Cardiovascular Revascularization Medicine 15 (2014) 284–288
Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
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)☆,☆☆ José Luis Winter, Dante Syvert Lindefjeld ⁎, Nicolás Veas, Eduardo Guarda, Martín Valdebenito, Manuel Méndez, Osvaldo Pérez, Karla Zuanic, María Mestas, Alejandro Martínez División de Enfermedades Cardiovasculares, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile Servicio de Hemodinamia, Hospital Sótero del Río, Santiago Chile
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Article history: Received 16 April 2014 Received in revised form 30 June 2014 Accepted 7 July 2014 Keywords: Ticagrelor Clopidogrel Microvascular perfusion STEMI
a b s t r a c t 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. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Distal embolization of thrombotic material during primary angioplasty is associated with impaired microvascular reperfusion and adverse outcomes [1]. 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
☆ The authors declare that they have no conflict of interest. ☆☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Facultad Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago 8330024, Chile. Tel.: +56 223543218. E-mail address: [email protected] (D.S. Lindefjeld). http://dx.doi.org/10.1016/j.carrev.2014.07.001 1553-8389/© 2014 Elsevier Inc. All rights reserved.
(PCI) [2] 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 [3]. This favorable pharmacologic profile was evaluated in PLATO trial [4], 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 [5]. 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
J.L. Winter et al. / Cardiovascular Revascularization Medicine 15 (2014) 284–288
(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 [6], 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 [7]. MBG was assessed as previously defined [8] 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 N 1/2 but b2 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 [9].
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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 [10,11]. 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 [7,12], 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).
3. Results Between August 2012 and July 2013, 107 consecutive patients with STEMI were invited to participate in this study. Ninety-two patients were randomized, and after angioplasty, 70 patients were analyzed. In Fig. 1 are shown reasons for dropouts. Baseline characteristics of both groups are displayed in Table 1. Mean age of all patients was 58.8 ± 10 years. Patients treated with ticagrelor were younger than patients in clopidogrel group (55.1 ± 8.3 vs. 62.1 ± 10.5 years, p = 0.04), with no other differences in the prevalence of comorbidities. Mean ischemic time was 4.4 ± 2.7 h in ticagrelor and 4.3 ± 2.6 h in clopidogrel group (p = 0.86). There were no significant differences in the elapsed time between loading doses and stent deployment (35.2 ± 36.4 min in ticagrelor vs. 42.7 ± 29.5 min in clopidogrel, p = 0.36). No patients received IIb/IIIa antagonists prior or during primary angioplasty. No differences were observed in the utilization of MTA between groups (44% in ticagrelor vs. 47% in clopidogrel, p = 0.48).
4. Angiographic results Before angioplasty cTFC was lower in ticagrelor than in clopidogrel (81.1 ± 29.4 vs. 95.1 ± 17.5 frames, respectively, p = 0.014). After angioplasty, there were no differences between ticagrelor and clopidogrel in TIMI flow grade (TIMI flow grade 1, 2 or 3 were 2.9, 17.6, 79.4 % vs. 5.6, 25.0, 69.4 % respectively, p = 0.62), cTFC (24.6 ± 9.3 vs. 27.0 ± 13.4 frames respectively, p = 0.40, Fig. 2). Percentages of myocardial blush 1, 2 or 3 were 2.9, 20.6, 76.5 vs. 11.1, 19.4, 69.4 respectively (p = 0.41), as shown in Table 2. After stratifying both groups depending on the use of MTA, there were no differences in cTFC between these subgroups (22.7 ± 6.4 in ticagrelor without MTA and 26.6 ± 11.5 in ticagrelor with MTA vs. 26.0 ± 12.5 in clopidogrel without MTA and 28.2 ± 14.9 in clopidogrel with MTA; p = 0.58 post ANOVA).
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Fig. 1. Trial enrollment.
4.1. ST resolution The percentage of ST resolution did not show differences between groups (84.8 ± 23.4 in ticagrelor vs. 70.8 ± 33.7 % in clopidogrel, p = 0.36). 5. Discussion In this randomized study, ticagrelor was not superior in angiographic and electrocardiographic parameters of microvascular perfusion after angioplasty. In patients with acute coronary syndrome, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke [4]. In the PLATO subgroup of 7544 patients with STEMI ticagrelor significantly reduced the incidence of death, myocardial infarction and stent thrombosis without increases in major bleeding [13]. The mechanisms that could explain these results are a faster and more potent platelet inhibition produced by ticagrelor. In the ONSET/ OFFSET study [3], patients with stable coronary disease received a loading dose of ticagrelor or clopidogrel. Ticagrelor achieved a mean
time to maximal platelet inhibition of approximately 2 hours compared to 7.8 hours in the clopidogrel group. In the same study, at the steady state, the mean maximal percentage of platelet inhibition was higher in ticagrelor patients (93% vs. 58%). Even though in ONSET/OFFSET study ticagrelor showed a potent and faster antiplatelet activity, the use of a loading dose of this drug was not associated with better microvascular flow and ST elevation resolution in our patients. One important issue that could have influenced all these results is the time between the loading dose of antiplatelet drugs and PCI. Even though the ONSET/OFFSET trial demonstrated a fast and potent platelet inhibition in stable patients, the pharmacodynamics of this drug might be different in the acute setting. In a recent study by Parodi [14] et al, 50 STEMI patients were randomized to ticagrelor or prasugrel previous to primary angioplasty and residual platelet activity was assessed in all patients. In this experience, even though there were no differences in terms of platelet inhibition between both groups, only half of patients achieved effective levels of platelet inhibition at 2 hours (60% in ticagrelor group) with a mean time of 5 ± 4 hours to obtain a value of less than 240 platelet reactive units.
J.L. Winter et al. / Cardiovascular Revascularization Medicine 15 (2014) 284–288 Table 1 Clinical characteristics and relevant information during angioplasty in both groups.
Male sex n (%) Age (years) Diabetes n(%) Dyslipidemia n (%) Hypertension n (%) Smoker n (%) Previous MI n (%) Ischemic time (h) Loading time (min) LVEF (%) Killip n (%) 1 2 3 4 Culprit lesion n (%) LAD LCX RCA Number of stents Pre dilation n (%) Post dilation n (%) Manual thrombus aspiration n (%)
Ticagrelor (n = 34)
Clopidogrel (n = 36)
p value
27 (79%) 55.1 ± 8.3 11 (32%) 9 (26%) 18 (52%) 24 (70%) 0 (0%) 4.4 ± 2.7 35.2 ± 36.4 50.4 ± 8.8
25 (69%) 62.1 ± 10.5 8 (22%) 7 (19%) 23 (63%) 19 (52%) 2 (5%) 4.3 ± 2.6 42.7 ± 29.5 46.8 ± 8.9
0.34 0.04 0.34 0.48 0.35 0.12 0.16 0.86 0.36 0.18 0.54
26 (76%) 8 (23%) 0 (0%) 0 (0%)
27 (75%) 9 (25%) 0 (0%) 0 (0%)
17 (50%) 4 (11%) 13 (38%) 1.24 ± 0.49 23 (67%) 15 (44%) 15 (44%)
13 (36%) 9 (25%) 14 (38%) 1.14 ± 0.35 23 (63%) 9 (25%) 17 (47%)
0.29
0.34 0.74 0.09 0.48
In our experience, no differences were found in angiographic parameters of reperfusion between groups. These results are similar to a recent sub study of PLATO trial were angiographic outcomes were assessed in 2616 patients [15]. According to their results, ticagrelor was not superior to clopidogrel in terms of TIMI flow grade, cTFC and TIMI thrombus grade. Importantly, 21.3% of their patients had been pretreated with clopidogrel. In this study the time between loading dose and PCI was 40 minutes, which is similar to our experience (38 minutes). One of the advantages of our study is that none of the patients was receiving clopidogrel at the time of randomization and none of them received IIb/IIIa antagonist prior or during PCI, so there are no other confounding antiplatelet drugs that could affect microvascular flow. Even though ticagrelor did not improve angiographic parameters of microvascular circulation, there are other “non-platelet” effects of this drug that could provide potential benefits in patients with acute coronary syndromes. Ticagrelor has shown to increase adenosine plasma concentration and enhances adenosine coronary vasodilatory response. In an experience of 40 healthy patients randomized to ticagrelor or placebo, the response to the infusion of adenosine over coronary flow velocity was significantly increased in the ticagrelor group [16]. More recently, Bonello et al [17] randomized 60 patients presenting with an acute coronary syndrome, to ticagrelor or
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Table 2 Measurements of thrombus grade and microvascular flow in both groups.
Thrombus grade n (%) 1 2 3 4 5 TFG post PCI n (%) 0 1 2 3 TIMI Blush grade n (%) 1 2 3 cTFC before angioplasty (frames) cTFC after angioplasty (frames) cTFC ≤ 23 n (%) ST resolution (%)
Ticagrelor (n = 34)
Clopidogrel (n = 36)
0 (0%) 7 (20%) 8 (23%) 10 (29%) 9 (26%)
0 (0%) 4 (11%) 8 (22%) 10 (27%) 14 (38%)
0 (0%) 1 (3%) 6 (17%) 27 (79%)
0 (0%) 2 (5%) 9 (25%) 25 (69%)
1 (3%) 7 (20%) 26 (76%) 81.1 ± 29.4 24.6 ± 9.3 18 (52%) 84.8 ± 23.4
4 (11%) 7 (19%) 25 (69%) 95.1 ± 17.5 27.0 ± 13.4 20 (55%) 70.8 ± 33.7
p value 0.60
0.62
0.41
0.01 0.62 0.82 0.36
clopidogrel and measured adenosine plasma concentration. Patients receiving ticagrelor showed higher levels of adenosine in plasma associated with an inhibition of adenosine uptake of red blood cells. This increase in adenosine plasma concentration could explain some of the benefit of this drug in acute coronary syndrome patients. Another possible explanation of our results and those obtained in the angiographic PLATO substudy [15], could be due to the effects of mechanical trauma and embolization produced by PCI. Distal embolization of atherothrombotic debris during PCI is associated to mechanical occlusion of microvessels and to activation of coagulation and inflammation pathways [18,19]. This theory is supported by the experiences with mesh-covered stents in acute coronary syndromes. These devices improve microvascular flow compared with standard stents in STEMI probably by excluding and preventing distal embolization of friable atheromatous debris [20,21], independent of antiplatelet agent used during the procedure. However, studies with distal protection devices and experiences with aspiration thombectomy showed more conflicting results [22,23]. Our study was performed in a limited number of patients. Even though a small sample size, the obtained results were similar to the sub analysis of a cohort of PLATO trial [15]. Another possible limitation of our study is that the level of antiplatelet activity was not assessed to evaluate if this lack of differences could be explained by lower platelet reactivity in one of the groups. On the other hand, there were significant differences in age between both groups, and this difference could affect the results of our study. Even though age is considered an
Fig. 2. (A) Corrected TIMI frame count (cTFC) after angioplasty in patients receiving clopidogrel and ticagrelor. (B) Percentage of myocardial blush grade 0, 1, 2 and 3 in both groups after angioplasty.
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important factor in terms of prognosis, to our best knowledge there are no studies that describe that cTFC could be affected by age. In conclusion, compared to clopidogrel, the use of ticagrelor loading dose prior to angioplasty in STEMI is not associated with an improvement in microvascular flow parameters or electrocardiographic signs of reperfusion.
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Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
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)☆,☆☆ José Luis Winter, Dante Syvert Lindefjeld ⁎, Nicolás Veas, Eduardo Guarda, Martín Valdebenito, Manuel Méndez, Osvaldo Pérez, Karla Zuanic, María Mestas, Alejandro Martínez División de Enfermedades Cardiovasculares, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile Servicio de Hemodinamia, Hospital Sótero del Río, Santiago Chile
a r t i c l e
i n f o
Article history: Received 16 April 2014 Received in revised form 30 June 2014 Accepted 7 July 2014 Keywords: Ticagrelor Clopidogrel Microvascular perfusion STEMI
a b s t r a c t 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. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Distal embolization of thrombotic material during primary angioplasty is associated with impaired microvascular reperfusion and adverse outcomes [1]. 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
☆ The authors declare that they have no conflict of interest. ☆☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Facultad Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Santiago 8330024, Chile. Tel.: +56 223543218. E-mail address: [email protected] (D.S. Lindefjeld). http://dx.doi.org/10.1016/j.carrev.2014.07.001 1553-8389/© 2014 Elsevier Inc. All rights reserved.
(PCI) [2] 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 [3]. This favorable pharmacologic profile was evaluated in PLATO trial [4], 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 [5]. 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
J.L. Winter et al. / Cardiovascular Revascularization Medicine 15 (2014) 284–288
(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 [6], 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 [7]. MBG was assessed as previously defined [8] 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 N 1/2 but b2 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 [9].
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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 [10,11]. 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 [7,12], 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).
3. Results Between August 2012 and July 2013, 107 consecutive patients with STEMI were invited to participate in this study. Ninety-two patients were randomized, and after angioplasty, 70 patients were analyzed. In Fig. 1 are shown reasons for dropouts. Baseline characteristics of both groups are displayed in Table 1. Mean age of all patients was 58.8 ± 10 years. Patients treated with ticagrelor were younger than patients in clopidogrel group (55.1 ± 8.3 vs. 62.1 ± 10.5 years, p = 0.04), with no other differences in the prevalence of comorbidities. Mean ischemic time was 4.4 ± 2.7 h in ticagrelor and 4.3 ± 2.6 h in clopidogrel group (p = 0.86). There were no significant differences in the elapsed time between loading doses and stent deployment (35.2 ± 36.4 min in ticagrelor vs. 42.7 ± 29.5 min in clopidogrel, p = 0.36). No patients received IIb/IIIa antagonists prior or during primary angioplasty. No differences were observed in the utilization of MTA between groups (44% in ticagrelor vs. 47% in clopidogrel, p = 0.48).
4. Angiographic results Before angioplasty cTFC was lower in ticagrelor than in clopidogrel (81.1 ± 29.4 vs. 95.1 ± 17.5 frames, respectively, p = 0.014). After angioplasty, there were no differences between ticagrelor and clopidogrel in TIMI flow grade (TIMI flow grade 1, 2 or 3 were 2.9, 17.6, 79.4 % vs. 5.6, 25.0, 69.4 % respectively, p = 0.62), cTFC (24.6 ± 9.3 vs. 27.0 ± 13.4 frames respectively, p = 0.40, Fig. 2). Percentages of myocardial blush 1, 2 or 3 were 2.9, 20.6, 76.5 vs. 11.1, 19.4, 69.4 respectively (p = 0.41), as shown in Table 2. After stratifying both groups depending on the use of MTA, there were no differences in cTFC between these subgroups (22.7 ± 6.4 in ticagrelor without MTA and 26.6 ± 11.5 in ticagrelor with MTA vs. 26.0 ± 12.5 in clopidogrel without MTA and 28.2 ± 14.9 in clopidogrel with MTA; p = 0.58 post ANOVA).
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Fig. 1. Trial enrollment.
4.1. ST resolution The percentage of ST resolution did not show differences between groups (84.8 ± 23.4 in ticagrelor vs. 70.8 ± 33.7 % in clopidogrel, p = 0.36). 5. Discussion In this randomized study, ticagrelor was not superior in angiographic and electrocardiographic parameters of microvascular perfusion after angioplasty. In patients with acute coronary syndrome, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke [4]. In the PLATO subgroup of 7544 patients with STEMI ticagrelor significantly reduced the incidence of death, myocardial infarction and stent thrombosis without increases in major bleeding [13]. The mechanisms that could explain these results are a faster and more potent platelet inhibition produced by ticagrelor. In the ONSET/ OFFSET study [3], patients with stable coronary disease received a loading dose of ticagrelor or clopidogrel. Ticagrelor achieved a mean
time to maximal platelet inhibition of approximately 2 hours compared to 7.8 hours in the clopidogrel group. In the same study, at the steady state, the mean maximal percentage of platelet inhibition was higher in ticagrelor patients (93% vs. 58%). Even though in ONSET/OFFSET study ticagrelor showed a potent and faster antiplatelet activity, the use of a loading dose of this drug was not associated with better microvascular flow and ST elevation resolution in our patients. One important issue that could have influenced all these results is the time between the loading dose of antiplatelet drugs and PCI. Even though the ONSET/OFFSET trial demonstrated a fast and potent platelet inhibition in stable patients, the pharmacodynamics of this drug might be different in the acute setting. In a recent study by Parodi [14] et al, 50 STEMI patients were randomized to ticagrelor or prasugrel previous to primary angioplasty and residual platelet activity was assessed in all patients. In this experience, even though there were no differences in terms of platelet inhibition between both groups, only half of patients achieved effective levels of platelet inhibition at 2 hours (60% in ticagrelor group) with a mean time of 5 ± 4 hours to obtain a value of less than 240 platelet reactive units.
J.L. Winter et al. / Cardiovascular Revascularization Medicine 15 (2014) 284–288 Table 1 Clinical characteristics and relevant information during angioplasty in both groups.
Male sex n (%) Age (years) Diabetes n(%) Dyslipidemia n (%) Hypertension n (%) Smoker n (%) Previous MI n (%) Ischemic time (h) Loading time (min) LVEF (%) Killip n (%) 1 2 3 4 Culprit lesion n (%) LAD LCX RCA Number of stents Pre dilation n (%) Post dilation n (%) Manual thrombus aspiration n (%)
Ticagrelor (n = 34)
Clopidogrel (n = 36)
p value
27 (79%) 55.1 ± 8.3 11 (32%) 9 (26%) 18 (52%) 24 (70%) 0 (0%) 4.4 ± 2.7 35.2 ± 36.4 50.4 ± 8.8
25 (69%) 62.1 ± 10.5 8 (22%) 7 (19%) 23 (63%) 19 (52%) 2 (5%) 4.3 ± 2.6 42.7 ± 29.5 46.8 ± 8.9
0.34 0.04 0.34 0.48 0.35 0.12 0.16 0.86 0.36 0.18 0.54
26 (76%) 8 (23%) 0 (0%) 0 (0%)
27 (75%) 9 (25%) 0 (0%) 0 (0%)
17 (50%) 4 (11%) 13 (38%) 1.24 ± 0.49 23 (67%) 15 (44%) 15 (44%)
13 (36%) 9 (25%) 14 (38%) 1.14 ± 0.35 23 (63%) 9 (25%) 17 (47%)
0.29
0.34 0.74 0.09 0.48
In our experience, no differences were found in angiographic parameters of reperfusion between groups. These results are similar to a recent sub study of PLATO trial were angiographic outcomes were assessed in 2616 patients [15]. According to their results, ticagrelor was not superior to clopidogrel in terms of TIMI flow grade, cTFC and TIMI thrombus grade. Importantly, 21.3% of their patients had been pretreated with clopidogrel. In this study the time between loading dose and PCI was 40 minutes, which is similar to our experience (38 minutes). One of the advantages of our study is that none of the patients was receiving clopidogrel at the time of randomization and none of them received IIb/IIIa antagonist prior or during PCI, so there are no other confounding antiplatelet drugs that could affect microvascular flow. Even though ticagrelor did not improve angiographic parameters of microvascular circulation, there are other “non-platelet” effects of this drug that could provide potential benefits in patients with acute coronary syndromes. Ticagrelor has shown to increase adenosine plasma concentration and enhances adenosine coronary vasodilatory response. In an experience of 40 healthy patients randomized to ticagrelor or placebo, the response to the infusion of adenosine over coronary flow velocity was significantly increased in the ticagrelor group [16]. More recently, Bonello et al [17] randomized 60 patients presenting with an acute coronary syndrome, to ticagrelor or
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Table 2 Measurements of thrombus grade and microvascular flow in both groups.
Thrombus grade n (%) 1 2 3 4 5 TFG post PCI n (%) 0 1 2 3 TIMI Blush grade n (%) 1 2 3 cTFC before angioplasty (frames) cTFC after angioplasty (frames) cTFC ≤ 23 n (%) ST resolution (%)
Ticagrelor (n = 34)
Clopidogrel (n = 36)
0 (0%) 7 (20%) 8 (23%) 10 (29%) 9 (26%)
0 (0%) 4 (11%) 8 (22%) 10 (27%) 14 (38%)
0 (0%) 1 (3%) 6 (17%) 27 (79%)
0 (0%) 2 (5%) 9 (25%) 25 (69%)
1 (3%) 7 (20%) 26 (76%) 81.1 ± 29.4 24.6 ± 9.3 18 (52%) 84.8 ± 23.4
4 (11%) 7 (19%) 25 (69%) 95.1 ± 17.5 27.0 ± 13.4 20 (55%) 70.8 ± 33.7
p value 0.60
0.62
0.41
0.01 0.62 0.82 0.36
clopidogrel and measured adenosine plasma concentration. Patients receiving ticagrelor showed higher levels of adenosine in plasma associated with an inhibition of adenosine uptake of red blood cells. This increase in adenosine plasma concentration could explain some of the benefit of this drug in acute coronary syndrome patients. Another possible explanation of our results and those obtained in the angiographic PLATO substudy [15], could be due to the effects of mechanical trauma and embolization produced by PCI. Distal embolization of atherothrombotic debris during PCI is associated to mechanical occlusion of microvessels and to activation of coagulation and inflammation pathways [18,19]. This theory is supported by the experiences with mesh-covered stents in acute coronary syndromes. These devices improve microvascular flow compared with standard stents in STEMI probably by excluding and preventing distal embolization of friable atheromatous debris [20,21], independent of antiplatelet agent used during the procedure. However, studies with distal protection devices and experiences with aspiration thombectomy showed more conflicting results [22,23]. Our study was performed in a limited number of patients. Even though a small sample size, the obtained results were similar to the sub analysis of a cohort of PLATO trial [15]. Another possible limitation of our study is that the level of antiplatelet activity was not assessed to evaluate if this lack of differences could be explained by lower platelet reactivity in one of the groups. On the other hand, there were significant differences in age between both groups, and this difference could affect the results of our study. Even though age is considered an
Fig. 2. (A) Corrected TIMI frame count (cTFC) after angioplasty in patients receiving clopidogrel and ticagrelor. (B) Percentage of myocardial blush grade 0, 1, 2 and 3 in both groups after angioplasty.
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important factor in terms of prognosis, to our best knowledge there are no studies that describe that cTFC could be affected by age. In conclusion, compared to clopidogrel, the use of ticagrelor loading dose prior to angioplasty in STEMI is not associated with an improvement in microvascular flow parameters or electrocardiographic signs of reperfusion.
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