A Trial Comparing the Ischemic Preconditioning Effects of Ticagrelor and Clopidogrel in Humans

A Randomized, Controlled, Open Label Trial Comparing the Ischemic Preconditioning Effects of Ticagrelor and Clopidogrel in Humans

Antiplatelet therapy remains a cornerstone in the treatment of acute and chronic coronary artery disease. Aspirin was the first such therapy to prove its benefits in acute myocardial infarction. Compared to aspirin monotherapy, the combination of aspirin and clopidogrel, a thienopyridine P2Y12 inhibitor, has been demonstrated to reduce adverse event rates among patients with acute coronary syndromes (with or without ST-segment elevation) and those receiving intracoronary stents. In the Triton-TIMI 38 trial a novel thienopyridine, prasugrel, was compared to clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Although prasugrel significantly reduced recurrent myocardial infarction, bleeding rates were increased and no improvement in cardiac or all-cause mortality was demonstrated. However, in 2009, the authors of the PLATO trial demonstrated an unexpected cardiovascular mortality benefit with ticagrelor over clopidogrel, an endpoint not previously met by any other antiplatelet agent against an active comparator. Based on the reproducible adverse events seen in the DISPERSE, DISPERSE-2, and PLATO trials, an adenosine-mediated effect of ticagrelor is proposed.

Hypothesis: The aim of this study is to test the hypothesis that ticagrelor produces pharmacologic ischemic preconditioning, an undescribed potential off-label property of ticagrelor that could represent a plausible mechanism for its effects on cardiovascular mortality.

Inclusion Criteria:

• Undergoing clinically-indicated PCI for stable or progressive exertional angina without rest angina, ST-segment shift, or elevated CK-MB or troponin-T or I
• Willing and able to give informed consent and to comply with study procedures
• Found to have single or two-vessel obstructive, non-occlusive (≥ 70% but < 100% stenosis), coronary artery disease with plans for treatment of all lesions by PCI
• Target lesion location in the proximal or mid coronary vessel with reference diameter ≥ 2.5 mm

Exclusion Criteria:

• Known allergy to aspirin, clopidogrel, or ticagrelor
• Need for concomitant cardiac procedure, such as valve repair or replacement
• Age ≥ 75
• Concomitant theophylline/aminophylline use
• Baseline ECG with infarct or conduction abnormalities (i.e. LVH with repolarization abnormality, bundle branch block, ST-segment abnormalities)
• Presenting with an ST-segment elevation or non ST-segment elevation myocardial infarction
• Evidence of prior myocardial infarction by cardiac imaging
• Depressed left ventricular systolic function (ejection fraction < 50%)
• Clinical congestive heart failure
• End-stage renal disease
• Presence of coronary collaterals on diagnostic coronary angiography
• Presence of coronary thrombus on diagnostic coronary angiography
• Diffuse obstructive disease (≥ 70% stenosis) in the distal segment of the target vessel
• Left main and/or three-vessel coronary artery disease
• Concomitant need for Warfarin therapy