SeriesClinical evidence for oral antiplatelet therapy in acute coronary syndromes
Introduction
Acute coronary syndromes are a leading cause of mortality, morbidity, and loss of productivity. The major pathophysiological mechanism underlying unstable angina and myocardial infarction is atherosclerotic plaque rupture with resultant coronary thrombosis. Platelets adhere to ruptured plaques, aggregate, and release secondary messengers, which result in further thrombosis and vasoconstriction, and serve as a surface for activation of the clotting cascade. As a result, antiplatelet therapies have led to major advances in the treatment of acute coronary syndromes and the prevention of recurrent events. With key components of the thrombotic process targeted, obligate increases in bleeding exist. The past 25 years has seen the completion of various large-scale clinical trials that have investigated the efficacy and safety of several pharmaceutical agents, including aspirin and P2Y12 antagonists, alone or in combination (table 1). These trials provide evidence to guide patient management in balancing the efficacy and safety of pharmaceutical compounds, the pharmacology of which is described in detail in a companion Series paper.8
Section snippets
Aspirin
Historically, the first antiplatelet agent to show benefit in acute myocardial infarction was aspirin, which blocks the production of thromboxane A2. The first major trial,1 ISIS-2, showed the additive benefits of thrombolysis and low-dose aspirin in patients with ST-segment elevation acute myocardial infarction. The Antithrombotic Trialists' collaboration summarised the evidence for the benefit of aspirin in vascular disease, and showed that low-dose aspirin reduced vascular events (6·7% vs
Combination of clopidogrel with aspirin
The CURE trial2 was the landmark trial that established the benefits of addition of the P2Y12 receptor blocker, clopidogrel, to aspirin in patients with non-ST-segment elevation acute coronary syndromes, showing a 20% reduction in the composite outcome of cardiovascular death, myocardial infarction, and stroke, compared with placebo over 9–12 months of therapy. No increase in TIMI major bleeding was noted with the combination of aspirin and clopidogrel, but a 38% increase in the trial primary
Limitations of clopidogrel
Clopidogrel has substantial limitations in the management of acute coronary syndromes with a modest inhibition of platelet aggregation and a delayed onset and offset of action. Although no accepted test or specific target goal exists for platelet inhibition, variability in response to clopidogrel is substantial,22, 23 with estimations that 4–34% of patients have an inadequate response dependent on the method and cut point used. These patients are at high risk of subsequent clinical events
Prasugrel
Prasugrel is a second-generation thienopyridine that, similarly to clopidogrel, needs conversion from an inactive form to an active metabolite by use of cytochromes.35 Unlike clopidogrel, however, prasugrel is rapidly and more wholly metabolised to its active components. This metabolic difference allows prasugrel to have a more rapid onset, higher levels of platelet inhibition, and less interpatient response variability than clopidogrel.36
The major clinical outcomes trial of prasugrel,
Ticagrelor
Ticagrelor is a direct-acting P2Y12 antagonist that does not need metabolic activation and is therefore not dependent on cytochrome P450 enzymes. The drug acts rapidly and has more potent and consistent antiplatelet effects than clopidogrel. Ticagrelor was compared with clopidogrel in patients with acute coronary syndromes in the PLATO trial,45 which enrolled 18 624 patients with moderate to high risk of unstable angina, or non-ST-segment elevation myocardial infarction, or patients with
Vorapaxar
Vorapaxar is a competitive antagonist of the protease-activated receptor, which is a major thrombin receptor on human platelets. Vorapaxar has been studied in two major trials of patients with acute coronary syndromes: TRACER11 and TRA 2P–TIMI 50.12 TRACER enrolled 12 944 patients with non-ST-segment elevation acute coronary syndromes and compared vorapaxar with placebo, in addition to standard therapy, which included aspirin plus clopidogrel in 92% of patients. The combination primary endpoint
Cilostazol
Cilostazol is an orally available cyclic adenosine monophosphate phosphodiesterase III inhibitor that has vasodilatory and antiplatelet effects. This agent is predominantly used for the management of intermittent claudication associated with peripheral arterial disease. Cilostazol has been studied in small studies (predominantly in Asia) as a component of triple antiplatelet therapy with aspirin and clopidogrel. One meta-analysis58 suggests that a strategy of cilostazol, in addition to standard
Combined therapy with aspirin and either prasugrel or ticagrelor
Since both prasugrel and ticagrelor have shown superior outcomes to clopidogrel in pivotal trials, these novel agents are now preferred to clopidogrel as a first-line therapy in conjunction with aspirin, for most patients with acute coronary syndromes, as endorsed by both European and US guidelines.39, 40, 41 Prasugrel is a preferred option for patients undergoing percutaneous coronary intervention (except for patients with a previous history of stroke or transient ischaemic attack, with a
Personalised antiplatelet therapy
In view of the high cost and bleeding risk of the novel agents, and the availability of clopidogrel as a generic drug, it might seem important to identify patients with a poor clopidogrel response (based on platelet-function testing or genotyping) and give them either a high dose of clopidogrel or the novel agents, and use the standard dose of clopidogrel in good responders. However, this approach is currently not recommended in routine practice, by guidelines;39, 40 first, a large genotypic
When to start therapy with oral-antiplatelet agents
Substantial diagnostic uncertainty often exists in patients with suspected acute coronary syndromes in the early phases of management, and some patients might either eventually have other final diagnoses (including some contraindications to antiplatelet therapy, such as aortic dissection) or need urgent surgery (in which case, after the patients have received a potent oral antiplatelet agent, the risk of bleeding would be increased). The diagnostic uncertainty is greatest in patients with
Optimum duration of therapy
Patients with acute coronary syndromes are at high risk of recurrence66 and therefore should receive combined antiplatelet therapy for the initial post-acute coronary syndrome period and subsequently remain indefinitely on single antiplatelet therapy. In addition to the prevention of recurrences, combined antiplatelet therapy also contributes to the prevention of stent thrombosis in the large proportion of patients with acute coronary syndromes who have stents. There is, however, some
Patients needing oral anticoagulation
A subset of patients with acute coronary syndromes need permanent oral anticoagulation (eg, because of a prosthetic heart valve or atrial fibrillation). In these patients, the treatment of combined antiplatelet therapy and oral anticoagulation is complex. Typically, management of acute coronary syndromes will entail an initial period of triple therapy, combining aspirin, clopidogrel, and oral anticoagulation, which increases the risk of bleeding.71, 72 To minimise bleeding, it seems reasonable
Management of patients undergoing CABG
In patients with acute coronary syndromes, a few will need CABG surgery. Although it is recommended to continue aspirin throughout the perioperative period, it is desirable, in most patients, to withhold P2Y12 receptor blockers before and during surgery to minimise bleeding (unless patients are highly unstable). In very unstable patients or those with new stents, injectable reversible antiplatelet agents, such as glycoprotein IIb/IIIa receptor blockers or, in the future, cangrelor, might allow
Conclusions
Antiplatelet therapy improves cardiovascular outcomes after acute coronary syndromes. A broad and comprehensive dataset from large-scale trials allows for evidence-based decisions regarding these therapies (figure 3). The combination of aspirin with a potent inhibitor of the P2Y12 receptor (prasugrel or ticagrelor) is recommended in most patients with acute coronary syndromes, but patient factors and bleeding risk should be considered in the choice of agents. Additional data from trials of
References (80)
- et al.
Rapid desensitization procedure for patients with aspirin hypersensitivity undergoing coronary stenting
Am J Cardiol
(2005) - et al.
Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study
Lancet
(2001) - et al.
A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial
J Am Coll Cardiol
(2006) - et al.
Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial
Lancet
(2010) - et al.
Coronary stent placement in patients with acute myocardial infarction: comparison of clinical and angiographic outcome after randomization to antiplatelet or anticoagulant therapy
J Am Coll Cardiol
(1997) - et al.
Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials
Lancet
(2003) - et al.
Variability in platelet responsiveness to clopidogrel among 544 individuals
J Am Coll Cardiol
(2005) - et al.
Clopidogrel loading dose adjustment according to platelet reactivity monitoring in patients carrying the 2C19*2 loss of function polymorphism
J Am Coll Cardiol
(2010) - et al.
Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding
J Am Coll Cardiol
(2013) - et al.
A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study
J Am Coll Cardiol
(2012)
Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study
Lancet
Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data
J Am Coll Cardiol
Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial
Lancet
Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial
Lancet
Prasugrel versus clopidogrel for patients with unstable angina or non-ST-segment elevation myocardial infarction with or without angiography: a secondary, prespecified analysis of the TRILOGY ACS trial
Lancet
Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study
Lancet
Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial
Lancet
Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study
Lancet
Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome
J Am Coll Cardiol
Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial
JACC Cardiovasc Interv
Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data
Lancet
Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial
J Am Coll Cardiol
Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention
J Am Coll Cardiol
Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data
Lancet
Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial
Lancet
Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial
J Am Coll Cardiol
Mortality benefit with prasugrel in the TRITON-TIMI 38 coronary artery bypass grafting cohort: risk-adjusted retrospective data analysis
J Am Coll Cardiol
Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome)
J Am Coll Cardiol
Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group
Lancet
Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation
N Engl J Med
Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation
N Engl J Med
Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial
Lancet
Dose comparisons of clopidogrel and aspirin in acute coronary syndromes
N Engl J Med
Prasugrel versus clopidogrel in patients with acute coronary syndromes
N Engl J Med
Prasugrel versus clopidogrel for acute coronary syndromes without revascularization
N Engl J Med
Pharmacology of antithrombotic agents: an exploration of oral antiplatelet and anticoagulant therapies
Lancet
Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis
Lancet
Design and rationale for the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial
Am Heart J
Thrombin-receptor antagonist vorapaxar in acute coronary syndromes
N Engl J Med
Vorapaxar in the secondary prevention of atherothrombotic events
N Engl J Med
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