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Clopidogrel Resistance Clopidogrel (a platelet P2Y 12 receptor blocker) is used with aspirin in patients who undergo coronary artery stenting or who have an acute coronary syndrome (ACS) to reduce the risk of subsequent cardiovascular events such as stent thrombosis or recurrent ACS.

Clopidogrel resistance

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Page 1: Clopidogrel resistance

Clopidogrel Resistance

Clopidogrel (a platelet P2Y12 receptor blocker) is used with aspirin in patients who undergo coronary artery stenting or who have an acute coronary syndrome (ACS) to reduce the risk of subsequent cardiovascular events such as stent thrombosis or recurrent ACS.

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Platelet activation and aggregation play crucial pathophysiological roles in the development of ischemic events during and after acute coronary syndromes (ACS) and percutaneous coronary interventions (PCIs)

Adenosine diphosphate (ADP) is a major secondary agonist released from the dense granules of platelets activated by primary agonists.

N Engl J Med. 350 2004:277-280.

The ADP-P2Y12 receptor interaction plays a central role in the sustained activation of glycoprotein (GP) IIb/IIIa receptors leading to stable platelet-rich thrombus generation at the site of vessel wall injury.

J Clin Invest. 113 2004:340-345.

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Central role of adenosine diphosphate P2Y12 receptor interaction in platelet activation and aggregation during occurrence of ischemic events and stent thrombosis.

After plaque rupture, tissue factor and collagen are exposed leading to platelet activation. Three important pathways (thrombin-PAR-1 receptor, thromboxane A2-TP receptor, and adenosine diphosphate P2Y12 receptor) amplify the response. The adenosine diphosphate P2Y12 interaction plays a central role.

J Am Coll Cardiol. 2010;56(12

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Stimulation of the P2Y12 receptor sustains the activation of the GP IIb/IIIa and GP-Ia/Ii a receptors, leading to stabilization of platelet aggregates.

Thromb Haemost 2001;86:222–32.

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P2Y12 Receptor Antagonism

The P2Y12 receptor is the target of several antagonists that have proven therapeutic value for the prevention of cardiovascularevents.

Ticlopidine, clopidogrel, prasugrel, and ticagrelor are approved oral antagonists, whereas the intravenous compound cangrelor and the orally active BX-667,which both reversibly block the P2Y12 receptor, are in clinical development.

Ticlopidine is only infrequently prescribed due to its unfavorable safety profile, where as clopidogrel is the most widely used antiplatelet agent.

Prasugrel and ticagrelor represent novel P2Y12 receptor inhibitors.

J A C C V O L . 6 , N O . 1 1 , 2 0 1 3

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Clopidogrel Clopidogrel, a second-generation, thienopyridinetype, irreversible inhibitor of the P2Y12 receptor, is a prodrug,requiring complex enteric and hepatic metabolism by the cytochrome P450 (CYP) enzymes (Fig. 2).

After absorption, the majority of clopidogrel (up to 85-90%) is metabolized by carboxyesterase-1 to an inactive carboxylicacid derivative.

The hepatic conversion of clopidogrel to its active metabolite, is a 2-step process via the formation of 2-oxo-clopidogrel. In these 2 steps, CYP2C19 appears to have the most prominent role, with lesser involvement from CYP2B6, CYP1A2, CYP3A/A5, and CYP2C9. J A C C : V O L . 6 , N O . 1 1 , 2 0 1 3

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The maximum mean inhibition of ADP induced platelet aggregation of 40% to 60% is achieved within 2 to 6 h in healthy individuals and in patients with stable angina after administration of a loading dose of 600 mg of clopidogrel, which reflects the extensive hepatic metabolism of the prodrug.

Br J Clin Pharmacol 2007;63: 421–30

Active metabolite of clopidorel, irreversibly inhibits the P2Y12 receptor, is a cornerstone of oral antiplatelet therapy in the secondary prevention of coronary artery disease and in the immediate treatment of ACS and PCI.

A significant reduction in ischemic complications in a wide range of coronary artery disease patients has been demonstrated in major randomized controlled trials by adding clopidogrel to aspirin treatment.

Annu Rev Pharmacol Toxicol. 46 2006:277-300.

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Dual antiplatelet therapy combining aspirin and clopidogrel is the standard care for patients who have acute coronary syndromes (ACS) or are undergoing percutaneous coronary intervention (PCI), according to the current ACC/AHA 2013 guidelines.

O’Gara et al 2013 ACCF/AHA STEMI Guideline Executive Summary

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However, despite the administration of dual antiplatelet therapy, some patients do develop recurrent cardiovascular ischemic events, with stent thrombosis being the most catastrophic. Hellenic J Cardiol. 2010; 51: 83-86.

Patients who display little attenuation of platelet reactivity under clopidogrel therapy are recognized as low- or non-responders, or clopidogrel-resistant. Hellenic J Cardiol. 2007; 48: 352-363

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Definitions of Clopidogrel Non Responsiveness/ Low Responsiveness/Resistance

Low responsiveness is defined by evidence of persistent activity of the specific target of an antiplatelet agent, such as evidence of P2Y12 activation after clopidogrel treatment. Low responsiveness, which is determinedby a specific laboratory assay, may be associatedwith adverse clinical outcome. (Am J Cardiol 2009;104:227–233

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There are multiple definitions of clopidogrel non-responsiveness 

1.Gurbel et al: Change in inhibition of platelet aggregation (IPA) of < 10% using light transmittance aggregometry (LTA)

2.Angiolillo et al: IPA < 40% by LTA 

3.Lau et al: Platelet aggregation >= to 70% by LTA 

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Clopidogrel non-responsiveness is reported to vary between 4% and 44% among different populations. It should be kept in mind that HPR is dependent on the cut-off value used for each assay: the higher the cut-off, the lower the percent of patients with HPR. Thromb Res. 2007; 120: 311-321.

PREVALENCE

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Clopidogrel Resistance: World Experience

Investigators n Patients Clopidogrel Dose Resistance (mg Load)

1. Jaremo et al 18 PCI 300 28% (J Invest Med. 2002;252:233)

2. Gurbel et al 92 PCI 300 31-35% (Circulation 2003;107:2908)

3. Muller et al. 105 PCI 600 5-11% (Thromb Haemost. 2003;89:783)

4. Mobley et al 50 PCI 300 30% (Am J Cardiol. 2004;93:456)

5. Lepantalo et al. 50 PCI 300 40% (Eur Heart J. 2004;25-476)

6. Angiolillo et al. 48 PCI 300 44% (Thromb Res. 2005;115:101)7. Matetzky et al. 60 PCI 300 25% (Circulation 2004;109:3171.)8. Dzieweierz 31 PCI 300 23% (Kardiol Pol. 2005 ;62:108)9. Gurbel et al. 192 PCI 300/600 8-32% (J Am Coll Cardiol. 2005;45:1392)10. Lev Et al. 150 PCI 300 24% (J Am Coll Cardiol. 2006;47:27)

Total 616 5-44%

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Am J Cardiol 2009;104:227–233

Measuring the Effect of Aspirin and Clopidogrel onPlatelet Function

Several laboratory assays are commonly used to assess aspirin and clopidogrel response.

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Platelet aggregation can be quantitatively measured byrecording the transmission of a light beam across a suspension of constantly agitated platelet-rich plasma with various agonists, a process known as light transmittance aggregometry (LTA).

LTA may be subject to several methodologic variables that may also lead to variance in the prevalence of low responders. These may include the concentration of agonist (e.g., adenosine diphosphate [ADP] 5, 10, or 20mol/L or arachidonic acid at various concentrations), thenature of the anticoagulant used to prepare the sample, and the LTA cutoff value used to define low response.

Light transmittance aggregometry (LTA). Am J Cardiol 2009;104:227–233

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The detection of non responsiveness to clopidogrel hasbeen most widely based on LTA using ADP as an agonist.

There may be overlap between the results of ADP-induced platelet aggregation in non treated and treated patients. Therefore, it is preferable to perform LTA before and after clopidogrel treatment to determine the absolute change in aggregation (baseline aggregation minus post-treatment aggregation) and to establish a percentage of inhibition.

There is no consensus regarding thresholds to define low response. However, low response has been defined in most studies as </=10% reduction in LTA (from baseline to post-treatment).

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VerifyNow has been designed as a point-of-care test. It is based on the turbidimetric optical detection of platelet aggregation stimulated by a specific agonist (arachidonic acid for aspirin and ADP for clopidogrel) in whole blood.

Whole blood is transferred into cartridges containing a lyophilized preparation of human fibrinogen– coated beads and an agonist.

Using the VerifyNow assay, 240 clopidogrel reaction units has been defined as the threshold for clopidogrel low response.

This cutoff was derived from several studies using receiver-operating characteristic curve analysis, in which a value of 240 clopidogrel reaction units was identified as the optimal cut off to predict cardiovascular death and nonfatal myocardial infarction (MI) at 12 month follow-up.

VerifyNow Am J Cardiol 2009;104:227–233

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VERIFYNOW Point of Care Test

It measures the rate and extent of changes in light transmittance caused by platelet aggregation in a pre-set tube in which whole blood in placed

It thus mimics light transmission aggregometry

Samples containing inhibited platelets will produce low level of light transmittance while samples containing normally functioning platelets will aggregate more rapidly, resulting in higher level of light transmittance

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The Vasodilator stimulated phosphoprotein (VASP) phosphorylation assay uses flow cytometry to measure the specific inhibition of the biochemical target of clopidogrel via the P2Y12 receptor. In patients treated with P2Y12 inhibitors, the phosphorylated state of VASP is a specific intracellular marker of residual P2Y12 receptor reactivity.

This assay has the advantage of specifically assessing the P2Y12 receptor activity. The results are reported as a percentage value of Platelet Reactivity Index (PRI)

VASP

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Consensus and Update on the Definition of On-Treatment Platelet Reactivity to Adenosine Diphosphate Associated With Ischemia and Bleeding J Am Coll Cardiol. 2013;

Evidence for P2Y12 Receptor Reactivity Associated With Post-PCI Ischemic and Bleeding EventsSimilar to previously proposed high on-treatment platelet reactivity to ADP associated with post-PCI ischemic events, recent data suggest that low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding. Cutoff values for both ischemic and bleeding events based on various platelet function assays have been shown. In addition, both ischemic and bleeding events are influenced by various demographic variables. ACS = acute coronary syndromes; BMI = body mass index; CABG = coronary artery bypass graft; DM = diabetes mellitus; MA = maximum amplitude; MEA = multiplate analyzer; PRI = platelet reactivity index; PRU = P2Y12 reaction units; ST = stent thrombosis; TEG = thrombelastography; VASP = vasodilator stimulated phosphoprotein-phosphorylation.

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Consensus and Update on the Definition of On-Treatment Platelet Reactivity to Adenosine Diphosphate Associated With Ischemia and Bleeding J Am Coll Cardiol. 2013;62(24):2261-2273.

Therapeutic Window Concept for P2Y12 Receptor ReactivityEvidence for high and low on-treatment platelet reactivity to adenosine diphosphate (ADP) associated with post–percutaneous coronary intervention (PCI) ischemic and bleeding events based on (A) VerifyNow P2Y12 assay, (B) vasodilator stimulated phosphoprotein-phosphorylation assay, (C) Multiplate analyzer, and (D) thrombelastography platelet mapping assay following P2Y12 receptor blocker therapy. AU = arbitrary aggregation units.

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J Am Coll Cardiol. 2007;49(14):1505-1516.

Interindividual Variability in Platelet Aggregation profile (maximal 20 μmol/l ADP-induced platelet aggregation using light transmittance aggregometry) in patients (n = 135) in a steady state phase (>1 month) of combined aspirin (100 mg/day) and clopidogrel (75 mg/day) therapy.

Heterogeneous antiplatelet effects are observed in the overall patient population as depicted by the normal bell-shaped distribution of platelet aggregation. ADP = adenosine diphosphate

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Clopidogrel is a pro-drug that requires conversion into an active metabolite for biologic activity. Approximately 85 percent of absorbed clopidogrel is hydrolyzed by human carboxylesterase-1 into an inactive carboxylic acid metabolite, and 15 percent is metabolized into an active metabolite by hepatic cytochrome P450 (CYP). Hepatic biotransformation involves a two-step oxidative process. In the first step, the thiophene ring of clopidogrel is oxidized to form 2-oxo-clopidogrel by CYP2C19, CYP1A2, and CYP2B6. In the second step, CYP3A4, CYP2B6, CYP2C19, and CYP2C9 catalyze the formation of the active metabolite.

CYP2C19 is the major enzyme involved in the generation of clopidogrel active metabolite.

Drug Metab Dispos. 2009 Nov;37(11):2145-52

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Clopidogrel Response Variability

POTENTIAL CAUSES — clopidogrel response variability has been attributed to variability in active metabolite generation that is caused by: 1) Variable absorption, which is influenced by an ABCB1 gene

polymorphism 2) Functional variability in CYP isoenzyme activity, which is

influenced by single nucleotide polymorphisms (SNPs) 3) drug-drug interactions.

J Am Coll Cardiol. 2010;56(12):919-933.

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Hepatic biotransformation involves a two-step oxidative process. In the first step, the thiophene ring of clopidogrel is oxidized to form 2-oxo-clopidogrel by CYP2C19, CYP1A2, and CYP2B6. In the second step, CYP3A4, CYP2B6, CYP2C19, and CYP2C9 catalyze the formation of the active metabolite (R-130964). It has been proposed that CYP2C19 is the major enzyme involved in the generation of clopidogrel active metabolite.

J Am Coll Cardiol. 2010;56(12):919-933

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Factors Leading to Variability in Individual Responsiveness to Clopidogrel

J Am Coll Cardiol. 2007;49(14)

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Factors Linked to Clopidogrel Response Variability

1 Clinical factors• Age• Diabetes• ACS• BMI• Reduced LVEF• Renal failure• Inflammation• Smoking)• Sex• Platelet count• Fibrinogen levels• Underdosing• Compliance

Gene polymorphisms

CYP2C19*2 loss of function

CYP2C19*3, *4, *5, *6, *7,

*8, *9 loss of function

CYP2C19*17 gain of function

CYP2C9, gene variantS

CYP3A4, A5 gene variants

ABCB1 gene variants

ABCC3 gene variants

ITGB3 gene variants

IRS-1 gene variants

Drug–drug interactions

CCB

PPI, especially omeprazole

Ketoconazole

Siller-Matula et al. J A C C : V O L . 6 , N O . 1 1 , 2 0 1 3

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The degree of non-responsiveness also vary depending upon the timing following clopidogrel administration that responsiveness is tested.,Gurbel et al have shown that using the same assay and the same definition,

Duration of clopidogrel administration

Rate of non-responsiveness

2 hours 60%

one day 33%

one month 15%

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A (5 M ADP-induced Aggregation) at 24 h

Patie

n ts

(%) Resistance = 28% (300 mg)

Resistance = 8% (600 mg)

0

3

6

9

12

15

18

21

24

27

30

33

≤ −30(−30,−20]

(−20,−10](−10,0]

(0,10](10,20]

(20,30](30,40]

(40,50](50,60]

(60,70]> 70

300 mg clopidogrel

600 mg clopidogrel

Clopidogrel Response Variability (300 vs. 600 mg):Importance of Dose (n = 194)

(Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392)

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Mechanism of Clopidogrel Response Variability:

ClopidogrelBisulfate

Intestinal Absorption

Inactive Carboxylic Acid Metabolite

CYP3A4

CYP3A5

CYP2C19

Active Thiol Metabolite

P2Y12 Receptor

Inhibition of Platelet Aggregation (Wide Response Variability)

Limited absorption capacity with ceiling effect at 600mg loading dose

Hepatic P450Cytochromes

Drug-drug interaction with lipophilic statins,IVS10+12G>a polymorphism

Genetic polymorphisms

Genetic polymorphisms

Multistep Conversion

15%

Esterases

85%

~30%75mg/day for 30days

Post-PCI

~30%-40%75mg/day for 5-7days

volunteers

~30%-40%300 mg load

Post-PCI

~30%-50%600 mg load

Post-PCI

~1.4x 150mg/d vs. 75mg/d for 30days Post-PCI2

(Gurbel PA et al. Thromb Res. 2006 (Epub), . Taubert et al. Clin Pharmacol. 2006, .von Beckerth et al. Eur Heart J. 2007 (epub))

P-glycoprotein(MDR1 3435T genotype)1

?

SmokingCYP1A2

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Genes Associated Withthe Response Variability to Clopidogrel

• Multiple genes (CYP2C19 ABCB1, PON-1, ITGB3, P2Y12) involved in clopidogrel absorption, activation, and inhibition of the P2Y12 receptor have been shown to correspond with either high or low platelet reactivity.

• Among several polymorphisms of CYP2C19, the two most frequent variants associated with loss-of-function are CYP2C19*2, a G681A mutation in exon 5 resulting in an aberrant splice site leading to the production of a truncated, non-functioning protein and CYP2C19*3, a G636A mutation in exon 4 CYP2C19*2 resulting in a premature stop codon.

• The *17 variant is associated with increased gene transcription and increased enzyme function.

• CYP2C19*2 (loss-of-function allele) is frequent, with approximately 15% of Caucasians and up to 30% Asian being carriers of at least 1 of these alleles.

Siller-Matula et al. J A C C :, V O L . 6 , N O . 1 1 , 2 0 1 3

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The capacity of clopidogrel to inhibit ADP-induced platelet aggregation shows wide inter subject variability. To determine whether frequent functional variants of genes coding for candidate cytochrome P450 (CYP) isoenzymes involved in clopidogrel metabolic activation (CYP2C19*2, CYP2B6*5, CYP1A2*1F, and CYP3A5*3 variants) influence the platelet responsiveness to clopidogrel.

They conducted a prospective pharmacogenetic study in 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg/d and observed that pharmacodynamic response to clopidogrel was significantly associated with the CYP2C19 genotype. Twenty of the subjects were wild-type CYP2C19 (*1/*1) homozygotes, while the other 8 subjects were heterozygous for the loss-of-function polymorphism CYP2C19*2 (*1/*2). Baseline platelet activity was not influenced by the CYP2C19 genotype. In contrast, platelet aggregation in the presence of 10 muM ADP decreased gradually during treatment with clopidogrel 75 mg once daily in *1/*1 subjects, reaching 48.9% +/- 14.9% on day 7 (P<.001 vs baseline), whereas it did not change in *1/*2 subjects (71.8% +/- 14.6% on day 7, P = .22 vs baseline, and P<.003 vs *1/*1 subjects).

Similar results were found with VASP phosphorylation. The CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet responsiveness to clopidogrel in young healthy male volunteers and may therefore be an important genetic contributor to clopidogrel resistance in the clinical setting.

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Clinical outcome associated with clopidogrel hyporesponsiveness(resistance)

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Platelet Reactivity And Early Drug-Eluting Stent Thrombosis

• 1608 consecutive patients with CAD and planned drug eluting stent implantation

• All received a loading of 600 mg of clopidogrel prior to stenting

• Blood was obtained directly prior to PCI• ADP induced platelet aggregation was assessed with a point of

care assay: Multiple Electrode Platelet Aggregometry (MEA) (principle of impedance aggregometry)

• Poor response to clopidogrel was prospectively defined by a cutoff point at the upper quintile of MEA measurments

Sibbing et al. JACC 2009;53:849-56

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Clinical Characteristics Associated With Low Response to Cloopidogrel

normal response Low response p n = 1285 n = 323

BMI 27.3 + 4.2 28.3 + 4.9 < 0.001Ejection Fraction 54.9 + 10.9 53.2 + 12.6 0.03Diabetes mellitus 27.4% 34.1% 0.02Active smokers 12.1% 18.6% 0.002ACS 31.4% 39.9% 0.001Platelet count 213 + 6 236 + 64 < 0.001Time from loading (h) 4 (2-15.5) 3 (2-7) < 0.001

Sibbing et al. JACC 2009;53:849-56

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Results The upper quintile of patients according to MEA measurements (n 323) was defined as clopidogrel low responders. Compared with normal responders (n 1,285), low responders had a significantly higher risk of definite ST within 30 days (2.2% vs. 0.2%; p 0.0001). Mortality rates were 1.2% in low versus 0.4% in normal responders p 0.07). The composite of death or ST was higher in low versus normal responders (3.1% vs. 0.6%; p 0.001).

Conclusions Low response to clopidogrel assessed with MEA is significantly associated with an increased risk of ST. Further studies are warranted to evaluate the ability of MEA to guide antiplatelet therapy in patients undergoing PCI.

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Prospective, observational, referral center cohort study of 1789 consecutive patients with ACS undergoing PCI. Platelet reactivity was prospectively assessed by light transmittance aggregometry.

All patients received 325 mg of aspirin and a loading dose of 600 mg of clopidogrel followed by a maintenance dosage of 325 mg/d of aspirin and 75 mg/d of clopidogrel for at least 6 months.

Patients with HRPR as assessed by adenosine diphosphate test (≥70% platelet aggregation) received an increased dose of clopidogrel (150-300 mg/d) or switched to ticlopidine (500-1000 mg/d) under adenosine diphosphate test guidance.

The primary end point was a composite of cardiac death, myocardial infarction, any urgent coronary revascularization, and stroke at 2-year follow-up. Secondary end points were stent thrombosis and each component of the primary end point.

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Results The primary end point event rate was 14.6% (36/247) in patients with HRPR and 8.7% (132/1525) in patients with low residual platelet reactivity (absolute risk increase, 5.9%; P = .003).

Stent thrombosis was higher in the HRPR group compared with the low residual platelet reactivity group (6.1% [15/247] vs 2.9% [44/1525]; absolute risk increase, 3.2%; P = .01).

By multivariable analysis, HRPR was independently associated with the primary end point (hazard ratio, 1.49; 95% CI, 1.08-2.05; P = .02) and with cardiac mortality (hazard ratio, 1.81; 95% CI, 1.18-2.76; P = .006).

Conclusion Among patients receiving platelet reactivity–guided antithrombotic medication after PCI, HRPR status was significantly associated with increased risk of ischemic events at short- and long-term follow-up.

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They enrolled 8583 patients .

At 1-year follow-up, stent thrombosis had occurred in 70 (0·8%) patients, myocardial infarction in 269 (3·1%), clinically relevant bleeding in 531 (6·2%), and death in 161 (1·9%) patients.

High platelet reactivity on clopidogrel was strongly related to stent thrombosis (adjusted HR 2·49 p=0·001) and myocardial infarction (adjusted HR 1·42 p=0·01), was inversely related to bleeding (adjusted HR 0·73 p=0·002), but was not related to mortality (adjusted HR 1·20 [0·85-1·70], p=0·30).

High platelet reactivity on aspirin was not significantly associated with stent thrombosis (adjusted HR 1·46 [0·58-3·64], p=0·42), myocardial infarction, or death, but was inversely related to bleeding (adjusted HR 0·65 [0·43-0·99], p=0·04).

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Value of platelet reactivity in patients managed without percutaneous coronary intervention

JAMA. 2012;308(17):1785-1794

9326 participants, 27.5% were included in a platelet function substudy: 1286 treated with prasugrel and 1278 treated with clopidogrel.

Aspirin with either prasugrel (10 or 5 mg/d) or clopidogrel (75 mg/d); those 75 years or older and younger than 75 years but who weighed less than 60 kg received a 5-mg prasugrel maintenance dose.

Outcome Measures Platelet reactivity, measured in P2Y12 reaction units (PRUs), was performed at baseline, at 2 hours, and at 1, 3, 6, 12, 18, 24, and 30 months after randomization. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke through 30 months.

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Conclusions Among patients with ACS without ST-segment elevation and initially managed without revascularization, prasugrel was associated with lower platelet reactivity than clopidogrel, irrespective of age, weight, and dose.

Among those in the platelet substudy, no significant differences existed between prasugrel vs clopidogrel in the occurence of the primary efficacy end point through 30 months and no significant association existed between platelet reactivity and occurrence of ischemic outcomes.

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Treatment intensification in patients with high on-treatment platelet reactivity( clopidogrel resistance)

Dominick J. Angiolillo, AHA 2010 – Sunday, Nov 14, 2010

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153 Pt. for elective PCI patients were randomized to clopidogrel 150 mg/day (n 58) or 75 mg/day (n 95) for 4 weeks, with vasodilator stimulated phosphoprotein (VASP) assay-guided switching to clopidogrel 150 mg/day after 2 weeks in low responders (platelet reactivity index 69%).

All patients received aspirin 75 mg/day.

J Am Coll Cardiol Intv. 2008;1(6):631-638

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STUDY DESIGN

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Results After 2 weeks, clopidogrel 150 mg/day produced a significantly lower platelet reactivity index than clopidogrel 75 mg/day (43.9 17.3% vs. 58.6 17.7%; p 0.0001).

The proportion of low responders was significantly lower in patients randomized to clopidogrel 150 mg/day than in those randomized to clopidogrel 75 mg/day (8.6% vs. 33.7%; p 0.0004).

In the clopidogrel 75 mg/day group, 64.5% (20 of 31) of low responders became responders after switching to clopidogrel 150 mg/day for 2 weeks.

No major bleeds occurred during the study; the incidence of minor bleeds was similar in each treatment group.Conclusions In elective PCI patients, a 150-mg/day clopidogrel maintenance dose produces greater inhibition of platelet function than clopidogrel 75 mg/day. In low responders to clopidogrel 75 mg/day, switching to clopidogrel 150 mg/day overcomes low responsiveness in a majority of patients. These findings warrant further clinical evaluation

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TAILORED CLOPIDOGREL LOADING DOSE ACCORDING TO PLATELET REACTIVITY MONITORING DECREASE EARLY STENT

THROMBOSIS L Bonello, L Camoin-Jau, S Arques, , P . Rossi, C. Boyer, D Panagides, O Wittenberg, P Barragan, F Dignat-George, F Paganelli.

Am J Cardiol 2009;103:5-10

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DESIGN

Non-emergent PCI : ACS and Stable angina (n= 1122)

Loading dose (LD) -ASA 250mg -Clopidogrel 600mg VASP ≥ 50%

Randomization(n=429)

CONTROL (n =215) VASP-guided LD (n =214)

Up-to 3 additional LD of 600 mg every 24 hours until VASP < 50% before PCIMaintenance dose -ASA 160 mg

-Clopidogrel 75 mg

1° endpoint: Definite stent thrombosis (ARC definition)

2° endpoints: MACE including CV death, MI and U-TVRTIMI major and minor bleeding at 30 days

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Platelet reactivity monitoring• After a 600mg clopidogrel LD, poor responders (PRI ≥ 50%) received

additional 600mg bolus (max 2400 mg) until reaching therapeutic target.

Mean ±SD Control (n=84) VASP-guided (n=78) p

VASP after first LD, % 68 ±11 69±10 0.4

VASP after adjustment,% - 38 ±14* *<0.001

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Timing of early stent thrombosis

All early stent thrombosis occured during the first 7 days

Am J Cardiol 2009;103:5-10

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Secondary end-point: MACE

 Endpoint n, (%) Control (n= 214)

VASP-guided (n= 215)

p

Cardiovascular death 4 (1.8) 0 0.06

Myocardial infarction 10 (4.8) 1 (0.5) 0.01

Urgent revascularization 5 (2.3) 0 0.06

All MACE 19 (8.9) 1 (0.5) < 0.001

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CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCI

Shamir R. Mehta on behalf of the CURRENT Investigators

(N Engl J Med 2010;363:930-42.

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CURRENT-OASIS 7

25,086 patients with ACS following PCI,

Either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter) and Either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily).

The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days.

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RESULTS:The primary outcome occurred in 4.2% of patients assigned to double-dose clopidogrel as compared with 4.4% assigned to standard-dose clopidogrel (P=0.30). Double-dose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis among the 17,263 patients who underwent PCI (1.6% vs. 2.3%; P=0.001). Major bleeding occurred in 2.5% of patients in the double-dose group and in 2.0% in the standard-dose group (hazard ratio, 1.24; 95% CI, 1.05 to 1.46; P=0.01

There was no significant difference between higher-dose and lower-dose aspirin with respect to the primary outcome (4.2% vs. 4.4%; P=0.61) or major bleeding (2.3% vs. 2.3%; P=0.90).

Conclusion There was no significant difference between a 7-day, double-dose clopidogrel regimen and the standard-dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the primary outcome of cardiovascular death, myocardial infarction, or stroke

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The first large-scale, randomized study to investigate the clinical impact of giving high-dose (additional 600 mg loading dose and 150 mg maintenance dose) vs.

standard-dose clopidogrel for patients with HPR identified by theVerifyNow P2Y12 assay was the Gauging Responsiveness with A VerifyNow

assay—Impact on Thrombosis And Safety (GRAVITAS)trial.

• In the study, 41% of the 5479 patients were found to have HPR 12–24 h after PCI for stable angina or NSTE-ACS.

• ST-elevation MI were excluded. • The primary endpoint of cardiovascular death, myocardial infarction, or

stent thrombosis at 6 months was identical between high-dose and standard-dose groups (HR: 1.01, 95% CI: 0.58–1.76, P = 0.98).

• GUSTO moderate/severe bleeding events were also not significantly different; even numerically lower in the 150-mg group.

• A time-dependent post hoc analysis of the trial suggested that patients having PRU values ,208 at 30 days or 6 months had a significant clinical benefit in the primary endpoint, suggesting that the modest and variable effect of high-dose clopidogrel might be one reason for the negative findings, and the achieved level of platelet reactivity might be clinically important when high dose clopidogrel is given.

• JAMA 2011;305:1097–1105.

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The Responsiveness to Clopidogreland StentThrombosis2–ACS (RE-CLOSE-2 ACS) single-centre observational registry evaluated the clinical impact of increasing the dose of clopidogrel or switching to ticlopidine in 1789 ACS patients with HPR after PCI. According to the results, patients with HPR persisted at significantly higher risk for adverse ischaemic events despite the treatment adjustment withhigh-dose clopidogrel or ticlopidine, when compared with patients without HPR, including a higher risk for mortality.

JAMA 2011;306:1215–1223

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N Engl J Med 2012;367:2100-9

Assessment by a Double Randomization of a Conventional Antiplatelet Strategy vs. a Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption vs.

Continuation One Year after Stenting ( ARCTIC)

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Standard of care

VerifyNow P2Y12 + ASA

Drug (ASA, clopidogrel, prasugrel, GP2b3a I.) and Dose

adjustments if high platelet reactivity

Coronary angiogram and PCI

Stent-PCI

Rd

Standard of careDrug and Dose adjustments if high platelet reactivity at

Day 14

12-month FU

Stent-PCI

ARCTIC trial design

Primary endpoint at 12 months:• Death, MI, stroke, stent thrombosis,

urgent revascularizatio

High platelet reactivity during treatment with Aspirin was defined as 550 or more aspirin reaction units. High platelet reactivity during treatment with thienopyridine was defined as 235 or more platelet reaction units, 15% or less inhibition, as compared with a baseline.

randomly assigned 2,440 patients of stable angia or NSTE ACS

(n=1,213) (n=1,227)

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Inclusion / Exclusion

• Patients scheduled for

planned PCI

• DES implantation

• Consent and Rx before start

of PCI

• Primary PCI for STEMI

• Any PCI with planned use of

GPIIbIIai• BMS or oral anticoagulation

requirement

• Short life expectancy

• Bleeding diathesis

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Before the procedure, 7.6% of patients taking aspirin and 34.5% of those taking clopidogrel in the monitoring group had high platelet reactivity. Of those who responded poorly to clopidogrel, 80% were reloaded with a high dose of clopidogrel (600 mg) on the table before the start of the procedure, and 3% received a loading dose of prasugrel (60 mg).

Administration of glycoprotein IIb/IIIa inhibitors was also five times greater in the monitoring group vs. the conventional care group (P<.001).

At 2 to 4 weeks after implantation, fewer patients had high platelet reactivity. Patients in the monitoring group, however, were more likely to be taking a high dose of aspirin (>100 mg) or a high dose of clopidogrel (≥150 mg) or prasugrel.

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Primary Endpoint to 1 year

The primary end point occurred in 34.6% of the patients in the monitoring group, as compared with 31.1% of those in the conventional-treatment group

P=0.10). (Death, MI, stroke, stent thrombosis, urgent revascularization)

HR = 1.13 [0.98-1.29]p= 0. 096

ConventionalMonitoring

100 200 3000

34.6%

31.1%

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Similarly, there was no difference in the main secondary endpoint of stent thrombosis or any urgent revascularization, which occurred in 4.9% of those in the monitoring group and 4.6% of the conventional care group (P = 0.77).

The rate of major bleeding events also did not differ significantly between treatment arms (monitoring, 2.3% vs. conventional care, 3.3%; P=.15).

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J Am Coll Cardiol. 2014;64(4):361 368.

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(Circulation. 2009;119:3215-3222.)

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Response evaluation

Aspirin Poor Response

Aspirin reaction units (ARU) >550 ⎯ ASA orally ≥80 mg for at least 5 days and /or i.v. 500 mg ASA

15 mins or more before

Clopidogrel Poor Response

< 40% platelet inhibition ⎯ 600 mg clopidogrel LD at least 2 hours before or ⎯ 300 mg clopidgrel LD at least 6 hours before or ⎯ 75 mg clopidogrel MD for at least 7 days

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Tailored GP IIb/IIIa Receptor Blockade According to Clopidogrel Resistance

• 149 Clopidorel resistant patients• Resistance defined by inhibition < 30% using light

transmission aggregometry• Elective PCI• Randomized to :

– Conventional therapy: 600 mg Clopidogrel– Active therapy: 600 mg Clopidogrel + GP IIb/IIIa blockade

• Combined end-point of: death, periprocedural MI, stent thrombosis and recurrent ACS at 1 month

Cuisset et al. JACC Interventions. 2008;1:649-53

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Results The rate of cardiovascular events at 1 month was significantly lower in the “active group” than in the “conventional group”: 19% (n = 14) versus 40% (n = 30), p = 0.006. No patient in either group had post-procedural TIMI major bleeding or required transfusions.

Conclusions The present study suggested benefit of tailored antiplatelet therapy during elective PCI with GP IIb/IIIa antagonist for clopidogrel non responders without increased bleeding risk.

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Incidence of CV Events According to the Strategy*p < 0.01. ACS = acute coronary syndrome; CV = cardiovascular; PMI = periprocedural myonecrosis; ST = stent thrombosis.

Events According to GPIIb/IIIa Blockade in Clopidogrel Resistant Patients

Cuisset et al. JACC Interventions. 2008;1:649-53

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Response variability to clopidogrel has led to the developmentof more potent P2Y12 inhibitors such as prasugrel and ticagrelor.

The pharmacokinetics and pharmacodynamics of prasugrel and ticagrelor indicate that they provide more consistent, more rapid, and more potent platelet inhibition than clopidogrel.

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J Am Coll Cardiol 2012;59:2159–64)

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The TRITON-TIMI 38 study compared prasugrel (60 mg loading and 10 mg/day maintenance) to clopidogrel (300 mg loading and 75 mg/day maintenance) in patients with moderate-to-high-risk acute coronary syndrome (ACS) at 15 months. The primary composite endpoint of cardiovascular death, myocardial infarction and stroke was significantly lower in the prasugrel group than in the clopidogrel group (9.9% vs 12.1%, p<0.001).

There was no significant higher risk of major bleeding in the prasugrel group in patients not meeting any of these 3 criterion: age≥75 years, weight<60 kg, or a history of stoke or transient ischemic attack. N Engl J Med 2007;357:2001–15.

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Ticagrelor is a reversibly-binding, noncompetitive, direct-acting, oral P2Y12 antagonist.(1)

Ticagrelor therapy was associated with: Less MACE in ACS patients in PLATO trial.(2) More rapid onset, offset, and greater level of inhibition in ONSET/OFFSET Study.(3). Greater platelet inhibition in both clopidogrel responders and non-

responders in RESPOND Study.(4).

1. Gurbel PA et al. Expert Opin Pharmacother. 2010;11:2251-9. 2. Wallentin L et al. N Engl J Med. 2009;361:1045-57. 3. Gurbel PA et al. Circulation. 2009;120:2577-85. 4. Gurbel PA et al. Circulation. 2010;121:1188-99.

The PLATO (Platelet Inhibition and Patient Outcomes) trial has shown that ticagrelor reduced ischemic events by 16% and cardiovascular mortality by 21% as compared with clopidogrel. N Engl J Med 2009;361: 1045–57.

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Conclusions

• Results consistent with: - overall PLATO trial clinical outcomes - PLATO genetic substudy: ticagrelor was more clinically effective than clopidogrel irrespective of CYP2C19 genotype.

• First report demonstrating the superior antiplatelet effect of ticagrelor compared to clopidogrel irrespective of CYP2C19 genotype.

• Whereas CYP2C19 genotype influenced the antiplatelet effect of clopidogrel, there was no effect during ticagrelor therapy.

• Larger studies needed to examine the relative influences *2 and *17 on clopidogrel antiplatelet effects.

• Influence of CYP2C19 genotype in clopidogrel-treated patients most evident during maintenance and by the VerifyNow P2Y12 assay.

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Levine et al. JACC Vol. 58, No. 24, 20112011 ACCF/AHA/SCAI PCI Guideline

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ESC Guidelines for the management of acutecoronary syndromes in patients presenting

without persistent ST-segment elevationThe Task

European Heart Journal (2011) 32, 2999–3054

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Clinical guideline recommendations• Regarding the choice between available P2Y12-inhibitors, the 2011 ESC

guidelines on non-ST segment elevation acute coronary syndromes (NSTE-ACS) and the 2012 guidelines on ST-segment elevation myocardial infarction recommend prasugrel and ticagrelor for all ACS patients without contraindication, and clopidogrel is only recommended if these agents are not available.

• Despite the restrictive recommendations for clopidogrel, it still holds a class I indication in ACS due to the large differences in the availability of the new-generation P2Y12-inhibitors among European countries.

• According to the 2011 ACCF/AHA/SCAI guidelines for PCI, a P2Y12-inhibitor should be given for ACS patients without preferring novel P2Y12-inhibitors over clopidogrel.

• Similarly, the 2012 ACCF/AHA unstable angina/non-ST-segment elevation myocardial infarction guidelines and the 2013 ACCF/AHA ST-elevation myocardial infarction guidelines do not endorse one of the P2Y12-inhibitors over the other, acknowledging that large-scale, randomized clinical data on the use of prasugrel and ticagrelor are still limited.

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Summary• Multiple studies have confirmed marked response variability to clopidogrel therapy

and a significant prevalence of resistance/non-responsiveness.

• Aggregometry remains the gold standard in detection.

• VerifyNow more user-friendly assay.

• VASP-P is the most specific available measurement of incomplete P2Y12 blockade.

• A 600 mg loading dose is associated with less resistance, less response variability, and lower post-treatment aggregation- no conclusive data to support higher doses than 600 mg.

• Current data suggest that high ex vivo platelet reactivity to ADP/incomplete P2Y12

inhibition are risk factors for post-stenting ischemic events including SAT.

• Dose adjustment of clopidogrel ( high dose)

• Switch to potent P2Y12-inhibitor in patients with high on-treatment platelet reactivity

• Adding a third antiplatelet agent on top of DAPT in patients with high on-treatment platelet reactivity

• Current guidelines do not endorse one of the P2Y12-inhibitors over the other.