Role of Prasugrel, a Novel P2Y12 Receptor Antagonist, in the Management of Acute Coronary Syndromes

Abstract Aims To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). Methods and results In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting ≥3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked ∼30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4–11%). Conclusions Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable.

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Clopidogrel response variability and the advent of personalised antiplatelet therapy

Thrombosis and Haemostasis ◽

10.1160/th11-03-0167 ◽

2011 ◽

Vol 106 (08) ◽

pp. 265-271 ◽

Cited By ~ 24

Author(s):

Paul A. Gurbe ◽

Udaya S. Tantry

Keyword(s):

Antiplatelet Therapy ◽

Platelet Activation ◽

Acute Coronary Syndromes ◽

Ex Vivo ◽

Platelet Reactivity ◽

P2y12 Receptor ◽

Current Evidence ◽

Ischaemic Event ◽

Coronary Syndromes

SummaryPlatelet-mediated thrombosis is a dreaded clinical event and is the primary cause of acute coronary syndromes and post-percutaneous intervention (PCI) ischaemic events. There has been a long standing interest in the ex vivo quantification of platelet reactivity to assess the risk of thrombosis. Early studies demonstrated platelet activation and heightened platelet reactivity in acute coronary syndromes and after PCI. However, a demonstration that heightened reactivity actually precipitated the ischaemic event was lacking. Our knowledge of platelet receptor physiology and the advent of novel inhibitors have significantly advanced the field. The P2Y12 receptor has been shown to play a pivotal role in the amplification of platelet activation by multiple agonists and its inhibition has resulted in improved clinical outcomes. The most widely used drug to block P2Y12 receptor, clopidogrel is associated with resistance in selected patients and these patients have been shown to be at increased risk for post-PCI ischaemic event occurrence in multiple studies. Importantly, a threshold of high platelet reactivity has been demonstrated, and beyond this threshold ischaemic events occur precipitously. Based on the current evidence, it is rational to quantify the intensity of the ADP-P2Y12 interaction in the patient at the greatest risk for thrombosis-the PCI patient. However, there is only evidence from small clinical trials demonstrating the clinical efficacy of changing an antiplatelet regimen based on an ex vivo platelet function measurement. Moreover, there are numerous patients with vulnerable coronary anatomy that have not yet experienced plaque rupture; the prognostic role of a measurement of platelet reactivity in the latter group has never been studied. Large-scale trials are ongoing that will investigate the role of personalised antiplatelet therapy in the PCI patient.

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