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ORIGINAL ARTICLE
Year : 2023 | Volume
: 26
| Issue : 1 | Page : 54-58
Biosimilar tenecteplase versus alteplase in acute ischemic stroke: A real world study
Ayush Mohan, Snigdha Komakula, Suhas Murali, Pooja Anand, Dyuti Shah, VY Vishnu, Awadh Kishor Pandit, Ayush Agarwal, Deepti Vibha, Mamta Bhushan Singh, MV Padma Srivastava, Rohit Bhatia
Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
Correspondence Address:
Rohit Bhatia
Department of Neurology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/aian.aian_754_22
Abstract
Background and Purpose: There is an unmet need for a more effective thrombolytic agent in acute ischemic stroke (AIS) management. Various studies and meta-analysis suggest tenecteplase (TNK) as non-inferior over alteplase (rTPA). The present single-center study compares biosimilar TNK and rTPA in a tertiary care setting. Methods: Data of patients who presented with AIS and underwent intravenous thrombolysis (IVT) were recruited retrospectively from January 2018 to July 2021. Primary efficacy outcome was a modified Rankin score (mRS) at 90 days dichotomized at < = 2. Qualitative and quantitative variables were assessed using Chi-square test and Student's t-test, respectively. Results: A total of 160 patients, 103 in the rTPA and 57 in TNK group, were analyzed. The baseline characteristics were well matched apart from hypertension. Large artery atherosclerosis was the most frequent subtype of stroke among the two groups. Good functional outcome was seen in 47.92% of patients TNK and 64.77% of patients in rTPA group (p = 0.069). No difference was seen in the rates of any ICH (p = 0.29) and mortality at 3 months (p = 0.32) among the two groups. Conclusion: This present study observed no difference in the efficacy and safety between biosimilar TNK and rTPA. Our findings are in concordance with published trials showing equivalence between the two molecules.
Keywords: Biosimilar pharmaceuticals, fibrinolytic agents, ischemic stroke, tenecteplase, tissue plasminogen activator
Introduction 
Ischemic stroke is one of the most important causes of morbidity and mortality across the globe. Hyperacute treatment of acute ischemic stroke (AIS) aims at timely reperfusion to salvage the dying brain tissue. The original NINDS trial published in 1995 paved the way for thrombolytic therapy in AIS with timely administration of alteplase (rTPA).[1] However, search has been on for more efficient thrombolytic agents in AIS.[2] Tenecteplase (TNK) is a modified version of rTPA which has greater fibrin specificity; longer half-life, can be given as a bolus injection and may also have higher recanalization capability.[2] Recent meta-analysis[3],[4] has suggested that tenecteplase is non-inferior to alteplase; but the exact question of which among the two is superior still remains unanswered. Biosimilar TNK (Tenectase) was approved for use in India in 2017 for patients of AIS presenting within three hours. The present study describes our experience on the use of TNK from a single center at a tertiary care institute.
Material and Methods This is a single-center retrospective study of all patients with AIS who were eligible to receive intravenous thrombolysis with rTPA or TNK from January 2018 to July 2021. All patients with AIS who were eligible to receive intravenous thrombolysis (IVT) as per the institute protocol during this time period were included. The study was approved by the Institute Ethics Committee (IECPG/279/3/2021). Data was collected from medical records between January 01, 2018 and July 31, 2021. All clinically suspected acute stroke patients underwent an urgent non-contrast CT (NCCT) to rule out any intracranial hemorrhage followed by CT angiography (CTA) to rule out a large vessel occlusion (LVO). Eligible patients were given IVT as a standard of care, and the same was available free of cost in our institute (either rTPA 0.9 mg/kg to a maximum of 90 mg with 10% as a bolus and rest as an infusion over 1 hour or TNK 0.25 mg/kg to a maximum of 25 mg which was in line with previous trials.[5],[6],[7]) The decision to use either of the agents was made by the treating physician. Those with a LVO were emergently taken up for a endovascular therapy (EVT).
Details of demographic data, age, sex, pre-stroke mRS, baseline risk factors, NIHSS, and ASPECTS score, site of occlusion, stroke onset time, type of thrombolytic used, time of thrombolysis, endovascular treatment details (puncture time, type of device used, recanalization status assessed on TICI scale, time to recanalization, puncture to recanalization time), repeat vascular imaging (if done, based on the discretion of the treating physician) and complications like intracranial hemorrhage (ICH), extra cranial bleeding, angioneurotic edema, or any other adverse reaction were collected. ASPECTS score, NIHSS score (at 24 hours), and mRS and mortality at 90 days were recorded. The 90-day mRS was either recorded from the file during follow-up or telephonically.
Primary efficacy outcomes were defined as a functional outcome based on mRS at 90 days and recanalization TICI grade 2b/3 at first angiography run and end of EVT, where available. Secondary outcomes included early neurological improvement (ENI) defined as improvement in NIHSS by eight points = at 24-hour post-thrombolysis or a score of zero to one. Safety outcomes are defined as rate of any ICH, symptomatic ICH defined by the SITS MOST criteria and/or any systemic major or minor bleeding.
The analysis was done using STATA14 version. The qualitative variables were assessed using the Chi-square test. Mean and SD were used for quantitative variables, and Student's t-test for bivariate analysis. Two-tailed P value of <0.05 was taken as significant.
Results A total of 160 patients underwent thrombolysis during the study period; 103 received rTPA, and 57 received TNK. The baseline characteristics of two groups are shown in [Table 1]. Males were higher, and history of hypertension was more frequent in the TNK-treated group. Other baseline characteristics and risk factors were balanced among the two groups. Similarly, the baseline clinical and imaging characteristics were also balanced between the two groups. The median NIHSS was 9 (IQR 5-13) in rTPA-treated group and 8 (IQR 4-14) in the TNK group. Stroke was most commonly seen in the MCA territory in both the groups, and large artery atherosclerosis was the most frequent subtyping of the stroke as per TOAST classification. The time metrics of the two groups are outlined in [Table 2]. The rTPA-treated group presented later to the ER (median: onset to door (OTD) 120 mins; IQR: 80-180) as compared to TNK-treated group (median: 99 mins; IQR: 60-140). Door to CT (DTC) time, CT to needle (CTN) time, and door to needle (DTN) time were longer in the TNK-treated group as compared to the rTPA-treated group (p-value = 0.001, 0.04 and 0.0002 respectively). However, the onset to needle (OTN) time was equivalent in the two groups. Fifteen patients in the rTPA group and seven patients in the TNK group underwent EVT. The time metrics for EVT were similar for the two groups [Table 3].
Table 1: Baseline clinical and imaging characteristics and vascular risk factorsThere was no significant difference in the number of patients with a good functional outcome at three months [Table 4]. Median mRS at 3 months among the two groups [2 (IQR 1-4) in the rtPA group and 3 (IQR 1-4) in the TNK group; P = 0.17] was similar. In the ordinal shift analysis of mRS at three months, there was no difference among the two groups (p = 0.18) [Figure 1]. ENI was similar in the rTPA (30.1%) and TNK (26.3%) group. Among the patients undergoing EVT, no patients were found to have recanalization on the first run of angiography. No difference was seen in the grade of recanalization achieved at the end of DSA among the two groups (p = 1.0).
Figure 1: mRS* at 3 months: ordinal shift analysis (%). *mRS at 3 months data available for 88 patients in alteplase group and 48 patients in tenecteplase groupFourteen patients underwent subsequent repeat vascular imaging [Table 4]. Recanalization was seen in 70% of patients in rTPA group vs. 33.3% of patients in TNK group (p = 0.51). A higher proportion of patients in the TNK arm (8.77%) underwent decompressive hemicraniectomy (DCH) as compared to rTPA arm (1.94%) although the results were not statistically significant [Table 5]. On the contrary, ICH and systemic bleeding manifestations were seen more commonly in the rTPA versus TNK group. Mortality at three months was also similar among the two groups.
Discussion TNK was first approved in India in 2017 at a dose of 0.2 mg/kg based on previous trials by Parson M et al.,[5] Huang X et al.,[6] and Haley et al.[7]; and one 2-part study evaluating the molecule in Indian patients.[8] This study done in 2015 compared TNK at a dose of 0.2 mg/kg versus historical controls of the original NINDS rt-PA trial and demonstrated a clear superiority of TNK over rTPA in 3-month mRS outcomes, Barthel Index scores, and mortality. However there were significant differences in the baseline characteristics among the trial participants with NINDS study historical controls being older, with more significant vascular risk factors and more severe stroke. These factors and improvement in acute stroke management care in the ensuing three decades could have contributed to the significant results favoring TNK in that study.
In our study, patients treated with either rTPA or TNK showed no difference in the functional outcome at 3 months; the same is in line with the recently and previously published RCTs[5],[6],[7],[9],[10],[11],[12] comparing the two agents like AcT[11] trial from Canada and TASTE-A[12] trial which have also suggested equivalence among the two molecules. Meta-analysis involving trials have also demonstrated non-inferiority of tenecteplase in long-term functional outcomes with equal safety profile.[3],[4] Good outcome, ENI, and recanalization rates showed no significant difference between the groups.
The non-significant relative small increase in proportion of patients with ICH in TPA arm is likely related to the imbalance of patient numbers in both arms. Similarly, safety outcomes including sICH and mortality at 3 months were not found to be different among the two. The proportions of sICH, any ICH, and mortality seem high in rTPA arm, but this finding is not statistically significant. Recently published Trial NORTEST 2A[13] demonstrated greater harm with TNK Dosing of 0.4 mg/kg as compared to standard rTPA dose; keeping in line the previous evidence from various trials, our study also suggested that 0.25 mg/kg TNK dosage seems to be reasonable from the risk-benefit assessment. Another observational study done in India-TENVALT[14] reported similar outcomes to our study.
Interestingly, although the OTN time was similar among the two groups; the DTN time was shorter among the patients treated with rTPA. Proportion of patients receiving TNK (N = 26; 45.61%) was higher compared with rTPA (N = 20; 19.41%) during the active pandemic phase. Higher use of tenecteplase during the COVID pandemic period is likely due to its ease of administration and monitoring as previously suggested.[15] The trend of longer stroke metrics in the tenecteplase arm in the present study is possibly reflective of the issues related to stroke treatment workflows affected by the COVID pandemic.[16]
Among patients with LVO's, EXTEND-IA TNK[10] demonstrated superiority of TNK as compared to rTPA in patients with LVO (although trial was powered for non-inferiority and not superiority) with similar safety profiles. In our country, REOPEN trial (CTRI/2022/01/039473;TNK vs. rTPA in patients with LVO within 4.5 hour) is underway comparing the two thrombolytics in LVO population. Further large-scale head-to-head trials are ongoing in comparing rTPA and TNK in acute ischemic stroke: ATTEST 2 Trial (TNK vs. rTPA within 4.5 hours, superiority trial), ETERNAL LVO Trial (rTPA vs. TNK in patients with LVO in extended time window).
There are inherent limitations of our study. This was a single-centered retrospective observational study, the sample size is small, and the number among the two groups variable limited our ability to use more formal methods of analysis like propensity matching. Since this was a retrospective study, decision to use rTPA vs. TNK was made by the treating physician which could have introduced selection bias. Further, a subset of patients could not be followed up keeping in view the retrospective nature of the study and the COVID pandemic. However, the results are from a real-world use of a biosimilar TNK and are relevant for efficacy and cost in resource-limited settings.
Conclusion In our study, we found that biosimilar TNK has a similar efficacy and safety profile when compared to rTPA as observed in a real-world scenario. Further studies are needed and are ongoing to compare the two molecules.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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