Differential Effect of Ticagrelor Versus Prasugrel on Coronary Blood Flow Velocity in Patients With Non–ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Abstract

In the present study of patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) treated with percutaneous Background-Prasugrel and ticagrelor provide a superior anti-ischemic action than clopidogrel, with some of ticagrelor's benefits possibly attributed to adenosine-mediated mechanisms. We aimed to compare the effect of maintenance dose of ticagrelor versus prasugrel on coronary blood flow velocity (CBFV) during increasing doses of intravenously administered adenosine. Methods and Results-In a prospective, single-center, single-blind, crossover study, 56 patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention were randomized to receive either ticagrelor 90 mg BID or prasugrel 10 mg OD with a 15-day treatment period. At the end of each treatment period, CBFV by transthoracic Doppler echocardiography was assessed at baseline and under incremental doses (50 μg/kg per minute, 80 μg/kg per minute, 110 μg/kg per minute, and 140 μg/kg per minute) of adenosine infusion. Maximal CBFV area under the curve was higher for ticagrelor-treated than for prasugrel-treated patients, with a least squares mean difference of 7.16 (95% confidence interval, 2.61-11.7; P=0.003). Maximal CBFV/baseline CBFV ratio was higher with ticagrelor than prasugrel at 50, 80, and 110 μg/ kg per minute but not at 140 μg/kg per minute adenosine infusion rate, with mean difference (95% confidence interval) of 0.17 (0.08-0.26; P<0.001), 0.21 (0.02-0.41; P=0.03), 0.24 (0.01-0.47; P=0.04), and 0.14 (−0.12 to 0.4; P=0.3), respectively. Conclusions-In patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention, ticagrelor augments CBFV to a greater extent than prasugrel when incremental doses of adenosine are administered. Although exploratory, these results may represent a pleiotropic action of ticagrelor, possibly contributing to its beneficial effects in such patients. Clinical Methods Study ProtocolWe performed a prospective, single-center, single-blind, investigator-initiated, randomized, crossover study to compare the effect of ticagrelor versus prasugrel on adenosine-induced CBFV responses. Consecutive patients aged 18 to 75 years with NSTE-ACS undergoing PCI with drug-eluting stent implantation were included. Patients admitted with ST-elevation myocardial infarction were excluded to avoid possible influence of the infarcted myocardium and left ventricular remodeling to CBFV. 8 Other exclusion criteria were prior myocardial infarction, prior PCI, coronary artery bypass grafting, nonsinus rhythm, requiring hemodialysis, major periprocedural complications or suboptimal PCI result (residual stenosis >20% by visual assessment), contraindication for ticagrelor or prasugrel administration, weight <60 kg, age ≥75 years, risk for bleeding or bradycardic events, severe chronic obstructive pulmonary disease, requirement for oral anticoagulant, left ventricular ejection fraction <45%, left ventricular hypertrophy, diastolic dysfunction, severe valvular disease, an...

Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor

“…[13][14][15][16] Ticagrelor has also been shown to augment a number of physiological responses induced by adenosine, including increased coronary blood flow and adenosine-dependent inhibition of platelet aggregation. 15,17,18 Some adverse effects associated with ticagrelor include dyspnoea and ventricular pauses, effects also seen with intracoronary administration of exogenous adenosine. 19,20 The aim of this study was to further elucidate the molecular mode of action of ticagrelor on platelets beyond its well-established antagonism of the P2Y 12 R. Using isolated human platelets, we tested whether ticagrelor's inhibition of adenosine transport could contribute to changes in downstream signaling.…”

Causes of mortality with ticagrelor compared with clopidogrel in acute coronary syndromes

“…Both ventricular pauses and dyspnoea are common side effects of adenosine, and the potential mechanism by which ticagrelor causes ventricular pauses might be related to its off target effects of inhibiting reuptake of adenosine by erythrocytes and stimulating release of ATP 10 11. Higher levels of extracellular circulating adenosine might be advantageous in patients with ACS, and ticagrelor has been shown to increase adenosine-induced coronary blood flow velocity in non-ST-elevation-ACS patients undergoing percutaneous coronary intervention (PCI) 12. Other potential advantageous effects of adenosine include a preconditioning effect on the myocardium and anti-inflammatory effects 13 14.…”

Acute Coronary Syndrome: Focus on Antiplatelet Therapy

“…11 As well as being an additional mechanism for the antiplatelet effects of ticagrelor, 12 the increase in local adenosine levels enhances adenosine-mediated coronary blood flow. [13][14][15] Guideline Update: NSTE-ACS The AHA/ACC Task Force on Practice Guidelines has published a 2014 update for the care of patients with NSTE-ACS. 6 This update replaces the relevant parts of the 2007 ACC/AHA guidelines, 4 which were revised during focused updates in 2011 16 and 2012.…”