Author + information
- Gerasimos Siasos, MD, PhD,
- Dimitris Tousoulis, MD, PhD, FACC* ( and )
- Christodoulos Stefanadis, MD, PhD, FACC
- ↵*1st Cardiology Unit, Hippokration Hospital, Athens University Medical School, 69 South Karagiorga Street, Glifada, Athens 16675, Greece
We read with interest the paper by Ang et al. (1) in a previous issue of the Journal. The purpose of the study was to identify factors associated with lower platelet inhibition (PI) with clopidogrel in patients with cardiovascular disease. Their results showed that elevated plasma fibrinogen ≥375 mg/dl is a unique factor associated with lower PI in diabetic patients, whereas increased body mass index remains independently associated with lower PI after clopidogrel therapy. They also identify the presence of diabetes mellitus as a factor associated with lower PI. However, this finding was only significant in the presence of an elevated serum fibrinogen level. No other statistical association with PI was found in the multiple variable model.
Although these findings are interesting, other factors involving clopidogrel response have not been completely evaluated. For example, the impact of genetic polymorphisms or other genetic factors on clopidogrel response has not been evaluated in the study. It is well known that P2Y12receptor inhibition is implemented by an active metabolite of clopidogrel. Therefore, genetic variants of enzymes within the metabolic pathways (P450 enzymes) or downstream targets of the active metabolite (P2Y, platelet glycoproteins IIb/IIIa and Ia) might affect clopidogrel response. Moreover, the metabolic activity of the P450 enzymes varies considerably among individuals. Genetic polymorphisms of the cytochrome P450 isoenzymes such as CYP3A4*1B (rs2740574), CYP3A5*3 (rs776746), and CYP2C19*2 (rs4244285) have been implicated to modulated individual response to clopidogrel (2). However, only CYP2C19*2 (SNP rs4244285, AA genotype) polymorphism association with variable clopidogrel response has been validated in both healthy and acute coronary syndrome individuals (3). The association of platelet glycoproteins IIIa and P2Y12receptor polymorphisms with clopidogrel variable response has not been confirmed in previous studies (4), and it should also be examined in the study by Ang et al. (1).
Finally, other mechanisms, such as cellular factors (accelerated platelet turnover, reduced CYP3A metabolic activity, increased ADP exposure, up-regulation of P2Y pathways), or clinical factors (noncompliance, underdosing, poor absorption) may cause suboptimal clopidogrel response.
This interesting study by Ang et al. (1) sheds some light on mechanisms underlying reduced response of platelets to the antiaggregatory effect of clopidogrel. Although the limited number of patients with lower inhibition of platelet reactivity by clopidogrel makes the findings exploratory, further studies with a larger cohort of patients are needed to elucidate the multiple mechanisms involving clopidogrel response.
- American College of Cardiology Foundation
- Ang L.,
- Palakodeti V.,
- Khalid A.,
- et al.
- Angiolillo D.J.,
- Fernandez-Ortiz A.,
- Bernardo E.,
- et al.