P2Y12 inhibitors adjunctive to primary PCI therapy in STEMI: Fighting against the activated platelets

International Journal of Cardiology 163 (2013) 249–255

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Review

P2Y12 inhibitors adjunctive to primary PCI therapy in STEMI: Fighting against the activated platelets Dimitrios Alexopoulos ⁎ Department of Cardiology, Patras University Hospital, Rion 26500, Patras, Greece

a r t i c l e

i n f o

Article history: Received 17 August 2011 Received in revised form 24 October 2011 Accepted 26 November 2011 Available online 20 December 2011 Keywords: Platelets Clopidogrel Prasugrel Ticagrelor Primary PCI STEMI

a b s t r a c t Primary percutaneous coronary intervention (PPCI) is the reperfusion method of choice in ST elevation myocardial infarction (STEMI). However, STEMI represents a highly pre-thrombotic state with platelets being greatly activated, so that an effective adjunctive to PPCI antiplatelet treatment with P2Y12 inhibitors is crucial in order to achieve an optimal reperfusion result. Clopidogrel has been extensively used in clinical practice, although it may not be the ideal agent for this condition due to its rather slow, weak and variable platelet inhibition action. Newer, more potent P2Y12 inhibitors like prasugrel and ticagrelor have been introduced recently and present a particularly favorable action profile for the highly prethrombotic milieu of STEMI. The efficacy and safety issues with the P2Y12 inhibitor use in STEMI and the possible role of phenotyping and/ or genotyping for appropriate agent selection are discussed and several clinically important unanswered questions are raised. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction A timely performed primary percutaneous coronary intervention (PPCI) is the reperfusion method of choice in patients with ST elevation myocardial infarction (STEMI) as it offers the more effective restoration of vessel patency, less re-occlusion rate, improved residual left ventricular function, and better clinical outcome compared to the pharmacological reperfusion therapy. However, STEMI represents a highly pre-thrombotic state with the platelets being greatly activated, so that an effective adjunctive antiplatelet treatment with adequate platelet inhibition is crucial in order to achieve an optimal reperfusion result. The focus of this review is the highly prethrombotic milieu in STEMI patients undergoing PPCI and the role of P2Y12 inhibitors in overcoming platelet hyperactivity in these patients.

2. The importance of activated platelets It is well recognized that platelets play a key role in arterial thrombosis and in acute ischemic coronary syndromes [1]. The sequence of events leading to thrombosis involves the platelet adhesion to the vessel wall, platelet activation and surface fibrinogen binding site exposure. Platelets form microaggregates via fibrinogen bridging, degranulate and the α-granule glycoprotein Pselectin is translocated to the activated platelet surface with subsequent consolidation of the thrombotic plug [2]. As platelet ⁎ Tel/fax: + 30 2610992941. E-mail address: [email protected]. 0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.11.088

turnover is increased in STEMI, newly formed platelets with transient expression of inducible COX-2 enzyme may be released into the circulation, leading to thromboxane A2 production in amounts sufficient to initiate platelet aggregation [3]. The increased platelet volume seen in STEMI has been linked to impaired reperfusion, more frequent no reflow phenomenon and increased mortality in patients treated with PPCI [4]. Similarly, an inadequate myocardial blush, ST-segment resolution and lack of early and late left ventricular functional recovery have been linked with high platelet reactivity [5]. The enhanced platelet reactivity observed in STEMI compared to stable coronary disease is predictive of both the extent of myocardial damage as measured by plasma levels of CKMB and TnT and the clinical outcome in patients undergoing PPCI [6–8]. Platelets comprise one of the main constituents of thrombus aspirated from the coronary arteries of STEMI patients [9]. The composition of aspirated thrombi seems to be influenced by the ischemic time with platelet content decreasing with increasing ischemic time. ‘Fresh’ thrombi have the highest proportion of platelets, an observation with a possibly direct impact on the efficacy of drugs or devices used for coronary reperfusion particularly with PPCI [10]. These platelet-rich thrombi are small and very likely to embolize distally. Besides their critical contribution to microcirculatory thrombotic occlusion, platelets seem to significantly contribute to the microcirculatory dysfunction seen in STEMI. Platelets may evoke vasospasm through the release of serotonin, thromboxane A2, and free radical resulting in impaired myocardial perfusion and ischemia of the area at risk and may advance reperfusion injury [11,12]. Platelet may also interact with other morphotic elements of the blood and the

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macroscopically intact endothelium in the coronary microcirculation distally to the site of initial thrombus formation [13,14]. Finally, an enhanced sympathoadrenal activation has been suggested to play a role in thrombosis, while an increased concentration of circulating catecholamines may contribute to the increased platelet aggregation seen in STEMI [15,16]. The activated platelet in STEMI and how this influences adverse clinical outcomes are shown in Fig. 1. 3. Antiplatelet treatment in STEMI Following above, oral antiplatelet therapy has emerged as an integral component in the treatment of all STEMI patients with the P2Y12 inhibitors – in addition to aspirin – playing a central role in the effort to achieve urgently an effective platelet inhibition. However, in the setting of STEMI there are specific environment and conditions that can affect antiplatelet drug absorption, metabolism and subsequent pharmacokinetics and pharmacodynamics. Clopidogrel is the most commonly used platelet P2Y12 inhibitor used in PPCI. However, a variable response to clopidogrel has been described with many patients exhibiting high on-treatment platelet reactivity. This high reactivity particularly post PCI and in acute coronary syndrome (ACS) patients has been accompanied by an increased risk of adverse events during short-term and long-term follow up [17,18]. For the different methods of platelet function assessment, criteria for an inadequate response to clopidogrel predicting adverse events have been established using ROC analyses [19]. In the setting of STEMI, enhanced residual platelet reactivity despite treatment with clopidogrel in addition to aspirin has been described for at least 48 h following PPCI [20]. In a study by Matetzky et al., in 60 PPCI patients an inadequate platelet inhibition at day 6 was followed by an increased rate of 6 month cardiovascular events [21]. A lower clopidogrel efficacy as assessed by the VASP index seems to accompany MI patients with severe hemodynamic instability, probably due to splachnic and liver hypoperfusion and catecholamine use [22]. A 300 to 600 mg loading dose of clopidogrel is suggested by the 2009 ACC/ AHA guidelines focused update as soon as possible in patients with STEMI (Level of Evidence: C), while 600 mg loading dose is proposed by the 2010 ESC/EACTS guidelines on myocardial revascularization (Level of Evidence: C) [23,24]. However, few data exists about the onset of action and magnitude of platelet inhibition after a 600 mg loading dose of clopidogrel in PPCI patients. Studies showing a greater inhibition with faster onset of action with a 600-mg compared with a 300-mg clopidogrel loading dose have been performed mainly in stable or NSTE MI/ACS patients [25,26]. A strong association between the peak plasma concentration of unchanged clopidogrel and the active metabolite with the degree of inhibition of platelet aggregation has been described in STEMI patients. Clopidogrel bioavailability after a 600 mg loading dose is significantly impaired in STEMI patients as

compared to healthy volunteers, with the absolute plasma concentrations of unchanged clopidogrel (Cmax, AUC) being significantly lower in STEMI patients [27]. This has been attributed to a variably impaired intestinal absorption in STEMI patients [27,28]. A decreased cardiac output, an increased sympathetic drive, vasoconstriction of peripheral arteries and selective shunting with decreased gastro-intestinal perfusion have been implicated, as well as ANP release and subsequently reduced gut permeability and intestinal motility [29]. Genetic factors like the presence of the loss-of-function allele ABCB1 affecting clopidogrel absorption have been linked with higher rates of recurrent cardiovascular events in MI [30]. The above described high pretreatment platelet reactivity in STEMI patients seems to seriously affect the rapidity of the time-dependent inhibition of platelets after clopidogrel loading. Concerning studies with clinical outcome, the observational (though pre-specified) analysis of the Harmonizing Outcomes with RevascularIZatiON and stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, in 3602 STEMI patients undergoing PPCI stratified according to thienopyridine loading dose showed that a 600-mg compared with a 300-mg loading dose of clopidogrel was associated with lower 30-day rates of mortality, reinfarction, and stent thrombosis, without increased major bleeding [31]. In the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS CURRENT-OASIS 7 trial, comparing double clopidogrel (600 mg loading dose/150 mg QD for 7 days then 75 mg/ day) or standard (300 mg loading dose/75 mg QD) dose regimen administered on top of aspirin there were 6346 presented with STEMI mostly treated with PPCI. By 30 days, there was a 37% significant reduction in the risk of MI in patients treated with double-dose clopidogrel [1.9 vs 1.2%; hazard ratio 0.63 (95% CI 0.41–0.94)], but no mortality benefit was observed [32]. In the Korea Acute Myocardial Infarction registry involving 1447 and 1217 PPCI patients receiving 300 mg and 600 mg loading dose of clopidogrel, no differences in efficacy and safety between the two groups were found [33]. Thus, no single study until now has shown a decrease in mortality with clopidogrel when used in the setting of PPCI. Even after a 600-mg clopidogrel loading dose, the full antiplatelet effect of the drug is achieved only after 2 h, and with wide individual variability [34]. Since clopidogrel barely has time to be effective by the time PPCI is performed, in many cases it has been given after the procedure is completed. As a consequence, a window of time remains during which there is a reduced level of effectiveness even in responders. Notably, the value of clopidogrel pretreatment for PCI outside a STEMI has been questioned [35,36], while evidence supporting the early clopidogrel's role in patients managed with PPCI exists only in the form of data from registries and subgroup analyses. In a meta-analysis of 38 treatment groups, including 8429 patients, initial patency was higher in treatment groups in which patients

Fig. 1. Activation of platelets in STEMI and mechanisms influencing adverse clinical outcomes.

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received pretreatment with clopidogrel (34.3%; 95% CI, 32.9 to 35.8) compared with those in which patients did not receive clopidogrel before initial coronary angiography (25.8%; 95% CI, 24.5 to 27.1) and was followed by an improved outcome [37]. In a prospective registry involving 292 PPCI patients clopidogrel pretreatment in the emergency department or coronary care unit resulted in an improved myocardial perfusion and a significant reduction in the incidence of reinfarction at 30 days, compared to clopidogrel post PCI [38], while in another registry of 2014 PPCI patients pretreated with 600 mg of clopidogrel, longer duration of pretreatment was associated with significantly improved patency and with less reinfarction/ischemia, including stent thrombosis, without increased bleeding or differences in mortality [39]. The Clopidogrel Administered Prehospital to Improve Primary PCI in Patients with Acute Myocardial Infarction (CIPAMI) randomized study analyzes the effect of an early administration of 600 mg clopidogrel on the flow-rates in 654 STEMI patients. In the comparator group clopidogrel is not allowed before initial angiography. The results are expected shortly [40]. At the present time, no randomized controlled data are available with regard to the impact of pretreatment with clopidogrel before PCI in patients with STEMI. Data with clopidogrel use in STEMI and particularly PPCI patients are summarized in Table 1. 4. Newer agents — need for more potent platelet inhibition Prasugrel, like clopidogrel, is a P2Y12 receptor inhibitor, but because of metabolic differences in the generation of the active metabolite, this inhibition occurs more rapidly, consistently, and to a greater extent than standard or even high dose of clopidogrel [41–43]. Specifically, the 60 mg loading dose of prasugrel achieves faster, more consistent, and greater inhibition of platelet aggregation than does 600 mg of clopidogrel, with a significant effect seen 30 min after administration of prasugrel when no effect is detectable with clopidogrel [41,42]. In the SWAP (SWitching Anti Platelet) study, in patients on maintenance clopidogrel therapy after an acute coronary syndrome event, switching from clopidogrel to prasugrel was associated with a further reduction in platelet function by 1 week using prasugrel maintenance dose or within 2 h with the administration

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of a prasugrel loading dose [44]. The pharmacokinetic and pharmacodynamic advantages of prasugrel over clopidogrel are of particular interest when pretreatment is not possible, and fast inhibition of platelet aggregation as in the case of PPCI is desirable. In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial, prasugrel led to a reduction in major adverse cardiovascular events, but at the cost of increased bleeding [45]. In addition, post hoc analyses identified that patients with a history of stroke/transient ischemic attack had net harm, while patients older than 75 years or weighing less than 60 kg had no net benefit from prasugrel treatment. The US Food and Drug Administration has approved prasugrel but incorporated the above subgroup findings into its labeling by citing a contraindication against prasugrel use in patients with a history of stroke/transient ischemic attack or active pathological bleeding [46]. In the TRITON-TIMI 38 trial, among the 2438 patients enrolled with STEMI within 12 h and undergoing PPCI the primary endpoint of cardiovascular death, nonfatal MI or nonfatal stroke at 15 months occurred in 11.6% in the clopidogrel and in 10.2% in the prasugrel group, HR 0.87 (0.68–1.11), p = 0.2662. A prespecified analysis showed a 45% reduction in stent thrombosis with prasugrel, p = 0.0476. No difference in TIMI major bleeding unrelated to CABG surgery between the two groups was found [47]. Ticagrelor is the first reversibly binding oral P2Y12 receptor antagonist that provides faster, greater, and more consistent inhibition of platelet aggregation than clopidogrel [48,49]. In patients with stable coronary artery disease who had received a 300-mg clopidogrel LD, ticagrelor therapy was associated with greater platelet inhibition compared with clopidogrel treatment in both clopidogrel responders and nonresponders. During switching of therapies, ticagrelor produced a rapid enhancement in platelet inhibition in both clopidogrel responders and nonresponders, whereas changing to clopidogrel therapy was associated with a reduction in platelet inhibition [50]. In the Study of Platelet Inhibition and Patient Outcomes (PLATO) trial, 7544 acute coronary syndrome patients with ST elevation or left bundle-branch block (72% with PPCI) were allocated to either ticagrelor 180-mg loading dose followed by 90 mg twice daily or clopidogrel 300-mg loading dose (although 35.6% of patients received a

Table 1 STEMI data and clopidogrel. Study

Type

Patients

Clopidogrel dose

Results

Althoff et al. [20]

Pharmacodynamic

Matetzky et al. [21]

Pharmacodynamic

36 STEMI 30 elective PCI 60

300 mg or 600 mg or no LD if on chronic treatment 300 mg LD/75 mg MD

Heestermans et al. [27]

Pharmacodynamic/pharmacokinetic

600 mg

HORIZONS-AMI [31]

Randomized

11 PPCI 10 healthy volunteers 3602 PPCI stratified by clopidogrel loading dose

CURRENT-OASIS 7 [32]

Randomized

6346 STEMI, mostly PPCI

600 mg LD/150 mg MD vs 300 mg LD/75 mg MD

Choi et al. [33]

Registry

Vlaar et al. [37]

Meta-analysis

300 mg LD 600 mg LD 300 mg to 600 mg LD

Lev et al. [38]

Registry

1447 1217 8429 pretreatment vs no pretreatment 292 pretreatment vs no pretreatment

Larson et al. [39]

Registry

2014

600 mg LD

Enhanced residual platelet reactivity at 48 h in STEMI patients Inadequate platelet inhibition at day 6, predicting rate of events at 6 months Bioavailability significantly impaired in PPCI patients 600 mg 300 mg 30 day mortality 1.9% vs 3.1%, p = 0.03 Reinfarction 1.3% vs 2.3%, p = 0.02 Stent thrombosis 1.7% vs 2.8%, p = 0.04 30 day MI Double clopidogrel 1.2% Standard clopidogrel 1.9% No mortality benefit No difference in efficacy and safety between 300 mg and 600 mg groups Initial patency 34.3% vs 25.8% Improved outcome with pretreatment Improved myocardial perfusion, reduction of 30 days reinfarction with pretreatment Longer duration of pretreatment: improved patency, less reinfarction/ischemia, stent thrombosis, no increased bleeding or differences in mortality

600 mg vs 300 mg

300 mg to 600 mg LD

STEMI = ST elevation myocardial infarction, PCI = percutaneous coronary intervention, PPCI = primary percutaneous coronary intervention, LD = loading dose, and MD = maintenance dose.

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clopidogrel loading dose of at least 600 mg) followed by 75 mg daily for 6 to 12 months. The primary end point (myocardial infarction, stroke, or cardiovascular death) was reduced with ticagrelor compared to clopidogrel (9.4% versus 10.8%; HR = 0.87, p = 0.07). The risk of stroke was higher with ticagrelor (1.7% versus 1.0%; HR = 1.63, p = 0.02), but the rate of major bleeding was similar between the two groups [51]. The ACC/AHA guidelines propose that prasugrel 60 mg should be given as soon as possible for PPCI (class IB). However, they do not endorse explicitly one of the thienopyridines over the other. In contrast, the ESC/EACTS guidelines on myocardial revascularization suggest prasugrel or ticagrelor (IB for both) and clopidogrel 600 mg loading dose, followed by 75 mg daily, to be used primarily if these more effective ADP receptor blockers are contraindicated or unavailable [24]. Of note, the recently published 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-tohigh risk of ischaemic events (e.g. elevated troponins), regardless of initial treatment strategy and including those pre-treated with clopidogrel. Similarly, prasugrel (60-mg loading dose, 10-mg daily dose) is recommended for P2Y12-inhibitor-naïve patients (especially diabetics) in whom coronary anatomy is known and who are proceeding to PCI unless there is a high risk of life threatening bleeding or other contraindications. A 600-mg loading dose of clopidogrel is recommended for patients scheduled for an invasive strategy only when ticagrelor or prasugrel is not an option [52]. The comparative outcome results of the TRITON and PLATO studies in patients with PPCI are presented in Table 2. Of note that TRITON-TIMI 38 was a trial in patients with STEMI or UA/SNTEMI and planned PCI – performed in 99% of the cases – who had no pretreatment with clopidogrel and the study drug was given post angiography. The exemption was for patients with STEMI treated with PPCI in whom randomization could take place without knowledge of coronary anatomy, just after informed consent was obtained and the study drug was started earlier potentially in the emergency department. In contrast, PLATO was a trial in NSTE-ACS and STEMI patients with the intention to perform PPCI was planned, in clopidogrel treated or naïve, starting in the emergency department, and so the full spectrum of acute coronary syndrome patients started the study drug very early. PCI was performed overall in 61% of the PLATO patients. Interestingly, in the PPCI patients, the median time from onset of pain to randomization was 3.8 h and 5.3 h in the TRITON-TIMI 38 and PLATO respectively. Concerning the type of stents used in the two trials, in the TRITON-TIMI 38 PPCI patients drug-eluting stent (only) was used in 27%, while in PLATO 20.9% of STEMI patients received at least one drug-eluting stent. The introduction of intravenous agents antagonizing the P2Y12 receptor with a rapid onset of action created expectations, as their Table 2 Comparative outcome results between TRITONa and PLATOb studies in STEMI/PPCI patients.

Death/MI/stroke TRITON PLATO Stent thrombosis TRITON PLATO Bleeding (TIMI major unrelated to CABG) TRITON PLATO a

Clopidogrel

Prasugrel

Ticagrelor

11.6% 10.8%

10.2% (p = 0.27) N/A

N/A 9.4% (p = 0.07)

2.7% 2.4%

1.5% (p = 0.0476) N/A

N/A 1.6% (p = 0.03)

1.9% 2.2%

3.1% (p = 0.11) N/A

N/A 2.5% (p = 0.6)

Data from 2438 PPCI treated patients [Ref. 44]. b Data from 7544 patients with ST elevation or left-bundle branch block of whom 5439 (72.1%) were treated with PPCI [Ref. 48].

properties might be particularly attractive in the acute setting of PPCI. Cangrelor was tested in the Comparison of IV Cangrelor to Clopidogrel in coronary stenting CHAMPION PCI study in 8716 patients administered 30 min before PCI and was found to be not superior to 600 mg of clopidogrel in reducing the composite end point of death from any cause, MI, or ischemia-driven revascularization at 48 h [53]. In the Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition CHAMPION PLATFORM, 5362 patients who had not been treated with clopidogrel received either cangrelor or placebo at the time of PCI, followed by 600 mg of clopidogrel. The primary composite endpoint of death, MI, or ischemia-driven revascularization at 48 h did not differ between cangrelor and placebo, although the prespecified secondary end points of stent thrombosis and death were lower in the cangrelor group, with no significant increase in the rate of transfusion [54]. Elinogrel is another direct-acting, reversible, intravenous P2Y12 receptor antagonist that was tested versus placebo in the ERASE-MI study in STEMI patients before PPCI. The study was terminated prematurely and did not show any differences in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction frame count or ST resolution between the two groups [55]. Advantages and disadvantages of clopidogrel, prasugrel, ticagrelor, cangrelor and elinogrel for use in PPCI are shown in Table 3. A meta-analysis of randomized trials that compare the new P2Y12 inhibitors with clopidogrel to determine whether they improve the clinical outcome was recently presented [56]. In 13,028 STEMI patients from the TRITON, the ERASE MI, the PLATO and the CHAMPION a pooled analysis revealed a significant decrease in death, major adverse events and stent thrombosis and an increase in stroke with the new agents, with similar major or minor bleedings. The analysis restricted to PPCI (after exclusion of the secondary PCI of the TRITON STEMI study), showed a significant decrease in death (OR 0.78, p = 0.004), major adverse events (OR 0.84, p = 0.006), and stent thrombosis (OR 0.67, p b 0.001) with the new agents, without an increase in major or minor bleeding (OR = 1). However, stroke was increased (OR 1.48, p = 0.02). Overall, it appears that the new P2Y12 inhibitors have a risk/benefit ratio particularly favorable in PPCI patients. A preponderant benefit was observed in PPCI and might be explained by the greatest thrombotic situation encountered and the need for urgent strong platelet inhibition.

5. Role of phenotyping and genotyping to guide antiplatelet treatment in STEMI In recent years many studies have focused on patient responsiveness to antiplatelet therapies with P2Y12 antagonists. This has been made possible by the development of several methods of measuring platelet function in various clinical and research situations. Although the optimal level of ex vivo platelet inhibition to have an impact on clinical outcomes in vivo is unclear, rapid, easily used, point-of care system of platelet reactivity determination might have a valuable

Table 3 Advantages/disadvantages of P2Y12 inhibitors used in PPCI.

Rapidity of action Potency Variable response Genetic polymorphism influence Clinical experience Side effects a

Clopidogrel

Prasugrel

Ticagrelor

Cangrelora

Elinogrel

++ + ++++ ++++

++++ +++ − −

++++ +++ − −

++++ +++ − −

++++ +++ − −

++++ Rare

++ Rare

− More common

− Rare

− More common

Data for cangrelor are not from PPCI patients.

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role in the assessment of in STEMI patients and theoretically – as data are still missing – in guiding antiplatelet choice. It is well known that patients treated with clopidogrel carrying a reduced-function CYP2C19 allele have significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did non-carriers. In both however the TRITON and PLATO genetic sub-studies, the beneficial effect of prasugrel and ticagrelor respectively was present irrespective of the presence of a dysfunctional CYP2C19 allele [57,58]. It is also possible that the enhanced efficacy of newer agents is mostly or only confined to those individuals with clopidogrel-resistant alleles. These observations may be particularly important in the case of STEMI. A schematic summarizing the differences in metabolism among clopidogrel, prasugrel and ticagrelor, explaining the variability of response to clopidogrel and the possible role of phenotyping and genotyping in STEMI patients is depicted in Fig. 2. Needless to say that for genotyping to have a useful role in the choice of antiplatelet agent in STEMI, the method used should be easy to perform, rapid, accurate and pointof-care. The Genotyping Infar ct Patients to Adjust and Normalize Thienopyridine Treatment (GIANT, ClinicalTrials.gov Identifier: NCT01134380) study in PPCI patients is in progress and tries to evaluate whether adjustment of treatment based on genetics (increase clopidogrel, switch to prasugrel or switch to clopidogrel) results in different outcomes between carriers and noncarriers. A general drawback of early oral antiplatelet treatment – particularly with prasugrel – before PPCI is the increased risk of major bleeding if urgent coronary artery bypass graft surgery is required. The rates of “immediate” coronary artery bypass surgery, however, are very low (3%) even in patients with STEMI who present to coronary artery bypass surgery-capable hospitals [59]. Another safety concern in STEMI patients is the effect – if any – of the frequent concomitant use of IIb/IIIa inhibitors with the more potent P2Y12 inhibitors. This, however, was not the case in the TRITON study as the risk of Thrombolysis in Myocardial Infarction major or minor bleeding with prasugrel versus clopidogrel was not significantly different in patients who were or were not treated with GP IIb/IIIa inhibitor [60].

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With the available data, the preferred antiplatelet therapy in STEMI patients undergoing PPCI should be prasugrel or ticagrelor — if there are no contraindications for their use. These agents should be given for 15 or 12 months respectively, according to the TRITON-TIMI 38 and PLATO trial duration of treatment. With no doubt, there are several unanswered questions with clinical relevance for the PPCI patient management with P2Y12 inhibitors. 1) It is necessary to reload with clopidogrel patients that are on chronic clopidogrel treatment and suffer a STEMI or switching to prasugrel/ticagrelor is preferable? 2) Is prasugrel or ticagrelor superior to 600-mg clopidogrel loading dose if the agents are administered very early i.e. in the ambulance or emergency room? 3) Is it useful to identify the possible clopidogrel resistance or the genotype early in PPCI and accordingly modify antiplatelet treatment? Will this practice affect outcome? 4) If the newer, more potent P2Y12 inhibitors have been given early, is the addition of intravenous glycoprotein IIb/IIIa inhibitors of any help? 5) If there is a relative contraindication or specific condition accompanied by increased bleeding risk i.e. low body weight, age > 75 years, are a shorter duration of treatment (1 week? 1 month ?) or a lower dose an alternative solution?

6. Conclusions A prethrombotic milieu caused by the highly activated platelet is characteristic of STEMI. The optimal PPCI results necessitate a rapid and efficient platelet inhibition. The most extensively so far used clopidogrel seems not to be the ideal agent due to its rather slow action and a variable response which is occasionally caused by genetic variability. The newer P2Y12 inhibitors (prasugrel, ticagrelor) in their initial phase III studies appear more efficacious than clopidogrel. Remarkably, no increase in bleeding was observed with these agents in the setting of STEMI. In the future, the application of phenotyping and/or genotyping may facilitate the selection of the antiplatelet agent with the best efficacy/safety balance in order to optimize PPCI results.

Fig. 2. Differences in metabolism among clopidogrel, prasugrel and ticagrelor explaining the variability of response to clopidogrel and the possible role of phenotyping and genotyping in STEMI patients.

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Conflict of interest The author has received lecturing honoraria from Astra-Zeneca, Sanofi-Aventis and Eli-Lilly.

[25]

[26]

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