Thrombolytic Therapy After Return of Spontaneous Circulation in Patients With STEMI From Medically Underdeveloped Areas: A Case Series

Abstract

Case series

Patients: Male, 52-year-old • Male, 64-year-old • Female, 67-year-old • Male, 36-year-old • Male, 68-year-old Male, 62-year-old • Female, 82-year-old • Male, 74-year-old • Fenale, 72-year-old • Male, 51-year-old Male, 62-year-old • Male, 82-year-old

Final Diagnosis: Return of spontaneous circulation in STEMI

Symptoms: Cardiac arrest

Clinical Procedure: —

Specialty: Cardiology

Objective: Management of emergency care

Background

Although current guidelines classify prolonged cardiopulmonary resuscitation (CPR) as a relative contraindication to thrombolytic therapy, this treatment may serve as a viable reperfusion strategy for patients with ST-segment elevation myocardial infarction (STEMI) who achieve return of spontaneous circulation (ROSC) when primary percutaneous coronary intervention (PCI) cannot be performed in a timely manner or is unavailable. This case series evaluated the safety and efficacy of thrombolytic therapy after ROSC in 12 patients with STEMI.

Case Reports

Twelve patients with STEMI (9 men and 3 women; mean age, 64.33 years) who had just returned to continuous spontaneous circulation via CPR received thrombolytic therapy at 3 hospitals (Hospital I, 1 patient; Hospital II, 9 patients; Hospital III, 2 patients) between April 2007 and February 2021. Electrocardiography showed anterior wall elevation in 66.7% and inferior wall elevation in 33.3% of patients; the ischemic site was independent of CPR duration (P=0.890). CPR duration was associated with a higher incidence of rib fractures (P=0.02) but not bleeding complications (P=0.160). Binary logistic regression analysis showed no correlation between CPR duration and grade of bleeding complications (odds ratio=1). Of the 8 long-term survivors, 1 had mild neurological sequelae.

Conclusions

Our findings support the safety and feasibility of post-ROSC thrombolysis as a therapeutic option for patients with STEMI after comprehensive clinical evaluation, particularly in resource-limited settings where primary PCI is unavailable. This approach achieves restoration of coronary perfusion and has a potential neuroprotective effect in survivors of cardiac arrest.

Introduction

Cardiac arrest (CA) remains a leading cause of mortality, responsible for approximately half of all cardiovascular disease–related deaths. Most sudden cardiac arrests result from lethal arrhythmias, primarily triggered by acute myocardial infarction, particularly ST-segment elevation myocardial infarction (STEMI) [1]. Although cardiopulmonary resuscitation (CPR) is the initial intervention for patients with STEMI after cardiac arrest, early reperfusion therapy is critical to improve long-term survival. Reperfusion strategies include thrombolytic therapy, primary percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG). Current guidelines recommend primary PCI as the preferred reperfusion strategy for patients with STEMI, ideally within 120 min of hospital admission [2,3]. However, in medically underdeveloped regions, timely primary PCI is often unavailable, making thrombolytic therapy a viable alternative.

Recent studies have increasingly demonstrated the efficacy of thrombolytic therapy in STEMI management [3–6]. Additionally, PCI after thrombolysis has been proposed for patients unable to undergo immediate primary PCI [4,5]. There is evidence that administering thrombolytic therapy within 6 h of symptom onset can prevent 30 early deaths per 1000 treated patients; treatment benefits are strongly time dependent [2]. Although prolonged CPR is considered a relative contraindication to thrombolysis [2], this approach may constitute a feasible reperfusion option for patients with STEMI who achieve return of spontaneous circulation (ROSC) when primary PCI is delayed or inaccessible.

This case series investigated the safety and efficacy of thrombolytic therapy after ROSC in 12 patients from medically underdeveloped areas who had electrocardiographic manifestations of STEMI.

Case Reports

Population

From April 2007 to February 2021, we identified 19 patients with STEMI who achieved ROSC and were candidates for thrombolytic therapy. Of these, 12 patients (Hospital I: n=1; Hospital II: n=9; Hospital III: n=2) received thrombolysis and were included in this case series. The remaining 7 patients were excluded because family members declined thrombolytic treatment. The primary endpoint was patient follow-up at 1 year after ROSC, and the secondary endpoint was all-cause mortality.

Inclusion Criteria

Patients were included in this case series if they met the diagnostic criteria for STEMI, if the onset of cardiac arrest occurred within 120 min of successful CPR, if no absolute contraindication to thrombolytic therapy was present, if primary PCI was unavailable, and if signed informed consent for thrombolytic therapy was provided [2].

Thrombolytic Therapy Protocols

Thrombolytic therapy consisted of urokinase or prourokinase. Urokinase (1.5 million units) was dissolved in 100 mL of saline and infused intravenously over 30 min. Recombinant human prourokinase (rhPro-UK; 20 mg) was dissolved in 10 mL of saline and injected over 3 min; this was followed by dissolution of 30 mg of rhPro-UK in 90 mL of saline and infusion over 30 min.

Evaluation Criteria

Thrombolytic therapy success criteria consisted of [2]: ST-segment resolution greater than 50% at 60 to 90 min, typical reperfusion arrhythmia, and disappearance of chest pain.

The Bleeding Academic Research Consortium (BARC) definition for bleeding [7] was used to assess bleeding (computed tomography examination completed 24 h after thrombolytic therapy):

• Type 0: no evidence of bleeding

• Type 1: bleeding that is not actionable and does not prompt the patient to seek unscheduled evaluation, hospitalization, or treatment by a healthcare professional

• Type 2: any clinically overt sign of hemorrhage that is actionable but does not meet criteria for Type 3, Type 4, or Type 5 BARC bleeding

• Type 3: clinical, laboratory, and/or imaging evidence of bleeding with specific healthcare provider responses

• Type 4: CABG-related bleeding

• Type 5: fatal bleeding

Cerebral Performance Category (CPC) scores [8] were implemented as follows:

1. Good cerebral performance: conscious, alert, able to work, might have mild neurological or psychological deficit.

2. Moderate cerebral disability: conscious, sufficient cerebral function for independent activities of daily life, able to work in a sheltered environment.

3. Severe cerebral disability: conscious, dependent on others for daily support because of impaired brain function; ranges from ambulatory status to severe dementia or paralysis.

4. Coma or vegetative state: any degree of coma without meeting all brain death criteria; unawareness despite possible sleep–wake cycles and spontaneous eye opening, without environmental interaction; cerebral unresponsiveness.

5. Brain death: apnea, areflexia, electroencephalogram silence, and related findings.

Time management process of acute myocardial infarction:

1. Patient symptoms were clarified within 5 min of admission.

2. Electrocardiography (ECG) was completed and STEMI was identified within 10 min.

3. Individualized antiplatelet therapy was administered.

4. Myocardial biomarker testing was completed within 20 min.

5. A cardiovascular specialist completed the preoperative interview within 35 min of admission.

6. Preoperative examinations were completed and the patient was transferred to the operating room within 45 min.

7. Arterial puncture was successful within 90 min.

8. Reperfusion was successful within 120 min (Figure 1).

Figure 1.

Time management process of acute myocardial infarction. STEMI – ST-segment elevation myocardial infarction.

Statistical Analysis

Data are presented as mean and standard deviation or median for numerical variables. Unpaired 2-tailed t-tests were performed to compare means. Binary logistic regression was used to analyze the relationship between grade of bleeding and CPR duration. Analyses were conducted using SPSS 26.0 software. P-values <0.05 were considered significant.

Patient Characteristics

In total, 12 patients were included (in-hospital cardiac arrest [IHCA], n=6; out-of-hospital cardiac arrest [OHCA], n=6). All patients initially presented with chest pain and chest tightness. The mean age was 64.33 years, and 75% were men. The mean age of non-survivors was 71.75 years, higher than the 62.15 years observed in survivors (P<0.05). Five patients had a history of cardiovascular disease (coronary heart disease or cerebral infarction). ECG findings showed anterior wall involvement in 16.7%, extensive anterior wall involvement in 50%, and inferior wall involvement in 33.3%; the ischemic site was independent of CPR duration (P>0.05) (Figure 2). Comparison of IHCA and OHCA groups revealed no statistically significant differences in baseline characteristics (P>0.05). Among 5 patients who were taking long-term oral aspirin, 4 had hypertension and 1 had diabetes.

Figure 2.

Relationship between electrocardiography site and CPR duration. CPR – cardiopulmonary resuscitation.

Patients’ Sequelae and Outcomes

All 12 patients received dual antiplatelet therapy, 8 of whom received aspirin with clopidogrel; the remainder received aspirin with ticagrelor. Thrombolytic therapy, administered using urokinase (n=3) or rhPro-UK (n=9), was successful in 11 cases. Among these patients, 6 had no bleeding, 1 had BARC type 1 bleeding, 2 had BARC type 2 bleeding, and 1 had BARC type 5 bleeding. Rib fractures occurred in 7 patients (IHCA, n=3; OHCA, n=4); this occurrence was associated with CPR duration (P=0.02) but not with bleeding complications (P=0.160) (Figures 3, 4). Binary logistic regression analysis indicated no correlation between CPR duration and the grade of bleeding complications (odds ratio=1.00; 95% confidence interval, 0.05–20.83; P>0.05). Six patients underwent delayed PCI. Three patients died in-hospital (all in the OHCA group); survival outcome was not significantly associated with CPR duration (P=0.423) (Figure 5). Treatment outcomes did not significantly differ between IHCA and OHCA groups (Table 1). Only 1 of the 8 long-term survivors had mild neurological sequelae (Table 2).

Figure 3.

Relationship between rib fractures and duration of CPR. CPR – cardiopulmonary resuscitation.

Figure 4.

Relationship between rib fractures and BARC type. BARC – Bleeding Academic Research Consortium.

Figure 5.

Relationship between survival outcome and duration of CPR. CPR – cardiopulmonary resuscitation.

Table 1.

Comparison of treatment outcomes between IHCA and OHCA.

	Delayed treatment (min)	CPR duration (min)	GCS	Hospitalization length (days)
				ICU	General Ward
IHCA	0	20.83±12.71	8.67±3.93	5.33±4.37	9.83±3.06
OHCA	8.80±4.77	19.67±13.66	7.00±3.74	4.83±5.42	5.17±6.01
t		0.156	0.752	0.176	1.694
P		0.879	0.469	0.864	0.132

CPR – cardiopulmonary resuscitation; GCS – Glasgow Coma Scale; ICU – intensive care unit; IHCA – in-hospital cardiac arrest; OHCA – out-of-hospital cardiac arrest.

Table 2.

Patients’ clinical characteristics and treatment outcomes.

Patient number	Age	Sex	History of hyper-tension	History of diabetes	History of coronary heart disease	History of cerebral infarction	Smoker	Basic anti-platelet rherapy	Location of onset	ECG site	Delayed treatment (min)	CPR duration (min)
1	52	M	No	No	No	No	Yes	/	Out of hospital	Anterior wall	5	40
2	64	M	No	No	Yes	Yes	No	Aspirin	In hospital	Inferior wall	0	20
3	67	F	No	No	No	Yes	No	Aspirin	Out of hospital	Extensive anterior wall	15	30
4	36	M	No	No	No	No	Yes	/	Out of hospital	Extensive anterior wall	5	10
5	68	M	No	No	Yes	No	Yes	Aspirin	In hospital	Inferior wall	0	14
6	62	M	No	No	No	No	No	/	In hospital	Anterior wall	0	15
7	82	F	No	No	No	No	No	/	Out of hospital	Inferior wall	5	10
8	74	M	Yes	No	No	Yes	Yes	Aspirin	Out of hospital	Extensive anterior wall	6	5
9	72	F	Yes	No	No	No	No	/	In hospital	Inferior wall	0	40
10	51	M	Yes	No	No	No	Yes	/	In hospital	Extensive anterior wall	0	30
11	62	M	No	No	No	No	Yes	/	In hospital	Extensive anterior wall	0	6
12	82	M	Yes	Yes	Yes	No	No	Aspirin	Out of hospital	Extensive anterior wall	5	23

Patient number	Antiplatelet therapy	Drug type	Thrombolysis result	BARC type	Rib fractures	Hospitalization Length (days)		CPC Score	PCI	Prognosis		Sequela	Cause of death
						ICU	General Ward			30-Day	1-Year
1	Aspirin + clopidogrel	Urokinase	Successful	Type 2	Yes	3	8	1	No	Survival	Survival	Unresponsive	/
2	Aspirin + clopidogrel	Urokinase	Successful	Type 2	Yes	13	8	1	No	Survival	Death	Right limb muscle strength grade IV	Recurrent cardiac arrest
3	Aspirin + clopidogrel	Urokinase	Successful	Type 5	Yes	13	0	4	No	Death	/	Died	Digestive tract hemorrhage
4	Aspirin + clopidogrel	rhPro-UK	Successful	Type 0	No	3	14	1	Yes	Survival	Survival	/	/
5	Aspirin + clopidogrel	rhPro-UK	Successful	Type 0	No	4	9	1	No	Survival	Survival	/	/
6	Aspirin + clopidogrel	rhPro-UK	Successful	Type 1	No	4	9	1	Yes	Survival	Survival	/	/
7	Aspirin + clopidogrel	rhPro-UK	Failed	Type 0	No	0	0	5	No	Death	/	Died	Unsuccessful thrombolytic therapy
8	Aspirin + clopidogrel	rhPro-UK	Successful	Type 2	Yes	10	0	4	No	Death	/	Died	Severe cerebral dysfunction
9	Aspirin + ticagrelor	rhPro-UK	Successful	Type 0	Yes	7	6	1	Yes	Survival	Survival	/	/
10	Aspirin + ticagrelor	rhPro-UK	Successful	Type 0	Yes	4	13	1	Yes	Survival	Survival	/	/
11	Aspirin + ticagrelor	rhPro-UK	Successful	Type 0	No	0	14	1	Yes	Survival	Survival	/	/
12	Aspirin + ticagrelor	rhPro-UK	Successful	Type 2	Yes	0	9	1	Yes	Survival	Survival	/	/

BARC – Bleeding Academic Research Consortium; CPC – cerebral performance category; CPR – cardiopulmonary resuscitation; ECG – electrocardiography; F – Female; ICU – intensive care unit; M – Male; PCI – percutaneous coronary intervention; rhPro-UK – recombinant human prourokinase.

Although thrombolytic therapy was successful in patient 3, defined by ST-segment resolution greater than 50% at 60 min, gastrointestinal bleeding occurred, and hemoglobin dropped from 116 g/L to 50 g/L. Red blood cells (2800 mL) were transfused, but the patient failed to improve. No intracranial hemorrhage was detected via computed tomography during hospitalization. Brain function recovery was poor (CPC=4), and the patient died after further rescue attempts.

Patient 7 achieved ROSC 10 min after the first CPR, but subsequent thrombolytic therapy was unsuccessful, and another cardiac arrest occurred. ROSC was not achieved again.

In patient 8, thrombolytic therapy after ROSC was successful, and no cerebral hemorrhage occurred. However, the patient remained in a deep coma (CPC=4) and died after 10 days.

Patient 2 was successfully discharged after thrombolytic therapy but experienced sudden cardiac death 6 months later. This fatal event may have been related to the inability to perform the indicated delayed PCI.

Discussion

Cardiac arrest remains a leading cause of mortality worldwide, with survival rates heavily influenced by regional healthcare capacity. Although IHCA survival ranges from 18% to 30% in Europe and the United States [9], rates in regions such as Beijing, China remain substantially lower at 9.1% [10]. This disparity is even more pronounced for OHCA, where survival approaches 10% in the United States [11] but only 1.3% in Beijing [12]. These differences primarily reflect inconsistent access to post-resuscitation care, including timely PCI and other etiology-specific treatments that are widely available in developed healthcare systems but often inaccessible in medically under-resourced regions. In this context, evaluations concerning the safety and efficacy of alternative post-CPR treatment strategies when primary PCI is unavailable represent a critical priority for improving global cardiac arrest outcomes.

Early initiation of high-quality CPR remains a critical determinant of survival after cardiac arrest and complements subsequent etiology-specific treatments. Although ROSC can be achieved in some patients through optimal CPR, this outcome occurs less frequently in those with OHCA due to systemic challenges, including delays in CPR initiation and variable bystander response. These prehospital limitations contribute to the significantly higher mortality observed in OHCA populations compared with IHCA populations. This trend aligns with our findings: all 3 non-survivors were in the OHCA group.

After restoration of spontaneous circulation, some patients may exhibit STEMI features on ECG. Despite the timely diagnosis of STEMI in these patients, primary PCI often remains unavailable in resource-limited areas because of geographic and infrastructural constraints. In this clinical scenario, thrombolytic therapy becomes the only viable reperfusion strategy.

International registry data from Japan, the Netherlands, and Spain demonstrate consistent outcomes for patients with acute myocardial infarction and ROSC who receive primary PCI; hospital discharge rates range from 63% to 68% across these healthcare systems [13–15]. Our study revealed comparable outcomes with thrombolytic therapy, suggesting similar efficacy when PCI is unavailable or delayed. Notably, although current resuscitation guidelines consider prolonged CPR as a relative contraindication to thrombolysis because of bleeding risks [2–4], our findings indicate that this approach may be safe and effective in selected patients.

Patient 2 died 6 months after discharge due to recurrent cardiac arrest. This mortality was clinically attributed to unresolved coronary artery lesions that persisted after the initial PCI during hospitalization. The case underscores the potential need for delayed PCI in similar scenarios. Patient 3 died of gastrointestinal hemorrhage; this OHCA occurred with CPR initiation delayed by 15 min. The hemorrhage was likely multifactorial, involving prolonged aspirin therapy and ischemia-induced gastrointestinal mucosal injury. The outcome in this case suggests that thrombolytic strategies for patients with chronic antiplatelet use and gastrointestinal ischemia require cautious implementation or dose adjustment. Patient 7 experienced thrombolytic failure (incidence: 1/12, 8.3%), representing a mortality rate within expected parameters for thrombolytic interventions. The death of patient 8 was secondary to severe cerebral failure. Despite a history of cerebral infarction and chronic aspirin therapy, serial computed tomography imaging excluded hemorrhagic complications. Thus, neurological deterioration was attributed to pre-existing cerebrovascular disease with reduced tolerance of cerebral ischemia.

Among patients with prolonged gastrointestinal ischemia who are receiving antiplatelet therapy, thrombolytic decision-making should be approached cautiously; dose reduction may be warranted. In patients with pre-existing cerebral infarction who are undergoing thrombolysis, early neurological function assessment and timely intervention are necessary to reduce the risk of severe cerebral impairment. After thrombolysis, when the patient is stabilized, PCI should be performed as soon as clinically feasible to prevent recurrent cardiac arrest.

Thrombolytic therapy offers distinct pathophysiological advantages over PCI in myocardial reperfusion. Although PCI effectively restores epicardial blood flow, post-procedural microcirculatory dysfunction often persists, compromising tissue-level perfusion [16]. The underlying pathophysiology involves multiple mechanisms, including distal macroembolization or microembolization, localized thrombus formation, and oxygen free radical generation [17]. Angiographic studies consistently demonstrate distal embolization of atherosclerotic and thrombotic debris [18–20]. Thrombolytic agents may mitigate these effects through systemic fibrinolysis and more gradual restoration of blood flow.

In patients with STEMI who have achieved ROSC, microcirculatory dysfunction affects both coronary and cerebral vasculatures [21]. Experimental evidence from animal models supports this phenomenon. In a feline model of cardiac arrest and resuscitation, thrombolytic therapy improved cerebral no-flow areas, suggesting that fibrin microthrombosis contributes to post-resuscitation cerebral microcirculatory impairment [22]. Comparable findings were observed in canine and primate studies; heparin administration reduced mortality in dogs [23]. Clinical observations further corroborate these experimental results. Two studies showed prolonged cortical hypoperfusion after ROSC, and larger hypoperfused areas were correlated with worse neurological outcomes [23,24]. Porcine models using confocal laser endomicroscopy revealed rapid microvascular thrombosis formation driven by blood cell aggregation and endothelial adhesion [25]. Human studies support these findings, demonstrating that approximately 25% of survivors experience severe neurological disability that impairs functional recovery [26–28]. These collective observations support the cerebral hypoperfusion–intravascular coagulation hypothesis. Notably, in our cohort, only 1 of 8 long-term survivors exhibited mild neurological sequelae, suggesting a potential neuroprotective benefit of thrombolytic therapy in post–cardiac arrest care.

Although thrombolytic therapy demonstrates efficacy in most STEMI-related cardiac arrest cases, its use requires careful risk–benefit assessment in certain STEMI subtypes. Spontaneous coronary artery dissection, which predominantly affects young women without conventional cardiovascular risk factors, represents an important exception because fibrinolytic therapy may worsen the dissection [29,30]. In clinical settings where coronary angiography is unavailable to confirm the underlying STEMI etiology, the decision to perform thrombolytic therapy should be made cautiously based on individual clinical characteristics.

Beyond STEMI-related cardiac arrest, thrombolytic therapy demonstrates established efficacy in pulmonary embolism–induced arrest [31], particularly in patients with predisposing factors such as major orthopedic trauma (e.g., long bone fractures), prolonged immobilization, or hypercoagulable states. Successful use in these etiologies (STEMI and pulmonary embolism) reinforces the safety and efficacy profile of thrombolytic therapy.

Limitations

The main limitation of this case series is the small sample size, which reflects the number of patients with STEMI who received thrombolysis after ROSC. This limitation arose because intravenous thrombolysis is unlikely to be considered when timely primary PCI is available.

Conclusions

This case series provides clinical evidence supporting the safety and feasibility of post-ROSC thrombolysis as a therapeutic option for patients with STEMI after comprehensive clinical evaluation, particularly in resource-limited settings where primary PCI is unavailable. Our results demonstrate that this approach achieves dual therapeutic benefits: restoration of coronary perfusion and a potential neuroprotective effect in survivors of cardiac arrest.