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.     

Assessing post-treatment platelet reactivity: a focus on patient selection and setting

Dual antiplatelet therapy is critical to inhibit platelet reactivity in order to prevent ischemic reccurences in stented patients. However, studies have observed a variable blockade of the P2Y12 adenosine diphosphate receptor between patients following clopidogrel intake. This interindividual variability in the biological response is not uncommon with clopidogrel (about 50%) and even prasugrel (20%). High on-treatment platelet reactivity (HTPR) is correlated with thrombotic events following percutaneous coronary intervention. Several studies suggested that tailoring of antiplatelet therapy based on platelet reactivity (PR) monitoring could safely reduce the rate of major adverse cardiovascular events in HTPR patients. In addition, low on-treatment PR was recently associated with bleeding events both in patients treated with prasugrel and clopidogrel. Of importance, bleedings are associated with a poor prognosis in stented patients. Overall, the potential of PR monitoring to individualize antiplatelet therapy might benefit stented patients by reducing both ischemic and bleeding risks. However, such strategies remain to be evaluated in adequately designed large-scale randomized clinical trials.     

Platelet function tests for monitoring of acetylsalicylic acid: clinical significance in antiplatelet treatment

Several studies have demonstrated with the use platelet function tests (PFT) that subgroups of patients under acetylsalicylic acid (ASA) fail to produce the anticipated antiplatelet effect. This phenomenon as well as the clinical failure of ASA to protect patients from thromboembolic complications has been termed ASA resistance (AR) or ASA nonresponsiveness. Several subtypes of AR can be distinguished by PFT. The following PFT were used to characterize AR: optical aggregometry, platelet aggregation in whole blood, platelet function analyzer (PFA-100), platelet reactivity test or platelet aggregate ratio, flow cytometry and thromboxane B(2) generation. All PFT have in common that their widespread clinical use is substantially limited due to complex preanalytic factors, reduced specificity and poor reproducibility. PFT are not interchangeable for monitoring antiplatelet treatment. Three prospective clinical trials revealed a possible relationship between AR and subsequent cardiovascular events. There is a need for a simple and reliable assay for predicting the clinical efficacy of antiplatelet therapy. Recent data demonstrate that none of the currently available assays including the PFA-100 system are capable to accomplish these objectives.     

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.     

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.     

Pharmacogenomics in cardiovascular disease: focus on aspirin and ADP receptor antagonists

Antiplatelet agents like aspirin and adenosine diphosphate receptor antagonists are effective in reducing recurrent ischemic events. Considerable inter‐individual variability in the platelet inhibition obtained with these drugs has initiated a search for explanatory mechanisms and ways to improve treatment. In recent years, numerous genetic polymorphisms have been linked with reduced platelet inhibition and lack of clinical efficacy of antiplatelet drugs, particularly clopidogrel and aspirin. Consequently, attempts to adjust antiplatelet treatment according to genotype have been made, but the clinical benefit has been modest in studies performed so far. The progress in genome science over the last decade and the declining cost of sequencing technologies hold the promise of enabling genetically tailored antiplatelet therapy. However, more evidence is needed to clarify which polymorphisms may serve as targets to improve treatment. The present review outlines the panel of polymorphisms affecting the benefit of aspirin and adenosine diphosphate receptor antagonists, including novel and ongoing studies evaluating whether genotyping may be beneficial in tailoring antiplatelet therapy.     

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.     

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.     

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.     

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.     

Monitoring of antiplatelet therapy. Current limitations, challenges, and perspectives

Screening of platelet function can be performed by point-of-care testing followed by platelet aggregometry in response to agonists such as collagen, adenosine diphosphate, epinephrine, and arachidonic acid. Despite in use for decades, this technique is not well standardized. Monitoring of antiplatelet therapy is increasingly applied in patients at high risk for re-thrombosis or bleeding. To assess pharmacological inhibition of platelet function, agonist-induced platelet aggregation, thromboxane B2 (TxB2) and vasodilator-stimulated protein phosphorylation (VASP) are being measured. While serum TxB2 levels of < 2 ng/ml reflect aspirin-induced inhibition of cyclo-oxygenase-1 activity with high sensitivity, VASP exhibits a wide variability upon treatment with clopidogrel or prasugrel. Multiple studies reveal an association between high residual platelet reactivity and adverse cardiovascular events in patients on antiplatelet therapy. However, despite the plethora of platelet function assays currently under investigation, their use in daily practice cannot be recommended. This is due to several reasons: (i) there is no consensus on the method and a respective cut-off value associated with clinical adverse outcome, and (ii) data demonstrating any benefit of tailored antiplatelet therapy and its monitoring (based on assessment of platelet functions) are still limited. Thus, appropriate identification of 'resistant' or 'poor responders' to antiplatelet agents remains challenging in clinical practice.     

抗血小板治疗实验室监测之我见

抗血小板药物在各种动脉血栓性疾病防治中具有重要地位。虽然目前抗血小板药物多采用固定剂量给药,但不同患者对抗血小板治疗的反应性存在明显差异。治疗后的血小板高反应性或低反应性可能与血栓事件或出血事件风险相关。基于血小板功能检测的个体化抗血小板治疗方案可能有助于预防血栓或出血不良事件的发生,但目前仍缺乏上述治疗策略能够最终改善患者预后的确切临床证据。迄今为止,对于接受抗血小板治疗的患者是否应常规进行实验室监测仍存在诸多争议。本文对抗血小板治疗反应多样性的成因及血小板功能检测是否可用于指导个体化抗血小板治疗进行讨论。     

New antiaggregants and their importance for the practitioner

Since the introduction of Aspirin in the 1950s many substances have been introduced with an antiplatelet effect. Only few have been proved to be superior to aspirin in some clinical settings. Ticlopidin and its biochemical analog clopidogrel block the ADP-induced platelet aggregation. Clopidogrel having a better profile in terms of adverse events has been established over ticlopidin. It can be used for secondary prevention in patients with stroke, myocardial infarction or peripheral arterial disease instead of aspirin, certainly in cases with aspirin intolerance or with relapsing cardiovascular event under treatment with aspirin. For a general substitution of aspirin through clopidogrel hard evidence is still lacking. The combination aspirin + clopidogrel has been proved superior to aspirin in the treatment of patients with unstable angina or myocardial infarction without ST-segment elevation. For an extension of this indication to other clinical entities further evidence is needed. GPIIb/IIIa blockers are a well established treatment modality in patients undergoing coronary catheter interventions. Oral GPIIb/IIIa blockers, probably because of their pharmacokinetic profile, have proved to be insufficient in protecting from cardiovascular events compared to aspirin. Practical aspects concerning use of the newer antiplatelet agents during pregnancy, preoperatively and in spinal anesthesia are discussed.     

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 use in coronary heart disease and percutaneous coronary intervention.

Antiplatelet therapy has proven efficacy in the management of atherothrombosis. Clopidogrel, a thienopyridine, is a potent antiplatelet agent that achieves its antiplatelet effects by inhibiting the binding of adenosine 5' diphosphate to its platelet receptor. Large clinical trials have demonstrated a role for clopidogrel in the management of symptomatic atherosclerosis, acute coronary syndromes, and patients undergoing percutaneous coronary intervention. In this review, we discuss the pharmacology of clopidogrel including the mechanism of action, review the major clinical trials that have defined the current role of clopidogrel in coronary heart disease and percutaneous coronary intervention, and, finally, examine the concept of clopidogrel resistance and its potential clinical implications.     

三联抗血小板药物对非ST段抬高性急性冠脉综合征患者血清炎症因子及内皮功能的影响

目的探讨短期三联抗血小板药物对非ST段抬高性急性冠脉综合征(ACS)患者血清炎症因子和血管内皮功能的影响,为三联抗血小板药物治疗非ST段抬高性ACS提供进一步的临床依据。方法急性非ST段抬高性ACS患者82例,随机分为三联抗血小板药物治疗组(治疗组)和二联抗血小板治疗组(对照组);观察组患者给予阿司匹林、氯吡格雷、替罗非班三联抗血小板药物;对照组患者给予阿司匹林,氯吡格雷二联抗血小板药物。观察治疗48 h后患者血清炎症因子(hs-CRP、IL-6)及反映血管内皮功能的指标(ET-1、NO、PGI2)的水平变化情况。结果三联抗血小板药物较二联抗血小板药物更有效地降低非ST段抬高性ACS患者血清炎症因子及改善血管内皮功能,主要的不良反应为皮下瘀斑、牙龈出血。结论对于非ST段抬高性ACS患者,三联抗血小板药物在短期的抗炎、改善血管功能方面要优于二联抗血小板治疗,值得临床推广应用。     

经皮冠状动脉介入治疗术后应用泮托拉唑的临床效果观察

目的探讨泮托拉唑对经皮冠状动脉介入治疗(PCI)术后氯吡格雷抗血小板聚集和临床效果的影响。方法选取本院行PCI术的患者共92例,按随机原则将其分为治疗组和对照组,术前与术后均接受氯吡格雷及阿司匹林治疗,治疗组加用泮托拉唑。检测2组患者的血小板聚集率、血常规等指标,术后对患者进行随访。结果治疗组和对照组血小板聚集率分别为(29.93±10.48)%和(26.32±8.53)%,心肌缺血的发生率分别为8.7%和4.3%,2组间比较均无统计学差异,且均未发生严重的心血管以及出血等不良临床事件。结论泮托拉唑不会降低PCI术后氯吡格雷抗血小板聚集作用,不会增加临床心血管事件的发生率,同时能够明显降低消化道出血事件发生率。     

氯吡格雷吸收和代谢通路相关基因变异与临床个体化用药实践

氯吡格雷是一种新型噻吩吡啶类抗血小板药物,联合应用氯吡格雷及阿司匹林已经成为急性冠脉综合征及经皮冠状动脉介入支架术后患者的标准治疗方案。与氯吡格雷吸收和代谢通路相关的基因变异,使得患者对氯吡格雷的临床反应性存在显著的个体差异,部分患者出现氯吡格雷抵抗现象,增加临床不良事件的发生。确定相关基因变异对指导临床个体化用药实践意义重大。     

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.