Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel

Abstract

SummaryIt was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y 12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y 12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, twophase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18-24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18-24 h and 15 day reactivity to ADP (correlations 0.24-0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y 12 blockade with high-dose clopidogrel or even higher level P2Y 12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.

Factors Affecting Platelet Reactivity 2 Hours After P2Y₁₂ Receptor Antagonist Loading in Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction – Impact of Pain-to-Loading Time –

“…In patients undergoing elective PCI, pretreatment platelet reactivity predicted platelet reactivity 6 h after treatment with thienopyridines. 22 In 26 STEMI patients reported previously and included in this study, baseline platelet reactivity predicted platelet reactivity 2 h after ticagrelor LD, while in a large cohort of patients under ticagrelor maintenance dose, BASE (measured by VerifyNow), predicted platelet reactivity, although with a very low effect size. 23, 24 In line with the aforementioned reports, in an exclusively STEMI cohort described in the present study and treated with any of the 3 oral antiplatelet agents, pre-treatment platelet reactivity was positively associated with platelet reactivity 2 h after LD.…”

How I use laboratory monitoring of antiplatelet therapy

“…57,58 Esterases degrade ;85% of absorbed clopidogrel, leaving only ;15% to be converted by the cytochrome P-450 family of enzymes to the active metabolite required for inhibition of the platelet ADP receptor P2Y 12 . 51 Variability in clopidogrel pharmacokinetics and pharmacodynamics has been attributed to a number of factors, including patient noncompliance, absorption (eg, diet or polymorphisms in the transporter molecule ABCB1 54,59,60 ), smoking (which alters cytochrome P-450 levels), 61,62 polymorphisms in CYP2C19, 54-56 drugdrug interactions (eg, proton pump inhibitors [63][64][65] ), intrinsic variation in platelet function before exposure to clopidogrel, [66][67][68] and other clinical factors (obesity, renal dysfunction, diabetes mellitus, age, reduced left ventricular function, inflammation). 58 However, other as-yet unidentified factors also contribute to high ontreatment platelet reactivity.…”

Advances in the monitoring of anti-P2Y12therapy

“…ADP stimulation of platelets ex vivo in conjunction with a range of activation markers measured by flow cytometry has been successfully used to monitor clopidogrel responsiveness and has been shown to correlate with pre-treatment platelet reactivity [107][108][109].…”