Clopidogrel Withdrawal Is Associated With Proinflammatory and Prothrombotic Effects in Patients With Diabetes and Coronary Artery Disease

Abstract

Inhibition of the P2Y 12 pathway by the platelet antagonist clopidogrel is associated with a marked reduction in platelet reactivity. Recent reports have shown that P2Y 12 inhibition has anti-inflammatory effects as well. However, whether clopidogrel withdrawal is associated with proaggregatory and proinflammatory effects has not yet been explored. Since diabetic subjects are characterized by a prothrombotic and proinflammatory status, we hypothesize that these patients may be more vulnerable to these effects. A total 54 patients with diabetes on long-term (12 months) dual antiplatelet therapy (aspirin plus clopidogrel) were studied. Platelet aggregation (following 6 and 20 mol/l ADP stimuli) and inflammatory markers (Creactive protein and P-selectin expression) were assessed before and 1 month following clopidogrel withdrawal. Following clopidogrel withdrawal, aspirin responsiveness using platelet function analyzer-100 was determined as well. A significant increase in all the assessed platelet (P < 0.0001 for 6 and 20 mol/l ADP-induced aggregation) and inflammatory (P < 0.05 for C-reactive protein, P < 0.001 for P-selectin expression in resting platelets, and P < 0.0001 for P-selectin expression in ADP-stimulated platelets) biomarkers was observed following clopidogrel withdrawal. Low responders to aspirin had increased platelet aggregation profiles (P < 0.05 for 6 and 20 mol/l ADPinduced aggregation) but no differences in inflammatory markers. In conclusion, clopidogrel withdrawal is associated with an increase in platelet and inflammatory biomarkers in diabetic patients, supporting pleiotropic effects coupled with P2Y 12 receptor antagonism. Diabetes 55: 780 -784, 2006

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…Thus, the anti-inflammatory effects may account for the increased efficacy with the use of the P2Y 12 antagonist compared to aspirin. Indeed, clopidogrel withdrawal results in the re-emergence of inflammation in patients with diabetes and coronary artery disease (Angiolillo et al, 2006). Clopidogrel significantly reduces platelet-associated inflammatory markers in renal transplant patients with no clinical signs of atherosclerosis (Graff et al, 2005) and patients with stable coronary artery disease, for example P-selectin and CD40L release, platelet-leukocyte complexes and MMP9 release (Klinkhardt et al, 2002;Azar et al, 2006).…”

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

“…Increased levels of platelet reactivity and biomarkers including ADP-induced PA, hsCRP and CD62P were reported by Angiolillo et al after cessation of clopidogrel in a cohort of diabetic patients (55). The DECADES study (147) examined the effect of clopidogrel cessation on inflammation 12 months after DES-implantation in a non-diabetic population.…”

“…In human plasma, CRP exists as a cyclic, disc-shaped pentamer of 115 kDa (pentameric pCRP) (40) or as a monomeric or modified mCRP (52,53). At higher concentrations, pCRP evolves proinflammatory properties and has been associated with chronic diseases such as hypertension, metabolic syndrome and type 2 diabetes (54,55). In contrast, low concentration mCRP induces interleukin-8 (IL-8) secretion by neutrophils and human coronary artery endothelial cells, promotes monocyte migration, neutrophil-endothelial cell adhesion, and delays apoptosis of human neutrophils (53,56,57) along with different interactions with the complement cascade (58).…”

Prolonged Dual Antiplatelet Therapy Improves Clinical Outcomes in High‐risk Patients Implanted with Sirolimus‐eluting Stents

“…25,26 Clopidogrel also has antiinflammatory and antithrombotic effects. 27 For ''on-label'' indications (such as simple coronary stenosis), the benefits of DES outweigh their risks, the incidence of ST is low. 28 But for ''off-label'' (such as more complex coronary lesions) use of DES, the risk of ST is much higher than ''on-label'' use.…”