The Comparison of the Initial TIMI Flow Grade in Acute ST-Elevation Myocardial Infarction Patients Receiving Ticagrelor vs. Clopidogrel before Undergoing Primary Percutaneous Coronary Intervention: A Prospective Cohort Study

Objective Primary percutaneous coronary intervention (PCI) is the best treatment for acute ST-elevation myocardial infarction (STEMI). Evidence is in favor of ticagrelor over clopidegrel in STEMI patients regarding the reduction of stent thrombosis risk during and after PCI. We compared initial thrombolysis in myocardial infarction (TIMI) flow in STEMI patients on ticagrelor vs. clopidogrel. Methods This prospective cohort recruited 160 patients with acute STEMI, referred to the emergency department of Farshchian Heart Center, during March 2018–2019. Before angiography, the patients received clopidogrel (600 mg) or ticagrelor (180 mg) on top of aspirin. Initial TIMI flow was compared between the two groups as the primary outcome. A logistic regression was performed to calculate the predictors of initial TIMI flow. Analyses were performed using R, version 4.2.1. Results In ticagrelor and clopidogrel groups, the mean ± standard deviation age of the patients was 59.46 ± 13.11 and 61.34 ± 11.08 years (p value = 0.33), respectively. In the ticagrelor and clopidogrel groups, initial TIMI flow grades were as follows: 0 : 50% and 71.2%, I: 26.2% and 16.2%, II: 12.5% and 10%, and III: 12.9% and 2.5%, respectively (p value = 0.005). Final TIMI flow grades were as follows: I: 26.2% and 16.2%, II: 7.5% and 13.8%, and III: 66.3% and 70%, respectively (p value = 0.41). Ticagrelor was associated with significantly higher initial TIMI flow grade compared to the clopidogrel group (adjusted odds ratio: 2.90 (95% CI: 1.51–5.72)). Conclusion In STEMI patients who were candidates for primary PCI, ticagrelor administration led to a better initial TIMI flow grade compared to clopidogrel.


Introduction
Acute ST-segment elevation myocardial infarction (STEMI) is one of the most important causes of mortality around the globe.Te disease occurs following acute thrombotic occlusion of an epicardial coronary artery.Coronary artery occlusion usually occurs due to atherosclerotic plaque rupture and thrombosis [1].Timely reperfusion through primary percutaneous coronary intervention (PPCI) is the most important treatment to improve the prognosis of patients with STEMI [1,2].
Platelet activation, followed by aggregation, plays a key role in the process of STEMI.Administration of platelet P2Y12 inhibitors on top of aspirin before PPCI is considered an important therapeutic strategy that helps restores the perfusion to the ischemic area and prevents stent thrombosis [1][2][3].
Clopidogrel is an oral inhibitor of the platelet P2Y12 receptor that irreversibly inhibits platelet activation; it is an inactive prodrug that requires two stages of hepatic metabolism by cytochrome P 450 enzymes to become an active drug.Tis drug is afected by the process of absorption and metabolism, and the use of some medications can also afect its function [4,5].
Ticagrelor is known as a potent oral inhibitor of the P2Y12 receptor and is a member of the cyclopentyl-triazolopyrimidines family and is one of the new antiplatelet drugs.Being an active metabolite, the drug inhibits platelet activity directly and reversibly and does not require hepatic metabolism; therefore, it has a faster onset of action than clopidogrel, and its antiplatelet efect is more robust and stable.
In patients with a STEMI diagnosis candidate for PPCI, it sounds logical to prescribe more potent antiplatelet drugs, such as ticagrelor or prasugrel.It has been stated in the recent STEMI guidelines that ticagrelor and prasugrel are preferred over clopidogrel.When these drugs are not available or are contraindicated, clopidogrel could be used as the P2Y12 inhibitor.
Previous studies have shown that ticagrelor is more efective than clopidogrel in preventing stent thrombosis and ischemic events among acute coronary syndrome (ACS) patients without increasing the risk of major bleeding [5][6][7].Te impact of initial thrombolysis in myocardial infarction (TIMI) fow on the outcome of STEMI has been investigated in some studies.It has been shown that higher initial TIMI fow is associated with lower in-hospital as well as 30-, 90-, and 180-day mortality.In addition, its desirable efects on stent thrombosis, cardiogenic shock, fnal infarct size, microvascular obstruction, reinfarction, ST-segment resolution, and fnal TIMI fow after angioplasty have been demonstrated [8,9].
It is indicated in these studies that the initial TIMI fow of 2 and 3 was more benefcial in the clinical prognosis of patients compared to the initial TIMI fow of 0 or 1.On the other hand, in these studies, the initial TIMI fow was better in patients receiving ticagrelor than in patients taking clopidogrel [9,10].
Te impact of various P2Y12 inhibitors on STEMI outcomes is still a matter of debate.We evaluated the efect of ticagrelor on initial TIMI fow compared to clopidogrel in STEMI patients who are candidates for primary PCI (PPCI).

Study Design and
Participants.Tis prospective cohort study was performed in Farshchian Heart Center, Hamadan University of Medical Sciences, Hamadan, Iran, from March 2018 to March 2019.Patients with acute STEMI in whom PPCI was indicated and consented to participate in the study were included.Te diagnosis of acute STEMI was made according to the electrocardiograms prepared at admission to the emergency department and the necessary criteria for STEMI confrmation by experienced cardiologists.After STEMI was confrmed, patients were given a loading dose of clopidogrel (600 mg) or ticagrelor (180 mg) based on the discretion of the interventional cardiologist in charge of PPCI and prepared for emergency angiography and angioplasty.A loading dose of 325 milligrams of aspirin was prescribed for all aspirin-naive patients.Patients with a coronary artery bypass graft surgery history or ambiguous culprit vessels were excluded from the study.

Data Collection.
Data regarding the baseline demographics comprising age, sex, history of hypertension (HTN), diabetes mellitus (DM), dyslipidemia (DLP), and current cigarette smoking were collected.Baseline angiographic variables included pain-to-door time, pain-to-wire time, culprit vessel, coronary dominancy, initial TIMI fow, fnal TIMI fow, and TIMI thrombus grading.Te collected information about the antiplatelet drug prescribed before angiography was extracted from the patients' medical records, which were classifed into two groups: those who received ticagrelor and those who received clopidogrel.

2.3.
Outcomes.Te primary outcome was the initial TIMI fow grade before performing PPCI.Te secondary outcomes were the fnal TIMI fow grade, measured after PPCI, all-cause death, major adverse cardiovascular event (MACE, defned as a composite of all-cause death, myocardial infarction (MI), or stroke), and bleeding events defned according to the International Society on Trombosis and Haemostasis (ISTH) criteria [11].Te relevant recorded angiography and angioplasty flms were stored in the angiography unit system, and an independent interventional cardiologist, unaware of the patients' medical histories, determined the fndings such as the culprit vessel, dominant coronary system, vessel score, TIMI thrombus grade, initial TIMI fow, and fnal TIMI fow.
Te TIMI fow grade is a semiquantitative method for estimating epicardial coronary perfusion during angiography of infarct-related arteries.Te TIMI grade fow ranges from 0 to 3, in which Grade 0 (no perfusion): there is no antegrade fow beyond the occlusion point of the infarct-related artery.Grade 1 (penetration without perfusion): the contrast media pass distal to the obstruction point but "hang up" and fail to opacify the entire infarct-related artery distal to occlusion for the duration of the flming sequence.Grade 2 (partial perfusion): the contrast media pass across the occlusion point and opacify the entire infarct-related artery bed distal to the obstruction.Te rate of entry and clearance of contrast media into the infarct-related artery distal to the obstruction is slower than that in the opposite coronary artery.Grade 3 (complete perfusion): antegrade fow into the bed distal to the occlusion of the infarct-related artery is as fast as the antegrade fow into the proximal bed, and contrast clearance from the involved bed is as prompt as that from an uninvolved bed in the same vessel or the opposite artery [12].

2
Cardiology Research and Practice Te TIMI thrombus grade was classifed according to the presence and size of the thrombus from grade 0 to 5 (Supplementary Table S1) [13].

Ethical Consideration.
Informed consent was obtained from all participants.Tis study was approved by the Ethics Review Board of the Hamadan University of Medical Sciences.In all steps of the study, we strictly adhered to the Declaration of Helsinki [14].

Statistical Analysis.
Te data normality was checked using the Kolmogorov-Smirnov test.Qualitative variables were displayed as numbers and percentages.Chi-squared and Mann-Whitney U tests were used to analyze the differences between the nominal and ordinal qualitative variables between the two groups.Quantitative variables were displayed as the mean (standard deviation (SD)) or median (interquartile range (IQR)) and were analyzed using the Mann-Whitney U test or the independent t-test.Furthermore, an ordered logistic regression model was created to analyze the predictors of the primary outcome, and the results were reported as the odds ratio (OR) and 95% confdence interval (CI).Te statistical signifcance level was considered less than 0.05.Data were analyzed using R version 4.2.1.

Baseline Characteristics.
From March 2018 to March 2019, 160 patients were included in the study, of whom 80 received clopidogrel and 80 received ticagrelor.No significant diference was observed between the treatment groups in terms of demographic characteristics and classical coronary artery disease risk factors (Table 1).
Tere was no signifcant diference between the groups regarding the mean (SD) pain-to-door time (154.18(44.84) mins vs. 151.68(42.31) mins, p value � 0.71) and pain-to-wire time (244.62 (44.57) mins vs. 240.71(44.6) mins, p value � 0.58).A signifcant diference was observed between patients receiving ticagrelor and clopidogrel in terms of the culprit vessels (p value � 0.027).However, no signifcant diference was observed between the ticagrelor and clopidogrel groups in terms of the TIMI thrombosis grade (p value � 0.364), a marker of thrombus burden among STEMI patients, and dominant coronary system (p value � 0.056) (Table 1).

Primary Outcome.
A statistically signifcant diference was shown between the groups receiving ticagrelor and clopidogrel in terms of the initial TIMI fow grade (p value � 0.022 and p value � 0.005, yielded from Chi-squared and Mann-Whitney U tests, respectively).In the post hoc Chi-squared analysis, only the TIMI fow grade 0 showed a signifcant diference (ticagrelor: 40 (50%) vs. clopidogrel: 59 (71.2%), p value � 0.047).Overall, the diference between the two treatment groups in terms of the initial TIMI fow grade was statistically signifcant in favor of ticagrelor.No signifcant statistical diference was observed between ticagrelor and clopidogrel treatment groups in terms of the fnal TIMI fow grade (after angioplasty) (Table 2).Te plot in Figure 1 visualizes the proportion of the initial TIMI score based on the treatment group and the trend of TIMI score change from initial to fnal angiograms.
An ordered logistic regression model was built to calculate the predictors of the primary outcome, the initial TIMI fow score.Te logistic model was adjusted for age, sex, hypertension, diabetes mellitus, dyslipidemia, smoking, and treatment group (ticagrelor or clopidogrel).Te results showed that ticagrelor was associated with a signifcantly higher TIMI fow grade compared to the clopidogrel group (adjusted OR: 2.90 (95% CI: 1.51-5.72),p value � 0.001).Te results are given in Table 3.

Secondary
Outcomes.Two (2.5%) all-cause deaths happened in the ticagrelor group and 3 (3.75%)deaths happened in the clopidogrel group and the diference was statistically not signifcant (p value � 0.65, yielded from Chisquared test).No MI or stroke occurred in either group; thus, MACE happened in 2 (2.5%) and 3 (3.75%)patients in the ticagrelor and clopidogrel groups, respectively (no signifcant diference between the groups with a p value � 0.65, yielded from Chi-squared test).Two (2.5%) minor gastrointestinal bleeding events occurred in the ticagrelor group and no bleeding occurred in the clopidogrel group, showing no signifcant diference between the groups (p value � 0.16, yielded from Chi-squared test).
An ordered logistic regression model was built to calculate the predictors the fnal TIMI score.Te model was adjusted for age, sex, hypertension, diabetes mellitus, dyslipidemia, smoking, initial TIMI score, and treatment group (ticagrelor or clopidogrel).None of the covariates were signifcantly associated with the fnal TIMI fow score.Te results are represented in the Supplementary Table S2.

Discussion
Tis prospective study aimed to compare the initial TIMI fow in STEMI patients referred for PPCI who were treated with either ticagrelor or clopidogrel.Patients in the ticagrelor and clopidogrel groups had no signifcant diference in age, sex, or TIMI thrombus grade.Te initial TIMI fow grade of the culprit artery was signifcantly higher in the ticagrelor group compared with that of the clopidogrel group.Furthermore, ticagrelor, compared to clopidogrel, signifcantly increased the odds of TIMI fow score improvement.However, there was no signifcant diference between the treatment groups in terms of the fnal TIMI fow grade.
PPCI is the standard and preferred treatment in STEMI with acceptable efcacy compared to other treatment options [15].In a clinical trial conducted in 2019 by Cao et al. [16], the short-term outcomes of the STEMI patient candidates for PPCI who received ticagrelor or clopidogrel were compared.Tere was no signifcant diference between the two groups regarding TIMI fow grade zero, grade I, and grade II; However, grade III TIMI fow was more frequent in the ticagrelor group than in the clopidogrel group (p � 0.016).

Cardiology Research and Practice
In an analysis of the Bremen STEMI registry conducted by Schmucker et al. in 2019 [17], the efcacy and safety of ticagrelor compared to clopidogrel in elderly STEMI patients who underwent PPCI were evaluated.Tere were 7466 STEMI patients, of whom 1087 patients over 75 were selected.It was observed that the initial TIMI fow of zero in the clopidogrel group was signifcantly higher than the ticagrelor group (p � 0.04), and there was no signifcant diference between the two groups in terms of fnal TIMI fow, which are consistent with the results of our study.
In a systematic review conducted in 2019 to compare ticagrelor with clopidogrel in managing patients with acute myocardial infarction, the results of studies published in databases over the last ten years have shown that ticagrelor reduces the size of infarction and mortality compared to clopidogrel.However, the results based on angiographic studies did not indicate a signifcant diference between the two treatment methods [18].
In a study by Dai et al. [1] in 2017 on 4162 STEMI patients treated by PPCI, the results showed that the initial TIMI fow of the ticagrelor group was far superior to the clopidogrel group without signifcant diference in hemorrhagic events.Despite the smaller volume of our study, the results were consistent with that of Dai et al. [1].
Zhu et al. [19] in 2015 in China and Winter et al. [20] in 2014 in Chile also showed that the ticagrelor loading dose, in the early stages of acute myocardial infarction, inhibits platelet activity more efectively than clopidogrel, resulting in a better initial TIMI fow; however, the fnal TIMI fow did not difer much between the two groups, in line with the results of our study.
Studies have shown that better initial TIMI fow in STEMI patients is associated with a smaller size of infarction and microvascular occlusion [3].It has been hypothesized that an initial TIMI fow of 2 or 3 compared to 0 or 1 is associated with shorter ischemia duration and a signifcant Data are presented as numbers (%).* p value <0.05. 2 Chi-squared test. 3Chi-squared post hoc analysis with Bonferroni correction. 4 Mann-Whitney U test.  1 Data are presented as numbers (%) or the mean ± standard deviation (SD). 2 Chi-squared test. 3Chi-squared post hoc analysis with Bonferroni correction. 4 Mann-Whitney U test. 5 Independent t test. 4 Cardiology Research and Practice reduction in myocardial damage.Infarct size and microvascular obstruction could independently predict adverse left ventricular remodeling and major adverse cardiovascular events in STEMI patients.Assuming similar time delays from symptom onset to PPCI in both groups, patients with initial TIMI of 2 and 3 probably have shorter ischemic times compared to those with initial TIMI of 0 and 1.Another possible beneft is that the visible trajectory of the culprit vessel with TIMI 2 or 3 will lead to more straightforward wiring and possibly faster reperfusion.
Patients with higher initial TIMI fow before angioplasty will be more likely to have a higher TIMI fow after angioplasty.Tey will also have lower in-hospital as well as 30day and 180-day mortality, stent thrombosis, reinfarction, and cardiogenic shock [6].Other studies showed that despite having a signifcant efect on reducing cardiovascular mortality, myocardial infarction, and stent thrombosis compared to clopidogrel, ticagrelor administration is not associated with higher rates of cerebrovascular accidents (CVA) and bleeding risk [21,22].Ticagrelor has improved platelet inhibition in the early hours as well as maintenance treatment of STEMI patients [5]; hence, prehospital administration of ticagrelor has been recommended for patient candidates for PPCI [8].
Pretreatment with P2Y12 inhibitors was supported by strong recommendation at the time of our study (2018-2019), according to the 2017 European Society of Cardiology (ESC) guideline for the management of STEMI (class I and level of evidence A) [23].On this basis, our patients were pretreated with ticagrelor or clopidogrel, and we did not compare them in this regard.In the recently published ESC guideline for the management of ACS, the pretreatment with P2Y12 inhibitors in STEMI is of a class IIb indication (weak recommendation), while in non-ST segment elevation ACS, routine pretreatment with P2Y12 inhibitors in patients whose coronary anatomy is not known and an early invasive strategy is planned and contraindicated (class III recommendation) [24].
Te strengths of the present study are the prospective cohort design and comparison of initial TIMI fow among subjects receiving clopidogrel or ticagrelor in a relatively sufcient sample size.Te limitations of this study are the lack of randomization and possibly the efect of confounding variables on the study results.

Conclusion
In STEMI patients who were candidates for PPCI, administering the antiplatelet drug ticagrelor on top of aspirin before angiography was associated with better initial TIMI fow grade and higher probability of improvement in TIMI fow compared to clopidogrel and aspirin.

Figure 1 :
Figure 1: Graphical representation of the TIMI score based on the treatment groups and the trend of the TIMI score change from initial to fnal sessions.TIMI: thrombolysis in myocardial infarction.

Table 2 :
Initial and fnal TIMI fow grades of the culprit vessel in the treatment groups.

Table 1 :
Baseline demographic and angiographic characteristics.

Table 3 :
Ordered logistic regression of the predictors of the initial TIMI score.p value <0.05.† Model adjusted for age, sex, hypertension, diabetes mellitus, dyslipidemia, smoking, baseline TIMI fow score, and treatment group.