Abstract
Tenecteplase (TNK) is a fibrinolytic drug that is administrated in a single bolus, recommended in eligible patients with acute ischemic stroke prior to mechanical thrombectomy. This study explores its usefulness in adverse situations, such as the SARS-CoV-2 pandemic. We conducted a retrospective study involving consecutive patients with suspected acute ischemic stroke treated either with intravenous fibrinolysis with alteplase during 2019 or with TNK (.25 mg/kg) between March 2020 and February 2021. A comparative analysis was made to compare patient treatment times and prognosis. A total of 117 patients treated with alteplase and 92 with TNK were included. No significant differences were observed in age, main vascular risk factors or previous treatments. The median National Institutes of Health Stroke Scale was 8 in the alteplase group and 10 in those treated with TNK (P = .13). Combined treatment with mechanical thrombectomy was performed in 47% in the alteplase group and 46.7% in the TNK group; Thrombolysis In Cerebral Infarction scale 2b-3 recanalization was achieved in 83% and 90.7%, respectively (P = .30). There was a decrease in onset-to-needle median time (165 min vs 140 min, P < .01) and no significant variations in door-needle median time. There was no significant difference in the incidence of symptomatic hemorrhagic transformation in mortality or functional independence at 3 months. The easier administration of TNK has improved the accessibility of fibrinolytic therapy, even in adverse circumstances, such as the COVID-19 pandemic. Its use appears to be safe and effective, even in patients who are not candidates for mechanical thrombectomy.
Keywords: Acute stroke, tenecteplase, fibrinolysis
Introduction
Tenecteplase (TNK) is a genetically modified variant of alteplase with three molecular changes that give it a 4-times longer half-life, 14-times more affinity for fibrin, and 8-times more resistance to plasminogen activator inhibitor-1. 1 This allows its administration in a single bolus, unlike alteplase, which requires continuous infusion for 1 h. 2
The 2019 AHA/ASA guidelines consider the use of TNK in patients with ischemic stroke with National Institutes of Health Stroke Scale (NIHSS) < 5 or in patients who are also eligible to undergo mechanical thrombectomy, and its use is increasing in routine clinical practice. 3 There is evidence that TNK is at least not inferior to alteplase in efficacy and safety in the treatment of acute ischemic stroke,4,5 demonstrating a higher rate of arterial recanalization and a better prognosis than alteplase in patients who are candidates for mechanical thrombectomy. 6 Different doses have been proposed, but .25 mg/kg is the one that accumulates the greatest evidence of effectiveness with a lower rate of intracranial hemorrhages. 7
The rapid administration of TNK in a single bolus also provides practical benefits. On the one hand, it facilitates the transfer of patients if a “drip and ship” care strategy is followed. On the other hand, its easier use might provide additional benefits in situations with higher healthcare pressure, such as the experienced in the coronavirus disease 2019 (COVID-19) pandemic. This study explores the usefulness of TNK in daily clinical practice and in adverse situations, such as the SARS-CoV-2 pandemic.
Materials and Methods
Inclusion and Exclusion Criteria
This was a unicenter comparative and retrospective study, including consecutive patients with acute ischemic stroke and treated with intravenous fibrinolysis with alteplase during 2019 or with TNK at a dose of .25 mg/kg between March 2020 and February 2021, if they presented less than 4.5 h of evolution and met the usual inclusion and exclusion criteria according to the AHA/ASA guidelines. 3 Patients were included consecutively from March to December 2020 during the COVID-19; if they had any symptoms compatible with COVID-19, they were trialed to specific areas for clinical evaluation and neuroimaging work-up. Before the study, the hospital pharmacy approved the use of TNK for patients with large vessel occlusion who were candidates for thrombectomy, according to the available recommendations. 3 During the pandemic, due to the difficulties of administering fibrinolytic treatment with perfusion in the emergency department, the drug was approved for optional use in patients without large vessel occlusion due to its greater ease of administration. This study has the approval of the Ethics Committee of the Hospital Universitario 12 de Octubre (Ref. 20/521), which waived the need for patient consent. Data supporting the findings of this study are available from the corresponding author upon reasonable request.
Study Design
We initially recorded characteristics of patients: initial dependency status obtained using the modified Rankin scale (mRS), demographic variables, description of the main risk factors for stroke, and previous antithrombotic treatment. In addition, we recorded the characteristics of ischemic stroke: clinical severity using the NIHSS scale, baseline computed tomography (CT) scan involvement using the Alberta Stroke Program Early CT Score (ASPECTS), time metrics, and etiology according to the SSS-TOAST classification. 8 Mechanical thrombectomies were analyzed by their angiographic outcome with the modified treatment in cerebral infarction (mTICI) score as well as the number of passes performed. Immediate clinical follow-up was carried out recording complications, including hemorrhagic transformations using the classification developed for the European Cooperative Acute Stroke Study – II (ECASS II). 9 In addition, a 3-month follow-up was carried out, where the final dependency status was also obtained using the mRS.
Statistical Methods
This study includes descriptive variables, percentages for binary variables, and mean and standard deviation for continuous variables and median and interquartile range for discrete variables. A comparative analysis was made between the two groups using the Student t-test (or the Mann-Whitney U test in cases of deviation from a normal distribution) for continuous variables or using the χ2 test for categorical variables. A logistic regression analysis was performed to assess bleeding complications and prognosis, adjusted for the main confounding factors associated with a worse prognosis of fibrinolysis (age, initial NIHSS and onset-to-needle time). 10 Statistical significance was considered when P values were below .05. Data were analyzed using STATA v.15.1 (Stata Corp LP, TX).
Results
Basal Characteristics
A total of 209 patients were studied, 117 treated with alteplase and 92 with TNK, respectively representing 16.7% and 14.2% of the total number of acute strokes seen in the emergency department. There were no significant differences in the baseline characteristics of the patients, with a similar mean age and a similar proportion of vascular risk factors except for a higher proportion of patients with chronic kidney disease, higher in the TNK group (5.1% vs 13.0%, P = .04). There were no significant differences in previous treatment or previous functional status, or stroke etiology.
Procedure
On arrival, no significant differences where observed in NIHSS scale (median 8 (IQR 3-17) in alteplase group vs 10 (IQR 5-18) in TNK group, P = .13), or disabling symptoms on admission (85% vs 93%, P = .07). Combined treatment with fibrinolysis and mechanical thrombectomy did not show significant differences in arterial recanalization between the alteplase and TNK groups (TICI 2b-3 83.0% vs 90.7%, P = .27; TICI 2c-3 69.8% vs 76.7%, P = .45). Concerning stroke care times, the TNK group had a shorter time from symptom onset to initiation of fibrinolytic treatment (median 165 vs 140 min, P < .01), with a greater reduction in time from onset to hospital arrival (100 vs 90 min) and a similar door-to-needle time in both periods (median 55 min).
Complications
There were no significant differences in the complications of interventional treatment, highlighting that one patient in the alteplase group and two patients in the TNK group suffered an arterial perforation that caused clinically significant subarachnoid hemorrhage to the patients. No increase in the total number of patients with any type of hemorrhagic transformation (15.4% vs 20.7%, P = .32) or symptomatic hemorrhagic transformation (5.1% vs 4.3%, P = .79, one of them secondary to arterial perforation during the mechanical thrombectomy in the alteplase group and two in the TNK group). See Table 1.
Table 1.
Characteristics, time metrics and outcomes.
| Alteplase (N = 117) | Tenecteplase (N = 92) | P value | |
|---|---|---|---|
| Baseline characteristics | |||
| Male, n (%) | 55 (47.0%) | 45 (48.9%) | .79 |
| Age, median (IQR) | 74 (62 – 83) | 76 (61 – 83) | .96 |
| Hypertension, n (%) | 86 (73.5%) | 69 (75.0%) | .81 |
| Dyslipidemia, n (%) | 63 (53.8%) | 50 (54.3%) | .94 |
| Diabetes, n (%) | 24 (20.5%) | 23 (25.0%) | .44 |
| Tobacco use, n (%) | 19 (16.2%) | 20 (21.7%) | .31 |
| Atrial fibrillation, n (%) | 23 (19.7%) | 25 (27.1%) | .20 |
| Prior stroke, n (%) | 24 (20.5%) | 16 (17.4%) | .57 |
| Ischemic cardiopathy, n (%) | 13 (11.1%) | 8 (8.7%) | .56 |
| Chronic kidney disease, n (%) | 6 (5.1%) | 12 (13.0%) | .04 |
| Prestroke treatments | |||
| Antiplatelet agent † | 41 (35,0%) | 25 (27.1%) | .22 |
| Anticoagulant (VKA) ‡ | 3 (2.6%) | 2 (2,2%) | .85 |
| † Thirty-two with acetylsalicylic acid, six with clopidogrel, and three with both in the alteplase group; and 20 with acetylsalicylic acid, four with clopidogrel, and one with both in TNK group. | |||
| ‡ All of them with INR <1.7 on arrival at the hospital. | |||
| Prestroke disability | |||
| mRS 0-1 | 100 (85.5%) | 83 (90.1%) | |
| mRS 2 | 11 (9,4%) | 4 (4,4%) | |
| mRS 3 or 4 | 6 (5.1%) | 5 (5.4%) | .37 |
| Stroke severity and CT findings | |||
| NIHSS, median (IQR) | 8 (3 – 17) | 10 (5 – 18) | .13 |
| Disabling symptoms | 100 (85.5%) | 86 (93.5%) | .07 |
| ASPECTS score, median (IQR) | 10 (9 - 10) | 10 (9 - 10) | .64 |
| Mechanical Thrombectomy | |||
| IVT + MT | 53 (45.3%) | 43 (46.7%) | .84 |
| TICI 2b-3 | 44 (83.0%) | 39 (90.7%) | .27 |
| TICI 2c-3 | 37 (69.8%) | 33 (76,7%) | .45 |
| Stroke metrics | |||
| Onset-to-needle (minutes), median (IQR) | 165 (135 – 210) | 140 (120 – 168) | <.01 |
| Onset-to-door (minutes), median (IQR) | 100 (69 – 135) | 90 (63 – 106) | .06 |
| Door-to-needle (minutes), median (IQR) | 55 (45 – 76) | 55 (44 – 69) | .32 |
| Safety Outcomes | |||
| Intracranial hemorrhage, n (%) | 18 (15.4%) | 19 (20.7%) | .32 |
| Symptomatic intracranial hemorrhage, n (%)* | 6 (5.1%) | 4 (4.3%) | .79 |
| HI1 or HI2 | 4 (3.4%) | 7 (7.6%) | .18 |
| PH1 | 8 (6.8%) | 4 (4.4%) | .44 |
| PH2 | 1 (.9%) | 1 (1.1%) | .86 |
| Remote parenchymal hematoma | 1 (.9%) | 4 (4.4%) | .10 |
| Focal subarachnoid hemorrhage | 4 (3,4%) | 4 (4.4%) | .73 |
| Diffuse subarachnoid hemorrhage * | 1 (.9%) | 4 (4,4%) | .10 |
| * One patient in the alteplase group and two patients in the TNK group suffered an arterial perforation that caused clinically significant subarachnoid hemorrhage to the patients. | |||
| Outcome ** | |||
| Excelent outcome (mRS 0-1 or equal to prestroke value) | 67/112 (59.8%) | 51 (56.7%) | .65 |
| Favorable outcome (mRS 0-2 or equal to prestroke value) | 83 (74.1%) | 58 (64.4%) | .13 |
| In-hospital death | 8 (6.8%) | 7 (7.6%) | .83 |
| Mortality at 3 months | 15 (13.4%) | 14 (15.6%) | .66 |
| ** 3 months follow up in 112 patients in the alteplase group (95.7%) and 90 patients in the TNK group (97.8%). | |||
| Stroke Cause | |||
| Cardioembolism | 28 (23.9%) | 35 (38.0%) | |
| Atherosclerosis | 41 (35.0%) | 27 (29.3%) | |
| Arterial disection | 4 (3,4%) | 2 (2,2%) | |
| Undetermined cause | 30 (25.6%) | 11 (12.0%) | |
| Uncommon cause | 3 (2.6%) | 4 (4,3%) | |
| Small vessel disease | 5 (4.3%) | 7 (7.6%) | |
| Stroke MIMIC | 6 (5.1%) | 6 (6.5%) | .10 |
ASPECTS: Alberta stroke programme early computerized tomography score; HI: hemorrhagic infarction; IQR: interquartile range; IVT: intravenous thrombolysis; mRS: modified Rankin scale; MT: mechanical thrombectomy; N: number; NIHSS: national institute of health stroke scale; PH: parenchymal hemorrhage; TICI: thrombolysis in cerebral infarction; TNK: Tenecteplase; VKA: vitamin K antagonists.
Prognosis
No significant differences were observed in prognosis, either in the percentage with excellent (59.8% vs 56.7%, P = .65) or favorable (74.1 vs 64.1%, P = .13) prognosis, or in overall mortality at 3 months (13.4% vs 15.6%, P = .66). There were also no differences in bleeding complications and prognosis (independence and mortality) between the two groups, adjusted for the main confounding factors (age, initial NIHSS and onset-to-needle time) (Table 2).
Table 2.
Multivariable analysis of relevant outcomes between alteplase and tenecteplase (adjusted by age, National Institute of Health Stroke Scale at arrival and onset-to-needle time).
| Odds Ratio (IC 95%) | P value | |
|---|---|---|
| Excelent outcome (mRS 0-1 or equal to prestroke value) | 1.05 (.54 – 2.05) | .88 |
| Favorable outcome (mRS 0-2 or equal to prestroke value) | 0,63 (0,30 – 1,33) | .23 |
| Intracranial hemorrhage | 1,33 (0,62 – 2,86) | .46 |
| Symptomatic intracranial hemorrhage | 0,74 (0,18 – 2,89) | .66 |
| In-hospital death | 0,67 (0,17 – 2,58) | .55 |
| Mortality at 3 months | 0,48 (0,14 – 1,61) | .24 |
mRS: Modified Rankin Scale. †
Discussion/Conclusion
In March 2020, at the beginning of the SARS-CoV-2 pandemic, stroke care was affected in the Madrid Region. 11 The COVID-19 pandemic has led to a reduction in the identification of acute stroke and a worsening of femoral door-to-needle and door-to-puncture times, especially in patients with respiratory symptoms12-14 due to the necessity of additional protection measures and occupation of services exclusively for patients with suspected infection. In our center, fibrinolytic treatment was switched to TNK instead of alteplase due to its simpler administration, which would favor access in a difficult health situation experienced in our region.
The main strength of the study, the cohort of patients, treated presented with representative characteristics and heterogeneous severity, suggests that it is a drug with efficacy and safety similar to those described in the literature,4,5 comparing consecutive patients treated for one year. The experience of the use of TNK in clinical practice has been described, 15 and in our case, we also show the benefits of its use in adverse circumstances.
The rapid administration of TNK could lead to greater safety for healthcare workers by limiting their direct contact with the material (a potential fomite and source of infection during its transport and removal) and with the patient, thus reducing the need for close monitoring during the 60-minute alteplase infusion before a negative COVID-19 test was available. In our experience, the use of TNK during the pandemic has maintained door-to-needle time, helping to avoid worsening treatment times despite the collapse of the healthcare system.12-14,16
The main limitation of the study is that the patient cohorts are not completely comparable since this is not a randomized study and that the cohorts were from two different time periods. However, a multivariable analysis was performed with the main factors that could produce a confounding bias, in order to minimize this potential risk.
Although there are no significant differences in severity as measured by the NIHSS scale, we found a trend towards a higher severity in patients treated with TNK; one of the main indicators being a shorter time from symptom onset to hospital arrival. This may be due to a lack of access for patients with minor strokes or to the saturation of the health care system (which initially led to a lower identification of acute ischemic strokes) or to the new recommendation introduced in the 2019 AHA/ASA guidelines of not treating patients with non-disabling ischemic strokes. 3 Despite this, no significant differences were found in patient prognosis, with a similar proportion of patients with hemorrhagic transformation, as well as in the proportion of patients with excellent or favorable prognosis or at 3 months, and no increase in mortality despite the excess workload on the healthcare care system.
In conclusion, the use of TNK as a fibrinolytic treatment can facilitate access to this treatment in patients with ischemic stroke of < 4.5 h of evolution, especially in situations of overload of the emergency services experienced by the COVID-19. 16
Acknowledgments
We would like to thank the entire Neurology, Radiology, Emergency, Internal Medicine, Anesthesia, and ICU teams for their work performed to continue treating stroke patients despite the difficulties experienced.
Footnotes
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.
ORCID iD
Alberto Rodríguez-López https://orcid.org/0000-0001-5860-2061
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