Comparative clinical effectiveness of thrombolytic agents streptokinase versus alteplase versus tenecteplase in the management of ST-segment elevation myocardial infarction: a systematic review and meta-analysis

INTRODUCTION

Globally cardiovascular diseases are the leading cause of death, taking an estimated 17.9 million lives (32%) each year. Heart attacks and strokes account for 85% of these deaths.¹ Acute coronary syndrome (ACS) is a group of conditions characterized by a sudden decrease in myocardial perfusion, which includes ST-segment elevation myocardial infarction (STEMI), non–ST-segment elevation myocardial infarction (NSTEMI), or unstable angina. STEMI represents about 30% of all ACS cases, and is marked by transmural myocardial ischemia resulting in myocardial injury.² Common feature of myocardial ischemia is chest pain-equivalent symptoms which includes dyspnoea, epigastric pain, and pain in the left arm. In STEMI, the pain tends to be more persistent and heavier. For patients presenting with ACS, electrocardiography should be performed immediately (within 10 minutes of presentation) to distinguish between STEMI and non–ST-segment elevation.^1,3,4

STEMI results in myocardial injury or necrosis and remains a major cause morbidity and mortality worldwide While Primary percutaneous coronary intervention (PCI) is preferred reperfusion therapy, due to its limitations, fibrinolytic therapy is often preferred. The treatment of MI includes, aspirin tablets, to dissolve arterial blockage injection of thrombolytics (tissue plasminogen activator) streptokinase or urokinase in blood within 3 hours of the onset of a heart attack and painkillers.⁵ The management of patients with STEMI and NSTEMI has evolved considerably over decades, with better understanding early reperfusion needs and protocol based pharmacotherapy.^6,7 Thrombolytic therapy plays an important role in management of STEMI. Depending on the location of such thrombi and emboli, they may manifest themselves in the form of varied thromboembolic disorders like stroke, pulmonary embolism, deep vein thrombosis, arterial thrombosis, acute myocardial infarction (AMI) and retinal artery occlusion.⁸ When electrocardiography suggests STEMI, rapid reperfusion with primary percutaneous coronary intervention (PCI) within 120 minutes reduces mortality from 9% to 7%. If PCI within 120 minutes is not possible, fibrinolytic therapy with alteplase, reteplase, or tenecteplase at full dose should be administered for patients younger than 75 years without contraindications and at half dose for patients 75 years or older (or streptokinase at full dose if cost is a consideration), followed by transfer to a facility with the goal of PCI within the next 24 hours.³ Alteplase showed better reperfusion than Streptokinase, also accelerated alteplase infusion showed better patient outcome than non-accelerated infusion.⁹ According to many studies a fibrin-specific agent should be preferred. Single-bolus weight-adjusted tenecteplase is equivalent to accelerated tPA in reducing 30-day mortality, and is safer in various aspects.^10,11 A 30-day post-discharge health-related quality of life (HRQoL) among patients with acute myocardial infarction (AMI), using the Seattle Angina questionnaire (SAQ) was conducted in India, 44% experienced angina within 30 days. Physical limitation was 58.3% (IQR: 41.7–77.8). Patient satisfaction and quality of life 81.3% and 66.7 respectively.¹²

This study intends to provide evidence-based insights to physicians at rural settings, and healthcare policymakers, by comparing interventions across key outcome parameters such as effectiveness, efficacy, safety, adverse events, and treatment success.

This review will also emphasize the broader significance of selecting appropriate fibrinolytic agents, particularly in resource-limited settings where cost-effectiveness, drug availability, and patient safety are crucial considerations.

Objectives

The objectives of the study were: to systematically review the published literature and identify reperfusion success with fibrinolytic agents i.e. streptokinase, alteplase and tenecteplase in management of ST-segment elevation myocardial infraction, and to compare the clinical efficacy, safety, and humanistic outcomes of the fibrinolytic therapy in patients with ST-segment elevation myocardial infraction.

METHODS

The systematic review was registered in The International Prospective Register of Systematic Reviews (PROSPERO) CRD420251072502. The study is reported according to the preferred reporting items for systematic reviews and meta-analysis extension (PRISMA).

Inclusion criteria

Types of studies

Studies that included patients with severe chest pain diagnosed with ST elevation myocardial infraction with ECG showing more than 1 mm elevation in 2 contagious leads. Eligible studies assessed the reperfusion, efficacy and/or safety of TNK versus TPA versus SK in managing MI. Studies that didn't mention TNK. TPA and/or STK in the title but mentioned fibrinolytics or thrombolytics were selected for full-text screening, if a conclusion could not be reached on abstract screening.

No restriction was placed on the publication date, follow-up duration, and sample size. Besides systematic reviews, case study and case report no other restriction was placed on the study design.

Types of participants

Studies where patients (≥40 years of age) with severe chest pain and reaching CHC/SDH or DH within 12 hours and diagnosed with ST elevation myocardial infraction with ECG showing more than 1 mm elevation in 2 contagious leads. In female, leads V2 and V3 showing more than 1.5 mm of elevation. In male <40 years of age, leads V2 and V3 showing more than 2.5 mm of elevation and in male >40 years of age showing more than 2 mm of elevation.

Outcome measures

The studies that reported reperfusion rate of the fibrinolytic agents, mortality, adverse cardiovascular events, bleeding complication, incidents of reinfarction and health related quality of life.

Exclusion criteria

Type of study

Overlapping/repetitive studies, systematic reviews, non-English studies and conference abstracts were excluded.

Search strategy

A comprehensive literature search was conducted on PubMed, web of science and Embase. We developed the search terms for “STEMI”, “fibrinolytic agents” and “outcomes”. For the clinical condition STEMI, we developed the search terms as "Myocardial Infarction", "ST-segment Elevation Myocardial Infarction" "ST elevation myocardial infarction" and "STEMI". For fibrinolytic agents, the search teams developed were "Thrombolytic Therapy", “fibrinolysis”, “reperfusion therapy”, “reperfusion”, "Streptokinase", “alteplase”, “tenecteplase”, “tPA”, “T-Plasminogen Activator”, “TNK”, "Fibrinolysis", “lysis”, “clot dissolve” and "Fibrinolytic Agents". For outcomes the search terms used were "management”, “efficacy”, “effectiveness”, "Adverse effects", “adverse events” “complication” and “mortality”. Boolean operators “AND” and “OR” were used along with truncation to refine the search. The reference list of recognized studies will be further explored to search for additional papers. Furthermore, an extensive search of grey literature will be conducted in accordance with the specified timelines.

Selection of studies

Firstly, all the studies were uploaded on Rayyan software, the included study in the review was screened and duplicates were removed. The two reviewers ZA and TR independently screened title/abstract of the studies. Those that fit the inclusion criteria was considered for the next stage of screening and the rest was excluded.

All the eligible studies full texts were retrieved, and both reviewers independently assessed the full papers for their eligibility for final inclusion and data extraction. In-case of disagreement, issue was resolved by discussion.

The selection process of the studies is depicted in the flow diagram following the PRISMA guidelines.

Study characteristics

Selection of studies

A total of 1280 studies were selected and were uploaded on Rayyan software, the included study in the review was screened and 158 duplicates were removed. The two reviewers ZA and TR independently screened title/abstract of the 1122 studies. Those that fit the inclusion criteria was considered for the next stage of screening and the 1048 were excluded. All the eligible studies (n=74) full texts were retrieved, and both reviewers independently assessed the full papers for their eligibility for final inclusion and data extraction. Studies were excluded based on different outcome of interest, different drugs or combinations, full text unavailability, different population, different study design and foreign languages. In-case of disagreement, issue was resolved by discussion. We narrowed to a total of 15 studies. The selection process of the studies is depicted in the flow diagram following the PRISMA guidelines.

Data extraction and quality assessment

Two investigators (ZA and TR) independently extracted data from text, tables and figures. Any discrepancies were resolved by discussion and consensus with a third reviewer (NAY). For each of the included trials, the following data were extracted: publication year, drugs used, number of patient in each group and treatment details (reperfusion, 30 days’ mortality, major and minor bleeding, major adverse cardiovascular events and recurrence). Study quality and risk of bias were critically appraised using the updated Cochrane collaboration risk-of-bias tool V.2, Newcastle-Ottawa for cohort studies, JBI critical appraisal tools for the analytical cross-sectional studies and quasi-experimental study.

Outcome

The predetermined primary outcome was reperfusion followed by 30 days’ mortality, major and minor bleeding and major adverse cardiovascular events. Table 1 shows study characteristics such as author and year of publication, sample size, study setting and design and outcome. From these studies Table 2 was extracted showing summary of various events occurring for the given fibrinolytics.

RESULTS

A total of 1280 unique records were identified through electronic searches using four online databases, from which 158 duplicates were removed. Of these, 1048 were excluded based on title and abstract alone. After screening the full text of the remaining 74 articles, 12 studies were found to meet the inclusion criteria, as summarised on the PRISMA flow diagram (Figure 1).²⁵ The risk of bias assessment was done using ROB2, JBI and New Ottawa checklist for each study according to their study design and 9 studies showed low risk and 2 showed high risk.

Clinical outcomes

A total of two studies compared Streptokinase versus Alteplase and 10 studies compared Streptokinase vs Tenecteplase. Out of all, 9 studies evaluated vessel reperfusion based on TIMI grades. The overall pooled proportion demonstrated a significant improvement in reperfusion with thrombolytic therapy 62.80%; 95% CI: 53.98-71.62%.

The subgroup analysis revealed that streptokinase was associated with a significant improvement in vessel reperfusion by 56.57%; 95% CI: 41.67-71.47%. Similarly, tenecteplase demonstrated a significant reperfusion by 71.29%, 95% CI: 63.08-79.41%.

Eight studies evaluated 30-day mortality following thrombolytic therapy. The overall pooled analysis demonstrated a significant reduction in 30-day mortality with thrombolytic use 4.05%; 95% CI: 2.68-6.48%. In the subgroup analysis, Streptokinase was associated with a 6% mortality rate 95% CI: 2.27-8.04%, while tenecteplase demonstrated a significantly lower pooled mortality 3.64%; 95% CI: 0-7.84%.

Of all, six studies reported major bleeding events following thrombolytic therapy. The overall pooled analysis demonstrated low risk of major bleeding i.e. 3.77%; 95% CI: 0.84-6.70%; I²=86.9%; p<0.0001). In the subgroup analysis, streptokinase was associated with a pooled major bleeding risk of 4.39% (95% CI: 0.00-8.9). Tenecteplase showed a comparatively lower bleeding risk of 0.92% (95% CI: 0.03-1.80%), whereas alteplase demonstrated a slightly higher risk of 7.52% (95% CI: 0.00-22.20%).

Five out of 12 studies reported minor bleeding The overall pooled analysis demonstrated a 6.50% risk of minor bleeding 95% CI: 2.80-10.21%, with high heterogeneity (I²=85.1%). In the subgroup analysis, streptokinase was significantly associated with 8.39% risk of minor bleeding risk (95% CI: 2.91-13.88%; I²=86%), whereas tenecteplase showed a comparatively lower risk of 3.52% (95% CI: 0.00-7.44%; I²=60.1%). And 7 studies reported MACE, the overall pooled analysis demonstrated MACE rate of 11.34% (95% CI: 7.60-15.08%, I²=91.2%). In the subgroup analysis, streptokinase demonstrated significant MACE risk of 11.27% (95% CI:5.56-16.47%; I²=90.8%), while tenecteplase demonstrated a significant risk of 11.04% (95% CI: 3.44-18.64; I²=90.8%). Alteplase exhibited a slightly higher MACE risk of 11.87% (95% CI: 6.92-16.82; I²=70%). The Overall outcome suggested that fibrin-specific thrombolytic i.e. Tenecteplase is superior than non-fibrin-specific thrombolytics i.e. Streptokinase in terms of reperfusion, 30-days mortality and major and minor bleeding and MACEs.

DISCUSSION

This systematic review and meta-analysis comprehensively compared the clinical efficacy and safety of different thrombolytic agent streptokinase, alteplase, and tenecteplase in the management of STEMI. Early revascularisation remains the cornerstone of successful management of patients with STEM. The pooled evidence from 15 studies demonstrates that thrombolytic therapy significantly improves reperfusion and reduces short-term mortality in STEMI patients, with notable variations in outcomes among different agents. Our findings reaffirm that fibrin-specific agents (alteplase and tenecteplase) offer superior clinical efficacy compared to the non-fibrin-specific streptokinase. In terms of reperfusion success, both alteplase and tenecteplase achieved higher rates of TIMI grade 3 flow restoration, reflecting better microvascular perfusion.^17,19 The reduction in 30-day mortality was also most evident with tenecteplase, followed by alteplase, while streptokinase though still effective showed a comparatively higher mortality risk. These results align with previous large-scale trials such as GUSTO and ASSENT, which established the mortality and reperfusion benefits of fibrin-specific agents over older thrombolytics.²⁶

An important implication of these findings is the clinical and operational advantage of tenecteplase. Its single-bolus administration simplifies logistics, shortens door-to-needle time, and reduces the need for continuous infusion monitoring. These properties make TNK particularly suitable for pre-hospital or peripheral healthcare settings, where infrastructure for PCI or prolonged infusion may be limited. Tenecteplase yielded the lowest pooled mortality (RR=0.04; 95% CI: 0.02–0.08; I²=89.5%; p<0.0001), followed closely by alteplase (RR=0.06; 95% CI: 0.06–0.06; I²=0%; p=0.4195), whereas streptokinase though effective showed comparatively higher mortality risk (RR=0.06; 95% CI: 0.03–0.08; I²=96.5%; p<0.0001), possibly reflecting its lower fibrin specificity and higher immunogenic potential. Overall, this systematic review underscores that tenecteplase and alteplase outperform streptokinase in terms of reperfusion efficacy, mortality reduction, and safety, supporting their preferential use in the management of STEMI. Streptokinase, though widely used, may be less efficient and associated with greater heterogeneity in clinical outcomes. Thus, this analysis supports the preferential use of fibrin-specific agents in the thrombolytic management of STEMI.

CONCLUSION

This systematic review concludes that fibrin-specific thrombolytics, particularly tenecteplase and alteplase, demonstrate superior efficacy and safety compared to streptokinase in the management of STEMI. Both agents significantly improve reperfusion success and reduce 30-day mortality with a lower incidence of bleeding complications. Among them, tenecteplase offers added operational advantages due to its single-bolus administration and favourable safety profile, making it a practical choice in resource-limited settings where timely PCI is not feasible.

Funding: HTAIn Regional Resource Hub Hyderabad, Department of Health Research MoHFW. Government of India

Conflict of interest: None declared

Ethical approval: Not required

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