Intravenous thrombolysis with tenecteplase versus alteplase combined with endovascular treatment of anterior circulation tandem occlusions: A pooled analysis of ETIS and TETRIS

Abstract

Background:

Tandem occlusions are a singular large vessel occlusion entity involving specific endovascular and perioperative antithrombotic management. In this context, data on safety and efficacy of prior intravenous thrombolysis (IVT) with tenecteplase is scarce. We aimed to compare IVT with tenecteplase or alteplase in patients with acute tandem occlusions intended for endovascular treatment.

Patients and methods:

A retrospective pooled analysis of two large observational registries (ETIS (Endovascular Treatment of Ischemic Stroke) and TETRIS (Tenecteplase Treatment in Ischemic Stroke)) was performed on consecutive patients presenting with anterior circulation tandem occlusion treated with IVT using either alteplase (ETIS) or tenecteplase (TETRIS) followed by endovascular treatment between January 2015 and June 2022. Sensitivity analyses on atherosclerosis related tandem occlusions and on patient treated with emergent carotid stenting were conducted. Propensity score overlap weighting analyses were performed.

Results:

We analyzed 753 patients: 124 in the tenecteplase and 629 in the alteplase group. The overall odds of favorable outcome (3-month modified Rankin score 0–2) were comparable between both groups (49.4% vs 47.1%; OR = 1.10, 95%CI 0.85–1.41). Early recanalization, final successful recanalization and mortality favored the use of tenecteplase. The occurrence of any intracranial hemorrhage (ICH) was more frequent after tenecteplase use (OR = 2.24; 95%CI 1.75–2.86). However, risks of symptomatic ICH and parenchymal hematoma remained similar. In atherosclerotic tandems, favorable outcome, mortality, parenchymal hematoma, early recanalization, and final successful recanalization favored the tenecteplase group. In the carotid stenting subgroup, PH were less frequent in the tenecteplase group (OR = 0.18; 95%CI 0.05–0.69).

Conclusion:

In patients with tandem occlusions, IVT with tenecteplase seemed reasonably safe in particular with increased early recanalization rates. These findings remain preliminary and should be further confirmed in randomized trials.

Graphical abstract

Keywords

Tandem thrombectomy intravenous thrombolysis tenecteplase alteplase

Introduction

Among large-vessel occlusion strokes (LVOS), anterior circulation tandem occlusions remain a challenge in terms of acute phase management. If the benefit of reperfusion therapies including intravenous thrombolysis (IVT) and endovascular treatment has already been established, several questions remain regarding the optimal approach in this setting.^1,2 Indeed, tandem occlusions constitute a singular entity with specific features such as their bifocal occlusion pattern, their two main etiologies (internal carotid artery (ICA) atherosclerosis or dissection) and the possibility of an emergent carotid stenting, potentially combined with a single or even a more “aggressive” antiplatelet therapy.^3–8

Over the last years, the benefit of IVT for LVOS intended for mechanical thrombectomy (MT) has been questioned through several randomized clinical trials.^9–11 Overall, these studies did not demonstrate the non-inferiority of MT alone in comparison to bridging therapy (IVT followed by MT).¹² Consequently, international guidelines still recommend prior IVT before MT.^12,13 In these trials, the evaluated thrombolytic agent was alteplase, a recombinant tissue plasminogen activator. More recently, tenecteplase, a genetically modified fibrin-specific variant of alteplase with longer half-life, has emerged as an interesting alternative with promising safety and efficacy reported in two major randomized trials. First, in the EXTEND-IA TNK trial comparing tenecteplase and alteplase in LVOS, tenecteplase use was associated with increased odds of early recanalization and improved clinical outcome.¹⁴ Second in the AcT trial, which included non-selected acute ischemic strokes with or without large-vessel occlusion, tenecteplase was non-inferior to alteplase.^15,16

Even though tenecteplase use is increasing, questions persist regarding its place in daily practice, especially in specific circumstances such as tandem occlusions. To date, little data is available comparing these two thrombolytic agents in tandem occlusions treated with endovascular approach.¹⁷ Our aim was to compare the safety and efficacy of tenecteplase and alteplase in the setting of acute tandem occlusions intended for endovascular treatment.

Methods

The data supporting this study are available from the corresponding author upon reasonable request.

Study design and population

We conducted a retrospective pooled analysis of two large registries: ETIS (Endovascular Treatment of Ischemic Stroke), between January 2015 and June 2022, and TETRIS (Tenecteplase Treatment in Ischemic Stroke), between January 2015 and June 2021. Details regarding these registries have previously been published.^18,19 Briefly, ETIS (NCT03776877) is an ongoing multicenter prospective observational study collecting data of consecutive patients with LVOS undergoing MT. Informed consent was obtained from patients or their relatives. TETRIS (NCT05534360) is a retrospective multicenter registry based on prospective local databases in five stroke centers, collecting consecutive patients receiving IVT with tenecteplase at the acute phase of an ischemic stroke. Patients were informed of their participation and offered the possibility to withdraw, in compliance with French law regarding retrospective studies of anonymized standard care data.

Inclusion criteria for the current study were: (1) tandem occlusion of the anterior circulation detected on initial imaging and confirmed during endovascular procedure; (2) receiving initial IVT with either alteplase or tenecteplase; (3) intended endovascular treatment. We excluded patients who did not receive IVT before endovascular treatment, with isolated cervical or isolated intracranial ICA occlusions and posterior circulation tandem occlusions.

Tandem occlusion was defined as an acute bifocal occlusion including an occlusion or near-occlusive stenosis of the cervical ICA along with a second distinct intracranial occlusion (intracranial ICA, M1, or M2 middle cerebral artery (MCA)). In both ETIS and TETRIS registries, cases of tandem occlusions were locally reviewed by a trained senior neuroradiologist or neurologist.

Treatment

Acute reperfusion therapies indications were locally decided, on a case-by-case basis, according to standard guidelines, patient status, local protocols, and multidisciplinary discussion. IVT was administered according to usual recommendations, in the absence of contraindication, immediately after initial imaging. Among participating centers, available thrombolytic agent was either alteplase (ETIS) or tenecteplase (TETRIS). Alteplase was administered at a dose of 0.9 mg/kg (maximum 90 mg), 10% of which as an intravenous bolus followed by a 1-h infusion. Tenecteplase was given in a single 0.25 mg/kg (maximum 25 mg) intravenous bolus.

Endovascular procedure was performed under general anesthesia, conscious sedation, or local anesthesia only according to patient condition, local protocol, and anticipated difficulty of MT. Endovascular strategy was left to the discretion of the interventionist. In particular, decision to perform carotid stenting was taken by the operator according to several criteria: cervical lesion etiology; intracranial recanalization status after MT; prior IVT; circle of Willis functionality; and local protocol. Intraoperative antithrombotic therapy such as intravenous aspirin, GpIIbIIIa inhibitor, cangrelor, or heparin could also be used according to local habits and intra-operative angiographic features.

Collected data, definitions, and outcomes

Baseline patient, imaging, and timeframe data along with therapeutic, procedural, and etiologic characteristics were collected. Angiographic and imaging data were locally assessed by senior neuroradiologists. Three-month modified Rankin Scale (mRS) scores were collected by certified investigators during routinely scheduled visits or by trained research nurses during a standardized telephone interview. Baseline, angiographic and day-1 imaging data were locally assessed by experienced neuroradiologists or neurologists.

Primary outcome was favorable outcome at 3 months, defined by a mRS ⩽ 2 or equal to pre-stroke mRS. Excellent outcome was defined by a 3-month mRS ⩽ 1. Early neurological improvement was defined by NIHSS of 0 or 1 at day-1 or a diminution of at least four points between admission and day 1. Intracranial hemorrhage (ICH) was evaluated on day-1 imaging according to the ECASS-III classification. Any ICH described ICH of all types detected in systematic day-1 imaging, either symptomatic or not. Symptomatic ICH (sICH) was defined as any intracranial hemorrhages on the 24-h imaging associated with an increase of four points or more on the NIHSS within 24 h attributable to the ICH. Parenchymal hematoma (PH) occurrence was also investigated. Variation of ASPECTS between initial imaging and day-1 was collected to explore infarct extension. Intracranial and cervical arterial patency were also assessed on day-1 imaging. Intracranial patency at day-1 aimed to assess the patency of initially occluded intracranial proximal artery. Procedural outcomes were successful recanalization (defined by final modified Thrombolysis in Cerebral Infarction (mTICI) 2b, 2c or 3), excellent recanalization (final mTICI 2c-3), early recanalization (defined as mTICI 2b, 2c or three on the initial intracranial angiographic run, before any MT maneuver), number of MT passes and procedural complication (including embolus in a new territory, perforation, severe vasospasm, or other).

Statistical analysis

Quantitative variables were expressed as means (standard deviation, SD) in the case of normal distribution or medians (interquartile range) otherwise. Categorical variables were expressed as numbers (percentage). Normality of distributions was assessed using histograms and the Shapiro-Wilk test. Patients were divided into two groups according to the IVT agent (alteplase or tenecteplase).

Patient’s characteristics were described according the study groups and the magnitude of the between-group differences were assessed by calculating the absolute standardized differences; an absolute standardized difference >10% was interpreted as a meaningful difference.

We estimated the effect size of tenecteplase against alteplase (considered as reference group) on main angiographic and clinical outcomes before and after taking account of the potential confounding factors using propensity score (PS) overlap weighting (PSOW) method (2). The PS was estimated using a non-parsimonious multivariable logistic regression model, with the study group as the dependent variable and all of the characteristics listed in Table 1 as covariates.

Table 1.

Baseline characteristics according to the thrombolytic used before thrombectomy in the overall study population.

Characteristic	Unadjusted sample			Overlap weighted sample
Characteristic	Alteplase (n = 629)	Tenecteplase (n = 124)	ASD, %	Alteplase (n = 629)	Tenecteplase (n = 124)
Age, mean (SD)	64.6 (14.0)	67.8 (11.9)	22.1	66.8 (13.0)	66.8 (13.0)
Men	460 (73.1)	76 (61.3)	25.4	404 (64.2)	80 (64.2)
Direct admission to CSC	187 (29.7)	35 (28.2)	3.2	175 (27.9)	35 (27.9)
Unknow onset time	153 (24.4)	16 (12.9)	29.9	93 (14.8)	18 (14.8)
Medical history
History of hypertension	313 (49.7)	67 (54.2)	9.0	337 (53.6)	66 (53.6)
Diabetes melitus	87 (13.9)	14 (11.3)	7.9	77 (12.2)	15 (12.2)
Current smoking	177 (28.2)	40 (32.4)	9.2	203 (32.2)	40 (32.2)
History of previous stroke	44 (7.0)	13 (10.5)	12.4	60 (9.6)	12 (9.6)
Pre-stroke antiplatelet medication	121 (19.2)	22 (17.7)	3.8	116 (18.4)	23 (18.4)
Pre-stroke anticoagulant medication	38 (6.0)	7 (5.6)	2.5	31 (5.0)	6 (5.0)
Admission systolic blood pressure, mean (SD)	149 (33)	145 (31)	12.9	146 (26.3)	146 (26.3)
Admission NIHSS score, median [IQR]	16 [11–20]	15 [9–19]	16.4	15 (10–19)	15 (10–19)
Admission ASPECTS, median [IQR]	8 [6–9]	7 [6–9]	5.6	7 (6–9)	7 (6–9)
Pre-stroke mRS > 1	33 (5.2)	10 (8.3)	12.3	50 (7.9)	10 (7.9)
Intracranial occlusion site
Intracranial ICA	171 (27.2)	43 (34.7)	31.7	206 (32.8)	41 (32.8)
M1 MCA	361 (57.4)	55 (44.4)		305 (48.5)	60 (48.5)
M2 MCA	92 (14.7)	22 (17.7)		109 (17.3)	21 (17.3)
Others^,*	4 (0.7)	4 (3.2)		9 (1.4)	2 (1.4)
Stroke etiology
Large artery atherosclerosis	342 (54.3)	58 (46.4)	16.5	137 (21.8)	27 (21.8)
Dissection	134 (21.3)	28 (22.7)		315 (50.0)	62 (50.0)
Others^**	154 (24.4)	38 (30.9)		177 (28.2)	35 (28.2)
Thrombectomy performed^***	581 (92.4)	104 (93.9)	4.9	582 (92.6)	85 (85.0)
Process times, min, median [IQR]
Onset to IVT^****	150 [125–195]	160 [120–200]	3.2	150 (125–195)	160 (120–200)
Onset to imaging	117 [91–153]	112 [84–163]	6.0	115 (90–152)	115 (90–152)
Imaging to IVT	40 [28–60]	40 [23–70]	5.6	40 (27–59)	40 (27–59)

ASPECTS: Alberta Stroke Program Early CT Score; CSC: comprehensive stroke center; EVT: endovascular treatment; IQR: interquartile range; IVT: intravenous thrombolysis; mRS: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale; SD: standard deviation. Propensity score was calculated with all parameters in this Table 1.

Values are expressed as number (%) unless otherwise indicated. Values were calculated after handing missing data using multiple imputation procedure. Propensity score was calculated with all parameters in this Table.

Others included posterior cerebral artery and M3.

Cardio-embolic, unidentified, unknown, or missing data.

***

Defined by at least one intracranial mechanical thrombectomy pass performed.

****

Not included in propensity score.

Because of missing data in patient characteristics and outcomes, we estimated the effect size of tenecteplase versus alteplase in PSOW adjusted analyses after handling missing covariates values by multiple imputation (4) using a regression switching approach (chained equations with m = 10 (5)). Imputation procedure was performed under the missing at random assumption using all variables listed in Table 1 and all outcomes with a predictive mean matching method for quantitative variables and multinomial or binary logistic regression model for categorical variables. In each imputed dataset, PS were calculated to provide PSOW-adjusted effect sizes. We therefore combined these adjusted effect sizes from each imputed dataset using Rubin’s rules (6).

The PSOW- adjusted effect sizes of tenecteplase versus alteplase were estimated using weighted logistic regression models for binary outcomes and using weighted linear regression models for quantitative outcomes. Using alteplase group as reference, we derived from these regression models odds ratio (ORs) or mean differences as treatment effect size measures, with their 95% confidence intervals (CIs). Regarding the difference in any ICH between the two group, we performed a subgroup analysis according to the type of 24-h cerebral imaging (MRI vs CT) by including into the weighted logistic regression model, the study group, the type of imaging, and the corresponding interaction term. Comparison in the overall distribution of mRS was performed using a weighted ordinal logistic regression model (shift). Common odds ratio (cOR) for 1-point improvement in mRS was derived from this model as effects size. Our main analysis covered the whole study group. In order to investigate typical presentation (atherosclerosis) and specific treatment strategies (emergent carotid stenting) of tandem occlusions, sensitivity analyses restricted to patients with atherosclerosis as tandem occlusion etiology and restricted to patients with emergent cervical carotid stenting during the endovascular procedure were done by using the same methodology described for the whole study group. Statistical testing was conducted at the two-tailed α-level of 0.05. Data were analyzed using the SAS software version 9.4 (SAS Institute, Cary, NC).

Results

Study population and treatment description

During the study period, 629 patients with tandem occlusions treated with alteplase and 124 with tenecteplase prior to endovascular treatment were consecutively enrolled in the ETIS and TETRIS registries. Among them, large artery atherosclerosis was the identified etiology in 400 patients (342[85.5%] in the alteplase and 58[14.5%] in the tenecteplase group), and 256 patients were treated with cervical stenting (209[81.6%] in the alteplase and 47[18.6%] in the tenecteplase groups) constituting the secondary analysis populations.

Baseline characteristics after handling missing values by multiple imputation in the overall study population according to the thrombolytic used are described in Table 1 (see Supplemental Table 1 for those before handling missing values). Although several meaningful differences were observed, the two study groups prior to PSOW were well balanced for most patient characteristics.

Regarding treatment strategy, patient workflow and cervical ICA stenting were globally comparable between both groups. However, patients in the tenecteplase group were less often treated under general anesthesia and received more frequently intraoperative heparin and aspirin (Supplemental Tables 1 and 2). Intraoperative “aggressive” antiplatelet therapy (including intravenous GpIIbIIIa inhibitors or cangrelor or oral clopidogrel or ticagrelor) was comparable between both groups. Median symptoms onset to IVT times were comparable in the alteplase (150 min [IQR 125–195]) and tenecteplase (160 min [120–200]) groups.

Outcomes and IVT agents in main analysis population

In the main population analysis, after PSOW, no significant difference was found regarding the primary endpoint: the odds of 3-month favorable outcome were similar in alteplase and tenecteplase groups (47.1% vs 49.4%; OR 1.10; 95%CI 0.85–1.41; p = 0.48; Table 2 and Figure 1(a)). Similarly, no difference was found regarding excellent outcome. However, patients treated with tenecteplase had a lower risk of 3-month mortality (OR 0.59; 95%CI 0.40–0.87). Also, patients treated with tenecteplase had higher chances of early recanalization (OR 4.21; 95%CI 2.69–6.61), final excellent recanalization after MT (OR 1.42; 95%CI 1.13–1.78) and intracranial artery patency at day-1 (OR 2.31; 95%CI 1.43–3.72). However, the occurrence of any ICH was higher in the tenecteplase group (OR 2.24; 95%CI 1.75–2.86). In a subgroup analysis according to the type of day-1 cerebral imaging (MRI vs CT), the difference in any ICH in disfavor of IV tenecteplase were only observed in patients selected on MRI-imaging (OR 2.79; 95%CI 1.94–4.03; p-het = 0.005; Supplemental Table 3). No difference was found in sICH and PH occurrence according to the thrombolytic agent. The odds of cervical ICA patency at day-1 were comparable between both groups. Procedural complications occurred less frequently in the tenecteplase group (OR 0.34; 95%CI 0.17–0.68). This was mostly driven by embolus in new territories which occurred in 36 patients in the alteplase group compared to three in the tenecteplase group.

Table 2.

Propensity-score overlap weighting effect size of IV tenecteplase against IV alteplase before intention to treat thrombectomy in all patients with tandem occlusion.

Characteristic	Alteplase (n = 629)	Tenecteplase (n = 124)	Effect size (95%CI)	p-value
Clinical outcomes
Favorable outcome¹	296 (47.1)	61 (49.4)	1.10 (0.85–1.41)	0.48
Excellent outcome²	195 (31.0)	33 (26.8)	0.81 (0.62–1.06)	0.13
Three-month mortality	114 (18.1)	14 (11.5)	0.59 (0.40–0.87)	0.008
Hemorrhagic transformation
Any ICH	295 (46.9)	82 (66.4)	2.24 (1.75–2.86)	<0.001
PH	88 (14.0)	14 (11.5)	0.78 (0.55–1.09)	0.15
sICH	69 (10.9)	14 (11.5)	1.06 (0.75–1.51)	0.74
Day-1 outcomes
Early neurological improvement	262 (41.6)	56 (45.4)	1.16 (0.92–1.47)	0.20
ASPECTS shift, mean (95%CI)³	–0.88 (–1.13–0.63)	–1.04 (–1.38–0.69)	–0.16 (–0.59–0.27)	0.46
Intracranial patency	535 (85.1)	115 (92.9)	2.31 (1.43–3.72)	0.001
Cervical ICA patency	441 (70.1)	82 (66.3)	0.84 (0.63–1.13)	0.24
Procedural outcomes
Early intracranial recanalization	22 (3.5)	16 (13.1)	4.21 (2.69–6.61)	<0.001
Final mTICI 2b-3	513 (81.6)	101 (81.5)	0.99 (0.77–1.29)	0.97
Final mTICI 2c-3	320 (50.8)	74 (59.5)	1.42 (1.13–1.78)	0.002
Number of passes >3⁴	123 (19.6)	22 (18.0)	0.89 (0.65–1.22)	0.48
Procedural complications⁵	59 (9.4)	4 (3.5)	0.34 (0.17–0.68)	0.004

ASPECTS: Alberta stroke program early CT score; CI: confidence intervals; ICH: intracerebral hemorrhage; IPTW: inverse probability of treatment weighting; IQR: interquartile range; IVT: intravenous thrombolysis; mRS: modified Rankin scale; mTICI: modified thrombolysis in cerebral infarction; NIHSS: National institutes of health stroke scale; PH: parenchymal hemorrhage (type 1 and 2); sICH: symptomatic intracerebral hemorrhage.

Values n (%) are estimated in PSOW cohort unless otherwise indicated.

Pre-specified primary outcome defined as a 3-month mRS score ⩽2, or equal to pre-stroke mRS score.

Defined as a 3-month mRS score ⩽1, or equal to pre-stroke mRS score.

Baseline-adjusted mean difference.

Calculated after PSOW on patients who underwent thrombectomy (581 in the alteplase and 104 in the tenecteplase group). Descriptive parameters and effect sizes (odds ratio or mean difference) were calculated after handling missing values for variables included in the propensity score using multiple imputations.

Detailed procedural complications: embolus in a new territory (alteplase group: n = 36; tenecteplase group: n = 3); intracranial arterial perforation (alteplase group: n = 21; tenecteplase group: n = 1); severe vasospasm (alteplase group: n = 2; tenecteplase: n = 0).

Figure 1.

Propensity-score overlap weighting effect size of IV tenecteplase against IV alteplase before intention to treat thrombectomy on distribution of 3-month modified Rankin Scale. (a) Main analysis population: cOR = 1.06 (95%CI, 0.84−1.35), p = 0.59. (b) Patients with large artery atherosclerosis: cOR = 1.32 (95%CI, 0.98−1.79), p = 0.069. (c) Patients treated with cervical stenting: cOR = 0.79 (95%CI, 0.53−1.18), p = 0.25. Rates are estimated in PSOW cohort. Common odds ratios (cOR) were calculated for one-point improvement using a weighted ordinal logistic regression model.

Outcomes and IVT agents in secondary analysis population

Baseline characteristics in the two sensitivity analysis populations are detailed in Supplemental Table 2.

In the sensitivity analysis restricted to patients with an atherosclerotic etiology (Table 3, Figure 1(b)), we found a significant association favoring tenecteplase for the following outcomes: favorable functional outcome (OR 1.86; 95%CI 1.26–2.74), mortality (OR 0.42; 95%CI 0.23–0.80), early intracranial recanalization (OR 5.53; 95%CI 2.93–10.4), excellent final recanalization (OR 1.80; 95%CI 1.20–2.70), parenchymal hemorrhage (OR 0.56; 95%CI 0.33–0.94), day-1 intracranial patency (OR 2.55; 95%CI 1.12–5.83) and early neurological improvement (OR 1.77; 95%CI 1.28–2.44). However, the rate of any ICH was higher in the tenecteplase group (OR 1.39; 95%CI 1.02–1.89). The odds of final intracranial favorable recanalization, number of total passes >3 and cervical ICA patency at day-1 were similar between groups.

Table 3.

Propensity-score overlap weighting effect size of IV tenecteplase against IV alteplase before intention to treat thrombectomy in patients with large artery atherosclerosis etiology.

Characteristic	Alteplase (n = 315)	Tenecteplase (n = 57)	Effect size (95%CI)	p-value
Clinical outcomes
Favorable outcome¹	145 (46.0)	35 (61.3)	1.86 (1.26–2.74)	<0.001
Excellent outcome²	105 (33.2)	19 (32.6)	0.97 (0.68–1.39)	0.88
Three-month mortality	52 (16.5)	4 (7.8)	0.42 (0.23–0.80)	0.009
Hemorrhagic transformation
Any ICH	151 (47.8)	32 (55.9)	1.39 (1.02–1.89)	0.036
PH	40 (12.6)	4 (7.4)	0.56 (0.33–0.94)	0.030
sICH	33 (10.4)	4 (6.4)	0.58 (0.31–1.09)	0.092
Day-1 outcomes
Early neurological improvement	127 (40.4)	31 (54.5)	1.77 (1.28–2.44)	<0.001
ASPECTS shift, mean (95%CI)³	−0.90 (−1.25−0.54)	−0.85 (−1.38−0.32)	0.05 (−0.54−0.64)	0.873
Intracranial patency	266 (84.4)	53 (93.1)	2.55 (1.12–5.83)	0.028
Cervical ICA patency	230 (72.9)	44 (77.6)	1.29 (0.89–1.87)	0.18
Procedural outcomes
Early intracranial recanalization	11 (3.6)	10 (17.1)	5.53 (2.93–10.4)	<0.001
Final mTICI 2b-3	262 (83.2)	48 (84.6)	1.11 (0.71–1.72)	0.65
Final mTICI 2c-3	162 (51.4)	37 (65.5)	1.80 (1.20–2.70)	0.005
Number of passes >3⁴	51 (16.1)	7 (12.1)	0.89 (0.65–1.22)	0.48
Procedural complications⁵	32 (10.0)	1 (1.4)	NA	NA

ASPECTS: Alberta stroke program early CT score; CI: confidence intervals; ICH: intracerebral hemorrhage; IPTW: inverse probability of treatment weighting; IQR: interquartile range; IVT: intravenous thrombolysis; mRS: modified Rankin Scale; mTICI: modified thrombolysis in cerebral infarction; NIHSS: National institutes of health stroke scale; PH: parenchymal hemorrhage (type 1 and 2); sICH: symptomatic intracerebral hemorrhage. Values n (%) are estimated in PSOW cohort unless otherwise indicated.

Pre-specified primary outcome defined as a 3-month mRS score ⩽2, or equal to pre-stroke mRS score.

Defined as a 3-month mRS score ⩽1, or equal to pre-stroke mRS score.

Baseline-adjusted mean difference.

Calculated after PSOW on patients who underwent thrombectomy. Descriptive parameters and effect sizes (odds ratio or mean difference) were calculated after handling missing values for variables included in the propensity score using multiple imputations.

Detailed procedural complications: embolus in a new territory (alteplase group: n = 20; tenecteplase group: n = 1); intracranial arterial perforation (alteplase group: n = 12; tenecteplase group: n = 0).

Among patients who were treated with emergent cervical carotid stenting during the initial endovascular procedure Table 4, Figure 1(c)), we observed comparable results regarding favorable outcome (OR 0.95; 95%CI 0.61–1.49) and mortality (OR 0.72; 95%CI 0.35–1.49). Early recanalization (OR 7.06; 95%CI 2.26–21.8), PH (OR 0.18; 95%CI 0.05–0.69) occurrence and delta in day-1 ASPECTS (OR 0.30; 95%CI −0.28–0.88) favored the tenecteplase group. However, day-1 cervical ICA patency was less frequent in the tenecteplase group (OR 0.48; 95%CI 0.25–0.94).

Table 4.

Propensity-score overlap weighting effect size of IV tenecteplase against IV alteplase before intention to treat thrombectomy in patients with cervical stenting.

Characteristic	Alteplase (n = 209)	Tenecteplase (n = 47)	Effect size (95%CI)	p-value
Clinical outcomes
Favorable outcome¹	103 (49.2)	23 (48.0)	0.95 (0.61–1.49)	0.82
Excellent outcome²	76 (36.3)	12 (24.9)	0.58 (0.34–1.01)	0.052
Three-month mortality	36 (17.3)	6 (13.2)	0.72 (0.35–1.49)	0.37
Hemorrhagic transformation
Any ICH	105 (50.2)	27 (57.4)	1.33 (0.78–2.25)	0.28
PH	27 (13.1)	1 (2.9)	0.18 (0.05–0.69)	0.013
sICH	21 (10.0)	6 (12.3)	1.26 (0.70–2.27)	0.45
Day-1 outcomes
Early neurological improvement	80 (38.2)	22 (46.3)	1.39 (0.93–2.10)	0.11
ASPECTS shift, mean (95%CI)³	−0.98 (0.20−1.37)	−0.68 (−1.15−0.21)	0.30 (−0.28–0.88)	0.005
Intracranial patency	187 (89.4)	45 (95.5)	2.98 (0.45–19.51)	0.24
Cervical ICA patency	171 (81.6)	32 (68.3)	0.48 (0.25–0.94)	0.033
Procedural outcomes
Early intracranial recanalization	3 (1.5)	4 (9.5)	7.06 (2.28–21.8)	0.001
Final mTICI 2b-3	187 (89.6)	40 (85.6)	0.69 (0.38–1.27)	0.23
Final mTICI 2c-3	129 (61.6)	30 (63.8)	1.09 (0.67–1.79)	0.72
Number of passes >3⁴	33 (15.6)	7 (15.8)	1.01 (0.52–1.95)	0.98
Procedural complications⁵	18 (8.5)	3 (5.7)	0.61 (0.18–2.02)	0.40

Values n (%) are estimated in PSOW cohort unless otherwise indicated.

Pre-specified primary outcome defined as a 3-month mRS score ⩽2, or equal to pre-stroke mRS score.

Defined as a 3-month mRS score ⩽1, or equal to pre-stroke mRS score.

Baseline-adjusted mean difference.

Detailed procedural complications: embolus in a new territory (alteplase group: n = 14; tenecteplase group: n = 0); intracranial arterial perforation (alteplase group: n = 2; tenecteplase group: n = 2); severe vasospasm (alteplase group: n = 2; tenecteplase: n = 1).

Discussion

In this multicenter retrospective pooled analysis of two large French registries, we found novel evidence regarding the safety and efficacy of prior IVT with tenecteplase compared to alteplase for acute tandem occlusions intended for MT. In the main analysis, despite similar 3-month functional outcomes, tenecteplase was associated with lower mortality, higher odds of early recanalization, final excellent recanalization, and ICH although both groups did not differ in terms of sICH and PH. In the sensitivity analysis restricted to atherosclerotic tandem occlusions, tenecteplase use was associated with improved functional outcome, lower mortality and PH rates and higher chances of early recanalization, final excellent recanalization and early neurological improvement. Among patients with emergent carotid stenting, despite comparable functional outcomes, PH were rarer in the tenecteplase group.

Our results are in line with those of the EXTEND-IA TNK trial, which reported increased rates of early recanalization and improved clinical outcomes with tenecteplase in LVOS intended for MT.¹⁴ However, this trial included only few patients with tandem occlusions (10 patients treated with tenecteplase and 12 with alteplase) limiting its interpretation in this setting. To date, no specific data from the AcT trial regarding tandem occlusion were presented.¹⁶ Hence, for less common LVOS subtypes such as tandem occlusions, data from large observational real-life registries remain essential. In this sense, our results are novel and bring new lights on the safety and efficacy of tenecteplase for this specific LVOS pattern. Interestingly, as reported in previous tenecteplase studies, we also observed significantly higher odds of early intracranial recanalization in the tenecteplase group despite higher thrombus burden and regularly feared limited efficacy of IVT in tandem occlusions.² Clinical outcomes also tended to favor tenecteplase with a lower mortality rate in the primary analysis. However, odds of favorable functional outcome were similar and there was no difference in the mRS shift analysis. Still, higher rates of favorable outcome, early neurological improvements and decreased mortality rate were found among the atherosclerotic tandem subpopulation. Mortality rates were consistently reduced in the tenecteplase group in the primary analysis and in the secondary analysis focused on atherosclerotic tandems. This might be related to a direct benefit of tenecteplase itself compared to alteplase (increased odds of early recanalization and excellent final recanalization along with comparable risk of sICH and PH). However, our results should be interpreted with caution as our study was retrospective and potentially subject to selection bias. Overall, while tenecteplase appears at least as effective and safe as alteplase in tandem occlusions, its possible superiority over alteplase should be investigated through dedicated randomized trials.

Along with achieving intracranial recanalization, the other main question dealing with tandem occlusion is the treatment of the cervical ICA. Despite ongoing trials (TITAN, ClinicalTrial.gov ID: NCT03978988; PICASSO, NCT05611242 and START, NCT05902000), emergent carotid stenting is already widely performed, especially in cases of atherosclerotic etiology.^3,8,20,21 However, endovascular treatment potentially implies additional antithrombotic medication, especially single or even “aggressive” antiplatelet therapies.^5–7 In this context, additional antithrombotic treatment to maintain intracranial and cervical arterial patency must always be balanced with the ICH risk. With patients receiving tenecteplase being excluded from ongoing tandem occlusion RCTs, the need for additional data is substantial.²⁰ Regarding the ICH risk associated with prior tenecteplase in tandem occlusions, we report novel and reassuring findings. First, we found increased odds of any ICH among patients treated with tenecteplase both in the main population and in the atherosclerotic tandem occlusion subgroup. Several hypotheses could explain this finding: (i) it could be specifically due to tenecteplase, although there are little data available on asymptomatic ICH risk after tenecteplase; (ii) it could be linked to the more frequent use of intraprocedural aspirin and heparin in the tenecteplase group (Supplemental Tables 1 and 2), which have been shown in the MR-CLEAN-MED trial to increase the ICH risk²²; (iii) differences in early post-operative antithrombotic therapies could have been confounding factors. These data were not collected in our registries. However, the absence of detected difference in terms of ICH risk in the stented subpopulation, who is particularly prone to receive early additional antithrombotic, renders this hypothesis less plausible. Still, increased rates of any ICH should be tempered by reassuring data regarding sICH and PH. Indeed, among both primary and sensitivity analyses, these safety outcomes were comparable between both groups. We even observed lower PH rates in the tenecteplase group in the atherosclerotic and stented subpopulations. While these findings could support a reasonably safe use of tenecteplase in tandem occlusions, considering the increased odds of any ICH, we still strongly recommend to cautiously discuss the use of additional antithrombotic agents on a case-by-case basis and after taking into account the entire clinical and imaging features.

Durable cervical ICA patency is also primordial in tandem occlusion, as early reocclusion has already been proven associated with worse clinical prognosis.^23–25 Our study did not reveal an influence of tenecteplase on day-1 cervical ICA patency. Given its pharmacological properties and on the basis of our results, it is likely that tenecteplase does not directly provide an increased likelihood of durable ICA patency, either with or without carotid stenting. However, given the safety features discussed above, there might be an interest of prior tenecteplase in case of emergent ICA stenting combined with antiplatelet therapy.

We also observed significantly higher rates of procedural complications in the alteplase group. This finding was relatively unexpected. Most of these were embolus in new territories, which were less frequent with tenecteplase. Several hypotheses can be discussed. First, tandem occlusions have already been reported to be associated with specifically increased procedural risk in comparison with other types of LVOS.²⁶ There might be an effect related to local endovascular and pharmacological protocols and experience among the centers involved in these two registries. Still, procedural complication rates remained in line with published data.²⁶ Second, there might be a potential implication of each thrombolytic in their ability to recanalize migrated distal thrombus fragments occurring during retrieving maneuvers of MT. These questions should be specifically explored through dedicated study.

Our work presented several limitations. Although data were prospectively collected in two multicenter registries, our study was retrospective with known limitations inherent to its non-randomized design. Potential confounding by measured or unmeasured variables cannot be ruled out, even after PS adjustment methods and may have influenced our results. Missing data in some covariates, which were used in the PS calculation, represented another limitation. Although we used multiple imputations to handle missing data, we cannot exclude that they could introduce a bias in estimates. Then, despite harmonization in methodology and variable definitions, residual differences between both registries might have introduced bias. Given the rarity of tandem occlusions, our study population size was limited, which affected the statistical power of our analyses. While imaging was systematically locally reviewed by trained neuroradiologists and neurologists, it was not centralized, which could have affected tandem occlusion identification and etiological assessment. Also, since acute tandem occlusion management remains imperfectly codified, it can result in different endovascular strategy and antithrombotic medications during the procedure and the early postoperative phase.²⁷ Importantly, our study may underestimate early recanalization rates with alteplase, as per inclusion criteria a number of patients experiencing early intracranial recanalization and clinical improvement after IVT and before admission in the MT-capable center were not included in the ETIS registry. Finally, emergent carotid stenting rates in our cohort were relatively low and might reflect selection bias.

Conclusion

In our study, in tandem occlusions intended for MT, tenecteplase was associated with similar 3-month functional outcome but lower mortality rates and higher chances of early intracranial recanalization than alteplase. Despite increased odds of any ICH after tenecteplase, sICH and PH occurrence remained comparable with both thrombolytics. In atherosclerotic tandem occlusions, functional outcome, mortality, early neurological improvement, early recanalization, and PH favored tenecteplase. Among patients with emergent carotid stenting, PH were rarer in the tenecteplase group. Overall, our study revealed reasonable safety and efficacy features of tenecteplase in comparison to alteplase in the setting of tandem occlusions. Randomized trials should be considered to confirm these encouraging findings.

Supplemental Material

sj-docx-1-eso-10.1177_23969873231206894 – Supplemental material for Intravenous thrombolysis with tenecteplase versus alteplase combined with endovascular treatment of anterior circulation tandem occlusions: A pooled analysis of ETIS and TETRIS

Supplemental material, sj-docx-1-eso-10.1177_23969873231206894 for Intravenous thrombolysis with tenecteplase versus alteplase combined with endovascular treatment of anterior circulation tandem occlusions: A pooled analysis of ETIS and TETRIS by Gaultier Marnat, Bertrand Lapergue, Benjamin Gory, Maeva Kyheng, Julien Labreuche, Guillaume Turc, Stephanze Olindo, Igor Sibon, Jildaz Caroff, Didier Smadja, Nicolas Chausson, Frederic Clarençon, Pierre Seners, Romain Bourcier, Raoul Pop, Jean-Marc Olivot, Mikael Mazighi, Solène Moulin, Kevin Janot, Christophe Cognard, Sonia Alamowitch and Gaspard Gerschenfeld in European Stroke Journal

Supplemental Material

sj-docx-2-eso-10.1177_23969873231206894 – Supplemental material for Intravenous thrombolysis with tenecteplase versus alteplase combined with endovascular treatment of anterior circulation tandem occlusions: A pooled analysis of ETIS and TETRIS

Supplemental material, sj-docx-2-eso-10.1177_23969873231206894 for Intravenous thrombolysis with tenecteplase versus alteplase combined with endovascular treatment of anterior circulation tandem occlusions: A pooled analysis of ETIS and TETRIS by Gaultier Marnat, Bertrand Lapergue, Benjamin Gory, Maeva Kyheng, Julien Labreuche, Guillaume Turc, Stephanze Olindo, Igor Sibon, Jildaz Caroff, Didier Smadja, Nicolas Chausson, Frederic Clarençon, Pierre Seners, Romain Bourcier, Raoul Pop, Jean-Marc Olivot, Mikael Mazighi, Solène Moulin, Kevin Janot, Christophe Cognard, Sonia Alamowitch and Gaspard Gerschenfeld in European Stroke Journal

Supplemental Material

sj-docx-3-eso-10.1177_23969873231206894 – Supplemental material for Intravenous thrombolysis with tenecteplase versus alteplase combined with endovascular treatment of anterior circulation tandem occlusions: A pooled analysis of ETIS and TETRIS

Supplemental material, sj-docx-3-eso-10.1177_23969873231206894 for Intravenous thrombolysis with tenecteplase versus alteplase combined with endovascular treatment of anterior circulation tandem occlusions: A pooled analysis of ETIS and TETRIS by Gaultier Marnat, Bertrand Lapergue, Benjamin Gory, Maeva Kyheng, Julien Labreuche, Guillaume Turc, Stephanze Olindo, Igor Sibon, Jildaz Caroff, Didier Smadja, Nicolas Chausson, Frederic Clarençon, Pierre Seners, Romain Bourcier, Raoul Pop, Jean-Marc Olivot, Mikael Mazighi, Solène Moulin, Kevin Janot, Christophe Cognard, Sonia Alamowitch and Gaspard Gerschenfeld in European Stroke Journal

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Local ethics committee approval was obtained (IDRCB number: 2017-A03457-46).

Informed consent

Patients were informed of their participation and offered the possibility to withdraw, in compliance with French law regarding retrospective studies of anonymized standard care data.

Guarantor

GM is the guarantor for the present study.

Contributorship statement

GM and GG researched literature, conceived the study. GM, BL, SA and GG were involved in protocol development, gaining ethical approval and patient recruitment. MK and JL were involved in data and statistical analysis. GM wrote the first draft of the manuscript. All authors collected data and reviewed and edited the manuscript and approved the final version of the manuscript.

ORCID iDs

Gaultier Marnat

Guillaume Turc

Solène Moulin

Christophe Cognard

Sonia Alamowitch

Gaspard Gerschenfeld

Supplemental material

Supplemental material for this article is available online.

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