Comparison of Intracoronary Versus Intravneous Tiroban in Acute STEMI Patients Undergoing Primary PCI

Objective: This study aimed to investigate the effect of intracoronary tiroban compared to intravenously administered tiroban in acute ST-elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI). Methods: This study included 180 patients who were admitted with the diagnosis of acute STEMI and undergoing primary PCI. Patients were randomized into an observation group (n = 90) and control group (n = 90). Both groups received typical treatments, such as aspirin and clopidogrel/ticagrelor. During the procedure, the observation and control groups were administered intracoronary (IC) or intravenous (IV) injections of tiroban, respectively, followed by an intravenous infusion of tiroban for 24 hours. Changes in thrombolysis in myocardial infarction (TIMI) ow grading, TIMI myocardial perfusion grade 3 (TMP grade 3), thrombus aspiration, brain natriuretic peptide (BNP) levels, creatine kinase peak and inammatory factor levels, infarct size, resolution of the sum of ST ‐ segment elevation (Sum ‐ STR) two hours after the operation, and cardiac functional parameters were investigated before and/or after treatment and 6 months after discharge. The incidence of major adverse cardiovascular events (MACE) and adverse reactions (AEs) such as bleeding were compared between the two groups. Results: There were no statistically signicant differences observed in the indices of BNP, creatine kinase peak, cardiac functional parameters, thrombus aspiration, or incidence of bleeding between the two groups before treatment. Following treatment, TIMI ow grading and TMP grade 3 were improved in the observation group that received intracoronary tiroban compared to the control group (p = 0.022 and p = 0.014, respectively). Additionally, the Sum ‐ umi two hours after operation in the observation group was better than that in the control group (p = 0.029). The incidence of MACEs in patients given IC tiroban administration was lower than that in those given IV tiroban (p = 0.012). Furthermore, levels of glutamic oxaloacetictransaminase (AST), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and myocardial troponin I (TNI) in the observation group was signicantly decreased compared to the control group after ve days of treatment (p = 0.039, p = 0.040, p = 0.001, and p = 0.041, respectively). Functional heart parameters including CO and LVEF were signicantly improved in the observation group 6 months after discharge. Conclusion: This study found that IC administration of tiroban in patients with STEMI who underwent PPCI improved TIMI, TMP ow and CO and LVEF 6 months after and reduced CRP, ESR, and TNI. However, between the two groups was comparable. These ndings suggest that IC administration should be applied in certain acute STEMI patients. left-ventricular C-reactive sedimentation rate


Introduction
Acute ST-elevation myocardial infarction (STEMI) is the most severe form of coronary artery disease, contributing to increased morbidity, mortality, and rehospitalization. Primary percutaneous coronary intervention (PPCI) is accepted as the most effective therapy for STEMI [1][2][3][4]. However, the restoration of large-vessel ow does not necessarily equate to recovery of myocardial tissue perfusion and lessening of ischemia-reperfusion injury. Studies demonstrated that serious cardiovascular adverse events, such as cardiac failure, cardiogenic shock, malignant arrhythmia, and sudden cardiac death, appear after PPCI, due to a lack of effective myocardial perfusion and insu cient oxygen supply in the myocardium [3][4][5].
Thromboembolic complications range from 5-25% in STEMI patients undergoing PPCI with slow ow or no-re ow complications, also promoting morbidity and mortality [6,7]. Glycoprotein IIb/IIIa inhibitors (GPI) reduce brous protein in plasma and block the GP IIb/IIIa receptor to inhibit platelet aggregation. GPI is recommended for use in STEMI patients undergoing PPCI with hyperthrombotic burden or as a prophylactic treatment when the risk of thrombi formation is signi cant [8][9][10]. Yet, optimal application of GPIs to prevent thromboembolic complications remains to be determined. The current study investigated whether intracoronary (IC) administration of the GPI tiro brin has an advantage over intreavneous IV administration in STEMI patients undergoing PCI with a hyperthrombotic burden.

Study design
The study protocol was approved by the local ethics committee (Approval #: 201601B003). The study enrolled patients between January 1, 2019, and February 28, 2021 who were diagnosed with STEMI and undergoing PPCI with hyperthrombotic burden. The included patients consented to participate in the study who were informed consent. STEMI was de ned in accordance with acute myocardial infarction (AMI) guidelines [1]. This study was a prospective, randomized, open-label trial. All included patients received the same drug regimen, except for the administration route of GPI, including ACEIs/ARBs, βblockers, and statins in accordance with the guidelines for the management of AMI [1,2,4]. The included patients were randomized into either IC or IV bolus of GPI (tiro ban, 10 µg/kg, 1-3 min) with subsequent intravenous infusion over 24 hours, at 0.15 µg/kg per minute. All researchers involved in this study were physicians.

Study endpoints
The primary endpoints were the indices of coronary artery and myocardial perfusion, including thrombolysis in myocardial infarction (TIMI) ow grading, TIMI myocardial perfusion grade 3 (TMP grade 3), the number of thrombus aspirations in the operation, resolution of the sum of ST-segment elevation (Sum-STR) two hours after the operation, and certain blood indicies. These included brain natriuretic peptide (BNP), creatine kinase (CK) and isoenzyme (CK-MB), serum glutamic pyruvic transaminase (ALT), glutamic oxaloacetictransaminase (AST), N-terminal pro-brain natriuretic peptide (NT-pro-BNP), blood uric acid (UA), blood glucose, glycosylated haemoglobin A1c (HbA1c), serum urea, serum creatinine (Cr), and myocardial troponin I (TNI). Other study endpoints were left-ventricular end-diastolic dimension (LVEDD), left-ventricular ejection fraction (LVEF), and cardiac output (CO). Additionally, the study examined in ammatory factors in serum including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum tumour necrosis factor (TNF-α), transforming growth factor-β1 (TGF-β1), interleukin-6 (IL-6), and interleukin-10 (IL-10). The second endpoints were bleeding events and major adverse cardiovascular events (MACEs) following PPCI. Bleeding events were classi ed by the Global Utilization of Streptokinase and GPI for Occluded Coronary Arteries (GUSTO) criteria. MACEs were de ned as sudden cardiac death, angina pectoris, nonfatal reinfarction, target vessel rethrombosis, and heart failure. Of note, the study examined HbA1c as a primary endpoint among patients with diabetes.

Follow-up
All data were collected in the hospital. CK, CKMB, cTnI, UA, NT-pro-BNP, blood glucose, serum urea, and Cr were assessed immediately on presentation and again at 6 AM on day 2 post-procedure. ALT, AST, HbA1c, CRP, TNF-α, TGF-β1, IL-6, and IL-10 were assessed on day 2 post-procedure. Some indices, including ALT, AST, cTnI, CRP, UA, ESR, serum urea, and Cr, were tested again at 6 AM on day 5 post-procedure. Cardiac functional parameters, including LVEDD, LVEF, and CO, were determined on days 5 or 6 post-procedure and 6 months after discharge. ECGs were collected before PPCI and at two hours after PPCI. The Sum-STR was obtained to determine if there was difference between the two groups. According to the guidelines issued by the European Society of Cardiology and the American College of Cardiology/American Heart Association [1,5,11], a Sum-STR ≥ 50% was considered effective myocardial perfusion and a Sum-STR < 50% was taken as incomplete or ineffectual myocardial perfusion. TIMI and TMP grades were used to evaluate coronary blood ow and myocardial perfusion and were determined during the procedure. The determination of TIMI and TMP grade was made by two experienced physicians. TIMI ow grade was classi ed as 0, 1, 2, or 3. A TIMI ow grade of 0 is de ned as no-re ow in the culprit artery; TIMI ow grade 1 is de ned as partial contrast penetration without distal vessel lling; TIMI ow grade 2 indicates full perfusion with slow lling and clearance rates; and TIMI ow grade 3 indicates full perfusion with normal lling and clearance rates. TMP ow was also graded into 0, 1, 2, or 3. TMP ow was classi ed as follows: grade 0 indicated no myocardial perfusion in the distribution of the infarct vessel; grade 1, slight penetration of contrast medium, without clearance from the coronary microcirculation; grade 2, moderate penetration of contrast medium, with slow clearance from the coronary microcirculation; and grade 3, normal myocardial perfusion with normal blush. In this study, TIMI ow grade 3 and TMP ow grades 2-3 were considered good coronary perfusion and e cient myocardial perfusion. In addition, bleeding events and MACEs that occurred within the hospital were recorded.
Statistical analyses PASS 15.0 software was used to calculate the sample size. Indicators of myocardial perfusion were noted signi cantly improved in a high-dose treatment group (20 µg/kg) over the medium-dose group (10 µg/kg), while resolution of the Sum-STR two hours after operation was 92.21% in the high-dose treatment group and 74.07% in the medium-dose group [5]. In our study, results in the IC group were expected to be consistent with those of the high-dose group. We sought to achieve 90% power at a 5% signi cance level (2-sided). Therefore, 85 patients per group were estimated to be needed to demonstrate a treatment effect. The current study included 90 patients in both the control and experimental groups.
Statistical analyses were performed using SPSS 20.0 (SPSS Inc., Chicago, IL). Continuous variables were analyzed using the Student's t test and are expressed as mean ± SD. Dichotomous variables were analyzed using the chi-square test. All comparisons were two-tailed, and p < 0.05 was considered statistically signi cant.

Results
A total of 184 STEMI patients were randomized into either IC or IV bolus tiro ban (10 µg/kg, 1-3 min), with both groups receiving an intravenous infusion over 24 hours at 0.15 µg/kg per minute (Fig. 1). Four patients were excluded because of no follow-up, resulting in 90 patients in the IC and IV cohorts. Baseline characteristics of the included patients are presented in Table 1 between the IC and IV groups were also similar (see Table 1). Routine treatments and the baseline biochemical criterion were not found to be signi cantly different between the two groups (Tables 2 and  3).    Table 4). Markers of kidney function, including serum urea, Cr, and UA, were not signi cantly different between groups (p =0.749, p = 0.412, and p = 0.163, respectively; Table 4). In addition, the study showed no difference in LA, LVEDD, CO, or LVEF between groups (p = 0.163, p = 0.160, p = 0.555, and p = 0.360, respectively; Table 5). However, various indicators of cardiac function, including CO and LVEF 6 months after discharge, were increased, albeit modestly, in the observation group (p = 0.019 and p = 0.026, respectively; Table 5). Still, TIMI ow grade 3 after PPCI, TMP ow grades 2-3 after PPCI, Sum-STR ≥ 50%, and in-hospital MACEs were improved in the IC versus the IV gorup (p = 0.022, p = 0.014, p = 0.029, and p = 0.012, respectively). Bleeding events were not signi cantly different between the two groups (p = 0.703).
Tiro ban is a highly speci c, reversible antagonist of platelet GP IIb/IIIa receptor. It inhibits platelet aggregation by binding to the glycoprotein IIb/IIIa complex, thereby reducing thrombi levels. In the current randomized study, IC administration of tiro ban to STEMI patients with angiographic intracoronary thrombus signi cantly improved TIMI and TMP ow and improved Sum-STR, consistent with other reports [5,[18][19][20][21]. However, there were no signi cant bene ts observed in terms of in-hospital cardiac function, or hepatic and kidney function. Sum-STR can re ect early microcirculation and myocardial recovery from ischemia and reperfusion injury after PPCI in STEMI patients. The present study found that the number of patients with sum-STR ≥ 50% was signi cantly higher in patients given IC tiro ban versus patients treated with IV tiro ban. We postulate that IC tiro ban provided for increased targeted delivery of the drug compared to standard IV administration and that this accounted for, in part, the study ndings.
The chnages in in ammatory markers observed may be secondary to injury-related hypoxia. CRP, TNF-α, TGF-β1, IL-6, IL-10, and ESR are deemed early markers of in ammation and tissue damage. Markers of in ammation and cTNI are correlated to myocardial ischemia and injury and are useful for diagnosis and evaluation when treating AMI [3,[22][23][24][25][26][27][28][29]. In ammatory marker and cTnI levels positively correlated with culprit artery thrombosis, no-re ow of the culprit artery, and MACEs [22,25,26], as previous studies have also shown [5,18]. We found that cTNI, AST, CRP, and ESR levels were signi cantly lower in STEMI patients given IC tiro ban compared to IV by day 6 post-procedure. However, IC therapy was not associated with obvious differences in CK, CKMB, cTnI, NT-pro-BNP, blood glucose, HbA1C, ALT, AST, CRP, TNF-α, TGF-β1, IL-6, or IL-10 on day 2, or UA on day 6 post-procedure. The incidence rate of MACEs was lower in IC treated versus IV treated patients, with acute heart failure being the largest contributor to this difference. However, we did not observe a signi cant difference in sudden cardiac death, angina pectoris, nonfatal reinfarction, or target vessel revascularization among treatment groups. In addition, we observed a statistically signi cant difference in cardiac ultrasound ndings including CO and LVEF 6 months after discharge.
The present study has several limitations. First, this study sample size was small and likely genetically non-diverse. Second, this study did not conduct an economic bene t analysis. Third, the follow-up duration was short and limited to in-hospital time and 6 months after discharge. Future studies should include longer follow-up. Finally, this study was not a double-blind trial, which may have introduced observer and patient bias.

Conclusions
Compared to IV administration, IC tiro ban administration in STEMI patients with intracoronary thrombus reduced myocardium infarct size; improved TIMI, TMP ow and cardiac function, including CO and LVEF 6 months after discharge; lowered levels of certain im ammation-associated proteins; and reduced MACEs. These bene ts were obtained through a simple change in the route of administration and without increasing the expense of care. IC tiro ban should be considered more often in AMI patients with increased thombosis.

Declarations Author Contributions
Xiuying Tang conceived and designed the experiment. Xiuying Tang and Runjun Li performed the experiment and analysed the data. Xiuying Tang and Runjun Li wrote rst draft of the paper.

Con ict of interest
The authors declare that they have no con icts of interest in relation to the manuscript.
Source of funding: The study is supported by Hebei Provincial Department of Science and Technology Plan Project (No.17277777D).

Data availability statements
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.