P2Y₁₂ inhibitors, such as clopidogrel, prasugrel, and ticagrelor, play an integral role in the secondary prevention of ischemic events, including myocardial infarction (MI) or stent thrombosis after percutaneous coronary intervention (PCI).^1,2 These medications act by interrupting the process by which adenosine diphosphate (ADP) binds to P2Y₁₂ receptors, leading to platelet activation and the development of a stable platelet rich thrombus.³ However, studies have demonstrated that there is substantial variability in patient responsiveness to clopidogrel, with a significant proportion of patients (16-50%) considered to be nonresponders.^4,5 Because clopidogrel remains the most prescribed P2Y₁₂ inhibitor due to cost considerations and lower bleeding risk, there have been intense efforts to identify nonresponders and determine whether adjustments to antiplatelet regimens guided by platelet function testing will improve clinical outcomes. Despite these efforts, studies have failed to identify the clinical utility of platelet function testing.

Four ADP-stimulated assays have been evaluated on their ability to predict clinical outcomes in PCI patients, including vasodilator stimulated phosphoprotein light transmission aggregometry.^6-9 These ex-vivo assays measure either intracellular signaling pathways or the level of platelet aggregation after ADP stimulation of platelets.¹⁰ Despite differences in methodologies, these assays have good inter-assay correlation.¹¹ However, at this time, there is no consensus on optimal testing methodology or the cutoff values defining high platelet reactivity. In addition, platelet reactivity assays measure overall platelet reactivity and not just the impact of P2Y₁₂ inhibitors. Thus, patient comorbidities such as diabetes can also affect the results of these assays and further confound interpretation of the assay results.¹²

Multiple large observational studies have described the association between high platelet reactivity while on clopidogrel and increased rates of nonfatal MI, definite/probable stent thrombosis, and cardiovascular mortality.^8,13-15 For example, the ADAPT-DES (Assessment of Dual AntiPlatelet Therapy With Drug Eluting Stents) study was a prospective, multicenter registry of patients who were treated successfully with drug-eluting stents (DES) and dual antiplatelet therapy. Unlike other registries that included mostly stable patients, the ADAPT- DES registry included all-comers. Of the 8,582 patients enrolled, 48.3% had stable ischemic heart disease, and 51.7% presented with acute coronary syndromes (ACS), including 9.5% of patients with ST-elevation MI. Stent thrombosis occurred in 0.8% and MI in 3.1% of patients at 1 year. High platelet reactivity was an independent predictor of stent thrombosis (hazard ratio [HR] 2.49 [1.43-4.31], p = 0.001) and MI (HR 1.42 [1.09-1.86], p = 0.01) at 1 year, but high platelet reactivity was not a predictor of mortality.¹⁵ Although high platelet reactivity is associated with higher rates of ischemic outcomes, the positive predictive value of high platelet reactivity is low because of the very low rates of stent thrombosis and ischemic events with current generation DES. Because the majority of patients with high platelet reactivity will not have any adverse events, the ability of platelet function testing to identify which patients will have events is limited.

In addition, platelet function testing may have limited prognostic value in ACS patients who do not undergo revascularization. In the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, patients with stabilized ACS who were managed medically were randomized to treatment with either prasugrel or clopidogrel.¹⁶ Treatment with prasugrel was associated with greater and more consistent P2Y₁₂ receptor inhibition and lower rates of high platelet reactivity compared with clopidogrel (p < 0.001). However, the benefit of improved platelet inhibition was not associated with significant clinical improvements and was not an independent predictor of composite ischemic clinical outcomes.¹⁶ Therefore, direct correlations between high platelet reactivity and clinical outcomes could not be drawn in this population.

Given the prognostic value of high platelet reactivity in patients undergoing PCI, it is reasonable to hypothesize that individually tailoring anti-platelet therapy based on platelet function testing with more intensive P2Y₁₂ inhibition in patients with high platelet reactivity could improve clinical outcomes. If a patient has high platelet reactivity while on clopidogrel, several treatment options exist, including increasing the dose of clopidogrel, switching from clopidogrel to a newer antiplatelet agent, or adding a third antiplatelet agent. However, using platelet reactivity to drive clinical decision-making has not been demonstrated to have an impact on clinical outcomes. For example, a single-center, observational registry evaluated the impact of either increasing clopidogrel dosing or switching to ticlopidine therapy in ACS patients with high platelet reactivity after PCI.¹⁷ After treatment adjustment, median platelet reactivity decreased from 76% to 64% (interquartile range [IQR] 54-75%; p < 0.001) in patients with high platelet reactivity (defined as platelet aggregation ≥70% by light transmittance aggregometry of platelets with ADP). Nonetheless, even after adjustment, the high platelet reactivity group continued to have significantly higher rates of adverse ischemic events compared with patients without high platelet reactivity.

In addition, several randomized trials have failed to demonstrate improvement in clinical outcomes when using platelet function tests in clinical decision-making. The GRAVITAS (Gauging Responsiveness With A VerifyNow Assay-Impact On Thrombosis And Safety) trial was the first randomized study to evaluate the impact of high-dose compared to standard-dose clopidogrel for high platelet reactivity patients.¹⁸ In this study, 2,214 patients were enrolled after PCI for non-ST elevation ACS or stable angina; patients with ST-elevation MI were excluded. The primary endpoint was cardiovascular death, MI, or stent thrombosis at 6 months. Of the enrolled patients, 41% had high platelet reactivity (≥230 platelet reactivity units) at 12-24 hours after PCI. Despite documented lower platelet reactivity with high-dose clopidogrel (high-dose 211 platelet reactivity units [IQR 155-262 platelet reactivity units] vs. standard-dose 250 platelet reactivity units [IQR 206-298], p < 0.001), there was no difference in event rates between the two groups (2.3% in both groups; HR 1.01 [0.58-1.76], p = 0.97).

Platelet function testing has not been found to be beneficial with the use of new P2Y₁₂ inhibitors. The TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study attempted to evaluate whether treatment with prasugrel in patients with high platelet reactivity would improve clinical outcomes.¹⁹ A total of 423 patients with stable angina who underwent successful PCI with DES and with high platelet reactivity were randomized to receive either clopidogrel or prasugrel. An interim analysis performed after 236 patients completed their 6 month follow-up demonstrated that treatment with prasugrel led to significantly lower platelet reactivity (mean [IQR] 80 platelet reactivity units [42-124] vs. 241 [194-275], p < 0.001) at 3 months. However, only one primary endpoint event (cardiac death or MI) had occurred. As a result of the lower-than-expected rate of ischemic events, the study steering committee stopped the trial for futility.

In contrast to prior studies that evaluated the utility of platelet function measured only after PCI, the ARCTIC (Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and Interruption Versus Continuation of Double Antiplatelet Therapy, One Year After Stenting) trial evaluated the impact of adjusting P2Y₁₂ treatment based on platelet function testing performed before and after PCI on outcomes. A total of 2,440 patients with stable angina or non-ST elevation ACS undergoing PCI were randomized to either monitoring with platelet function testing with treatment intervention or to standard of care without platelet function testing. Monitored patients received platelet function testing before stent implantation and during the maintenance phase. Treatment adjustments, which included using GP IIb/IIIa inhibitors before/during the index procedure, higher dose of clopidogrel, or switching to prasugrel, were made according to a predefined treatment algorithm. At 1 year, there was no significant difference in the rate of death, MI, stent thrombosis, stroke, or urgent revascularization (HR 1.13 [0.98-1.29], p = 0.10).²⁰ Furthermore, a landmark analysis failed to demonstrate a significant difference in stent thrombosis, stroke, or urgent revascularization between discharge and 1-year follow-up.²¹ Therefore, adjustment of P2Y₁₂ inhibition strategies based on platelet function testing performed prior to or after PCI failed to improve ischemic outcomes in low- to moderate-risk patients.

Based on the limited benefit of adjusting anti-platelet therapy according to platelet function testing, the 2011 American College of Cardiology (ACCF)/American Heart Association (AHA)/ Society for Cardiac Angiography and Interventions Guideline for Percutaneous Coronary Intervention provides Class IIb recommendations (Level of Evidence C) that 1) platelet function testing may be considered in patients at high risk for poor clinical outcomes, and 2) in patients treated with clopidogrel with high platelet reactivity alternative agents might be considered.²² Furthermore, the routine clinical use of platelet function testing to screen patients treated with clopidogrel who are undergoing PCI is not recommended. In the 2011 ACCF/AHA Focused Update of the guidelines for the management of patients with unstable a or non-ST elevation MI, performing platelet function testing to determine platelet inhibitory response in patients with unstable angina or non-ST elevation MI (or after ACS and PCI) on thienopyridine therapy may be considered if results of testing may alter management (Class IIb).²³ In addition, the limited utility of platelet function testing is reiterated in the 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes.²⁴

In conclusion, high platelet reactivity in patients receiving a P2Y₁₂ inhibitor after PCI is associated with worse ischemic outcomes; however, multiple large, randomized studies have failed to demonstrate any clinical improvement when P2Y₁₂ inhibitor treatments are adjusted based on platelet function testing. The reason behind the lack of demonstrable benefit from tailored point of care adjustment in P2Y₁₂ inhibition is likely multifactorial. The clotting cascade is composed of multiple pathways, and increasing the inhibition of a single specific receptor may not overcome other thrombotic pathways, which are likely to also be activated in the patient with high platelet reactivity. Furthermore, with current generation DES, ischemic event rates including stent thrombosis and MI are significantly lower than with first-generation DES. As a result, it is increasingly difficult to demonstrate clinically meaningful improvements with therapy adjustments. Thus, although it is intuitive that platelet function testing-guided P2Y₁₂ therapy should improve ischemic outcomes in high-risk patient cohorts undergoing PCI, large randomized trials have failed to demonstrate its clinical utility to change clinical practice. Therefore, platelet function testing should not be used in routine clinical practice and should remain a research tool until a patient population that benefits from this testing can be identified.

References

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19. Trenk D, Stone GW, Gawaz M, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012;59:2159-64.
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Keywords: Acute Coronary Syndrome, Adenosine, Adenosine Diphosphate, Angina, Stable, Angina, Unstable, Angiography, Blood Platelets, Comorbidity, Diabetes Mellitus, Drug-Eluting Stents, Medical Futility, Myocardial Infarction, Percutaneous Coronary Intervention, Phosphoproteins, Platelet Activation, Platelet Activation, Platelet Aggregation, Platelet Aggregation Inhibitors, Platelet Function Tests, Platelet Membrane Glycoprotein IIb, Prospective Studies, Random Allocation, Randomized Controlled Trials as Topic, Secondary Prevention, Stroke, Thrombosis, Ticlopidine, Vasodilator Agents, Acute Coronary Syndrome

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