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Cardiol Res Pract. 2013; 2013: 195456.
Published online 2013 February 19. doi:  10.1155/2013/195456
PMCID: PMC3590496

P2Y12 Receptor Inhibitors in Acute Coronary Syndromes: What Is New on the Horizon?


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 (TXA2), 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 [1820].

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 [2426].

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 [3640].

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].

Table 1
Studies assessing genetic polymorphism and response to clopidogrel.

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 [4648]. 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 [5659]. 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 [6063]. 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 [6466].

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, 7072] (Table 2).

Table 2
Characteristics of platelet function assays [122].

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.

Table 3
Outcome studies with different inhibition of platelet aggregation.

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 P2Y12 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%, P < 0.001), 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.


1. Cohen M. Improving long-term ACS management: is there a role for the new antiplatelets? Journal of Interventional Cardiology. 2012;25(5):425–432. [PubMed]
2. Bhatheja R, Mukherjee D. Acute Coronary syndromes: unstable angina/non-ST elevation myocardial infarction. Critical Care Clinics. 2007;23(4):709–735. [PubMed]
3. Stone GW, Aronow HD. Long-term care after percutaneous coronary intervention: focus on the role of antiplatelet therapy. Mayo Clinic Proceedings. 2006;81(5):641–652. [PubMed]
4. Gladding P, Webster M, Ormiston J, Olsen S, White H. Antiplatelet drug nonresponsiveness. American Heart Journal. 2008;155(4):591–599. [PubMed]
5. Taubert D, Kastrati A, Harlfinger S, et al. Pharmacokinetics of clopidogrel after administration of a high loading dose. Thrombosis and Haemostasis. 2004;92(2):311–316. [PubMed]
7. Hall R, Mazer CD. Antiplatelet drugs: a review of their pharmacology and management in the perioperative period. Anesthesia and Analgesia. 2011;112(2):292–318. [PubMed]
8. Hochholzer W, Trenk D, Frundi D, et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation. 2005;111(20):2560–2564. [PubMed]
9. Slugg PH, Much DR, Smith WB, Vargas R, Nichola P, Necciari J. Cirrhosis does not afffect the pharmacokinetics and pharmacodynamics of clopidogrel. Journal of Clinical Pharmacology. 2000;40(4):396–401. [PubMed]
10. Deray G, Bagnis C, Brouard R, et al. Clopidogrel activities in patients with renal function impairment. Clinical Drug Investigation. 1998;16(4):319–328. [PubMed]
11. Bhatt DL. Prasugrel in clinical practice. The New England Journal of Medicine. 2009;361(10):940–942. [PubMed]
12. Wiviott SD, Antman EM, Braunwald E. Prasugrel. Circulation. 2010;122(4):394–403. [PubMed]
13. Dobesh PP. Pharmacokinetics and pharmacodynamics of prasugrel, a thienopyridine P2Y12 inhibitor. Pharmacotherapy. 2009;29(9):1089–1102. [PubMed]
14. Martin MT, Spinler SA, Nutescu EA. Emerging antiplatelet therapies in percutaneous coronary intervention: a focus on prasugrel. Clinical Therapeutics. 2011;33(4):425–442. [PubMed]
15. Small DS, Wrishko RE, Ernest CS, et al. Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end-stage renal disease. Journal of Clinical Pharmacy and Therapeutics. 2009;34(5):585–594. [PubMed]
16. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. The New England Journal of Medicine. 2007;357(20):2001–2015. [PubMed]
17. Wrishko RE, Ernest CS, Small DS, et al. Population pharmacokinetic analyses to evaluate the influence of intrinsic and extrinsic factors on exposure of prasugrel active metabolite in TRITON-TIMI 38. Journal of Clinical Pharmacology. 2009;49(8):984–998. [PubMed]
18. Trumel C, Payrastre B, Plantavid M, et al. A key role of adenosine diphosphate in the irreversible platelet aggregation induced by the PAR1-activating peptide through the late activation of phosphoinositide 3-kinase. Blood. 1999;94(12):4156–4165. [PubMed]
19. Wihlborg AK, Wang L, Braun OO, et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24(10):1810–1815. [PubMed]
20. Nawarskas JJ, Clark SM. Ticagrelor: a novel reversible oral antiplatelet agent. Cardiology in Review. 2011;19(2):95–100. [PubMed]
21. Kowalczyk M, Banach M, Mikhailidis DP, Hannam S, Rysz J. Ticagrelor—a new platelet aggregation inhibitor in patients with acute coronary syndromes. An improvement of other inhibitors? Medical Science Monitor. 2009;15(12):MS24–MS30. [PubMed]
22. Anderson SD, Shah NK, Yim J, Epstein BJ. Efficacy and safety of ticagrelor: a reversible P2Y12 receptor antagonist. Annals of Pharmacotherapy. 2010;44(3):524–537. [PubMed]
23. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with mild hepatic impairment. Journal of Clinical Pharmacology. 2011;51(7):978–987. [PubMed]
24. Storey RF, Bliden KP, Ecob R, et al. Earlier recovery of platelet function after discontinuation of treatment with ticagrelor compared with clopidogrel in patients with high antiplatelet responses. Journal of Thrombosis and Haemostasis. 2011;9(9):1730–1737. [PubMed]
25. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009;120(25):2577–2585. [PubMed]
26. Storey RF, Husted S, Harrington RA, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. Journal of the American College of Cardiology. 2007;50(19):1852–1856. [PubMed]
27. Alexopoulos D, Galati A, Xanthopoulou I, et al. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. Journal of the American College of Cardiology. 2012;60(3):193–199. [PubMed]
28. Norgard NB. Cangrelor: a novel P2Y12 receptor antagonist. Expert Opinion on Investigational Drugs. 2009;18(8):1219–1230. [PubMed]
29. Berger JS, Roe MT, Gibson CM, et al. Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: the Early Rapid ReversAl of Platelet ThromboSis with Intravenous Elinogrel before PCI to Optimize REperfusion in Acute Myocardial Infarction (ERASE MI) American Heart Journal. 2009;158(6):998.e1–1004.e1. [PubMed]
30. Sabatine MS. Novel antiplatelet strategies in acute coronary syndromes. Cleveland Clinic Journal of Medicine. 2009;76(supplement 1):S8–S15. [PubMed]
31. Michelson AD, Cattaneo M, Eikelboom JW, et al. Aspirin resistance: position paper of the working group on aspirin resistance. Journal of Thrombosis and Haemostasis. 2005;3(6):1309–1311. [PubMed]
32. Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. Journal of the American College of Cardiology. 2010;56(12):919–933. [PubMed]
33. Santilli F, Vazzana N, Liani R, Guagnano MT, Davì G. Platelet activation in obesity and metabolic syndrome. Obesity Reviews. 2012;13(1):27–42. [PubMed]
34. Gurbel PA, Antonino MJ, Tantry US. Recent developments in clopidogrel pharmacology and their relation to clinical outcomes. Expert Opinion on Drug Metabolism and Toxicology. 2009;5(8):989–1004. [PubMed]
35. Qureshi Z, Hobson AR. Clopidogrel “resistance”: where are we now? Cardiovascular Therapeutics. 2013;31(1):3–11. [PubMed]
36. Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clinical Pharmacokinetics. 2002;41(5):343–370. [PubMed]
37. Lau WC, Waskell LA, Watkins PB, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation. 2003;107(1):32–37. [PubMed]
38. Lau WC, Gurbel PA. The drug-drug interaction between proton pump inhibitors and clopidogrel. Canadian Medical Association Journal. 2009;180(7):699–700. [PMC free article] [PubMed]
39. Abraham NS. Prescribing proton pump inhibitor and clopidogrel together: current state of recommendations. Current Opinion in Gastroenterology. 2011;27(6):558–564. [PubMed]
40. Burkard T, Kaiser CA, Brunner-La Rocca H, et al. Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial. Journal of Internal Medicine. 2012;271(3):257–263. [PubMed]
41. Cuisset T, Morange PE, Alessi MC. Recent advances in the pharmacogenetics of clopidogrel. Human Genetics. 2012;131(5):653–664. [PubMed]
42. Karaźniewicz-Łada M, Danielak D, Główka F. Genetic and non-genetic factors affecting the response to clopidogrel therapy. Expert Opinion on Pharmacotherapy. 2012;13(5):663–683. [PubMed]
43. Hulot JS, Collet JP, Silvain J, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration. A systematic meta-analysis. Journal of the American College of Cardiology. 2010;56(2):134–143. [PubMed]
44. Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. The Journal of the American Medical Association. 2010;304(16):1821–1830. [PMC free article] [PubMed]
45. Holmes DR, Dehmer GJ, Kaul S, Leifer D, O’Gara PT, Stein CM. ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American college of cardiology foundation task force on clinical expert consensus documents and the American heart association. Journal of the American College of Cardiology. 2010;56(4):321–341. [PubMed]
46. Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2c19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010;121(4):512–518. [PubMed]
47. Tiroch KA, Sibbing D, Koch W, et al. Protective effect of the CYP2C19*17 polymorphism with increased activation of clopidogrel on cardiovascular events. American Heart Journal. 2010;160(3):506–512. [PubMed]
48. Frére C, Cuisset T, Gaborit B, Alessi MC, Hulot JS. The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. Journal of Thrombosis and Haemostasis. 2009;7(8):1409–1411. [PubMed]
49. Holmes MV, Perel P, Shah T, Hingorani AD, Casas JP. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. The Journal of the American Medical Association. 2011;306(24):2704–2714. [PubMed]
50. Mega JL, Close SL, Wiviott SD, et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. The Lancet. 2010;376(9749):1312–1319. [PMC free article] [PubMed]
51. Wallentin L, James S, Storey RF, et al. 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. The Lancet. 2010;376(9749):1320–1328. [PubMed]
52. Bouman HJ, Schömig E, van Werkum JW, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nature Medicine. 2011;17(1):110–116. [PubMed]
53. Sibbing D, Koch W, Massberg S, et al. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. European Heart Journal. 2011;32(13):1605–1613. [PubMed]
54. Hulot JS, Collet JP, Cayla G, et al. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circulation: Cardiovascular Interventions. 2011;4(5):422–428. [PubMed]
55. Bonello L, Pansieri M, Mancini J, et al. High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes. Journal of the American College of Cardiology. 2011;58(5):467–473. [PubMed]
56. Farid NA, Smith RL, Gillespie TA, et al. The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metabolism and Disposition. 2007;35(7):1096–1104. [PubMed]
57. Rehmel JLF, Eckstein JA, Farid NA, et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metabolism and Disposition. 2006;34(4):600–607. [PubMed]
58. Williams ET, Jones KO, Ponsler GD, et al. The biotransformation of prasugrel, a new thienopyridine prodrug, by the human carboxylesterases 1 and 2. Drug Metabolism and Disposition. 2008;36(7):1227–1232. [PubMed]
59. Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. Journal of Thrombosis and Haemostasis. 2007;5(12):2429–2436. [PubMed]
60. Alexopoulos D, Panagiotou A, Xanthopoulou I, et al. Antiplatelet effects of prasugrel versus double clopidogrel in patients on hemodialysis and with high on-treatment platelet reactivity. Journal of Thrombosis and Haemostasis. 2011;9(12):2379–2385. [PubMed]
61. Alexopoulos D, Xanthopoulou I, Davlouros P, et al. Prasugrel overcomes high on-clopidogrel platelet reactivity in chronic coronary artery disease patients more effectively than high dose (150 mg) clopidogrel. American Heart Journal. 2011;162(4):733–739. [PubMed]
62. Alexopoulos D, Dimitropoulos G, Davlouros P, et al. Prasugrel overcomes high on-clopidogrel platelet reactivity post-stenting more effectively than high-dose (150-mg) clopidogrel: the importance of cyp2c19 (*)2 genotyping. JACC: Cardiovascular Interventions. 2011;4(4):403–410. [PubMed]
63. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. The New England Journal of Medicine. 2009;360(4):354–362. [PubMed]
64. Neubauer H, Kaiser A, Busse B, Mügge A. Identification, evaluation and treatment of prasugrel low-response after coronary stent implantation—a preliminary study. Thrombosis Research. 2010;126(5):e389–e391. [PubMed]
65. Angiolillo DJ, Badimon JJ, Saucedo JF, et al. A pharmacodynamic comparison of prasugrel versus high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy in diabetes MellitUS (OPTIMUS)-3 Trial. European Heart Journal. 2011;32(7):838–846. [PMC free article] [PubMed]
66. Alexopoulos D. Prasugrel resistance: fact or fiction. Platelets. 2012;23(2):83–90. [PubMed]
67. Xanthopoulou I, Stavrou EF, Kassimis G, Goudas P, Alexopoulos D. Resistance to high-maintenance dose of prasugrel treated by ticagrelor: a case report. Platelets. In press. [PubMed]
68. Teng R. Pharmacokinetic, pharmacodynamic and pharmacogenetic profile of the oral antiplatelet agent ticagrelor. Clinical Pharmacokinetics. 2012;51(5):305–318. [PubMed]
69. Michelson AD. Methods for the measurement of platelet function. American Journal of Cardiology. 2009;103(3, supplement):20A–26A. [PubMed]
70. Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW. Comparison of methods to evaluate clopidogrel-mediated platelet inhibition after percutaneous intervention with stent implantation. Thrombosis and Haemostasis. 2009;101(2):333–339. [PubMed]
71. Bouman HJ, Parlak E, van Werkum JW, et al. Which platelet function test is suitable to monitor clopidogrel responsiveness? A pharmacokinetic analysis on the active metabolite of clopidogrel. Journal of Thrombosis and Haemostasis. 2010;8(3):482–488. [PubMed]
72. Sibbing D, Braun S, Jawansky S, et al. Assessment of ADP-induced platelet aggregation with light transmission aggregometry and multiple electrode platelet aggregometry before and after clopidogrel treatment. Thrombosis and Haemostasis. 2008;99(1):121–126. [PubMed]
73. Price MJ, Endemann S, Gollapudi RR, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. European Heart Journal. 2008;29(8):992–1000. [PubMed]
74. Marcucci R, Gori AM, Paniccia R, et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay a 12-month follow-up. Circulation. 2009;119(2):237–242. [PubMed]
75. Sharma RK, Voelker DJ, Sharma R, Reddy HK, Dod H, Marsh JD. Evolving role of platelet function testing in coronary artery interventions. Vascular Health and Risk Management. 2012;8:65–75. [PMC free article] [PubMed]
76. Codner P, Vaduganathan M, Rechavia E, et al. Clopidogrel response up to six months after acute myocardial infarction. American Journal of Cardiology. 2012;110(3):321–325. [PubMed]
77. Jang J, Lim J, Chang K, et al. A comparison of INNOVANCE PFA P2Y and VerifyNow P2Y12 assay for the assessment of clopidogrel resistance in patients undergoing percutaneous coronary intervention. Journal of Clinical Laboratory Analysis. 2012;26(4):262–266. [PubMed]
78. Gibbs NM. Point-of-care assessment of antiplatelet agents in the perioperative period: a review. Anaesthesia and Intensive Care. 2009;37(3):354–369. [PubMed]
79. Breet NJ, van Werkum JW, Bouman HJ, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. The Journal of the American Medical Association. 2010;303(8):754–762. [PubMed]
80. Sibbing D, Braun S, Morath T, et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. Journal of the American College of Cardiology. 2009;53(10):849–856. [PubMed]
81. Mangiacapra F, Patti G, Barbato E, et al. A therapeutic window for platelet reactivity for patients undergoing elective percutaneous coronary intervention: results of the ARMYDA-PROVE (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity for Outcome Validation Effort) study. JACC: Cardiovascular Interventions. 2012;5(3):281–289. [PubMed]
82. Kushner FG, Hand M, Smith SC, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with st-elevation myocardial infarction (Updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation. 2009;120(22):2271–2306. [PubMed]
83. Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-st-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation. 2012;126(7):875–910. [PubMed]
84. Mehta SR, Tanguay JF, Eikelboom JW, 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. The Lancet. 2010;376(9748):1233–1243. [PubMed]
85. Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. The New England Journal of Medicine. 2012;367(14):1297–1309. [PubMed]
86. Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. The Lancet. 2009;373(9665):723–731. [PubMed]
87. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. The New England Journal of Medicine. 2009;361(11):1045–1057. [PubMed]
88. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. The New England Journal of Medicine. 2009;361(24):2318–2329. [PubMed]
89. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. The New England Journal of Medicine. 2009;361(24):2330–2341. [PubMed]
90. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124:e574–e651. [PubMed]
91. Hamm CW, Bassand JP, Agewall S, et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC) European Heart Journal. 2011;32(23):2999–3054. [PubMed]
92. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. European Heart Journal. 2012;33(20):2569–2619. [PubMed]
93. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. The Lancet. 2005;366(9497):1607–1621. [PubMed]
94. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. The New England Journal of Medicine. 2005;352(12):1179–1189. [PubMed]
95. Barker CM, Murray SS, Teirstein PS, Kandzari DE, Topol EJ, Price MJ. Pilot study of the antiplatelet effect of increased clopidogrel maintenance dosing and its relationship to CYP2C19 genotype in patients with high on-treatment reactivity. JACC: Cardiovascular Interventions. 2010;3(10):1001–1007. [PubMed]
96. Bonello L, Paganelli F, Arpin-Bornet M, et al. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. Journal of Thrombosis and Haemostasis. 2007;5(8):1630–1636. [PubMed]
97. Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM, Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. The British Medical Journal. 2011;343d4588 [PMC free article] [PubMed]
98. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. The Lancet. 2009;373(9660):309–317. [PubMed]
99. Collet JP, Hulot JS, Anzaha G, et al. High doses of clopidogrel to overcome genetic resistance: the randomized crossover clovis-2 (clopidogrel and response variability investigation study 2) JACC: Cardiovascular Interventions. 2011;4(4):392–402. [PubMed]
100. Fontana P, Hulot JS, de Moerloose P, Gaussem P. Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects. Journal of Thrombosis and Haemostasis. 2007;5(10):2153–2155. [PubMed]
101. Geisler T, Schaeffeler E, Dippon J, et al. CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics. 2008;9(9):1251–1259. [PubMed]
102. Giusti B, Gori AM, Marcucci R, et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. American Journal of Cardiology. 2009;103(6):806–811. [PubMed]
103. Giusti B, Gori AM, Marcucci R, et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10+12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenetics and Genomics. 2007;17(12):1057–1064. [PubMed]
104. Gladding P, Webster M, Zeng I, et al. The pharmacogenetics and pharmacodynamics of clopidogrel response. An analysis from the princ (plavix response in coronary intervention) trial. JACC: Cardiovascular Interventions. 2008;1(6):620–627. [PubMed]
105. Harmsze A, van Werkum JW, Bouman HJ, et al. Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation. Pharmacogenetics and Genomics. 2010;20(1):18–25. [PubMed]
106. Hochholzer W, Trenk D, Fromm MF, et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. Journal of the American College of Cardiology. 2010;55(22):2427–2434. [PubMed]
107. Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006;108(7):2244–2247. [PubMed]
108. Jinnai T, Horiuchi H, Makiyama T, et al. Impact of CYP2C19 polymorphisms on the antiplatelet effect of clopidogrel in an actual clinical setting in Japan. Circulation Journal. 2009;73(8):1498–1503. [PubMed]
109. Kim IS, Jeong YH, Park Y, et al. Platelet inhibition by adjunctive cilostazol versus high maintenance-dose clopidogrel in patients with acute myocardial infarction according to cytochrome P450 2C19 genotype. JACC: Cardiovascular Interventions. 2011;4(4):381–391. [PubMed]
110. Lee JM, Park S, Shin DJ, et al. Relation of genetic polymorphisms in the cytochrome P450 gene with clopidogrel resistance after drug-eluting stent implantation in Koreans. American Journal of Cardiology. 2009;104(1):46–51. [PubMed]
111. Maeda A, Ando H, Asai T, et al. Differential impacts of CYP2C19 gene polymorphisms on the antiplatelet effects of clopidogrel and ticlopidine. Clinical Pharmacology and Therapeutics. 2011;89(2):229–233. [PubMed]
112. Oh IY, Park KW, Kang SH, et al. Association of cytochrome P450 2C19*2 polymorphism with clopidogrel response variability and cardiovascular events in Koreans treated with drug-eluting stents. Heart. 2012;98(2):139–144. [PubMed]
113. Park KJ, Chung HS, Kim SR, Kim HJ, Han JY, Lee SY. Clinical, pharmacokinetic, and pharmacogenetic determinants of clopidogrel resistance in Korean patients with acute coronary syndrome. Korean Journal of Laboratory Medicine. 2011;31(2):91–94. [PMC free article] [PubMed]
114. Park KW, Park JJ, Lee SP, et al. Cilostazol attenuates on-treatment platelet reactivity in patients with CYP2C19 loss of function alleles receiving dual antiplatelet therapy: a genetic substudy of the CILON-T randomised controlled trial. Heart. 2011;97(8):641–647. [PubMed]
115. Pettersen AAR, Arnesen H, Opstad TB, Seljeflot I. The influence of CYP 2C19*2 polymorphism on platelet function testing during single antiplatelet treatment with clopidogrel. Thrombosis Journal. 2011;9, article 4 [PMC free article] [PubMed]
116. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. The New England Journal of Medicine. 2009;360(4):363–375. [PubMed]
117. Shuldiner AR, O’Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. The Journal of the American Medical Association. 2009;302(8):849–858. [PMC free article] [PubMed]
118. Umemura K, Furuta T, Kondo K. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects. Journal of Thrombosis and Haemostasis. 2008;6(8):1439–1441. [PubMed]
119. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26(8):1895–1900. [PubMed]
120. Suh JW, Koo BK, Zhang SY, et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. Canadian Medical Association Journal. 2006;174(12):1715–1722. [PMC free article] [PubMed]
121. Smith SMG, Judge HM, Peters G, et al. Common sequence variations in the P2Y12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy. Platelets. 2006;17(4):250–258. [PubMed]
122. Oestreich JH, Smyth SS, Campbell CL. Platelet function analysis: at the edge of meaning. Thrombosis and Haemostasis. 2009;101(2):217–219. [PMC free article] [PubMed]
123. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004;109(25):3171–3175. [PubMed]
124. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING study. Journal of the American College of Cardiology. 2005;46(10):1820–1826. [PubMed]
125. Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention. Is the current antiplatelet therapy adequate? Journal of the American College of Cardiology. 2007;49(6):657–666. [PubMed]
126. Migliorini A, Valenti R, Marcucci R, et al. High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease. Circulation. 2009;120(22):2214–2221. [PubMed]
127. El Ghannudi S, Ohlmann P, Meyer N, et al. Impact of P2Y12 inhibition by clopidogrel on cardiovascular mortality in unselected patients treated by percutaneous coronary angioplasty: a prospective registry. JACC: Cardiovascular Interventions. 2010;3(6):648–656. [PubMed]

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