Antiplatelet agents in acute coronary syndrome

Arun Natarajan, specialist registrar in cardiology, Essex Cardiothoracic Centre, Basildon. Reviewed by Gerald Clesham, consultant cardiologist, Essex Cardiothoracic Centre

Monday, 12 January 2009

Key learning points

• Aspirin is the cornerstone of secondary prevention and is continued lifelong following acute coronary syndrome (ACS) 
• “Aspirin resistance” in certain individuals is thought to limit the usefulness of aspirin 
• Clopidogrel is the thienopyridine of choice and is commenced (along with aspirin) with loading doses during non-ST-segment elevation myocardial infarction and PCI and continued for at least 1 year thereafter 
• Recent trials have also shown benefit of clopidogrel in ST-segment elevation myocardial infarction 
• There is no evidence for dual aspirin and clopidogrel therapy in primary prevention or long-term (beyond 1 year) secondary prevention in stable patients 
• GP IIb/IIIa inhibitors have become less important since the widespread use of clopidogrel and are used only during primary PCI and in high-risk cases 
• Newer antiplatelet agents such as prasugrel, cangrelor and ticagrelor are on the horizon

Antiplatelet agents are central to the treatment of acute coronary syndrome (ACS). A variety of antiplatelet agents are used and act via different platelet receptors and pathways (Figure 1). Although there is a clear benefit of these agents, there is considerable variability in individuals’ responsiveness to antiplatelet agents. Multiple genetic, iatrogenic and environmental factors have been implicated [1]. The three main classes of antiplatelet agents used in ACS are reviewed below.

Figure 1. Sites of action of aspirin, thienopyridines and glycoprotein (GP) IIb/IIIa inhibitors. Thromboxane and intraplatelet granule constituents that are released into the surrounding area on platelet activation recruit more platelets to the site of injury and augment platelet activation.

The role of platelets in ACS [2]

When vulnerable lipid-rich atherosclerotic plaques with relatively thin fibrous caps undergo erosion or rupture, they lead to the exposure of highly thrombogenic extracellular matrix (ECM) beneath the damaged endothelial layer. Circulating platelets adhere to the collagen and von Willebrand factor contained in the ECM. Adhered platelets change shape forming pseudopodia and undergo activation – intraplatelet granules release agonists such as adenosine diphosphate (ADP) thrombin and serotonin which enhance the activation process and recruit more platelets to the site.

Figure 2: Critical atherosclerosis in a coronary artery.

Simultaneously, thromboxane is synthesized from arachidonic acid within platelets and further augments activation. Platelet activation leads to a conformational change in the glycoprotein (GP) IIb/IIIa receptor (fibrinogen receptor) on the platelet surface. This crucial step leads to fibrinogen binding and cross-links platelets, i.e. platelet aggregation. Thrombin generated at the injury site converts fibrinogen to fibrin and consolidates the loosely clumped platelets into a growing thrombus. The degree of luminal occlusion by the thrombus and accompanying vasospasm determine the degree of myocardial damage and subsequent morbidity.

Aspirin

Aspirin acetylates and irreversibly inactivates intraplatelet cycloxygenase enzyme which mediates thromboxane production and thus inhibits platelet aggregation  [3]. As new platelets are continuously being produced a regular regimen of aspirin is essential. Low-dose aspirin (75 mg daily in the UK) is efficacious and cost-effective and forms the bedrock of secondary prevention of coronary heart disease (CHD). Aspirin withdrawal has in fact been shown to cause recurrence of ACS [4]. An authoritative meta-analysis by the Antiplatelet Trialists’ Collaboration found that the benefit of aspirin may be limited in patients with diabetes mellitus [5]. The role of aspirin in primary prevention is contentious. There is evidence that aspirin in individuals without known CHD but with risk factors, reduces the risk of adverse events [6, 7]. However, numerous other studies found no benefit of aspirin in primary prevention in patients with diabetes [8]. The recently published POPADAD trial [9] in diabetic subjects without clinical CHD found no benefit of aspirin use in the longer term. Nevertheless, the American Heart Association [10] and American Diabetes Association [11] recommend aspirin for primary prevention in patients with diabetes.

Aspirin resistance

Biochemically, this refers to the inability of aspirin to inhibit platelet production of thromboxane and therefore platelet aggregation [12, 13]. Clinically, it is defined as the recurrence of thromboembolic events in patients prescribed therapeutic doses of aspirin [12, 13]. Estimates of the prevalence of this state vary widely (5 to 57%), depending on the method of platelet function assessment, definition of “aspirin resistance” and the clinical characteristics of the populations tested [13]. Several possible causes for “aspirin resistance” have been proposed including reduced bioavailability of aspirin, alternative sources of  thromboxane production, alternative pathways of platelet activation, increased turnover of platelets, genetic polymorphisms of enzymes and receptors involved in platelet activation and drug interactions [12].

Studies reporting “aspirin resistance” [13] however, had clear limitations – small sample sizes, confounding factors which could not be accounted for, varying protocols of aspirin dosing, non-agreement between tests of platelet function and importantly, a lack of a coherent connection between “aspirin resistance” and clinical events [13]. Furthermore, the term “aspirin resistance” does not provide much information on the mechanistic pathways responsible for aspirin failure and therefore is of limited use to clinicians [14].  Currently there are no standardised methods of testing for “aspirin resistance”.

Therefore a number of unanswered questions remain: Is the phenomenon real? Can laboratory methods detect it consistently? And finally, can it reliably predict risk of thrombotic events?

Thienopyridines

Thienopyridine derivatives induce irreversible alterations of the platelet ADP receptor P2Y₁₂ and inhibit aggregation. As they inhibit platelet aggregation by a mechanism different from that of aspirin they can add to its effects. Clopidogrel is now the most widely used thienopyridine derivative, after ticlopidine was sidelined because of side effects such as neutropenia [15]. The newer agent prasugrel is still not licensed for use in the UK. The CAPRIE study, one of the first randomized trials of clopidogrel found it to be comparable to aspirin in terms of efficacy and safety [16]. The CURE study paved the way for use of clopidogrel in combination with aspirin in NSTEMI ACS [17].

Cardiovascular events occurred in 16.5 percent of the patients treated with combination therapy compared to 18.8 percent of the patients treated with aspirin alone in the CURE study, over a 3-12 months period (RR, 0.86; 95 percent CI, 0.79 to 0.94; P<0.001). The benefit of combination therapy during PCI and for up to one year thereafter has also been established [18, 19]. More recently the ground-breaking COMMIT [20] trial, a Chinese study of over 45,000 patients and the CLARITY-TIMI 28 [21] demonstrated added benefit of clopidogrel use along with aspirin and thrombolysis in STEMI patients albeit over a shorter term. COMMIT showed that clopidogrel prevented 10 major vascular events per 1000 patients treated, importantly without any increase in major bleeding.

Figure 3: A patient suffering a cardiovascular event has undergone an angiopasty. The image shows the pre and post angiopasty views.

Apart from a subgroup analysis of the CAPRIE subjects [22] no other major randomized trial demonstrated special benefits of clopidogrel use in diabetic patients. There is also no demonstrable benefit of dual antiplatelet therapy in long-term secondary or primary prevention as demonstrated by the large CHARISMA study [23]. In fact, there was an increased event rate in the primary prevention arm in CHARISMA, suggesting that aggressive antiplatelet therapy must be reserved for high-risk groups only. On a parallel note, a dual antiplatelet approach showed no added benefit in secondary prevention of ischemic cerebrovascular events in the MATCH study [24].

The novel thienopyridine prasugrel has been shown in laboratory-based studies to be more potent than clopidogrel. Prasugrel plus aspirin was compared against clopidogrel plus aspirin in ACS patients in the TRITON-TIMI 38 trial [25]. Although, there was a significant reduction in cardiovascular endpoints, for each death from cardiovascular causes prevented there was approximately one additional episode of fatal bleeding caused by prasugrel. This reiterates the menace of bleeding that accompanies aggressive antiplatelet therapies. For this very reason, clopidogrel is withheld for at least 5 days prior to coronary artery bypass surgery. Dual therapy with aspirin and clopidogrel is however, crucial in the prevention of late stent thrombosis especially in those with drug-eluting stents [26]. Nevertheless, continuation of dual therapy beyond one year is still hotly debated. Currently in the UK, use of dual therapy beyond one year is at the cardiologist’s discretion, for instance in individuals with repetitive atherothrombotic episodes. The phenomenon of “clopidogrel resistance” has been proposed and is thought to involve variable responsiveness of individuals to this agent [27]. Mechanisms similar to those responsible for “aspirin resistance” have been described.

NICE guidance published in July 2004 [28] recommends use of clopidogrel in combination with aspirin in NSTEMI ACS in moderate- to high-risk ACS patients i.e., those with clinical signs and symptoms, accompanied by one or both of the following:

1. new ECG changes indicating ongoing myocardial ischaemia
2. raised cardiac biomarkers such as troponin.

NICE recommends dual antiplatelet therapy for 12 months following NSTEMI [28] and 4 weeks following STEMI [29] followed by lifelong aspirin. But many clinicians now continue dual therapy for one year in STEMI patients as well. Guidance on ACS is currently being reviewed by NICE and will hopefully be updated soon. In the event of PCI occurring during STEMI, dual therapy is continued for one year irrespective of the type of ACS or stent used (bare-metal or drug-eluting). Current practice of antiplatelet therapy in the UK is summarized in Table 1.

Platelet glycoprotein IIb/IIIa receptor inhibitors

Platelet GP IIb/IIIa inhibitors administered intravenously have high potency, rapid onset of action and short half lives. They are used primarily in coronary care units and cath labs as adjunctive agents in patients with ACS, especially those undergoing PCI. The GP IIb/IIIa receptor binds fibrinogen and as this is the final common pathway in platelet aggregation, these agents can impair platelet-dependent thrombus formation irrespective of the metabolic pathway responsible for initiating it [30]. The three agents currently used in the UK have varying molecular structures and pharamacological features:

1) Abciximab - a monoclonal antibody, with tight receptor binding and slow reversibility of platelet inhibition

 2) Eptifibatide - a cyclic peptide, selective inhibitor and a short half-life

3) Tirofiban - a non-peptide antagonist, causes rapid and selective blockade (5 min) with quick reversibility (4-6 hours) [31].

Use of GP IIb/IIIa inhibitors is not consistent across the UK and up-to-date guidance is lacking (Table 1). Clear benefit of abciximab in primary PCI (following STEMI) has been demonstrated in numerous randomized trials [32] and current UK practice conforms to this. But GP IIb/IIIa inhibitors are not recommended for use during thrombolysis in STEMI. The importance of GP IIb/IIIa agents in treatment of NSTEMI seems to have decreased with the widespread use of clopidogrel. Prior to the aggressive use of clopidogrel the different GP IIb/IIIa inhibitors were shown in a wide array of trials to reduce cardiovascular endpoints. Currently their use is mostly in patients who have unstable symptoms, raised troponin levels or are likely to have PCI within 72 hours. The ISAR-REACT-2 trial clearly demonstrated that use of GP IIb/IIIa agents in addition to aspirin and 600 mg of clopidogrel is beneficial only in the subset of patients with raised troponin levels [33]. There is still ongoing debate about the timing of initiation of these agents, i.e., upstream use versus use in the cath lab after determining coronary anatomy. The ACUITY-Timing trial showed that upstream use did not add benefit and in fact increased bleeding risk [34]. Interestingly, resistance to GP IIb/IIIa inhibitors has not been an issue unlike with aspirin and clopidogrel.

NICE guidance on the use of GP IIb/IIIa receptor inhibitors was published in September 2002 [37] and predates widespread use of clopidogrel. This is currently under review. NICE recommends intravenous use of a GP IIb/IIIa  inhibitor in addition to conventional antithrombotic therapy in high-risk patients with NSTEMI especially in those with unstable symptoms and haemodynamic profiles, raised troponin levels and due to undergo immediate PCI. NICE also recommends their use in those with diabetes or  complex coronary disease, even during elective PCI. This probably was based on meta-analyses [35] [36] that demonstrated benefit in diabetic subgroups but many of the trials in these analyses were from the pre-clopidogrel era. The more recent ISAR-SWEET trial failed to demonstrate benefit of abciximab in diabetic patients undergoing elective PCI, pretreated with clopidogrel [38]. Indeed in today’s UK practice use of these agents in the elective setting is rare.

New drugs

Two non-thienopyridine antagonists of P2Y₁₂ cangrelor (intravenous) and ticagrelor (oral) are currently being tested in phase III studies or already being launched by the manufacturers. Newer targets on platelets are also being evaluated such as antibodies or aptamers that target the collagen receptor GP VI or the von Willebrand factor receptor GP Ib on the platelet surface and thromboxane receptors [39].

Patients on anticoagulants

Difficulties arise when patients requiring long-term anticoagulation such as those with prosthetic heart valves, atrial fibrillation or venous thromboembolism need to be treated for ACS and require stent implantation. There are no unified guidelines and current treatment is tailored individually at the cardiologist’s discretion. Generally triple therapy (aspirin, clopidogrel and warfarin) is used only in the first few weeks following ACS/PCI and if antiplatelet agents are required in the longer term, a combination of clopidogrel and warfarin is preferred. Aspirin when administered with warfarin worsens the risk of GI bleeding in the longer term [40].

Elderly patients

Bleeding risk increases with age and is especially high in elderly women. There are no specific protocols for antithrombotic use in the elderly, but again, treatment will have to be tailored to the requirements of each individual after assessing risk-benefit profile.

Table 1. Current use of antiplatelet agents in ACS in the UK.

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Author and reviewers competing interests: none.

Images: Wellcome.