ß-blockers are associated with decreased leucocyte-platelet aggregate formation and lower residual platelet reactivity to adenosine diphosphate after angioplasty and stenting.

BACKGROUND: The beneficial effects of ß-blockers on the long-term prognosis of patients with cardiovascular disease may in part be attributable to decreased platelet activation. In this prospective cohort study, we sought to investigate the impact of concomitant ß-blocker therapy on sensitive markers of platelet activation and aggregation. MATERIALS AND METHODS: Monocyte-platelet (MPA) and neutrophil-platelet aggregate (NPA) formation in vivo and in response to the platelet agonist adenosine diphosphate (ADP) were determined by flow cytometry in 258 patients undergoing angioplasty and stenting. On-treatment residual platelet reactivity to ADP was assessed by multiple electrode aggregometry (MEA). RESULTS: One hundred seventy-five patients of the study population (67·8%) received ß-blockers. Treatment with ß-blockers was associated with significantly lower MPA and NPA formation in vivo and in response to ADP compared to patients without ß-blockers (all P ≤ 0·01). The inverse associations of MPA and NPA formation with ß-blocker therapy remained statistically significant after adjustment for differences in patient characteristics by multivariate linear regression analyses (all P < 0·05). Moreover, high levels of MPA in response to ADP as well as high levels of NPAin vivo and in response to ADP were significantly less frequent in patients with ß-blocker treatment (all P < 0·05). Finally, on-treatment residual platelet reactivity to ADP by MEA was significantly lower in patients receiving ß-blockers (P = 0·005). CONCLUSION: ß-Blockers are associated with decreased leucocyte-platelet aggregate formation and lower on-treatment residual platelet reactivity to ADP in patients with dual antiplatelet therapy following angioplasty and stenting.

Calcium-Channel Blockers Attenuate the Antiplatelet Effect of Clopidogrel.

AIMS: Dihydropyridine calcium-channel blockers (CCBs) inhibit cytochrome 3A4 and could therefore interfere with the conversion of clopidogrel to its active form. The impact of CCBs on the antiplatelet effect of clopidogrel has not been studied with assays directly capturing platelet activation to adenosine diphosphate (ADP), so far. We therefore sought to investigate platelet activation in response to ADP by flow cytometry in clopidogrel-treated patients without and with CCBs. METHODS: Platelet surface P-selectin expression and activated glycoprotein (GP) IIb/IIIa in response to ADP were determined by flow cytometry in 302 patients on dual antiplatelet therapy with aspirin and clopidogrel after successful angioplasty with stent implantation. RESULTS: Ninety-two patients (30.5%) received CCBs. Patients with concomitant CCB therapy showed significantly higher platelet surface expressions of P-selectin and activated GPIIb/IIIa in response to ADP than patients without CCBs (both P ≤ 0.03). Moreover, the fold increase of P-selectin and activated GPIIb/IIIa in response to ADP was significantly more pronounced in patients taking CCBs (both P ≤ 0.03). The associations of ADP-inducible activated GPIIb/IIIa and fold increase of activated GPIIb/IIIa after the addition of ADP with CCB therapy remained significant after adjustment for differences in patient characteristics and factors that were previously associated with clopidogrel response by multivariate regression analyses (both P < 0.05). High levels of ADP-inducible P-selectin and activated GPIIb/IIIa were seen significantly more frequent in patients with CCBs than in patients without CCB therapy (both P ≤ 0.01). CONCLUSION: Dihydropyridine CCBs attenuate the effect of clopidogrel on ADP-inducible platelet activation in patients undergoing angioplasty and stenting for cardiovascular disease.

Human neutrophil α-defensins are associated with adenosine diphosphate-inducible neutrophil-platelet aggregate formation and response to clopidogrel in patients with atherosclerosis.

Human neutrophil α-defensins (HNPs) are antimicrobial peptides stored primarily in the azurophilic granules of polymorphonuclear leukocytes. Recently, it was shown that HNPs act as platelet agonists. We hypothesized that HNP levels are associated with the formation of neutrophil-platelet aggregates, and that they influence the response to clopidogrel therapy. HNP levels were determined by a commercially available enzyme-linked immunosorbent assay in 305 patients undergoing angioplasty and stenting for atherosclerotic cardiovascular disease. Neutrophil-platelet aggregates were measured by flow cytometry, and on-treatment platelet reactivity was determined using the VerifyNow P2Y12 and aspirin assays. HNP levels did not correlate with the formation of neutrophil-platelet aggregates in vivo (r = 0.05, P = 0.4). In contrast, HNP levels correlated significantly with adenosine diphosphate (ADP)-inducible neutrophil-platelet aggregate formation (r = 0.13, P = 0.04). On-treatment platelet reactivity by the VerifyNow P2Y12 assay was significantly more pronounced in patients with high HNP levels compared with patients with low HNP levels (211 P2Y12 reaction units [PRU; range, 143-293 PRU] vs 181 PRU [range, 129-237 PRU], P = 0.009). This association remained significant after adjusting for high-sensitivity C-reactive protein and interleukin 6 by multivariate regression analysis (P = 0.007). Moreover, high on-treatment residual platelet reactivity by the VerifyNow P2Y12 assay was more frequent in patients with high HNP levels than in patients with low HNP levels (40% vs 26.6%, P = 0.01). In conclusion, HNP levels are associated with ADP-inducible neutrophil-platelet aggregate formation and clopidogrel-mediated platelet inhibition. High levels of HNPs may, in part, be responsible for the observed response variability to clopidogrel.