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Table of Contents    
META-ANALYSIS
Year : 2022  |  Volume : 70  |  Issue : 4  |  Page : 1454-1459

Short-Term Efficacy Outcomes of Tenecteplase versus Alteplase for Acute Ischemic Stroke: A Meta-Analysis of 5 Randomized Trials


1 Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil
2 Division of Neurosurgery, University of São Paulo, São Paulo, São Paulo, Brazil

Date of Submission17-Feb-2021
Date of Decision25-Oct-2021
Date of Acceptance25-Nov-2021
Date of Web Publication30-Aug-2022

Correspondence Address:
Leticia E Requiao
Bahiana School of Medicine and Public Health, Av. Dom João VI, 275, Brotas, Salvador, Bahia, 40290-000
Brazil
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.355108

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 » Abstract 


Tenecteplase (TNK) has been shown to be noninferior to Alteplase (ALT) for long term efficacy and safety outcomes. Whether this also applies to short term efficacy outcomes such as early clinical improvement and recanalization is unknown. To compare TNK and ALT regarding the short term efficacy outcomes: early neurological improvement and recanalization. The PRISMA was used to conduct a meta analysis, adapted to noninferiority analysis. The primary outcome was early (24–72 h) neurological improvement, defined as either NIHSS score 0 or reduction of at least 8 points compared to baseline. Recanalization was a secondary outcome. The noninferiority margin was set at 6.5%. Search strategy yielded 5 randomized clinical trials (1585 patients: 828 TNK, 757 ALT). Mean age was 70.8, 58.8% were men, mean baseline NIHSS was 7, and mean onset to treatment time was 148 min. Patients in intervention group received TNK at doses of 0.1 mg/kg (6.8%), 0.25 mg/kg (24.6%), and 0.4 mg/kg (68.6%), while all ALT patients received 0.9 mg/kg. In random effects meta analysis, TNK was noninferior to ALT for the primary outcome, early major neurological improvement (risk difference 8% in favor of TNK, 95% CI 1%–15%). Recanalization was also noninferior for the TNK compared to the ALT group (risk difference 9% in favor of TNK, 95% CI 6% to 23%). Fixed effects models yielded similarly noninferior results and signaled for a possible TNK superiority for both early neurological improvement and recanalization. TNK is noninferior to ALT at the short term efficacy outcomes: early neurological improvement and recanalization.


Keywords: Acute ischemic stroke, fibrinolytic agent, tenecteplase, therapy, tissue-type plasminogen activator
Key Message: The focus of this article was short-term efficacy outcomes as early major neurological improvement and recanalization. Those outcomes have significance as they are potent predictors of a favorable patient recovery.


How to cite this article:
Requiao LE, Oliveira RS, Reis LS, B Assis AP, G Moreno BN, Cordeiro LR, Solla DF. Short-Term Efficacy Outcomes of Tenecteplase versus Alteplase for Acute Ischemic Stroke: A Meta-Analysis of 5 Randomized Trials. Neurol India 2022;70:1454-9

How to cite this URL:
Requiao LE, Oliveira RS, Reis LS, B Assis AP, G Moreno BN, Cordeiro LR, Solla DF. Short-Term Efficacy Outcomes of Tenecteplase versus Alteplase for Acute Ischemic Stroke: A Meta-Analysis of 5 Randomized Trials. Neurol India [serial online] 2022 [cited 2022 Oct 7];70:1454-9. Available from: https://www.neurologyindia.com/text.asp?2022/70/4/1454/355108




Ischemic stroke is the leading cause of disability and the third cause of mortality after heart disease and cancer.[1] Thus, it is extremely important to predict the prognostic and outcome of this disease. Some studies show that a high level of biomarkers, as high-sensitivity C-reactive Protein (hsCRP), increases the risk of cerebrovascular events.[2] According to a randomized controlled trial (RCT), the hsCRP has an important role in this scenario, especially among recent lacunar stroke patients.[3] Thrombolytic treatment with Alteplase (ALT), recombinant tissue plasminogen activator (rt-PA), is the established standard therapeutic strategy within 4.5 h after symptoms onset for the management of ischemic stroke in the acute phase.[4] Besides that, up to 2/3 of patients with large artery occlusions may not achieve recanalization and less than half of the patients treated have complete reperfusion by 24 h.[5] The short half-life of ALT, requiring continuous infusion for approximately 1 h, and the risk of intracerebral hemorrhage are other disadvantages of the method.[6]

Thus, Tenecteplase (TNK), a genetically engineered mutant tissue plasminogen activator (tPA), emerges as an alternative therapy to minimize such effects. This fibrinolytic has been associated with a more rapid coronary reperfusion and significantly reduced the rate of major bleeds compared with ALT—the reason why TNK is already the preferred fibrinolytic agent in myocardial infarction.[5],[6],[7],[8],[9] In stroke treatment, TNK has shown several advantages as well, including less disruption of hemostasis, longer free plasma half-life, allowing single intravenous bolus administration, higher recanalization rates, and more resistance to plasminogen activator inhibitor (PAI), which allows faster clot lysis compared with ALT. Several studies demonstrated that TNK's efficacy and safety profile were similar to ALT's in acute ischemic stroke patients.[5],[6],[7],[8],[9],[10]

A recent meta-analysis[11] evaluated the noninferiority of TNK compared to ALT for the treatment of acute ischemic stroke. TNK was noninferior to ALT for the disability-free outcome [modified Rankin Scale (mRS) score, 0–1] at 3 months post-stroke and for functional independence.

The aim of this meta-analysis is to compare TNK and ALT regarding the short-term efficacy outcomes, early neurological improvement and vessel recanalization, which were not assessed by the previous systematic review. These outcomes are of special interest considering the contemporary discussions regarding the added benefit of thrombolysis before thrombectomy.


 » Methods Top


The authors declare that all supporting data are available within the article (in the online-only data supplement) and the cited published randomized trials.

Protocol and registration

The protocol for this meta-analysis was not previously registered.

Eligibility criteria

We included RCTs only. Studies with interventions other than thrombolytic treatment with ATL versus TNK were excluded. Studies were included if they met the following criteria: (1) randomized clinical trial; (2) patients enrolled with acute ischemic stroke who were eligible for thrombolysis; (3) allocation to TNK versus comparator ALT; and (4) treatment initiated up to 6 h after the onset of the index event. In three of five studies, patients received TNK at a dose of 0.25 mg per kilogram of body weight (maximum dose, 25 mg) or ALT at a dose of 0.9 mg per kilogram (maximum dose, 90 mg).[6],[9],[12] In one study, patients were given TNK 0.4 mg/kg (to a maximum of 40 mg) or ALT 0.9 mg/kg (to a maximum of 90 mg).[7] In another study, patients received TNK at doses of 0.1, 0.25, and 0.4 mg/kg or ALT at the standard dose 0.9 mg/kg.[13]

Types of outcome measures

We included trials if they reported any of our outcome measures.

Primary outcome

The primary outcome is early neurological improvement in 24–72 h measured by Nation Institutes of Health Stroke Scale (NIHSS) score. This outcome was evaluated at 24 h in all but one study, which evaluated the neurological improvement at 72 h. Neurological improvement was defined as either NIHSS score of 0 or a reduction of at least 8 points compared to baseline.

Secondary outcome

The secondary outcome is lesion recanalization in 24–48 h. Vessel recanalization was assessed in three out of five studies, all by computed tomography angiography (CTA).

Information sources and search

This meta-analysis was conducted in accordance to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.[14] We conducted our search on April 13, 2020, restricting the results to trials published in English and whose protocols were registered at ClinicalTrials.gov. We developed the MEDLINE search strategy including subject headings and free text terms relevant to acute ischemic stroke, TNK, and ALT. The descriptors “Alteplase,” “Tenecteplase,” “Acute Ischemic Stroke,” and the Boolean operator “and” were used, resulting in the following research formula: “((alteplase) AND tenecteplase) AND acute ischemic stroke).” The reference lists of selected articles were also checked.

Study selection

We screened all titles, abstracts, and keywords of publications identified by the search to assess their eligibility. We obtained full-texts of all possibly eligible manuscripts based on our inclusion criteria. We included a PRISMA flowchart of our study selection.

Data collection

Key data were extracted by one reviewer (L.R.) and checked by the second (L.C.). They resolved disagreements by discussion and, if necessary, by involving a third review author (R.S.).

Assessment of risk of bias in included studies

To assess the studies risk of bias, we used the Cochrane Risk of Bias Tool.

Data analysis, summary measures, and synthesis of results

The noninferiority margin was set at 6.5%, as per a recent major noninferiority design trial of different fibrinolytic regimens for acute ischemic stroke (AIS).[15] The noninferiority margins were set at the same values for the primary and secondary outcomes. Treatment effects were measured by the pooled risk difference (RD) with 95% confidence intervals (CI).

We processed data and performed quantitative analyses using Review Manager 5.4 (Review Manager (RevMan) [Computer program]. Version 5.4. The Cochrane Collaboration, 2020.). The primary analyses were performed with random-effects models, regardless of the statistical amount of heterogeneity, to take heterogeneous designs and participants into account. Fixed effects models are presented as sensitivity analyses because statistical heterogeneity was limited.


 » Results Top


Study selection

The search strategy yielded 74 results, of which we excluded 57 after reading titles and abstracts [Figure 1]. We retrieved the remaining 17 articles for detailed evaluation and among them, we identified 05 eligible RCT for inclusion.
Figure 1: Prisma Flowchart

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Study characteristics

Detailed characteristics of each trial are shown in [Table 1]. The 5 RCT enrolled a total of 1585 patients (828 TNK, 757 ALT). Across all trials, mean age was 70.8, 58.8% were men, mean baseline Nation Institutes of Health Stroke Scale (NIHSS) was 7, and mean onset to treatment time was 148 min. All ALT patients received the standard 0.9 mg/kg dosing, of which 10% was administered in bolus in the first minute and the remaining 90% over 60 min. Patients in the TNK group received a bolus administration at doses of 0.1 mg/kg in 6.8% of patients, 0.25 mg/kg in 24.6%, and 0.4 mg/kg in 68.6%.
Table 1: Study Characteristics

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Risk of bias within studies

The general risk of bias was intermediate to low in all studies. An overview is given in the “Risk of bias summary” [Figure 2], and the “Risk of bias graph”.
Figure 2: Risk of bias summary using the Cochrane Collaboration's tool

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Results of individual studies and Synthesis of results

The primary outcome of early major neurological improvement in 24–72 h, was available for all patients and trials. Each study's and the pooled results are depicted in [Figure 3]. In random-effects meta-analysis (panel A), TNK was noninferior to ALT, with a risk difference of 8% favoring TNK (95% CI 1%–15%) and a suggestion of superiority. The lower 95% CI bound met the noninferiority criteria. These findings were replicated by the fixed-effects model (panel B).
Figure 3: (a) Random-effects meta-analysis concerning the primary outcome. (b) Fixed-effects meta-analysis concerning the primary outcome

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The secondary outcome, recanalization, was available for 339 patients from 3 trials. Recanalization was also noninferior for the TNK compared to the ALT group (risk difference 9% favoring TNK, 95% CI -6% to 23%) because the lower 95% CI bound of -6% fell within the -6.5% margin [[Figure 4], random-effects model, panel A]. The fixed-effects model reinforced the noninferiority of TNK and suggested a possible superiority (risk difference 10% favoring TNK, 95% CI 1%–18%, panel B).
Figure 4: (a) Random-effects meta-analysis concerning the secondary outcome. (b) Fixed-effects meta-analysis concerning the secondary outcome

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 » Discussion Top


Until 2019, systematic reviews on TNK versus ALT included fewer trials.[10],[16],[17],[18] The Burgos and Saver meta-analysis published in 2019 was the first study to demonstrate with accumulated evidence from five previous clinical trials—the same examined here—the noninferiority of TNK. Their primary efficacy end point was disability-free outcome (mRS score, 0–1) at 3 months post-stroke, while the additional efficacy outcomes were functional independence (mRS, 0–2) at 3 months and reduced level of disability (mRS shift analysis) at 3 months.[11] Therefore, their research focused on long-term efficacy outcomes.

Hence, we present here the first meta-analysis to assess the short-term efficacy outcomes comparing TNK versus ALT. The demonstrated noninferiority reinforces the findings of the previous meta-analysis. Moreover, short-term outcomes are potent predictors of a favorable patient recovery.

TNK was noninferior compared to ALT concerning the first outcome of early major neurological improvement in 24–72 h. The risk difference point estimate significantly favored TNK, also suggesting a possible superiority.

Saposnik et al. clinical trial published in 2005 described major neurologic improvement at 24 h after administration of rt-PA in acute stroke as a powerful predictor of good outcome at 3 months.[19] Thus, early NIHSS score improvement after thrombolytic administration is an appropriate measurement to compare rt-PA's clinical potential with that of other thrombolytic drugs.

TNK was also noninferior for short-term recanalization. It is important to stress that recanalization is strongly associated with improved functional outcomes and reduced mortality, being an appropriate biomarker of therapeutic activity in early phase trials of thrombolytic treatment in acute ischemic stroke, as suggested by a previous meta-analysis.[20] The result of our meta-analysis reinforces the EXTEND-IA TNK trial finding regarding recanalization and reduces its uncertainty. Additionally, the DIRECT-MT trial[21] –a study comparing the safety and efficacy of administering intravenous ALT previously to endovascular thrombectomy versus proceeding with the endovascular thrombectomy alone—showed that thrombolysis before thrombectomy is associated with higher odds of successful reperfusion before angiography (7.0% vs. 2.4%) and overall successful reperfusion (84.5% vs. 79.4%).

TNK offers highly desirable feasibility advantages over ALT. TNK is viewed as way more practical, as it is administered as a one-time bolus dose, instead of as an hour-long infusion. As such, TNK has the potential to accelerate door-in to door-out times for patients in need of intravenous thrombolysis followed by endovascular thrombectomy. Potential disadvantages of TNK's all-at-once administration are the impossibility of infusion interruption after a partial dose if hemorrhage is suspected and longer serum half-life, which may delay hemostasis return.[11] Even so, these characteristics did not seem to significantly alter TNK's clinical outcome unfavorably in the trials we have assessed. The drug's benefits seem to outweigh the possible weaknesses of its administration's mechanism.

The fact that short-term recanalization was not available in all studies (only 3 out of 5) is a potential limitation of our study. Some of the trials' characteristics can also be potential limitations of our review. Almost seventy percent of the individuals received TNK at 0.4 mg/kg, while only 6.8% received TNK at 0.1 mg/kg. Thus, it was difficult to make an accurate dose-related interpretation. Furthermore, although the general demographic features, such as age and sex, were quite homogeneous, patients presenting severe NIHSS baseline scores were under-represented.

It should be noted that gender differences are in the distribution of stroke subtype, severity, and outcomes. It has been shown that lacunar stroke are more common in men and cardioembolic stroke, the most severe ischemic stroke subtype, are more common in women. In addition, women have higher in-hospital mortality, disabled, and are less likely to receive thrombolysis treatment than men. Thus, future studies are needed to analyze whether these fibrinolytic agents show gender differences in patients with acute ischemic stroke.[22]


 » Conclusion Top


TNK is noninferior to ALT at the short-term efficacy outcomes: early neurological improvement and recanalization.

Authorship

All authors have made substantial contributions to all of the following: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, and (3) final approval of the version to be submitted.

Non-standard abbreviations and acronyms

  • AIS: Acute ischemic stroke
  • ALT: Alteplase
  • CI: Confidence intervals
  • CTA: Computed tomography angiography
  • hsCRP: high-sensitivity C-reactive protein
  • mRS: Modified Rankin scale
  • NIHSS: National Institute of Health Stroke Scale
  • PAI: Plasminogen activator inhibitor
  • PRISMA: Preferred reporting items for systematic reviews and meta-analyses
  • RCT: Randomized clinical trial
  • RD: Risk difference
  • Rt-PA: Recombinant tissue plasminogen activator
  • tPA: Tissue plasminogen activator
  • TNK: Tenecteplase


Financial support and sponsorship

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Di Napoli M, Schwaninger M, Cappelli R, Ceccarelli E, Di Gianfilippo G, Donati C, et al. Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic stroke: A statement for health care professionals from the CRP pooling project members. Stroke 2005;36:1316-29.  Back to cited text no. 2
    
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Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med 2012;366:1099-107.  Back to cited text no. 6
    
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Coutts SB, Berge E, Campbell BCV, Muir KW, Parsons MW. Tenecteplase for the treatment of acute ischemic stroke: A review of completed and ongoing randomized controlled trials. Int J Stroke 2018;13:885-92.  Back to cited text no. 8
    
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Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med 2018;378:1573-82.  Back to cited text no. 9
    
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Burgos AM, Saver JL. Evidence that tenecteplase is noninferior to alteplase for acute ischemic stroke: Meta-analysis of 5 randomized trials. Stroke 2019;50:2156-62.  Back to cited text no. 11
    
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Huang X, Cheripelli BK, Lloyd SM, Kalladka D, Moreton FC, Siddiqui A, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): A phase 2, randomised, open-label, blinded endpoint study. Lancet Neurol 2015;14:368-76.  Back to cited text no. 12
    
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Haley EC, Thompson JLP, Grotta JC, Lyden PD, Hemmen TG, Brown DL, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke results of a prematurely terminated randomized clinical trial. Stroke 2010;41:707-11.  Back to cited text no. 13
    
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Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ 2009;339:b2700.  Back to cited text no. 14
    
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Anderson CS, Robinson T, Lindley RI, Arima H, Lavados PM, Lee T, et al. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. N Engl J Med 2016;374:2313-23.  Back to cited text no. 15
    
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Huang X, MacIsaac R, Thompson JLP, Levin B, Buchsbaum R, Haley EC, et al. Tenecteplase versus alteplase in stroke thrombolysis: An individual patient data meta-analysis of randomized controlled trials. Int J Stroke 2016;11:534-43.  Back to cited text no. 17
    
18.
Xu N, Chen Z, Zhao C, Xue T, Wu X, Sun X, et al. Different doses of tenecteplase vs alteplase in thrombolysis therapy of acute ischemic stroke: Evidence from randomized controlled trials. Drug Des Devel Ther 2018;12:2071-84.  Back to cited text no. 18
    
19.
Saposnik G, Di Legge S, Webster F, Hachinski V. Predictors of major neurologic improvement after thrombolysis in acute stroke. Neurology 2005;25;65:1169-74.  Back to cited text no. 19
    
20.
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21.
Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, et al. Endovascular thrombectomy with or without intravenous alteplase in acute stroke. N Engl J Med 2020;382:1981-93.  Back to cited text no. 21
    
22.
Arboix A, Cartanyà A, Lowak M, García-Eroles L, Parra O, Oliveres M, et al. Gender differences and woman-specific trends in acute stroke: Results from a hospital-based registry (1986-2009). Clin Neurol Neurosurg 2014;127:19-24.  Back to cited text no. 22
    


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