Ticagrelor, a P2Y12 antagonist, is well known for its rapid, high-potent inhibition of platelet aggregation by pharmacokinetic studies . In the PLATO study, ticagrelor, compared to clopidogrel, reduced the incidence of myocardial infarction, stroke, cardiovascular death and definite stent thrombosis, during 12-month follow-up in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) [2,3]. To date, the effect of early ticagrelor administration versus treatment at the time of PCI has not been well studied. The ATLANTIC study demonstrated that prehospital administration of ticagrelor did not improve pre-PCI coronary reperfusion compared to in-hospital treatment .
We aimed to compare the effectiveness of antiplatelet therapy by measuring the differences in residual thrombus burden after PCI by optical coherence tomography (OCT) between immediate and delayed initiation of ticagrelor in patients with ACS.
This was a prospective, randomized study involving eight Korean centers. Patients presented with non-ST-elevation ACS (NSTE-ACS) were screened between July 2016 and November 2017. All patients who were scheduled to undergo coronary angiography between 4 and 72 h after randomization were eligible. Patients with NYHA class III or IV heart failure or known left ventricular ejection fraction <30% and hemodynamic or electrical instability were excluded. Patients were randomized 1:1 to receive 180 mg of ticagrelor either immediately after a diagnosis of NSTE-ACS was made (early treatment group) or after diagnostic coronary angiography but prior to PCI (delayed treatment group). Patients randomized to the early treatment group received a maintenance dose of 90 mg every 12 h until the time of catheterization. Both the early treatment group and the delayed treatment group have received aspirin loading dose of 300 mg after the diagnosis of NSTE-ACS, and maintained 100 mg a day until angiography was done. After PCI, patients were maintained on ticagrelor and aspirin. Patients were followed through their index hospitalization. The study was approved by the institutional ethics committee at each participating hospital and informed consent was obtained prior to the enrollment.
The primary end point of this study was residual thrombus burden assessed by post-PCI OCT. A frequency-domain OCT system was used. Statistical analyses were performed using SPSS v. 12.5 for Windows and P < 0.05 was considered to indicate a statistically significant difference.
A total of 100 patients enrolled in the study were randomly assigned to either early treatment group (n = 50) or delayed treatment group (n = 50) (Fig. 1). There was no significant difference in baseline patient characteristics between the groups (Table 1). The degree of platelet inhibition was significantly higher in the early treatment group than in the delayed treatment group [P2Y12 reaction units (PRU), 70.6 ± 62.1 versus 227.2 ± 76.6; P < 0.001]. The median interval between the administration of ticagrelor and PCI in the early treatment group was 854 min. The primary end points of this study, thrombus area, length, volume and thrombus burden were not different between two groups (Table 1). No stent thrombosis or major bleeding occurred.
To our knowledge, this is the first study that prospectively compared the effects of early versus delayed administration of ticagrelor on residual thrombus burden after PCI with OCT in patients with NSTE-ACS. We hypothesized that early administration of ticagrelor would lead to more profound suppression of platelet reactivity at the time of PCI, and therefore, would lead to smaller residual thrombus burden. Indeed, our results showed that the early treatment group had lower values of PRU at the time of PCI; nevertheless, no significant difference in residual thrombus burden was found between the two groups. Possible explanations include the following: (1) the time difference of 14 h was not long enough to see the difference in thrombus burden. However, in real world practice, the usual time delay between presentation to a hospital and catheterization in patients with NSTE-ACS is 22 h . (2) Although ticagrelor is a potent P2Y12 inhibitor, it may not be potent enough to show difference in thrombus burden. (3) The number of patients was small. Moreover, a significant number of patients did not undergo post-PCI OCT imaging.
The earliest administration of ticagrelor may be preferable to achieve early efficacy, but in cases in which NSTE-ACS is not clearly diagnosed, it should be considered to delay the loading of P2Y12 inhibitor until the angiographic lesion is observed. Prospective larger scale randomized controlled trials are needed to investigate the clinical outcomes such as myocardial infarction, cardiac death, stroke and major bleeding events.
To conclude, early administration of ticagrelor at the time of presentation showed a greater level of platelet inhibition, but did not show benefit in reduction of thrombus burden following PCI in patients presenting with NSTE-ACS.
This study was supported by AstraZeneca. Dr. Jang has received educational grants and consulting fees from Abbott Vascular and Medicure, and consulting fees from Lycotec.
ClinicalTrials.gov identifier: NCT01916902.
Conflicts of interest
There are no conflicts of interest.
1. Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol. 2007; 50:1852–1856
2. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009; 361:1045–1057
3. Steg PG, James S, Harrington RA, Ardissino D, Becker RC, Cannon CP, et al; PLATO Study Group. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a platelet inhibition and patient outcomes (PLATO) trial subgroup analysis. Circulation. 2010; 122:2131–2141
4. Montalescot G, van ‘t Hof AW, Lapostolle F, Silvain J, Lassen JF, Bolognese L, et al; ATLANTIC Investigators. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med. 2014; 371:1016–1027
5. Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N, et al; TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy)–Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein iib/iiia inhibitor tirofiban. N Engl J Med. 2001; 344:1879–1887