malek la 2010 cardiol clopidogrel p81

8/8/2019 Malek LA 2010 Cardiol Clopidogrel p81

1/7

Fax +41 61 306 12 34

E-Mail [email protected]

Original Research

Cardiology 2010;117:8187DOI:10.1159/000320093

Cytochrome P450 2C19 Polymorphism,Suboptimal Reperfusion and All-Cause Mortalityin Patients with Acute Myocardial Infarction

ukasz A. Maek a Jakub Przyuskia Mateusz piewak b Mariusz Kopotowskia Grayna Kostrzewac Mariusz Kruk b Rafa Poskic Adam Witkowskia Witold Ruyod

Departments of a

Interventional Cardiology and Angiology, andb

Coronary Artery Disease and Structural HeartDiseases, Institute of Cardiology,cDepartment of Medical Genetics, Centre of Biostructure, Medical University of Warsaw, and d Institute of Cardiology, Warsaw, Poland

up (11.5%). Four-year mortality tended to be higher in car-riers of CYP2C19 * 2 (17.9%) versus non-carriers (9.8%; p =0.09), but the only independent predictors of death were age(HR = 2.0, 95% CI = 1.42.8, p = 0.0001) and suboptimal re-perfusion (HR = 3.6, 95% CI 1.58.8, p = 0.004).Conclusions: The CYP2C19 * 2 allele is an independent predictor of subop-timal reperfusion in patients with AMI undergoing PCI withstenting after pretreatment with clopidogrel and may in-crease the risk of all-cause mortality.

Copyright 2010 S. Karger AG, Basel

Introduction

Clopidogrel, along with aspirin, is a cornerstone of an-tiplatelet therapy in the setting of acute myocardial in-farction (AMI) [1] . According to current guidelines, pa-tients with AMI ! 75 years of age without contraindi-cations should receive a 300600 mg loading dose of clopidogrel as soon as possible after the first medical con-tact [2]. Administrating clopidogrel prior to stenting inAMI has been shown to improve reperfusion and out-comes in comparison to no administration prior to stent

Key WordsAcute myocardial infarction Antiplatelet agents Cytochrome P450 Mortality Polymorphism Reperfusion

AbstractObjectives: To determine whether the 681 G1 A (*2) poly-morphism of cytochrome P450( CYP2C19 ) is related to subop-timal reperfusion and mortality in patients with acute myo-cardial infarction (AMI) pretreated with clopidogrel.Meth-ods: The study included 276 consecutive patients with AMIin whom percutaneous coronary intervention (PCI) withstenting was attempted. Four-year follow-up for all-causemortality was obtained. Results: There were 15 failed proce-dures (5.4%). In the remaining 261 patients, suboptimal re-perfusion (post-PCI TIMI flow! 3) was observed in 12.6% of the cases. There were 56 carriers (50 heterozygous and 6 ho-mozygous) of CYP2C19 * 2 . The prevalence of carriers in pa-tients with suboptimal flow was 39.4% in comparison to18.9% in the other patients (p = 0.01). Independent predic-tors of suboptimal reperfusion were initial TIMI flow 1(OR = 5.9, 95% CI 2.216.2, p = 0.001) andCYP2C19 * 2 (OR = 2.9,95% CI 1.36.6, p = 0.01). Thirty patients died during follow-

Received: June 1, 2010Accepted after revision: July 7, 2010Published online: October 6, 2010

ukasz A. Maek, MD, PhDDepartment of Interventional Cardiology and Angiology Institute of Cardiology, Alpejska 42

PL04-628 Warszawa (Poland)Tel. +48 22 343 4269, Fax +48 22 613 3819, E-Mail lmalek @ ikard.pl

2010 S. Karger AG, Basel00086312/10/11720081$26.00/0

Accessible online at:www.karger.com/crd
http://dx.doi.org/10.1159%2F000320093http://dx.doi.org/10.1159%2F000320093


2/7

Maek et al.Cardiology 2010;117:818782

implantation [3] . Therefore, various factors affecting bio-availability of clopidogrel such as less effective hepaticmetabolism to its active metabolite may potentially leadto suboptimal reperfusion and influence prognosis. Theplatelet response to clopidogrel and prognosis in patientswith AMI have recently been demonstrated to be signifi-cantly worse in carriers of the genetic variant 681 G 1 A(* 2) of cytochrome P450 (CYP2C19) which takes part inbiotransformation of clopidogrel [47] . This has beenmainly attributed to the higher incidence of stent throm-bosis [8, 9]. None of the studies has analyzed the influ-ence of G681A CYP2C19 polymorphism on the effect of mechanical reperfusion. It seems plausible that G681ACYP2C19 polymorphism affecting the bioavailability of clopidogrel is related to suboptimal reperfusion in AMI,which in turn is one of the main risk factors of adverseoutcomes, as demonstrated in many clinical trials andregistries [1014]. We decided to test this hypothesis inpatients with AMI who received a pre-hospital 300- or600-mg loading dose of clopidogrel.

Materials and Methods

The study included 276 consecutive patients (aged 60 8 11years, 67% male) with AMI (80% with ST-elevation myocardialinfarction and 20% with non-ST-elevation myocardial infarction)admitted to a single center in 2005 in whom percutaneous coro-nary intervention (PCI) with stenting was attempted. All patientsreceived a pre-hospital 300-mg oral loading dose of aspirin fol-lowed by daily regimen of 75 mg and a 300- or 600-mg loading

dose of clopidogrel followed by 75 mg daily for at least 1 month.Exclusion criteria included lack of pretreatment with aspirin and/or clopidogrel, participation in clinical trials on other oral P2Y12inhibitors and the use of thrombectomy during the index proce-dure. We used the contemporary definition of AMI, with the fol-lowing criteria satisfying the diagnosis: elevated markers of myo-cardial necrosis (troponin or creatine kinase) with ischemic symp-toms or development of pathologic Q waves in the ECG or ECGchanges indicative of ischemia [15]. Flows in the infarct-relatedartery before and at the end of PCI were assessed by means of theThrombolysis In Myocardial Infarction (TIMI) flow grading sys-tem, as described previously [16]. Suboptimal reperfusion was de-fined as post-PCI TIMI flow ! 3 assessed independently by 2 ex-perienced interventional cardiologists blinded to the findings of

genetic testing and outcomes. The data on the following risk fac-tors of suboptimal reperfusion were included: age, diabetes, timefrom the onset of pain to PCI, initial TIMI flow grade ^ 1, andheart failure at admission (Killip scale 6 2) [12]. A failed procedurewas defined as inability to cross the occlusion with a guidewire orto inflate a balloon due to technical difficulties related to proce-dures in very tortuous, severely calcified or small arteries. Theclinical endpoint of the study was 4-year all-cause mortality as-sessed retrospectively for all patients with the use of the GeneralElectronic Population Death Registry System of the Polish Minis-

try of Internal Affairs and Administration. An informed consentwas obtained from each participating patient. The study was ap-proved by the local ethics committee. The investigation con-formed to the principles outlined in the Declaration of Helsinki.

Genetic AnalysisGenetic testing was performed on blood samples taken at the

first blood draw after admission to hospital. PCR for the CYP2C19 polymorphism typing was performed in a total volume of 5 lcontaining: 200 ng of DNA, 1.5 pmol of each primer (forwardprimer 5 -CAG AGC TTG GCA TAT TGT ATC-3 and reverseprimer 5 -TAG TAA ACA CAA AAC TAG TCA ATG-3 ), 100 M of each dNTPs, 0.5 l of 10! reaction buffer, 0.3 l of magnesiumchloride and 1 unit of Taq DNA polymerase (Fermentas, Lithua-nia). PCR processing consisted of an initia l denaturation for 5 minat 95 C, followed by 30 cycles of 30 s at 95 C, 60 s at 52 C, and60 s at 72 C, and by a f inal extension for 10 min at 72 C. The PCRproduct was then digested with SmaI for 4 h in 30 C, yielding 2fragments of 210 bp and 113 bp in the case of A allele. For G allele,a single band of 323 bp was observed.

Statistical AnalysisAll results for continuous variables were expressed as means

8 SD for variables with normal distribution or as medians withIQR for variables without normal distribution. The 2 test or Fish-ers exact test was used to analyze the relations between categori-cal variables, when appropriate. Students t test or Mann-Whitney rank sum test was applied to compare any continuous variableswith or without normal distribution, respectively. CYP2C19poly-morphism was tested for deviation from Hardy-Weinberg equi-librium with the use of the 2 test. Multivariable stepwise logis-tic regression which included risk factors of post-PCI TIMI flow! 3 with p ^ 0.01 in univariate analysis (initial TIMI flow andCYP2C19polymorphism) was used to find independent variablesof suboptimal reperfusion. The C-statistic for the model was0.870. The occurrence of all-cause mortality in carriers and non-

carriers of the CYP2C19* 2 variant and in patients with post-PCITIMI flow = 3 or TIMI flow ! 3 was compared with the use of Kaplan-Meier curves and log-rank test. A univariate analysis wasapplied to compare baseline demographic, clinical and angio-graphic characteristics and medical treatment between patientswith and without the clinical endpoint. Additionally, a multivari-able Cox-proportional hazards model was developed to evaluatethe relationship between the occurrence of all-cause mortality and baseline or angiographic parameters with p ^ 0.01 in univariate analysis (age, TIMI flow post-PCI, CYP2C19 polymor-phism). The C-statistic for the model was 0.881. The results arereported with 95% CI. All tests were 2-sided with the significancelevel of p ! 0.05. All statistical analyses were performed with Med-Calc statistical software 10.0.2.0 (MedCalc, Mariakerke, Bel-

gium).

Results

The procedure failed in 15 cases (5.4%). The remaining261 participants in the study who were included in thefinal analysis underwent re-opening of the infarct-relatedartery and stent placement. Suboptimal reperfusion was


3/7

CYP2C19 Polymorphism, TIMI Flow andMortality in AMI

Cardiology 2010;117:8187 83

observed in 33 cases (12.6%). The median loading dose of clopidogrel was 300 mg (300 mg in 74%, and 600 mg in26%).

There were 6 homozygous carriers of the CYP2C19* 2 allele (2.3%), 50 heterozygous carriers (19.2%) and 205non-carriers of the CYP2C19* 2 allele (78.5%). The ob-served genotype distribution did not deviate from theHardy-Weinberg equilibrium. There were no significantdifferences in baseline or angiographic characteristicsas well as medications before and after admission be-tween the CYP2C19* 2 allele carriers and non-carriers.

For the purpose of the study, patients were dividedinto carriers of the CYP2C19* 2 allele (homozygous andheterozygous) and non-carriers of the CYP2C19* 2 allele.

Suboptimal ReperfusionThe relation between established risk factors of subop-

timal reperfusion and post-PCI TIMI flow is presented intable 1. Suboptimal reperfusion occurred more often inolder patients, in those with infarct-related artery ob-struction at the first contrast injection, and in patientswith CYP2C19* 2 allele. There was also a trend towards ahigher incidence of post-PCI TIMI ! 3 flow in patientswith diabetes. However, the only independent predictorsof suboptimal reperfusion were infarct-related artery obstruction at the first contrast injection (OR = 5.9, 95%CI 2.216.2, p = 0.001) and CYP2C19* 2 genetic variant(OR = 2.9, 95% CI 1.36.6, p = 0.01).

Clinical OutcomeThirty patients died during the follow-up (11.5%), in-

cluding 6 in-hospital deaths (2.2%). Those who died wereolder, more likely to have a history of myocardial infarc-tion, multivessel coronary artery disease (table 2) and alower post-PCI TIMI f low (fig. 1a). There was also a trend

Table 1. Established risk factors of suboptimal reperfusion according to TIMI flow classification in the group studied

Risk factor TIMI = 3(n = 228, 87.4%)

TIMI


4/7


towards higher mortality rates in patients with hyperlipid-emia, peripheral artery disease, history of heart failure andBMI ! 25 (table 2). Overall, there was a high rate of pre-scription of in hospital/on discharge drugs known to im-prove survival. However, patients who died were less likely to receive statins, beta-blockers and angiotensin-convert-ing enzyme inhibitors or angiotensin receptor blockers,but more of them were on diuretic agents ( table 3).

Four-year mortality rates tended to be higher in carri-ers of the CYP2C19* 2 variant (17.9%) in comparison tonon-carriers (9.8%; HR 1.9, 95% CI 0.94.0, p = 0.09;

fig. 1b). The only independent predictors of death in themultivariable analysis were age (for every 10 years HR =2.0, 95% CI = 1.42.8, p = 0.0001) and post-PCI TIMIflow ! 3 (HR = 3.6, 95% CI 1.58.8, p = 0.004).

Discussion

Previous studies with short- and long-term follow-upsafter PCI in AMI have demonstrated that post-PCI TIMIflow is independently related to prognosis [1014] . Pa-

Table 2. Baseline and angiographic characteristics according to outcome

Parameter Patients withoutoutcome event(n = 231, 88.5%)

Patients whodied(n = 30, 11.5%)

p

Baseline

Age, years 59.2 (11) 69.7 (10.1)


5/7


Cardiology 2010;117:8187 85

tients with suboptimal reperfusion usually have infarct of a larger extent and are more likely to undergo adverse left ventricular remodeling and develop chronic heart fail-ure. One of the key modifiable factors responsible for theoptimal angiographic effect of mechanical reperfusion isadequate platelet inhibition at the time of a PCI proce-dure performed during AMI. This is obtained with thepre-hospital administration of oral antiplatelet drugssuch as aspirin and clopidogrel. The concentration of clopidogrel active metabolite in plasma depends on thetime and dose of the drug administered as well as on theefficacy of clopidogrel hepatic metabolism. The onset of desirable platelet inhibition ranges from 6 h after admin-istration of a 300-mg loading dose to 2 h after adminis-tering a 600-mg loading dose [17] . High loading doses of clopidogrel related to a faster onset of action have beendemonstrated to be related to a better TIMI flow andmore favorable prognosis after PCI in AMI [18] . There-fore, it seemed plausible that patients with inadequate he-patic metabolism of clopidogrel to its active metaboliteare more likely to present with a suboptimal TIMI flowpost-PCI. This hypothesis was confirmed in our study.We demonstrated that the effect of mechanical reperfu-sion was worse in carriers of the CYP2C19* 2 genetic vari-ant in comparison to other patients with AMI who hadbeen pre-treated with a 300- or 600-mg loading dose of clopidogrel.

Several recent studies and their meta-analysis haveshown that carriers of the reduced-function CYP2C19 * 2

allele affecting clopidogrel biotransformation are relat-ed to a greater than 50% increased risk for adverse car-diovascular events and a nearly 3-fold increased riskfor stent thrombosis in the setting of pretreatmentwith clopidogrel (300600 mg) [58, 19, 20] . However,none of those studies analyzed the relation between theCYP2C19 * 2 allele and impaired myocardial perfusion.Moreover, those studies did not include a long-term fol-low-up and therefore were less likely to observe the effectof CYP2C19 polymorphism on mortality related to pro-gression into chronic heart failure in patients with sub-optimal reperfusion after PCI in AMI. In the univari-ate analysis, we were able to demonstrate that carryingCYP2C19 * 2 allele is related to a trend towards increasedall-cause mortality. However, we cannot fully excludethe possibility that this finding is simply a result of thesmall sample size. Therefore it should be seen as hypoth-esis-generating and definitely requires validation onlarge clinical sample.

Although our study is mainly mechanistic withoutdirect clinical implications it provides clues for largerclinical trials using the information on the CYP2C19 polymorphism to individualize antiplatelet treatment inAMI. Screening for CYP2C19 * 2 variant identifies 2030% of patients who are significantly less likely to beprotected by clopidogrel and who may potentially ben-efit from other strategies of antiplatelet treatment [21] .Those include switching to other antiplatelet drugs thatare not affected by the CYP2C19 polymorphism and

Table 3. Medications after admission according to outcome

Medication Patients withoutoutcome event(n = 231, 88.5%)

Patients whodied(n = 30, 11.5%)

p

Gp IIb/IIIa inhibitors 88 (38) 16 (53) 0.16

Aspirin 225 (97.5) 28 (93) 0.23Clopidogrel 231 (100) 30 (100) 1.00300-mg loading dose 168 25 0.27600-mg loading dose 63 5

Statin 216 (93.5) 25 (83) 0.03Beta-blocker 218 (94) 25 (83) 0.04ACE inhibitor or ARB 218 (94) 25 (83) 0.04Calcium-channel blocker 40 (17.5) 2 (7) 0.19Long-acting nitrate 19 (8) 0 0.15Diuretic agent 35 (15) 14 (47) 0.0001Aldosterone antagonist 39 (17) 10 (33) 0.06Warfarin 10 (4) 1 (3) 1.00

Data are n (%). ACE = Angiotensin-converting enzyme; ARB = angiotensin receptor blocker.


6/7


may be used instead. No influence of CYP2C19 poly-morphism was found for prasugrel, which is a newP2Y12 receptor inhibitor predominantly metabolizedby esterases and not by cytochrome P450 enzymes [22] .The reduced-function variant does not affect the bio-chemical properties of other new P2Y12 receptor inhib-itors which do not require metabolism to become active,such as ticagrelor (awaiting approval for clinical use) orelinogrel (now in the phase IIb of clinical testing) [23,24]. Another strategy that may be potentially useful incarriers of CYP2C19 variant is the periprocedural ad-ministration of glycoprotein IIb/IIIa inhibitors, as dem-onstrated in patients undergoing elective PCI who werepoor responders to aspirin and/or clopidogrel and whobenefited from being administered a high-dose bolus of tirofiban [25] . It should be noted, however, that we didnot include the use of GP IIb/IIIa inhibitors as a factorknown to improve reperfusion, because in our groupthose drugs were mainly administered as a bail-outtherapy. In fact, patients with post-PCI TIMI ! 3 weremore likely to receive GP IIb/IIIa inhibitors than thosewith TIMI = 3 (data not presented).

Our study has some limitations. First of all, we haveincluded all patients with AMI instead of pure ST-eleva-tion myocardial infarction patients, there was a variabil-ity of loading dose of clopidogrel and we assessed all-cause mortality instead of cardiac mortality only. How-ever, these kinds of patient characteristics are similar tosome other studies on the role of CYP2C19 polymor-phism in AMI [6, 7] , allowing direct comparisons. Sec-ondly, it is possible that polymorphisms of CYP2C19may also have affected biological response to other cardiovas-cular agents, which in turn may have affected survival.

Furthermore, in our study, the patients who died less fre-quently received some of the drugs known to improvesurvival, such as statins, beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptorblockers, which might have influenced the results. How-ever, the differences in the use of those drugs between thegroups studied were relatively small and therefore we de-cided not to include the data on those medications in themultivariable analysis. It should be also mentioned thatthe frequency of GP IIb/IIIa inhibitor administration inour study was lower than observed in current practice.Finally, although we believe that our study is hypothesis-generating it is mainly based on associations between ge-netic variant and outcomes and not on true analyses of cause and effect.

Conclusions

The CYP2C19* 2 allele is an independent predictor of suboptimal reperfusion in patients with AMI undergoingPCI with stenting after being pre-treated with clopidogreland may increase the risk for all-cause mortality.

Acknowledgment

The study was supported by a scientific grant from the Insti-tute of Cardiology, Warsaw (2.44/VII/08).

Disclosure Statement

The authors declare no conflicts of interest.

References

1 Michelson AD: Antiplatelet therapies for thetreatment of cardiovascular disease. Nat Rev Drug Discov 2010; 9: 154169.

2 Kushner FG, Hand M, Smith SC Jr, King SB3rd, Anderson JL, Antman EM, Bailey SR,

Bates ER, Blankenship JC, Casey DE Jr,Green LA, Hochman JS, Jacobs AK, Krum-holz HM, Morrison DA, Ornato JP, PearleDL, Peterson ED, Sloan MA, Whitlow PL,Williams DO: 2009 focused updates: ACC/AHA guidelines for the management of pa-tients with ST-elevation myocardial infarc-tion (updating the 2004 guideline and 2007focused update) and ACC/AHA/SCAIguidelines on percutaneous coronary intervention (updating the 2005 guideline and

2007 focused update) a report of the Ameri-can College of Cardiology Foundation/American Heart Association Task Force onPractice Guidelines. J Am Coll Cardiol 2009;54: 22052241.

3 Rabbani LE, Iyengar S, Dangas GD, GrinesCL, Cox DA, Garcia E, Tcheng JE, Griffin JJ,Guagliumi G, Stuckey T, Turco M, Stant J,Fahy M, Lansky AJ, Mehran R, Stone GW: Im-pact of thienopyridine administration priorto primary stenting in acute myocardial in-farction. J Interv Cardiol 2009; 22: 378384.

4 Frere C, Cuisset T, Morange PE, Quilici J,Camoin-Jau L, Saut N, Faille D, Lambert M,Juhan-Vague I, Bonnet JL, Alessi MC: Effectof cytochrome p450 polymorphisms on

platelet reactivity after treatment with clo-pidogrel in acute coronary syndrome. Am JCardiol 2008; 101: 10881093.

5 Malek LA, Kisiel B, Spiewak M, GrabowskiM, Filipiak KJ, Kostrzewa G, Huczek Z, Plos-

ki R, Opolski G: Coexisting polymorphismsof P2Y12 and CYP2C19 genes as a risk factorfor persistent platelet activation with clo-pidogrel. Circ J 2008; 72: 11651169.

6 Collet JP, Hulot JS, Pena A, Villard E, EsteveJB, Silvain J, Payot L, Brugier D, Cayla G,Beygui F, Bensimon G, Funck-Brentano C,Montalescot G: Cytochrome P450 2C19polymorphism in young patients treatedwith clopidogrel after myocardial infarction:a cohort study. Lancet 2009; 373: 309317.


7/7


Cardiology 2010;117:8187 87

7 Simon T, Verstuyft C, Mary-Krause M,Quteineh L, Drouet E, Mneveau N, Steg PG,Ferrires J, Danchin N, Becquemont L;French Registry of Acute ST-Elevation andNon-ST-Elevation Myocardial Infarction(FAST-MI) Investigators: Genetic determi-nants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363

375.8 Giusti B, Gori AM, Marcucci R, Saracini C,Sestini I, Paniccia R, Buonamici P, Antoni-ucci D, Abbate R, Gensini GF: Relation of cy-tochrome P450 2C19 loss-of-function poly-morphism to occurrence of drug-elutingcoronary stent thrombosis. Am J Cardiol2009; 103: 806811.

9 Sibbing D, Stegherr J, Latz W, Koch W, Me-hill i J, Drrler K, Morath T, Schmig A, Kas-trati A, von Beckerath N: Cytochrome P4502C19 loss-of-function polymorphism andstent thrombosis following percutaneouscoronary intervention. Eur Heart J 2009; 30:916922.

10 Kawamoto T, Yoshida K, Akasaka T, Hozumi

T, Takagi T, Kaji S, Ueda Y: Can coronary blood flow velocity pattern after primary percutaneous transluminal coronary angi-ography predict recovery of regional left ven-tricular function in patients with acute myo-cardial infarction? Ci rculation 1999; 100:339345.

11 Morishima I, Sone T, Okumura K, Tsuboi H,Kondo J, Mukawa H, Matsui H, Toki Y, Ito T,Hayakawa T: Angiographic no-reflow phe-nomenon as a predictor of adverse long-termoutcome in patients treated with percutane-ous transluminal coronary angioplasty forfirst acute myocardial infarction. J Am CollCardiol 2000; 36: 12021209.

12 Mehta RH, Harjai KJ, Cox D, Stone GW, Bro-

die B, Boura J, ONeill W, Grines CL; Pri-mary Angioplasty in Myocardial Infarction(PAMI) Investigators: Clinical and angio-graphic correlates and outcomes of subopti-mal coronary flow in patients with acutemyocardial infarction undergoing primary percutaneous coronary intervention. J AmColl Cardiol 2003; 42: 17391746.

13 De Luca G, vant Hof AW, de Boer MJ,Hoorntje JC, Gosselink AT, Dambrink JH,Ottervanger JP, Zijlstra F, Suryapranata H:Impaired myocardial perfusion is a majorexplanation of the poor outcome observed inpatients undergoing primary angioplasty forST-segment-elevation myocardial infarctionand signs of heart failure. Circulation 2004;

109: 958961.14 Bolognese L, Carrabba N, Parodi G, SantoroGM, Buonamici P, Cerisano G, AntoniucciD: Impact of microvascular dysfunction onleft ventricular remodelling and long-termclinical outcome after primary coronary an-gioplasty for acute myocardial infarction.Circulation 2004; 109: 11211126.

15 The Joint European Society of Cardiology/Amercian College of Cardiology Commit-tee: Myocardial infarction redefined a con-sensus document of The Joint European So-ciety of Cardiology/American College of Cardiology Committee for the redefinitionof myocardial infarction. Eur Heart J 2000;21: 15021513.

16 Chesebro JH, Knatterud G, Roberts R, BorerJ, Cohen LS, Dalen J, Dodge HT, Francis CK,Hillis D, Ludbrook P, et al: Thrombolysis inMyocardial Infarction (TIMI) Trial, Phase I.A comparison between intravenous tissueplasminogen activator and intravenousstreptokinase: clinical findings through hos-pital discharge. Circulation 1987; 76: 142154.

17 Montalescot G, Sideris G, Meuleman C, Bal-dit-Sollier C, Lel louche N, Steg PG, Slama M,Milleron O, Collet JP, Henry P, Beygui F,Drouet L; ALBION Trial Investigators: Arandomized comparison of high clopidogrelloading doses in patients with non-ST-seg-ment elevation acute coronary syndromes:

the ALBION (Assessment of the Best Load-ing Dose of Clopidogrel to Blunt Platelet Ac-tivation, Inflammation and Ongoing Necro-sis) tria l. J Am Coll Cardiol 2006; 48: 931938.

18 Fefer P, Hod H, Hammerman H, Segev A,Beinart R, Boyko V, Behar S, Matetzky S:Usefulness of pretreatment with high-doseclopidogrel in patients undergoing primary angioplasty for ST-elevation myocardial in-farction. Am J Cardiol 2009; 104: 514518.

19 Mega JL, Close SL, Wiviott SD, Shen L,Hockett RD, Brandt JT, Walker JR, AntmanEM, Macias W, Braunwald E, Sabatine MS:Cytochrome p-450 polymorphisms and re-sponse to clopidogrel. N Engl J Med 2009;360: 354362.

20 Mega JL: CYP2C19 and clinical outcomeswith clopidogrel: a collaborative meta-anal-

ysis. American Heart Association Confer-ence, Orlando, 2009.21 Sweeny JM, Gorog DA, Fuster V: Antiplatelet

drug resistance. Part 1: mechanisms andclinical measurements. Nat Rev Cardiol2009; 6: 27382.5.

22 Mega JL, Close SL, Wiviott SD, Shen L,Hockett RD, Brandt JT, Walker JR, AntmanEM, Macias WL, Braunwald E, Sabatine MS:Cytochrome P450 genetic polymorphismsand the response to prasugrel: relationship topharmacokinetic, pharmacodynamic, andclinical outcomes. Circulation 2009; 119:25532560.

23 Wallentin L, Becker RC, Budaj A, CannonCP, Emanuelsson H, Held C, Horrow J, Hus-

ted S, James S, Katus H, Mahaffey KW, Scir-ica BM, Skene A, Steg PG, Storey RF, Har-rington RA; PLATO Investigators, Freij A,Thorsn M: Ticagrelor versus clopidogrel inpatients with acute coronary syndromes. NEngl J Med 2009; 361: 10451057.

24 Gurbel PA, Blinden KP, Antonino MJ, Ste-phens G, Gretler DD, Jurek MM, Pakyz RE,Shuldiner AR, Conley PB, Tantry US: The ef-fect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the rela-tion to CYP2C19 * 2 genotype: first experi-ence in patients. J Thromb Haemost 2010; 8:4353.

25 Campo G, Valgimigli M, Frangione A, Luc-carelli S, Cangiano E, Cavazza C, Fileti L,

Ferrari R; 3T/2R Investigators: Evaluation of platelet inhibition by tirofiban in patientsstratified according to aspirin and clopido-grel responsiveness: the 3T/2R (Tailoringtreatment with tirofiban in patients showingresistance to aspirin and/or resistance toclopidogrel). J Am Coll Cardiol 2010; 55: 255256.

malek la 2010 cardiol clopidogrel p81

Documents