Determinants of subacute response to clopidogrel: relative impact of CYP2C19 genotype and PGE1/adenylate cyclase signalling

- A potential basis for clopidogrel resistance extends beyond impaired bioactivation.
- Impaired “downstream” PGE1/adenylate cyclase signalling is a potential modulator.
- Pre-clopidogrel PGE1 platelet response predicted clopidogrel response at 7 days.
- This was a stronger multivariate associate of response than bio-activator genotype.

Backgroundand Hypotheses: The signal transduction pathway modulated by activation or blockade of platelet P2Y12 receptors is linked to PGE1-stimulated adenylate cyclase effects, but this link's impact on P2Y12 receptor antagonist response is uncertain. We therefore tested the hypothesis that pre-treatment platelet responsiveness to PGE1 predicts subsequent responsiveness to clopidogrel.MethodsIn order to maximise heterogeneity of platelet responsiveness to PGE1 we investigated both healthy subjects (n = 30) and patients with CHD undergoing elective coronary stenting (n = 22), all genotyped for common CYP2C19 variants associated with clopidogrel sensitivity (CS). We determined baseline pre-clopidogrel platelet sensitivity to the inhibitory effects of PGE1 by ADP-induced whole blood aggregation. Clopidogrel was administered for 7 days utilising a weight-based regimen. CS was expressed as change (Δ) in ADP-induced aggregation and in VASP-phosphorylation (VASP-P). We used univariate and multivariate analysis to correlate such parameters with PGE1 sensitivity, BMI and presence/absence of CHD.ResultsIn the study cohort, pre-treatment responsiveness to PGE1 varied widely (70 ± 28 [standard deviation (SD)]% inhibition of aggregation: range 10 to 100%). In the entire study cohort, pre-treatment PGE1 sensitivity correlated with CS irrespective of genotype. On univariate analysis, CS was not significantly greater for patients without than those with loss-of-function mutations. Moreover, at multivariate analysis, PGE1 sensitivity, but not genotype, was a strong correlate of ΔADP and ΔVASP-P (P < 0.0001 for both).ConclusionsThe integrity of the cAMP pathway is a major determinant of subacute CS.