Platelet Function Testing and Genotyping Improve Outcome in Patients Treated With Antithrombotic Agents

Abstract

HomeCirculationVol. 125, No. 10Platelet Function Testing and Genotyping Improve Outcome in Patients Treated With Antithrombotic Agents Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBPlatelet Function Testing and Genotyping Improve Outcome in Patients Treated With Antithrombotic Agents Paul A. Gurbel, MD and Udaya S. Tantry, PhD Paul A. GurbelPaul A. Gurbel From the Sinai Center for Thrombosis Research, Baltimore, MD. Search for more papers by this author and Udaya S. TantryUdaya S. Tantry From the Sinai Center for Thrombosis Research, Baltimore, MD. Search for more papers by this author Originally published13 Mar 2012https://doi.org/10.1161/CIRCULATIONAHA.111.031195Circulation. 2012;125:1276–1287IntroductionThe only reason P2Y12 inhibitors are administered in addition to aspirin is to improve the prevention of thrombosis. The clinical efficacy of adding clopidogrel to aspirin as a secondary prevention strategy in patients with high-risk coronary artery disease is well established.1 There are no effects of clopidogrel on any receptor other than P2Y12 to explain the magnitude of the clinical benefit. All of the established clinical effects are attributed to reduced platelet responsiveness to ADP.2 Therefore, the patient with inadequate P2Y12 inhibition determined by ex vivo testing logically has an increased risk for thrombosis. Persistent ischemic event occurrence and the irrefutable demonstration of clopidogrel antiplatelet response variability are 2 potent arguments against the widely practiced nonselective or one-size-fits-all strategy of administering clopidogrel therapy. Observational studies conducted in thousands of patients have led to an international consensus that high on-treatment platelet reactivity (HPR) to ADP is a major risk factor for post–percutaneous coronary intervention (PCI) ischemic event occurrence.3,4 Moreover, the recent 2011 American and European guidelines have given a Class IIb recommendation for platelet function testing or genotyping if the results of testing may alter management.5–7 Furthermore, the Society of Thoracic Surgeons gave a Class IIb recommendation for platelet function testing to determine the timing of surgery in patients on clopidogrel therapy (Level of Evidence C).8 These recommendations for personalizing antiplatelet therapy are unprecedented and acknowledge that a large body of data has accrued demonstrating the relation of HPR to ischemic risk in the PCI-treated patient. Finally, the evidence of diminished effectiveness of clopidogrel in poor metabolizers (those having 2 loss-of-function [LoF] cytochrome P450 [CYP] 2C19 alleles) has been recognized by the Food and Drug Administration (FDA) boxed warning about treatment with clopidogrel.9Response by Krishna on p 1287The Great Paradox: Reluctance to Quantify the ADP-P2Y12 Interaction in Clinical PracticeMyocardial infarction (MI) and stent thrombosis are catastrophic events that occur in patients with coronary artery disease. Overwhelming evidence exists that thrombus generation resulting from platelet activation and aggregation at the sites of plaque rupture and endothelial cell erosion is the primary process involved in the occurrence of the latter clinical events.10 Although thromboxane A2 and ADP act synergistically during platelet aggregation, the ADP-P2Y12 receptor interaction plays a central role in sustaining the activation of glycoprotein IIb/IIIa receptors by amplifying the response to agonists. P2Y12 activation also modulates platelet procoagulant activity, P-selectin expression, and inflammation (Figure 1).11 Numerous pharmacodynamic studies demonstrated the strong relation between the occurrence of stent thrombosis and clopidogrel nonresponsiveness or HPR.4 The prothrombotic effects of the P2Y12 platelet receptor serve as the rationale for its pharmacological inhibition as a key strategy to prevent MI and stent thrombosis.Download figureDownload PowerPointFigure 1. Central role of adenosine diphosphate P2Y12 receptor interaction in platelet activation and aggregation during the occurrence of ischemic events and stent thrombosis. After plaque rupture, tissue factor and collagen are exposed, leading to platelet activation. Three important pathways (thrombin–protease activated receptor-1, thromboxane [Tx] A2-thromboxane receptor, and ADP-P2Y12 receptor) amplify the response. The ADP-P2Y12 interaction plays a central role. PCI indicates percutaneous coronary intervention. Adapted from Bonello et al,4 with permission of the publisher. Copyright © 2011, Elsevier.Because the development of all P2Y12 inhibitors is fundamentally based on a comparative assessment of ex vivo effects, we must ask why there is reluctance to use the same methodology to ensure that an optimal antiplatelet effect is present in patients. The most widely used method to assess platelet function during the development of P2Y12 inhibitors is conventional aggregometry. However, point-of-care assessment now allows rapid assessment of platelet reactivity, strongly correlates with aggregometry, and has been associated with clinical outcomes.12,13 Despite the fundamental importance of unblocked P2Y12 receptors in the genesis of thrombosis, physicians largely do not objectively assess the intensity of the ADP-P2Y12 interaction in their high-risk patients treated with clopidogrel, and instead use a nonselective or one-size-fits-all approach.5 The latter remains one of the most curious paradoxes in cardiovascular medicine. Aspirin and a P2Y12 inhibitor are arguably the most important pharmacological agents administered to the high-risk PCI/acute coronary syndrome (ACS) patient because of their intended actions to block platelet reactivity, yet there is reluctance to confirm that therapy is actually effective in the treated patient. The nonselective treatment approach with oral antiplatelet agents is unique compared with the objective assessments and adjustments made after administration of most drugs used to treat patients with cardiovascular disease. In fact, personalized parenteral antithrombotic therapy is widely administered for PCI. Weight-adjusted heparin and glycoprotein IIb/IIIa inhibitor administration is the standard of care, and activated clotting time is used to determine an optimal level of anticoagulation. Some examples of other drugs and assessments for personalizing therapy are β-blockers and heart rate/blood pressure, statins and cholesterol levels, antihypertensives and blood pressure, insulin and glucose levels, diuretics and renal function/patient weight, and warfarin and international normalized ratio.Degree of Ex Vivo Inhibition of Platelet Reactivity to ADP: A Predictor of Preclinical and Clinical EfficacyClopidogrel: Strong Support for the Platelet HypothesisCadroy et al14 demonstrated that adding 75 mg/d clopidogrel to 325 mg/d aspirin for 10 days significantly decreased 5 μmol/L ADP–induced platelet aggregation compared with aspirin administration alone in healthy volunteers. The degree of platelet inhibition measured ex vivo was reflected by a decrease in arterial thrombus formation at arterial wall shear rates in a parallel-plate collagen-coated perfusion chamber assay. Furthermore, the antiplatelet and antithrombotic effects were more pronounced and appeared earlier (at 90 minutes) when a 300-mg clopidogrel loading dose was administered (Figure 2A and 2B). The work by Cadroy et al provided strong evidence that the ex vivo measurement of platelet inhibition resulting from the addition of a P2Y12 blocker predicted the ex vivo antithrombotic response. The clinical relevance of the ex vivo measured effects on platelet function resulting from clopidogrel plus aspirin therapy was put to the test in numerous trials involving patients with a broad spectrum of coronary artery disease, including non–ST-segment–elevation ACS and ST-segment–elevation MI.15–19 These trials demonstrated the superiority of adding clopidogrel to aspirin in reducing major adverse cardiac events. Finally, a meta-analysis performed in 79 262 patients enrolled in the above trials conclusively demonstrated that adding clopidogrel to aspirin is associated with a significant decrease in MI (odds ratio=0.82; P<0.001), stroke (odds ratio=0.82; P=0.002), and mortality (odds ratio=0.94; P=0.026; Figure 3).20 In these trials, the major driving factor for clinical efficacy was the significant reduction in MI observed with clopidogrel therapy. These trials provided further evidence for the platelet hypothesis, which states that pharmacological treatment strategies associated with a superior reduction in platelet function (by the addition a P2Y12 inhibitor to aspirin) will result in superior clinical outcomes by reducing the occurrence of thrombosis.10Download figureDownload PowerPointFigure 2. A, Enhanced ex vivo platelet inhibition by the addition of clopidogrel to aspirin and early enhancement of effect by a clopidogrel loading dose (LD). B, Enhanced ex vivo antithrombosis in perfusion chamber analysis by the addition of clopidogrel to aspirin and early enhancement of antithrombotic effect by a clopidogrel loading dose. MD indicates maintenance dose. Adapted from Cadroy et al.21Download figureDownload PowerPointFigure 3. Enhanced in vivo antithrombotic effect by the addition of clopidogrel to aspirin observed across a wide spectrum of coronary artery disease in large-scale randomized trials and a meta-analysis of these trials. ASA indicates aspirin; CLP, clopidogrel; MI, myocardial infarction; OR, odds ratio; NSTE ACS, non–ST-segment–elevation acute coronary syndromes; STEMI, ST-segment–elevation myocardial infarction; CAD, coronary artery disease; CURE indicates Clopidogrel in Unstable Angina to Prevent Recurrent Events; CREDO, Clopidogrel for the Reduction of Events During Observation; CLARITY, Clopidogrel as Adjunctive Reperfusion Therapy; COMMIT, Clopidogrel and Metoprolol in Myocardial Infarction Trial; and CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance. Data derived from Gurbel et al1 and Helton et al.20Further evidence that ex vivo platelet function measurements correlate with clinical response comes from the PCI cohort of the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT OASIS-7) trial.21 Previously, it was demonstrated that a 600-mg clopidogrel loading dose produced greater platelet inhibition and was associated with less response variability and resistance compared with a 300-mg loading dose (Figure 4).22 Once again, the clinical response mirrored the pharmacodynamic response: A high loading dose followed by 7 days of 150-mg maintenance therapy was associated with a reduction in 30-day ischemic event occurrence, including stent thrombosis, in the PCI cohort of OASIS-7.21Download figureDownload PowerPointFigure 4. Greater ex vivo platelet inhibition and less response variability after a 600-mg clopidogrel load compared with a 300-mg load in percutaneous coronary intervention patients measured at 24 hours after loading. Resistance is defined as absolute change in maximal aggregation from pretreatment (ΔA) ≤10%. Adapted from Gurbel et al,22 with permission of the publisher. Copyright © 2011, Elsevier.TRITON and PLATO: More Strong Support for the Platelet HypothesisGreater levels of active metabolite generation during prasugrel therapy (60-mg load/10 mg daily) were associated with greater platelet inhibition compared with clopidogrel therapy (600-mg load/75 mg daily).23 In a phase 2 trial, prasugrel was associated with a faster onset of action and greater platelet inhibition than high-dose clopidogrel.24 The clinical relevance of these superior inhibitory effects measured ex vivo was put to the test in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 study. In that study, prasugrel therapy was associated with less major adverse cardiac event occurrence than clopidogrel therapy in high-risk ACS patients undergoing PCI. The effect of prasugrel therapy on the occurrence of stent thrombosis was dramatic (≈50% reduction).25In the Multi-Centre Randomized, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease (ONSET/OFFSET) study, ticagrelor, a direct-acting P2Y12 receptor blocker, was associated with a more rapid onset of action, a greater level of inhibition during maintenance therapy, and a more rapid offset of pharmacodynamic effect than clopidogrel.26 In the Randomized, Double-Blind, Outpatient, Crossover Study of the Anti-Platelet Effects of AZD6140 Compared With Clopidogrel in Patients With Stable Coronary Artery Disease Previously Identified as Clopidogrel Non-Responders or Responders (RESPOND) study, ticagrelor therapy was associated with greater platelet inhibition compared with clopidogrel in both clopidogrel responders and nonresponders. Ticagrelor was extremely effective in reducing the prevalence of HPR within 30 minutes of therapy.27 The superior pharmacodynamic effects observed in the ONSET/OFFSET and RESPOND studies were mirrored by the superior clinical efficacy of ticagrelor observed in the Platelet Inhibition and Patient Outcomes (PLATO) trial.28The results of the ex vivo platelet function measurements during prasugrel and ticagrelor therapy in conjunction with the results of the TRITON and PLATO trials lend powerful support for the platelet hypothesis. In trials enrolling more than 100 000 high-risk patients, the clinical response to an antiplatelet regimen has always reflected the ex vivo response to that regimen.20,25,28 Thus, an objective assessment of platelet function to ensure adequate inhibition and to optimize outcomes in clopidogrel-treated patients is logical.Understanding the Mechanisms Responsible for the Variable Antiplatelet Effect of Clopidogrel and the Role of the CYP2C19 LoF Allele: The Rationale for Genetic TestingThe unpredictable antiplatelet response to clopidogrel was reported nearly a decade ago in Circulation; ≈30% of PCI patients were resistant (≤10% decrease in platelet aggregation from baseline) at 24 hours after a 300-mg load, and this prevalence of resistance persisted at 5 days and fell to ≈15% at 30 days after PCI during 75-mg/d maintenance therapy.29 Similar observations have been made in numerous subsequent studies involving thousands of PCI patients.4 In a recent study reported in this journal, ADP-induced platelet aggregation in ≈42% of stable coronary artery disease patients after aspirin and a 600-mg clopidogrel loading dose was in the same range observed in ≈50% of patients treated with 75–100 mg per day aspirin alone26 (Figure 5).Download figureDownload PowerPointFigure 5. Cumulative frequency distribution of aggregation in stable coronary artery disease (CAD) patients treated with aspirin, clopidogrel plus aspirin, or ticagrelor plus aspirin. ADP-induced platelet aggregation in ≈42% of stable CAD patients after aspirin plus 600-mg clopidogrel loading dose was in the same range observed in ≈50% of patients treated with 75–100 mg per day aspirin alone. These patients have also been defined as having high on-treatment platelet reactivity (see Reference 4). Adapted from Gurbel et al.26Clopidogrel is a prodrug that requires metabolic activation by CYPs to a reactive metabolite (Figure 6).30 CYP isoenzyme activity is influenced by single-nucleotide polymorphisms primarily of the gene encoding the CYP2C19 isoenzyme and interactions with other drugs. These influences contribute to variable and, in some cases, insufficient active metabolite generation, leading to resistance.4 Common LoF polymorphisms of CYP2C19 and CYP2C9 have been associated with decreased clopidogrel active metabolite exposure and less platelet inhibition.31 Less plasma active metabolite exposure (34% relative reduction; P<0.001) and a reduction in platelet aggregation (9% absolute reduction; P<0.001) were demonstrated in healthy carriers of at least 1 CY2C19 LoF allele compared with noncarriers.32 In the first genome-wide association study, conducted in healthy subjects, CYP2C19*2 was the only single-nucleotide polymorphism associated with clopidogrel response variability. In a replication study of PCI patients, carriers of the CYP2C19*2 allele had an ≈2.4-times-higher cardiovascular event rate compared with noncarriers.33 Elsewhere, it was reported that patients carrying 2 LoF alleles had a 1.98-times-higher rate of cardiovascular events than noncarriers among acute MI patients, and the risk was even higher (3.6 times) among patients who underwent PCI.34 In a collaborative meta-analysis of clinical trials involving primarily patients who underwent PCI (91%), an increased risk of the composite end point of cardiovascular death, MI, or stroke among carriers of 1 LoF allele (1.6 times) and carriers of 2 LoF alleles (1.8 times) compared with noncarriers was reported. A significantly increased risk of stent thrombosis in both carriers of 1 LoF allele (2.7 times) and 2 LoF alleles (4 times) compared with noncarriers was also observed.35Download figureDownload PowerPointFigure 6. Clopidogrel response variability is a pharmacokinetic problem influenced primarily by the activity of cytochrome P450 isoenzymes in the generation of the active metabolite. Absorption may be affected by polymorphism of the ABCB1 gene. The activity of hepatic cytochrome isoenzymes is influenced by drug-drug interactions, single-nucleotide polymorphisms, and environmental influences (smoking). PPI indicates proton pump inhibitor. Adapted from Bonello et al,4 with permission of the publisher. Copyright © 2011, Elsevier.Subsequent retrospective analyses of trials involving mainly non-PCI patients failed to demonstrate a significant association between CYP2C19 LoF allele carriage and adverse clinical outcomes. The relation of the gain-of-function allele (CYP2C19*17) carrier status and ABCB1 genotype (gene encoding the intestinal transporter protein that participates in clopidogrel absorption) to the antiplatelet response of clopidogrel and clinical outcomes in clopidogrel-treated patients is inconclusive at this time.32–38 Most recently, a single-nucleotide polymorphism of the gene encoding paraoxonase-1 was linked to the pharmacokinetic and pharmacodynamic effects of clopidogrel and stent thrombosis.39 However, in a substudy of the Gauging Responsiveness With A VerifyNow Assay–Impact on Thrombosis and Safety (GRAVITAS) trial and another study, there was no influence of the paraoxonase-1 polymorphism on platelet reactivity during clopidogrel therapy.40,41Taken together, these findings show that LoF allele carrier status is an important independent predictor of the pharmacodynamic response to clopidogrel and the outcomes of high-risk clopidogrel-treated patients who have undergone PCI. The strong relation of carriage to the occurrence of stent thrombosis is noteworthy and is a major rationale for determining the genotype of the PCI patient being considered for or already treated with clopidogrel.Addressing the Problem of CYP2C19 LoF Allele Carriage: High-Dose Clopidogrel Is Not the Best RemedyIn May 2009, the FDA first added information about poor metabolizers to the Plavix drug label.9 Another pharmacodynamic study prompted the addition of a boxed warning. In this randomized crossover study, the pharmacokinetic and pharmacodynamic effects of clopidogrel were examined in 40 healthy subjects, 10 from each of the genetically predicted metabolizer groups (ultrarapid, extensive, intermediate, and poor metabolizers). Subjects were randomized to treatment with either a 300-mg load followed by 75 mg daily for 5 days or a 600-mg load followed by 150 mg/d clopidogrel for 5 days. Compared with the other groups, poor metabolizers had the lowest peak plasma concentrations of clopidogrel active metabolite and the least platelet inhibition regardless of dose. Among the poor metabolizers, active metabolite concentration and platelet inhibition were greater with the higher-dose regimen compared with the lower-dose regimen.42 On the basis of these results, the FDA noted that healthcare professionals should be aware that tests are available to determine genotype and that the antiplatelet response in poor metabolizers is increased by high-dose clopidogrel. The FDA also recommended the use of other antiplatelet medications or alternative dosing strategies for clopidogrel in poor metabolizers.9However, other studies indicated the limited influence that high-dose clopidogrel has in normalizing platelet reactivity in patients carrying the LoF allele and that the antiplatelet effect of 150 mg/d clopidogrel was negligible in poor metabolizers.43,44 The largest (n=1152) combined assessment of genotype and serial platelet function was reported in a recent substudy of the GRAVITAS trial. In that analysis, the CYP2C19 LoF allele was significantly associated with high post-PCI platelet reactivity during high-dose clopidogrel treatment (odds ratio=1.62 for 1 LoF and 11.2 for 2 LoF alleles). LoF homozygotes with HPR treated with high-dose clopidogrel had the same poor antiplatelet response as LoF homozygotes with HPR treated with standard-dose clopidogrel.40 All of these data suggest that the recommendation implied by the FDA that poor metabolizers be treated with a high-dose clopidogrel regimen that was based on a healthy volunteer study is not relevant for CAD patients treated with stents.In a randomized study of patients with stable CAD, the CYP2C19 genotype and single-nucleotide polymorphisms of genes encoding other isoenzymes did not affect prasugrel active metabolite formation or the magnitude of platelet inhibition during either the loading or maintenance phase of treatment.45 Furthermore, in a subanalysis of the TRITON-TIMI 38 trial, carriers of the LoF allele treated with clopidogrel had higher rates of the primary outcome (12.1% versus 8.0%; hazard ratio=1.53; P=0.01) and definite/probable stent thrombosis (2.6% versus 0.8%; hazard ratio=3.09; 95% confidence interval=1.19–8.00; P=0.02) compared with noncarriers. However, among prasugrel-treated patients, LoF carrier status was unrelated to outcomes.35,46 The CYP2C19 LoF genotype significantly influenced the antiplatelet effect of clopidogrel but not ticagrelor, a direct-acting P2Y12 receptor blocker, in stable coronary artery disease patients.47 Platelet reactivity in ticagrelor-treated patients was consistently lower than in clopidogrel-treated patients regardless of CYP2C19 genotype.47 Furthermore, in the genetic substudy of the PLATO trial, ticagrelor was associated with a reduced occurrence of cardiovascular events compared with clopidogrel regardless of genotype.37The Escalating Clopidogrel by Involving a Genetic Strategy (ELEVATE)–TIMI 56 trial, conducted in PCI patients, demonstrated that triple-dose clopidogrel (225 mg daily) achieved, on average, the same platelet inhibitory effect in heterozygous LoF allele carriers that standard-dose clopidogrel (75 mg daily) achieved in noncarriers. Daily doses up to 300 mg were not able to produce a similar level of platelet inhibition in poor metabolizers.48 Taken together, these most recent studies indicate that higher clopidogrel doses can overcome the diminished pharmacokinetic/pharmacodynamic effects observed in carriers of 1 LoF allele during standard-dose clopidogrel therapy, whereas prasugrel and ticagrelor are better alternatives than high-dose clopidogrel in carriers of 2 LoF alleles (poor metabolizers).The fundamental reason for genotyping clopidogrel-treated patients is to identify the high-risk phenotype, ie, HPR. However, clopidogrel metabolism is influenced by other administered drugs and agents that share metabolic pathways with clopidogrel such as proton pump inhibitors, calcium channel blockers, and cigarette smoke (Figure 6). In addition, on-treatment platelet reactivity to ADP is influenced by the coronary artery disease state, age, sex, diabetes mellitus, and obesity.4 The net cumulative effect of all of these influences is reflected in the final platelet reactivity phenotype. Although the genotype is permanent, the cumulative influence of other factors on platelet reactivity is dynamic. Therefore, assessment of platelet function may be more appropriate than genotyping to indicate the risk for ischemic event occurrence.Rationale for Platelet Function Testing: The Overwhelming Body of Evidence Linking HPR to Ischemic Event OccurrenceOver 30 translational research studies involving thousands of patients have evaluated the relation of platelet reactivity during clopidogrel treatment to the risk of post-PCI ischemic event occurrence.4 Each of these studies has reached the identical conclusion: Patients treated with PCI who have HPR are definitely at increased risk for ischemic events, including stent thrombosis. These overwhelmingly concordant findings from studies conducted at centers around the world provide the strongest rationale for ex vivo quantification of the intensity of the ADP-P2Y12 interaction in patients treated with PCI and clopidogrel. Barragan et al49 first demonstrated an association between a platelet reactivity index >50% measured by vasodilator-stimulated phosphoprotein phosphorylation and the occurrence of thrombotic events in a case-control study. At the same time, Matetzky et al,50 using aggregometry, observed that patients undergoing primary PCI for ST-segment–elevation MI who were in the lowest quartile of clopidogrel responsiveness had the highest rates of ischemic events during follow-up. Recent meta-analyses of studies using the VerifyNow point-of-care assay lend strong support for the prior observations.51Evidence for a ThresholdSmall early studies demonstrated that ischemic risk was not linearly related to on-treatment platelet reactivity but rather occurred above a moderate level of platelet reactivity to ADP. In the Platelet Reactivity in Patients and Recurrent Events Poststenting (PREPARE POST-STENTING) study, a threshold of ≈50% maximal postprocedural aggregation (20 μmol/L ADP) was associated with the occurrence of an ischemic event within 6 months.52 Similarly, in the Clopidogrel Effect on Platelet Reactivity in Patients With Stent Thrombosis (CREST) study, ≈40% aggregation (20 μmol/L ADP) was associated with stent thrombosis occurrence.53 In a third study, ≈40% preprocedural platelet aggregation (5 μmol/L ADP) among patients receiving clopidogrel and aspirin therapy before stenting was associated with an ischemic event occurring within 12 months.54 Subsequent studies have provided evidence for a threshold of platelet reactivity associated with ischemic event occurrence. The threshold concept also has significant implications for reducing bleeding risk because achieving levels of platelet reactivity below the threshold may not further reduce ischemic risk.3,4Cutoff values for HPR determined by receiver-operating characteristic curve analysis have been associated with a high negative predictive value for the occurrence of major adverse cardiac events.4 In the large Do Platelet Function Assays Predict Clinical Outcomes in Clopidogrel-Pretreated Patients Undergoing Elective PCI (POPULAR) study, multiple assays were used to measure platelet reactivity in PCI patients who were then followed up for ischemic event occurrence within 1 year.13 As expected from the overall low prevalence of event rates, the positive predictive value was low for all assays used in the POPULAR study and in all the aforementioned studies. Receiver-operating characteristic curve analysis identified an association of the VerifyNow assay, light transmittance aggregometry, and single platelet counting results with the occurrence of the composite primary end point, with an area under the curve of ≈0.62 for each assay. The addition of HPR as measured by the noted platelet assays to more classic clinical and procedural risk factors resulted in a statistically significant improvement of the area under the curve to ≈0.73.13The HPR threshold in the consensus statement was determined by receiver-operating characteristic curve analysis and is applicable only to the PCI population.4 However, on the basis of the group of patients from GRAVITAS treated with standard-dose clopidogrel, an even lower threshold (≈170 P2Y12 reaction units [PRUs]) was associated with much greater sensitivity for ischemic event occurrence. It was suggested that this “immunity to thrombosis” cutoff should be considered the new therapeutic target in the PCI patient because a major goal of the treating physician who performs platelet function testing is to ensure that the patient is out of the danger zone for stent thrombosis.55,56 During the early phase of ACS and/or PCI, disease activity is greatest, and the prevalence of clopidogrel nonresponsiveness level is higher. At that time, a potent antiplatelet regimen may provide the greatest net clinical benefit (reduction in ischemic events that outweighs the risk of bleeding events), whereas at time points further downstream from the ACS event, less intense antiplatelet effects may be desirable. The optimal HPR threshold at ≈30 days may therefore differ from the acute threshold during the index ACS hospitalization.HPR Is Not Just a Risk Predictor But a Modifiable Risk Factor: Current Evidence From Prospective StudiesThe large body of consistent data from observational studies is strong evidence that HPR is a risk predictor; a single post-PCI measurement