替奈普酶治疗急性缺血性卒中：一项更新的荟萃分析。

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【Abstract】 INTRODUCTION: Tenecteplase (TNK) has emerged as a promising alternative to alteplase (tPA) for intravenous thrombolysis in acute ischemic stroke (AIS). This study aimed to evaluate the efficacy and safety of TNK compared with tPA. METHODS: Following the PRISMA 2020 guidelines, PubMed, Web of Science, Cochrane Central, EBSCO, and Scopus were systematically searched from inception through January 2026 to identify randomized controlled trials (RCTs) and observational studies comparing TNK with tPA in adults with AIS. Effect estimates were pooled using fixed- or random-effects models according to the degree of heterogeneity and were reported as risk ratios (RRs), odds ratios (ORs), or mean differences (MDs) with 95% confidence intervals (CIs). RESULTS: Twenty-four studies (6 RCTs and 18 observational studies; total n = 20,592) involving patients with AIS were included. Compared with tPA, TNK was associated with a greater likelihood of excellent functional recovery (mRS 0-1) at 90 days (RR = 1.08; 95% CI: 1.01-1.15; p = 0.02) and a shorter door-to-needle time by an average of 4 min (MD = -4.20; 95% CI: -7.77 to -0.64; p = 0.02). Mortality was lower among patients treated with TNK (OR = 0.83; 95% CI: 0.73-0.94; p = 0.004). However, subgroup analyses restricted to RCTs showed no significant difference in mortality between the TNK and tPA groups (OR = 0.99; 95% CI: 0.82-1.21; p = 0.95). CONCLUSION: TNK provides efficacy and safety profiles comparable to those of tPA while offering a greater likelihood of excellent functional recovery, faster treatment initiation, and lower mortality in observational studies. Further high-quality RCTs are warranted to confirm these findings. SYSTEMATIC REVIEW REGISTRATION: CRD420251030320. 【Introduction】 Ischemic stroke is a significant cause of long-term disability and mortality, accounting for 62.4% of all strokes worldwide (). Intravenous thrombolysis using alteplase (0.9 mg/kg, to a maximum of 90 mg) remains the gold standard for the treatment of acute ischemic stroke (AIS) (). Its ability to dissolve arterial occlusions was first tested in ischemic heart disease patients in 1984, and it showed successful coronary artery opening in 75% of patients (). Despite its undisputed efficacy, alteplase has a narrow 4.5-h treatment window from stroke onset and suboptimal recanalization rates (). While alteplase was the only approved thrombolytic for AIS by the U. S. Food and Drug Administration (FDA) since 1996, tenecteplase (TNK) has become the second agent to be approved after nearly 30 years (). Studies suggest that TNK may outperform tPA in key aspects. Alteplase has a short half-life of 4 min and requires a 60-min-long infusion following bolus administration, in contrast to TNK, which has a longer half-life of 20 min (). Moreover, TNK has more fibrin-specific properties, which are very helpful in reducing systemic effects and fibrinogen depletion (). Furthermore, the optimal dose of TNK is 0.25 mg/kg for patients with AIS. In contrast, higher doses, such as TNK 0.40 mg/kg, should be avoided in patients with AIS due to increased risk of symptomatic intracranial hemorrhage (sICH) (). The EXTEND-IA TNK trial found higher early reperfusion rates in patients who took tenecteplase than those on alteplase (22% vs. 10%, p = 0.002) before thrombectomy (). However, NOR-TEST did not find a notable difference in clinical outcome, frequency of sICH, or mortality at 7 days, yet the TNK group showed a higher all-cause mortality at 90 days (26.3% vs. 9.1%) (), which underscores the need for investigating differences in efficacy and safety based on patient selection, dosing, and real-world applicability. This systematic review and meta-analysis evaluated data from randomized controlled trials (RCTs) and observational studies to compare the efficacy and safety of TNK with alteplase in the setting of acute ischemic stroke, with a particular focus on whether TNK is non-inferior to alteplase. The findings may help inform the use of TNK as an alternative to alteplase in acute ischemic stroke. 【Methodology】 【Protocol approval and registration】 This systematic review and meta-analysis followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline checklist (). The protocol for the current study was registered in PROSPERO with the following ID number: CRD420251030320. Due to the nature of this study, which involved secondary analysis of previously published data, ethical approval and informed consent were not required. 【Search strategy】 The electronic databases PubMed, Web of Science, Cochrane Central, EBSCO, and Scopus were systematically searched to extract all relevant articles published until January 2026. Across all databases, the search strategy was developed using predefined keywords encompassing stroke-related terms (minor stroke, transient ischemic attack, cerebral stroke, cerebral infarction, cerebrovascular disease, cerebral ischemia, cerebrovascular disorders, cerebrovascular accident, brain ischemia, acute stroke, brain infarction, light stroke, mild stroke, silent stroke), thrombolytic agents (tenecteplase, TNK-tPA, TNK, TNKase, rhTNK-tPA), comparator terms (alteplase, rt-PA, tissue plasminogen activator, plasminogen activator tissue type), and methodological descriptors (randomized controlled trial, controlled clinical trial, randomized, placebo-controlled, drug therapy, clinical trial, random assignment, trial, study groups, cohort study, retrospective study, prospective study). The exact Boolean search strings used for each database are provided in . In addition, the reference lists of all included studies were manually screened to identify any relevant studies not captured by electronic search. No gray literature sources or trial registries were consulted. 【Study selection criteria】 The studies were eligible for inclusion if they were published in English and included patients aged ≥18 years who were diagnosed with AIS. Eligible study designs included RCTs and cohort studies. Studies must have completed their trials and were required to report at least one neurological outcome, such as NIHSS before and after 24 h or mRS at 90 days. In addition, studies had to report at least one predefined efficacy or safety outcome to be eligible for inclusion. Studies were excluded if they involved patients under 18 years of age, patients without a confirmed diagnosis of AIS, patients who did not receive TNK, or studies that did not directly compare TNK with alteplase (single-arm studies). Additionally, studies not reporting the required neurological outcomes, incomplete or ongoing clinical trials without outcome data, non-english language articles, case reports, case–control studies, cross-sectional studies, systematic reviews, literature reviews, editorials, conference abstracts and animal studies were excluded. Studies that did not have available data to get effect estimates were excluded. 【Screening】 Two reviewers (F.A. and B.A.) independently screened all articles retrieved through the search process. Initial screening based on titles and abstracts was conducted using Rayyan software (). Articles that met the inclusion criteria proceeded to full-text screening, which was also performed independently by the same reviewers. Any disagreements were discussed and resolved through consensus. When a consensus could not be reached, a third reviewer (H.A.) was consulted to resolve the disagreement. 【Data extraction】 Two reviewers (H.A. and F.A.) independently extracted data from each study. Extracted information included study title, authors, publication year, journal, country of origin, study design, number of participants, demographics, TNK dosage, timing of administration, and site of vessel occlusion. 【Risk of Bias assessment and certainty of evidence assessment】 Risk of bias was assessed using the Cochrane risk of bias tool 2 (ROB2) for randomized controlled trials and the Newcastle-Ottawa Scale (NOS) for cohort studies (, ). The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach was used to assess the certainty of the evidence. The quality of evidence was classified as high, moderate, low, or very low. All procedures were conducted using GRADEpro software. 【Outcome measures】 The primary efficacy outcomes assessed in this review were the improvement in NIHSS score at 24 h, improvement of mRS at 3 months, door-to-needle time (DTN), and onset-to-needle time (OTN). The secondary outcomes concerned the safety of both interventions, such as sICH, parenchymal hematoma, mortality rate, and angioedema. These outcomes were chosen to comprehensively evaluate the functional recovery and potential adverse events associated with thrombolytic treatment in patients with AIS, thereby providing a detailed comparison between tenecteplase and alteplase. Comprehensive definitions of all outcomes are presented in . 【Data analysis】 This meta-analysis utilized findings from the studies included in the search to determine the efficacy and safety of tenecteplase compared to alteplase in patients diagnosed with AIS. Statistical analysis was conducted using the RevMan Manager (RevMan) Version 5.4 software, which aided in pooling the study results and evaluating overall treatment effects (). Heterogeneity across studies was examined using the Cochrane-based Q statistic and I2 test, which determined the type of model to be further used in the analysis. A random-effects model was applied when substantial heterogeneity was present (p < 0.05, I2 > 50%). In cases where heterogeneity was minimal (I2 < 50%, p > 0.05), a fixed-effects model was used instead. Standardized mean differences (SMD) for continuous outcomes and odds ratios (OR) for dichotomous variables were used to express the effects of treatment; each had a 95% confidence interval (CI). p-values below 0.05 were regarded as statistically significant. Subgroup analysis was performed to explore potential reasons for the high heterogeneity present in some of the outcomes. The subgroup was considered valid if at least two studies fit its criteria. The studies were subgrouped based on the implemented study design and the TNK dose used. Sensitivity analysis was also conducted in general to discern if exclusion of any of the studies led to a significant change in the results. Additionally, due to the availability of an adequate number of studies, a funnel plot could be charted to assess the publication bias. 【Results】 【Search results】 illustrates the PRISMA flow chart depicting the study inclusion steps in our review. Using our search strategy, we retrieved 3,503 studies from five databases. Of them, 589 duplicates were identified and removed. Further screening based on title and abstract excluded 2,817 studies. After assessing the eligibility of the remaining 90 studies based on the full text, 66 were excluded. Finally, 24 studies were included in this systematic review and meta-analysis (, ). PRISMA flowchart. 【Summary of study characteristics】 presents the baseline characteristics of the studies investigating. A total of 24 studies were included, comprising a mix of RCTs and cohort studies. These studies involved 20,592 patients, with 10,421 patients in the TNK group and 10,171 in the tPA group. The mean age of patients was 68.7 ± 14.5 years in the TNK group and 68.5 ± 14.7 years in the tPA group. Gender distribution was similar across both arms, with males comprising 57.8% of the TNK group and 57.6% of the tPA group. Sites of arterial occlusion varied across studies, most commonly involving the internal carotid artery (ICA), middle cerebral artery (MCA1, MCA2, MCA3), basilar artery, and tandem occlusions. In terms of dosing, TNK was most frequently administered at 0.25 mg/kg, while tPA was given at the standard 0.9 mg/kg. Some studies used capped doses for TNK (e.g., 0.2 mg/kg with a 20 mg max) (, , ), and one study used a slightly higher Tenecteplase dose of 0.4 mg/kg (). Both drugs were typically given as single boluses in the acute stroke setting. Study characteristics. TNK; Tenecteplase, tPA; Tissue plasminogen activator, SD; standard deviation, RCT; Randomized controlled trial, ICA; Internal carotid artery, MCA; Middle cerebral artery. *Estimated mean and standard deviations. 【Quality assessment】 Among the six RCTs, two were judged to have a low overall risk of bias, while four were rated as having an unclear risk. The uncertainty in these four trials stemmed mainly from limited reporting within key ROB2 domains. In Wang (), Logallo (), Meng (), and Parsons (), concerns were noted in the deviations from intended interventions domain due to insufficient details on adherence to treatment protocols. Additionally, Logallo () showed concerns in the outcome measurement domain because assessor blinding was not clearly described. Other than this, all RCTs demonstrated low risk regarding missing outcome data, outcome measurement except (), and selective reporting, indicating consistent and unbiased assessment (). For the 18 retrospective and prospective cohort studies. Sixteen studies were rated as low risk, with total scores ranging from 7 to 9. Two studies—Henderson () and Hendrix ()—received moderate-risk ratings, each scoring 6/9. These ratings were primarily driven by limitations in the comparability domain, including baseline imbalances between exposed and non-exposed groups, along with incomplete or inadequately reported follow-up. Such limitations reduced confidence in the accuracy and certainty of outcome ascertainment compared with the higher-scoring cohort studies (). Risk of bias for RCTs. NOS score for cohort studies. 【Certainty of evidence (GRADE assessment of outcomes)】 summarizes the certainty of evidence for all critical and important outcomes that was assessed by the GRADE approach as shown in. Outcomes mRS (0–1), sICH, mortality rates, and rate of incidence of angioedema were found to have a high certainty of evidence indicating that the effect estimates are very likely to be close to the true effect. On the other hand, the certainty of evidence was deemed moderate for several other outcomes, including rates of achieving mRS (), improvement of mRS more than 4, mean mRS at 3 months, NIHSS at 24 h, and rate of parenchymal hematoma. These outcomes were downgraded to one level mainly due to either a serious risk of bias in some of the studies used or concerns about inconsistency due to the unexplained heterogeneity between the studies. The mRS (0–2) was considered to have low certainty of evidence due to the presence of both serious risk of bias and substantial statistical heterogeneity. Certainty of evidence. There was evidence of significant statistical heterogeneity across the included studies (I2 > 50%). However this inconsistency was attributed to the difference in study design (RCT vs Cohort). Evidence was downgraded one level for serious risk of bias based on limitations found across both study designs. RCTs (4 of 6) had unclear risk due to limited reporting on adherence to protocols (Meng, Parsons) and lack of clear assessor blinding (Logallo). Cohort studies (, ) were rated moderate-risk due to limitations in the comparability domain (baseline imbalances and inadequate follow-up). There was evidence of substantial statistical heterogeneity across the included studies (I2 > 50%). This inconsistency was only present between cohort studies and was not fully explained by pre-specified subgroup analyses (e.g., dosage or patient age). There was evidence of substantial statistical heterogeneity across the included studies (I2 > 50%). This inconsistency was not fully explained by pre-specified subgroup analyses (e.g., dosage or patient age). 【Outcomes】 summarizes the outcomes of the meta-analysis whether related to efficacy or safety endpoints. Summary of outcomes. *p – value is significant. TNK; Tenecteplase, tPA; Tissue plasminogen activator, MD; Mean difference, OR; Odds ratio; CI; Confidence interval, mRS; Modified Rankin scale, NIHSS; National Institutes of Health Stroke Scale, sICH; Symptomatic intracranial hemorrhage. 【Primary outcomes】 【mRS】 In this meta-analysis, the likelihood of achieving an mRS (0–1) was significantly higher in the TNK group compared to the tPA group (, RR = 1.08; 95% CI: 1.01–1.15; p = 0.02). Conversely, no significant difference was found in the overall improvement of an mRS (0–2) between the TNK and tPA groups (, RR = 1.03; 95% CI: 0.97–1.10; p = 0.30). Similarly, there was no significant difference in the overall improvement of an mRS () (, RR = 1.07; 95% CI: 0.84–1.36; p = 0.58). Finally, the mean mRS at 3 months also showed no significant difference between the TNK and tPA groups (, MD = −0.24; 95% CI: −0.72 – 0.25; p = 0.34). (A) RR of mRS (0–1). (B) RR of mRS (0–2). (C) RR of mRS (). (D) MD of mRS at 3 months. 【NIHSS】 There was no significant difference in the rates of improvement of the NIHSS of more than 4 points between the TNK and tPA groups (, OR = 1.27; 95% CI; 0.76–2.14, p = 0.36). Similarly, there was no significant difference in the mean NIHSS 24 h post-treatment in the TNK group when compared to the tPA group (, MD = −0.60; 95% CI; −1.20 – 0.01, p = 0.05). (A) OR of NIHSS of more than 4 points. (B) MD of mean NIHSS 24 h post-treatment. 【Duration of intervention】 There was no significant difference in the OTN time in the TNK group compared to the tPA group (, MD = −3.78; 95% CI; −8.71 – 1.14, p = 0.13), however, TNK had significantly faster DTN time compared to the tPA group (, MD = −4.20; 95% CI; −7.77 – 0.64, p = 0.02). (A) MD of mean onset-to-needle time. (B) MD of mean door-to-needle time. 【Secondary outcomes】 【Bleeding】 There was no significant difference in the rates of sICH in the TNK group compared to the tPA group (, OR = 0.99; 95% CI; 0.82–1.20, p = 0.94). This was also the case when parenchymal hemorrhage was considered (, OR = 0.95; 95% CI; 0.78–1.15, p = 0.59). (A) OR of sICH. (B) OR of parenchymal hemorrhage. 【Mortality rate】 The mortality rate was significantly less in the TNK group compared to the tPA group (, OR = 0.83; 95% CI; 0.73–0.94, p = 0.004). OR of mortality rate. 【Angioedema】 There was no significant difference in the incidence of angioedema in the TNK group compared to the tPA group (, OR = 1.25; 95% CI; 0.60–2.60, p = 0.55). OR of angioedema. 【Subgroup analysis】 The main outcomes that were eligible to be analyzed based on study design were; the rate of an mRS score (0–1), (0–2), mean mRS at 3 months, and the NIHSS after 24 h. Our analysis revealed that there was no heterogeneity between the studies following an RCTs for the mRS score (0–1), (0–2) (; respectively). No change of heterogeneity was noticed in the mean mRS at 3 months, and the NIHSS after 24 h (; respectively). Despite this, our analysis revealed that there was no significant difference between the subgroups for all four outcomes (p = 0.29, p = 0.79, p = 0.17, p = 0.61; respectively). Similarly, the outcomes that were eligible to be analyzed based on TNK dose were; the rate of an mRS score (0–2), and mean mRS at 3 months. The dose used for the subgroups were 0.25 mg/kg and 0.2 mg/kg. Our analysis revealed no significant difference between the subgroups for both outcomes (; p = 0.32, ; p = 0.99; respectively). Subgroup analysis was performed based on study design to clearly report the contribution of observational studies to the results. Eligible outcomes included: sICH, and mortality rates. No significant difference was found between the RCTs and cohort groups for sICH rates (; p = 0.10). However, for mortality rates, studies f