Ticagrelor mitigates ischaemia–reperfusion induced vascular endothelial dysfunction in healthy young males – a randomized, single‐blinded study

Weisshaar, Stefan; Litschauer, Brigitte; Eipeldauer, Matthias; Hobl, Eva‐Luise; Wolzt, Michael

doi:10.1111/bcp.13378

Cited by 12 publications

(15 citation statements)

References 48 publications

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“…However, ticagrelor treatment did not protect against the development of endothelial dysfunction despite therapeutic efficacy by ticagrelor treatment as demonstrated by adequate degree of platelet inhibition. These results suggesting that ticagrelor does not confer protection against ischemia-reperfusion injury in patients 1 year after ACS are in contrast to those of Weisshaar et al showing a protective effect of ticagrelor against endothelial ischemia-reperfusion injury in healthy humans, 17 and to previous animal studies demonstrating cardioprotective effects of ticagrelor both when given as an acute loading dose and as chronic treatment. [12][13][14]27 The specific reasons for the discrepancies in results are presently unclear.…”

Section: Discussioncontrasting

confidence: 94%

“…10,11 Accordingly, ticagrelor has been shown to attenuate myocardial ischemia-reperfusion injury in an adenosine-dependent manner in rat 12,13 and pig models 14,15 of coronary artery occlusion and reperfusion. In healthy humans, ticagrelor increases coronary blood flow 16 and attenuates endothelial dysfunction induced by ischemia-reperfusion compared to clopidogrel, 17 but there is conflicting evidence concerning its effect on endothelial function in patients with established coronary artery disease. 6 Furthermore, any protective effect of ticagrelor against ischemia-reperfusion injury has not been evaluated in patients with established coronary artery disease.…”

Section: Introductionmentioning

confidence: 99%

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Ticagrelor Does Not Protect Against Endothelial Ischemia-Reperfusion Injury in Patients With Coronary Artery Disease

Verouhis

Ekström

Settergren

et al. 2020

J Cardiovasc Pharmacol Ther

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Background: Ticagrelor is a recommended P2Y12 receptor inhibitor after acute coronary syndrome (ACS). Its superiority has been suggested to rely on pleiotropic effects beyond platelet inhibition. Experimental studies indicate that ticagrelor may protect from ischemia-reperfusion injury but no data are available from such studies on patients. This study aimed to determine if chronic ticagrelor treatment protects against endothelial ischemia-reperfusion injury in patients with a previous ACS. Methods: Patients with a previous ACS were studied with flow mediated dilatation of the left brachial artery to determine the degree of endothelial ischemia-reperfusion injury before and after discontinuation of ticagrelor treatment, which had been continuous since 1 year. Each patient underwent 3 identical examinations. The first examination (Visit A) was at the end of ticagrelor treatment and the following 2 (Visit B and C) were after cessation of this treatment with an interval of 2 to 4 weeks. Results: Ischemia and reperfusion induced significant impairment of endothelial function at all 3 occasions (absolute decline in flow mediated dilatation 3.0% ± 0.7 at Visit A (p < 0.001), 1.9% ± 0.9 at Visit B (p < 0.05) and 1.9% ± 0.4 at Visit C (p < 0.0001)). However, there was no difference in the degree of endothelial ischemia-reperfusion injury or baseline endothelial function between the visits. Conclusion: Chronic ticagrelor treatment in patients 1 year after an ACS does not protect against endothelial ischaemia-reperfusion injury. Nor is it associated with better basal endothelial function compared to after discontinuation of treatment.

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Section: Discussioncontrasting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Ticagrelor Does Not Protect Against Endothelial Ischemia-Reperfusion Injury in Patients With Coronary Artery Disease

Verouhis

Ekström

Settergren

et al. 2020

J Cardiovasc Pharmacol Ther

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“…Animal data also suggest that the P2Y 12 receptor antagonists ticagrelor and cangrelor have pleiotropic effects, potentially through adenosine-like and anti-inflammatory effects, that afford even greater protection against tissue injury than clopidogrel (Adamski et al, 2014;Cohen & Downey, 2017;Nanhwan et al, 2014;Yang et al, 2012). The protective effect has been translated to humans using endothelial function as endpoint (Weisshaar, Litschauer, Eipeldauer, Hobl, & Wolzt, 2017). It still remains unknown to what extent a direct cardioprotective effect of ticagrelor is involved in the mechanisms underlying its superior effect over that of clopidogrel in patients with acute myocardial infarction (Wallentin et al, 2009), including those with or without ST elevation who undergo planned revascularization (Cannon et al, 2010).…”

Section: Anti-platelet Agentsmentioning

confidence: 99%

Co‐morbidities and co‐medications as confounders of cardioprotection—Does it matter in the clinical setting?

Kleinbongard

Bøtker

Ovize

et al. 2020

British J Pharmacology

106

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The translation of cardioprotection from robust experimental evidence to beneficial clinical outcome for patients suffering acute myocardial infarction or undergoing cardiovascular surgery has been largely disappointing. The present review attempts to critically analyse the evidence for confounders of cardioprotection in patients with acute myocardial infarction and in patients undergoing cardiovascular surgery. One reason that has been proposed to be responsible for such lack of translation is the confounding of cardioprotection by co-morbidities and co-medications. Whereas there is solid experimental evidence for such confounding of cardioprotection by single co-morbidities and co-medications, the clinical evidence from retrospective analyses of the limited number of clinical data is less robust. The best evidence for interference of co-medications is that for platelet inhibitors to recruit cardioprotection per se and thus limit the potential for further protection from myocardial infarction and for propofol anaesthesia to negate the protection from remote ischaemic conditioning in cardiovascular surgery.

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“…17 However, in a recent study of healthy males undergoing forearm ischemia, ticagrelor (oral dose and maintenance dose), compared with clopidogrel, attenuated ED assessed by FBF in response to the endotheliumdependent vasodilator acetylcholine. 18 Mechanisms potentially involved in this effect (Table 2) 3,19 might primarily relate to the aforementioned increase in plasma adenosine levels and release of ATP triggered by ticagrelor. Both mediators stimulate vasodilation, adenosine mainly via a direct effect on vascular smooth muscle cells, and ATP by promoting release from the endothelium of vasodilatory factors such as NO and endothelial hyperpolarizing factor.…”

Section: Pleiotropic Effects Of Ticagrelormentioning

confidence: 99%

Does Ticagrelor Improve Endothelial Function?

Moulias

Xanthopoulou

Alexopoulos

2018

J Cardiovasc Pharmacol Ther

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Ticagrelor is a P2Y receptor antagonist with proven clinical benefit in patients with acute coronary syndrome. Apart from its principal antiplatelet action, pleiotropic effects have been implicated in the clinical profile of ticagrelor, including a potentially beneficial impact on endothelial function. In light of the common presence and prognostic value of endothelial dysfunction in patients with coronary artery disease, several clinical studies have investigated the postulated effect of ticagrelor on endothelial function, yielding conflicting results. Limitations of the relevant studies as well as substantial differences in patient population, study design, and methods may account for these controversial findings. Most of these studies, however, support a beneficial impact of ticagrelor on endothelial function, which seems to be significant in the higher risk patients. In order to elucidate this effect, further research efforts should aim to clarify how quickly does endothelial function respond to ticagrelor, how sustained this response is during the dosing intervals and in the long term, which mechanisms are implicated, and whether this pleiotropic action is clinically significant. Future studies should include larger and diverse populations of patients, assess endothelial function at several time points after treatment initiation, and use multiple methods of endothelial function measurement, while implementing strict methodology. Nevertheless, the extent of the clinical benefit of ticagrelor attributable to actions beyond its potent and consistent antiplatelet effect remains uncertain.

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Ticagrelor mitigates ischaemia–reperfusion induced vascular endothelial dysfunction in healthy young males – a randomized, single‐blinded study

Abstract: Our data indicate that ticagrelor treatment exerts a greater vascular salutary effect than clopidogrel during reperfusion after an acute vascular occlusion. IR-induced vascular injury cannot be prevented completely by administration of these antiplatelet agents at standard clinical doses.

Cited by 12 publications

References 48 publications

Ticagrelor Does Not Protect Against Endothelial Ischemia-Reperfusion Injury in Patients With Coronary Artery Disease

Ticagrelor Does Not Protect Against Endothelial Ischemia-Reperfusion Injury in Patients With Coronary Artery Disease

Co‐morbidities and co‐medications as confounders of cardioprotection—Does it matter in the clinical setting?

Does Ticagrelor Improve Endothelial Function?

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