The Evidence Base for Platelet Function Testing in Patients Undergoing Percutaneous Coronary Intervention
2010; Lippincott Williams & Wilkins; Volume: 3; Issue: 3 Linguagem: Inglês
10.1161/circinterventions.109.928861
ISSN1941-7632
Autores Tópico(s)Coronary Interventions and Diagnostics
ResumoHomeCirculation: Cardiovascular InterventionsVol. 3, No. 3The Evidence Base for Platelet Function Testing in Patients Undergoing Percutaneous Coronary Intervention Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBThe Evidence Base for Platelet Function Testing in Patients Undergoing Percutaneous Coronary Intervention Matthew J. Price Matthew J. PriceMatthew J. Price From the Division of Cardiovascular Diseases, Scripps Clinic, La Jolla, Calif. Originally published1 Jun 2010https://doi.org/10.1161/CIRCINTERVENTIONS.109.928861Circulation: Cardiovascular Interventions. 2010;3:277–283is corrected byCorrectionClopidogrel therapy significantly reduces cardiovascular events in patients presenting with acute coronary syndrome (ACS)1,2 and in patients undergoing percutaneous coronary intervention (PCI),3 yet cardiovascular events, including stent thrombosis, continue to occur after PCI despite the ischemic benefit conferred by clopidogrel. Minimizing the incidence of stent thrombosis is a central goal for stent manufacturers, pharmaceutical companies, regulatory bodies, and practicing interventional cardiologists, and professional societies have formally recommended prolonged thienopyridine therapy after drug-eluting stent implantation in the absence of randomized controlled clinical trials.4 A growing body of data supports the contention that the level of platelet reactivity on clopidogrel therapy ("on-treatment" platelet reactivity) is an independent risk factor for ischemic and thrombotic events post-PCI and that the intensification of platelet inhibition may improve outcomes in at-risk patients. The introduction of point-of-care and clinical laboratory-based platelet function assays has made it feasible to consider the routine evaluation of on-treatment platelet reactivity in the patient undergoing PCI.5,6 The current data set provides clinicians with a strong scientific rationale for the use of platelet function assays in daily practice.Response by Kalyanasundaram and Berger on p 283Clopidogrel Metabolism and the Mechanism of Response VariabilityClopidogrel is a prodrug that requires biotransformation into an active metabolite to exert its inhibitory effect on platelet aggregation. Approximately 85% of absorbed clopidogrel is hydrolyzed by esterases in the gut into an inactive form, and the remainder is converted into an active metabolite by the hepatic cytochrome P450 (CYP) system through a 2-step oxidative process.7 The active metabolite irreversibly binds and antagonizes the P2Y12 ADP receptor for the life of the platelet. The platelet inhibitory response to clopidogrel varies substantially among patients according to ex vivo measurements,8 with many patients having persistently high platelet reactivity despite clopidogrel treatment. Genetic polymorphisms that affect the catalytic activity of the CYP2C19 isoenzyme are associated with reduced levels of the clopidogrel active metabolite and, in turn, higher levels of platelet reactivity on clopidogrel therapy.9 Carriers of a loss-of-function CYP2C19 allele have higher cardiovascular events when treated with clopidogrel after myocardial infarction (MI) compared with noncarriers.10–12 However, the major loss-of-function allele CYP2C19*2 accounts for only 12% of the variation in clopidogrel response; thus, the majority of the variation in platelet response to clopidogrel remains unexplained.13 The more consistent antiplatelet effect observed with prasugrel compared with clopidogrel is explained by more efficient generation of prasugrel's active metabolite, which has no more inherent inhibitory effect on the P2Y12 receptor than that of clopidogrel.14Most Relevant Descriptor of the Platelet Inhibitory Effect of Clopidogrel in Clinical Practice Is On-Treatment Platelet ReactivitySubstantial confusion arises from the different terms used to describe the platelet inhibitory effect of clopidogrel. The inhibitory effect of an antiplatelet agent can be described by the absolute or relative change in aggregation before and after antiplatelet exposure (ie, the Δ or inhibition of platelet aggregation, respectively). Alternatively, the inhibitory effect can be described by the residual platelet reactivity during therapy (also referred to as on-treatment reactivity). The latter requires only a single blood sample after antiplatelet initiation (eg, before PCI in a patient on maintenance clopidogrel therapy). Although both measurement approaches can be used to describe an antiplatelet effect, they are not interchangeable; they may identify different sets of patients with potentially different risks of subsequent events.15 On-treatment reactivity should be the primary measurement used clinically because it is the most practical and has the greatest amount of prospective clinical data to support diagnostic cutoffs for the identification of at-risk patients.5,16On-Treatment Platelet Reactivity Is a Risk Factor for Cardiovascular Events After PCIPlatelet reactivity satisfies the criteria required by a variable to be considered a risk factor for a given clinical outcome.17 First, the relationship between on-treatment reactivity and thrombotic events is biologically plausible. Second, there is a strong and consistent association across studies between a lack of clopidogrel effect around the time of PCI and subsequent ischemic and thrombotic events.5 Third, there is evidence for a dose-response relationship: ADP-induced platelet aggregation is an independent predictor of a 30-day major adverse clinical event after PCI when considered as a continuous variable,18 and increasing event rates are observed across quartiles of on-treatment reactivity.19–23Diagnostic Cutoffs for High On-Treatment Reactivity Have Been Determined for Several Platelet Function AssaysSeveral methods are available to measure on-treatment platelet reactivity (Table 1). Diagnostic cutoffs for high on-treatment reactivity according to various platelet function assays have been prospectively determined using receiver operating characteristic curve analysis, which is a standard approach for evaluating the performance of a diagnostic test and defining a cut point that optimizes both sensitivity and specificity.24 Platelet function on clopidogrel therapy according to multiple electrode aggregometry using the Multiplate analyzer was examined in 1608 patients undergoing PCI with drug-eluting stents. The optimal cutoff value according to receiver operating characteristic curve analysis to predict the occurrence of 30-day stent thrombosis was 468 aggregation units per minute, which provided 70% sensitivity and 84% specificity21 and a negative predictive value of >99% (D. Sibbing, MD, personal communication, 2010). Multivariate analysis showed that high on-treatment reactivity according to multiple electrode aggregometry was a strong, independent predictor of stent thrombosis, with a hazard ratio of 10.95 (95% CI, 2.3 to 52.0; P=0.003). The VerifyNow P2Y12 assay has been prospectively examined in 4 studies at different centers involving a total of 2275 patients undergoing PCI for stable and unstable coronary artery disease.20,23,25,26 Each study found through receiver operating characteristic curve analysis that this platelet function assay is able to discriminate between patients with and without subsequent events. The studies calculated a consistent optimal diagnostic cutoff point between 235 and 240 P2Y12 reaction units, which provided a negative predictive value of >96%. In 680 patients undergoing PCI for ACS, on-treatment reactivity greater than the diagnostic cutoff point (240 P2Y12 reaction units) was strongly and independently associated with a higher risk of cardiovascular death (hazard ratio, 2.55; 95% CI, 1.08 to 6.07; P=0.034) and nonfatal MI (hazard ratio, 3.36; 95% CI, 1.49 to 7.58; P=0.004) at 1-year follow-up.20 Similarly, in 1052 patients undergoing elective PCI, on-treatment reactivity greater than the receiver operating characteristic curve-derived diagnostic cutoff point (236 P2Y12 reaction units) was associated with a markedly higher risk of the 1-year composite end point of death, nonfatal MI, definite stent thrombosis, and stroke (odds ratio, 2.53; 95% CI, 1.63 to 3.91; P 50%VN P2Y12Agglutination of fibrinogen-coated beads by platelets in the presence of ADP (20 μmol) and PGE1True POC assay; largest number of patients studied with clinical outcomesAssociation with clinical outcomes not well studied for surrogate measurement of percent inhibition provided by device without baseline preclopidogrel samplePRU >235–240Multiplate analyzer (MEA)Change in electrical conductance between a pair of electrodes as platelets adhere after exposure to ADPWhole-blood assayAssociation with clinical outcomes shown only in large single-center study; not currently available in the United States>468 AU/minPlateletWorksDifference in single-platelet counts by cell counter after stimulation with ADP vs baselineWhole-blood assayAssociation with clinical outcomes from single-center study; results highly depend on time between-sample collection and testing>80.5%AU indicates aggregation units; LTA, light transmittance aggregometry; ROC, receiver operator characteristic curve analysis; MEA, multiple electrode aggregometry; n/a, not applicable; POC, point-of-care; PGE1, prostaglandin E1; PRI, platelet reactivity index; PRU, P2Y12 reaction units; VASP, vasodilator-stimulated phosphoprotein phosphorylation analysis; and VN, VerifyNow.Light transmittance aggregometry and vasodilator-stimulated phosphoprotein phosphorylation analysis also can be used to identify patients at risk for thrombotic and ischemic events after PCI. Both techniques are time intensive and require substantial specimen processing and specialized training that hinders their practicality in the clinical setting. Firm diagnostic cutoff points for these methods are weakened by the lack of uniform agonist concentrations used in published studies with light transmittance aggregometry and the relatively small total number of patients studied with vasodilator-stimulated phosphoprotein.27,28 Therefore, these techniques currently cannot be recommended for clinical decision making outside of experienced laboratories.It is conceivable that on-treatment platelet reactivity in a particular patient may decrease over time after the acute phase of their coronary artery disease is resolved. However, 2 small studies demonstrated that the effect of clopidogrel measured soon after PCI seemed durable over 1 month29 and 1 year of follow-up.30 In any regard, such potential temporal variation does not seem to have substantial clinical relevance: a single measurement of platelet reactivity on clopidogrel therapy around the time of PCI is an independent predictor for cardiovascular events at 30-day,18,21,22,26 6-month,25,28,31,32 and 1-year follow-up,20,23,33 even in patients initially presenting with ACS or MI.Alternative Antiplatelet Strategies Can Intensify Platelet Inhibition in Patients With High On-Treatment ReactivitySeveral approaches have been shown to reduce platelet reactivity in patients identified by platelet function testing as at risk for cardiovascular events post-PCI, including increasing the clopidogrel dose34–37; adding cilostazol35,38; or switching to ticlopidine,39 prasugrel,14 or potentially ticagrelor.40 In the acute setting, administration of a glycoprotein IIb/IIIa inhibitor also may be considered.41 The appropriate strategy may be dictated by the patient's comorbidities (eg, avoiding cilostazol in patients with left ventricular dysfunction), contraindications (eg, avoiding prasugrel in patients with a clinical history of stroke or transient ischemic attack or substantial bleeding risk), lack of insurance coverage for additional clopidogrel, or possibly CYP2C19 genotype.42 The Genotype Information and Functional Testing study (clinicaltrials.gov identifier NCT00992420) will help to clarify whether CYP2C19 genotype affects the incremental response to high-dose clopidogrel in patients with high on-treatment reactivity on standard therapy.Rationale for Optimizing Antiplatelet Therapy After PCI Using Platelet Function Testing Is Consistent With the Current Paradigm of Antiplatelet Therapy Selection in Interventional CardiologyThe goal of antiplatelet therapy after PCI is to maximize ischemic benefit while minimizing the risk of bleeding. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38)43 and the Study of Platelet Inhibition and Patient Outcomes (PLATO)44 confirmed the hypothesis that greater and more consistent P2Y12 inhibition reduces ischemic events, including stent thrombosis after PCI for ACS. Both trials also demonstrated that a nonselective strategy for potent P2Y12 inhibition is associated with significantly increased rates of major non-coronary artery bypass graft-related bleeding. Intensive antiplatelet therapy provides the greatest net clinical benefit in patients with the highest ischemic risk, whereas it provides little ischemic benefit and potential net clinical harm in patients at low ischemic risk.45 As noted earlier, large prospective studies have demonstrated that the hazard for post-PCI events in patients treated with clopidogrel is concentrated in the minority of patients with high on-treatment reactivity; the majority of patients treated with clopidogrel (≈70%) seem to be at low ischemic risk (Figure). The on-treatment reactivity provided by the recommended dosages of prasugrel and ticagrelor is generally lower than the bottom range of on-treatment reactivity with clopidogrel,46,47 and lower levels of on-treatment reactivity are associated with increased rates of bleeding.43,48 Therefore, patients with high platelet reactivity on clopidogrel should have the greatest net clinical benefit with intensified P2Y12 inhibition given their substantially increased risk for ischemic events, whereas treating patients with adequate on-treatment reactivity with newer P2Y12 inhibitors may provide little ischemic benefit but increase the relative chance of bleeding. In patients with ACS, such a selective approach to aggressive P2Y12 inhibition would likely provide substantial cost savings with the advent of generic clopidogrel.Download figureDownload PowerPointFigure. Hazard ratios for cardiovascular death and nonfatal MI by quartiles of P2Y12 reaction unit values in patients treated with clopidogrel undergoing PCI for ACS. Risk appears concentrated in the patients with the highest on-treatment reactivity. Adapted with permission from Marcucci et al. Circulation. 2009;119:237–427.20 CV indicates cardiovascular; PRU, P2Y12 reaction units.Initial Data From Randomized Trials Support the Principle of Individualized P2Y12 Inhibitor Therapy in Patients Undergoing PCIThe efficacy of selective intensification of platelet inhibition in patients with high platelet reactivity on clopidogrel therapy has been tested in 2 small randomized trials. In the Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel (3T2R) study, the use of periprocedural tirofiban in patients with clopidogrel nonresponsiveness reduced the rate of periprocedural MI and 30-day major adverse clinical events.41 Another small randomized study demonstrated that routine abciximab therapy compared with conventional management decreased 30-day major adverse clinical events in patients with high on-treatment reactivity undergoing elective PCI.49 A strategy of repeated clopidogrel-loading doses guided by vasodilator-stimulated phosphoprotein phosphorylation analysis to achieve adequate on-treatment platelet reactivity before PCI (platelet reactivity index 230Clop 75 mg/dayClop reload, then 150 mg/dayCV death, MI, and ST6 min2800TRIGGER-PCI (NCT00910299)Elective PCIVN P2Y12PRU >208Clop 75 mg/dayPrasugrel 60 mg/10 mgCV death and MI6 min2150DANTE (NCT00774475)ACSVN P2Y12PRU >240Clop 75 mg/dayClop 150 mg/dayCV death, MI, and TVR12 min442ARCTIC (NCT00827411)Elective PCIVN P2Y12<15%Standard of care (no PFT)PFT-guided (GPIIb/IIIa inhibitor, iterative increases in clop maintenance dose)Death, MI, stroke, urgent TVR, and ST12 min2500Clop indicates clopidogrel; CV, cardiovascular; GPIIb/IIIa, glycoprotein IIa/IIIa; PFT, platelet function testing; PRU, P2Y12 reaction units; ST, stent thrombosis; TVR, target vessel revascularization; and VN, VerifyNow.Several important questions regarding platelet function-guided antiplatelet therapy will not be answered by any currently planned trial. For example, in patients undergoing PCI for ACS, would the selective use of prasugrel or ticagrelor only in patients with high on-clopidogrel platelet reactivity and standard clopidogrel in the remainder of patients maximize net clinical benefit and be cost saving compared with the uniform administration of prasugrel or ticagrelor? Could the use of a generic agent such as cilostazol, which may have a greater inhibitory effect than high-dose clopidogrel in patients with high on-treatment reactivity,35 effectively (and cheaply) reduce ischemic events in at-risk patients? Randomized trials provide the most rigorous data for an evidence-based approach to clinical decision making, but market forces may prevent the production of such data for platelet function testing beyond the currently planned studies. The companies that develop and market platelet function assays do not have sufficient capital to independently support large clinical trials; clopidogrel shortly will lose its patent protection and will have no patron with an economic interest to demonstrate whether it may provide superior net clinical benefit in the majority of patients with ACS compared with newer agents; and larger pharmaceutical companies who already have garnered Food and Drug Administration approval for their drugs may not be incentivized to expand their label beyond the current ACS population or to risk narrowing their label to only a select patient population. Therefore, clinicians must base their decisions regarding optimal antiplatelet therapy after PCI on sound scientific rationale and the best available medical evidence, although the most rigorous evidence may be limited beyond the specific scenarios tested by pending randomized trials.ConclusionPlatelet reactivity on clopidogrel therapy varies widely among individuals. High on-treatment platelet reactivity around the time of PCI is a risk factor for subsequent adverse cardiovascular events, whereas stronger levels of platelet inhibition are associated with increased rates of major bleeding. Point-of-care and clinical laboratory-based platelet function assays are available that can identify patients at high risk for ischemic events after PCI using diagnostic cutoff points derived from multiple prospective studies. The presence of high on-treatment reactivity based on these cutoff points provides incremental prognostic information beyond clinical and procedural characteristics. Several different therapeutic approaches can intensify platelet inhibition in the patient with high on-treatment reactivity. The proof of principle for an individualized approach to antiplatelet therapy has been demonstrated in small randomized trials. Ongoing multicenter randomized clinical trials such as GRAVITAS: Gauging Responsiveness With A VerifyNow Assay-Impact On Thrombosis And Safety (GRAVITAS, clinicaltrials.gov identifier NCT00645918) and Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel (TRIGGER-PCI, clinicaltrials.gov identifier NCT00910299) will provide further clarity regarding the safety and efficacy of individualized antiplatelet therapy in the patient undergoing PCI. Even with the results of these studies, definitive randomized data supporting the optimal and most cost-effective antiplatelet regimen post-PCI may not be obtained because of the lack of market incentive to provide funding for further trials. For now, the clinical use of platelet function testing must be based on sound scientific rationale and the consistent data derived from prospective observational studies.DisclosuresDr Price has received research grants from Bristol Meyers Squibb/Sanofi Aventis and Accumetrics and has received consulting fees and honoraria from Daiichi Sankyo/Lilly, AstraZeneca, Bristol Meyers Squibb, Sanofi Aventis, Accumetrics, Boston Scientific, Abbott Vascular, The Medicines Company, and Johnson and Johnson. Dr Price is also the principal investigator of the GRAVITAS trial.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.This article is Part I of a 2-part series. 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