Pharmacodynamic response to clopidogrel and outcomes in the ARCTIC randomized trial

Abstract

Background: The ARCTIC trial failed to demonstrate improvements in outcomes with platelet-function monitoring and treatment adjustment for PCI Aim: To analyze clinical outcome according to clopidogrel pharmacodynamic (PD) response using the VerifyNow assay just before PCI. Methods: Among patients randomized in the monitoring arm of the ARCTIC trial (n=1213), 419 (34.5%) had high on-treatment platelet reactivity (HPR patients) before PCI and underwent treatment adjustment. We compared the occurrence of the composite primary end point (PEP) of death, MI, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation in patients presenting HPR to clopidogrel before PCI (n=419), non-HPR patients (n=794) and patients randomized in the conventional arm without PD evaluation (n=1227). Safety bleeding endpoints were also analyzed. Results: HPR to clopidogrel was associated with higher age, female gender, higher bodyweight, diabetes and PPI use (all p <0.05). HPR patients underwent more aggressive antiplatelet strategy than non-HPR patients due to the study protocol, with significant more frequent use of GPIIbIIIa inhibitors (79.2% vs. 5.2%, p<0.01), clopidogrel LD (80.2% vs 3.5%, p<0.001) or prasugrel LD before PCI (3.3% vs 0.1%, p<0.001) as compared with non-HPR patients. High clopidogrel MD (150mg or more) (82.6% vs. 32.1%, p<0.001) or prasugrel 10mg MD (18.6% vs. 4.4%%, p<0.001) was also significantly more frequent in HPR patients at discharge as compared with non-HPR patients. The PEP occurred in 34.6% of the patients with HPR who underwent treatment adjustment, in 34.6% of the non-HPR patients (HR 0.97 [0.80; 1.19], p= 0.8) and in 31.1% of the patients randomized in the conventional arm (HR 1.11 [0.91; 1.34] p= 0.31 and 1.14 [0.97; 1.33], p=0.11) for both comparisons). Despite using a much stronger antiplatelet strategies in HPR patients, major bleeding did not differ between HPR patients as compared with non-HPR patients (2.6% vs. 2.1%, respectively, HR 1.19 [0.56; 2.54] p= 0.65) or from patients randomized in the conventional arm of the ARCTIC study (2.6% vs. 3.3%, HR 0.78 [0.40; 1.53] p= 0.47). Conclusion: In ARCTIC, the prognosis of patients with HPR before PCI leading to antiplatelet therapy adjustment did not differ from patients without HPR and without adjustment of therapy. Although, this subgroup analysis comforts the main finding of the study, the hypothesis that tailoring might have corrected impaired prognosis associated with HPR in this high-risk group of patients cannot be eliminated by the ARCTIC study.