Pre-PCI P2Y12 inhibitor administration and stent-induced endothelial dysfunction and inflammation in ACS

Effects of clopidogrel vs. prasugrel vs. ticagrelor on endothelial function, inflammatory parameters, and platelet function in patients with acute coronary syndrome undergoing coronary artery stenting: a randomized, blinded, parallel study

Literature - Schnorbus B, Daiber A, Jurk K et al., - Eur Heart J. 2020. https://doi.org/10.1093/eurheartj/ehz917

Introduction and methods

Coronary artery stenting has been found to be associated with an immune/inflammatory response and impaired coronary and peripheral endothelial responsiveness. Although the precise mechanisms are unclear, some evidences exists that suggests that mechanical trauma may lead to endothelial dysfunction [1,2]. This may trigger adverse vascular reactions, such as in-stent restenosis and in-stent thrombosis [3]. The degree of endothelial dysfunction early after stenting has prognostic value [4,5].

Platelet function and endothelial function interact, which is particularly relevant in the setting of acute coronary syndromes (ACS). After stenting, the combination of platelet activation and mechanical injury induce, through mediators of inflammation and oxidative stress, leucocyte chemotaxis, platelet aggregation and endothelial dysfunction [6].

The P2Y12 inhibitors clopidogrel and ticagrelor have been shown to improve endothelial function in patients with stable coronary artery disease, albeit transiently in the case of clopidogrel [7-9]. It is unclear to date whether different P2Y12 inhibitors act differently in this regard.

This study [7] therefore studied the impact of anti-aggregants on endothelial function, as assessed by conduit artery flow-mediated dilation (FMD), platelet inhibition, and inflammatory biomarkers in a randomized, blinded fashion in a group of patients undergoing stenting (PCI) in the setting of an ACS. The primary endpoint was change in FMD at 1 day, 1 week and 1 month after PCI in 90 patients with unstable angina (n=41) or NSTEMI (n=49) randomized to clopidogrel (single dose of 600 mg, followed by 75 mg o.d.), prasugrel (once 60 mg, then 10 mg o.d.) or ticagrelor (once 180 mg, then 90 mg bid). Initially, 56 patients were randomized and treated at the end of the screening visit, but after an EMA-recommended amendment of the study protocol, randomization and study drug administration in 34 patients were changed to immediately following PCI.

Main results

After first drug administration in the original study protocol, FMD improved in all treatment groups, by 1.5% with clopidogrel, 1.9% with prasugrel and 0.8% for ticagrelor (P=0.727). At 1 day after PCI, FMD was decreased by 3.8% with clopidogrel (P=0.008 vs. screening) and 3.5% (P<0.001) but not with prasugrel (-0.7%, P=0.734).
Prasugrel showed an improvement in the primary endpoint compared to clopidogrel (mean difference: 2.13, 95%CI: 0.68-3.58, P=0.0047) and ticagrelor (mean difference: 1.57, 95%CI: 0.31-2.83, P=0.155). Ticagrelor and clopidogrel did not differ significantly with regard to the primary endpoint (0.55%, 95%CI: -0.73 to 1.82, P=0.39).
The observed differences were seen also when only NSTEMI patients were analysed, but not when the analysis was limited to patients with unstable angina.
An interaction was seen between effect of drug and timing of administration, such that with the original protocol prasugrel was significantly different from both clopidogrel and ticagrelor, but these comparisons showed no significant differences with the protocol after the amendment.
In the cohort that underwent the original protocol, plasma biomarkers were assessed. After PCI, IL-6 levels were significantly lower in the prasugrel group as compared to clopidogrel and ticagrelor, and a similar trend was seen for sE-selectin. Other biomarkers did not differ between treatments.
ADP-induced platelet aggregation capacity was lower in the prasugrel and ticagrelor groups at 2 hours after the first administration, and with prasugrel at 1 day and 1 month post-PCI.

Conclusion

This study compared the effect of three P2Y12 inhibitors on markers of endothelial function, platelet function and inflammation/oxidative stress in patients undergoing PCI for ACS, to assess whether these agents can mitigate the consequences of the mechanical injury to the vascular wall and endothelium provoked by PCI. Administering antiplatelet therapy just before PCI improved FMD with all P2Y12 inhibitors tested. Prasugrel prevented the endothelial dysfunction associated with stenting and more potently inhibited platelet aggregation. When drugs were administered directly after PCI, the protective effect of prasugrel was not seen.

References

Show references

1. Papp J, Kenyeres P, Toth K. Clinical importance of antiplatelet drugs in cardiovascular diseases. Clin Hemorheol Microcirc 2013;53:81–96.

2. Reinhart WH. Platelets in vascular disease. Clin Hemorheol Microcirc 2013;53: 71–79.

3. Park DW, Yun SC, Lee JY, et al. C-reactive protein and the risk of stent thrombosis and cardiovascular events after drug-eluting stent implantation. Circulation 2009;120: 1987–1995.

4. Warnholtz A, Ostad MA, Heitzer T, et al. Effect of tirofiban on percutaneous coronary intervention-induced endothelial dysfunction in patients with stable coronary artery disease. Am J Cardiol 2005;95:20–23.

5. Spiro JR, Digby JE, Ghimire G, et al. Brachial artery low-flow-mediated constriction is increased early after coronary intervention and reduces during recovery after acute coronary syndrome: characterization of a recently described index of vascular function. Eur Heart J 2011;32:856–866.

13. Gori T. Endothelial function: a short guide for the interventional cardiologist. Int J Mol Sci 2018;19.

6. Ostad MA, Nick E, Paixao-Gatinho V, et al. Lack of evidence for pleiotropic effects of clopidogrel on endothelial function and inflammation in patients with stable coronary artery disease: results of the double-blind, randomized CASSANDRA study. Clin Res Cardiol 2011;100:29–36.

7. Warnholtz A, Ostad MA, Velich N, et al. A single loading dose of clopidogrel causes dose-dependent improvement of endothelial dysfunction in patients with stable coronary artery disease: results of a double-blind, randomized study. Atherosclerosis 2008;196:689–695.

8. He M, Li D, Zhang Y, et al. Effects of different doses of ticagrelor on platelet aggregation and endothelial function in diabetic patients with stable coronary artery disease. Platelets 2019;30:752–761.

9. Schnorbus B, Daiber A, Jurk K, et al. Effects of clopidogrel, prasugrel and ticagrelor on endothelial function, inflammatory and oxidative stress parameters and platelet function in patients undergoing coronary artery stenting for an acute coronary syndrome. A randomised, prospective, controlled study. BMJ Open 2014;4:e005268.

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