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Ticagrelor (Brilinta; AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA) is a direct acting, reversible, oral P2Y12 inhibitor.1) In the PLATelet inhibition and patient Outcomes (PLATO) study, compared to clopidogrel (Plavix; Bristol-Myers Squibb/Sanofi Pharmaceuticals, Bridgewater, NJ, USA), ticagrelor reduced the rate of death from vascular causes, myocardial infarction (MI), or stroke in patients with acute coronary syndrome.2) Prevention of MI and stent thrombosis, and thus cardiac death, may result from fast, potent and consistent inhibition of platelets by ticagrelor.3) However, the mechanism of ticagrelor benefits has not been fully elucidated. Recent animal studies demonstrated that ticagrelor reduces reperfusion injury and limits myocardial infarct size.4),5) On the contrary, in an electrocardiography substudy of the PLATO trial, ticagrelor did not improve ST-segment resolution in patients with ST-segment elevation.6) To date, data are limited regarding whether or not ticagrelor reduces myocardial infarct size compared with clopidogrel.
In the current issue of the Korean Circulation Journal, Yun et al.7) reported the results of a single-center, randomized, open-label study that compared the effects of ticagrelor and clopidogrel on myocardial infarct size assessed by technetium-99m tetrofosmin single-photon emission computed tomography (SPECT) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). In the ticagrelor group, patients received a 180-mg loading dose followed by a maintenance dose of 90 mg twice daily. In the clopidogrel group, patients received a 600-mg loading dose followed by a maintenance dose of 75 mg daily. A total of 194 patients were eligible and 92 patients in the clopidogrel group and 96 patients in the ticagrelor group were finally evaluated with respect to myocardial infarct size. Infarct size was similar (32.8%±29.2% in the ticagrelor group compared to the clopidogrel group 28.1%±34.5%, p=0.170). Although this study was not a large study, sample size was not so small compared with other studies regarding infarct size and it was based on rational assumptions. Baseline characteristics of enrolled patients were representative. Only 6 patients did not undergo SPECT, which minimized selection bias. I would like to commend and congratulate the authors for this study. However, the major limitation of this study was that infarct size was measured by SPECT. Although correlation between infarct size measured using SPECT and cardiac magnetic resonance imaging (CMR) was good as the authors stated in the manuscript, CMR is superior to SPECT for measuring infarct size, especially when an infarct is small or nontransmural. In addition to infarct size, CMR can assess microvascular obstruction. In the post hoc analysis of the Complete Versus Lesion-Only PRImary PCI Trial-CMR (CvLPRIT-CMR) substudy, ticagrelor was associated with smaller infarct size and lower microvascular obstruction incidence versus clopidogrel in patients with STEMI.8) The only randomized trial to compare ticagrelor and clopidogrel for infarct size using CMR was performed by our group.9) A total of 110 patients with STEMI undergoing primary PCI were randomly assigned to the ticagrelor group (180-mg loading does, 90 mg twice daily thereafter) or the clopidogrel group (600-mg loading dose, 75 mg daily thereafter) in a 1:1 ratio. CMR examinations were available in 45 and 50 patients of the ticagrelor group and the clopidogrel group, respectively. Myocardial infarct size was significantly smaller in the ticagrelor group than in the clopidogrel group (21.5%±10.9% vs. 26.5%±11.3%, p=0.030). The extent of microvascular obstruction was also significantly smaller and the myocardial salvage index tended to be greater in the ticagrelor group than in the clopidogrel group (3.9%±4.1% vs. 6.4%±6.3%, p=0.020 and 41.9%±10.8% vs. 38.3%±8.7%, p=0.080, respectively). However, the cardioprotective effect of ticagrelor may be not tremendous because traditional surrogates for myocardial injury such as myocardial blush grade or complete ST-segment resolution were not significantly different between ticagrelor and clopidogrel in the current study as well as ours.
How ticagrelor reduces myocardial infarct size is uncertain. Ticagrelor may facilitate reperfusion more completely or rapidly, and decrease myocardial infarct size compared with clopidogrel. However, the results of our study suggest a platelet-independent cardioprotective effect of ticagrelor because the degree of platelet inhibition was comparable between the ticagrelor and clopidogrel groups at the time of PCI. There was no significant difference in residual platelet reactivity at the time of PCI between ticagrelor and clopidogrel (P2Y12 reaction units by VerifyNow; 216.1±83.6 vs. 231.0±64.0, p=0.340). Ticagrelor achieved faster and greater antiplatelet effects than clopidogrel in several studies, but, in patients with STEMI undergoing primary PCI, both ticagrelor and prasugrel exhibited an initial delay in the onset of their antiplatelet action.10) In animal studies, ticagrelor and clopidogrel achieved a similar degree of platelet inhibition in spite of a significant difference in myocardial infarct size and ticagrelor reduced reperfusion injury and myocardial infarct size by increasing myocardial adenosine levels and activating adenosine receptors.4),5)
In summary, a CMR study, but not a SPECT study, demonstrated that ticagrelor had cardioprotective effects with respect to reducing myocardial infarct size and microvascular obstruction in patients with STEMI undergoing primary PCI. Benefits of ticagrelor observed in the PLATO trial may result from reducing myocardial injury as well as prevention of recurrent vascular events.
Conflict of Interest: The author has no financial conflicts of interest.
The contents of the report are the author's own views and do not necessarily reflect the views of the Korean Circulation Journal.