European perspective on the use of antiplatelet agents in atherothrombotic disease
Department of Cardiology, Hospital General Universitario Gregorio Marañón, Doctor Esquerdo 46, 28007 Madrid, Spain
* Corresponding author. Tel: +34 91 426 5880, Fax: +34 91 586 8276, E-mail address: faviles{at}secardiologia.es
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Abstract |
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 Top Abstract IntroductionAntiplatelet agents in coronary...Stable chronic coronary artery...Non-ST-elevation acute coronary...ST-elevation acute myocardial...Stent thrombosisEuro heart surveys:...ConclusionsFundingReferences |
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Platelets are components of normal haemostasis, but under certain circumstances, they contribute to coronary occlusion and myocardial ischaemia. Several drugs have been investigated for decades to modulate platelet adhesion and aggregation in coronary artery disease. Although these drugs improve the symptoms and prognosis of millions of patients by reducing arterial thrombosis, they pose a variable risk of haemorrhagic complications. The European Society of Cardiology has published several recommendations on antiplatelet therapy that will be reviewed in this article, together with data from the real-world daily use of these drugs.
Key Words: Coronary artery disease • Acute coronary syndrome • Antiplatelet agents • Clopidogrel • Glycoprotein IIb/IIIa inhibitors
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Introduction |
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TopAbstractIntroductionAntiplatelet agents in coronary...Stable chronic coronary artery...Non-ST-elevation acute coronary...ST-elevation acute myocardial...Stent thrombosisEuro heart surveys:...ConclusionsFundingReferences |
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Coronary artery disease (CAD) is the leading cause of cardiovascular (CV) death in industrialized countries.1 This condition can evolve in two different ways: progressive formation of safe non-vulnerable atherosclerotic plaques leads to stable CAD, and, atherosclerotic plaque rupture with consequent thrombosis and partial or complete vessel occlusion is the main pathophysiological mechanism responsible for acute coronary syndromes (ACS).
In every clinical setting of CAD and from the perspective of antiplatelet treatment, the therapeutic objectives vary somehow (Table 1). Apart from that aspect, there is still another scenario that has been related to the management of antiplatelet therapy: the risk of stent thrombosis.
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In this review, we will focus on the main antiplatelet drugs available to avoid thrombotic complications in CAD, their indications, and their use in daily practice.
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Antiplatelet agents in coronary artery disease |
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TopAbstractIntroductionAntiplatelet agents in coronary...Stable chronic coronary artery...Non-ST-elevation acute coronary...ST-elevation acute myocardial...Stent thrombosisEuro heart surveys:...ConclusionsFundingReferences |
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Although there are
20 different agents that have been shown to inhibit platelet aggregation, three classes, acetylsalicylic acid, thienopyridines, and glycoprotein (GP) IIb/IIIa inhibitors are most frequently used in clinical practice.2 The characteristics of these drugs are summarized in Table 2.
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Stable chronic coronary artery disease |
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TopAbstractIntroductionAntiplatelet agents in coronary...Stable chronic coronary artery...Non-ST-elevation acute coronary...ST-elevation acute myocardial...Stent thrombosisEuro heart surveys:...ConclusionsFundingReferences |
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Previous studies have shown that aspirin administered in doses of 75–150 mg/day reduces all-cause mortality, CV mortality, non-fatal myocardial infarction (MI), and stroke3,4 in patients with stable CAD.
Ticlopidine has been replaced by clopidogrel, which has comparable efficacy but a better safety profile. Results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial showed that dual antiplatelet therapy (DAT) with clopidogrel and low-dose aspirin did not reduce the primary endpoint of CV death, MI, or stroke in the population of patients treated. Therefore, the European Society of Cardiology (ESC) has stated that the combination therapy with aspirin and clopidogrel cannot be recommended for patients with stable angina pectoris and further, the combination has been associated with an increased bleeding risk.5 However, clopidogrel is mandatory in aspirin-intolerant patients with significant risk of arterial thrombosis.6 On the other hand, pre-treatment of non-selected patients with clopidogrel before planned angiography results in better outcomes of percutaneous coronary intervention (PCI).7
Interestingly, in asymptomatic individuals without a diagnosis of CAD, aspirin reduces MI, and death due to CAD, but increases gastrointestinal bleeding and haemorrhagic stroke.8 Therefore, aspirin is not recommended in the general population as a primary prevention.
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Non-ST-elevation acute coronary syndromes |
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TopAbstractIntroductionAntiplatelet agents in coronary...Stable chronic coronary artery...Non-ST-elevation acute coronary...ST-elevation acute myocardial...Stent thrombosisEuro heart surveys:...ConclusionsFundingReferences |
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Several trials and two meta-analyses1–3 have indicated that aspirin in patients with unstable angina reduces death, MI, and vascular events by >50% with little effect on bleeding.
Data from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial have clearly demonstrated the benefit of adding clopidogrel to aspirin in patients during the acute phase and for 9–12 months after ACS. In this trial, a significant risk reduction in death from CV causes, non-fatal MI, or stroke was observed in patients allocated to receive DAT. After this trial, the recommendations from the ESC included aspirin for all patients presenting with non-ST-segment elevation ACS (NSTE-ACS), and also clopidogrel, which should be maintained for 12 months unless there is an excessive risk of bleeding.1 ESC recommendations for antiplatelet drugs in NSTE-ACS are summarized in Table 3.
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GP IIb/IIIa inhibitors have been used in both conservative and invasive strategies. In the conservative approach, the meta-analysis performed by Boersma et al.9 demonstrated significant benefit when compared with placebo in death or MI at 30 days, which became clearer in high-risk populations (diabetics, ST-segment depression, and troponin-positive patients). However, another meta-analysis published by Roffi et al.10 confirmed this benefit only in patients referred for invasive procedures (PCI). Based on the results of the Global Use of Strategies to Open Occluded Arteries in ACS (GUSTO-IV-ACS), which did not show any benefit of abciximab and an increased bleeding risk, this drug cannot be recommended for NSTE-ACS patients, except when submitted to PCI.11 Conversely, eptifibatide in the Platelet GP IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, and tirofiban in the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) trial, reduced death, MI, and refractory ischaemia in intermediate- to high-risk patients. Thus, the ESC recommendation for GP IIb/IIIa inhibitors (Table 3) for these patients is either eptifibatide or tirofiban for initial early treatment in addition to DAT.
In the case of invasive strategy, two meta-analyses have shown a significant risk reduction for death and MI at 30 days when GP IIb/IIIa inhibitors are used before and during PCI. In these patients, abciximab is preferred based on the results of the C7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE), Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 2), and do Tirofiban And ReoPro Give similar Efficacy Trial (TARGET) trials. In all of these trials, abciximab reduced the risk of death, MI, and the need for urgent revascularization at 30 days. Specifically, ISAR-REACT 2 showed that triple antiplatelet therapy (aspirin, 600 mg of clopidogrel, and abciximab) is superior to DAT in moderate- to high-risk patients submitted to PCI. The use of eptifibatide or tirofiban in this invasive strategy is not as well established.
Another important issue is the type of revascularization. Indeed, when anatomy is known and PCI is planned to be performed with GP IIb/IIIa inhibitors, the most powerful evidence is for abciximab. In patients treated with PCI, consideration should also be given to the type of stent to be implanted, depending on known comorbidities and the potential need for non-cardiac surgery (requiring temporary withdrawal of DAT). If coronary artery bypass graft surgery is planned, eptifibatide and tirofiban can be discontinued at the time of surgery, but abciximab needs earlier withdrawal and fresh platelet transfusions (fresh-frozen plasma or cryoprecipitate may be considered as well).1
Regarding adjunctive therapy, GP IIb/IIIa inhibitors must be combined with an anticoagulant. Although most of the trials carried out with these inhibitors used unfractionated heparin, low-molecular weight heparin like enoxaparin can be safely used without compromising efficacy. The Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial suggested bivalirudin as an alternative to GP IIb/IIIa inhibitors plus heparin. Although results showed better net clinical outcome in terms of death, MI, urgent revascularization, and bleeding with bivalirudin alone, there was a trend towards a higher ischaemic risk that was significant in patients not pre-treated with clopidogrel.
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ST-elevation acute myocardial infarction |
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TopAbstractIntroductionAntiplatelet agents in coronary...Stable chronic coronary artery...Non-ST-elevation acute coronary...ST-elevation acute myocardial...Stent thrombosisEuro heart surveys:...ConclusionsFundingReferences |
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Like in the non-ST-elevation scenario, aspirin is mandatory in the ST-elevation ACS. The first dose has to be chewed and between 150–325 mg, and a lower dose (75–160 mg) given orally daily thereafter. If oral ingestion is not possible, it can be given intravenously (250 mg).12
Two trials have been reported that support the use of clopidogrel in ST-elevation ACS. In the Clopidogrel and Metoprolol in MI Trial/Second Chinese Cardiac Study (COMMIT-CCS-II) trial, clopidogrel in addition to aspirin reduced the composite endpoint of death, re-infarction, and stroke, with no differences in haemorrhagic complications compared with aspirin alone. In the Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in MI (CLARITY-TIMI) 28 trial, the results were also superior for clopidogrel compared with placebo. Therefore, clopidogrel should be added to aspirin in patients receiving thrombolytic therapy (and extrapolating, also in primary PCI with a loading dose of 600 mg). In elderly patients (aged >75 years), the loading dose is not clear, especially if they received thrombolysis. No data are available from clinical trials about long-term clopidogrel treatment in ST-elevation ACS patients. Again, extrapolating from experience in patients with non-ST-elevation, as well as from those undergoing PCI, long-term therapy with clopidogrel (i.e. 1 year) could be useful in patients with ST-elevation MI [class IIa/level of evidence C, from the last update of the American College of Cardiology/American Heart Association (ACC/AHA) guidelines].13
Regarding GP IIb/IIIa inhibitors, tirofiban and eptifibatide are less investigated in ST-elevation ACS.14 However, results from five randomized trials in primary PCI [ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT), Intracoronary Stenting and Antithrombotic Regimen-2 (ISAR-2), Abciximab Before Direct Angioplasty and Stenting in MI Regarding Acute and Long-term Follow-up (ADMIRAL), Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC), Abciximab and Carbostent Evaluation (ACE)] and one meta-analysis,15 suggest that stenting plus abciximab is the best reperfusion strategy by reducing mortality, target vessel revascularization, and major adverse cardiac events at 6 months after PCI.
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Stent thrombosis |
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TopAbstractIntroductionAntiplatelet agents in coronary...Stable chronic coronary artery...Non-ST-elevation acute coronary...ST-elevation acute myocardial...Stent thrombosisEuro heart surveys:...ConclusionsFundingReferences |
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In the particular scenario of stent implantation, early interruption of DAT increases the risk of acute stent thrombosis, which carries a particularly adverse prognosis (mortality from 15 to 45% at 1 month). Interruption of DAT long after drug eluting-stent (DES) implantation may expose the patient to late stent thrombosis.1 Indeed, discontinuation of DAT is the major predictor of stent thrombosis-related events.16 If interruption of DAT becomes mandatory (urgent surgery or major bleeding), there is no proven efficacy alternative therapy. Only in the case of no-DES implantation, it may be reasonable to postpone the surgery for 1 month before withdrawing DAT.1
Effectiveness of DAT to avoid acute thrombosis seems higher in patients, who have been pre-treated with clopidogrel or with a loading dose (300 mg at least 6 h before PCI or 600 mg if therapy is initiated during PCI). Finally, DAT should be extended to at least 1 year when using DES, and longer for patients at high risk of thrombosis or in whom thrombosis is predicted to have fatal consequences.
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Euro heart surveys: antiplatelets real-world use |
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TopAbstractIntroductionAntiplatelet agents in coronary...Stable chronic coronary artery...Non-ST-elevation acute coronary...ST-elevation acute myocardial...Stent thrombosisEuro heart surveys:...ConclusionsFundingReferences |
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Euro heart surveys provide us with valuable feedback on the use of these drugs. In stable CAD, the use of evidence-based antiplatelet therapy is far less than ideal; only 78% of the patients with known CAD received aspirin after being evaluated by a cardiologist.17 In the ACS setting, rates of administration of aspirin were acceptable (96–98%). Nevertheless, the utilization of thienopyridines and GP IIb/IIIa inhibitors from the years 2000–04 was far from the optimum.18 Indeed, in the last Euro Heart Survey for Coronary Revascularization, a final remark stated that ‘the main area for improvement pertains to the underuse of adjunctive pharmacology'.19
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Conclusions |
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TopAbstractIntroductionAntiplatelet agents in coronary...Stable chronic coronary artery...Non-ST-elevation acute coronary...ST-elevation acute myocardial...Stent thrombosisEuro heart surveys:...ConclusionsFundingReferences |
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Platelets play a pivotal role in the CAD spectrum after natural or man-made arterial wall injury. Aspirin benefits overall prognosis of patients with asymptomatic or stable CAD. DAT with aspirin and clopidogrel improves outcomes in patients with any type of ACS. GP IIb/IIIa inhibitors benefit prognosis of high-risk patients and make PCI easier, safer and more effective, both in the setting of NSTE-ACS and also in ST-elevation ACS. Abciximab appears to be the more evidence-based treatment in this setting. Finally, DAT is the only effective tool against DES late and very late thrombosis.
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Funding |
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TopAbstractIntroductionAntiplatelet agents in coronary...Stable chronic coronary artery...Non-ST-elevation acute coronary...ST-elevation acute myocardial...Stent thrombosisEuro heart surveys:...ConclusionsFundingReferences |
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Financial support provided by Daiichi Sankyo, Inc. and Eli Lilly and Company.
Conflict of interest: none declared.
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