Ticagrelor to Reduce Myocardial Injury in Patients With High-Risk Coronary Artery Plaque

Objectives The goal of this study was to determine whether ticagrelor reduces high-sensitivity troponin I concentrations in patients with established coronary artery disease and high-risk coronary plaque. Background High-risk coronary atherosclerotic plaque is associated with higher plasma troponin concentrations suggesting ongoing myocardial injury that may be a target for dual antiplatelet therapy. Methods In a randomized, double-blind, placebo-controlled trial, patients with multivessel coronary artery disease underwent coronary 18F-fluoride positron emission tomography/coronary computed tomography scanning and measurement of high-sensitivity cardiac troponin I. Patients were randomized (1:1) to receive ticagrelor 90 mg twice daily or matched placebo. The primary endpoint was troponin I concentration at 30 days in patients with increased coronary 18F-fluoride uptake. Results In total, 202 patients were randomized to treatment, and 191 met the pre-specified criteria for inclusion in the primary analysis. In patients with increased coronary 18F-fluoride uptake (120 of 191), there was no evidence that ticagrelor had an effect on plasma troponin concentrations at 30 days (ratio of geometric means for ticagrelor vs. placebo: 1.11; 95% confidence interval: 0.90 to 1.36; p = 0.32). Over 1 year, ticagrelor had no effect on troponin concentrations in patients with increased coronary 18F-fluoride uptake (ratio of geometric means: 0.86; 95% confidence interval: 0.63 to 1.17; p = 0.33). Conclusions Dual antiplatelet therapy with ticagrelor did not reduce plasma troponin concentrations in patients with high-risk coronary plaque, suggesting that subclinical plaque thrombosis does not contribute to ongoing myocardial injury in this setting. (Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND]; NCT02110303)

C oronary plaque rupture is the most common cause of acute coronary thrombosis and myocardial infarction (1). Patients who have an increased risk of recurrent plaque rupture events may benefit from intensification of secondary prevention therapy (2). In this regard, the addition of a P2Y 12 receptor antagonist to low-dose aspirin reduces the risk of cardiovascular death, myocardial infarction, and stroke in patients with recent (3) or previous (4) myocardial infarction. Ticagrelor is an oral, reversible antagonist of the platelet adenosine diphosphate P2Y 12 receptor. It provides faster, more potent, and more consistent P2Y 12 inhibition than clopidogrel (5). In the PLATO (Platelet Inhibition and Patients Outcomes) trial of 18,624 patients presenting with acute coronary syndrome, ticagrelor was superior to clopidogrel for the prevention of cardiovascular events and death (3). Moreover, the prolonged use of dual antiplatelet therapy after myocardial infarction continues to reduce cardiovascular events, albeit at the expense of increased rates of major bleeding (4). Thus, there is a clinical need to improve the risk stratification of patients to enable physicians to better select "vulnerable" patients who may benefit from extended duration of dual antiplatelet therapy.
A novel approach for assessing patients at high risk of coronary plaque rupture is using positron emission tomography (PET) and coronary computed tomography angiography (CTA). This technique uses the radiotracer 18 F-fluoride to identify regions of increased disease activity in coronary artery plaques.
Previous studies have shown that coronary 18 F-fluoride uptake correlates with a high-risk cardiovascular profile and identifies ruptured coronary plaques in patients with recent myocardial infarction (6,7). Importantly, we have previously reported an association between increased coronary 18 F-fluoride uptake and higher plasma high-sensitivity cardiac troponin I concentrations in patients with stable coronary artery disease (7). Silent plaque rupture is common, and subclinical plaque thrombus formation is a frequent incidental post-mortem finding in patients with multivessel coronary artery disease who have died of noncardiovascular causes (8). This result suggests that coronary 18 F-fluoride uptake may identify highrisk plaque that is associated with thrombus formation and subclinical myocardial injury from microemboli. If correct, this would potentially be modifiable with intensive dual antiplatelet therapy.
The current study assessed whether coronary 18 F-fluoride activity identifies patients with stable multivessel coronary artery disease who respond favorably to ticagrelor as assessed by a reduction in high-sensitivity cardiac troponin I concentrations. The analysis of coronary 18 F-fluoride activity has been previously described (6,7). In brief, visual assessment for increased coronary 18  SAMPLE SIZE. In patients with increased coronary 18 F-fluoride uptake, we previously reported that mean AE SD troponin concentrations were more than double those in patients without increased coronary 18 Ffluoride uptake (7.9 AE 9.3 ng/l vs. 3.1 AE 1.9 ng/l; p ¼ 0.047) (7). It was estimated that ticagrelor would reduce the troponin concentration by one-half. Fortyeight patients per treatment arm were required to achieve 80% power at 2-sided p < 0.05. After allowing for 15% dropout, we estimated that 55 patients will be required per treatment arm. Previous studies had found that 45% of patients with advanced but stable coronary artery disease exhibited increased coronary 18 F-fluoride uptake; thus, a total sample size of 250 patients was estimated to be required to identify 110 patients with increased coronary 18 Figure 2).

METHODS
The geometric mean troponin I concentration at baseline was 3.8 (geometric SD: 2.9) ng/l in patients      effect using ticagrelor (3,14). Second, our unique study design enabled high-risk patients with multivessel coronary disease and in vivo evidence of disease activity to be precisely phenotyped before randomization in a manner that can seldom be achieved in larger clinical outcome trials (3,15). Finally, this study is the first prospective randomized controlled trial to use high-sensitivity cardiac troponin I concentrations as a surrogate outcome measure for assessing future cardiovascular risk.
In trying to understand why P2Y 12   Unstimulated (upper panels) and adenosine diphosphate (20 mmol/l)-stimulated (lower panels) levels of platelet activation (P-selectin expression) and platelet-monocyte aggregates.  (7,19,20). In our cohort, the frequency of 18  A key question is whether troponin measurements below the 99th centile reflect subclinical plaque rupture with accompanying distal microvascular embolization, as has previously been posited (21). In this regard, some therapies directed at reducing the risk of atherosclerotic plaque rupture, such as pravastatin, both modify troponin concentrations and reduce the risk of myocardial infarction (22,23). In contrast, strategies that have failed to show a reduction in cardiovascular events in the context of stable coronary artery disease, such as coronary revascularization, attenuation of plaque inflammation, and  Abbreviations as in Table 3.
inhaled therapies for respiratory disease, have not correlated with a reduction in serial troponin concentration (24)(25)(26) (27,28). In this study, high-sensitivity cardiac troponin I concentrations were higher in patients with 18 F-fluoride activity, although the differences were small and below the established risk stratification threshold of 5 ng/l (9,22,29). It therefore seems unlikely that troponin at these concentrations reflects subclinical plaque rupture, and it is perhaps unsurprising that ticagrelor treatment did not result in an early or late reduction in troponin concentration.

CENTRAL ILLUSTRATION Using Coronary 18 F-Fluoride to Identify Patients Who May Benefit From Intensified Dual
Antiplatelet Therapy

Allocated Treatment
Ticagrelor Placebo Previous reports have suggested that there is a high incidence of subclinical intracoronary thrombus in patients with apparently stable coronary artery disease. Indeed, some have suggested that this outcome occurs in as many as 1 in 7 patients (8). If this is the case, it would seem that intracoronary thrombus does not track with troponin. This suggests that better noninvasive markers of coronary thrombosis, such as novel PET tracers (30) or noninvasive imaging (31), are needed to use as biomarkers of cardiovascular risk and antithrombotic therapeutic efficacy.
STUDY LIMITATIONS. The current study had a modest sample size to assess the impact of ticagrelor on a readily available plasma biomarker, and a larger study would be required to assess clinical outcomes of ticagrelor use in patients with stable coronary artery disease and coronary 18  TRANSLATIONAL OUTLOOK 1: Although this study used an early biomarker (30-day plasma high-sensitivity cardiac troponin I concentration) to evaluate drug efficacy, coronary 18 F-fluoride activity did not seem to be useful in identifying patients who may benefit from extended P2Y 12 inhibition.
TRANSLATIONAL OUTLOOK 2: A detailed phenotype of coronary plaque disease activity using PET is both feasible and practical in the setting of a randomized, placebo-controlled trial.