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</svg> Receptor Inhibitors in Acute Coronary Syndromes: What Is New on the Horizon?

Oprea, Adriana Dana; Popescu, Wanda M.

doi:https://doi.org/10.1155/2013/195456

Cardiology Research and Practice

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Review Article | Open Access

Volume 2013 | Article ID 195456 | https://doi.org/10.1155/2013/195456

Receptor Inhibitors in Acute Coronary Syndromes: What Is New on the Horizon?

Adriana Dana Oprea¹and Wanda M. Popescu¹

Academic Editor: Ping-Yen Liu

Received13 Oct 2012

Accepted21 Dec 2012

Published19 Feb 2013

Abstract

Dual antiplatelet therapy with aspirin and a P2Y₁₂ receptor inhibitor represents the cornerstone therapy for patients with acute coronary syndromes or undergoing percutaneous interventions, leading to a reduction of subsequent ischemic events. Variable response to clopidogrel has received close attention, and pharmacokinetic, pharmacodynamic, and pharmacogenomic factors have been identified as culprits. This led to the introduction of newer, potentially safer, and more effective antiplatelet agents (prasugrel and ticagrelor). Additionally, several point-of-care assays of platelet function have been developed in recent years to rapidly screen individuals on antiplatelet therapy. While the routine use of platelet function testing is uncertain and not currently recommended, it may be useful in instances when the degree of platelet inhibition may be uncertain such as high-risk patients undergoing percutaneous coronary intervention or when there may be a suspected pharmacodynamic interaction with other drugs. The current paper focuses on the P2Y₁₂ receptor inhibitors and their pharmacogenetics and indications in patients with acute coronary syndromes or receiving percutaneous coronary interventions as well as the applicability of platelet function testing in this clinical context.

1. Introduction

The clinical presentation of patients with coronary atherosclerosis is either as stable angina or as an acute coronary syndrome (ACS). The ACSs represent the more acute clinical manifestations of coronary artery disease (CAD) and include unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI), and ST elevation myocardial infarction (STEMI). Despite maximal therapy, 5%–10% of patients with ACS will suffer a recurrent cardiac event or death within the first month after the initial presentation. While patients with stable angina have only narrowing of their coronary arteries, those with ACS have atheromatous plaque rupture and acute thrombus formation. Therefore, it is well recognized that platelet activation and aggregation play a central role in the physiopathology of ACS. In addition to aspirin and anticoagulants, antiplatelet agents represent an important therapeutic step for this patient population, with newer and more potent agents becoming available on the market [1, 2].

During an acute coronary event, vascular wall injury exposes collagen that leads to adhesion of inactive platelets, which subsequently become activated. Platelet activation results in degranulation and secretion of adenosine diphosphate (ADP), thromboxane A2 (T_XA2), and platelet-activating factor (PAF) [3, 4]. Two G protein-coupled receptors, P2Y₁ and P2Y₁₂, are responsible for platelet aggregation, with the P2Y₁ receptor initiating a weak platelet activation while binding of P2Y₁₂ receptor resulting in a slower but progressive platelet aggregation.

Several antiplatelet agents are used during an ACS episode, each blocking a different pathway of the platelet aggregation. Aspirin irreversibly inhibits cyclooxygenase COX2, the enzyme that mediates the first step in the biosynthesis of TxA2 from arachidonic acid. The ADP receptor blockers (P2Y₁₂ inhibitors) prevent binding of the ADP to a specific platelet receptor, therefore, inhibiting the activation of the GP IIb/IIIa complex and thus platelet aggregation. GP IIb/IIIa antagonists interfere with the final common pathway of platelet aggregation (the cross-bridging of platelets by fibrinogen binding to the GP IIb/IIIa receptor) and may also prevent adhesion of other platelets to the vessel wall.

This paper focuses on the newer generation P2Y₁₂ inhibitors, with the exception of the first generation thienopyridine (ticlopidine), their advantages, limitations, and clinical applicability in the setting of ACS.

2. Pharmacokinetics and Pharmacodynamics

2.1. Antiplatelet Drugs Available on the Market

2.1.1. Clopidogrel

Clopidogrel is a second-generation thienopyridine introduced after ticlopidine, which irreversibly inhibits the P2Y₁₂ receptor and has a bioavailability of 50% after oral absorption. Clopidogrel is a prodrug with no antiplatelet activity of its own. Fifteen percent of the absorbed drug is metabolized by the liver in a 2-step process into an active metabolite (R130964) responsible for the inhibition of platelet aggregation (IPA). The remainder 85% is transformed by esterases into an inactive carboxylic acid metabolite (SR 26334).

Doses up to 600 mg lead to a peak plasma level within 1 to 2 hours, but maximal platelet aggregation inhibition can be reached in some cases 4–6 h after a loading dose [5]. The half-life of clopidogrel is 6 hours after a single dose and 8 hours for its active metabolite [6]. Administration of a 75 mg oral dose of clopidogrel results in 40% to 60% level of IPA after 3 to 7 days. A loading dose of 600 mg similar response can lead to similar levels of IPA after 2 hours only [7, 8]. Clopidogrel is equally eliminated in feces and urine. Moderate renal and hepatic impairments do not require dose adjustments [9, 10]. The irreversible binding of the P2Y₁₂ receptor results in the antiaggregant effects of clopidogrel lasting for the lifespan of platelet, 7–10 days.

2.1.2. Prasugrel

Prasugrel is a newer generation thienopyridine approved for patients with unstable angina or myocardial infarction who undergo percutaneous coronary intervention (PCI) [11].

Similar to clopidogrel, prasugrel is an irreversible P2Y₁₂ inhibitor requiring metabolic activation by intestine and blood esterases. Unlike clopidogrel, it requires only one metabolic step, versus two steps. The resulting metabolite is then oxidized by cytochrome P450 (CYP) to an active metabolite (R-138727) responsible for the antiplatelet effects [12]. Peak plasma concentration is reached within 30 minutes of absorption and elimination half-life is approximately 7 hours [13]. As with clopidogrel, moderate hepatic or renal impairment does not require dose adjustments [14, 15]. The maximum IPA (75% to 85%) is achieved between 2 and 4 hours after a loading dose. Compared to clopidogrel, prasugrel is more potent and has a more rapid onset of action at both loading and maintenance doses [11].

The recommended loading dose for prasugrel is 60 mg, followed by a 10 mg daily dose. Patients weighing less than 60 kg, older than 75 years, or with a previous history of stroke or transitory ischemic attacks require reduction of the dose to 5 mg daily due to increased risk of fatal bleeding [16, 17].

2.1.3. Ticagrelor

Ticagrelor (AZD6140) is a selective, reversible P2Y₁₂ inhibitor that belongs to a new class of antiplatelet agents, the cyclopentyl-triazolo-pyrimidines. It is approved for use in combination with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). In addition to antiplatelet effects, ticagrelor blocks the ADP-mediated vasoconstriction and is thought to increase the adenosine-induced coronary blood flow [18–20].

In addition to being a reversible antiplatelet agent, ticagrelor is also a noncompetitive antagonist of the P2Y₁₂ receptor. Ticagrelor does not directly inhibit ADP binding to the P2Y₁₂ receptor but induces a conformational change making it unable to trigger platelet activation [20]. Since it does not require any biotransformation, it is immediately active after oral administration resulting in a more rapid onset of action and a more pronounced platelet inhibition as compared to other P2Y₁₂ inhibitors [21]. Ticagrelor’s effects correlate with drug plasma levels, its activity being independent of the ADP concentration [22].

Both ticagrelor and its metabolite have linear pharmacokinetics up to a dose of 100 mg twice a day [20]. Ticagrelor is excreted in the feces and it does not require dose adjustments in patients with renal failure [23]. Unlike clopidogrel or prasugrel, patients with impaired liver function or who take medications able to inhibit the CYP3A4 should receive a reduced dose of ticagrelor [22]. Ticagrelor is faster acting and exhibits greater degree of IPA (approximately 80% at 2 hours) when compared with clopidogrel. Despite its reversibility and rapid onset, it has a slow offset, with 20% inhibition present 3 days after stopping therapy. Compared to clopidogrel, there is a faster recovery of the platelet function, with similar IPAs present 5 days after stopping clopidogrel and 3 days after stopping ticagrelor [24–26].

Compared to prasugrel, patients with high on-treatment platelet reactivity while on clopidogrel presenting with ACS demonstrated higher IPAs while on ticagrelor [27].

Ticagrelor has a half-life of 7 to 8.5 hours. The recommended loading dose is of 180 mg followed by 90 mg dose twice daily in addition to aspirin 75–100 mg daily [20, 22].

2.2. Antiplatelet Drugs in Development

2.2.1. Cangrelor

Cangrelor is a direct-acting, reversible P2Y₁₂ antagonist undergoing phase III trials. Unlike the other P2Y₁₂ antagonists, cangrelor is administered intravenously. The major therapeutic advantage of this drug is its very short half-life leading to prompt termination of its effect upon stopping the infusion. Initiation of a cangrelor infusion results in a rapid onset of action and an almost complete IPA within 30 minutes. Cangrelor clearance does not depend on renal function. At infusion rates between 2 and 4 μg/kg/min, patients demonstrate an 80% IPA, with platelet function recovering within 5 minutes after infusion discontinuation [28].

2.2.2. Elinogrel

Elinogrel (PRT060128), a quinazoline-2,4-dione is another direct, potent and reversible inhibitor of the platelet P2Y₁₂ receptor. Phase II trials have been completed, but further investigations are currently halted. Unlike cangrelor, it is designed to be administered both orally and intravenously. Elinogrel has a plasma half-life of approximately 12 h and achieves almost complete platelet inhibition within 15 minutes after intravenous administration. It does not require metabolization to an active compound and it is excreted equally by the liver and the kidney.

The lack of metabolization to an active substance makes elinogrel less susceptible to resistance, as compared to clopidogrel [29, 30].

3. Resistance and Pharmacogenetics

Resistance to antiplatelet agents is a well-described phenomenon, consisting either of presence of inadequate platelet inhibition or the occurrence of a recurrent event while on a therapeutic dose of an antiplatelet agent. More recently, the term resistance has been restricted to the laboratory evidence of high on-treatment platelet reactivity (HTPR), while the clinical presence of a recurrent event has been termed treatment failure [31, 32].

Resistance to clopidogrel is a well-recognized phenomenon, with 15–30% of patients having inadequate platelet inhibition while on a therapeutic dose. This poor responsiveness to clopidogrel in certain patient population, as assessed by platelet function testing, has led to studies looking at the potential causes for resistance, the correlation of hypo- or nonresponsiveness to therapy with clinical outcomes (major adverse cardiac events) and at ways to overcome this problem (either by increased dosing or by a prescribing a different antiplatelet agent).

Several mechanisms are involved in resistance to clopidogrel: inadequate dosing or absorption, drug interactions, and genetic polymorphisms.

Inadequate dosing can be a factor of resistance in obese patients. Absorption can be impaired in patients with cardiogenic shock or with loss of the P-glycoprotein transporter function [33, 34]. Other patient population demonstrating an inadequate response to clopidogrel are the diabetic or insulins resistant patients [35]. In these patients, the normal effects of insulin on the platelet leading to aggregation are impaired.

Drug interactions represent a major component of clopidogrel resistance. Statins, proton pump inhibitors (PPIs), ketoconazole, and erythromycin interact with different CYP enzymes, thereby decreasing the conversion of clopidogrel to the active metabolite [36–40].

Clopidogrel is metabolized to its active form by the CYP enzymes, a super family of microsomal drug-metabolizing enzymes. Functional CYP polymorphisms consist of deletions, duplications, and mutations creating inactive gene products leading to increased or decreased metabolism of the drug. Clopidogrel’s metabolism involves 2 steps. The first step leads to the formation of 2-oxo-clopidogrel, which subsequently is transformed into the active metabolite [41]. Enzymes involved in the metabolism of clopidogrel include CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5. CYP2C19, with its gene located on chromosome 10, seems to be the most important enzyme involved in clopidogrel’s metabolism. The CYP2C19*1 allele is associated with full enzyme activity while CYP2C19*2 and *3 variants are most frequently associated with poor responsiveness to clopidogrel. These alleles have been termed “loss of function alleles” and are more frequent in the Asian rather than in the Caucasians population. Many studies have confirmed an impaired response to clopidogrel either in healthy volunteers or patients carrying the CYP2C19*2 or *3 allele, evidenced by platelet function tests or by an increased incidence of MACE [41, 42] (Table 1). More importantly, the difference in clopidogrel metabolism appears to be present not only in homozygous patients but also heterozygote patients [43, 44]. Due to this evidence, the FDA has added a black box warning for patients with genetic variants of the CYP2C19 gene who are poor metabolizers and receive clopidogrel therapy. These patients are at particular high risk of a poor response to therapy and thus an increased rate of cardiovascular events [45].

On the other hand, the *17 allele (gain-of-function allele) is associated with CYP enzyme upregulation, increasing the clopidogrel metabolism by 30%, therefore, leading not only to an adequate antiplatelet response but also to potentially increased bleeding episodes [46–48]. However, a recent meta-analysis did not find any association between the genotype (*17) and the rate of cardiovascular events or bleeding [49].

ABCB1 is another gene receiving attention as potentially responsible for clopidogrel resistance. ABCB1 encodes the P-glycoprotein efflux transporter responsible for the intestinal absorption of clopidogrel. A certain genetic variant (ABCB1 3435C-T) has been linked to an increased ischemic event while on clopidogrel, but other studies have not confirmed it [50, 51].

Paraoxonase 1 (PON1) is a HDL-associated enzyme that is involved in the second step of clopidogrel metabolism. Its common polymorphism, Q192R, influences platelet inhibition [52]. Recent studies offer contradictory information regarding the association between PON1 polymorphism and a lower degree of platelet aggregation or an increased risk of stent thrombosis [53, 54].

The relationship between polymorphisms of the gene encoding the P2Y₁₂ receptor and a response variability to clopidogrel therapy was also studied, but the data remains inconclusive [42].

Resistance to prasugrel is less prevalent, with fewer than 6% of patients qualifying as poor responders on a maintenance dose of prasugrel of 10 mg daily. In the setting of PCI, a significant number of patients did not achieve adequate platelet inhibition after a loading dose of 60 mg of prasugrel, thus, being at an increased risk for MACE [55]. However, as compared to clopidogrel, prasugrel’s metabolism depends mostly on CYP3A4 and CYP2B6 enzymes and to a lesser extent on CYP2C9 and CYP2C19 [56–59]. On the other hand, prasugrel’s metabolism involves just one step versus 2 steps for clopidogrel. These differences in metabolism as well as its increased potency relative to clopidogrel make prasugrel less susceptible to resistance. Patients demonstrating “resistance” to clopidogrel, based on HTPR, seem to have an adequate response to prasugrel therapy [60–63]. Possible mechanisms responsible for prasugrel resistance include poor patient compliance, drug absorption disturbances, drug interactions (the concomitant use of CYP3A4 inhibitors), drug underdosing, increased platelet turnover, and P2Y₁₂ receptor polymorphism [64–66].

Ticagrelor is primarily metabolized via the cytochrome CYP3A4 enzyme, which leads to faster, greater, and more consistent antiplatelet effects as compared to clopidogrel. Ticagrelor therapy can also overcome nonresponsiveness in patients with treatment failure while on clopidogrel. Its pharmacodynamics is not influenced by CYP2C19 and ABCB1 genotypes. As such, patients resistant to both clopidogrel and prasugrel seem to be effectively treated with ticagrelor [67, 68].

4. Platelet Testing

Platelet function testing, as means to monitor antiplatelet therapy results, has received a lot of attention in the last decade. As detailed above, certain patient populations can be less responsive or even nonresponsive to P2Y₁₂ inhibitors (mainly to clopidogrel). In such patients, platelet function assays have been extensively investigated. The main goal was to tailor drug dosing to therapeutic response and therefore prevent MACE. Several platelet function tests are available on the market, each with their own advantages and disadvantages [69].

Light transmission aggregometry (LTA) is considered the gold-standard platelet function test. Initial studies showed a good correlation between the residual platelet activity while on clopidogrel and MACE. LTA measures the response of platelets to ADP in platelet-rich plasma. However, it is a method that is labor intensive and operator dependent, and results may not be consistent between laboratories. These limitations led to development of newer tests [32, 70–72] (Table 2).

The VerifyNow P2Y₁₂ assay (Accumetrics, San Diego, CA, USA) is a fast, standardized point-of-care platelet test, which measures the platelet-induced aggregation by ADP as an increase in light transmittance in whole blood. The assay contains ADP that induces platelet activation and PGE1 that improves the specificity of detecting P2Y₁₂ receptor inhibition. Light transmittance increases due to the fact that activated platelets bind fibrinogen-coated beads. The instrument measures this change in the optical signal and reports results in P2Y₁₂ Reaction Units (PRUs). A higher PRU reflects greater ADP-mediated platelet reactivity [70]. Studies have shown increased ischemic event rates and suboptimal platelet inhibition with VerifyNow results reported as PRU > 240 [32, 73, 74].

The vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay represents a highly specific platelet function test. This test measures the inhibition of VASP phosphorylation by ADP, mediated by the P2Y₁₂ receptor. Citrated blood is incubated with either prostaglandin E1 (PGE1) or PGE1 and ADP, followed by immunolabeling with CD61 platelet specific antibody and a VASP-P monoclonal antibody or a negative isotopic control antibody.

The platelet reactivity index (PRI) recorded is determined according to a standardized flow cytometric assay [70, 71]. PRI > 50% by VASP analysis is currently the accepted evidence of HTPR [75].

Multiple electrode platelet aggregometry (MEA) is based on impedance aggregometry and measures platelet function in diluted whole blood. Compared to LTA, centrifugation is not necessary and the results can be obtained in approximately 10 minutes. The adhesion of activated platelets to the electrodes leads to an increase of impedance, which is detected for each sensor unit separately and transformed to aggregation units (AU) [70, 72]. The cutoff for HTPR using MEA is 47 AU [76].

The INNOVANCE PFA P2Y from the PFA-100 system (Siemens, Marburg, Germany) is a rapid and easy test which uses PGE1 as the AC activator. The presence of the platelet activator and the high shear rates, under standardized conditions, lead to platelet adhesion, activation, and aggregation resulting in the formation of a platelet plug. The device measures the time necessary for a platelet plug to be formed expressed as closure time. A closure time less than 106 s was proposed a measure of clopidogrel resistance in one study [77].

Impact-R (DiaMed, Cressier, Switzerland) measures platelet adhesion and aggregation under high shear conditions [75].

Plateletworks (Helena Laboratories, Beaumont, TX, USA) is another point-of-care monitor of platelet count and function using whole blood. The test is based on platelet aggregation in the presence of a platelet agonist. In patients without platelet dysfunction, the presence of ADP reduces the platelet count to approximately zero, due to the aggregation of most platelets. In contrast, in the presence of platelet inhibition by P2Y₁₂ antagonists, not all the platelets aggregate reducing the difference between the initial platelet count and the postagonist count. The ratio between the aggregated platelets in the agonist sample and the platelet count in the reference tube x 100% is used as the degree of platelet aggregation [75, 78].

Several studies correlated the results of platelet function tests with the rate of MACE, the most comprehensive one being the POPULAR study (Do Platelet Function Assays Predict Clinical Outcome in Clopidogrel-Pretreated Patients Undergoing Elective PCI). This was a prospective, observational single-center study of 1069 patients undergoing coronary stenting that were treated with clopidogrel. In this trial, the residual platelet function measured by LTA, VerifyNow, VASP, Plateletworks, INNOVANCE PFA P2Y, IMPACT-R assay, and PFA-100 was used to predict MACE and ischemic stroke [79]. Only LTA, VerifyNow, and Plateletworks were significantly associated with the primary end-point. In a prospective study of 1608 patients with CAD, a low response to clopidogrel as assessed with MEA was significantly associated with an increased rate of drug eluting stent thrombosis [80]. Other studies assessing the accuracy of various platelet function tests in predicting MACE in patients on antiplatelet therapy are summarized in Table 3.

A recent prospective study suggests that a therapeutic window for platelet reactivity may be identified using the VerifyNow assay. This “therapeutic window” refers to an “ideal” level of platelet inhibition in which patients would be at a lower risk for both bleeding and ischemic events [81].

5. Clinical Applications of the P2Y Inhibitor Therapy in ACS

Dual antiplatelet therapy with aspirin and a P2Y₁₂ receptor inhibitor is a standard therapy for patients with ACS. The clinical advantages and disadvantages of prasugrel and ticagrelor over clopidogrel, as discussed below, led to updates in the ACCF/AHA recommendations [82, 83].

Clopidogrel is the most commonly used P2Y₁₂ inhibitor in the treatment of ACS. The CURRENT-OASIS 7 trial compared a standard loading dose of 300 mg clopidogrel versus a double loading dose (600 mg) in patients with ACS. When analyzing the entire cohort of patients, the primary outcomes (cardiovascular death, myocardial infarction, and stroke at 30 days), as well as the expanded secondary composite outcome that included recurrent ischemia, did not differ significantly between the two groups. However, in the subset of patients undergoing PCI, the double loading dose clopidogrel resulted in a significantly reduced rate of stent thrombosis [84].

The TRITON-TIMI 38 trial (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction) compared prasugrel (a 60 mg loading dose and a 10 mg daily maintenance dose) to clopidogrel (a 300 mg loading dose and a 75 mg daily maintenance dose) in patients with ACS who were referred for PCI. Prasugrel therapy was associated with significantly reduced rates of ischemic events (9.9% versus 12.1%, ), including stent thrombosis, but with an increased risk of major bleeding (2.4% versus 1.8%), including fatal bleeding [16].

In a new randomized, double-blinded study of patients with UA or NSTEMI not undergoing revascularization, prasugrel did not significantly reduce the frequency of death from cardiovascular causes, myocardial infarction, or stroke, as compared with clopidogrel, and similar risks of bleeding were observed [85].

A subanalysis of the TRITON-TIMI 38, including only the patients with STEMI, concluded that prasugrel was more effective than clopidogrel for prevention of ischemic events, without an apparent excess in bleeding [86].

Ticagrelor was directly compared to clopidogrel in the PLATO (platlet inhibition and patient outcomes) trial. In this multicenter, double-blind, randomized trial, ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of nonprocedure-related bleeding as compared to clopidogrel (300 to 600 mg loading dose, 75 mg daily thereafter) [87].

Cangrelor has been directly compared to clopidogrel in patients with ACS undergoing PCI in two phase II trials (CHAMPION PLATFORM and CHAMPION PCI). Cangrelor was not found to be superior to placebo as far as the composite rate of death, myocardial infarction, or ischemia-driven revascularization at 48 hours but decreased the number of in-stent thromboses at 48 h and death from any cause [88, 89].

Elinogrel was evaluated as an adjunct medication in patients receiving PCI for ACS in the ERASE-MI phase II trial, with no reported increase in adverse effect (bleeding) as compared to placebo [29].

5.1. Patients with UA/NSTEMI

The 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients with Unstable Angina/Non-ST Elevation Myocardial Infarction recommends clopidogrel or ticagrelor in patients with UA/NSTEMI at the time of presentation, regardless of whether PCI is planned or not [83].

For patients undergoing PCI, clopidogrel 600 mg, prasugrel 60 mg, or ticagrelor 180 mg should be administered ideally prior to the procedure. For these patients, clopidogrel 75 mg, prasugrel 10 mg, or ticagrelor 90 mg twice daily are recommended to be continued for 12 months regardless of whether they receive a bare metal or a drug eluting stent [83, 90].

For patients with UA/NSTEMI selected for conservative therapy, either clopidogrel or ticagrelor should be administered for 12 months [83].

The 2011 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation recommend ticagrelor (180 mg loading dose, 90 mg twice daily) for all patients at moderate-to-high risk of acute non-ST elevation coronary events or prasugrel (60 mg loading dose, 10 mg daily dose) for P2Y₁₂-inhibitor-naive patients (especially diabetics) in whom coronary anatomy is known and who are proceeding to PCI, if there is no risk of life-threatening bleeding (class IB). For patients not able to take ticagrelor or prasugrel, the ESC guidelines recommend a 300 mg loading dose of clopidogrel for patients medically treated and 600 mg if PCI is planned [91].

5.2. Patients with STEMI

The 2009 ACC/AHA Focused Update on the Guidelines for the Management of Patients with ST Elevation Myocardial Infarction recommends a loading dose of clopidogrel (300–600 mg) or prasugrel (60 mg) in patients with STEMI undergoing PCI [82]. At the time of the guidelines publication, ticagrelor had not been FDA approved. The 2012 ESC guidelines recommend prasugrel and ticagrelor (class IB) or clopidogrel (class IC) as peri-PCI therapeutic adjuncts [92].

There is evidence that even in patients presenting with STEMI, treated with fibrinolysis and not with primary PCI, clopidogrel reduces the risk of MACE [93, 94].

Tailoring the antiplatelet therapy to the results of genetic testing or platelet function testing is not routinely recommended. Current guidelines suggest that these tests should be considered only in patients with high risk of poor outcomes. When such patients are identified, changing the therapy from clopidogrel to prasugrel or ticagrelor is a class IIB recommendation [45, 90].

6. Conclusions

Dual antiplatelet therapy is the cornerstone long-term treatment for patients presenting with ACS. Premature discontinuation of antiplatelet therapy leads to dire consequences. The significant failure rate of clopidogrel therapy has led to extensive research on the pharmacogenetics of the drug as well as on the role of platelet function testing in adjusting the antiplatelet therapy. Currently, these tests are not routinely recommended. However, in high-risk patients treated with potent P2Y₁₂ inhibitors, a personalized antiplatelet therapy tailored according to the results of platelet assays may prove to be beneficial in lowering the risk of spontaneous or perioperative bleeding while not increasing the thrombosis risk. The introduction on the market of newer antiplatelet agents, like ticagrelor or prasugrel, may obviate the need for such testing. If FDA approved, the novel reversible, intravenous P2Y₁₂ inhibitors (cangrelor or elinogrel) may become potential therapeutic options especially in the perioperative and periprocedural setting where the current oral agents need to be stopped days in advance in order to prevent excessive bleeding.

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Copyright © 2013 Adriana Dana Oprea and Wanda M. Popescu. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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