Abstract
Coronary artery disease is one of the leading causes of death globally. Despite the increased number of percutaneous coronary intervention (PCI) capable facilities, fibrinolytic therapy is still being utilized especially in rural areas. No studies have directly compared tenecteplase and reteplase in patients with ST-elevation myocardial infarction (STEMI).
Purpose
The aim of this study is to compare the efficacy and safety of both agents in patients with acute STEMI.
Methods
This was a multicenter retrospective observational study comparing tenecteplase and reteplase in patients with acute STEMI. The primary outcome was the incidence of failed thrombolysis. Secondary outcomes included the incidence of major bleeding, cardiogenic shock, re-infarction and mortality.
Results
A total of 282 patients were included, 229 and 53 received tenecteplase and reteplase, respectively. The incidence of failed thrombolysis was 33.2% in the tenecteplase group compared to 20.8% in the reteplase group (adjusted odds ratio 0.53, 95% confidence interval 0.25-1.1; p = 0.089). The incidence of major bleeding was 0.9% in the tenecteplase group and 5.7% in the reteplase group (p = 0.017). There was no significant difference in mortality or other secondary outcomes.
Conclusion
There was no difference in the primary outcome of failed thrombolysis between tenecteplase and reteplase; however, major bleeding events were significantly higher in the reteplase group. Randomized controlled trials are needed to confirm our findings.
Key Points
Patients suffering from STEMI who do not undergo PPCI are managed using thrombolytic therapy.
Tenecteplase and Reteplase are two thrombolytic therapies that have comparable outcomes to Alteplase but are easier to use.
We compared Tenecteplase to Reteplase in terms of ST segment elevation resolution and major bleeding.
When compared to Reteplase, Tenecteplase had similar outcomes in term of efficacy, but bleeding was lower.
Results of our study could help in choosing the right thrombolytic in catastrophic situations when there is no access to PPCI (Eg: during COVID-19 pandemic) or rural areas where time to PPCI exceeds 120 min.
Introduction
Coronary artery diseases (CAD) are one of the leading global causes of morbidity and mortality. 1 The burden of the disease is higher in low- and middle-income countries when compared to high income countries. 2 ST-segment elevation myocardial infarction (STEMI) is a life-threatening emergency that requires intermediate interventions to restore the myocardial blood flow and prevent complications and death. 3 International guidelines recommend primary percutaneous coronary intervention (PPCI) in patients presenting with STEMI. 4
Thrombolytic therapy has been used as an alternative to primary percutaneous coronary interventions (PPCI) in patients presenting to rural hospitals with no cardiac catheterization centers or where there is a delay to PCI of more than 120 min. 4 The guidelines recommend the use of a fibrin-specific agent such as tenecteplase, alteplase or reteplase. The guidelines did not recommend or suggest a specific agent. Available thrombolytic therapies include streptokinase, alteplase, reteplase and tenecteplase. Due to its lower efficacy and potential adverse effects, streptokinase is no longer recommended as first line thrombolytic therapy. Alteplase has better efficacy and safety when compared to streptokinase, 5 but its complex administration makes it less appealing.
Tenecteplase and reteplase are two of the relatively new thrombolytic agents which are characterized by the ease of use and shorter administration time compared to alteplase. Reteplase is a second-generation tissue plasminogen activator which is administered intravenously as two doses of 10 units separated by a duration of 30 min. 6 The GUSTO III trial which compared reteplase to alteplase showed that reteplase was non-superior to alteplase in terms of efficacy and similar outcomes in terms of bleeding. 7 Tenecteplase is genetically engineered from alteplase and is administered rapidly as a single intravenous bolus and the dose is weight-based. 8 ASSENT II trial which compared tenecteplase to alteplase showed similar efficacy outcomes and lower risk of bleeding 9 Tenecteplase has a relatively longer initial half-life compared to reteplase 20 to 24 min versus 13 −16 min. Tenecteplase is primarily cleared through liver metabolism while reteplase is cleared by the liver and kidney.6,8
In this study, our aim is to compare the safety and efficacy of tenecteplase to reteplase in patients with STEMI.
Materials and Methods
Study Design and Setting
This is a multicenter retrospective study that compared the safety and efficacy of tenecteplase versus reteplase in patients with acute STEMI. Patients from two different hospitals in Qatar were included in this study (a specialized heart hospital and a community hospital with a cardiology department). The study period was between February 2015 and June 2018. The thrombolytic agent choice was based on the treating physician preference. Both agents were readily available and there were not any local guidelines that recommend a specific thrombolytic agent. This study is approved by the Hamad Medical Corporation Institutional Review Board (IRB# MRC-01-19-114).
Inclusion and Exclusion Criteria
Patients were included if they were at least 18 years old, diagnosed with an acute STEMI, and received tenecteplase or reteplase. Patients were excluded from the study if they were pregnant, the primary endpoint could not be assessed due to missing electrocardiograms (ECGs), received tenecteplase or reteplase for indications other than STEMI, or received incorrect thrombolytic dose.
Endpoints
The primary endpoint was failed thrombolysis defined as less than 50% resolution of ST segment elevation on the electrocardiogram (ECG) after thrombolytic administration.
Secondary endpoints included: Mortality at 30 days, Thrombolysis in myocardial infarction (TIMI) 3 flow if PCI is done, In-hospital Mortality, re-infarction, cardiogenic shock, ejection fraction post thrombolytics, time to PCI post thrombolytics, hospital length of stay (LOS), mortality at 24 h, rescue PCI/Failed thrombolysis, second time use of fibrinolytic therapy (Repeated Thrombolysis).
Safety endpoints included major bleeding defined according to the International Society of Thrombosis and Hemostasis (ISTH) as any of the following:
Bleeding in a critical site Bleeding that causes hemodynamic instability Hemoglobin drop of more than or equal to 2 g/dl or required 2 units of packed red blood cells.
Data Collection Procedures
The primary outcome was determined through the following procedure: The ECG interpretation was done blindly by two cardiologists; Both cardiologists compared the maximum ST elevation before thrombolysis and ST elevation 90 min post thrombolysis. In case of discrepancy between the two physicians, a blinded senior cardiology consultant interpreted the ECG for the final decision.
Data points were collected through an automated report from the electronic medical record and manual chart review.
Statistical Analysis
Data were reported as mean and standard deviation or median and interquartile range (IQR) for, and number (percentage). The primary outcome was adjusted for use of aspirin, P2Y12 use, history of Myocardial Infarction (MI), anterior MI, door to needle time. For secondary outcomes: Chi square was used to compare categorical data, T-Test was used for normally distributed continuous data and Mann Whitney U Test for non-parametric data. All p values were two-sided, and results of statistical tests with p value of less than 0.05 were considered significant and all analysis was done with IBM SPSS Statistics version 28 Armonk, NY: IBM Corp.
Results
A total of 341 patients were assessed for eligibility of which 282 patients were included in this study, 229 received tenecteplase and 53 received reteplase (Figure 1). Approximately 77% of the patients (n = 216) were treated at the specialized heart hospital and 36.9% and 50% of patients received thrombolytic therapy in 2016 and 2017, respectively. Most patients (97.2%) were males and of an Asian ethnicity (82.6%). The median age was approximately 51 years. 42% of the patients had a past medical history of diabetes mellitus and 35.1% had hypertension. Only 4.3% had a history of a myocardial infarction and 52.5% were active smokers.
Flow chart for participants allocation.
The baseline characteristics were well balanced between the two groups except of the median baseline Hemoglobin A1c (HbA1c) which was higher in the reteplase group 6.9% compared to 6% in the tenecteplase group (p = 0.008). Table 1 summarizes the baseline characteristics.
Baseline Characteristics.
DBP: Diastolic Blood Pressure; HR: Heart rate; Hgb: Hemoglobin; HbA1C: Glycated Hemoglobin; SBP: Systolic Blood Pressure; N: number of patients; MI: Myocardial Infarction; SD: Standard Deviation.
The median door to needle was 54 min. Most patients (46.1%) were diagnosed with anterior MI. All the patients received therapeutic anticoagulation. The use of guideline directed therapies were similar between both treatment groups; however, the use of statins during the first 24 h was significantly higher in the reteplase group compared to the tenecteplase group (90.6% vs 46.7%, p < 0.001). The use of intravenous nitroglycerin was more common in the reteplase group (35.8% vs 10.9%, p < 0.001), this is shown in Table 2.
Other Therapies.
The primary outcome of failed thrombolysis occurred in 76 patients (33. 2%) in the tenecteplase group compared to 11 (20.8%) in the reteplase group (adjusted odds ratio 0.53, 95% confidence interval 0.25-1.1; p = 0.09). The incidence of major bleeding was lower in the tenecteplase group (0.9%) compared to 5.7% in the reteplase group (p = 0.017). The incidence of hemoglobin drops 2 g within 48 h of thrombolytics was lower in the tenecteplase group (9.2%) compared to 22.6% in the reteplase group (p = 0.006). There were no statistically significant differences in the rest of the secondary outcomes between the 2 groups (Table 3). The incidence of cardiogenic shock was similar between the two groups. Table 3 summarizes the secondary outcomes.
Secondary Outcomes.
The hospital length of stay and the peak troponin concentration were similar between the 2 groups (Table 4). 200 patients underwent PCI post thrombolytics. The median time to PCI post thrombolytics 17.5 h in the tenecteplase group and 20 h in the reteplase group. Other exploratory outcomes are described in Table 4.
Other Outcomes.
Only in patients who had PCI done (n = 200).
Tenecteplase n = 208 and Reteplase n = 50.
Tenecteplase n = 221.
Discussion
To our knowledge, this was one of the first studies to directly compare the outcomes of tenecteplase and reteplase in the acute management of STEMI. There was no difference in the primary outcome of failed thrombolysis between tenecteplase and reteplase. However, reteplase was associated with higher incidence of major bleeding when compared to tenecteplase. There were no differences in other secondary outcomes (cardiogenic shock, re-infarction, in-hospital mortality, mortality at 24 h, 30-days mortality and stroke).
The results of this study are similar to previous studies comparing each agent of the studied thrombolytics to alteplase. In the ASSENT II trials, the incidence of non-cerebral bleeding was lower in the tenecteplase arm compared to alteplase (26.1% vs 28.4% p = 0.0003) and the need for blood transfusion was also lower in the tenecteplase group compared to alteplase (4.3% vs 5.2% P = 0.0002). 9 In the GUSTO III trial, reteplase was non-superior to alteplase in terms of the primary efficacy outcome of 30-day mortality. 7 The incidence of major bleeding was similar between the two agents. The comparable bleeding profile between reteplase and alteplase may explain the higher incidence of major bleeding with reteplase in our study as tenecteplase had lower incidence of major bleeding when compared to alteplase.
The median age of patients in this study was 51 years of age. This is less than the average age of patients in other studies which was 61 years. This variation is due to the different demographics in the Middle East. Most patients presented with anterior MI (46.5%) which is similar to the ASSENT II and GUSTO III trials (39.4% and 47%).7,9 Most patients received aspirin (93%) which was comparable to previous studies. More patients in the tenecteplase group received statins within the first 24 h when compared to the reteplase group (87.9% vs 46.4%), which was higher than ASSENT II but it was not reported in the GUSTO III trial. Killip score was not calculated in this study. However, the median ejection fraction post thrombolytic therapy was 45%, and only 6.7% of the patients developed cardiogenic shock.
Zia-Behbahani and colleagues conducted an indirect meta-analysis comparing reteplase and tenecteplase. 10 The meta-analysis included eight studies, five of which comparing tenecteplase to alteplase and three studies comparing reteplase to alteplase. The indirect comparison showed that there was no significant difference in mortality, TIMI flow, or major bleeding.
Recent evidence shows that despite the increased number of PCI facilities, this did not lead to improved access to PCI especially in rural areas, and developing countries.11,12 Moreover, there was a rise in the use of thrombolytics during the time of COVID-19 pandemic. This is especially the case in patients presenting to PCI non-capable rural facilities. 13 This sheds light on the importance of the results of our study. The use of alteplase has fallen out of favor in recent years. A lot of centers have been switching to tenecteplase for the acute stroke and acute pulmonary embolism. In Qatar, starting 2018 patients admitted with STEMI were managed with PPCI 24/7 if no contraindications existed. However, a rise in the use of thrombolytic therapy was noticed during COVID-19 pandemic.
This study has several limitations. The retrospective design of the study means that there is high risk of bias introduction. We attempted to control this by adjusting for several confounders as mentioned in the methods section. Next is the lower number of patients who received reteplase. Also, the primary efficacy outcome was dependent only on the ST elevation resolution after the use of thrombolytics. Other outcomes like chest pain resolution and the rise in troponins one hour after thrombolytics administration were not included. However, the success of thrombolytic therapy was evaluated through the analysis of the electrocardiogram by two independent blinded cardiologists, which was not described in previous studies. The number of major bleeding event were low given the study sample size, however; the incidence of major bleeding in this study is similar to ASSENT II and GUSTO III trials.7,9
Conclusion
The incidence of failed thrombolysis was similar between tenecteplase and reteplase. Tenecteplase was associated with a lower incidence of major bleeding compared to reteplase. Further randomized controlled trials are needed to confirm our findings.
Footnotes
Author Contributions
AM, SM and AF (the first three authors) are equal contributors as first author. AF is the corresponding author. AM, SM and AF helped in all study roles and wrote the manuscript .The rest of the authors helped in data analysis and reviewing the manuscript.
The authors have no financial/ non-financial disclosures to report.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Grant from Hamad Medical Corporation (HMC): MRC-01-19-114 Hamad Medical Corporation (Qatar).
Ethical approval granted by HMC MRC.
Hamad Medical Corporation, (grant number MRC-01-19-114).
