The Impact of Fexofenadine Hydrochloride on the Prognosis of Patients Post-Acute Myocardial Infarction: A Randomized Clinical Trial (FEND Ⅱ)
Phase: PHASE3
Conditions: Zhejiang University
Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

 
 
FEND II: Fexofenadine Hydrochloride 
Study Protocol for MI Prognosis 
Study Protocol 
The Impact of Fexofenadine Hydrochloride on the Prognosis of 
Patients Post-Acute Myocardial Infarction: A Randomized Clinical 
Trial (FEND Ⅱ) 
FEND Ⅱ Study Protocol 
Version No.: V1.3 
December 15, 2025 
Principal Investigator: 
Hu Xinyang, PhD 
Department of Cardiovascular Medicine, 
The Second Affiliated Hospital of Zhejiang University School of Medicine 
National Key Laboratory of Transvascular Implantable Devices 
88 Jiefang Road, Hangzhou 310009, China 
E-mail: hxy0507@zju.edu.cn 
1. Study Background 
Myocardial infarction (MI) and subsequent heart failure are among the leading causes of 
death in patients with cardiovascular diseases in China. Myocardial cell death following MI 
triggers the activation of fibroblasts. Although fibroblasts play a reparative role, their 
excessive activation and the overdeposition of extracellular matrix can form fibrotic tissue, 
ultimately leading to heart failure. Currently, while a series of measures can reduce early 
mortality after MI, there is a lack of effective therapeutic approaches targeting pathological 
fibrosis post-MI. Therefore, inhibiting the excessive activation of cardiac fibroblasts and 
reducing cardiac fibrosis after MI are crucial scientific issues and clinical needs that urgently 
require resolution. 
Although the mechanisms driving organ-specific fibrosis have not been fully elucidated, 
fibrosis in different tissues and organs is characterized by the persistent abnormal activation 
of myofibroblasts mediated by multiple signals such as transforming growth factor (TGF), 
platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). Drugs targeting 
these abnormal signals have achieved certain efficacy in clinical trials, such as nintedanib and 
pirfenidone. Our preliminary work found that the expression of flavin-containing 

 
 
monooxygenase 2 (FMO2) in cardiac tissue is significantly reduced after MI. Downregulation 
of FMO2 in cardiac fibroblasts leads to impaired cardiac function, increased collagen 
deposition, and aggravated fibrosis, suggesting that FMO2 can also serve as a therapeutic 
target for cardiac fibrosis. 
Through high-throughput screening of the FDA drug library, we previously identified that 
fexofenadine hydrochloride significantly promotes FMO2 expression. Fexofenadine 
hydrochloride is a third-generation H1 receptor antagonist primarily used for the treatment of 
allergic diseases such as seasonal allergic rhinitis and chronic idiopathic urticaria¹⁰. However, 
the efficacy and safety of fexofenadine hydrochloride in the treatment of acute myocardial 
infarction remain unclear. Our preliminary mouse studies demonstrated that fexofenadine 
hydrochloride can significantly improve cardiac function and reduce fibrosis after MI in mice, 
with no significant adverse effects on liver and kidney function within the effective dose 
range. We also verified the safety of this drug in human cardiac organoids. Furthermore, we 
initiated a prospective, multicenter, randomized controlled clinical trial to evaluate the 
efficacy and safety of fexofenadine hydrochloride in patients with acute ST-segment elevation 
myocardial infarction (STEMI). Based on this, the present clinical study aims to assess the 
efficacy and safety of fexofenadine hydrochloride in improving the prognosis of acute MI. 
2. Study Objectives 
To evaluate the prognostic effect of fexofenadine hydrochloride in patients with MI through a 
large-sample, multicenter randomized controlled study. 
3. Study Design and Methods 
3.1 Study Design 
An investigator-initiated, multicenter, double-blind, placebo-controlled, superiority 
randomized controlled clinical trial. Participating centers include: The Second Affiliated 
Hospital of Zhejiang University School of Medicine, Ruijin Hospital Affiliated to Shanghai 
Jiao Tong University School of Medicine, Fuwai Central China Cardiovascular Hospital, West 
China Hospital of Sichuan University, The First Affiliated Hospital of Wenzhou Medical 
University, The Second Affiliated Hospital of Wenzhou Medical University, The First 
Affiliated Hospital of Harbin Medical University, The Second Affiliated Hospital of 
Chongqing Medical University, etc. 
Additional study sites may be added subsequently. 
3.2 Patient Enrollment 
Patients with acute ST-segment elevation myocardial infarction (STEMI) will be enrolled 
from multiple centers and randomly assigned to the fexofenadine treatment group or the 
placebo group. 
3.3 Study Period 

 
 
Recruitment period: 24 months. Follow-up time points: 6th, 12th, 24th, and 60th months after 
enrollment. 
3.4 Inclusion Criteria 
1. 
Age ≥ 18 years old. 
2. 
Able to verbally confirm understanding of the trial risks, benefits, and treatment options 
of fexofenadine hydrochloride therapy. He/she or his/her legal representative must provide 
written informed consent prior to participating in the clinical trial. 
3. 
Acute ST-segment elevation myocardial infarction (STEMI) occurring within 7 days, 
with diagnostic criteria including: 
i) Typical clinical symptoms: such as severe crushing pain in the retrosternal or precordial 
area, usually lasting more than 10-20 minutes, which may radiate to the left upper arm, jaw, 
neck, back, or shoulders, etc.; 
ii) Elevated serum cardiac troponin (cTn): at least one measurement above the upper limit of 
normal (99th percentile of the reference upper limit); 
iii) ST-segment elevation: new ST-segment elevation at the J point in 2 adjacent leads. 
4. 
Echocardiography indicating segmental wall motion abnormalities. 
3.5 Exclusion Criteria 
1. 
Need for long-term use of fexofenadine hydrochloride or other H1 receptor inhibitors. 
2. 
Previous coronary artery bypass grafting (CABG) surgery. 
3. 
History of severe renal failure with estimated glomerular filtration rate (eGFR) < 30 
ml/min. 
4. 
History of severe liver dysfunction. 
5. 
History of concurrent severe infection, hepatobiliary obstruction, or malignant tumor. 
6. 
Expected life expectancy of less than 2 years due to non-cardiac diseases. 
7. 
Currently receiving immunosuppressive therapy. 
8. 
Pregnant, potentially pregnant, or lactating women. 
9. 
Contraindication to the study drug or examinations. 
10. Failure to provide written informed consent. 
11. Presence of mechanical complications (ventricular septal defect, papillary muscle 
dysfunction, acute mitral regurgitation), refractory cardiogenic shock unresponsive to 
vasopressors, acute left heart failure or pulmonary edema, or malignant arrhythmias 
uncontrolled by antiarrhythmic drugs at enrollment. 
3.6 Patient Follow-up 
Clinical follow-up will be conducted via telephone or outpatient visits at 6th, 12th, 24th, and 

 
 
60th months after enrollment. 
3.7 Primary Endpoint 
Incidence of major adverse cardiovascular and cerebrovascular events (MACCE) within 24 
months after randomization, including all-cause death, recurrent myocardial infarction, stroke, 
hospitalization for heart failure, outpatient or emergency visits due to worsening heart failure, 
and repeat revascularization driven by angina pectoris. 
3.8 Secondary Endpoints 
1. 
All-cause death at 24 and 60 months after randomization. 
2. 
Recurrent myocardial infarction at 24 and 60 months after randomization. 
3. 
Stroke at 24 and 60 months after randomization. 
4. 
Hospitalization for heart failure or outpatient/emergency visits due to worsening heart 
failure at 24 and 60 months after randomization. 
5. 
Repeat revascularization driven by angina pectoris at 24 and 60 months after 
randomization. 
6. 
Comparison of the difference in left ventricular ejection fraction (LVEF%) measured by 
echocardiography between the two groups at 24 months after randomization compared to 
baseline. 
7. 
Comparison of the difference in left ventricular end-systolic diameter (LVIDs) measured 
by echocardiography between the two groups at 24 months after randomization compared to 
baseline. 
8. 
Comparison of the difference in left ventricular end-diastolic diameter (LVIDd) 
measured by echocardiography between the two groups at 24 months after randomization 
compared to baseline. 
9. 
Comparison of New York Heart Association (NYHA) functional classification between 
the two groups at 24 months after randomization. 
10. Comparison of Kansas City Cardiomyopathy Questionnaire (KCCQ) scores between the 
two groups at 24 months after randomization. 
11. Incidence of adverse events related to fexofenadine. 
3.9 Safety Assessment 
Incidence of serious and non-serious adverse events within 24 months of fexofenadine 
hydrochloride administration. 
Adverse events (AE) include: 
1. 
Cardiac adverse reactions (including tachycardia, palpitations). 
2. 
Nervous system reactions (including headache, somnolence, dizziness). 
3. 
Psychiatric reactions (including sleep disorders, anxiety). 

 
 
4. 
Gastrointestinal reactions (including diarrhea, nausea). 
5. 
Immune-related skin reactions (including rash, urticaria, pruritus). 
Serious adverse events (SAE) include: 
Severe allergic/hypersensitivity reactions (including angioedema, chest tightness, dyspnea, 
other systemic immediate allergic reactions). 
3.10 Enrollment 
All patients with acute ST-segment elevation myocardial infarction will be screened for 
eligibility to participate in this study. Members of each study team will review the patient's 
medical history to determine compliance with inclusion and exclusion criteria. If eligible, the 
patient can be registered and enrolled in the study after signing the written informed consent 
form. Prior to collecting study data, participants will be informed of study details, including: 
(1) this is an investigator-initiated clinical study; (2) participation is voluntary, and there will 
be no penalty for withdrawal; (3) potential risks and benefits of participation. Vulnerable 
populations will be excluded in accordance with the inclusion and exclusion criteria. 
3.11 Study Methods 
3.11.1 Study Design 
Patients with acute ST-segment elevation myocardial infarction will be randomly assigned in 
a 1:1 ratio to the placebo group or the fexofenadine hydrochloride group for efficacy and 
safety assessment. 
3.11.2 Randomization Method 
Eligible patients will be randomly assigned to the placebo group or the fexofenadine 
hydrochloride treatment group in a 1:1 ratio after recruitment, with the randomization process 
conducted via an online system by the research institution. 
3.11.3 Study Blinding 
Drugs in the placebo group and the treatment group are identical in appearance and packaging, 
and participants are unaware of their group assignment. Throughout the study, blinding will 
be maintained during the generation of the randomization code, drug coding, patient 
medication administration, data monitoring, data management, and statistical analysis, and 
investigators are unaware of the patients' group assignments and medication status. 
3.11.4 Drug Treatment 
Patients in both groups will receive current standard drug therapy in accordance with the 2023 
European Society of Cardiology (ESC) Guidelines for the Management of Acute Coronary 
Syndromes, including dual antiplatelet therapy with aspirin/indobufen + ticagrelor/clopidogrel, 
statins for lipid-lowering, metoprolol, ACEI/ARB drugs for anti-cardiac remodeling, etc., 
with updates in line with guideline revisions. On this basis, additional treatments are as 

 
 
follows: 
Fexofenadine hydrochloride group: Fexofenadine hydrochloride tablets, 60 mg, twice daily, 
orally for 24 months. 
Placebo group: White starch tablets identical in appearance and packaging, twice daily, orally 
for 24 months. 
Treatment initiation time: Immediately after randomization. 
After providing informed consent, enrolled patients will be randomly assigned to receive 
fexofenadine hydrochloride or placebo. The fexofenadine hydrochloride group will receive 60 
mg BID orally for 24 months. Patients assigned to the placebo group will receive identically 
appearing starch tablets orally for 24 months. 
Note: The usual dose of fexofenadine hydrochloride for the treatment of seasonal allergic 
rhinitis and chronic idiopathic urticaria is 60 mg bid. Large-scale randomized controlled 
clinical studies have shown that long-term use (1 year) of different doses of fexofenadine 
hydrochloride (20-240 mg QD) has no significant safety impact on healthy volunteers. 
3.11.5 Study Content 
(1) In-hospital Management 
1. 
Signing of Informed Consent 
Each participant or their legal representative must provide informed consent before initiating 
any study-related procedures. 
2. 
Physical Examination 
Complete and document a physical examination, including heart rate, blood pressure, height, 
and weight. 
3. 
Medical History 
Complete a detailed medical history record, including age, gender, NYHA functional status, 
risk factors (hypertension, smoking, diabetes, etc.), and previous cardiovascular diseases 
(including myocardial infarction, percutaneous coronary intervention, etc.). 
4. 
Laboratory Examinations 
Including routine blood test + C-reactive protein (CRP), liver function, renal function, and 
routine lipid profile. 
5. 
Electrocardiogram (ECG) 
Record a 12-lead ECG at baseline. Document cardiovascular events such as severe 
arrhythmias occurring during hospitalization. 
6. 
Echocardiography 
Complete at least one echocardiographic examination within 3 days after MI. 
(2) Post-discharge Follow-up (6th, 12th, 24th, and 60th months) 
Laboratory Examinations 

 
 
Including routine blood test + CRP, liver function, renal function, and routine lipid profile. 
Safety and the patient's clinical status will be assessed at each follow-up time point after drug 
administration. 
1. 
Medical History 
Complete a detailed medical history record, supplementing any medical events occurring after 
enrollment in the trial (including symptoms, potential drug side effects, physical status, 
recurrence of MI/interventional events/hospitalization, death, etc.), as well as patient 
medication adherence. 
2. 
Physical Examination 
Complete and document a physical examination, including heart rate and blood pressure. 
3. 
Electrocardiogram (ECG) 
Routinely record a 12-lead ECG at 6th, 12th, and 24th months after MI. 
4. 
Echocardiography 
Complete an echocardiographic examination at 6th, 12th, 24th, and 60th months after MI. 
3.11.6 Data Collection 
Items 
Baseline 
(Before 
Discharge, 
≤3 days) 
Follow-up 
(3 months 
±14 days) 
Follow-up 
(6 months 
±30 days) 
Follow-up 
(12 
months 
±30 days) 
Follow-up 
(24 
months 
±90 days) 
Follow-up 
(60 
months 
±90 days) 
Inclusion/
Exclusion 
Criteria 
O 
 
 
 
 
 
Signing of 
Informed 
Consent 
O 
 
 
 
 
 
Medical 
History 
Informatio
n (Age, 
gender, 
height, 
weight, 
risk 
factors, 
clinical 
past 
O 
 
 
 
 
 

 
 
history, 
NYHA 
functional 
status, 
previous 
history of 
heart 
disease) 
Medical 
History 
Informatio
n (Any 
medical 
events 
after 
enrollmen
t in the 
trial) 
 
O 
O 
O 
O 
O 
Medicatio
n History* 
O 
O 
O 
O 
O 
O 
Physical 
Examinati
on 
O 
△ 
△ 
△ 
△ 
△ 
Vital 
Signs 
O 
△ 
△ 
△ 
△ 
△ 
Coronary 
Angiograp
hy 
Images# 
O 
 
 
 
 
 
Laborator
y 
Examinati
ons 
(Routine 
blood test 
+ CRP, 
liver 
function, 
renal 
O 
 
△ 
△ 
△ 
△ 

 
 
function, 
routine 
lipid 
profile) 
12-lead 
ECG 
O 
 
△ 
△ 
△ 
△ 
Echocardi
ographic 
Results 
(LVEF%, 
LVIDd, 
LVIDs) 
and 
Original 
Images 
O 
 
O 
O 
O 
O 
NYHA 
Functional 
Classificat
ion 
O 
 
 
 
O 
O 
KCCQ 
Score 
 
 
 
 
O 
O 
MACE 
Events 
 
O 
O 
O 
O 
O 
Drug 
Distributi
on 
O 
O 
O 
O 
O 
 
Drug-
related 
Adverse 
Reactions 
 
O 
O 
O 
O 
 
Medicatio
n 
Adherenc
e 
 
O 
O 
O 
O 
 
The timeline for data collection is shown in the table above: 

 
 
Compulsory coronary angiography or laboratory 
blood tests during follow-up are prohibited. If a 
participant experiences an endpoint event, it is 
recommended to collect ECG and coronary 
angiography data. 
*Medication-related information includes the patient's medication status before admission and 
after discharge. 
O: Mandatory item. 
△: Non-mandatory but recommended. 
3.12 Statistical Methods 
Primary Endpoint 
Statistical Methods 
Analysis Time Point 
Incidence of major adverse 
cardiovascular events 
(MACE, including cardiac 
death, non-fatal MI, non-
fatal stroke, readmission for 
heart failure, etc.) within 24 
months after randomization 
Survival analysis, Kaplan-
Meier survival curve, Log-
rank test 
24th month after 
randomization 
Secondary Endpoints 
Statistical Methods 
Analysis Time Point 
All-cause death at 24 and 60 
months after randomization 
Survival analysis, Kaplan-
Meier survival curve, Log-
rank test 
24th and 60th months after 
randomization 
Recurrent myocardial 
infarction at 24 and 60 
months after randomization 
Survival analysis, Kaplan-
Meier survival curve, Log-
rank test 
24th and 60th months after 
randomization 
Stroke at 24 and 60 months 
after randomization 
Survival analysis, Kaplan-
Meier survival curve, Log-
rank test 
24th and 60th months after 
randomization 
Hospitalization for heart 
failure or 
outpatient/emergency visits 
due to worsening heart 
Survival analysis, Kaplan-
Meier survival curve, Log-
rank test 
24th and 60th months after 
randomization 

 
 
failure at 24 and 60 months 
after randomization 
Repeat revascularization 
driven by angina pectoris at 
24 and 60 months after 
randomization 
Survival analysis, Kaplan-
Meier survival curve, Log-
rank test 
24th and 60th months after 
randomization 
Difference in left ventricular 
ejection fraction (LVEF%) 
measured by 
echocardiography compared 
to baseline after 
randomization 
T-test, Wilcoxon rank-sum 
test 
24th month after 
randomization 
Difference in left ventricular 
end-systolic diameter/body 
surface area% measured by 
echocardiography compared 
to baseline after 
randomization 
T-test, Wilcoxon rank-sum 
test 
24th month after 
randomization 
Difference in left ventricular 
end-diastolic diameter/body 
surface area% measured by 
echocardiography compared 
to baseline after 
randomization 
T-test, Wilcoxon rank-sum 
test 
24th month after 
randomization 
NYHA functional 
classification at 12 and 24 
months after randomization 
Wilcoxon rank-sum test, 
Chi-square test 
24th month after 
randomization 
KCCQ score at 12 and 24 
months after randomization 
T-test, Wilcoxon rank-sum 
test 
24th month after 
randomization 
Incidence of drug-related 
adverse events 
Chi-square test 
1st, 3rd, 6th, 12th, and 24th 
months after randomization 
4. Sample Size Calculation 
This study adopts a 1:1 sample size ratio between the experimental group and the control 
group, with a one-sided α value set at 0.025 and a power (1-β) of 0.8. Based on preliminary 
study results and relevant clinical data (referring to PARADISE-MI, EMPACT-MI, COLCOT, 

 
 
FLAVOUR series studies), event rate estimation will be performed using Kaplan-Meier 
survival analysis. Assuming an event rate of 16.5% in the control group and 13.2% in the 
experimental group, the expected enrollment period is 2 years. The sample size will be 
calculated using PASS software. Considering a 10% dropout rate, 1402 patients will need to 
be enrolled in each group, totaling 2804 patients. 
5. Data Management and Confidentiality 
5.1 Data Management 
Study data will be retained for at least 3 years after the completion of study outcomes 
(including relevant papers, research reports, etc.). Unauthorized processing of study data 
without patient authorization or research institution approval is prohibited. If study data is 
stored electronically, it is recommended to back up the data to optical discs regularly, 
especially for important data which requires multiple backups. Relevant software should be 
used to ensure timely data storage, and special attention should be paid to the security of 
electronic data storage. 
The review committee or ethics committee will conduct regular audits or inspections of data 
security. Its main responsibility is to systematically and independently verify all study-related 
processes and documents to determine whether the implementation of the study process, the 
accuracy of data recording, analysis, and reporting comply with the study protocol, good 
clinical practice (GCP), International Council for Harmonisation (ICH) guidelines, and any 
regulatory requirements. 
5.2 Data Confidentiality 
Throughout the study, the health information of all patients must be kept confidential, and 
unauthorized access to data is prohibited. Each patient will be assigned a unique identification 
number, and patient data will be stored in locked cabinets at the clinical center with data 
encryption to restrict data access. Relevant regulations on the confidentiality of patient 
information should be roughly informed to patients in the informed consent form. In 
accordance with relevant regulations on the protection of patient health information, relevant 
health personnel are entitled to access study data. 
6. Informed Consent 
This study intends to recruit patients with acute ST-segment elevation myocardial infarction. 
To protect vulnerable populations, pregnant women, minor patients, patients with mental 
illness or cognitive impairment, and staff and students of the research center will be excluded. 
Prior to collecting study data, the following details of the study must be informed to patients: 
1. This is a Phase IV clinical study; 2. Patient participation is strictly voluntary, and no 
compensation is required for withdrawing from the study; 3. Patients can withdraw from the 
study at any time; 4. Potential risks and benefits are disclosed; 5. Necessary communication 
and contact will be maintained. 
Participants will have sufficient time to understand the study and ask questions before 

 
 
participating. They will be informed of the study purpose, available treatments, randomization 
assignment, the need to cooperate with outpatient follow-up and complete some auxiliary 
examinations. The patient's decision to accept or refuse to participate in the study will not 
affect clinical diagnosis and treatment. 
All patients or their legal representatives must sign the informed consent form after fully 
understanding the study before conducting any study-related activities and treatments. Those 
who do not sign the informed consent form are not eligible to participate in the study. A copy 
of the signed informed consent form will be made, with the original retained in the patient's 
medical record and the copy provided to the patient or their legal representative for 
safekeeping. All study-related data must be supported by medical records, cardiovascular 
angiography images, blood test results, ECG, echocardiography, and cardiac magnetic 
resonance results. The acquisition of these data is mainly to support routine medical care and 
basic research. 
7. Reporting and Management of Adverse Events 
7.1 Reporting of Adverse Events 
All adverse events: Timely measures should be taken for management, and events should be 
recorded in the case report form (CRF). 
Serious adverse events (SAE): Timely measures should be taken for management, and events 
should be recorded in the CRF. The investigator will decide whether to discontinue or reduce 
the drug dosage. The ethics committee, drug clinical trial institution, and sponsor should be 
immediately notified, and the national and provincial drug regulatory authorities should be 
reported within 24 hours. SAEs must be reported through the "Hospital Intranet Adverse 
Event and Near-Miss Non-Punitive Reporting System". Specific procedures: see the figure 
below. 
![img](Serious Adverse Event Occurrence (events requiring hospitalization, prolonged 
hospitalization, disability, impairment of work capacity, life-threatening conditions, death, 
congenital malformations, etc.)) 
• 
No emergency treatment required 
• 
Emergency treatment required, immediate reporting 
• 
Report within 24 hours 
• 
Hospital Medical Affairs Department: 3880, 3881 
• 
Note: For night-time reports, please call the general duty room: 660000 
• 
Responsible for proper handling 
• 
State Drug Administration Safety Supervision Department Pharmaceutical Research 
Supervision Office: 010-88363228 
• 
Provincial Food and Drug Administration Registration Office: 88903275 
• 
Ethics Committee: 87783969 

 
 
• 
Sponsor/CRO 
• 
Report to the Adverse Event and Near-Miss Non-Punitive Reporting System via the 
hospital intranet 
• 
Conduct follow-up and summarize handling opinions 
• 
Report to the hospital leadership in charge) 
7.2 Management of Adverse Events 
1. 
Cardiac adverse reactions (including tachycardia, palpitations): Complete laboratory 
biochemical examinations, ECG, echocardiography, etc. If necessary, perform cardiac 
electrophysiological examinations to clarify the cause. For patients with severe symptoms, 
discontinue fexofenadine hydrochloride and administer antiarrhythmic drugs if necessary. 
2. 
Nervous system reactions (including headache, somnolence, dizziness, etc.): Consult a 
neurologist for auxiliary diagnosis, complete neurological physical examinations and imaging 
examinations to rule out emergency conditions such as intracranial hemorrhage and infection. 
Administer analgesic drugs and physical therapy if necessary. 
3. 
Psychiatric reactions (including sleep disorders, anxiety, etc.): Consult a psychiatrist for 
auxiliary diagnosis, complete relevant scales to assess the patient's emotional and sleep status. 
Administer hypnotic drugs or anti-anxiety medications if necessary. 
4. 
Gastrointestinal reactions (including diarrhea, nausea, etc.): Consult a gastroenterologist 
for auxiliary diagnosis, supplement body fluids via oral or intravenous infusion, and 
administer antidiarrheal, antiemetic, and other symptomatic drugs if necessary. 
5. 
Immune-related skin reactions (including rash, urticaria, pruritus, etc.): Consult a 
dermatologist for auxiliary diagnosis. Perform histopathological examination if diagnosis is 
difficult. Apply topical moisturizers or hormonal ointments locally. For patients with severe 
skin lesions, administer oral/intravenous hormones and immunosuppressive therapy. 
Management of serious adverse events: 
Severe allergic/hypersensitivity reactions (including angioedema, chest tightness, dyspnea, 
flushing, other systemic immediate allergic reactions, etc.): During the treatment of severe 
allergic reactions, close monitoring of cardiac function, blood pressure, respiration, and blood 
oxygen saturation should be performed. If severe dyspnea occurs due to laryngeal edema or 
bronchospasm, tracheal intubation or tracheotomy should be considered, and cricothyrotomy 
may be performed in emergency situations. For patients with grade II or above severe allergic 
reactions, epinephrine intramuscular injection is the first choice, administered at a dose of 
0.01 mg/kg body weight, with a maximum single dose not exceeding 0.5 mg, at a 
concentration of 1 mg/ml (1:1000). If the effect is unsatisfactory after 5-15 minutes, repeat the 
administration. For patients with grade IV reactions who have experienced or are about to 
experience cardiac or respiratory arrest, epinephrine should be administered intravenously at a 
single dose of 0.5-1 mg, at a concentration of 0.1 mg/ml (1:10000). For patients with grade III 
reactions who have established venous access and are under monitoring, epinephrine can be 
administered intravenously at a single dose of 0.1-0.2 mg, at a concentration of 0.1 mg/ml 
(1:10000). If the effect is unsatisfactory after 3-5 minutes, repeat the administration. H1 

 
 
receptor antagonists, β2 receptor agonists, and glucocorticoids can be used as second-line 
medications. Fluid resuscitation can be used for patients with severe allergic reactions 
accompanied by circulatory instability, with a usual fluid volume of 20 ml/kg, adjusted 
according to the patient's condition. After the patient is rescued from danger, monitoring 
should be continued for at least 12 hours, including monitoring of heart rate, rhythm, blood 
pressure, respiration, blood oxygen saturation, and urine output. 
8. Protection Measures for Vulnerable Populations 
Patients with acute MI are critically ill and clinically considered a vulnerable population. This 
study will take all necessary measures to fully protect the privacy rights, right to life and 
health, right to informed consent, and other rights and interests of vulnerable participants. 
8.1 Right to Privacy 
High attention should be paid to and protection provided for the privacy of vulnerable 
participants. Investigators will assume confidentiality responsibilities, using de-identified data 
instead of the participants' personal information to ensure the anonymity of participants. In 
addition, during the recruitment and informed consent process, investigators are obligated to 
inform patients of the study's confidentiality system, and participants can only participate in 
the trial after understanding and agreeing. 
8.2 Right to Life and Health 
The right to life and health of vulnerable participants should be protected as the most 
important and fundamental right. The drugs used in this study are all marketed drugs, and 
their safety has been confirmed in previous clinical trials. The dosage and administration are 
in accordance with drug instructions and clinical practice. In addition, participants will 
receive regular follow-up during the study period, and adverse events will be promptly 
managed and reported. The clinical event committee will assess whether participants can 
continue to participate in the trial. Furthermore, during the informed consent process, the risks, 
benefits, and compensation for damages associated with participating in the trial will be fully 
informed to participants, who can only participate after understanding and accepting them. 
8.3 Right to Informed Consent 
Informed consent is a prerequisite for vulnerable participants to participate in clinical trials. 
Investigators will fully inform participants of the study content, risks, benefits, rights 
protection, compensation for damages, etc., and answer participants' questions. Participants 
must sign the informed consent form after fully understanding the study before participating. 
For participants who lack the capacity for independent decision-making, verbal consent 
should be obtained from the participants themselves, and their legal representatives should 
sign the informed consent form. 
9. References 
1. 
Lindstrom, M. et al. Global Burden of Cardiovascular Diseases and Risks Collaboration, 

 
 
1990-2021. Journal of the American College of Cardiology 80, 2372-2425, 
doi:10.1016/j.jacc.2022.11.001 (2022). 
2. 
Zhang, Q. et al. Signaling pathways and targeted therapy for myocardial infarction. 
Signal transduction and targeted therapy 7, 78, doi:10.1038/s41392-022-00925-z (2022). 
3. 
González, A., Schelbert, E. B., Díez, J. & Butler, J. Myocardial Interstitial Fibrosis in 
Heart Failure: Biological and Translational Perspectives. Journal of the American College of 
Cardiology 71, 1696-1706, doi:10.1016/j.jacc.2018.02.021 (2018). 
4. 
Graziani, F., Varone, F., Crea, F. & Richeldi, L. Treating heart failure with preserved 
ejection fraction: learning from pulmonary fibrosis. European journal of heart failure 20, 
1385-1391, doi:10.1002/ejhf.1286 (2018). 
5. 
Zhao, M. et al. Targeting fibrosis, mechanisms and clinical trials. Signal transduction and 
targeted therapy 7, 206, doi:10.1038/s41392-022-01070-3 (2022). 
6. 
Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for 
fibrotic disease. Nature medicine 18, 1028-1040, doi:10.1038/nm.2807 (2012). 
7. 
King, T. E., Jr. et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary 
fibrosis. The New England journal of medicine 370, 2083-2092, 
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