Where Is the Significance of Measuring Platelet Function? Is the Answer in High Bleeding Risk Patients?

Percutaneous coronary intervention (PCI) is now performed worldwide for the treatment of coronary artery disease, and dual antiplatelet therapy (DAPT) is mainstream for reducing ischemic and thrombotic events after PCI.¹ Although antithrombotic therapy has beneficial effects for patients with increased atherosclerotic disease or populations in aging societies, there are racial differences and individual variability in the response to P2Y₁₂ receptor inhibitors, aspirin, or vitamin K-dependent anticoagulants.

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High residual on-treatment platelet reactivity has been reported to be associated with an increased risk of adverse events in patients taking a P2Y₁₂ receptor inhibitor after PCI,² and thus in conjunction with platelet function assays new potent antiplatelet agents have been developed to improve clinical outcomes, and, moreover, the dose or duration of antiplatelet agents has been also evaluated to reduce the bleeding risk as well as the ischemic/thrombotic risk. Light transmittance aggregometry, VeryfyNowP2Y₁₂ and Plateletworks assays had modest ability to discriminate between patients having and not having cardiovascular events in patients receiving DAPT after PCI;³ however, none of the monitoring tools was able to provide accurate prognostic information to identify patients at high bleeding risk (HBR). For now the value of platelet reactivity is merely as a risk marker, but not intervention means in changing a type, dose, or duration of antiplatelet agent.

Bleeding risk scores have been recently demonstrated using various items.^4–6 Each item is described in the Table, irrespective of being major or minor, as well as the distribution of points for each factor, and it is easy to compare the factors of each bleeding score, although this form may be rough and crude. In 2019, the Academic Research Consortium-High Bleeding Risk (ARC-HBR) criteria were proposed to define HBR in clinical trials evaluating the safety and effectiveness of devices and drug regimens for patients undergoing PCI.⁷ In Japan, the JCS 2020 guidelines focused update on antithrombotic therapy in patients with coronary artery disease presented a Japanese version of the HBR criteria.⁸ An ‘East Asian paradox’ has been described: East Asian patients have a similar or even a lower rate of ischemic/thrombotic events after PCI compared with Western patients, despite a higher level of platelet reactivity during DAPT, but rather have a higher bleeding risk. In such a situation, the ARC-HBR criteria were reported to be beneficial and applicable to Japanese patients undergoing PCI in a validation study.^9,10

Table. Representative Bleeding Scores

		PARIS	PRECISE-DAPT	CREDO-Kyoto	ARC-HBR	Japanese version-HBR
History	Age	○	○		○	○
Physical size	BMI or BW	○				○(frail)
Blood sampling	WBCs		○
Blood sampling	Hb/RBCs	○	○		○	○
Blood sampling	Platelets			○	○	○
Kidney	Renal function	○	○	○	○	○
Taste	Smoking	○
Heart	MI history			○
Heart	Heart failure			○		○
Heart	Atrial fibrillation			○
Internal medicine	Oral anticoagulant or triple ATT	○			○	○
Internal medicine	NSAIDs or steroids				○	○
Brain	Intracranial hemorrhage-related diseases or ischemic stroke				○	○
Bleeding	Bleeding history or diathesis		○		○	○
Medical history	Major surgery or major trauma				○	○
Medical history	Malignancy			○	○	○
Vessel	PVD			○		○
Liver	Cirrhosis				○	○

Irrespective of major or minor item, and the distribution of points for each factor, each item is presented in the same table. Although this presentation may be rough and crude, it is easy to compare the factors of each bleeding score. ARC-HBR, Academic Research Consortium-High Bleeding Risk; ATT, antithrombotic therapy; BMI, body mass index; BW, body weight; DAPT, dual antiplatelet therapy; Hb, hemoglobin; MI, myocardial infarction; NSAID, nonsteroidal anti-inflammatory drug; PVD, peripheral vascular disease; RBC, red blood cell; WBC, white blood cell.

In this issue of the Journal, Iijima et al¹¹ report that both ischemic/thrombotic and bleeding risks were higher in HBR patients than in non-HBR patients. Moreover, high platelet reactivity in HBR patients was associated with ischemic/thrombotic risk, but not with bleeding risk. As shown in figure 2A of their paper, high platelet reactivity and non-high platelet reactivity subgroups of non-HBR patients demonstrated a dissociation in ischemic/thrombotic event rates from an early stage. On the other hand, among the HBR patients, the event curves for the high platelet reactivity and non-high platelet reactivity subgroups overlapped at the beginning and a dissociation occurred from 1 month after PCI. As shown in figure 2B, there was no difference in bleeding risk between high platelet reactivity and non-high platelet reactivity subgroups of both HBR and non-HBR patients. They conclude that maintaining adequate platelet reactivity during DAPT may be an important factor in improving clinical outcomes, especially for HBR patients. These results are significant and of interest for both HBR patients and the tools used to assay platelet function. Enough inhibition of platelet aggregation is especially needed in the early stage after PCI. Despite numerous data on the association between high platelet reactivity and adverse outcomes, there are almost no data concerning the benefit of personalized antiplatelet therapy based on the results of platelet function testing. However, the present study indicates the necessity of platelet function tests, and there still might be room for optimization of antiplatelet therapy.

Where is the sweet spot for the significance of measuring platelet reactivity in patients receiving DAPT after PCI? The answer may be in patients at HBR after PCI, not in all patients after PCI. If a study could be performed in HBR patients alone, but not in the total patients including both HBR and non-HBR patients, it may reveal the possibility that personalized antiplatelet management according to measurement of platelet reactivity leads to better clinical outcomes in patients after PCI.

The trial abbreviation of PENDULUM can be translated as “Furiko” in Japanese, with the suggestion of swinging back and forth between bleeding and ischemic/thrombotic risks. The main study from the PENDULUM registry showed an association between high platelet reactivity and cardiovascular events in Japanese patients undergoing PCI.¹² As a subanalysis, the ARC-HBR criteria were reported to be applicable to Japanese patients and that renal dysfunction, use of anticoagulant, acute coronary syndrome, low body weight, and heart failure were independent predictive factors of bleeding events.¹³ Another study of PENDULUM indicated that single antiplatelet therapy with a potent antiplatelet agent may reduce bleeding risk without increasing ischemic/thrombotic risk compared with DAPT in patients after PCI.¹⁴

When we have arrived at the answer of what, how much, and how long we should prescribe, the implementation of personalized antiplatelet therapy may be already near in the selected patients at HBR, although only in part. Although the ABCD-GENE score (age, body mass index, chronic kidney disease, diabetes mellitus, and genotyping) was recently proposed to identify patients with high on-treatment platelet reactivity without platelet function testing,¹⁵ this paper by the PENDULUM team reminds us that personalized antiplatelet therapy and future studies are very much expected.

Disclosure

K.T. and H.O. are members of Circulation Journal’s Editorial Team.

References

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