Atorvastatin combined with ticagrelor prevent ischemia-reperfusion induced vascular endothelial dysfunction in healthy young males – A randomized, placebo-controlled, double-blinded study

Abstract Background Atorvastatin and ticagrelor have been shown to prevent against tissue injury in animals. It is unclear if these beneficial effects are also detectable in humans. We studied the effect of high-dose atorvastatin combined with ticagrelor loading on endothelial dysfunction in a model of forearm vascular ischemia-reperfusion (IR) injury. Methods 32 healthy subjects (n=16 per group) were enrolled in this randomized, placebo-controlled, double-blinded trial. Forearm blood flow (FBF) measurements in response to increasing intra-arterial doses of the vasodilator acetylcholine (ACh; endothelium-dependent agonist) and glyceryltrinitrate (GTN; endothelium-independent) were performed before and after a cuff-induced 20min forearm ischemia, respectively. FBF reactivity was assessed prior to any pharmacological intervention and after 14days intake of 80mg atorvastatin once daily or placebo, followed by an oral loading dose of 180mg ticagrelor. In addition, lipoprotein parameters and platelet aggregation were evaluated. Results Ticagrelor loading mitigated ischemia-induced endothelial dysfunction and in combination with repeated atorvastatin dosing the response to ACh during reperfusion was completely normalized (FBF ACh AUC ratio post- vs. pre-ischemia: 0.81 [ticagrelor] vs. 1.04 [atorvastatin+ticagrelor]; P=0.001). As expected, GTN-induced vasodilation was not affected by IR injury. Atorvastatin significantly reduced total and low density lipoprotein cholesterol concentrations, while high density lipoprotein cholesterol and triglyceride levels remained unchanged. Conclusion Chronic atorvastatin treatment combined with ticagrelor loading prevents against endothelial dysfunction after acute forearm ischemia. Ticagrelor alone mitigated the impaired endothelium-dependent FBF response as compared to no pharmacological intervention. Clinical trial registration URL: https://clinicaltrials.gov. Unique identifier: NCT02910778.