Angiographic and electrocardiographic parameters of myocardial reperfusion in angioplasty of patients with ST elevation acute myocardial infarction loaded with ticagrelor or clopidogrel (MICAMI—TICLO trial)

Abstract

Introduction

Ticagrelor has been shown to improve outcomes in patients with ACS. However, the effects of this drug on parameters of microvascular flow in patients presenting with ST-segment elevation myocardial infarction (STEMI) have not been completely evaluated.

Methods

Ninety-two patients presenting with STEMI where randomized to a loading dose of clopidogrel (600 mg) or ticagrelor (180 mg) before undergoing primary angioplasty. We assessed angiographic and electrocardiographic parameters of myocardial reperfusion. Blinded operators calculated angiographic corrected TIMI Frame count (cTFC) and myocardial blush grade (MBG) before and after stent implantation. ST segment resolution was also measured in all patients. Primary endpoint was cTFC after PCI. Secondary endpoints were cTFC prior to PCI, TIMI flow grade, MBG and the percentage of ST resolution.

Results

Of the 92 randomized patients, 70 patients were analyzed. Mean age of patients was 58.8 ± 10 years. Patients presented with a mean ischemic time of 4.4 ± 2.6 hours. There were no significant differences in the time between loading dose and stent deployment (35.2 ± 36.4 in ticagrelor and 42.7 ± 29.5 min in clopidogrel, p = 0.36). cTFC before angioplasty was significantly lower in ticagrelor than in clopidogrel (81.1 ± 29.4 vs. 95.1 ± 17.5 frames respectively, p = 0.01). After angioplasty there were no differences between ticagrelor and clopidogrel in cTFC (24.6 ± 9.3 vs. 27.0 ± 13.4 frames respectively, p = 0.62); MBG grade 3 was present in 76.4 vs. 69.4% of patients, respectively (p = 0.41). The percentage of ST resolution did not show any differences between groups (84.8 ± 23.4 in ticagrelor vs. 70.8 ± 33.7 in clopidogrel, p = 0.36).

Conclusion

Compared with clopidogrel, ticagrelor loading in patients presenting with STEMI is not associated with an improvement of angiographic and electrocardiographic parameters of myocardial reperfusion after angioplasty.

Highlights

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We examined angiographic and electrocardiographic parameters of reperfusion in patients presenting with ST elevation myocardial infarction loaded with ticagrelor or clopidogrel.
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Patients received a loading dose of ticagrelor (180 mg) or clopidogrel (600 mg).
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Corrected TIMI frame count, myocardial blush grade and the percentage of ST resolution were assessed after primary angioplasty.
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No differences were found between ticagrelor and clopidogrel in terms of angiographic and electrocardiographic parameters of reperfusion.

1 Introduction

Distal embolization of thrombotic material during primary angioplasty is associated with impaired microvascular reperfusion and adverse outcomes . A greater level of platelet inhibition with IIb/IIIa antagonists has been shown to improve perfusion of the myocardium before and after percutaneous coronary intervention (PCI) and the search for potent oral antiplatelet agents has provided several new drugs available to clinical practice. Ticagrelor is a reversible P2Y12 antagonist which produces faster and greater platelet inhibition in patients with stable coronary disease . This favorable pharmacologic profile was evaluated in PLATO trial , and ticagrelor was associated with a significant improvement in clinical outcomes compared to clopidogrel. Besides its antiplatelet activity, ticagrelor has been shown to increase extracellular adenosine availability . This systemic effect could be beneficial at the myocardium, providing microvascular vasodilatation, which could lead to better microvascular flow in patients with ongoing ischemia.

There are few data regarding the effects of ticagrelor upon angiographic and electrocardiographic parameters of myocardial reperfusion in patients presenting with ST elevation myocardial infarction (STEMI) who are undergoing primary angioplasty. The objective of this study was to compare the effects of ticagrelor and clopidogrel on angiographic and electrocardiographic criteria of reperfusion in patients with STEMI who were treated with primary angioplasty.

2 Methods

This was an open label randomized study. Patients were randomized in the emergency department, using closed envelopes, if they presented with ST segment elevation myocardial infarction (STEMI) with less than 12 hours of onset of symptoms and were candidates for primary angioplasty. STEMI was defined as symptoms suggesting acute myocardial ischemia lasting more than 30 minutes and ST segment elevation of more than 0.1 mV in two or more leads on the ECG or newly diagnosed left bundle branch block (LBBB). Exclusion criteria were: a) cardiogenic shock, b) thrombolysis within the last 24 hours, c) oral anticoagulation therapy or current use of P2Y12 antagonists. All patients gave written informed consent approved by the local ethics committee.

Study treatment: All patients received 500 mg of acetylsalicylic acid in the emergency department , and then were randomized to receive a loading dose of 180 mg of ticagrelor or 600 mg of clopidogrel. Angiography was performed according to standard protocols, loaded with non-fractioned heparin for an activated clotting time of more than 300 seconds. Manual thrombus aspiration (MTA) and IIbIIIa antagonist (Abciximab) during primary angioplasty was left at the operator decision.

Patients who had the following angiographic findings were excluded from data analysis: a) in stent thrombosis, b) multivessel disease with need of immediate multiple revascularization, c) STEMI secondary to bypass or mammary graft occlusion, d) target vessel with a diameter of less than 2 mm. After angioplasty, patients continued antiplatelet therapy with aspirin 100 mg once daily with either ticagrelor 90 mg bid or clopidogrel 75 mg daily. Loading time was defined as the time between drug loading and stent deployment.

After the procedure, one experienced operator blinded to treatment assignment calculated TIMI flow grade, corrected TIMI frame count (cTFC) and TIMI thrombus grade and myocardial blush (MBG) in all patients.

In brief, cTFC refers to the number of cineframes needed for the dye to reach standardized distal landmarks to assess an index of coronary blood flow as a continuous variable. The first frame used for TIMI frame counting is the first frame in which the dye fully enters the artery and the last frame is when contrast meets defined anatomical landmarks depending on the culprit artery. The cTFC was converted when necessary to be based on the most common filming speed of 30 frames per second .

MBG was assessed as previously defined where in MBG 0, there is minimal or no myocardial blush; in MBG 1, contrast stains the myocardium, and this stain persists on the next injection; in MBG 2, contrast enters the myocardium but washes out slowly so that the dye is strongly persistent at the end of the injection; and in MBG 3, there is normal entrance and exit of contrast in the myocardium so that the dye is mildly persistent at the end of the injection.

TIMI thrombus grade is defined previously as follows: TIMI thrombus grade 0, no cineangiographic characteristics of thrombus are present; TIMI thrombus grade 1, possible thrombus is present, with such angiography characteristics as reduced contrast density, haziness, irregular lesion contour, or a smooth convex “meniscus” at the site of total occlusion suggestive but not diagnostic of thrombus; TIMI thrombus grade 2, there is definite thrombus, with greatest dimensions ≤ 1/2 the vessel diameter; in TIMI thrombus grade 3, there is definite thrombus but with greatest linear dimension > 1/2 but < 2 vessel diameters; in TIMI thrombus grade 4, there is definite thrombus, with the largest dimension ≥ 2 vessel diameters; and in TIMI thrombus grade 5, there is total occlusion .

ST score was calculated with 12 lead electrocardiograms at baseline and 90 minutes after the procedure. The absolute level of ST segment elevation was measured 20 ms after the J point, using the TP segment as the isoelectric baseline. ST score was calculated by one expert blinded to treatment assignment, using previously validated algorithms as the sum of elevation in V1–6, I, and aVL for anterior infarction and as the sum of elevation in leads II, III, aVF, V5, and V6 for non-anterior infarction . The percentage of ST score resolution was obtained comparing the 90-minute versus baseline ST score.

Primary endpoint was cTFC after PCI in all patients treated with the study drugs before PCI. Secondary endpoints were cTFC prior to PCI, TIMI flow grade, MBG and the percentage of ST resolution in both groups.

2.1 Sample size and statistical analysis

Sample size was calculated using Kelsey method based in our primary endpoint. Trials describe a mean cTFC of 25 ± 7 frames after angioplasty with clopidogrel loading , and we expected a 20% improvement in cTFC with a loading dose of ticagrelor considering a significance level of 5% and 80% power. For that purposes, 35 patients per group were needed to evaluate this hypothesis. Continuous variables were expressed as mean ± SD, and categorical variables were expressed as percentages (%). The distribution of continuous variables was determined by the Kolmogorov–Smirnov test. Comparisons were performed using Student t-test and ANOVA for normally distributed variables and Mann–Whitney-U test for non-normally distributed variables. Data analysis was performed using the SPSS statistical software v16.0 (SPSS Inc., Chicago, IL).