Prognosis in Patients with ST-Segment Elevation Myocardial Infarction Reperfused by PHDP: 1-Year MACEs Follow-Up

Abstract

This study explored 1-year follow-up of Parmaco-invasive strategy with half-dose recombinant human prourokinase (PHDP) in patients with acute ST-segment elevation myocardial infarction (STEMI). The follow-up endpoints were major adverse cardiovascular events (MACEs) occurring within 30 days and 1 year, as well as postoperative bleeding events. The study ultimately included 150 subjects, with 75 in the primary percutaneous coronary intervention (PPCI) group and 75 in the PHDP group. This study found that the PHDP group had a shorter FMC-reperfusion time (42.00 min vs 96.00 min, P < 0.001). During PCI, the PHDP group had a lower percutaneous transluminal coronary angioplasty (PTCA) (P = 0.021), intropin (P = 0.002) and tirofiban (P < 0.001) use. And the incidence of intraoperative arrhythmia, malignant arrhythmia, and slow flow/no-reflow was lower in the PHDP group (P < 0.001). At the 30-day follow-up, there was a significantly higher proportion of patients in the PPCI group who were readmitted due to unstable angina (P = 0.037). After 1 year of follow-up, there was no statistically significant difference in MACEs between the two groups (P = 0.500). The incidence of postoperative major bleeding, intracranial bleeding, and minor bleeding did not differ between the PHDP and PPCI groups (P > 0.05). The PHDP facilitates early treatment of infarct-related vessels, shortens FMC-reperfusion time, and does not increase the risk of MACEs.

Keywords

ST-segment elevation myocardial infarction recombinant human prourokinase fibrinolysis percutaneous coronary intervention major adverse cardiovascular events‌

Introduction

ST-segment elevation myocardial infarction (STEMI) is a severe type of coronary heart disease characterized by secondary thrombosis resulting from the rupture and erosion of unstable coronary plaques, leading to complete occlusion of the coronary vessels. It is the leading cause of death and disability. The key to treating patients with STEMI is early, rapid, and complete opening of the infarct-related artery (IRA).¹ Contemporary guidelines recommend primary percutaneous coronary intervention (PPCI) as the preferred reperfusion option for patients with STEMI, especially when performed timely by experienced interventional cardiologists.^2–4 According to statistics, in countries where PPCI can be fully implemented, the one-year mortality rate of STEMI patients has been decreasing annually.⁵ However，geographical factors, weather conditions, availability of local resources, and the structure of regional and national health network systems often contribute to delays in performing PPCI. These delays can result in higher rates of morbidity and mortality.^6,7 For example, in China, the rate of PPCI treatment within 12 h for STEMI patients in provincial, prefectural, and county-level hospitals has gradually decreased (83.8%, 61.5%, 31.6%), while the in-hospital mortality rate in tertiary hospitals has shown an increasing trend (3.1%, 5.3%, 10.2%).⁸ As a result, a combination of fibrinolysis and early PCI (within 3–24 h) becomes an alternative reperfusion option for hospitals that are not eligible for PPCI or experience significant delays in FMC-PCI due to various reasons.

Studies have shown that patients in the delayed PCI and late PCI treatment groups, when compared to pharmaco-invasive (PhI) treatment, experience higher mortality rates. However, it is important to note that the risk of bleeding is higher with PhI treatment.⁹ The STREAM-2 study suggests that in cases where PPCI treatment is not feasible and there are no contraindications, a half-dose tenecteplase combined with PCI regimen can be applied, as long as excessive anticoagulation is avoided.¹⁰ Recombinant human prourokinase (rhPro-UK) belongs to the third generation of thrombolytic drugs. It is a new plasminogen activator that specifically targets plasminogen at the site of the blood clot. Its advantages include strong selectivity, a high rate of opening blocked blood vessels, and a low risk of bleeding. Furthermore, STEMI patients receiving thrombolytic therapy do not have an increased risk of major adverse cardiovascular events (MACEs).¹¹ In the Pharmaco-Invasive Strategy with Half-Dose Recombinant Human Prourokinase (PHDP) trial, we investigated the strategy of early fibrinolysis with half-dose recombinant human prourokinase administered before transferring patients to the cardiac center, followed by routine coronary artery angiography (CAG), in STEMI patients who presented within 12 h of symptom onset.¹² We discovered that the PHDP resulted in similar MACEs rates compared to PPCI alone during the 30-day follow-up period. With further increase in sample size, we found that the effectiveness of PHDP treatment for STEMI is not inferior to PPCI and does not increase the risk of bleeding or incidence of major adverse cardiovascular and cerebrovascular events during patient hospitalization.¹³ However, it was unknown whether these follow-up results changed with long-term follow-up. Our trial aimed to report the one-year follow-up findings comparing the two reperfusion strategies in the PHDP trial.

Materials and Methods

Study Design and Population

The design and primary endpoints of the PHDP trial have been previously reported.^13,14 This trial was a single-center, prospective, open-label, non-inferiority, randomized trial. The study included patients aged 18–80 years with STEMI who were attended from September, 2019, to December, 2021, at the Chest Pain Center of Chengde Central Hospital, Hebei Province, China. Patients were consecutively included if they presented within 12 h of symptom onset and were diagnosed with STEMI on their qualifying electrocardiogram (in two or more contiguous leads ≥ 0.2 mV in lead V2 or V3 or ≥ 0.1 mV in other leads) or had a left bundle-branch block.

Study Procedure

After obtaining written informed consent, patients were randomly assigned to either PHDP or PPCI alone in a 1:1 ratio, based on the reperfusion strategy. Randomization was conducted using a random digit table. All enrolled patients received immediate administration of aspirin 300 mg and a P2Y12 receptor antagonist (300 mg clopidogrel or 180 mg ticagrelor) before reperfusion therapy. Patients assigned to PHDP received a loading dose of unfractionated heparin (60 U/kg) before thrombolysis, followed by a maintenance dose of 12 U/kg/h, with intravenous heparin infusion maintained for at least 48 h. Subsequently, it was switched to subcutaneous injection of low molecular weight heparin (5000 U every 12 h) for 5–7 days.^3,4,14 The half-dose regimen of rhPro-UK (Shanghai Tasly Pharmaceutical Co. LTD, Specifications 5 mg/piece, product No: S20110003) is as follows: initially, 10 mg is administered intravenously within 3 min, followed by infusion of the remaining 15 mg over 30 min, totaling 25 mg. After receiving half-dose rhPro-UK thrombolysis, if thrombolysis fails, rescue PCI is immediately performed; if thrombolysis is successful, PCI is performed 3–24 h later. Patients assigned to PPCI alone were treated according to the standard guidelines of the European Society of Cardiology (ESC) for the management of STEMI.⁴ All CAG were performed in our catheterization laboratory by experienced interventional cardiologists. Using the Seldinger technique via the radial or femoral artery, patients underwent multi-position angiography. The angiographic results were evaluated by at least two physicians with years of experience in coronary intervention, and in case of disputes, a consensus decision was reached with a third experienced physician. Perioperative management and medication were administered to all patients according to existing guidelines.³ Intraoperatively, medications were administered based on changes in patient condition, and standard dual antiplatelet therapy was administered postoperatively for at least one year.

Endpoints and Definitions

Data were collected from the Chest Pain Center of Chengde Central Hospital. The clinical information was obtained from electronic medical records and procedure records, which included details about the patients’ general condition, risk factors, and past history of coronary heart disease. Additionally, information about adverse cardiovascular events during PCI was also collected. Upon admission, the patients’ height and weight were measured, and their body mass index (BMI) was calculated. Adverse cardiovascular events during PCI included arrhythmia, malignant arrhythmia (such as atrioventricular block, intraventricular block, cardiac arrest, pulseless electrical activity, electro-mechanical separation, ventricular tachycardia, ventricular flutter, and ventricular fibrillation), as well as slow flow or no-reflow.

Clinical outcomes were obtained from the electronic medical record system and telephone follow-up. The primary endpoint, which has been previously reported, was the occurrence of MACEs within 30-days and 1-year.^9,10,14 MACEs included death from any cause, cardiac death, cardiac arrest, hospitalization for chronic heart failure or unstable angina, PCI or coronary artery bypass grafting, and nonfatal myocardial infarction. Bleeding complications were classified according to the GUSTO severity criteria.^14,15

Statistical Analysis

Kaplan-Meier curves were utilized to display the MACEs rates over time, categorized based on randomization assignment. Prior to comparing continuous variables, data normality was assessed using the Shapiro-Wilk test. Independent samples t-tests or Mann-Whitney U tests were employed, depending on applicability. Chi-square tests were used to examine differences between categorical variables. Hazard ratios were calculated using a Cox proportional-hazards model, with treatment as the sole factor. The results include the norm in a 95% confidence interval from the Cox proportional-hazards model and the nominal two-sided P-value from a log-rank test. After multifactorial correction, the factors taken into account were age, smoking, diabetes, hypertension, hypertriglyceridemia, hypercholesterolemia, anterior myocardial infarction, number of diseased vessels, and culprit's vessels. All analyses were performed using SPSS 26.0 software (IBM Corporation, Armonk, NY, USA), and the graphs were generated using Prism 8 (GraphPad) and R software version 4.1.2. A two-tailed P-value less than 0.05 was considered statistically significant.

Results

Baseline Characteristics of Patients

The flow chart of the trial is shown in Figure 1. Out of a total of 277 patients, 122 were excluded based on the following exclusion criteria: contraindication for fibrinolysis, emergency coronary artery bypass grafting, cardiogenic shock, and inability to provide written informed consent. In the PHDP arm, two patients refused angiography after fibrinolysis (77 vs 75 with PHDP). In the PPCI arm, three patients died before meeting the primary efficacy endpoint (78 vs 75 with PPCI). This study included only 150 STEMI patients, with a mean age of (57.67 ± 10.89) years and 123 (82.00%) males.

Figure 1.

Flowchart of the trial.

Baseline clinical and procedural characteristics for all eligible patients are provided in Tables 1 and 2. Notably, there were significant cardiovascular adverse events observed during PCI, including arrhythmia (18.67% of patients at PHDP), malignant arrhythmia (4.00% of patients at PHDP), and slow flow or no-reflow (5.33% of patients at PHDP). The percutaneous transluminal coronary angioplasty (PTCA) in the PPCI group was significantly higher than in the PHDP group (P = 0.021). Additionally, the median time from first medical contact (FMC) to reperfusion was longer in the PPCI group compared to the PHDP group (P < 0.001). The use of intropin (P = 0.002) and tirofiban (P < 0.001) during PCI was lower in the PHDP group compared to the PPCI group. It is worth mentioning that none of the patients meeting the inclusion criteria were lost to long-term follow-up for the endpoint.

Table 1.

Baseline Characteristics of Patients.

Characteristic	PHDP (n = 75)	PPCI (n = 75)	t/χ² /z	P value
Age (y)	57.45 ± 9.69	57.89 ± 12.04	−0.247	0.806
Male	66 (88.00%)	57 (76.00%)	3.659	0.056
BMI (kg/m²)	26.71 (23.89, 28.37)	25.62 (23.44, 28.08)	−0.419	0.675
Weight (kg)	75.00 (65.00, 83.00)	72.50 (64.25, 82.00)	−0.876	0.381
Smoking	61 (81.33%)	51 (68.00%)	3.524	0.060
Drinking	30 (40.00%)	36 (48.00%)	0.974	0.324
Previous History
Hypertension	39 (52.00%)	36 (48.00%)	0.240	0.624
Diabetes mellitus	18 (24.00%)	25 (33.33%)	1.597	0.206
Hypercholesterolemia	15 (20.00%)	22 (29.33%)	1.758	0.185
Hypertriglyceridemia	28 (37.33%)	33 (44.00%)	0.691	0.406
Previous angina pectoris	31 (41.33%)	29 (38.67%)	0.111	0.739
Previous coronary intervention	5 (6.67%)	6 (8.00%)	0.098	0.754
Ischemic stroke	8 (10.67%)	8 (10.67%)	0.000	1.000
Hemorrhagic stroke*	0 (0.00%)	2 (2.67%)	-	0.497
Breathing breaths/min	18.00 (17.00, 20.00)	18.00 (18.00, 20.00)	−0.966	0.344
Heart rate beats/min	76.67 ± 16.98	73.84 ± 16.01	1.049	0.296
Pulse (beats/min)	76.67 ± 16.98	73.84 ± 16.01	1.049	0.296
SBP mm Hg	137.57 ± 25.83	134.36 ± 22.48	0.813	0.418
DBP mm Hg	85.52 ± 16.04	83.41 ± 13.98	0.858	0.392
Infarct location			0.107	0.744
Anterior	38 (50.67%)	36 (48.00%)
Non-anterior	37 (49.33%)	39 (52.00%)
Killip class			−1.755	0.079
I	58 (77.33%)	67 (89.33%)
II-IV	17 (22.67%)	8 (10.67%)

Fisher exact probability method. BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; PHDP, pharmaco-invasive strategy with half-dose recombinant human prourokinase; PPCI, primary percutaneous coronary intervention.

Table 2.

Procedural Characteristics in The Two Groups.

Characteristics	PHDP (n = 75)	PPCI (n = 75)	χ²	P value
Coronary artery disease			3.276	0.194
Single vessel disease	27 (36.00%)	34 (45.33%)
Bifurcation lesions	21 (28.00%)	24 (32.00%)
Three branch lesions	27 (36.00%)	17 (22.67%)
Infarct-related artery			2.601	0.272
LAD	41 (54.67%)	40 (53.33%)
LCX	15 (20.00%)	9 (12.00%)
RCA	19 (25.33%)	26 (34.67%)
Number of stents placed intraoperatively in PCI			2.604	0.259
0	22 (29.33%)	14 (18.67%)
1	50 (66.67%)	56 (74.67%)
≥2	3 (4.00%)	5 (6.67%)
PTCA	59 (78.67%)	69 (92.00%)	5.327	0.021
Thrombus aspiration*	0 (0.00%)	2 (2.67%)	-	0.497
FMC-Reperfusion time	42.00 (29.00,57.00)	96.00 (76.00,151.00)	−8.776	＜0.001
Intraoperative cardiovascular adverse events in PCI	19 (25.33%)	51 (68.00%)	27.429	＜0.001
Arrhythmia	14 (18.67%)	47 (62.67%)	30.088	＜0.001
Malignant arrhythmia	3 (4.00%)	21 (28.00%)	16.071	＜0.001
Slow flow or no-reflow	4 (5.33%)	25 (33.33%)	18.852	＜0.001
Therapeutic medications
Clopidogrel	34(45.33%)	32(42.67%)	0.108	0.742
Ticagrelor	41(54.67%)	43(57.33%)	0.108	0.742
Intropin	12 (16.00%)	29 (38.67%)	9.700	0.002
Sodium nitoprusside *	0 (0.00%)	1 (1.33%)	-	1.000
Tirofiban	15 (20.00%)	39 (52.00%)	16.667	<0.001
Atropine *	3 (4.00%)	3 (4.00%)	-	1.000
Norepinephrine *	2 (2.67%)	1 (1.33%)	-	1.000

Fisher exact probability method. RCA, right coronary artery; LAD, left anterior descending artery; LCX, left circumflex artery; PTCA, percutaneous transluminal coronary angioplasty; FMC, first medical contact; PHDP, pharmaco-invasive strategy with half-dose recombinant human prourokinase with half-dose recombinant human prourokinase; PPCI, primary percutaneous coronary intervention.

Clinical Endpoints

During the 30-days follow-up period, the proportion of patients readmitted with unstable angina pectoris was significantly higher in the PPCI group compared to the PHDP group (0.00% vs 8.00%, P = 0.037) (Table 3). In the PHDP group, the rate of MACEs was 2.67% (2 out of 150 patients), whereas in the PPCI group, it was 10.67% (8 out of 150 patients) (HR, 0.24; 95% CI 0.070 to 0.840; P = 0.053). Figure 2. illustrates the Kaplan-Meier 30-days event-free survival curves for the PHDP arm and the PPCI-treated arm (P = 0.053 by log-rank test).

Figure 2.

Kaplan-Meier survival curve of 30d MACEs in two groups.

Table 3.

Clinical Outcomes.

Projects	PHDP (n = 75)	PPCI (n = 75)	χ²	P value
Follow-up 30-days
MACEs	2 (2.67%)	8 (10.67%)	3.857	0.050
All-cause death	0 (0.00%)	0 (0.00%)	-	-
Cardiac death	0 (0.00%)	0 (0.00%)	-	-
Cardiac arrest	0 (0.00%)	0 (0.00%)	-	-
Nonfatal myocardial infarction	2 (2.67%)	1 (1.33%)	0.000	1.000
Revascularization with PCI or CABG*	1 (1.33%)	4 (5.33%)	0.828	0.363
Unstable angina-related hospitalizations	0 (0.00%)	6 (8.00%)	4.340	0.037
Heart failure-related hospitalizations*	0 (0.00%)	0 (0.00%)	-	-
Follow-up one year
MACEs	13 (17.33%)	16 (21.33%)	0.385	0.535
All-cause death	0 (0.00%)	0 (0.00%)	-	-
Cardiac death	0 (0.00%)	0 (0.00%)	-	-
Cardiac arrest	0 (0.00%)	0 (0.00%)	-	-
Nonfatal myocardial infarction	5 (6.67%)	3 (4.00%)	0.132	0.716
Revascularization with PCI or CABG*	4 (5.33%)	4 (5.33%)	0	1.000
Unstable angina-related hospitalizations	9 (12.00%)	12 (16.00%)	4.498	0.480
Heart failure-related hospitalizations*	1 (1.33%)	0 (0.00%)	-	1.000

Fisher exact probability method. MACEs, major adverse cardiovascular events; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; PHDP, pharmaco-invasive strategy with half-dose recombinant human prourokinase; PPCI, primary percutaneous coronary intervention.

The duration of follow-up from enrollment of the first patient to completion of long-term follow-up for the last patient enrolled was one year, and no patients were lost to follow-up. After one year of follow-up, the incidence of MACEs in the PHDP group was 17.33%, which was lower than that in the PPCI group (21.33%). However, there was no statistically significant difference between the two groups (P = 0.535), and no cases of all-cause death, cardiac death, or cardiac arrest were observed in either group (0.00% vs 0.00%). The rates of nonfatal myocardial infarction (6.67% vs 4.00%, P = 0.716), revascularization with PCI or coronary artery bypass grafting (CABG) (5.33% vs 5.33%, P = 1.000), heart failure-related hospitalizations (1.33% vs 0.00%, P = 1.000), and unstable angina-related hospitalizations (12.00% vs 16.00%, P = 0.480) were similar between the two groups (Table 3). The survival curves in Figure 3. show that the cumulative survival rate for MACEs tended to be numerically higher for the PHDP group compared to the PPCI group beyond the one year of follow-up, but this difference was not statistically significant (P = 0.500 by log-rank test).

Figure 3.

Kaplan-Meier survival curve of one year MACEs in two groups.

Cox regression analysis revealed no significant difference in the risk of MACEs, non-fatal myocardial infarction, revascularization, and readmission for unstable angina between the two groups at both 30-days and 1-year of follow-up (P > 0.05) (Table 4). This suggests that the outcome after treatment with the PHDP strategy was comparable to that of PPCI. The adjusted results also indicated similar prognoses for both groups (Table 5). The safety outcomes at one-year follow-up are presented in Table 6. The rates of major bleeding events (0.00% vs 4.00%, P = 0.243) and intracranial hemorrhage (1.33% vs 0.00%, P = 1.000) were similar between the groups. However, minor bleedings were more frequently observed in the PHDP group compared to the PPCI group (42.67% vs 33.33%, respectively), with no significant difference between the groups (P = 0.239).

Table 4.

Univariate COX Regression Analysis of the Relationship Between Reperfusion Therapy Strategy and Adverse Endpoints After PCI.

Projects	30-days		One-year
Projects	HR ( 95% CI )	P value	HR ( 95% CI )	P value
MACEs	0.244 (0.052–1.151)	0.075	0.779 (0.375–1.620)	0.504
Nonfatal myocardial infarction	1.973 (0.179–21.758)	0.579	1.633 (0.390–6.833)	0.502
Revascularization with PCI or CABG	0.244 (0.027–2.187)	0.208	0.964 (0.241–3.855)	0.958
Unstable angina-related hospitalizations	0.015 (0–10.525)	0.209	0.713 (0.300–1.692)	0.443

MACEs, major adverse cardiovascular events; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; PHDP, pharmaco-invasive strategy with half-dose recombinant human prourokinase; PPCI, primary percutaneous coronary intervention; HR, heart rate; CI, confidence interval.

Table 5.

Multivariate COX Regression Analysis of the Relationship Between Reperfusion Therapy Strategy and Adverse Endpoints After PCI.

Projects	30-days		One-year
Projects	HR ( 95% CI )	P value	HR ( 95% CI )	P value
MACEs	0.243(0.046–1.270)	0.093	0.782(0.367–1.666)	0.524
Nonfatal myocardial infarction	1.913(0.133–27.480)	0.633	1.186(0.261–5.388)	0.825
Revascularization with PCI or CABG	0.165(0.015–1.865)	0.145	0.719(0.167–3.097)	0.658
Unstable angina-related hospitalizations	0(0–1.077)	0.955	0.776(0.319–1.889)	0.576

The hazard ratios of the above endpoint events in the PHDP group were all based on the PPCI group as a reference. Multivariate regression models were adjusted for covariates age, smoking, diabetes, hypertension, hypertriglyceridemia, hypercholesterolemia, anterior myocardial infarction, number of diseased vessels, and culprit's vessels. HR, heart rate; CI, confidence interval.

Table 6.

Safety Endpoint Events in the Two Groups.

Projects	PHDP (n = 75)	PPCI (n = 75)	χ²	P value
Minor non-ICH bleeding	32 (42.67%)	25 (33.33%)	1.387	0.239
Major non-ICH bleeding	0 (0.00%)	3 (4.00%)	1.361	0.243
ICH bleeding	1 (1.33%)	0 (0.00%)	-	1.000

ICH, indicates intracranial hemorrhage; PHDP, pharmaco-invasive strategy with half-dose recombinant human prourokinase; PPCI, primary percutaneous coronary intervention.

Discussion

Due to a combination of lifestyle, social, and environmental factors, STEMI has emerged as a significant public health concern. According to data from the World Health Organization, nearly 80% of developing countries experience an annual increase of 3 million STEMI cases.¹⁶ The death rate remains high due to variations in medical resources, technology, and inadequate treatment systems.^10,14 Since a large majority of STEMI patients are initially referred to non-primary PPCI equipped institutions, timely performance of PPCI poses a serious challenge in many countries worldwide. Despite significant efforts to minimize transfer times, delays related to PPCI continue to be common in real-world practice.¹⁷ The Prospective Study on the Impact of Primary Health Care-Delivered PPCI (PHDP) was designed to investigate the one-year prognosis of STEMI patients treated with PHDP versus PPCI. It has been reported that the recanalization rate of the PHDP strategy was 85.33% (64/75) in patients aged 18–80 years with STEMI symptoms occurring within 12 h.¹³ However, further studies are needed to validate the 30-days and one-year MACEs in order to establish a solid foundation for STEMI interventional treatment strategies.

A critical aspect of the prognosis of STEMI is the time it takes to receive treatment.^4,18 Studies have shown that for every 30-min delay in acute myocardial infarction treatment, the one-year morbidity and mortality rate increases by 7.5%.¹⁹ To minimize the total time of myocardial ischemia, it is important to reduce delays at various stages, including the patient's delay, pre-hospital system delay, and in-hospital rescue delay.² Opening the IRA in a timely and thorough manner is crucial for restoring myocardial perfusion and improving patients’ clinical prognosis.¹ Current guidelines recommend PPCI as the preferred reperfusion treatment strategy for STEMI.^2–4 However, despite national efforts to establish STEMI networks, timely PPCI is still challenging due to factors such as distance, weather, and limited resources.⁶ Clinicians often face delays in obtaining acceptance for PPCI, and this can significantly reduce its clinical efficacy, potentially leading to a higher incidence of MACEs. Moreover, studies have shown that the yearly probability of no-reflow and slow flow in PCI is approximately 5%-29%.^20–22 These conditions directly or indirectly contribute to left ventricular remodeling (such as ventricular aneurysm and cardiac rupture), reduced cardiac function, MACEs, malignant arrhythmia, cardiogenic shock, increased rate of hospitalization, higher mortality, and significantly impact patient prognosis.²⁰ Various causes can lead to delays and intraoperative complications, which somewhat diminish the advantages of PPCI. The French FAST-MI study indicates that patients who undergo delayed PCI (>120 min) have lower 5-year survival rates compared to those who receive PhI treatment (89.8% vs 79.5%, adjusted HR 1.51; 1.13-2.02). However, the 5-year survival rates between PhI and PPCI treatments are similar (89.8% vs 88.2%, adjusted HR 1.02; 0.75-1.38).¹⁸ The WEST study and the GRACIA-2 study showed that the drug-intervention strategy was not inferior to PPCI in terms of efficacy but also resulted in significant benefits for patients in long-term follow-up.^23,24 This study found that the PHDP group had a shorter FMC-reperfusion time (42.00 min vs 96.00 min, P < 0.001). This is attributed to the prompt initiation of treatment upon STEMI diagnosis, in the absence of contraindications for thrombolysis. Such timely intervention effectively reduces myocardial ischemia duration and enhances patient prognosis. Previous studies have shown that the effectiveness of PHDP treatment in STEMI patients is not inferior to PPCI. In 30-day and 1-year follow-ups, there was no statistically significant difference in the incidence of MACEs between the two groups. Therefore, in situations where immediate PPCI is unavailable, timely thrombolysis to open the vessel followed by transfer for PCI could be a viable alternative.¹³

Numerous studies have reported an increased risk of bleeding associated with PhI treatment. Norwegian scholars conducted a median 2.5-year follow-up of STEMI patients undergoing PPCI (≤120 min), delayed PCI (121–180 min), late PCI (>180 min), and PhI treatment. They found that compared to PhI treatment, although the mortality rate was higher in the delayed PCI and late PCI treatment groups, the risk of major bleeding was higher with PhI treatment.⁹ This risk seems to be more significant in the elderly population. Auffret V et al²⁵ investigated the safety of PhI versus PPCI treatment in STEMI patients aged ≥ 70 years and found a higher risk of intracranial hemorrhage with the PhI regimen (2.3% vs 0.0%, P = 0.03). Considering the bleeding risk, many doctors in clinical practice choose to avoid the PhI regimen after weighing the pros and cons. If these patients cannot reach a hospital capable of PPCI treatment within 120 min, they may miss the optimal treatment window. However, the PhI strategy with a half-dose fibrinolytic regimen seems to be an effective reperfusion method for eligible STEMI patients. STREAM²⁶ is a randomized controlled trial comparing PPCI with fibrinolysis (full-dose tenecteplase thrombolysis + 6–24 h transport PCI). Due to a higher risk of intracranial hemorrhage in the fibrinolysis group, the dose of tenecteplase was reduced to 50% for patients over 75 years old, which resulted in no further observed cases of intracranial bleeding. After one year of follow-up, the all-cause mortality rates between the two groups were similar (6.7% vs 5.9%, P = 0.49; risk ratio, 1.13; 95% CI, 0.79–1.62).²⁷ The STREAM-2 study¹⁰ further adjusted the age of participants to ≥ 60 years and found that half-dose PhI had clinical outcomes comparable to PPCI, even though there were 6 cases of intracranial hemorrhage in the half-dose PhI group, three of which were due to protocol violations. The EARLY-MYO trial¹⁴ have also indicated that reducing the dosage of thrombolytic drugs can decrease the bleeding risk for patients. Unlike the STREAM study, this research compares the effectiveness and safety of PCI after thrombolysis with a half dose (50 mg) of alteplase (PhI) and PPCI treatments in patients with STEMI. Additionally, the dual antiplatelet therapy used in this study consists of aspirin (300 mg) and a loading dose of P2Y12 receptor antagonists (300-600 mg clopidogrel or 180 mg ticagrelor). The results showed that the efficacy of the PhI group is non-inferior to the PPCI group. Although patients treated with ticagrelor during thrombolysis have a higher risk of bleeding compared to clopidogrel, at the 30-day follow-up, no major bleeding events were observed in either group. Besides，the TREAT trial compared ticagrelor and clopidogrel in patients with STEMI treated with thrombolysis. At 30-day follow-up, both groups had similar rates of major bleeding (absolute difference, −0.18%; 95% CI, −0.89% to 0.54; P = 0.001 for noninferiority) defined by the Platelet Inhibition and Patient Outcomes criteria and by the Bleeding Academic Research Consortium types 3 to 5 bleeding.²⁸ At 12-month follow-up, the ticagrelor group continued to demonstrate favorable outcomes regarding major bleeding (HR: 0.82; 95% CI: 0.51 to 1.33; p = 0.43).²⁹ Based on these numerous studies, we want to investigate whether PHDP treatment can reduce the risk of bleeding in STEMI patients. In previously published studies, we listed exclusion criteria, including patients at high risk of bleeding.^13,30 Because using half-dose drugs for thrombolysis reduces the risk of bleeding, and to achieve baseline data balance between the PPCI group and the PHDP group, clinicians randomly selected either clopidogrel or ticagrelor when administering P2Y12 receptor antagonists. The results showed no statistically significant difference in the usage rate of P2Y12 receptor antagonists between the two groups (P = 0.742). In this series of studies, it was previously reported that both groups had no Major bleeding during hospitalization, and the incidence of Minor bleeding (P = 0.200) showed no statistically significant difference.¹³ After one year of follow-up, there was one case of intracranial hemorrhage in the PHDP group, and minor bleeding incidents were more common in the PHDP arm than PPCI arm, but the difference was not statistically significant. Thus, when PPCI is unavailable, and the attending physician judges that the patient has no contraindications to thrombolysis, then PHDP can be used as an alternative approach.

The PHDP aims to minimize bleeding events caused by full-dose drug-interventional strategies and prevent complications such as cardiac rupture, arrhythmia, slow flow, and no-reflow that can occur during PCI. Among the complications observed during PCI, reperfusion arrhythmia, including ventricular tachycardia and ventricular fibrillation, is the most common, with an incidence rate of 2–5.7%.³¹ In a prospective study comparing the effect of half-dose prourokinase drugs with STEMI thrombolysis on cardiovascular adverse events during angiography or PCI, initiating the PHDP strategy when STEMI patients developed clinical symptoms in the prehospital or emergency department setting resulted in a lower incidence of cardiovascular adverse events during coronary angiography or PCI, with a higher success rate.³² This study found that the incidence of intraoperative arrhythmia, malignant arrhythmia, and slow flow/no-reflow was remarkably lower in the PHDP group compared to other groups. This reduced the use of intropin, tirofiban and PTCA during PCI, thereby reducing the risk of cardiovascular adverse events during the procedure. Furthermore, the PHDP strategy significantly reduced the damage caused by PCI-related reperfusion, and no all-cause or cardiac deaths were observed. Additionally, in the 30-day follow-up, the rate of unstable angina-related hospitalizations in the PHDP group was significantly lower than in the PPCI group (0.00% vs 8.00%，P = 0.037). This difference may be attributed to the quicker administration of reperfusion therapy to patients in the PHDP group. However, this discrepancy was no longer observed at the one-year follow-up (12.00% vs 16.00%，P = 0.480), emphasizing the necessity for further investigation to determine the safety of PHDP.

Several limitations need to be mentioned in our study. Firstly, it is important to note that the patients enrolled in this study were at low risk, and those with major diseases were excluded. Therefore, the high rate of successful fibrinolysis with half-dose rhPro-UK may not be applicable to all populations and requires further testing. Secondly, the echocardiographic assessments during follow-up were incomplete, which prevented a comprehensive comparison of cardiac function. It would be beneficial to continue monitoring the disparity in left ventricular function between the two groups during the chronic phases. Lastly, this study was a single-center trial with a follow-up duration of one year. Multi-center trials and longer follow-up periods are necessary to externally validate and further investigate the safety of PHDP.

Conclusions

This trial aims to reduce intraoperative malignant events and MACEs in order to better protect cardiac function and improve clinical prognosis. In areas with limited access to medical technology, the PHDP facilitates early treatment of infarct-related vessels, effectively shortens FMC-reperfusion time, and does not increase the risk of MACEs. It reduced the recurrence of unstable angina, and it can serve as a safe and effective alternative reperfusion therapy strategy for a significant percentage of people with STEMI.

Footnotes

Abbreviations and Acronyms

Acknowledgments

The PHDP investigators thank Shuliang Zhang, MD, Bo Liu, MD, Zhiguo Chen, MD; all the medical staff in the cardiology and emergency departments; and the patients, ethics committee members, and staff who participated in this study.

Author Contributions

Donglei Luo contributed to the design and conduct of the study; project administration; funding acquisition; review and approval of the manuscript; and decision to submit the manuscript for publication. Jingtao Guo contributed to the design and conduct of the study; project administration; funding acquisition; preparation and editing the manuscript; and decision to submit the manuscript for publication. Jie Dou and Jie Gao contributed to the collection, analysis, management, and interpretation of the data; preparation and editing the manuscript; and decision to submit the manuscript for publication. Jinlong Zhang contributed to the project administration and decision to submit the manuscript for publication. Huihui Yang, Ruoling Guo, and Chao Jiang contributed to the collection and management of the data; review and approval of the manuscript; and decision to submit the manuscript for publication. Jiang Zhou and Xiaomei Yu contributed to the project administration and decision to submit the manuscript for publication. Bo Liu contributed to the revision of the manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics Statement

The Ethics Committee approved the trial protocol and authorized this trial at Chengde Central Hospital/Second Clinical College of Chengde Medical University.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the S&T Program of Chengde (NO. 201804A013 and NO. 202109A019), the Medical Science Research Project of Hebei Province (NO. 20200348), Project of Chengde Central Hospital (No. YJKT20220001).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

ORCID iDs

Jie Gao

Jie Dou

Donglei Luo

References

Bhatt

Lopes

Harrington

. Diagnosis and treatment of acute coronary syndromes: A review. JAMA. 2022;327(7):662-675. doi:10.1001/jama.2022.0358

Chinese Society of cardiology of Chinese medical association; editorial board of Chinese journal of cardiology. Zhonghua Xin Xue Guan Bing Za Zhi. 2019;47(10):766-783. doi:10.3760/cma.j.issn.0253-3758.2019.10.003

Levine

Bates

Bittl

, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines: An update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction, 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes, and 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation. 2016;134(10):e123-e155. doi:10.1161/CIR.0000000000000404

Ibanez

James

Agewall

, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119-177. doi:10.1093/eurheartj/ehx393

Thrane

Olesen

KKW

Thim

, et al. Mortality trends after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2023;82(10):999-1010. doi:10.1016/j.jacc.2023.06.025

Alyamani

Campbell

Navarese

Welsh

Bainey

. Safety and efficacy of intracoronary thrombolysis as adjunctive therapy to primary PCI in STEMI: A systematic review and meta-analysis. Can J Cardiol. 2021;37(2):339-346. doi:10.1016/j.cjca.2020.03.034

Rosselló

Huo

Pocock

, et al. Global geographical variations in ST-segment elevation myocardial infarction management and post-discharge mortality. Int J Cardiol. 2017;245(2017):27-34. doi:10.1016/j.ijcard.2017.07.039 IF: 3.2 Q2 B2

Yang

Wang

, et al. Association of hospital-level differences in care with outcomes among patients with acute ST-segment elevation myocardial infarction in China. JAMA Netw Open. 2020;3(10):e2021677. Published 2020 Oct 1. doi:10.1001/jamanetworkopen.2020.21677

Jortveit

Pripp

Halvorsen

. Outcomes after delayed primary percutaneous coronary intervention vs. Pharmaco-invasive strategy in ST-segment elevation myocardial infarction in Norway. Eur Heart J Cardiovasc Pharmacother. 2022;8(5):442-451. doi:10.1093/ehjcvp/pvab041

10.

Van de Werf

Ristić

Averkov

, et al. STREAM-2: Half-dose tenecteplase or primary percutaneous coronary intervention in older patients with ST-segment-elevation myocardial infarction: A randomized, open-label trial. Circulation. 2023;148(9):753-764. doi:10.1161/CIRCULATIONAHA.123.064521

11.

Fan

Jiao

, et al. Safety and efficacy of intracoronary recombinant human prourokinase administration in patients with acute myocardial infarction and ST-segment elevation: A meta-analysis of randomized controlled trials. Exp Ther Med. 2022;25(1):40. doi:10.3892/etm.2022.11739

12.

Gao

Wang

Liu

, et al. Efficacy of half-dose recombinant human prourokinase thrombolysis combined with early PCI in 48 patients with ST-segment-elevation myocardial infarction (STEMI). Asian J Surg. 2023;46(4):1658-1659. doi:10.1016/j.asjsur.2022.09.115

13.

Dou

Gao

Yang

, et al. Efficacy and safety of a pharmaco-invasive strategy using half-dose recombinant human prourokinase in patients with ST-segment elevation myocardial infarction during hospitalization. Clin Appl Thromb Hemost. 2024;30:1-9. doi:10.1177/10760296231221772 IF: 2.3 Q2 B4

14.

Ding

, et al. Efficacy and safety of a pharmaco-invasive strategy with half-dose alteplase versus primary angioplasty in ST-segment-elevation myocardial infarction: EARLY-MYO trial (early routine catheterization after alteplase fibrinolysis versus primary PCI in acute ST-segment-elevation myocardial infarction). Circulation. 2017;136(16):1462-1473. doi:10.1161/CIRCULATIONAHA.117.030582

15.

Kikkert

van Geloven

van der Laan

, et al. The prognostic value of bleeding academic research consortium (BARC)-defined bleeding complications in ST-segment elevation myocardial infarction: A comparison with the TIMI (Thrombolysis In Myocardial Infarction), GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), and ISTH (International Society on Thrombosis and Haemostasis) bleeding classifications. J Am Coll Cardiol. 2014;63(18):1866-1875. doi:10.1016/j.jacc.2014.01.069

16.

Chandrashekhar

Alexander

Mullasari

, et al. Resource and infrastructure-appropriate management of ST-segment elevation myocardial infarction in low- and middle-income countries. Circulation. 2020;141(24):2004-2025. doi:10.1161/CIRCULATIONAHA.119.041297

17.

Jollis

Granger

Zègre-Hemsey

, et al. Treatment time and in-hospital mortality among patients with ST-segment elevation myocardial infarction, 2018-2021. JAMA. 2022;328(20):2033-2040. doi:10.1001/jama.2022.20149

18.

Danchin

Popovic

Puymirat

, et al. Five-year outcomes following timely primary percutaneous intervention, late primary percutaneous intervention, or a pharmaco-invasive strategy in ST-segment elevation myocardial infarction: The FAST-MI programme. Eur Heart J. 2020;41(7):858-866. doi:10.1093/eurheartj/ehz665

19.

O'Gara

Kushner

Ascheim

, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):529-555. doi:10.1161/CIR.0b013e3182742c84

20.

Ndrepepa

Tiroch

Fusaro

, et al. 5-year Prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol. 2010;55(21):2383-2389. doi:10.1016/j.jacc.2009.12.054

21.

Svilaas

Vlaar

van der Horst

, et al. Thrombus aspiration during primary percutaneous coronary intervention. N Engl J Med. 2008;358(6):557-567. doi:10.1056/NEJMoa0706416

22.

Marzilli

Orsini

Marraccini

Testa

. Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction. Circulation. 2000;101(18):2154-2159. doi:10.1161/01.cir.101.18.2154

23.

Armstrong

; WEST Steering Committee. A comparison of pharmacologic therapy with/without timely coronary intervention vs. primary percutaneous intervention early after ST-elevation myocardial infarction: The WEST (Which Early ST-elevation myocardial infarction Therapy) study. Eur Heart J. 2006;27(13):1530-1538. doi:10.1093/eurheartj/ehl088

24.

Fernández-Avilés

Alonso

Peña

, et al. Primary angioplasty vs. early routine post-fibrinolysis angioplasty for acute myocardial infarction with ST-segment elevation: The GRACIA-2 non-inferiority, randomized, controlled trial. Eur Heart J. 2007;28(8):949-960. doi:10.1093/eurheartj/ehl461

25.

Auffret

Laurin

Leurent

, et al. Pharmacoinvasive strategy versus primary percutaneous coronary intervention for ST-segment elevation myocardial infarction in patients ≥70 years of age. Am J Cardiol. 2020;125(1):1-10. doi:10.1016/j.amjcard.2019.09.044

26.

Armstrong

Gershlick

Goldstein

, et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N Engl J Med. 2013;368(15):1379-1387. doi:10.1056/NEJMoa1301092

27.

Sinnaeve

Armstrong

Gershlick

, et al. ST-segment-elevation myocardial infarction patients randomized to a pharmaco-invasive strategy or primary percutaneous coronary intervention: Strategic Reperfusion Early After Myocardial Infarction (STREAM) 1-year mortality follow-up. Circulation. 2014;130(14):1139-1145. doi:10.1161/CIRCULATIONAHA.114.009570

28.

Berwanger

Nicolau

Carvalho

, et al. Ticagrelor vs clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: A randomized clinical trial. JAMA Cardiol. 2018;3(5):391-399. doi:10.1001/jamacardio.2018.0612

29.

Berwanger

Lopes

Moia

DDF

, et al. Ticagrelor versus clopidogrel in patients with STEMI treated with fibrinolysis: TREAT trial. J Am Coll Cardiol. 2019;73(22):2819-2828. doi:10.1016/j.jacc.2019.03.011

30.

Urban

Mehran

Colleran

, et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention. Circulation. 2019;140(3):240-261. doi:10.1161/CIRCULATIONAHA.119.040167

31.

Durak

Kudaiberdieva

Gorenek

. Prognostic implications of arrhythmias during primary percutaneous coronary interventions for ST-elevation myocardial infraction. Expert Rev Cardiovasc Ther. 2015;13(1):85-94. doi:10.1586/14779072.2015.987127

32.

Jiang

Gao

Luo

Guo

. Effect of pharmacoinvasive therapy with half-dose prourokinase on adverse cardiovascular events during angiography or percutaneous coronary intervention. Asian J Surg. 2022;45(3):890-891. doi:10.1016/j.asjsur.2021.11.065