Antiplatelet therapy in acute coronary syndromes

Introduction: Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes in the acute phase and in long-term management. Over the last few years, new antiplatelet drugs have been developed and the therapeutic landscape has rapidly evolved.

Areas covered: We review the available evidence and most recent data concerning all of the principal classes of antiplatelet agents, including aspirin, thienopyridines and glycoprotein IIb/IIIa inhibitors, as well the impact of the new drugs prasugrel and ticagrelor and the available data concerning cangrelor, elinogrel and PAR-1 inhibitors (still under development).

Expert opinion: This review considers the management of antiplatelet therapy in the light of recent advances, highlighting how to identify patients who will receive the greatest benefit from the older and newer agents, and underscoring the importance of carefully balancing the risks of ischaemia and bleeding in order to improve clinical outcomes. Finally, the paper discusses the potential role of functional and genetic tests in guiding the choice of antiplatelet therapy in a future perspective of ‘personalised medicine’.     

Combination antiplatelet therapy: implications for pharmacists

OBJECTIVES: To present two case reports of patients who received suboptimal oral antiplatelet therapy and to review recent changes in national guidelines for management of acute coronary syndromes. DATA SOURCES: Personal observation by the authors, and clinical practice guidelines and related clinical trials of the American Heart Association and the American College of Cardiology. SUMMARY: The American College of Cardiology and the American Heart Association revised the guidelines for administration of antiplatelet and anticoagulant therapy in patients with unstable angina and non-ST-segment elevation myocardial infarction in March 2002. Two cases observed by the authors illustrate the consequences of suboptimal antiplatelet therapy when a combination of two antiplatelet drugs should have been administered. CONCLUSION: Evidence from recent randomized controlled trials led to changes in the national guidelines for administration of oral antiplatelet therapy in patients with acute coronary syndromes. Pharmacists should be aware of these changes and counsel patients about appropriate administration of antiplatelet drugs.     

Combination antiplatelet therapy: implications for pharmacists

OBJECTIVES: To present two case reports of patients who received suboptimal oral antiplatelet therapy and to review recent changes in national guidelines for management of acute coronary syndromes. DATA SOURCES: Personal observation by the authors, and clinical practice guidelines and related clinical trials of the American Heart Association and the American College of Cardiology. SUMMARY: The American College of Cardiology and the American Heart Association revised the guidelines for administration of antiplatelet and anticoagulant therapy in patients with unstable angina and non-ST-segment elevation myocardial infarction in March 2002. Two cases observed by the authors illustrate the consequences of suboptimal antiplatelet therapy when a combination of two antiplatelet drugs should have been administered. CONCLUSION: Evidence from recent randomized, controlled trials led to changes in the national guidelines for administration of oral antiplatelet therapy in patients with acute coronary syndromes. Pharmacists should be aware of these changes and counsel patients about appropriate administration of antiplatelet drugs.     

Therapeutic potential of GP IIb/IIIa receptor antagonists in acute myocardial infarction

The management of acute myocardial infarction (AMI) has changed dramatically over the last two decades, with the addition of fibrinolytic agents and primary coronary intervention (PCI). The more recent development of the glycoprotein (GP) IIb/IIIa antagonists, a new class of potent antiplatelet drugs, has the potential to considerably enhance the treatment of AMI patients. A number of recent studies have highlighted the potential incremental benefits with adjunctive IIb/IIIa-targeted therapy. In this review, we will discuss the pathophysiology of myocardial infarction (MI), the physiology and role of platelets in thrombosis and describe the currently available drugs. We will briefly summarise the results of recent clinical trials, discuss some key forthcoming trials and attempt to describe how GP IIb/IIIa antagonists may directly impact the immediate and near future day-to-day care of patients with AMI.     

Antiplatelet therapy in early management of non-ST-segment elevation acute coronary syndrome: the 2002 and 2007 guidelines from North America and Europe

The American College of Cardiology, American Heart Association, and the European Society of Cardiology published updated guidelines in 2007 for patients with non-ST elevation acute coronary syndrome. In this article, we review the recommendations for antiplatelet therapy and supporting data, highlight new changes, and describe differences between the European and North American guidelines. The new guidelines provide more details regarding the selection of an early conservative versus an early invasive approach based on the patient's profile and balance between ischemic and bleeding risks. Important new recommendations include wider endorsement for low-dose aspirin maintenance therapy, longer duration of clopidogrel following percutaneous coronary intervention, additional guidance regarding surgery in selected patients on clopidogrel, identification of patients most likely to benefit from glycoprotein IIb/IIIa inhibitors (with appropriate dose modification in patients with renal failure), and the option to use early clopidogrel with bivalirudin in patients managed invasively who are at increased risk of bleeding. The new guidelines also discourage the concomitant use of nonsteroidal anti-inflammatory drugs and delineate indications for adding warfarin to antiplatelet therapy. Because antiplatelet therapy is the cornerstone of management of patients with non-ST elevation acute coronary syndrome, health care providers should make themselves familiar with the new data and latest guideline recommendations.     

Recent advances in antiplatelet agents

Platelet aggregation plays a key role in the pathogenesis of thromboembolic diseases such as myocardial infarction, stroke, unstable angina and peripheral artery disease. Until recently, aspirin was the only antiplatelet agent available to prevent or treat these events. Over the past several years, there has been a substantial expansion in the antiplatelet armamentarium as well as in the understanding of the clinical importance of antiplatelet therapy in limiting the complications of thrombosis. Aspirin was one of the first agents to be adopted and it remains as the standard therapy with the higher amount of available clinical information. Following aspirin, ADP receptor antagonists like ticlopidine and clopidogrel as well as phosphodiesterase inhibitors dipyridamole and cilostazol have been introduced. Glycoprotein (GP) IIb/IIIa receptor antagonists like eptifibatide, tirofiban and abciximab are the newer antiplatelet agents which act at the end of the common pathway of platelet aggregation. Although results of clinical studies with the first oral GPIIb/IIIa antagonists were disappointing, agents of the new generation might expand the potential application of GPIIb/IIIa targeted therapy. This review will highlight recent advances in the development of aspirin, phosphodiesterase inhibitors, ADP receptor antagonists and the platelet glycoprotein IIb/IIIa inhibitors. The emphasis of this paper has been placed on the chemical aspects of these agents.     

The role of antiplatelet therapy in the management of acute coronary syndromes

The benefit of aspirin use in the emergent care of acute coronary syndromes (ACS) has been well-established. Recent studies have further demonstrated the importance of antiplatelet therapy in the acute setting, primarily with the use of intravenous glycoprotein IIb/IIIa receptor inhibitors. Aspirin and the thienopyridines (ticlopidine and clopidogrel) are oral antiplatelet agents that interfere with platelet activation in complementary, but separate pathways. Combination therapy of aspirin with other antiplatelet agents has demonstrated a benefit for the management of ACS. This article reviews the pathophysiology of platelet activation in ACS, landmark trials regarding antiplatelet agents, and the current recommendations for the use of both intravenous and oral antiplatelet agents in the management of patients with ACS.     

The role of antiplatelet therapy in the management of acute coronary syndromes

The benefit of aspirin use in the emergent care of acute coronary syndromes (ACS) has been well-established. Recent studies have further demonstrated the importance of antiplatelet therapy in the acute setting, primarily with the use of intravenous glycoprotein IIb/IIIa receptor inhibitors. Aspirin and the thienopyridines (ticlopidine and clopidogrel) are oral antiplatelet agents that interfere with platelet activation in complementary, but separate pathways. Combination therapy of aspirin with other antiplatelet agents has demonstrated a benefit for the management of ACS. This article reviews the pathophysiology of platelet activation in ACS, landmark trials regarding antiplatelet agents, and the current recommendations for the use of both intravenous and oral antiplatelet agents in the management of patients with ACS.     

Evidence-Based Medical Therapy of Patients with Acute Coronary Syndromes

Acute coronary syndromes (ACS) present a major health challenge in modern medicine. With new clinical trials being conducted, our knowledge of latest therapies for ACS continually evolves. In this article, we review currently available medical therapies and provide evidence-based rationale for current pharmacologic therapies. Among the antiplatelet therapies, aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors demonstrate significant efficacy in reducing morbidity and mortality. Among the anticoagulants, unfractionated heparin and low molecular weight heparin, particularly enoxaparin sodium, remain the hallmarks of therapy against which newer anticoagulants are often compared. Bivalirudin has recently showed significant efficacy in decreasing cardiovascular events and mortality, but with potentially less risk of bleeding than heparin. Results of trials evaluating warfarin remain inconsistent regarding potential benefits. Finally, fondaparinux sodium, recently tested, shows promise as a powerful yet safe anticoagulant. Fibrinolysis is an acceptable modality for reperfusion if facilities equipped for primary percutaneous revascularization are not available. Regarding anti-ischemic therapy, beta-adrenoceptor antagonists and nitrates remain critical in the early management of ACS. Inhibitors of the renin-angiotensin-aldosterone system have also shown significant reductions in the morbidity and mortality of patients presenting with ACS, particularly in patients with left ventricular dysfunction and clinical heart failure, with ACE inhibitors being first-line agents and angiotensin receptor antagonists being a reasonable substitute if ACE inhibitors are not tolerated. Among the lipid-lowering therapies, statins (HMG-CoA reductase inhibitors) have been documented as being the most well tolerated and most efficacious therapies for ACS patients and data exist that they should be administered early in ACS management. Studies evaluating combination therapy (antiplatelet drugs, beta-adrenoceptor antagonists, ACE inhibitors, and lipid-lowering agents) show a clear benefit in mortality in patients with known coronary artery disease. Efforts to improve these key evidence-based medical therapies are numerous and include such programs as the American College of Cardiology's Guidelines Applied in Practice, international patient registries such as the Global Registry of Acute Coronary Events, and studies such as CRUSADE. Finally, patients with diabetes mellitus pose a challenge to clinicians both in terms of their glycemic control and in their apparent relative resistance to antiplatelet therapy. Studies involving ACS patients suggest that stringent glycemic control may result in benefits in both morbidity and mortality.     

Developments in antiplatelet therapy for acute coronary syndromes and considerations for long-term management

ABSTRACT

Objective: This article reviews the currently available antiplatelet therapies and emerging investigational drugs in the treatment of acutecoronary syndrome (ACS), and considerations for primary and secondary prevention in the long-term management of ACS patients undergoing percutaneous coronary intervention (PCI).

Research design and methods: Primary studies and reviews in the peer-reviewed, English-language literature were identified through searches of MEDLINE (1966–2008) using the terms ‘acute coronary syndrome’, ‘antiplatelet’, ‘aspirin’, ‘long-term management’, ‘P2Y₁₂ receptor’, and ‘thienopyridine’. Additional references were obtained by searching the reference lists of the identified articles. Articles were included if they were recently published and pertinent, patient-focused, and authors were recognized as leaders in the field. Current review is limited by literature search on single database.

Results: Platelets play a major role in atherogenesis and the formation of thrombi, the main events in the pathogenesis of ACS. Although aspirin is an effective antiplatelet agent, efficacy and safety data from a number of randomized clinical trials on atherothrombotic disease support the use of dual antiplatelet therapies such as aspirin and thienopyridines over single antiplatelet therapy for ACS and up to 1?year following ACS. Antiplatelet agents reduce, but do not eliminate, ischemic events after ACS due, in part, to variable individual response (or resistance) in antiplatelet agents, non-compliance, progression of atherosclerosis, modest inhibition of platelet aggregation (IPA) levels and other factors. Several antiplatelet agents, including novel P2Y₁₂-receptor antagonists and thrombin-receptor antagonists, are currently under investigation for ACS and primary and secondary prevention in the long-term management of patients undergoing PCI.

Conclusions: Current antiplatelet therapies have clinical benefits such as reducing immediate and long-term cardiovascular risk, but substantial residual risk remains indicating a need for new therapeutic agents. Additional large randomized trials are necessary to determine the most appropriate treatment regimens for ACS patients.     

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.     

Antiplatelet therapy and coronary artery bypass graft surgery: perioperative safety and efficacy

Background: Antiplatelet therapy is critical in the management of coronary artery disease. For patients undergoing coronary artery bypass graft surgery (CABG), controversy remains regarding the safety of preoperative antiplatelet therapy and the optimal postoperative antiplatelet regimen to maintain graft patency and reduce ischemic complications. Objective: The goal of this systematic review is to evaluate the risks and benefits of preoperative aspirin and clopidogrel therapy, to identify the optimal timing and dose of aspirin following CABG, and to assess the role of postoperative clopidogrel therapy. Methods: A systematic review was performed to retrieve relevant articles from the Medline database published between 1978 and 2008. Results: With respect to aspirin, the published data suggest that it should be held for 7 – 10 days preoperatively in patients undergoing elective CABG. However, in the current era of routine antifibrinolytic therapy and the high prevalence of patients with extensive atherosclerotic disease, this practice has been put into question. Clopidogrel should be held for at least 5 days before CABG to avoid perioperative bleeding complications. Following surgery, extensive evidence supports the use of aspirin, in doses of 100 – 325 mg daily, to be administered in 48 h postoperatively and continued indefinitely. Less is known regarding the use of clopidogrel following CABG, although it is now recommended as postoperative antiplatelet therapy in patients with recent acute coronary syndromes. Conclusion: Despite > 30 years of experience with antiplatelet agents during CABG, questions remain regarding their perioperative safety and efficacy. The results of continuing randomized controlled trials should further clarify the role of perioperative aspirin and clopidogrel therapy and help redefine the modern antiplatelet management of coronary artery bypass patients.     

Current immunosuppressive treatment after kidney transplantation

INTRODUCTION: Since 1995, several immunosuppressive drugs have entered the field of organ transplantation: tacrolimus, mycophenolate and the mTOR-inhibitors. Now treating physicians have a choice. AREAS COVERED: The authors review the important studies on immunosuppressive drugs used at present after kidney transplantation, published in the last three decades. This review also discusses the available evidence for selecting one of the calcineurin inhibitors, antiproliferative agents and induction therapy. Interesting new drugs are discussed briefly. EXPERT OPINION: Calcineurin inhibitors (CNIs) are considered, especially in de novo transplantation, to be the most effective maintenance drugs to prevent acute rejection. Combining CNI with mycophenolate or an mTOR-inhibitor has made it possible to reduce CNI dose and diminish nephrotoxicity. Uniform treatment regimes according to guidelines are useful but should leave room for adjustment to the needs of individual patients. Longer follow-up studies are needed to decide on the optimal maintenance treatment.     

Novel oral anticoagulants in the treatment of acute coronary syndromes: is there any room for new anticoagulants?

Thrombosis plays a key role in the pathophysiology of acute coronary syndromes (ACS). The management of patients with ACS includes interventional procedures and use of antithrombotic agents acutely, and dual antiplatelet therapy (aspirin and a P2Y12 receptor antagonist) for secondary prevention. However, patients with recent ACS remain at a substantial residual risk for recurrent ischemic events or death. The idea of follow-up treatment with an oral anticoagulant on top of standard therapy seems promising. Warfarin was the first oral anticoagulant thoroughly investigated in this direction, but the widespread long-term use of warfarin in ACS has been limited by challenges associated with pharmacodynamic/pharmacokinetic deficiencies of the drug and the risk of bleeding. Novel oral anticoagulants, such as direct thrombin inhibitors (DTIs) and FXa inhibitors overcome the downsides of VKAs. Ximelagatran was the first DTI, investigated and proven to be effective in prevention of recurrent ischemic events in ACS patients, but the drug association with hepatotoxicity prompted its withdrawal. Dabigatran etexilate, apixaban, darexaban (YM150) and TAK-442 were studied in phase II dose-escalation trials in order to determine the balance between clinical effectiveness and bleeding risk in daily use with dual antiplatelet therapy, with both positive and negative results. Rivaroxaban is the only agent that completed a phase III trial, showing reduction in recurrent ischemic events rate and death from cardiovascular causes as well as all-cause death. This review summarizes the data from completed and ongoing clinical trials of the new oral anticoagulants in patients with ACS.     

A critical appraisal of the functional evolution of P2Y12 antagonists as antiplatelet drugs

P2Y12 receptor mediated inhibition of platelet aggregation is one of the most explored and exploited pathways in antiplatelet drug therapy to prevent ischemic events in patients undergoing percutaneous coronary intervention (PCI) for the treatment of the acute coronary syndrome (ACS). Ticlopidine, Clopidogrel, Prasugrel, Ticagrelor, Cangrelor and Elinogrel are the P2Y12 inhibitors that act as antiplatelet drugs. In this review, the features of these drugs and the factors reported to be responsible for drug resistance or drug ineffectiveness were described. The features like drug metabolism, reversible or irreversible binding of drugs to their target protein and the mode of administration were observed to evolve along with the antiplatelet drugs. These features also include the drug-drug interactions, the pharmacogenetics and pharmacodynamics of P2Y12 inhibitors. We attempted to critically analyze how the desirable features were met by the P2Y12 inhibitors in the course of time. This review provides an overview of the evolution of P2Y12 inhibitors and may guide the researchers to develop better antiplatelet drugs in the future.     

Bleeding complications with glycoprotein IIb/IIIa inhibitors

The new class of antiplatelet drugs, the GPIIb/IIIa inhibitors, has proven to be effective in acute coronary syndromes including unstable angina and myocardial infarction as well as adjunct therapy for coronary interventions for preventing morbidity and mortality. As these drugs inhibit the final common pathway of platelet activation, effectively blocking the platelet aggregation response, potential bleeding is a concern with their use. The risk of bleeding has been demonstrated to be higher in patients treated with combination drug therapy (heparin, aspirin, thienopyridines, thrombolytics, oral anticoagulants), when antithrombotic drugs are not given on an individual weight basis and with late removal of vascular access sheaths. The early clinical trials have defined modifications in patient management that have effectively reduced bleeding. Pooled data from the more recent clinical trials, mostly in coronary intervention enrolling over 27,000 patients, show a bleeding rate of 3.6% in the drug group and 2.3% in the placebo group. Although this is acceptable, several unresolved issues remain to be addressed regarding the GPIIb/IIIa inhibitors. Thrombocytopenia occurs infrequently with all GPIIb/IIIa inhibitors but can be severe. The use of these drugs by oral administration presents new challenges with determining optimal dosing, drug-drug interactions and long-term effects. Incorporating point-of-care monitoring may enable better titration of these drugs to avoid bleeding complications. GPIIb/IIIa inhibitors are destined to become a mainstay therapy for cardiovascular treatment and over time these issues should be resolved.     

Direct thrombin inhibition with bivalirudin as an antithrombotic strategy in general and interventional cardiology

Antithrombotic therapy is a crucial component of interventional cardiology and currently involves the administration of both anticoagulant and antiplatelet agents. The implementation of standard dual or triple antiplatelet therapies has allowed percutaneous coronary intervention (PCI) with stent implantation to become the treatment of choice in most patients with acute coronary syndromes (ACS), particularly in patients with ST-segment elevation myocardial infarction. However, the combined use of antithrombotic agents increases the bleeding risk associated with coronary intervention, which is a concern due to the increasing evidence that bleeding complications are associated with a higher risk of ischaemic events and death. The shortcomings of currently available anticoagulant drugs have promoted the ongoing development of new, powerful anticoagulant agents that have both efficacy in the setting of PCI and a reduced risk of bleeding; one of these classes of agents targets the thrombin molecule, a key factor in the coagulation cascade, and belongs to the class of anticoagulants known as direct thrombin inhibitors (DTIs). Bivalirudin, a synthetic peptide, is a DTI with unique, favourable pharmacological properties that include predictable linear pharmacokinetics. Bivalirudin was approved as an anticoagulant in patients undergoing routine PCI in 2000 by the FDA (in 2004 in Europe and Australia) and more recently in patients with ACS undergoing PCI. The pharmacological properties of bivalirudin, along with current indications for its use, are discussed in this review, with a focus on the major completed and ongoing clinical trials with bivalirudin.     

New perspectives in antiplatelet therapy

Platelet activation is a complex mechanism of response to vascular injury and atherothrombotic disease, leading to thrombus formation. A wide variety of surface receptors -integrins, leucine-rich family receptors, G protein coupled receptors, tyrosine kinase receptors- and intraplatelet molecules support and regulate platelet activation. They are potential targets of antiplatelet therapy for the prevention and treatment of arterial thrombosis. Despite the overall clinical benefit of established antiplatelet drugs targeting cyclooxigenase-1 (COX-1), glycoprotein integrin αIIbβ3, and the purinergic P2Y(12) receptor of adenosine diphosphate, a significant proportion of treated patients continue to experience recurrent ischaemic events. This may be in partly attributed to insufficient inhibition of platelet activation. In addition, it should not be underestimated that these drugs are not immune from bleeding complications. The substantial progress in understating the regulation of platelet activation has played a key role in the development of novel antiplatelet agents. Current examples of drug under development and evaluation include: novel P2Y(12) receptor inhibitors (prasugrel, ticagrelor, cangrelor, and elinogrel), thrombin receptor PAR-1 antagonists (vorapaxar, atopaxar), new integrin glycoprotein IIb/IIIa inhibitors, and inhibitors targeting the thromboxane receptor (TP), phosphodiesterases, the collagen receptor glycoprotein VI, and intraplatelet signalling molecules. This review summarizes the mechanisms of action and current clinical evaluation of these novel antiplatelet agents.