Abstract
Background
Ticagrelor provides faster and more consistent platelet inhibition than clopidogrel; however, its effect on myocardial injury during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) remains uncertain.
Objectives
The aim of this pilot study was to assess the feasibility and preliminary effects of ticagrelor versus clopidogrel loading on myocardial injury in STEMI patients undergoing PCI, using cardiac magnetic resonance (CMR) imaging.
Methods
Thirty STEMI patients were randomized to receive aspirin with either clopidogrel (300 mg) or ticagrelor (180 mg) before PCI, followed by standard maintenance therapy. Myocardial injury was evaluated 4-10 days post-PCI using CMR parameters (infarct size, myocardial salvage index [MSI], microvascular obstruction [MVO], and infarct transmurality). Enzymatic infarct size and 5-year clinical outcomes were also analyzed.
Results
No significant differences in infarct size, MSI, MVO, or other CMR parameters were detected between the two groups. Left ventricular volume and function were comparable, with no major adverse cardiovascular events, stent thrombosis, or major bleeding over the 5-year follow-up period.
Conclusions
Ticagrelor and clopidogrel showed similar effects on CMR-based myocardial injury and long-term outcomes in STEMI patients undergoing PCI. These pilot findings are hypothesis-generating and support the feasibility and inform sample-size planning for future multicenter trials.
Keywords: Magnetic resonance imaging, Myocardial salvage index, Primary percutaneous coronary intervention, ST-segment elevation myocardial infarction
Abbreviations
AAR, Area at risk
ACS, Acute coronary syndrome
CMR, Cardiac magnetic resonance
LV, Left ventricle / left ventricular
MACE, Major adverse cardiovascular events
MI, Myocardial infarction
MRI, Magnetic resonance imaging
MSI, Myocardial salvage index
MVO, Microvascular obstruction
PCI, Percutaneous coronary intervention
PLATO, Platelet Inhibition and Patient Outcomes
SD, Standard deviation
STEMI, ST-elevation myocardial infarction
TIMI, Thrombolysis in myocardial infarction
INTRODUCTION
Dual antiplatelet therapy with a combination of aspirin and clopidogrel is standard for preventing adverse cardiac events in patients with acute coronary syndrome (ACS) and those undergoing percutaneous coronary intervention (PCI).1 The response to clopidogrel, a prodrug requiring metabolic activation, varies across patients,2 which has led to the use of newer agents such as ticagrelor. Unlike clopidogrel, ticagrelor does not require metabolic activation, is less affected by genetic variation, and provides faster and more consistent platelet inhibition.3,4
Small clinical and mechanistic studies have suggested that ticagrelor may offer advantages over clopidogrel, including increased adenosine levels and pleiotropic cardioprotective effects, as well as reductions in major adverse cardiovascular events (MACEs) and infarct size in patients with ST-segment elevation myocardial infarction (STEMI).5-7
Cardiac magnetic resonance (CMR) is used to assess myocardial damage. Some trials, such as CvLPRIT trial, have shown a reduction in infarct size with ticagrelor compared with that with clopidogrel.8 However, other studies have reported no significant difference.9 Owing to the conflicting results and a lack of long-term data, this study aimed to compare the effects of a 300 mg loading dose of clopidogrel with those of a 180 mg loading dose of ticagrelor on myocardial damage in STEMI patients undergoing primary PCI, as evaluated by contrast-enhanced magnetic resonance imaging (MRI).
METHODS
Study design and ethical approval
This single-blind, randomized controlled pilot trial was approved by the Taipei Veterans General Hospital Institutional Review Board and registered on ClinicalTrials. gov (NCT02792712). A summary of the study protocol and patient flow is presented in Figure 1.
Figure 1.
Flowchart showing patient flow and the design of randomization. CE-MRI, contrast-enhanced magnetic resonance imaging; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.
Study rationale
This trial was inspired by the Platelet Inhibition and Patient Outcomes (PLATO) Study, and aimed to explore the early-phase benefits and long-term cardioprotective mechanisms of ticagrelor in STEMI patients undergoing primary PCI via cardiac MRI to assess outcomes.
Sample size and participants
A sample size of 200 clopidogrel-naïve STEMI patients was calculated to detect a significant increase in the myocardial salvage index (MSI) with 80% power and a significance level of 0.05. Patients were randomized equally into ticagrelor or clopidogrel groups.
Inclusion/exclusion criteria
The inclusion criteria were: age ≥ 20 years, STEMI within 12 hours (chest pain > 30 minutes and ST elevation ≥ 1 mm in ≥ 2 contiguous leads or new left bundle branch block), planned PCI, and providing informed consent. The exclusion criteria were: symptom onset > 12 hours, malignancy, end-stage renal disease, contraindications to study drugs, or inability to consent.
Treatment protocol
The patients received 300 mg aspirin with either 300 mg clopidogrel or 180 mg ticagrelor before PCI, followed by maintenance therapy (100 mg aspirin daily plus 75 mg clopidogrel or 90 mg ticagrelor twice daily). The patients were randomized using a computer-generated allocation sequence managed by the interventional cardiologist. Given that the national door-to-balloon target in Taiwan is < 90 minutes, treatment delay was not expected to significantly influence outcomes. All patients presented with pre-PCI thrombolysis in myocardial infarction (TIMI) 0-1 flow and achieved post-PCI TIMI 2-3 flow.
Data collection and imaging
Baseline demographics and cardiovascular risk factors were recorded. The primary endpoint was myocardial infarct size as a percentage of the left ventricular (LV) mass, which was assessed by contrast-enhanced cardiac MRI 4-10 days post-PCI. The secondary endpoints included the extent of microvascular obstruction, number of LV segments (> 75% infarct transmurality), enzymatic infarct size (troponin-I at 72 hours and peak creatine kinase levels), and long-term clinical outcomes (MACEs [cardiac death, nonfatal myocardial infarction (MI), heart failure hospitalization, target vessel revascularization, and repeat PCI], stent thrombosis, and major bleeding over 5 years).
Cardiac MRI protocol
CMR was performed using 1.5T or 3T GE Discovery MR750 scanners with gadobutrol contrast. The protocol included cine steady-state free precession, T2-weighted imaging, first-pass perfusion, and delayed-enhancement sequences. Image post-processing was performed using ADW 4.4 and Reportcard software (GE Healthcare). LV volume and ejection fraction were calculated using the modified Simpson’s rule. The infarct size and area at risk (AAR) were quantified from late gadolinium enhancement and T2-weighted images, respectively. Transmural infarction was defined as hyperenhancement involving > 75% of the myocardial segment.
Statistical analysis
The normality of continuous variables was assessed using the Shapiro-Wilk test. Data are presented as mean ± standard deviation (SD) for normally distributed variables and median (interquartile range) for non-normally distributed variables. Continuous variables were analyzed using the t-test or the Wilcoxon rank-sum test, and categorical variables were analyzed using chi-square or Fisher’s exact tests. Time-to-event outcomes (e.g., MACEs) were assessed using Kaplan-Meier analysis. A p value < 0.05 was considered significant. Analyses were conducted using SAS version 9.1.
RESULTS
The TIGER trial enrolled patients from May 2016 to October 2018. This study included 30 patients who fulfilled our inclusion criteria at Taipei Veterans General Hospital and underwent CMR imaging. When the ticagrelor and clopidogrel groups were compared, no significant differences were observed in body mass index, body height, body weight, systolic blood pressure, diastolic blood pressure, hemoglobin, platelet count, incidence of hypertension, diabetes, hypercholesterolemia, total cholesterol, high-density lipoprotein, low-density lipoprotein, or triglyceride levels (Table 1).
Table 1. Baseline characteristics and CMR-derived parameters in patients receiving clopidogrel vs. ticagrelor.
| Ticagrelor (n = 16) | Clopidogrel (n = 14) | p value | |
| Age, years | 56.5 (54-64.8) | 58 (53-67.5) | 0.692 |
| Male, n (%) | 12 (75) | 14 (100) | 0.103 |
| Body mass index, kg/m2 | 27 (24.6-28) | 26.4 (22.4-29.5) | 0.868 |
| Body height, cm | 167 (156.3-172.8) | 165 (161-170.5) | 0.867 |
| Body weight, kg | 75 (67-80.5) | 70 (61.5-83.3) | 0.647 |
| SBP, mmHg | 123.5 (109.8-134.5) | 131 (110.8-140.3) | 0.693 |
| DBP, mmHg | 79 (71.3-93.3) | 78 (68.3-93) | 0.851 |
| Hemoglobin, g/dL | 14.9 (14.1-15.6) | 15.1 (14.1-15.3) | 0.729 |
| Platelet, /μL | 223500 (207750-268750) | 237000 (199500-296500) | 0.827 |
| Hypertension, n (%) | 10 (62.5) | 4 (28.6) | 0.063 |
| Diabetes mellitus, n (%) | 5 (31.3) | 4 (28.6) | 0.999 |
| Hypercholesterolemia, n (%) | 5 (31.3) | 4 (28.6) | 0.999 |
| Total cholesterol, mg/dL | 192.8 (170.5-221.3) | 165.8 (134-192.5) | 0.059 |
| HDL, mg/dL | 40.5 (31.5-44.7) | 29 (26-40) | 0.114 |
| LDL, mg/dL | 138.3 (115.5-148) | 108 (85.6-145.8) | 0.139 |
| Triglyceride, mg/dL | 145.5 (107.5-205.5) | 170 (83-257) | 0.554 |
| Fasting sugar, mg/dL | 164 (145-265) | 146 (127-208.3) | 0.187 |
| Uric acid, mg/dL | 5.3 (4.6-6.1) | 5.9 (5.1-6.8) | 0.297 |
| Creatinine, mg/dL | 1.1 (1-1.4) | 1.2 (1-1.3) | 0.693 |
| eGFR, mL/min/1.73 m2 | 71.4 (52.6-83.9) | 68.5 (61.2-78) | 0.901 |
| CK, U/L | 2949.5 (1092.3-3804.3) | 1364 (817.5-2465) | 0.135 |
| Use of drugs | |||
| Aspirin, n (%) | 14 (87.5) | 13 (92.9) | 0.626 |
| CCB, n (%) | 0 (0) | 2 (14.3) | 0.118 |
| ACEI, n (%) | 8 (50) | 6 (42.9) | 0.696 |
| ARB, n (%) | 1 (6.3) | 2 (14.3) | 0.464 |
| BB, n (%) | 9 (56.3) | 9 (64.3) | 0.654 |
| Digitalis, n (%) | 1 (6.3) | 0 (0) | 0.341 |
| K-sparing diuretics, n (%) | 2 (12.5) | 0 (0) | 0.171 |
| Loop diuretics, n (%) | 0 (0) | 1 (7.1) | 0.277 |
| Nitrates, n (%) | 2 (12.5) | 3 (21.4) | 0.513 |
| Alfa-blocker, n (%) | 0 (0) | 1 (7.1) | 0.277 |
| Anti-arrhythmia drugs, n (%) | 1 (6.3) | 0 (0) | 0.341 |
| Statins, n (%) | 14 (87.5) | 12 (85.7) | 0.886 |
| Radial access | 16 (100) | 14 (100) | ns |
| TIMI pre-PCI | |||
| TIMI 2/3, n (%) | 0 | 0 | ns |
| TIMI 0/1, n (%) | 16 | 14 | ns |
| TIMI post-PCI | |||
| TIMI 2/3, n (%) | 16 | 14 | ns |
| TIMI 0/1, n (%) | 0 | 0 | ns |
| Outcomes | |||
| All-cause mortality, n (%) | 0 (0) | 2 (14.3) | 0.118 |
| Cardiovascular death, n (%) | 0 (0) | 0 (0) | ns |
| Non-fatal reinfarction, n (%) | 0 (0) | 0 (0) | ns |
| Hospitalization for HF, n (%) | 0 (0) | 0 (0) | ns |
| Stent thrombosis, n (%) | 0 (0) | 0 (0) | ns |
| Major bleeding, n (%) | 0 (0) | 0 (0) | ns |
| Target vessel revascularization, n (%) | 0 (0) | 0 (0) | ns |
| Repeated PCI, n (%) | 8 (50) | 4 (28.6) | 0.232 |
| MRI parameters | |||
| Time to CMR (day) | 4.62 (4.0-6.0) | 3.85 (2.75-5.0) | 0.126 |
| LVEDV (mL) | 142.1 (119.5-149.3) | 139.4 (110.5-159.6) | 0.999 |
| LVEDVI (mL/m2) | 73.6 (67.4-83.8) | 73.8 (67.4-87.7) | 0.901 |
| LVEF | 46.8 (40.5-52) | 53.8 (48.3-60.9) | 0.096 |
| SV (mL) | 61 (55.2-78) | 71.3 (62-80.9) | 0.088 |
| CO (L/min) | 4.7 (3.9-5.7) | 4.7 (4.1-5.6) | 0.708 |
| Infarct size (%) | 23 (16.6-30.3) | 21 (14.9-24.4) | 0.253 |
| MVO area (%) | 0.6 (0.1-3.8) | 0.5 (0.1-2.7) | 0.803 |
| Area at risk | 43.3 (35.6-49.6) | 40 (32.4-47.3) | 0.603 |
| Myocardial Salvage Index (%) | 44.4 (32.5-56.3) | 48.1 (33.5-55.7) | 0.647 |
Values are expressed as median (interquartile range) or number (percentage).
ACEI, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; BB, beta-blocker; CCB, calcium channel blocker; CK, creatine kinase; CMR, cardiac magnetic resonance; CO, cardiac output; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HDL, high density lipoprotein; HF, heart failure; LDL, low density lipoprotein; LVEDV, left ventricular end-diastolic volume; LVEDVI, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; MVO, microvascular obstruction; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; SV, stroke volume; TIMI, thrombolysis in myocardial infarction.
In terms of procedural characteristics, there were no significant differences between the two groups in initial TIMI flow 0-1, use of radial access, or success rates of achieving TIMI flow 2/3 post-PCI.
The timing of CMR was similar between the two groups. MRI outcomes including left ventricular end-diastolic volume, left ventricular end-diastolic volume index, left ventricular ejection fraction, stroke volume, cardiac output, infarct size, microvascular obstruction extent, AAR, and MSI were comparable between the ticagrelor and clopidogrel groups (Table 1).
During the 5-year follow-up period, no cases of stent thrombosis, significant bleeding, MACEs, or TVR were noted in either group. Kaplan-Meier curves depicting repeated coronary interventions also revealed no significant differences between the two groups (Figure 2).
Figure 2.
Kaplan-Meier survival curves illustrating the incidence of repeated coronary interventions in the ticagrelor group versus the clopidogrel group. PCI, percutaneous coronary intervention.
DISCUSSION
In this randomized pilot study of STEMI patients undergoing primary PCI, ticagrelor did not significantly reduce infarct size or improve the MSI compared with clopidogrel. These neutral findings contrast with earlier mechanistic and small clinical studies suggesting potential cardioprotective advantages of ticagrelor, including faster onset, greater bioavailability, and pleiotropic effects on microvascular function and inflammatory pathways.10 MSI quantifies the proportion of at-risk myocardium salvaged by reperfusion, and it is a validated imaging biomarker for prognosis in acute MI;11 however, its sensitivity can be influenced by ischemic time, myocardial edema, and the timing of imaging.12
Ticagrelor achieves faster and more potent platelet inhibition than clopidogrel due to its higher bioavailability and independence from cytochrome P450 metabolism.13,14 By reaching a maximal effect within two hours versus up to six hours for a 300 mg clopidogrel loading dose, ticagrelor has been proposed to limit thrombus formation, distal embolization, vasoconstriction, and inflammation, thereby improving coronary microcirculation.15 Small randomized and mechanistic studies, including CMR assessments, have reported reduced microvascular resistance and smaller infarct size with ticagrelor compared with clopidogrel, although the results have been inconsistent.16-18 Large outcome trials such as PLATO7 showed that ticagrelor reduced cardiovascular events at the expense of more non-coronary artery bypass grafting major bleeding, whereas subsequent studies (TREAT,19 SWEDEHEART20) and observational data in Taiwan suggest similar ischemic and bleeding profiles in certain populations.21 Current guidelines22 recommend ticagrelor or prasugrel with aspirin for ACS, reserving clopidogrel for patients with high bleeding risk23 or contraindications.24 Despite reported reductions in infarct size and adverse remodeling in some clinical and experimental settings,25,26 the translation of these pleiotropic effects into consistent clinical benefits remains uncertain, reflecting heterogeneity in study designs, patient characteristics, and comorbidities.
Factors such as high-dose aspirin, caffeine, statins, and racial differences influence the effects of ticagrelor, with variable outcomes in trials such as PLATO7 and subsequent randomized controlled trials.27 For example, African Americans have been reported to show lower platelet reactivity, whereas greater platelet suppression has been reported in European Americans.28 In Asian patients, the efficacy and bleeding risk of ticagrelor have been reported to not be significantly different from non-Asian patients.29 Our findings also showed no significant difference in bleeding risk between ticagrelor and clopidogrel. However, bleeding risk varies according to the patients’ characteristics, procedures, and comorbidities.
To contextualize our neutral findings, Table 2 summarizes selected recent studies comparing ticagrelor with clopidogrel in STEMI or ACS patients. While a prospective cohort from Iran30 reported improved initial TIMI flow with ticagrelor, and population-based data from Sweden31 suggested a lower risk of MACEs in patients aged ≥ 75 years, a pragmatic randomized trial in Canada32 found no clear superiority of ticagrelor, and a large Chinese registry33 showed that cytochrome P450 2C19 genotype may identify subgroups more likely to benefit. Together with our pilot trial showing no significant difference in myocardial injury, these studies illustrate the heterogeneity of outcomes and underscore the need for individualized antiplatelet strategies tailored to bleeding risk, tolerability, and pharmacogenomic profiles.
Table 2. Comparison of the present pilot study with prior clinical studies evaluating ticagrelor versus clopidogrel in STEMI or ACS patients.
| Source | Study design | Study population | Aim of study | Results |
| Present study, 2025 | Pilot, single-blind, randomized controlled trial. | Ticagrelor group, n = 15 | To examine the effects of ticagrelor versus clopidogrel loading on myocardial injury in STEMI patients undergoing primary PCI. | No significant differences in myocardial injury or clinical outcomes between ticagrelor and clopidogrel. |
| Clopidogrel group, n = 15 | ||||
| Elahifar A et al.,30 2024 | Prospective cohort study of Farshchian Heart Center during March 2018-2019. | Ticagrelor group, n = 80 | Evaluated the effect of ticagrelor on initial TIMI flow compared with clopidogrel in STEMI patients who are candidates for primary PCI (PPCI). | In STEMI patients who were candidates for PPCI, ticagrelor administration led to a better initial TIMI flow grade compared with clopidogrel. |
| Clopidogrel group, n = 80 | ||||
| Marxer CA et al.,31 2025 | Healthcare data from the Stockholm CREAtinine Measurements (SCREAM) project, a healthcare utilization cohort including all adult residents in Stockholm (2011-2021). | Ticagrelor group, n = 2,295 | Aimed to conduct a population-based cohort study following the target trial emulation framework to evaluate the effectiveness and safety of DAPT with ticagrelor vs. clopidogrel on MACE and major bleeding in patients with ACS aged 75 years or older. | In ACS patients aged ≥ 75 years, ticagrelor was associated with a lower risk of MACE than clopidogrel. There were no differences in major bleeding, although the confidence interval was wide. |
| Clopidogrel group, n = 2,342 | ||||
| Kutcher SA et al.,32 2025 | Pragmatic, open-label, time-clustered (bimonthly between October 2018 and March 2021), randomized controlled trial. | Ticagrelor group, n = 450 | Compared the effectiveness and safety of ASA and ticagrelor or clopidogrel in patients with acute coronary syndrome from a single tertiary academic center in Montréal, Canada. | No strong evidence for the superiority of ticagrelor over clopidogrel in North American patients. |
| Clopidogrel group, n = 555 | ||||
| Tian H et al.,33 2025 | Post-hoc analysis from a prospective, single-center, real-world PCI registry between March 2016 and March 2023 in the General Hospital of Northern Theater Command in China. | Ticagrelor group, n = 2,931 | Conducted an analysis of a large-sample real-world dataset to evaluate potential influence from ticagrelor- vs. clopidogrel-based antiplatelet strategies in ACS patients with DM based on different CYP2C19 alleles. | The CYP2C19 genotype could be used to identify potential patients who would derive benefit from the ticagrelor-based antiplatelet strategy. Further research is warranted regarding the trade-off in bleeding complications. |
| Clopidogrel group, n = 7,445 |
ACS, acute coronary syndrome; ASA, acetylsalicylic acid; CYP2C19, cytochrome P450 2C19; DAPT, dual antiplatelet therapy; DM, diabete mellitus; MACE, major adverse cardiovascular events; PCI, percutaneous coronary intervention; PPCI, primary PCI; STEMI, ST-elevation myocardial infarction; TIMI, thrombolysis in myocardial infarction.
In this study, we used cardiac MRI to measure acute myocardial injury and showed that ticagrelor was as effective as clopidogrel in reducing myocardial injury in STEMI patients undergoing primary PCI, with no significant differences in infarct size, myocardial salvage, or long-term outcomes. Based on the observed variability in CMR-measured infarct size in this cohort (SD ≈ 8%), a future multicenter randomized trial powered at 80-90% with two-sided α = 0.05 would require approximately 80-110 patients per arm to detect a 3-5% absolute difference in infarct size. Such a study could incorporate standardized loading doses, early imaging time points, and prespecified secondary endpoints (e.g., MSI, clinical outcomes) to rigorously test whether ticagrelor confers incremental benefits over clopidogrel. These data underscore the need for adequately powered multicenter trials to confirm or refute our pilot findings and guide personalized antiplatelet therapy in STEMI.
This study has several limitations. First, it was a single-center trial with a limited sample size, restricting its statistical power and generalizability. Given the small sample size and observed variability in infarct size, the study was underpowered to detect modest differences; therefore, the neutral results should be interpreted as hypothesis-generating rather than conclusive. Second, CMR was performed during the acute phase, and edema may have influenced AAR estimation. Third, no follow-up imaging was conducted to assess infarct evolution or remodeling. Fourth, the clopidogrel loading dose was limited to 300 mg due to reimbursement constraints, which may have led to an underestimation of its maximal efficacy. Finally, post-discharge medical therapy and adherence were not fully controlled and may have influenced long-term outcomes. Larger, multicenter trials are warranted to confirm these findings and guide therapy.
CONCLUSION
In this randomized pilot study of STEMI patients undergoing primary PCI, ticagrelor demonstrated similar effectiveness to clopidogrel in limiting myocardial injury as assessed by CMR, with no significant differences in infarct size, MSI, or long-term clinical outcomes. Given the limited sample size, these results should be interpreted as hypothesis-generating; however, they support the feasibility and sample-size planning of adequately powered multicenter randomized trials for further confirmation.
DECLARATION OF CONFLICT OF INTEREST
All the authors declare that they have no conflicts of interest.
CONSENT FOR PUBLICATION
Not applicable.
AVAILABILITY OF DATA AND MATERIALS
The data presented in this study are available upon request from the corresponding author.
FUNDING
There was funding support from AstraZeneca.
AUTHOR CONTRIBUTIONS
Wang WT contributed to the data analysis, writing of the manuscript, interpretation of the data, and final review of the manuscript. Lee CY, Huang PH, Hsu PF, Leu HB, Lu TM, Chiou SH, Wang CT, and Huang SS contributed to the final review of the manuscript. Wu TC contributed to the idea initiation, data collection and analysis, data analysis, and final assessment of the manuscript.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data presented in this study are available upon request from the corresponding author.