nach oben

The Egyptian Journal of Neurology, Psychiatry and Neurosurgery

Erschienen in:

Open Access 01.12.2023 | Review

The efficacy and safety of tenecteplase compared with alteplase in adult patients with acute ischemic stroke: an updated systematic review and meta-analysis of ten randomized controlled trials

verfasst von: Karthikeyan Chinniah, Nizamudeen Shadakkathulla

Erschienen in: The Egyptian Journal of Neurology, Psychiatry and Neurosurgery | Ausgabe 1/2023

Abstract

Background

Alteplase (tPA) is the only thrombolytic agent approved by the USFDA for acute ischemic stroke (AIS). Various randomized controlled trials (RCTs) have reported that Tenecteplase (TNK) is non-inferior to tPA resulting in its approval in various countries. We compared the efficacy and safety of TNK with tPA in adult patients with AIS by performing an updated systematic review and meta-analysis of recently published RCTs. Thus, PubMed and Cochrane databases were searched for RCTs until April 27, 2023. Data is represented as log-odds ratio (logOR) with 95% confidence interval (CI). The efficacy outcome measures included early neurological improvement (ENI), recanalization, functional outcomes at 90-days (modified Rankin Scale (mRS) 0–1 and 0–2), any intracranial hemorrhage (ICH), symptomatic ICH, and mortality within 90-days.

Results

Ten RCTs involving 5105 adult patients with AIS were included. The rates of ENI (logOR: 0.11; 95%CI: − 0.02, 0.23; p-value: 0.09), recanalization (logOR: 0.33; 95%CI: − 0.02, 0.68; p-value: 0.07), mRS 0–1 at 90-days (logOR: 0.09; 95%CI: − 0.02, 0.21; p-value: 0.11), and mRS 0–2 at 90-days (logOR: 0.07; 95%CI: − 0.29, 0.44; p-value: 0.70) were comparable among TNK and tPA. Similarly, TNK and tPA were comparable regarding any ICH (logOR: 0.06; 95%CI: − 0.11, 0.24; p-value: 0.47), symptomatic ICH (logOR: − 0.14; 95%CI: − 0.47, 0.20; p-value: 0.42), and all-cause mortality (logOR: − 0.04; 95%CI: − 0.23, 0.15; p-value: 0.70).

Conclusions

Based on the included RCTs, TNK is comparable to tPA regarding efficacy and safety. Thus, TNK can be recommended as an alternative to tPA in adult patients with AIS.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Adverse event

AIS

Acute ischemic stroke

Confidence interval

ENI

Early neurological improvement

ICH

Intracranial hemorrhage

LogOR

Log-odds ratio

Meta-analysis

mRS

Modified Rankin Scale

NIHSS

National Institutes of Health Stroke Scale

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-analyses

RCT

Randomized controlled trial

ROB

Risk of bias

SICH

Symptomatic intracranial hemorrhage

TNK

Tenecteplase

tPA

Alteplase

Introduction

With around 6.5 million annual deaths, stroke is the second leading cause of death globally [1]. In 2019, acute ischemic stroke (AIS), the most common stroke type, resulted in 3.29 million deaths, and this is projected to rise to 4.90 million by 2030 [2]. In patients with AIS, thrombolysis is preferred [3], and Alteplase (tPA) is the drug of choice [4]. For more than two decades, tPA remains the only thrombolytic agent approved by the USFDA for AIS.

Though tPA produces rapid symptomatic improvement, when administered within the 4.5-h window period, and reduces the disability by 28% at 90-days [5], its utility is limited by the narrow time window, and adverse events (AEs) [6]. Alteplase is reported to have limited fibrinolytic activity, as less than 50% patients achieve recanalization [7]; and among these patients, only 50% recanalize within 2-h of tPA use [8]. Additionally, tPA is linked to the adverse effects involving the ischemic brain, including cytotoxicity and raised blood brain barrier permeability leading to cerebral edema [9].

Following the completion of ASSENT 2 Trial in 2000, Tenecteplase (TNK), a variant of tPA, was approved by the USFDA for thrombolysis in patients with acute myocardial infarction [10]. Tenecteplase was developed to overcome the limitations of tPA, and is associated with various advantages, including economical, longer plasma half-life, high fibrin specificity, improved plasminogen activator inhibitor-1 resistance, and can be administered as a single bolus against the requirement of an infusion pump for the administration of tPA, thereby making it useful in the pre-hospital set-up [11].

Though various randomized controlled trials (RCTs) have reported non-inferiority of TNK against tPA, regarding efficacy and safety, TNK remains to be approved in US for the treatment of AIS, while it is approved in other countries [12]. A recent meta-analysis (MA) concluded that TNK has better pharmacokinetic profile, higher rates of recanalization, as well as early neurological improvement (ENI), and thus can be used as an alternative to tPA [13]. However, this MA included studies of various design, in addition to RCTs, thus introducing heterogeneity in the findings. While another recent MA demonstrated no significant difference between TNK and tPA, regarding functional outcome at 90-days and safety outcomes, including mortality and symptomatic intracerebral hemorrhage (SICH) [14]. Various recently published RCTs with large sample size have reported favorable outcome with TNK relative to tPA [11, 15‐19]. Thus, in light of recently available evidences, we performed an updated MA with an aim to compare TNK with tPA in adult patients with AIS.

Materials and methods

Protocol registration

The present MAs adhere to the 2020 guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [20]. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; Registration number: CRD42023437364).

Data sources and search strategy

We performed a literature search in PubMed and Cochrane databases to identify all free full text RCTs evaluating the efficacy and safety of intravenous thrombolysis with TNK and tPA for the treatment of AIS. The search period ranged from database inception to the April 27, 2023, and the literature was limited to English language. The keywords used included: “acute ischemic stroke,” “acute cerebral infarction,” “cerebrovascular accident,” “brain vascular accident,” “tenecteplase,” “recombinant human TNK tissue-type plasminogen activator,” “alteplase,” and “tissue plasminogen activator.”

Eligibility criteria

This MA included RCTs fulfilling the following PICO criteria: population (P): adult patients with AIS and undergoing thrombolysis; intervention (I): intravenous TNK irrespective of the dose. Additionally, studies evaluating intraarterial TNK were excluded; control (C): tPA. Studies with no tPA as control group were excluded; outcomes (O): efficacy outcomes included early neurological improvement (ENI) based on ≥ 8 points reduction in the National Institutes of Health Stroke Scale (NIHSS), excellent neurological recovery based on modified Rankin Scale (mRS) 0–1, good neurological recovery based on mRS 0–2, and successful recanalization based on modified treatment in cerebral ischemia classification or Thrombolysis in Cerebral Infarction. Additionally, safety outcomes included any ICH, SICH, and all-cause mortality.

The articles in which patients did not have AIS, did not receive TNK and tPA, duplicate studies including the same patients presented in other included paper, non-randomized trials, single-arm trials, observational studies, review articles, case reports, case series, letters to editor, conference abstracts, and posters were excluded. This MA included only the free full text RCTs, while paid RCTs and original studies with other study designs were excluded.

Selection process

For data extraction separately, two authors (KC and NS) performed the title and abstract screening against the above-mentioned eligibility criteria. This was followed by a full text screening of any retained studies of the first screening step. In both the stages, any disagreement was resolved by discussion to reach a consensus. The references of previously published meta-analyses, review articles, and original articles were screened manually. Additionally, the manual search involved screening through the references of the included articles to retrieve any missed papers.

Data extraction

Following the study selection, data was extracted, by two authors (KC and NS), with the help of a preformed data extraction excel sheet. The extracted data included study characteristics (first author name, year of publication, country, study design, sample size in each group, intervention dosages, main eligibility criteria, and time window); baseline information (age, sex, number of patients in each group, onset to infusion time, NIHSS score, time from onset to thrombolysis, and relevant stroke risk factors); and efficacy as well as safety outcomes data mentioned above.

Risk of bias

Two authors evaluated all the studies for the risk of bias (ROB) by utilizing the “Cochrane RoB 2: a revised tool for assessing the risk of bias in RCTs” [21]. Any discrepancies arising during the entire process were handled through discussion.

Statistical analyses

With the help of STATA 10, a pairwise meta-analysis was performed to compare TNK (any dose) with tPA. From the included studies, dichotomous outcomes were used to generate log odds (logOR) with 95% confidence intervals (CIs). A meta-analysis was performed for each of the outcomes of interest. Heterogeneity was assessed with the I² statistic. If the I² statistic was > 50%, heterogeneity was considered significant and thus, the random effect model was used. Else, the fixed effect (Mantel–Haenszel) model was used. The pooled logORs were considered heterogenous if I² was > 50% and/or p-value < 0.05, based on Q-statistics. The publication bias was evaluated with the funnel plots. Statistical significance was considered at p < 0.05.

Data availability

The data supporting the findings of the present MA are available from the corresponding author on reasonable request.

Results

Search results and study selection

Using the PubMed and Cochrane databases, we found 544 articles. On screening, 175 and 249 articles were found to be duplicate and irrelevant, respectively. While, 120 full-text articles were thoroughly screened, resulting in inclusion of ten RCTs (Fig. 1) [11, 15‐18, 22‐26].

Characteristics of included studies

Based on the eligibility criteria, eight RCTs with a total patient population of 5105 were included [11, 15‐18, 22‐26], involving 2651 patients in the intervention group (TNK), and 2454 in the control group (tPA). Of ten RCTs, eight were multicentric [15, 18, 22, 23, 25, 26], while remaining two were single-centric [11, 24]. In two RCT, the time window within 3-h [15, 23], 4.5-h in seven RCTs [11, 18, 24‐26], and 6-h in one trial [22]. The summary and baseline characteristics of the included studies are depicted in Tables 1 and 2, respectively.

Table 1

Summary of the included studies

Study ID	Country	Study design	Sample size, TNK versus tPA	TNK Dosage	tPA dosage	Time window, h	Key inclusion criteria	Key exclusion criteria
Haley et al. 2010	United States	Phase 2B/3, multicenter, double-blinded, prematurely terminated RCT	50 versus 31	0.1 mg/kg, 0.25 mg/kg, 0.4 mg/kg	0.9 mg/kg	< 3	NIHSS > 0; If NIHSS = 1, requires significant deficit	Stroke in last 3 months; Major symptoms which are rapidly improving by the time of treatment
Parsons et al. 2012	Australia	Phase 2B, multicenter, PROBE	50 versus 25	0.25 mg/kg	0.9 mg/kg	< 6	NIHSS > 4; Occlusion of MCA/ACA/PCA; Perfusion volume > 120% core, and at least 20 ml; Core volume < 1/3 of MCA or 1/2 ACA/PCA territory	Premorbid mRS score ≥ 3; eGFR < 15 ml/min; Evidence of acute brainstem ischemia
Huang et al. 2015	Scotland	Phase 2, single center, PROBE	47 versus 49	0.25 mg/kg	0.9 mg/kg	< 4.5	Age 18 years or older; NIHSS > 0; Seizure at stroke onset	Premorbid mRS score ≥ 3; eGFR < 30 ml/min
Logallo et al. 2017	Norway	Phase 3, multicenter, PROBE	549 versus 551	0.4 mg/kg	0.9 mg/kg	< 4.5	Age 18 years or older; NIHSS > 0	Seizure at stroke onset and no visible occlusion on baseline CT; Clinical stroke < 2 months
Campbell et al. 2018	Australia and New Zealand	Phase 2, multicenter, PROBE	101 versus 101	0.25 mg/kg	0.9 mg/kg	< 4.5	Age 18 years or older; NIHSS > 0; Occlusion of ICA/MCA/BA	Premorbid mRS score ≥ 3
Menon et al. 2022	Canada	Phase 3, multicenter, PROBE	806 versus 771	0.25 mg/kg	0.9 mg/kg	< 4.5	Age 18 years or older; Eligible for endovascular thrombectomy	None
Kvistad et al. 2022	Norway	Phase 3, multicenter, PROBE	100 versus 104	0.4 mg/kg	0.9 mg/kg	< 4.5	Age 18 years or older; NIHSS ≥ 6	Premorbid mRS score ≥ 3
Li et al. 2022	China	Phase 2, multicenter, PROBE	177 versus 59	0.1 mg/kg, 0.25 mg/kg, 0.32 mg/kg	0.9 mg/kg	< 3	Age 18 years or older; NIHSS 4–25	Premorbid mRS score ≥ 3
Bivard et al. 2022	Australia	Phase 2, single center, PROBE	55 versus 49	0.25 mg/kg	0.9 mg/kg	< 4.5	Age 18 years or older	Premorbid mRS score > 3
Wang et al. 2023	China	Phase 3, multicenter, PROBE	716 versus 714	0.25 mg/kg	0.9 mg/kg	< 4.5	Age 18 years or older; NIHSS 5–25	Premorbid mRS score > 1

ACA Anterior cerebral artery, BA Basilar artery, CI Confidence interval, CT Computed tomography, eGFR estimated glomerular filtration rate, ICA Internal carotid, MCA Middle cerebral artery, mRS modified Rankin Scale, NIHSS National Institutes of Health Stroke Scale, PCA Posterior cerebral artery, PROBE Prospective randomized open blinded end-point, RCT Randomized controlled trial, TNK Tenecteplase, tPA Alteplase

Table 2

Baseline characteristics of the included studies

Study ID	Sample size, n		Age (years), mean ± SD/median (IQR)		Male, n (%)		Baseline NIHSS, mean ± SD/median (IQR)		Onset to treatment time, min, mean ± SD/median (IQR)
Study ID	TNK	tPA	TNK	tPA	TNK	tPA	TNK	tPA	TNK	tPA
Haley et al. 2010	TNK 0.1: 31	31	TNK 0.1: 67 ± 19	72 ± 16	TNK 0.1: 12 (39%)	17 (51%)	TNK 0.1: 8 (5–11)	13 (5–17)	NA	NA
	TNK 0.25: 31		TNK 0.25: 69 ± 15		TNK 0.25: 16 (52%)		TNK 0.25: 10 (6–15)
	TNK 0.4: 19		TNK 0.4: 68 ± 16		TNK 0.4: 13 (68%)		TNK 0.4: 9 (5–17)
Parsons et al. 2012	TNK 0.1: 25	25	TNK 0.1: 72 ± 6.9	70 ± 8.4	TNK 0.1: 13 (52%)	12 (48%)	TNK 0.1: 14.5 ± 2.3	14 ± 2.3	TNK 0.1: 3.1 ± 0.9 h	2.7 ± 0.8 h
Parsons et al. 2012	TNK 0.25: 25	25	TNK 0.25: 68 ± 9.4	70 ± 8.4	TNK 0.25: 13 (52%)	12 (48%)	TNK 0.25: 14.6 ± 2.3	14 ± 2.3	TNK 0.25: 3.0 ± 0.7 h	2.7 ± 0.8 h
Huang et al. 2015	47	49	71 ± 13	71 ± 12	30 (64%)	31 (63%)	12 (9–18)	11 (8–16)	184 ± 44	192 ± 45
Logallo et al. 2017	549	551	70.8 ± 14.4	71.2 ± 13.2	321 (58%)	339 (62%)	5.6 ± 5.4	5.8 ± 5.2	118 (79–180)	111 (80–174)
Campbell et al. 2018	101	101	70.4 ± 15.1	71.9 ± 13.7	58 (57%)	52 (51%)	17 (12–22)	17 (12–22)	125 (102–156)	134 (104–176)
Menon et al. 2022	806	771	73.33 ± 14.85	72.67 ± 15.6	424 (52.6%)	398 (51.6%)	10.33 ± 7.43	11 ± 8.14	135 ± 69.05	138 ± 69.1
Kvistad et al. 2022	100	104	73.2 ± 12.6	68.6 ± 15.6	45 (45%)	53 (51%)	13.4 ± 6.6	13.2 ± 6.4	103.16 ± 51.90	105 ± 52.62
Li et al. 2022	TNK 0.1: 60	59	TNK 0.1: 62.4 ± 11.1	66.5 ± 12.6	TNK 0.1: 48 (80%)	38 (64.41%)	TNK 0.1: 7.0 (5.0–10.0)	8.0 (5.0–12.0)	TNK 0.1: 154 (56–195)	153 (18–187)
	TNK 0.25: 57		TNK 0.25: 64.3 ± 12.8		TNK 0.25: 42 (73.68%)		TNK 0.25: 8.0 (5.0–12.0)		TNK 0.25: 149 (80–179)
	TNK 0.32: 60		TNK 0.32: 64.8 ± 12.1		TNK 0.32: 42 (70%)		TNK 0.32: 7.5 (6.0–12.0)		TNK 0.32: 147 (69–220)
Bivard et al. 2022	55	49	76 (60–84)	73 (61–80)	33 (60%)	30 (61%)	8 (5–14)	8 (5–17)	97 (68–157)	92 (66–31)
Wang et al. 2023	710	707	67 (58–73)	65 (58–72)	492 (69%)	479 (68%)	7 (5–10)	7 (6–10)	180 (135–222)	178.5 (135–230)

Study ID	Hypertension, n (%)		Diabetes mellitus, n (%)		Hyperlipidemia, n (%)		Atrial fibrillation, n (%)		Previous stroke/TIA, n (%)		Active smoker, n (%)		Premorbid mRS ≥ 3, n (%)
Study ID	TNK	tPA	TNK	tPA	TNK	tPA	TNK	tPA	TNK	tPA	TNK	tPA	TNK	tPA
Haley et al. 2010	TNK 0.1: 25 (81%)	22 (71%)	TNK 0.1: 6 (19%)	4 (13%)	TNK 0.1: 16 (52%)	17 (55%)	NA	NA	TNK 0.1: 6 (19%)	4 (13%)	TNK 0.1: 2 (6.5%)	7 (23%)	NA	NA
	TNK 0.25: 25 (81%)		TNK 0.25: 7 (23%)		TNK 0.25: 15 (48%)				TNK 0.25: 10 (32%)		TNK 0.25: 7 (23%)
	TNK 0.4: 17 (90%)		TNK 0.4: 4 (21%)		TNK 0.4: 8 (42%)				TNK 0.4: 5 (26%)		TNK 0.4: 0 (0%)
Parsons et al. 2012	TNK 0.1: 16 (64%)	15 (60%)	TNK 0.1: 8 (32%)	1 (4%)	TNK 0.1: 13 (52%)	9 (36%)	TNK 0.1: 9 (36%)	6 (24%)	NA	NA	TNK 0.1: 9 (36%)	1 (4%)	NA	NA
Parsons et al. 2012	TNK 0.25: 16 (64%)	15 (60%)	TNK 0.25: 6 (24%)	1 (4%)	TNK 0.25: 15 (60%)	9 (36%)	TNK 0.25: 13 (52%)	6 (24%)	NA	NA	TNK 0.25: 5 (20%)	1 (4%)	NA	NA
Huang et al. 2015	20 (43%)	28 (57%)	7 (15%)	7 (14%)	4 (9%)	7 (14%)	19 (40%)	15 (31%)	12 (26%)	11 (22%)	13 (28%)	10 (20%)	NA	NA
Logallo et al. 2017	246 (45%)	236 (43%)	72 (13%)	74 (13%)	61 (11%)	65 (12%)	50 (9%)	69 (13%)	119 (22%)	120 (22%)	169 (31%)	177 (32%)	27 (5%)	35 (6%)
Campbell et al. 2018	64 (63%)	63 (62%)	10 (10%)	18 (18%)	NA	NA	27 (27%)	40 (40%)	NA	NA	18 (18%)	11 (11%)	7 (7%)	12 (12%)
Menon et al. 2022	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Kvistad et al. 2022	56 (56%)	48 (46%)	17 (17%)	11 (11%)	30 (30%)	33 (32%)	9 (9%)	8 (8%)	NA	NA	24 (24%)	25 (24%)	NA	NA
Li et al. 2022	TNK 0.1: 43 (71.7)	42 (71.2)	TNK 0.1: 14 (23.3)	11 (18.6)	TNK 0.1: 17 (28.3)	11 (18.6)	TNK 0.1: 8 (13.3)	6 (10.2)	NA	NA	TNK 0.1: 25 (41.7)	24 (40.7)	0	0
	TNK 0.25: 37 (64.9)		TNK 0.25: 9 (15.8)		TNK 0.25: 13 (22.8)		TNK 0.25: 4 (7.0)				TNK 0.25: 25 (43.9)
	TNK 0.32: 35 (58.3)		TNK 0.32: 15 (25.0)		TNK 0.32: 10 (16.7)		TNK 0.32: 14 (23.3)				TNK 0.32: 21 (35.0)
Bivard et al. 2022	30 (55%)	31 (63%)	11 (30%)	17 (35%)	21 (38%)	22 (45%)	8 (15%)	7 (15%)	12 (21.82%)	13 (26.53%)	8 (15%)	9 (18%)	3 (5%)	6 (12%)
Wang et al. 2023	510 (72%)	512 (72%)	172 (24%)	207 (29%)	130 (18%)	160 (23%)	137 (19%)	146 (21%)	NA	NA	266 (38%)	276 (39%)	0	0

IQR Interquartile range, NIHSS National Institutes of Health Stroke Scale, SD Standard deviation, TIA Transient ischemic attack, TNK Tenecteplase, tPA Alteplase

Efficacy outcomes

Figure 2 illustrates the pairwise MA of all the efficacy outcome measures assessed between TNK and tPA. The rates of ENI (logOR: 0.11; 95%CI: − 0.02, 0.23; p-value: 0.09), recanalization (logOR: 0.33; 95%CI: − 0.02, 0.68; p-value: 0.07), mRS 0–1 at 90-days (logOR: 0.09; 95%CI: − 0.02, 0.21; p-value: 0.11), and mRS 0–2 at 90-days (logOR: 0.07; 95%CI: − 0.29, 0.44; p-value: 0.70) were comparable among TNK and tPA. There was no significant heterogeneity among the included studies regarding rates of ENI (I²: 46.20%; p-value: 0.06), recanalization (I²: 42.45%; p-value: 0.14), and mRS 0–1 (I²: 24.98%; p-value: 0.21), except mRS 0–2 (I²: 85.08%; p-value: 0.0001).

Safety outcomes

Figure 3 illustrates the pairwise MA of all the safety outcome measures assessed between TNK and tPA. Any ICH (logOR: 0.06; 95%CI: − 0.11, 0.24; p-value: 0.47), SICH (logOR: − 0.14; 95%CI: − 0.47, 0.20; p-value: 0.42), and all-cause mortality (logOR: − 0.04; 95%CI: − 0.23, 0.15; p-value: 0.70) were comparable among TNK and tPA. There was no significant heterogeneity among the included studies regarding rates of any ICH (I²: 49.02%; p-value: 0.05), SICH 0–1 (I²: 0.00%; p-value: 0.81), and all-cause mortality (I²: 31.07%; p-value: 0.16).

Risk of bias

Figure 4 illustrates the ROB assessed with the Cochrane ROB 2 tool. Overall, all the included RCTs had a low ROB. Additionally, all the RCTs had low ROB, when assessed with individual domains, including randomization process, deviation from the intended intervention, missing outcome data, measurement of the outcome, and selection of the reported result.

Publication bias

With the help of funnel plot, we assessed the publication bias. If the funnel plot had symmetric distribution, there was absence of publication bias. While, the presence of asymmetric distribution suggested publication bias. As illustrated in Fig. 5A, B, funnel plots for each outcome measure had standard symmetric distribution, thereby suggesting no publication bias in the included RCTs.

Discussion

The principal findings of the present pair-wise MA suggest that TNK and tPA were comparable regarding efficacy measures, including rates of ENI, recanalization, excellent functional outcome at 90-days, and good functional outcome at 90-days. Moreover, TNK and tPA were comparable regarding safety measures, including rates of any ICH, SICH, and all-cause mortality. Thus, the present MA, involving the data of 5105 adult patients with AIS, demonstrates non-inferiority of TNK over tPA.

The quality of evidence is high, as the included RCTs have a low ROB, the included patients as well as the study outcomes are clinically relevant, and the degree of heterogeneity is not significant (I² range: 0–49.02%), except mRS 0–2 (I²: 85.08%; p-value: 0.0001). Apart from quality of evidence and comparable outcome measures, TNK is economical and associated with ease of administration relative to tPA. Based on these merits, it is sufficient to recommend TNK over tPA in adult patients with AIS presenting within 4.5-h of onset.

Comparable efficacy and safety outcome measures among TNK and tPA, observed in the present MA, is consistent with the findings of recently published MA [14, 27]. Various RCTs have reported similar findings [15, 17, 18, 23‐25]. Parsons et al. reported that TNK resulted in significantly greater reperfusion and clinical improvement at 24-h relative to tPA. Tenecteplase (0.25 mg/kg) was superior to tPA for all efficacy outcomes, including absence of serious disability at 90-days [22]. Campbell et al. observed that TNK (0.25 mg/kg) led to significantly greater reperfusion and functional outcome at 90-days [26]. Bivard et al. evaluated the utility of TNK (0.25 mg/kg) in mobile stroke units and found that patients who received TNK had significantly smaller perfusion lesion volume and greater reduction in NIHSS at hospital arrival [11]. However, Kvistad et al. found that TNK led to significantly lower functional outcomes, higher rates of any ICH, and higher 90-days mortality [16]. This adverse outcome was ascribed to higher dose of TNK (0.4 mg/kg).

Better outcomes observed with TNK are attributed to its favorable pharmacokinetic properties, including a long duration of action, greater fibrin specificity, and more potent clot dissolution, resulting in faster vessel recanalization [28]. Moreover, the ability to administer TNK as a rapid, single bolus infusion permits give-and-go strategy, thereby reducing the administration time to around a minute. This results in reduced door-in to door-out time. This is of particular importance in remote settings with inadequate resources that lack access to thrombectomy centers, and rely on ambulances for transporting the patients to specialized stroke centers. This is contrary to tPA that requires multiple boluses and around 1-h for infusion [29].

A recently published randomized, controlled, non-inferiority trial comparing TNK with tPA in patients with AIS was not included in the present MA, as full-text of the article could not be retrieved. The ongoing phase 2 and 3 clinical trials comparing TNK with tPA in adult patients with AIS are: NCT03854500 (The Norwegian tenecteplase stroke trial 2 (NOR-TEST 2, Phase 3) [30], NCT05281549 (Thrombolysis treated with TNK-tPA in acute ischemic stroke patients (3T Stroke-II, Phase 2)) [31], NCT05745259 (Thrombolysis treated with TNK-tPA in acute ischemic stroke patients (3T Stroke-III, Phase 3)) [32], and NCT05626972 (Tenecteplase compared to alteplase for patients with large vessel occlusion suspicion before thrombectomy, Phase 3) [33]. Moreover, another phase 3 clinical trial, NCT04915729, is evaluating TNK and tPA for improvement in recovery of post-stroke physical activity [34]. Although the available evidence is sufficient to make a recommendation in favor of TNK relative to tPA in AIS, the results of ongoing studies are likely to add strength to the justification.

With inclusion of recently published RCT [18], the present MA provides the latest evidence for thrombolysis in adult patients with AIS. However, this MA has certain limitations, including: first, all the included RCTs, except one [23], had open-label and blinded outcome design, thereby introducing the performance bias. Second, the included RCTs differed in eligibility criteria, and methodology. Third, full-text of recently published RCT, Ferguson and Yadav [19], could not be retrieved. Forth, we did not compare the effect of various doses of TNK relative to tPA.

Conclusion

In the present MA, involving ten RCTs, we observed that TNK and tPA had comparable efficacy and safety. Based on the ease of administration and favorable pharmacokinetic profile, the present MA supports the use of TNK, as a reasonable alternative to tPA, for the treatment of adult patients with AIS.

Acknowledgements

Authors would like to thank acknowledge Science Plus and Dr. Vikas S. Sharma (MD), Principal Consultant, Maverick Medicorum^® (India), for statistical analyses and medical writing services.

Declarations

Not applicable.

Competing interests

The authors declare that they do not have any competing interests.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Feigin VL, Brainin M, Norrving B, Martins S, Sacco RL, Hacke W, et al. World Stroke Organization (WSO): global stroke fact sheet 2022. Int J Stroke. 2022;17(1):18–29. https://doi.org/10.1177/17474930211065917.CrossRefPubMed

Fan J, Li X, Yu X, Liu Z, Jiang Y, Fang Y, et al. Global burden, risk factors analysis, and prediction study of ischemic stroke, 1990–2030. Neurology. 2023. https://doi.org/10.1212/WNL.0000000000207387.CrossRefPubMedPubMedCentral

Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: a Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344–418. https://doi.org/10.1161/STR.0000000000000211.CrossRefPubMed

Ahmed N, Audebert H, Turc G, Cordonnier C, Christensen H, Sacco S, et al. Consensus statements and recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 11–13 November 2018. Eur Stroke J. 2019;4(4):307–17. https://doi.org/10.1177/2396987319863606.CrossRefPubMedPubMedCentral

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke (NINDS Study). N Engl J Med. 1995;333(24):1581–1587. https://doi.org/10.1056/NEJM199512143332401.

Miller DJ, Simpson JR, Silver B, Silver B. Safety of thrombolysis in acute ischemic stroke: a review of complications, risk factors, and newer technologies. Neurohospitalist. 2011;1:138–47. https://doi.org/10.1177/1941875211408731.CrossRefPubMedPubMedCentral

Bhatia R, Hill MD, Shobha N, Menon B, Bal S, Kochar P, et al. Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action. Stroke. 2010;41(10):2254–8. https://doi.org/10.1161/STROKEAHA.110.592535.CrossRefPubMed

Yeo LLL, Paliwal P, Teoh HL, Seet RC, Chan BP, Liang S, et al. Timing of recanalization after intravenous thrombolysis and functional outcomes after acute ischemic stroke. JAMA Neurol. 2013;70(3):353–8. https://doi.org/10.1001/2013.jamaneurol.547.CrossRefPubMed

Yepes M, Roussel BD, Ali C, Vivien D. Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends Neurosci. 2009;32(1):48–55. https://doi.org/10.1016/j.tins.2008.09.006.CrossRefPubMed

10.

Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators, Van De Werf F, Adgey J, Ardissino D, Armstrong PW, Aylward P, Barbash G, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999;354(9180):716–22. https://doi.org/10.1016/s0140-6736(99)07403-6.CrossRef

11.

Bivard A, Zhao H, Churilov L, Campbell BCV, Coote S, Yassi N, TASTE-A collaborators, et al. Comparison of tenecteplase with alteplase for the early treatment of ischaemic stroke in the Melbourne Mobile Stroke Unit (TASTE-A): a phase 2, randomised, open-label trial. Lancet Neurol. 2022;21(6):520–7. https://doi.org/10.1016/S1474-4422(22)00171-5.CrossRefPubMed

12.

Heran M, Lindsay P, Gubitz G, Yu A, Ganesh A, Lund R, et al. Canadian stroke best practice recommendations: acute stroke management, 7th edition practice guidelines update, 2022. Canad J Neurol Sci. 2022;19:1–94. https://doi.org/10.1017/cjn.2022.344.CrossRef

13.

Oliveira M, Fidalgo M, Fontão L, Antão J, Marques S, Afreixo V, et al. Tenecteplase for thrombolysis in stroke patients: systematic review with meta-analysis. Am J Emerg Med. 2021;42:31–7. https://doi.org/10.1016/j.ajem.2020.12.026.CrossRefPubMed

14.

Kobeissi H, Ghozy S, Turfe B, Bilgin C, Kadirvel R, Kallmes DF, et al. Tenecteplase vs. alteplase for treatment of acute ischemic stroke: a systematic review and meta-analysis of randomized trials. Front Neurol. 2023;14:1102463. https://doi.org/10.3389/fneur.2023.1102463.CrossRefPubMedPubMedCentral

15.

Li S, Pan Y, Wang Z, Liang Z, Chen H, Wang D, et al. Safety and efficacy of tenecteplase versus alteplase in patients with acute ischaemic stroke (TRACE): a multicentre, randomised, open label, blinded-endpoint (PROBE) controlled phase II study. Stroke Vasc Neurol. 2022;7(1): e000978. https://doi.org/10.1136/svn-2021-000978.CrossRef

16.

Kvistad CE, Næss H, Helleberg BH, Idicula T, Hagberg G, Nordby LM, et al. Tenecteplase versus alteplase for the management of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non-inferiority trial. Lancet Neurol. 2022;21(6):511–9. https://doi.org/10.1016/S1474-4422(22)00124-7.CrossRefPubMed

17.

Menon BK, Buck BH, Singh N, Deschaintre Y, Almekhlafi MA, Coutts SB, AcT Trial Investigators, et al. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial. Lancet. 2022;400(10347):161–9. https://doi.org/10.1016/S0140-6736(22)01054-6.CrossRefPubMed

18.

Wang Y, Li S, Pan Y, Li H, Parsons MW, Campbell BCV, TRACE-2 Investigators, et al. Tenecteplase versus alteplase in acute ischaemic cerebrovascular events (TRACE-2): a phase 3, multicentre, open-label, randomised controlled, non-inferiority trial. Lancet. 2023;401(10377):645–54. https://doi.org/10.1016/S0140-6736(22)02600-9.CrossRefPubMed

19.

Ferguson E, Yadav K. Intravenous tenecteplase compared with alteplase for acute ischemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial. CJEM. 2023;25(2):121–2. https://doi.org/10.1007/s43678-022-00432-8.CrossRefPubMed

20.

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372: n71. https://doi.org/10.1136/bmj.n71.CrossRefPubMedPubMedCentral

21.

Sterne JA, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366: l4898.CrossRefPubMed

22.

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(12):1099–107. https://doi.org/10.1056/NEJMoa1109842.CrossRefPubMed

23.

Haley EC Jr, Thompson JL, Grotta JC, Lyden PD, Hemmen TG, Brown DL, Tenecteplase in Stroke Investigators, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke. 2010;41(4):707–11. https://doi.org/10.1161/STROKEAHA.109.572040.CrossRefPubMedPubMedCentral

24.

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(4):368–76. https://doi.org/10.1016/S1474-4422(15)70017-7.CrossRefPubMed

25.

Logallo N, Novotny V, Assmus J, Kvistad CE, Alteheld L, Rønning OM, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 2017;16(10):781–8. https://doi.org/10.1016/S1474-4422(17)30253-3.CrossRefPubMed

26.

Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, EXTEND-IA TNK Investigators, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med. 2018;378(17):1573–82. https://doi.org/10.1056/NEJMoa1716405.CrossRefPubMed

27.

Thelengana A, Radhakrishnan DM, Prasad M, Kumar A, Prasad K. Tenecteplase versus alteplase in acute ischemic stroke: systematic review and meta-analysis. Acta Neurol Belg. 2019;119(3):359–67. https://doi.org/10.1007/s13760-018-0933-9.CrossRefPubMed

28.

Frühwald T, Gärtner U, Stöckmann N, Marxsen JH, Gramsch C, Roessler FC. In vitro examination of the thrombolytic efficacy of tenecteplase and therapeutic ultrasound compared to rt-PA. BMC Neurol. 2019;19(1):181. https://doi.org/10.1186/s12883-019-1404-5.CrossRefPubMedPubMedCentral

29.

Burgos AM, Saver JL. Evidence that tenecteplase is noninferior to alteplase for acute ischemic stroke: meta-analysis of 5 randomized trials. Stroke. 2019;50(8):2156–62. https://doi.org/10.1161/STROKEAHA.119.025080.CrossRefPubMed

30.

NCT03854500. The Norwegian Tenecteplase Stroke Trial 2 (NOR-TEST 2). https://www.clinicaltrials.gov/study/NCT03854500?distance=50&cond=stroke&intr=Tenecteplase%20&term=Alteplase&rank=2. Accessed 15 Jun 2023.

31.

NCT05281549. Thrombolysis Treated With TNK-tPA in Acute Ischemic Stroke Patients (3T Stroke-II). https://www.clinicaltrials.gov/study/NCT05281549?distance=50&cond=stroke&intr=Tenecteplase%20&term=Alteplase&rank=3. Accessed 15 Jun 2023.

32.

NCT05745259. Thrombolysis Treated With TNK-tPA in Acute Ischemic Stroke Patients (3T Stroke-III). https://www.clinicaltrials.gov/study/NCT05745259?distance=50&cond=stroke&intr=Tenecteplase%20&term=Alteplase&rank=5. Accessed 15 Jun 2023.

33.

NCT05626972. Tenecteplase Compared to Alteplase for Patients With Large Vessel Occlusion Suspicion Before Thrombectomy. https://www.clinicaltrials.gov/study/NCT05626972?distance=50&cond=stroke&intr=Tenecteplase%20&term=Alteplase&rank=9. Accessed 15 Jun 2023.

34.

NCT04915729. A Study in Chinese Patients to Compare How Tenecteplase and Alteplase Given After a Stroke Improve Recovering of Physical Activity. https://www.clinicaltrials.gov/study/NCT04915729?distance=50&cond=stroke&intr=Tenecteplase%20&term=Alteplase&rank=6. Accessed 15 Jun 2023.

Titel: The efficacy and safety of tenecteplase compared with alteplase in adult patients with acute ischemic stroke: an updated systematic review and meta-analysis of ten randomized controlled trials
verfasst von: Karthikeyan Chinniah
Nizamudeen Shadakkathulla
Publikationsdatum: 01.12.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: The Egyptian Journal of Neurology, Psychiatry and Neurosurgery / Ausgabe 1/2023
Elektronische ISSN: 1687-8329
DOI: https://doi.org/10.1186/s41983-023-00736-1

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

17.05.2024 Direkte orale Antikoagulanzien Nachrichten

Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.

Thrombektomie auch bei großen Infarkten von Vorteil

16.05.2024 Ischämischer Schlaganfall Nachrichten

Auch ein sehr ausgedehnter ischämischer Schlaganfall scheint an sich kein Grund zu sein, von einer mechanischen Thrombektomie abzusehen. Dafür spricht die LASTE-Studie, an der Patienten und Patientinnen mit einem ASPECTS von maximal 5 beteiligt waren.

Schwindelursache: Massagepistole lässt Otholiten tanzen

14.05.2024 Benigner Lagerungsschwindel Nachrichten

Wenn jüngere Menschen über ständig rezidivierenden Lagerungsschwindel klagen, könnte eine Massagepistole der Auslöser sein. In JAMA Otolaryngology warnt ein Team vor der Anwendung hochpotenter Geräte im Bereich des Nackens.

Schützt Olivenöl vor dem Tod durch Demenz?

10.05.2024 Morbus Alzheimer Nachrichten

Konsumieren Menschen täglich 7 Gramm Olivenöl, ist ihr Risiko, an einer Demenz zu sterben, um mehr als ein Viertel reduziert – und dies weitgehend unabhängig von ihrer sonstigen Ernährung. Dafür sprechen Auswertungen zweier großer US-Studien.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Background

Results

Conclusions

Publisher's Note

Introduction

Materials and methods

Protocol registration

Data sources and search strategy

Eligibility criteria

Selection process

Data extraction

Risk of bias

Statistical analyses

Data availability

Results

Search results and study selection

Characteristics of included studies

Efficacy outcomes

Safety outcomes

Risk of bias

Publication bias

Discussion

Conclusion

Acknowledgements

Declarations

Ethics approval and consent to participate

Consent for publication

Competing interests

Publisher's Note

Weitere Artikel der Ausgabe 1/2023

Bortezomib in the management of anti-NMDA receptor encephalitis

Clinical and radiological profile of cavernous sinus syndrome: a study from eastern part of India

Serum protein S-100B as a novel biomarker of diagnosis and prognosis of childhood epilepsy

Neuronal autoantibodies in a sample of Egyptian patients with drug-resistant epilepsy

Effect of propofol versus sevoflurane on auditory and cognitive functions: a randomized controlled trial

Malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in ischemic stroke: a systematic review

Leitlinien kompakt für die Neurologie

Neu im Fachgebiet Neurologie

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

Thrombektomie auch bei großen Infarkten von Vorteil

Schwindelursache: Massagepistole lässt Otholiten tanzen

Schützt Olivenöl vor dem Tod durch Demenz?

Update Neurologie