Strong Biological Plausibility to Measure Platelet Function

Indisputable evidence from multiple areas of research provides a powerful rationale for platelet function testing in patients with high-risk coronary artery disease (CAD). Mathematical models using hybrid dissipative particle dynamics/partial differential equation model and animal models using platelet-labeling techniques and confocal microscopy have confirmed the pivotal role of platelets during occlusive thrombus generation.^1-4 Histological studies have demonstrated platelet thrombi at the site of coronary occlusion and distally in the microvasculature of patients with unstable angina prior to death.^5,6 Sustained platelet activation has been reported following the index myocardial ischemic event.⁷ By expressing adhesion molecules, activated platelets bind to dysfunctional endothelium and facilitate the adhesion and internalization of macrophages, thereby playing a key role in the initiation and progression of atherothrombosis.^8,9 Platelets have been shown to oxidize low-density lipoprotein (LDL) cholesterol. Oxidized LDL is a major contributor to plaque vulnerability.^10,11 Intravascular imaging techniques have demonstrated an independent association between high platelet reactivity to adenosine diphosphate (ADP) and atherosclerosis burden, periprocedural myocardial infarction (MI), and vessel calcification.^12,13 High platelet reactivity has been also independently linked to culprit lesion burden and adverse plaque morphology.¹⁴ Taken together, all these observations strongly support a fundamental relationship between platelet reactivity and activation and cardiovascular (CV) risk.

P2Y₁₂ Plays a Central Role in Amplifying the Response to Other Agonists

Continuous downstream signaling from the P2Y₁₂ receptor is essential for the amplification of platelet aggregation in response to all agonists that degranulate the platelet and release ADP, leading to irreversible and stable platelet-rich thrombus generation (Figure 1).¹⁵ In this line, P2Y₁₂ has recently been shown to inhibit RASA3, an important GTPase-activating protein that inhibits platelet activation and maintains GP IIb/IIIa in an inactive state.¹⁶ The latter observation further solidifies the key role for P2Y₁₂ receptor during occlusive thrombosis generation and supports the measurement of the reactivity to ADP as an important marker of CV risk.

Figure 1. P2Y₁₂ Plays a Central Role in Amplifying the Response to Other Agonists

Link of High Platelet Reactivity to Thrombosis in Percutaneous Coronary Intervention Patients: Observational Studies

Earlier small observational studies demonstrated a strong relation of high platelet reactivity to ADP phenotype to both short- and long-term ischemic event occurrences, including periprocedural MI and stent thrombosis.^17-19 Subsequent observational studies using various methods to measure platelet reactivity to ADP have further reinforced the earlier findings.²⁰ The magnitude of the association between platelet reactivity and ischemic risk is strongly dependent on the level of CV risk in clopidogrel-treated patients. Platelet reactivity to ADP allowed the reclassification of 44% of the total population of clopidogrel-treated patients to a different risk level for the outcome of major adverse clinical events, mostly in intermediate or high-risk patients.²¹ In the ADAPT-DES (Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents) registry of 8,583 patients, high platelet reactivity to ADP as measured by the VerifyNow assay was independently associated with 30-day and 2-year definite/probable stent thrombosis and MI.^22,23 Further analyses demonstrated a monotonic association between successively higher P2Y₁₂ reaction units quintiles (less platelet inhibition) and stent thrombosis with the lowest P2Y₁₂ reaction units quintile (more platelet inhibition) with the greatest risk for clinically relevant bleeding.²³ The latter findings in a large patient population strongly support the concept of a "therapeutic window" during which platelet reactivity to ADP is associated with both ischemic event occurrence (upper threshold) and bleeding risk (lower threshold).²⁴

Therapy With More Potent P2Y₁₂ Inhibitors Than Clopidogrel: Less Thrombosis

Clopidogrel is the most widely used P2Y₁₂ receptor blocker to prevent recurrent ischemic events in high-risk patients with CAD. However, it is associated with major limitations such as delayed onset of action, wide inter-individual variability, and low response or nonresponse as indicated by high platelet reactivity in nearly one third of patients that is associated with post-percutaneous coronary intervention (PCI) ischemic event occurrences.²⁴ These limitations provided a strong rationale for the development and use of more potent P2Y₁₂ inhibitors such as prasugrel and ticagrelor. In two prospective large-scale clinical trials in high-risk CAD patients, the therapy with the latter agents was associated with a nearly 20% relative-risk reduction in the occurrence of thrombotic events versus clopidogrel.^25,26 These findings further solidify the "platelet hypothesis" that states that pharmacologic treatment strategies associated with lower platelet reactivity to ADP as determined by ex vivo methods translates into fewer thrombotic event occurrences.²⁷ There is no stronger biologically plausible explanation than greater P2Y₁₂ inhibition for the latter large-scale clinical trial results. However, increased bleeding in patients treated with ticagrelor and prasugrel further indicate that instead of blanket use of these potent agents, platelet function testing may assist in selecting patients who are most likely to benefit from treatment with these potent P2Y₁₂ receptor blockers.

Personalized Antiplatelet Therapy Trials

Small, prospective studies with tailored antiplatelet therapy provided initial evidence that high platelet reactivity may not be just a diagnostic marker but also a modifiable risk factor for post-PCI ischemic event occurrence. These trials used either tailored incremental clopidogrel loading doses (LDs) before PCI to overcome high platelet reactivity or selective GP IIb/IIIa receptor blocker administration in patients who had high platelet reactivity following clopidogrel loading. The latter approaches to overcoming high platelet reactivity were effective in reducing periprocedural as well as long-term ischemic outcomes.^28-31

Encouraged by the positive results of the latter studies, two large-scale personalized antiplatelet therapy studies explored the utility of modifying antiplatelet therapy based on platelet function testing to improve clinical outcomes: The GRAVITAS (Gauging Responsiveness With A VerifyNow Assay-Impact On Thrombosis And Safety) trial (n = 2,214) and 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) study (n = 2,440) (Figure 2).^32,33

Figure 2. Randomized Trials of Personalized Antiplatelet Therapy

Study (Ref)	Patients (n)	Treatment regimen to address high platelet reactivity	Outcome	Comments
Bonello et al. 28	Patients with coronary stenting, vasodilator stimulated phosphoprotein (VASP)  phosphorylation (PRI) >50% on 600 mg clopidogrel (VASP-guided group = 78 vs. control = 84)	Repeated clopidogrel LD to decrease VASP-Index <50%	1 month CV death, angiographically confirmed ST, recurrent acute coronary syndrome (ACS): 0% vs. 10%, p = 0.007 Major and minor bleeding: 5% vs. 4%, p = 1.0	Low n
Bonello et al. 29	Patients undergoing stenting (50% ACS), VASP-PRI>50% on 600mg clopidogrel LD (VASP-guided group = 215 vs. control = 214)	Repeated clopidogrel LD to decrease VASP-Index <50%	<30 day definite stent thrombosis: 0.5% vs. 4.2%, p <  0.01 CV death, recurrent ACS and urgent revascularization by coronary angioplasty or bypass surgery 0.5% vs. 8.9% Bleeding, 2.8% vs. 3.7%, p = 0.8	Despite a 2,400-mg LD of clopidogrel, 8% of patients in the VASP-guided group had VASP-PRI  > 50%
Campo et al. 30	Patients undergoing PCI and treated with 600/300 mg clopidogrel (n = 826)	GP IIb/IIIa inhibitor	Periprocedural MI was associated with poor responsiveness, hazard ratio = 1.25. GP IIb/IIIa inhibitor reduced periprocedural MI in poor responders (21.2% vs. 3.47%, p = 0.02), not in responders (6.3% vs. 6.5%, p = 0.8).	Comparatively low-risk patients with silent ischemia, stable angina, and low-risk unstable angina
Cuisset et al. 31	Elective PCI patients with 10 mcM ADP-induced aggregation >70%	GP IIb/IIIa inhibitor arm, n = 74 Conventional arm, n = 75	1 month any death, periprocedural MI, acute or subacute definite or probable ST, and recurrent ACS, 19% vs. 40%, p = 0.006	Low n
GRAVITAS 32	Stable (60%) and non-ST elevation ACS (40%) patients with P2Y12 reaction units >230 on clopidogrel (n = 2,214)	600 mg LD/150 mg maintenance dose or 75 mg maintenance dose for 6 months	6 month CV death, nonfatal MI, or stent thrombosis 2.3% vs. 2.3%	Mainly low-risk patients, low event rate High-dose clopidogrel is not sufficient to reduce high platelet reactivity VerifyNow P2Y12 assay to determine high platelet reactivity
ARCTIC (33)	63% stable CAD + 27% non-ST elevation MI treated drug-eluting stent (n = 2,440)	VerifyNow assay High platelet reactivity was >550 aspirin reaction units or >235 P2Y12 reaction units (total ~40%) GP IIb/IIIa inhibitor (30 during PCI) + additional ≥600mg clopidogrel (83%) or 60 mg prasugrel (2.3%)	1 year death, MI, ST, or urgent revascularization (mainly driven by MI) 34% vs. 31%, p = 0.1 No difference in bleeding	Mainly stable CAD patients VerifyNow assay Twice more patients were lost to follow up in the conventional arm than in the monitoring arm (3.8% vs. 1.9%). The event rate was mainly driven by periprocedural MI that was assessed by nonuniform methodology postprocedure. Prasugrel was administered in only <10% of patients.

These investigations failed to demonstrate the utility of platelet function testing in reducing the post-PCI ischemic risk. However, both investigations used the VerifyNow P2Y₁₂ assay to identify high platelet reactivity, included a population of patients who had low postdischarge event rates irrespective of platelet reactivity, and largely used the suboptimal remedy of high-dose clopidogrel to overcome high platelet reactivity. In addition, low postdischarge event rates resulted in trials that were not adequately powered to prove or disprove the utility of platelet function testing in personalizing antiplatelet therapy.

Role of Platelet Function Testing in Determining Eligible Patients for Long-Term Dual Antiplatelet Therapy

The results of the DAPT Study (Dual Antiplatelet Therapy Study) and the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) trial support long-term dual antiplatelet therapy without interruption in selected patients at high risk for ischemic events and lower risk for bleeding.^34,35 In this scenario, objective measurement of platelet function may improve the identification of candidates who are more likely to benefit from prolonged dual antiplatelet therapy.³⁶

Personalized Antiplatelet Therapy in Patients Undergoing Cardiac Bypass Surgery

Current guidelines recommend 5-7 days discontinuation of P2Y₁₂ receptor inhibitor treatment in patients undergoing coronary artery bypass grafting to allow adequate platelet function recovery, thereby avoiding excessive perioperative bleeding. Recent studies have demonstrated that preoperative platelet function testing in these patients may assist in optimizing the timing of surgery to reduce perioperative bleeding.³⁷ The utility of platelet function testing in patients undergoing coronary artery bypass grafting and PCI patients has been acknowledged in recent guidelines.^37-42

Conclusions

High platelet reactivity is consistent with the proposed Wilson-Jungner requirements⁴³ for a meaningful risk marker because 1) it has biological plausibility because it is a measure of the potential for platelet aggregation in vivo, which is the physiological process being targeted by the P2Y₁₂ inhibitor; 2) there is a strong, consistent association of high platelet reactivity with worse outcome across multiple studies, including observational studies, analyses of randomized clinical trials, and meta-analyses; 3) high platelet reactivity precedes the event; and 4) there is evidence of a dose-response relationship between the degree of platelet reactivity and outcome. In addition, there is evidence of a "therapeutic window" of P2Y₁₂ receptor reactivity that provides a rationale for measuring platelet function to assess both ischemic and bleeding risk. A potential explanation for the neutral results in the recent prospective personalized antiplatelet therapy trials may be related to the assay itself. Platelet agglutination to fibrinogen-coated beads in anticoagulated blood in the VerifyNow P2Y₁₂ assay may not optimally discriminate high-risk patients. In this line, other point-of-care assays such as analyzers that are based on impedance aggregometry and thrombelastography that measures platelet-fibrin clot strength may be more effective in discriminating risk. In the ongoing TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment For Acute Coronary Syndromes Trial) (n = 2,600), an analyzer-guided approach is being used to personalize antiplatelet therapy in patients with ACS who are treated with PCI.

Current evidence suggests that platelet function testing may be useful in the following scenarios: 1) Identification of PCI patients at increased risk for CV complications; 2) monitoring response to antiplatelet agents to assist in personalizing antiplatelet therapy in selected high-risk patients undergoing PCI and also select high-risk patients for prolonged dual antiplatelet therapy; and 3) assessment of pharmacodynamic effects to optimally time surgical procedures to reduce wait time and bleeding.

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Keywords: Acute Coronary Syndrome, Adenosine, Adenosine Diphosphate, Agglutination, Angina, Stable, Angina, Unstable, Angioplasty, Aspirin, Atherosclerosis, Blood Platelets, Cholesterol, LDL, Coronary Artery Bypass, Coronary Artery Disease, Coronary Occlusion, Drug-Eluting Stents, Electric Impedance, Endothelium, Fibrin, Fibrinogen, GTPase-Activating Proteins, Macrophages, Microscopy, Confocal, Microvessels, Myocardial Infarction, Percutaneous Coronary Intervention, Phenotype, Phosphoproteins, Phosphorylation, Physiological Processes, Platelet Activation, Platelet Aggregation, Platelet Aggregation Inhibitors, Platelet Function Tests, Platelet Membrane Glycoprotein IIb, Prospective Studies, Randomized Controlled Trials as Topic, Receptor, PAR-1, Receptors, Thromboxane A2, Prostaglandin H2, Registries, Risk Factors, Risk Reduction Behavior, Stroke, Thrombelastography, Thrombin, Thrombosis, Thromboxane A2, Ticlopidine, Vascular System Injuries, Vasodilator Agents

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