Trade‐Off Between Early Reperfusion and First‐Pass Effect With Tenecteplase Versus Alteplase Before Stroke Thrombectomy

Abstract

Background

Early reperfusion and first‐pass effect are key procedural end points in large‐vessel occlusion stroke thrombectomy. Because of greater fibrin specificity, tenecteplase may achieve higher early reperfusion rates compared with alteplase, yet impact of thrombolytic agents on first‐pass effect remains unclear.

Methods

Consecutive patients with anterior circulation large‐vessel occlusion stroke receiving intravenous thrombolysis before endovascular treatment at 2 US stroke centers were reviewed. Early reperfusion was defined as extended Thrombolysis in Cerebral Infarction ≥2b50 on initial angiography. First‐pass effect was defined as extended Thrombolysis in Cerebral Infarction 2c‐3 after a single pass. Multivariable logistic regression identified predictors of early reperfusion and first‐pass effect. Ordinal logistic regression assessed associations of thrombolytic agent, early reperfusion, and first‐pass effect with 90‐day modified Rankin Scale shift.

Results

Among 299 patients (tenecteplase 201, alteplase 98), early reperfusion occurred in 60 (20.1%) and was more frequent with tenecteplase compared with alteplase (24.4% versus 11.2%; adjusted odds ratio [OR], 2.31 [95% CI, 1.07–4.98]). Patients without early reperfusion were evaluated for first‐pass effect. Of 237 patients, first‐pass effect was less frequent with tenecteplase compared with alteplase (30.3% versus 40.2%; adjusted OR, 0.42 [95% CI, 0.23–0.79]). Early reperfusion and first‐pass effect each independently predicted better functional outcome, but functional outcomes were similar between tenecteplase and alteplase overall.

Conclusions

We observed higher early reperfusion rates with tenecteplase, but greater first‐pass effect with alteplase, while functional outcomes were comparable. This may suggest that the early reperfusion advantage of tenecteplase could be offset by downstream procedural variables such as first‐pass effect, highlighting the importance of jointly evaluating both reperfusion and procedural efficiency when comparing thrombolytic strategies.

Nonstandard Abbreviations and Acronyms

AcT

Alteplase Versus Tenecteplase

eTICI

extended Thrombolysis in Cerebral Infarction

ETIS

Endovascular Treatment in Ischemic Stroke

EVT

endovascular treatment

EXTEND‐IA TNK

Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra‐Arterial Tenecteplase

LVOS

large‐vessel occlusion stroke

NIHSS

National Institutes of Health Stroke Scale

TOAST

Trial of Org 10172 in Acute Stroke Treatment

Research Perspective.

What Is New?

• This study raises the question of whether early reperfusion and first‐pass effect should be considered truly independent end points, or whether their interplay needs to be evaluated together to accurately capture the effect of thrombolytic pretreatment.

What Question Should Be Addressed Next?

• Future research should investigate how thrombolytic choice alters clot characteristics and thereby shifts the balance between early reperfusion and first‐pass effect.

• Prospective studies incorporating detailed imaging and, ideally, clot histopathology will be needed to determine whether combined assessment of early reperfusion and first‐pass effect provides a more reliable measure of thrombolytic agent efficacy and procedural success.

Early reperfusion is a key procedural end point in large‐vessel occlusion stroke (LVOS) endovascular treatment (EVT) and is strongly associated with favorable functional outcomes. It refers to reperfusion occurring before EVT and is significantly enhanced by administration of bridging thrombolysis. ¹ , ² Tenecteplase, a newer fibrinolytic agent, has been associated with higher early reperfusion rates than traditional alteplase, yet results remain inconsistent across studies. ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ Heterogeneity in thrombus characteristics and methodological variability may account for these discrepancies. To date, only a subset of prior studies has incorporated detailed thrombus‐level imaging parameters, such as clot burden, thrombus length, thrombus permeability, and collateral status, all of which are known determinants of early reperfusion. Beyond these features, clot composition likely plays an important role that is not fully assessable with current imaging modalities. ¹⁴

We recently demonstrated significantly higher early reperfusion rates with tenecteplase compared with alteplase in anterior circulation LVOS treated with bridging thrombolysis and EVT. Consistent with prior literature, early reperfusion was associated with improved 90‐day functional outcomes. However, thrombolytic agent selection itself was not independently associated with functional outcome, suggesting that downstream procedural factors during EVT may compensate for differences in early reperfusion. ¹³ Given the higher early reperfusion rates observed with tenecteplase, comparable functional outcomes would be difficult to explain if not offset by downstream factors. This similarity in outcomes is unlikely to be driven by higher rates of symptomatic hemorrhage or less complete final reperfusion with tenecteplase, as neither has been shown to be worse compared with alteplase in prior studies. ¹¹ , ¹² , ¹⁵ These considerations motivated our assessment of first‐pass effect as a procedural metric that could help explain this offset during EVT. The first‐pass effect is an important procedural end point in LVOS. It is defined as (near‐) complete reperfusion achieved after a single EVT attempt and has been consistently linked to improved clinical outcomes following EVT. The impact of thrombolytic choice on first‐pass effect is still incompletely understood. ¹⁶ , ¹⁷ More compact fibrin architecture may increase clot stiffness and adherence to the endothelium, thereby raising friction during retrieval and reducing EVT efficiency. It is, therefore, plausible that tenecteplase's greater fibrin specificity could enhance first‐pass effect by softening thrombi, partially reducing clot burden, or decreasing fibrin–vessel wall adhesion and retrieval friction. ¹⁸ , ¹⁹

In this study, we evaluated whether among patients with anterior circulation LVOS who did not achieve early reperfusion and, therefore, proceeded to EVT, first‐pass effect differed between tenecteplase‐ and alteplase‐treated patients.

METHODS

Data Availability

The data that support the findings of this study are available from the corresponding author on reasonable request.

Study Design and Population

The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology guideline. We performed a retrospective observational cohort study of consecutive adults with anterior circulation LVOS treated at 2 US comprehensive stroke centers (January 2020–August 2024). ¹³ Eligible patients met the following criteria: (1) intravenous thrombolysis within 4.5 hours of last known well, (2) intracranial internal carotid artery or middle cerebral artery M1/M2 occlusion on baseline computed tomography angiography, and (3) referral for endovascular treatment (EVT). In May 2021, tenecteplase (0.25 mg/kg) replaced alteplase (0.9 mg/kg) as the standard intravenous thrombolysis, creating an alteplase‐treated early phase and a tenecteplase‐treated later phase. The protocol was approved by the institutional review board (Geisinger Institutional Review Board 2022‐0571) with waiver of informed consent. The diagnostic workup and treatment of all patients followed institutional protocols that are aligned with American Heart Association and American Stroke Association guidelines. ²⁰

Data Collection and Imaging Analysis

Clinical, demographic, vascular risk factor, and imaging data were obtained from a prospective registry supplemented by electronic health records. Computed tomography angiography images were independently assessed by 2 experienced neurointerventionalists (P.H. and O.G. with ≥5 years in practice), with disagreements resolved by consensus. Occlusion sites were classified as intracranial internal carotid artery, proximal M1, distal M1, or M2. Tandem occlusion was defined as any of the above intracranial occlusions with a concurrent cervical internal carotid artery occlusion. Thrombus characteristics were evaluated on baseline computed tomography angiography and included thrombus length (≤10 or >10 mm), clot burden score (≤7 or >7), and thrombus permeability. The clot burden score is a semiquantitative measure of thrombus extent within the anterior circulation, ranging from 0 to 10, with lower scores indicating larger thrombus burden. Thrombus permeability was assessed using the residual flow grade, which reflects contrast penetration through or around the thrombus. A grade of 0 indicates absence of contrast permeation, whereas grades 1 to 2 indicate increasing degrees of residual antegrade flow within or distal to the thrombus, suggesting partial permeability. Collateral circulation was assessed on computed tomography angiography using the Tan collateral score, which grades the extent of leptomeningeal collateral filling distal to the occlusion from 0 (no collateral supply) to 3 (complete collateral supply of the affected territory). For analysis, collateral status was dichotomized as poor (Tan score 0–1) or good (Tan score 2–3). ⁸ , ²¹ , ²² , ²³ , ²⁴ , ²⁵

Outcome Measures

Early reperfusion was defined as extended Thrombolysis in Cerebral Infarction (eTICI) grade ≥2b50 on the first angiographic run before thrombectomy. The eTICI scale is a widely used angiographic grading system that reflects the degree of downstream tissue reperfusion following vessel reopening, with grades ranging from 0 (no reperfusion) to 3 (complete reperfusion). An eTICI grade ≥2b50 indicates restoration of antegrade blood flow to at least 50% of the affected downstream vascular territory. In patients who did not proceed to EVT, early reperfusion was defined as vessel reopening confirmed on follow‐up vascular imaging. ⁸ , ²³ First‐pass effect was defined as achievement of near‐complete or complete reperfusion after a single thrombectomy device pass without rescue maneuvers, corresponding to eTICI grades 2c to 3, which reflect reperfusion of at least 90% or more of the affected downstream territory. Modified first‐pass effect was defined as eTICI grades 2b to 3 after the first pass, reflecting at least 50% reperfusion. ²⁶ Two patients with fragmented thrombus affecting multiple distal branches and resulting in eTICI 2a reperfusion (<50% reperfusion) were excluded from both early reperfusion and first‐pass effect analyses (Figure 1). Functional outcome at 90 days was assessed using the modified Rankin Scale, a global disability scale ranging from 0 (no symptoms) to 6 (death).

Figure 1. Flowchart of the entire study cohort and the early reperfusion and FPE fractions.

ER indicates early reperfusion; eTICI, extended Thrombolysis in Cerebral Infarction; FPE, first‐pass effect; mFPE, modified FPE; TNK, tenecteplase; and TPA, alteplase.

Statistical Analysis

Categorical variables are reported as counts and percentages, and continuous variables are reported as medians with interquartile ranges (25%–75%). Categorical comparisons used χ² or Fisher exact test, and continuous comparisons used the Mann–Whitney U test. Univariable logistic regression analyses were conducted to screen for candidate predictors of early reperfusion and first‐pass effect. Variables with P<0.15 were entered into the multivariable logistic regression model, and backwards stepwise elimination with a predefined retention threshold of P<0.05 was then applied to determine final models. The thrombolytic agent was retained a priori as the primary exposure. As a sensitivity analysis, we repeated the screening step using P<0.2, and analyses were repeated using multiple imputation with predictive mean matching for the 10 missing international normalized ratio measurements, which did not change the final multivariable results. Tables S1 and S2 present all univariable associations. Ordinal logistic regression was performed to examine the association between early reperfusion, first‐pass effect, and thrombolytic agent with ordinal shift in modified Rankin Scale at follow‐up. Confounding variables (age, baseline National Institutes of Health Stroke Scale [NIHSS] score, last‐known‐well‐to‐thrombolysis time, and thrombolysis‐to‐assessment time) for this model were chosen a priori based on their demonstrated prognostic significance in ischemic stroke clinical outcomes. ¹ Analyses were performed with IBM SPSS v25 and R v4.3.1, and figures were generated in GraphPad Prism v10.

RESULTS

Baseline Characteristics

The cohort included 299 patients, of whom 201 received tenecteplase and 98 received alteplase (Figure 1; Table 1). Compared with alteplase recipients, the tenecteplase group presented with a lower median NIHSS score (15 versus 17; P=0.013) and higher baseline computed tomography–Alberta Stroke Program Early CT [Computed Tomography] Score (10 versus 9; P=0.001). They were also more frequently admitted directly to a comprehensive stroke center (49.8% versus 30.6%; P=0.002) and had a higher prevalence of current smoking (57.7% versus 43.9%; P=0.024). Otherwise, baseline demographics, comorbidities, vitals and laboratory values, stroke workflows, and occlusion characteristics were similar between groups (Table 1).

Table 1.

Baseline and Outcome Metrics by Treatment Agent

Variable	Entire cohort (n=299)	Tenecteplase (n=201)	Alteplase (n=98)	P value
Demographics
Age, y	71 (62–81)	70 (62–80)	67 (46–95)	0.348
Female sex	133 (44.5)	87 (43.3)	46 (46.9)	0.551
White race	278 (93.0)	187 (93.0)	91 (92.9)	0.955
Prestroke mRS 0–1	255 (85.3)	173 (86.1)	82 (83.7)	0.583
Medical history
Hypertension	218 (72.9)	152 (75.6)	66 (67.3)	0.131
Diabetes	79 (26.4)	59 (29.4)	20 (20.4)	0.100
Hyperlipidemia	181 (60.5)	129 (64.2)	52 (53.1)	0.065
Cardiac disease	84 (28.1)	59 (29.4)	25 (25.5)	0.488
Atrial fibrillation	101 (33.8)	61 (30.3)	40 (40.8)	0.072
Stroke or TIA	92 (30.8)	69 (34.3)	23 (23.5)	0.056
Smoke ever	159 (53.2)	116 (57.7)	43 (43.9)	0.024
Antithrombotics any	131 (43.8)	90 (44.8)	41 (41.8)	0.631
Vitals and laboratory values
Systolic BP, mm Hg	151 (131–170)	151 (132–167)	150 (127–172)	0.843
Diastolic BP, mm Hg	83 (72–96)	83 (73–96)	82 (71–93)	0.518
Glucose, mg/dL	124 (109–155)	123 (106–158)	127 (111–152)	0.596
Platelets, ×1000/mm3	230 (183–287)	234 (186–289)	220 (180–277)	0.245
INR	1.04 (1.00–1.10)	1.00 (1.00–1.10)	1.09 (1.00–1.19)	0.005
Stroke workflow
CSC admission	130 (43.5)	100 (49.8)	30 (30.6)	0.002
LKW‐to‐door time (mins)	69 (48–114)	72 (49–118)	67 (46–95)	0.250
LKW‐to‐needle time (mins)	114 (90–162)	119 (90–164)	110 (99–161)	0.624
Needle‐to‐assessment time (mins)	84 (53–131)	78 (49–129)	94 (65–135)	0.171
Stroke severity and imaging
Baseline NIHSS score	16 (11–20)	15 (10–20)	17 (13–21)	0.013
ASPECTS	10 (9–10)	10 (9–10)	9 (9–10)	0.001
Site of occlusion
ICA	32 (10.7)	19 (9.5)	13 (13.3)	0.250
M1 MCA proximal	85 (28.4)	52 (25.9)	33 (33.7)
M1 MCA distal	94 (31.4)	69 (34.3)	25 (25.5)
M2 MCA	88 (29.4)	61 (30.3)	27 (27.6)
Tandem occlusion	51 (17.1)	33 (16.4)	18 (18.4)	0.674
Tan collateral score ≥2*	216/289 (74.7)	147 (73.1)	69/88 (78.4)	0.342
Clot burden score ≥8*	122/289 (42.2)	87 (43.3)	35/88 (39.8)	0.578
Thrombus permeability*	86/289 (29.8)	54 (26.9)	32/88 (36.4)	0.104
Clot length ≤10 mm*	134/289 (46.4)	98 (48.8)	36/88 (40.9)	0.218
TOAST classification
Cardioembolic	156 (52.2)	106 (52.7)	50 (51.0)	0.623
Atherothrombotic	76 (25.4)	49 (24.4)	27 (27.6)
Dissection	3 (1.0)	3 (1.5)	0 (0.0)
Other	64 (21.4)	43 (21.4)	21 (21.4)
Procedural characteristics†
First baseline eTICI 0	227 (95.8)	142 (94.7)	85 (97.7)	0.332
First‐pass aspiration	160 (67.5)	107 (71.3)	53 (60.9)	0.099
Total passes	2 (1–3)	2 (1–3)	2 (1–3)	0.859
Stent‐retriever use (any)	114 (48.1)	64 (42.7)	50 (57.5)	0.028
Outcomes
Final eTICI‡
0	8 (2.8)	3 (1.5)	5 (5.3)	0.130
1	1 (0.3)	1 (0.5)	0 (0)
2a	4 (1.4)	2 (1.0)	2 (2.1)
2b	115 (39.8)	84 (43.3)	31 (32.6)
2c	54 (18.7)	41 (21.1)	13 (13.7)
3	107 (37.0)	63 (32.5)	44 (46.3)
Functional outcome
mRS shift	2 (0–4)	2 (0–4)	2 (0–3)	0.307
mRS 0–2	168 (56.2)	109 (54.2)	59 (60.2)	0.328
mRS 0–3	195 (65.2)	129 (64.2)	66 (67.3)	0.589
mRS 6	63 (21.1)	43 (21.4)	20 (20.4)	0.845

Data are given as median (interquartile range), number (percentage), or number/total (percentage). ASPECTS indicates Alberta Stroke Program Early CT [Computed Tomography] Score; BP, blood pressure; CSC, comprehensive stroke center; eTICI, extended Thrombolysis in Cerebral Infarction; ICA, internal carotid artery; INR, international normalized ratio; LKW, last known well; MCA, middle cerebral artery; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack; and TOAST, Trial of Org 10172 in Acute Stroke Treatment classification.

^*Ten patients in the alteplase group had missing data.

^† Among 237 patients evaluated for first‐pass effect.

^‡ Not applicable to 10 patients who did not undergo digital subtraction angiography.

Factors Associated With Early Reperfusion

Early reperfusion was achieved in 60 patients (20.1%). In univariable testing, tenecteplase treatment, lower baseline NIHSS score, more distal occlusion site (distal M1 or M2 versus proximal M1 or internal carotid artery), absence of tandem occlusion, thrombus length ≤10 mm, higher clot burden score, and the presence of thrombus permeability were associated with early reperfusion (Table S1). Multivariable analysis identified tenecteplase use (adjusted odds ratio [aOR], 2.31 [95% CI, 1.07–4.98]), lower NIHSS score (aOR per point, 0.94 [95% CI, 0.90–0.99]), and thrombus permeability (aOR, 3.56 [95% CI, 1.84–6.86]) as independent predictors. Tandem occlusion was independently associated with lower odds of early reperfusion (aOR, 0.18 [95% CI, 0.05–0.62]) (Table 2).

Table 2.

Multivariable Logistic Regression Analysis for Predictors of Early Reperfusion

Variable	Adjusted odds ratio (95% CI)	P value
Tenecteplase (vs alteplase)	2.31 (1.07–4.98)	0.032
Tandem carotid occlusion	0.18 (0.05–0.62)	0.007
NIHSS score (per 1 point)	0.94 (0.90–0.99)	0.009
Thrombus permeability	3.56 (1.84–6.86)	<0.001

Covariates considered for the multivariable model were identified from the univariable analyses of the primary outcome presented in Tables S1 and S2 with variables meeting P<0.15 entered into the model.

NIHSS indicates National Institutes of Health Stroke Scale.

Factors Associated With First‐Pass Effect

Excluding 60 patients who achieved early reperfusion, and another 2 patients who had thrombi in >1 territory, resulted in 237 patients proceeding to EVT and being evaluated for achieving first‐pass effect. Of these 237 patients, 81 (34.2%) achieved first‐pass effect and 108 (45.6%) achieved modified first‐pass effect (Figure 1). In univariable analysis, both first‐pass effect and modified first‐pass effect were more frequent among those with coronary artery disease, thrombus length ≤10 mm, lower NIHSS score, and use of a first‐pass aspiration technique. Tenecteplase treatment was less common in the first‐pass effect group (Table S2). Multivariable analysis identified tenecteplase treatment was associated with reduced odds of first‐pass effect (aOR, 0.42 [95% CI, 0.23–0.79]), whereas thrombus length ≤10 mm (aOR, 1.89 [95% CI, 1.05–3.40]), first‐pass aspiration (aOR, 2.05 [95% CI, 1.08–3.91]), and coronary artery disease (aOR, 1.89 [95% CI, 1.05–3.40]) increased the likelihood (Table 3). For modified first‐pass effect, thrombus length ≤10 mm (aOR, 2.31 [95% CI, 1.31–4.06]), first‐pass aspiration (aOR, 2.40 [95% CI, 1.31–4.40]), and coronary artery disease (aOR, 2.01 [95% CI, 1.09–3.72]) were independent predictors.

Table 3.

Multivariable Logistic Regression Analysis for First‐Pass Effect

Variable	Adjusted odds ratio (95% CI)	P value
Tenecteplase (vs alteplase)	0.42 (0.23–0.79)	0.007
Coronary artery disease	1.94 (1.04–3.62)	0.038
Clot length ≤10 mm	1.89 (1.05–3.40)	0.033
First‐pass technique, aspiration (vs aspiration with stent retriever)	2.05 (1.08–3.91)	0.029

Covariates considered for the multivariable model were identified from the univariable analyses of the primary outcome presented in Tables S1 and S2 with variables meeting P<0.15 entered into the model.

Functional Outcomes

At 90 days, early reperfusion was associated with lower disability compared with no early reperfusion (OR, 2.24 [95% CI, 1.33–3.75]; Figure 2A). After adjustment for age, admission NIHSS score, time from last known well to intravenous thrombolysis, and intravenous thrombolysis–to–assessment interval, absence of early reperfusion remained independently linked to worse modified Rankin Scale outcomes (aOR, 2.09 [95% CI, 1.21–3.60]; P=0.008).

Figure 2. The 90‐day functional outcomes by prespecified subgroups.

Distribution of 90‐day mRS scores according to early reperfusion status (A), first‐pass effect status (B), and thrombolytic agent (C). mRS indicates modified Rankin Score; TNK, tenecteplase; and TPA, alteplase.

Patients achieving first‐pass effect (Figure 2B) demonstrated lower disability scores (OR, 1.85 [95% CI, 1.14–2.98]). After adjustment, absence of first‐pass effect was independently associated with a shift toward worse modified Rankin Scale outcomes (aOR, 1.82 [95% CI, 1.11–2.97]; P=0.017).

Across the cohort, 90‐day outcomes were similar between tenecteplase‐ and alteplase‐treated patients (OR, 0.80 [95% CI, 0.52–1.23]; P=0.307; Figure 2C; Table 1). Sensitivity analyses for multivariable analyses including subjects with imputed international normalized ratio (n=10) are presented in Table S3.

DISCUSSION

Our study showed that switching from alteplase to tenecteplase before EVT in LVOS changed the distribution of particular revascularization end points, with tenecteplase achieving higher thrombolysis‐mediated early reperfusion, but lower first‐pass effect compared with alteplase. Yet, 90‐day functional outcomes were similar between both agents, suggesting that differences in early reperfusion may be counterbalanced by downstream procedural factors during EVT, including first‐pass effect.

A hypothesis for explaining the early reperfusion–first‐pass effect interplay could be a clot phenotype shift among those patients proceeding to EVT. Because of its greater fibrin specificity, tenecteplase may preferentially lyse thrombi that are more susceptible to thrombolysis, resulting in early reperfusion in a subset of patients who would otherwise have undergone EVT. As a consequence, patients proceeding to EVT after tenecteplase treatment may represent a population with a higher proportion of more resistant clot phenotypes, while a larger fraction of softer, easier‐to‐remove thrombi remain present at the time of EVT in alteplase‐treated patients. This early reperfusion–first‐pass effect dynamic has not been systematically evaluated previously. The present study does not establish this interplay but it represents a hypothesis that warrants further investigation.

Recanalization and reperfusion are related but denote distinct processes. Recanalization refers to restoration of the occluded index artery and is typically graded using the revised Arterial Occlusion Lesion (rAOL) scale. Reperfusion reflects restoration of effective downstream tissue perfusion and is assessed with the Thrombolysis in Cerebral Infarction (TICI) scale. These processes may diverge when microvascular no reflow, distal (micro)embolization, impaired autoregulation, or capillary injury limit parenchymal perfusion despite angiographic vessel patency. ²⁷ , ²⁸

The intravenous AcT (Alteplase Versus Tenecteplase) randomized clinical trial enrolled 520 patients with LVOS and reported similar 90‐day functional outcomes between tenecteplase‐ and alteplase‐treated patients. Approximately 94% of participants were direct admissions to EVT‐capable centers. Early reperfusion rates were similar for tenecteplase and alteplase (9.2% versus 10.5%), contrasting with the EXTEND‐IA TNK (Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra‐Arterial Tenecteplase) trial (tenecteplase 22% and alteplase 10%), ⁷ and other studies (including ours) that reported higher early reperfusion with tenecteplase. ³ , ¹³ Notably, despite comparable early reperfusion rates in AcT, the investigators observed higher thrombus movement rates with tenecteplase compared with alteplase (19.4% versus 11.5%), and early recanalization (revised Arterial Occlusion Lesion 2b–3) with tenecteplase in 17.5% and alteplase in 14.6%. ¹¹ , ²⁹ Thrombus movement was associated with improved clinical outcomes, but tenecteplase itself did not independently confer an outcome advantage. ²⁹ These findings parallel our observations and support the concept that tenecteplase exerts a stronger biological effect on clot structure without translating into a net clinical benefit at 90 days compared with alteplase. In the AcT trial, tenecteplase‐mediated thrombus movement and recanalization did not translate to immediate improved downstream reperfusion. ²⁹ In a subsequent AcT analysis of 445 patients undergoing EVT with available procedural data, first‐pass effect was 35.0% with tenecteplase compared with 41.1% with alteplase (P=0.2). Interestingly, the median number of passes was 2 (interquartile range, 1–3) in the tenecteplase group and 1 (interquartile range, 1–2) in the alteplase group (P=0.07). ¹⁷ Further studies are required to explore whether differences in first‐pass effect and number of passes with tenecteplase versus alteplase are more pronounced in cohorts where a substantial fraction of tenecteplase‐treated patients achieve early reperfusion and, therefore, do not proceed to EVT. Such a scenario could be consistent with a redistribution of clot phenotypes encountered during EVT, whereby tenecteplase promotes earlier clot modification and recanalization, potentially reducing the pool of intact, more readibly retrievable thrombi encountered during EVT, whereas alteplase‐treated patients more often retain such targets, resulting in numerically higher first‐pass effect and other procedural efficiency metrics, such as number of passes.

In both AcT and our cohort, the alteplase group early reperfusion and first‐pass effect rates were comparable. In our cohort, tenecteplase yielded somewhat higher early reperfusion and correspondingly lower first‐pass effect rates than in AcT, which could be secondary to our ≈30‐minute longer needle‐to‐assessment interval, allowing more tenecteplase dwell time. Still, in both studies, 90‐day functional outcomes were similar between tenecteplase and alteplase, supporting the possibility that early reperfusion and procedural metrics interplay may balance long‐term results. Similar to the findings from AcT and our cohort, in the ETIS (Endovascular Treatment in Ischemic Stroke) registry, tenecteplase‐ and alteplase‐treated patients had similar functional outcomes. With thrombolysis‐to‐assessment times of 80 minutes for tenecteplase and 100 minutes for alteplase, early reperfusion rates were 18.6% and 13.5%, respectively, whereas first‐pass effect rates were 35.5% and 37.6%, respectively. ³⁰ Ultimately, any procedural efficiency advantage observed with alteplase is likely to compensate for lower thrombolysis‐mediated early reperfusion only when onset‐to‐procedure intervals are short, whereas in settings with longer delays, the benefit of earlier reperfusion achieved with tenecteplase may be less readily offset. Pooled data from the AcT and EXTEND‐IA TNK trials indicate that tenecteplase may confer a functional benefit that remains to be further supported by real‐world data. ³¹

Impact on Future Trial Design

Outcome assessment in EVT is moving toward earlier and more procedure‐focused measures. Examples are whether early reperfusion is seen after medical therapy, whether first‐pass effect is achieved during the procedure, and 24‐hour NIHSS score improvement on the clinical side. Focusing only on first‐pass effect, modified first‐pass effect, or reperfusion within 3 passes without taking clot characteristics into account may provide an incomplete picture. First‐pass effect rates have increased in recent years, partly from better devices and partly from more attention to this metric. The possible inverse link between early reperfusion and first‐pass effect may suggest that the choice of thrombolytic may influence the clot profile encountered during EVT. Recognizing this interplay early may have implications for trial design and end point selection in bridging thrombolysis cases because of potential shifts in clot phenotypes. Evaluating early reperfusion and first‐pass effect together may provide a more complete measure of procedural success and may play a role in explaining differences between tenecteplase and alteplase studies, as well as for assessing future thrombolytic agents.

Limitations

This study has several limitations. Its retrospective design and sequential period comparison introduce the potential for selection bias and unmeasured confounding, even though we adjusted for key baseline and imaging variables, and temporal trends were not observed. Being conducted within a single stroke system limits generalizability. Because this study compares sequential treatment periods, gradual changes in EVT practice over time, including evolving device selection and trend for increased use of aspiration as a first‐pass technique, may have introduced temporal confounding that cannot be fully accounted for. We focused only on anterior circulation LVOS, so our findings may not apply to posterior circulation strokes. Although current data do not indicate relevant early reperfusion and first‐pass effect differences between these territories, variations in clot composition have been reported and could contribute to discrepancies across studies. The most important limitation is that we did not obtain direct thrombus histopathology, which could have provided definitive evidence for the proposed selective depletion mechanism. Our results are hypothesis generating given the still limited literature on first‐pass effect with tenecteplase compared with alteplase and the ongoing debate on varying early reperfusion rates. The association between coronary artery disease and first‐pass effect does not have a clear biological basis. Although patients with coronary artery disease are often on antithrombotic therapy, which could in theory influence clot properties, this explanation remains speculative and is unlikely to fully account for the observed association. Given the number of evaluated covariates and end points, multiple comparisons could have introduced statistical noise that may produce associations without a clear biological foundation. Differences in case mix, inclusion criteria, and thrombolysis‐to‐assessment times compared with AcT and ETIS may also explain some variations in observed early reperfusion and first‐pass effect patterns.

CONCLUSIONS

Adoption of tenecteplase as the primary thrombolytic in LVOS was associated with higher early reperfusion but lower first‐pass effect rates among patients proceeding to EVT, whereas overall functional outcomes were similar between tenecteplase and alteplase. This pattern could suggest a potential redistribution of early procedural end points rather than a difference in long‐term clinical efficacy. If confirmed in prospective studies incorporating clot‐level phenotyping, this early reperfusion–first‐pass effect interplay may have important implications for end point selection and interpretation in future bridging thrombolysis trials.

Sources of Funding

The work was supported in part by the Geisinger Neusoscience Institute Clinical Research Fund.

Disclosures

None related to the presented work.

Outside this work, O.G. is consultant for Microvention, Rapid Medical, and Route 92; and has received research grants from Microvention. C.M.S. has research grants from Medtronic, Stryker, Penumbra, Cerenovus, Route 92, MIVI, Balt, Microvention, NICO, and National Institutes of Health/National Institute of Neurological Disorders and Stroke; consulting agreements with Medtronic, Stryker, Viz.ai, Balt, Microvention, and Werfen; and ownership of NTI and Reist. P.H. has received research grant support from Terumo Neuro.

Supporting information

Tables S1–S3