drug that has been shown in several trials to reduce clinical events such as cardiovascular death, stroke, and myocardial infarction when compared to aspirin in a broad range of patients with atherosclerotic vascular disease. Clopidogrel has also been shown to reduce the same events by 20% when added to aspirin in patients with unstable angina and also in patients undergoing coronary artery stenting. Despite this information being available for 5 to 10 years, guideline recommendations, and the knowledge that 5% of patients have major allergy to aspirin, New Zealand patients have only been able to receive funded clopidogrel for a short period, typically 3 weeks, after coronary artery stenting. We believe this is an example where New Zealanders have been denied treatments, despite a strong evidence-base, by PHARMAC's actions of delaying the funding of new drugs. We need to have a better process whereby New Zealanders can rapidly access new treatments.     

An update on the role of the quality of LDL in cardiovascular risk: the contribution of the universities of Palermo and Zurich

Low density lipoproteins (LDL) size seems to be an important predictor of cardiovascular events and progression of coronary artery disease and the predominance of small dense LDL have been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III. We recently showed increased LDL size or higher levels of small, dense LDL in different categories of patients at higher cardiovascular risk, such as those with coronary (including acute myocardial infarction) and non-coronary (including carotid disease, abdominal aortic aneurysm and peripheral arterial disease) forms of atherosclerosis or metabolic diseases (including type-II diabetes, polycystic ovary syndrome and growth hormone deficiency). Screening for the presence of small, dense LDL may potentially identify those with even higher risk and may contribute in directing specific treatments in order to prevent new cardiovascular events. This seems particularly true for statins and fibrates. Promising data are available for rosuvastatin, the latest statin molecule introduced in the market, and ezetimibe, a cholesterol absorption inhibitor. The most recent patents regarding these two hypolipidemic agents include the antiinflammatory, antithrombotic and antiplatelet activity (EP1626716B1 and CN1794987A for rosuvastatin) and the potential use for treatment of cholesterol-associated benign and malignant tumors and diabetes (US7098198 and US7071181 for ezetimibe).