Antiplatelet medications and their indications in preventing and treating coronary thrombosis

Platelets play a pivotal role in the pathophysiology of unstable angina, acute myocardial infarction, and complications following percutaneous coronary intervention. Three classes of platelet-inhibiting drugs, aspirin, thienopyridines and platelet glycoprotein IIb/IIIa inhibitors, are now commonly used for the prevention and treatment of disorders of coronary artery thrombosis. For the last several decades aspirin has been the sole option for antiplatelet therapy in the treatment and prevention of the manifestations of cardiovascular disease. However, a wider selection of antiplatelet agents, including the thienopyridines (ticlopidine and clopidogrel) and the platelet glycoprotein (GP)IIb/IIIa receptor antagonists, are now available and provide clinicians with the opportunity to potentially improve upon the previous gold standard of aspirin. This review summarizes these drugs and the scientific data that have led to their use in primary and secondary prevention, unstable angina, myocardial infarction, and percutaneous coronary intervention.     

Antiplatelet medications and their indications in preventing and treating coronary thrombosis

Platelets play a pivotal role in the pathophysiology of unstable angina, acute myocardial infarction, and complications following percutaneous coronary intervention. Three classes of platelet-inhibiting drugs, aspirin, thienopyridines and platelet glycoprotein IIb/ IIIa inhibitors, are now commonly used for the prevention and treatment of disorders of coronary artery thrombosis. For the last several decades aspirin has been the sole option for antiplatelet therapy in the treatment and prevention of the manifestations of cardiovascular disease. However, a wider selection of antiplatelet agents, including the thienopyridines (ticlopidine and clopidogrel) and the platelet glycoprotein (GP)IIb/IIIa receptor antagonists, are now available and provide clinicians with the opportunity to potentially improve upon the previous gold standard of aspirin. This review summarizes these drugs and the scientific data that have led to their use in primary and secondary prevention, unstable angina, myocardial infarction, and percutaneous coronary intervention.     

ST-elevation myocardial infarction: the role of adjunctive antiplatelet therapy

Antiplatelet therapy to reduce the risks of recurrent myocardial infarction and restenosis after primary percutaneous coronary intervention is critically important to optimize the early treatment of ST-segment elevation myocardial infarction (STEMI). Traditionally, acetylsalicylic acid (ASA; aspirin) has been recommended for patients with suspected STEMI, but this agent targets only one of several pathways of platelet aggregation. Antiplatelet agents with different inhibitory mechanisms may act synergistically with ASA. Glycoprotein IIb/IIIa inhibitors are generally not used with fibrinolytic agents in acute STEMI management; indeed, glycoprotein IIb/IIIa inhibitors plus bolus fibrinolytics increase the risk of intracranial hemorrhage. Aggressive antiplatelet therapy with clopidogrel reduces mortality in STEMI patients and offers significant clinical benefits, without an associated increase in major bleeding events. Recent trials support the development of an early and aggressive approach to more complete platelet inhibition using clopidogrel, in combination with ASA, for patients with STEMI.     

Efficacy of aspirin for secondary prevention in patients with peripheral artery disease

Evaluation of: Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA 301, 1909–1919 (2009).

Aspirin decreases the risk of cardiovascular events in patients with prior coronary heart or cerebrovascular disease. The American College of Cardiology/American Heart Association guidelines recommend a low-dose aspirin regimen (75–325 mg/day) to reduce the risk of cardiovascular events in patients with peripheral artery disease (PAD). However, the effect of aspirin for secondary prevention in patients with PAD has not been well established. The paper under evaluation performed a meta-analysis of 18 trials to investigate the effect of aspirin on cardiovascular events (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) in patients with PAD. The results of this meta-analysis in a PAD cohort revealed that treatment with aspirin did not significantly reduce the combined end point of cardiovascular events; however, aspirin resulted in a significant reduction in the incidence of nonfatal stroke. This analysis raises a number of questions regarding the overall efficacy of aspirin in PAD and what should be the optimal antiplatelet therapy in patients with PAD: aspirin, clopidogrel or perhaps a combination of aspirin and clopidogrel.     

Aspirin and clopidogrel resistance

Despite aspirin's and clopidogrel's proven benefit in reducing cardiovascular (CV) events, recurrent CV events still occur in patients receiving antiplatelet therapy. Many of these patients are resistant or only partially responsive to the antiplatelet effects of aspirin and clopidogrel, as determined by standard platelet assays. However, current clinical guidelines do not support routine screening for aspirin or clopidogrel resistance, in part because determination of the most appropriate screening test has not been established. This review attempts to (1) describe the phenomena of clinical aspirin and clopidogrel resistance (ie, treatment failure), (2) discuss the complexity of defining and identifying aspirin and clopidogrel resistance, (3) identify factors that may be responsible for aspirin and clopidogrel resistance, (4) outline several standard platelet function assays and their limitations, and (5) describe potential new antiplatelet therapies that may benefit aspirin- or clopidogrel-resistant patients.     

Interpreting the CHARISMA study. What is the role of dual antiplatelet therapy with clopidogrel and aspirin?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study (N Engl J Med 2006; 354:1706-1717, J Am Coil Cardiol 2007; 49:1982-1988) assessed the effect of dual antiplatelet therapy with clopidogrel (Plavix) and aspirin in patients at risk of atherothrombotic events. At a median of 28 months, the rate of the primary efficacy end point (a composite of myocardial infarction, stroke, and death from cardiovascular causes) was not significantly lower in the group receiving clopidogrel plus aspirin than in the group receiving placebo plus aspirin. However, one subgroup may have derived some benefit from the combination: those at higher risk owing to a history of myocardial infarction, ischemic stroke, or symptomatic peripheral arterial disease.     

Clopidogrel resistance in diabetic patient with acute myocardial infarction due to stent thrombosis

Stent thrombosis is a morbid complication after percutaneous coronary intervention. Dual antiplatelet therapy significantly reduces stent thrombosis risk and forms currently the basis in acute ST elevation myocardial infarction pharmacologic treatment. The introduction of clopidogrel has made a major advance in the acute coronary syndrome treatment. However, there is growing evidence about failure in antiplatelet response after clopidogrel, which may lead to subsequent risk of future thrombotic events. The antiplatelet inhibitory effect of clopidogrel varies widely among individuals. High on-treatment platelet reactivity has been repeatedly associated with a hazard for cardiovascular events, including stent thrombosis. Laboratory monitoring of antiplatelet therapy efficacy may help identify patients with insufficient antiplatelet response. Prasugrel therapy was repeatedly described as an effective method to overcome clopidogrel resistance. We report a case of diabetic patient in whom myocardial reinfarction due to stent thrombosis developed. Clopidogrel resistance was detected in this patient using light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation assessment. After prasugrel administration, no other ischemic event occurred, and patient was released to outpatient care in good general condition.     

Ex vivo--in vitro interaction between aspirin, clopidogrel, and the glycoprotein IIb/IIIa inhibitors abciximab and SR121566A

OBJECTIVES: To assess the interaction between aspirin and clopidogrel in healthy male volunteers and the interaction of the glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors abciximab and SR121566A with blood from those pretreated subjects (ex vivo-in vitro). METHODS: Aspirin (300 mg/day), clopidogrel (75 mg/day), or the combination of both drugs were administered orally for 8 days. Group 1 (n = 5) started with aspirin and group 2 (n = 5) with clopidogrel. From day 4 to day 8, subjects of both groups received the combined treatment. Blood from these subjects was spiked with abciximab (0.5 and 1.5 microg x mL(-1)) and SR121566A (31 and 62 ng x mL(-1)). RESULTS: In vivo, average bleeding times were 6.8 minutes at baseline, 20.3 minutes for clopidogrel alone (P < .01), 10.9 minutes for aspirin alone (difference not significant), and 24.0 minutes (P < .01) for the combined treatment. Fibrinogen binding to the platelet GPIIb/IIIa receptor was reduced for aspirin to 69% (difference not significant), to 63% for clopidogrel (difference not significant), and to 63% for the clopidogrel plus aspirin combination (P < .01). CD62 expression as a marker of platelet granular secretion was reduced to 66% by clopidogrel (P < .01) and to 41% by the combination of clopidogrel and aspirin; aspirin alone had no effect. In vitro, with pretreatment with aspirin and clopidogrel, inhibitory effects of the GPIIb/IIIa inhibitors on fibrinogen binding were additive to changes observed with aspirin or clopidogrel alone. No effect on CD62 expression was observed with either GPIIb/IIIa inhibitor. Aspirin and clopidogrel reinforced effects of the GPIIb/IIIa inhibitors on adenosine diphosphate (5 micromol/L)-induced aggregation in an additive manner, a supra-additive effect was observed with collagen (2 microg x mL(-1))-induced aggregation. CONCLUSION: The augmentation of the antiaggregatory effects of GPIIb/IIIa inhibitors by aspirin and clopidogrel and the lack of antisecretory effects of GPIIb/IIIa inhibitors may favor their combination with clopidogrel.     

反复发作的缺血性卒中

部分患者对抗血小板药物表现为低反应性或无反应, 接受抗血小板规范治疗后仍发生心脑血管事件。本例患者为63岁女性, 长期服用阿司匹林和氯吡格雷, 多次出现肢体乏力, 行头颅磁共振扫描均提示急性脑梗死。后经血小板聚集试验、闭合试验及基因检测证实, 该患者存在阿司匹林和氯吡格雷低反应性。改服西洛他唑, 随访1年余, 未再发生心脑血管事件。     

Dual antiplatelet therapy in patients with diabetes mellitus: special considerations

Diabetes mellitus (DM) is associated with higher rates of ischemic events in patients suffering from an acute coronary syndrome and/or undergoing percutaneous coronary intervention, thereby underscoring the need to develop more effective and specific strategies toward mitigation of the cardiovascular burden associated with DM. Platelet hyper-reactivity associated with DM is a central contributor to this high risk, since platelets are the key players in the processes underpinning atherothrombotic complications, thereby representing a specific therapeutic target. Oral dual antiplatelet therapy comprising the combination of aspirin (75–100 mg) and clopidogrel (75 mg) has been, for years, the standard antithrombotic treatment for patients with acute coronary syndrome and/or undergoing percutaneous coronary intervention. However, despite the use of this therapy, high rates of cardiovascular events continue to occur, especially within the cohort of patients with DM. These observations could be in part explained by an inadequate clopidogrel-induced platelet inhibition, which has been associated with impaired clinical outcomes. In particular, DM is associated with a higher prevalence of reduced responsiveness to standard dual antiplatelet therapy, which may contribute to the higher rates of ischemic events seen in this population. These findings have prompted the identification of alternative dual antiplatelet treatment regimens to optimize platelet inhibition. The present review aims to describe benefits and limitations of oral dual antiplatelet therapy with aspirin and clopidogrel (75 mg) and to appraise the evidence regarding alternative oral dual antiplatelet therapy regimens, which include higher doses of aspirin and clopidogrel or the combination of prasugrel or ticagrelor with aspirin, focusing on patients with DM.     

经皮冠状动脉介入术(PCI)后长期联合应用阿司匹林和氯吡格雷的临床观察

目的　观察PCI术后长期联合应用阿司匹林和氯吡格雷的疗效及安全性。方法　将行PCI的 166例非ST段抬高的急性冠脉综合征患者随机分为试验组 ( 85例 )和对照组 ( 81例 )。试验组在PCI术后长期联合应用 ( 3～ 12个月 ,平均 6个月 )阿司匹林和氯吡格雷至随访结束 ;对照组在PCI术后联合应用阿司匹林和氯吡格雷 1个月 ,以后长期应用阿司匹林。观察两组间主要心血管事件 (心血管性死亡、心肌梗死、心肌缺血复发进行靶血管再通治疗 )及出血事件 (严重出血、轻微出血 )的发生。结果　试验组发生 9例心血管事件 (心肌梗死 3例、靶血管再通治疗 6例 ) ;对照组发生 2 0例心血管事件 (心血管性死亡 1例 ,心肌梗死 5例 ,靶血管再通治疗 14例 ) ,两组间有显著性差异 (P <0 .0 5 ) ;两组间均无严重出血发生 ,轻微出血事件无显著性差异 ( 3vs 2 ,P >0 .0 5 )。结论　PCI术后长期联合应用阿司匹林和氯吡格雷安全、有效 ,可减少PCI术后心血管事件的发生 ,出血并发症无明显增加     

Drugs for percutaneous coronary interventions

Many combinations of anticoagulants and antiplatelet drugs have been used to treat patients undergoing a percutaneous coronary intervention (PCI). Among anticoagulants, enoxaparin has some theoretical advantages over unfractionated heparin, but in clinical trials no advantage in outcome has been demonstrated in PCI. Bivalirudin, a direct thrombin inhibitor, has been associated with a lower risk of bleeding than unfractionated heparin. Among antiplatelet drugs, use of clopidogrel plus aspirin has led to a reduction in cardiovascular events; all patients undergoing PCI should receive both. Addition of a GP IIb/IIIa inhibitor may lower mortality rates further, particularly in high-risk patients such as diabetics.     

The platelet in diabetes: focus on prevention of ischemic events

Accelerated atherosclerosis and the increased risk of thrombotic vascular events in diabetes may result from dyslipidemia, endothelial dysfunction, platelet hyperreactivity, an impaired fibrinolytic balance, and abnormal blood flow. There is also a correlation between hyperglycemia and cardiovascular (CV) events. The importance of platelets in the atherothrombotic process has led to investigation of using antiplatelet agents to reduce CV risk. A meta-analysis conducted by the Antiplatelet Trialists' Collaboration demonstrated that aspirin reduced the risk of ischemic vascular events as a secondary prevention strategy in numerous high-risk groups, including patients with diabetes. Based on results from placebo-controlled randomized trials, the American Diabetes Association recommends low-dose enteric-coated aspirin as a primary prevention strategy for people with diabetes at high risk for CV events. Clopidogrel is recommended if aspirin allergy is present. There is occasionally a need for an alternative to aspirin or for additive antiplatelet therapy. Aspirin in low doses inhibits thromboxane production by platelets but has little to no effect on other sites of platelet reactivity. Agents such as ticlopidine and clopidogrel inhibit ADP-induced platelet activation, whereas the platelet glycoprotein (Gp) IIb/IIIa complex receptor antagonists block activity at the fibrinogen binding site on the platelet. These agents appear to be useful in acute coronary syndromes (ACSs) in diabetic and nondiabetic patients. A combination of clopidogrel plus aspirin was more effective than placebo plus standard therapy (including aspirin) in reducing a composite CV outcome in patients with unstable angina and non-ST segment elevation myocardial infarction. In a meta-analysis of six trials in diabetic patients with ACSs, intravenous GpIIb-IIIa inhibitors reduced 30-day mortality when compared with control subjects. Results from controlled prospective clinical trials justify the use of enteric-coated low-dose aspirin (81-325 mg) as a primary or secondary prevention strategy in adult diabetic individuals (aged >30 years) at high risk for CV events. Recent studies support the use of clopidogrel in addition to standard therapy, as well as the use of GpIIb-IIIa inhibitors in ACS patients.     

Bioactive peptides and proteins as alternative antiplatelet drugs

Antiplatelet drugs reduce the risks associated with atherothrombotic events and show various applications in diverse cardiovascular diseases including myocardial infarctions. Efficacy of the current antiplatelet medicines including aspirin, clopidogrel, prasugrel and ticagrelor, and the glycoprotein IIb/IIIa antagonists, are limited due to their increased risks of bleeding, and antiplatelet drug resistance. Hence, it is important to develop new effective antiplatelet drugs, with fewer side-effects. The vast repertoire of natural peptides can be explored towards this goal. Proteins and peptides derived from snake venoms and plants represent exciting candidates for the development of novel and potent antiplatelet agents. Consequently, this review discusses multiple peptides that have displayed antiplatelet aggregation activity in preclinical drug development stages. This review also describes the antiplatelet mechanisms of the peptides, emphasizing the signaling pathways intervened by them. Also, the hurdles encountered during the development of peptides into antiplatelet drugs have been listed. Finally, hitherto unexplored peptides with the potential to prevent platelet aggregation are explored.     

Ticagrelor for acute coronary syndromes

Ticagrelor is a potent P2Y12 adenosine diphosphate receptor antagonist characterized by a rapid onset, consistent and reversible antiplatelet effect, and an acceptable safety profile compared with existing adenosine diphosphate receptor blockers. In the large Phase III trial, PLATO, ticagrelor significantly reduced the composite of cardiovascular death, myocardial infarction, or stroke as well as cardiovascular and all-cause mortality compared with clopidogrel in patients presenting with acute coronary syndromes. With its favorable impact on mortality, ticagrelor changes the landscape of anti-thrombotic therapy for patients with acute coronary syndromes.     

Clopidogrel and proton pump inhibitors: is there a significant drug-drug interaction?

Dual antiplatelet therapy with aspirin and clopidogrel is among the most efficacious treatment for patients after acute coronary syndromes and for those who have had a percutaneous coronary intervention and coronary stent implantation. Patients who are treated with dual antiplatelet therapy are usually also ordered medications that reduce the secretion of gastric acid (such as H2 receptor blockers or proton pump inhibitors [PPIs]) in order to decrease the risk of gastrointestinal bleeding and dyspepsia. Numerous observational studies reported that omeprazole (a PPI) attenuates the antiplatelet activity and clinical effectiveness of clopidogrel and causes adverse cardiovascular events. Based on these findings, several medical agencies in the world have issued communications regarding the negative interaction between clopidogrel and PPIs, urging clinicians to evaluate the need for starting treatment with a PPI in patients taking clopidogrel. There are studies that reported contradicting findings, suggesting that there is no significant interaction between clopidogrel and PPIs. Only one prospective, randomized, double-blind, placebo-controlled clinical trial examined the interaction between clopidogrel and omeprazole and did not demonstrate cardiovascular harm among the patients who were treated with clopidogrel and omeprazole, as compared to those who were treated with clopidogrel and placebo. In this article, the authors review the current studies that reported a possible drug-drug interaction between clopidogrel and PPIs, particularly omeprazole.     

Clopidogrel resistance: myth or reality?

Platelets have a central role in the development of arterial thrombosis and subsequent cardiovascular events. An appreciation of this complex process has made antiplatelet therapy the cornerstone of cardiovascular disease management. Dual antiplatelet therapy with aspirin and clopidogrel has been approved for the secondary prevention of cardiovascular events and is currently part of the postpercutaneous coronary intervention treatment regimen. However, subacute stent thrombosis continues to occur in 1% to 2% of patients despite dual antiplatelet therapy. Studies have shown interindividual variations in response to clopidogrel, where a cohort of patients seems to be resistant to the antithrombotic effects of clopidogrel. Furthermore, there is an apparent link between clopidogrel resistance and clinical outcomes. Currently, there is neither a universally accepted definition of clopidogrel resistance nor an agreement on the phenomenon's mechanism. This review highlights the origins of clopidogrel resistance, the current problems that exist with its definition, and discusses the future implications and relevant challenges it poses for the clinician.     

Medical management of stable coronary artery disease

All patients with stable coronary artery disease require medical therapy to prevent disease progression and recurrent cardiovascular events. Three classes of medication are essential to therapy: lipid-lowering, antihypertensive, and antiplatelet agents. Lipid-lowering therapy is necessary to decrease low-density lipoprotein cholesterol to a target level of less than 100 mg per dL, and physicians should consider a goal of less than 70 mg per dL for very high-risk patients. Statins have demonstrated clear benefits in morbidity and mortality in the secondary prevention of coronary artery disease; other medications that can be used in addition to statins to lower cholesterol include ezetimibe, fibrates, and nicotinic acid. Blood pressure therapy for patients with coronary artery disease should start with beta blockers and angiotensin-converting enzyme inhibitors. If these medications are not tolerated, calcium channel blockers or angiotensin receptor blockers are acceptable alternatives. Aspirin is the first-line antiplatelet agent except in patients who have recently had a myocardial infarction or undergone stent placement, in which case clopidogrel is recommended. Anginal symptoms of coronary artery disease can be treated with beta blockers, calcium channel blockers, nitrates, or any combination of these. Familiarity with these medications and with the evidence supporting their use is essential to reducing morbidity and mortality in patients with coronary artery disease.     

Modern antiplatelet agents in coronary artery disease

Dual antiplatelet therapy is well recognized in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions. Despite clinical benefits of aspirin and clopidogrel therapy, a number of limitations curtail their efficacy: slow onset of action, variability in platelet inhibitory response and potential drug–drug interactions. Furthermore, the single platelet-activation pathway targeted by these agents allows continued platelet activation via other pathways, ensuring incomplete protection against ischemic events, thus, underscoring the need for alternate antiplatelet treatment strategies. A number of novel antiplatelet agents are currently in advance development and many have established superior effects on platelet inhibition, clinical outcomes and safety profile than clopidogrel in high-risk patients. The aim of this review is to provide an overview of the current status of P2Y12 receptor inhibition and PAR-1 antagonists in determining a future strategy for individualized antiplatelet therapy.     

Platelet inhibition beyond conventional antiplatelet agents: expanding role of angiotensin receptor blockers, statins and selective serotonin reuptake inhibitors

Aspirin, dipyridamole, cilostazol, thienopyridines and glycoprotein IIb/IIIa inhibitors represent the classical examples of the established antiplatelet agents commonly used for the secondary prevention in patients after vascular events. Obviously, the era of expanding antiplatelet regimens and indications may require new agents as the substitutes, or additions to the available strategies. However, recent results of the majority of antiplatelet trials strongly suggest boarder line advantages in clinical outcomes, and higher associated bleeding risks with the novel antiplatelet agents or/and regimens. Moreover, unexpected failures, such as lack of efficacy of clopidogrel and aspirin combination for ischaemic stroke prevention (MATCH), or use of the same antiplatelet regimen for the primary vascular prevention (CHARISMA) raise legitimate concerns that the concept 'the more the better' may not be valid. Broad use of statins, angiotensin receptor blockers and selective serotonin reuptake inhibitors may be in part responsible for the lack of impressive results with the antiplatelet therapy because each of these drug classes per se inhibits platelets. In this review, we discuss the available evidence and potential clinical significance of these findings.