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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 1  |  Issue : 1  |  Page : 8-14

Multicentric, randomized, double-blind, comparative study in STEMI patients to establish clinical biosimilarity of biosimilar tenecteplase with reference product


1 Medical Affairs Group, DALC, Reliance Life Sciences, Navi Mumbai, Maharashtra, India
2 Clinical Research Group, DALC, Reliance Life Sciences, Navi Mumbai, Maharashtra, India

Date of Submission18-Oct-2018
Date of Decision08-May-2019
Date of Acceptance14-Jun-2019
Date of Web Publication13-Dec-2019

Correspondence Address:
Dr. Prasad Apsangikar
Reliance Life Sciences, R-282, TTC Area of MIDC, Thane Belapur Road, Rabale, Navi Mumbai - 400 701, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ACCJ.ACCJ_6_18

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  Abstract 


Objectives: Tenecteplase (TNK) is an established third-generation class 1A thrombolytic. The objective of the present study was to establish clinical biosimilarity of TNK biosimilar in a comparative phase III study with the reference product in the patients of ST elevation myocardial infarction (STEMI). Materials and Methods: In the double-blind, randomized, comparative clinical study 105 individuals were enrolled (70 in biosimilar TNK arm and 35 in the reference arm). Primary endpoint was thrombolysis in myocardial infarction (TIMI) 3-flow rate of the infarct-related artery at 90 min and all-cause mortality rate at 30 days' post dosing. Secondary endpoints considered were 50% resolution of elevated ST segment at 90 min, re-infarction till day 30, change in the left ventricular ejection fraction at day 30, events of ventricular tachyarrhythmias till day 30, and comparative pharmacokinetics. Immunogenicity was assessed along with the evaluation of safety at day 30. Results: TIMI grade 3-flow rate was achieved in 29 (43.28%) individuals in biosimilar arm and 14 (41.18%) individuals in the reference arm. The difference between the groups was statistically not significant (P = 0.8396). Four (5.71%) all-cause mortality were reported in biosimilar TNK arm compared to 2 (5.71%) in reference arm (all-cause mortality rate at 30 days' post dosing) and the difference between the two arms was statistically not significant (P = −1.00). Conclusion: Biosimilar TNK demonstrated biosimilar equivalence with the reference product in terms of the efficacy and safety analysis in this Phase III study and may be considered as a suitable alternative to reference TNK in patients with STEMI.

Keywords: STEMI, tenecteplase, thrombolysis, thrombolysis in myocardial infarction


How to cite this article:
Apsangikar P, Chaudhry S, Naik M, Deoghare S, Joseph J. Multicentric, randomized, double-blind, comparative study in STEMI patients to establish clinical biosimilarity of biosimilar tenecteplase with reference product. Ann Clin Cardiol 2019;1:8-14

How to cite this URL:
Apsangikar P, Chaudhry S, Naik M, Deoghare S, Joseph J. Multicentric, randomized, double-blind, comparative study in STEMI patients to establish clinical biosimilarity of biosimilar tenecteplase with reference product. Ann Clin Cardiol [serial online] 2019 [cited 2020 Aug 9];1:8-14. Available from: http://www.onlineacc.org/text.asp?2019/1/1/8/273002




  Introduction Top


Tenecteplase (TNK) is a genetically engineered variant of the alteplase molecule. Three different mutations result in an increase of the plasma half-life, of the resistance to plasminogen-activator inhibitor[1] and of the thrombolytic potency against platelet-rich thrombi. Among available agents in clinical practice, TNK is the most fibrin-specific molecule and can be delivered as a single bolus intravenous injection. Several large-scale clinical trials have enrolled more than 27,000 patients with acute myocardial infarction (AMI). TNK is equivalent to front-loaded alteplase in terms of mortality and is the only bolus thrombolytic drug for which this equivalence has been formally demonstrated.[1] TNK appears more potent than alteplase when symptoms duration lasts more than 4 h. In addition, TNK significantly reduces the rate of major bleeds and the need for blood transfusions.[1] According to a recent experience published, data of 15,222 patients who had STEMI and received weight-adjusted TNK injection were analyzed. Overall, 95.43% of patients had clinically successful thrombolysis (CST).[2] In the different subgroups, hypertensives, diabetics, smokers, and hyperlipidemic patients had CST rates comparable to the general patient data. CST rates were significantly lower in the elderly patients (>70 years; 92.11%; P < 0.0001), in patients with history of ischemic heart disease (93.86%; P¼ 0.0004) and in patients receiving delayed treatment (>6 h after onset of chest pain; 85.38%; P < 0.0001).[2] The efficacy of a half-dose TNK strategy compared to full-dose TNK and primary percutaneous coronary intervention in the elderly where it was shown to have similar efficacy.[3]

Biosimilars can have a major impact on the affordability and availability of premium biologics in all markets.[4] Apart from the physicochemical and biological characterization compared to the innovator product, it is equally important to establish the clinical similarity of the biosimilar with the innovator product according to the guidelines and geographical regulations. The present study is the phase III double-blind comparative clinical study of TNK biosimilar from Reliance life Sciences (TenecteRel™) to establish the clinical biosimilarity with innovator reference TNK.


  Materials and Methods Top


This was a double-blind, prospective, multi-center, randomized, two-arm, parallel group, active-control, comparative clinical study to evaluate efficacy and safety of biosimilar TNK/reference TNK in patients with ST-segment elevation myocardial infarction (STEMI). The study was approved by the Drug Controller General of India office, and the Clinical Trials Registry India (CTRI) registration number is CTRI/2016/09/007230. A total of 105 individuals were enrolled in the study, i.e., 70 individuals in biosimilar TNK arm and 35 individuals in the reference arm across 14 centers in India. The primary efficacy endpoint was the rate of thrombolysis in myocardial infarction (TIMI) 3-flow of the infarct-related artery at 90 min and all-cause mortality rate at 30 days' post dosing. A sample size of 105 individuals in a 2:1 ratio (Biosimilar TNK/reference TNK) was based on previous studies with angiographic endpoint, patency rate of 55%–65% at 90 min for a power of 80%. The innovator TNK being well established clinically, with an appropriate statistical plan approved from the regulatory authorities the individuals were distributed in 2:1 ratio for an enhanced exposure to the biosimilar TNK.

The centralized randomization provided by reliance statistical team was followed across all sites and individuals were assigned to the treatment groups according to randomization.

All individuals who had given written informed consent to participate in the study were assigned a sequential individual number at the screening visit. Individuals were randomly assigned to the two treatment groups in a 2:1 ratio. The randomization schedule was generated by statistician at Reliance Life Sciences. Once individual was found to be eligible for randomization, the site requested a randomization code for the subject. Randomization was managed centrally. The individual identification number was a unique number containing site number and patient number.

Of these 105 individuals, 101 individuals completed 90-min evaluation post dosing without any major protocol deviations that could affect efficacy assessments. Hence, these 101 individuals were included in per protocol population. All randomized individuals received study medication as per study protocol and were considered for intent to treat (ITT)/safety population. The first 24 individuals (12 individuals in each arm) were considered for pharmacokinetic analysis. A total of 57 patients on biosimilar TNK arm and 28 patients on reference arm completed the study. [Table 1] shows the individual disposition.
Table 1: Summary of subject disposition [ITT population (n=105)]

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Male and female individuals in the range of 18–65 years of age who presented with chest pain and/or equivalent symptoms within 6 h and diagnosis of ST-elevation myocardial infarction (STEMI) who were ready to consent and adhere to the study visit schedule and requirements were enrolled for the study. Individuals with left bundle branch block (LBBB), history of contraindication to the use of thrombolytics were excluded. individuals with internal active bleeding or known history of hemorrhagic diathesis, any known history of stroke or stroke of unknown origin in preceding 6 months, history of intracranial tumor, arteriovenous malformation, cerebral aneurysm, major surgery, parenchymal biopsy, ocular surgery and/or significant trauma within the past 2 months (this includes any trauma associated with the current AMI), high-risk individuals as per TIMI risk scoring[5] and individual with any other contraindications for thrombolysis were excluded from the study.

TNK (biosimilar TNK and reference TNK) was administered by single intravenous recommended dose based on the weight of the individual over approximately 10 s. A preexisting intravenous line could be used for administration of TNK in 0.9% sodium chloride solution only. Antithrombotic adjunctive therapy with platelet inhibitors and anticoagulants was allowed according to the relevant treatment guidelines for the management of patients with ST-elevation myocardial infarction. Unfractionated heparin or enoxaparin and antiplatelet agents were allowed as a concomitant therapy as per institutional standards. Acetylsalicylic acid was initiated as soon as possible after symptom onset.

Statistical analyses were performed using the SAS® statistical software (Version: 9.3; SAS® Institute Inc., USA). Comparative analysis was performed for primary and secondary endpoint data. Primary endpoint analysis, the proportion of individuals with rate of TIMI 3 flow of the infarct-related artery at 90 min and all-cause mortality rate at 30 days' post dosing between the treatment groups was estimated with their 95% confidence intervals.

The pharmacokinetic assessment was done in the first 24 individuals (12 individuals in each arm). A total of 14 samples (5 ml each) were collected for pharmacokinetic assessment. First sample (predose) was collected just prior to drug administration (0.00 h) and subsequent samples were collected at 5, 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h after the drug administration. Individuals were hospitalized for at least first 48 h after drug administration for efficacy, safety, and pharmacokinetic assessments. Laboratory investigations, electrocardiogram (ECG), and echocardiography were performed as per study schedule. The angiogram at 90 min was done after considering the clinical condition, other investigations such as ECG and risks associated with the procedure for individual subjects. The investigator decided the need of angiogram to evaluate the perfusion status based on the above considerations. The pharmacodynamic assessment was based on the ST elevation resolution at 90 min and cardiac enzymes level. The study duration for individual subjects was up to 30 days and subjects will be followed at 6 months and 1 year for survival data.

The primary endpoint was TIMI 3-flow rate of the infarct-related artery at 90 min and all-cause mortality rate at 30 days' post dosing. As the primary endpoint data for TIMI perfusion grades were individual to investigator assessment, the main primary endpoint was all-cause mortality rate at 30 days post dosing. Secondary endpoints considered were 50% resolution of elevated ST segment at 90 min, re-infarction till day 30, changes in the left ventricular ejection fraction assessed by echocardiography at day 30, events of ventricular tachyarrhythmias as determined at each ECG time-point till day 30, change from baseline in cardiac enzymes level, pharmacokinetic parameters assessment after the first dose, immunogenicity assessment at day 30 and evaluation of safety based on adverse events, physical examinations, vital signs, ECGs, echocardiography and safety laboratory tests at study visit (day 30).


  Results Top



  Efficacy Results Top


In biosimilar TNK arm, the mean age of the individuals was 52.5 years, mean height was 161.7 cm and mean weight was 64.5 kg. Of 70 individuals randomized in study arm, 54 (77.14%) individuals were male and 16 (22.86%) individuals were female.

In reference arm, the mean age of the individuals was 50.0 years, mean height was 162.7 cm and mean weight was 66.9 kg. Of 70 individuals randomized in biosimilar TNK arm, 33 (94.29%) individuals were male and 2 (5.71%) individuals were female.

The demographic characteristics of the individuals enrolled in biosimilar TNK and reference arms were comparable for age, height, and weight [Table 2].
Table 2: Demographics and Baseline Characteristics

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In biosimilar TNK arm, the mean age of the individuals was 52.5 years, mean height was 161.7 cm and mean weight was 64.5 kg. Of 70 individuals randomized in biosimilar TNK arm, 54 (77.14%) individuals were male and 16 (22.86%) individuals were female. In reference arm, the mean age of the individuals was 50.0 years, mean height was 162.7 cm and mean weight was 66.9 kg. Of 70 individuals randomized in the reference arm, 33 (94.29%) individuals were male and 2 (5.71%) individuals were female. The demographic characteristics of the individuals enrolled in biosimilar TNK and reference arms were comparable for age, height, and weight [Table 2].

History of preexisting risk factor has been included in study listings. Cardiac enzyme levels (creatine phosphokinase [CPK], CPK MB, Troponin T, and Troponin I) were monitored at baseline, 8, 16, 24, 48 h and predischarge. Cardiac enzyme levels were comparable between the groups.

During the study, vital signs were monitored at regular intervals and were comparable in the study and innovator groups.

Change in the left ventricular ejection fraction was assessed by echocardiography performed at baseline (within 48 h after admission) to day 30. The mean change from baseline in the left ventricular ejection fraction was 5.1% in biosimilar TNK arm and 6.0% in the reference arm. The difference between the two arms was statistically not significant (P = 0.6692). All patients enrolled in the study were with a definitive diagnosis of ST-elevation myocardial infarction (STEMI).

All parameters required for assessment of TIMI risk score (age, history of diabetes, hypertension or angina, systolic blood pressure <100 mmHg, Heart rate >100, Killip Class II-IV, Weight <67 kg, anterior ST elevation or LBBB and Time to treatment >4 h) were evaluated separately at baseline. However, analysis of TIMI risk score was not done as it was not required as per protocol defined study eligibility criteria.

Of 105 individuals enrolled in the study, angiography was performed in 101 individuals (i.e., 67 individuals in biosimilar TNK arm and 34 individuals in reference arm] at any time point. Of these 101 individuals, TIMI grade 3-flow rate was achieved in 29 (43.28%) individuals in biosimilar TNK arm and 14 (41.18%) individuals in the reference arm. The difference between the groups was statistically not significant (P = 0.8396) [Table 3].
Table 3: Summary of TIMI grade 3 flow rate of the infarct related artery (PP population)

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Out of 105 enrolled individuals (ITT/safety population), 29 (41.43%) individuals in biosimilar TNK arm and 14 (40.00%) individuals in reference arm achieved TIMI grade 3-flow rate. The difference between the groups was statistically not significant (P = 0.8884). In this study, total 06 deaths were reported i.e. 04 (5.71%) in biosimilar tenecteplase arm and 02 (5.71%) in reference arm. Of these 8 reported deaths in one year, 6 deaths were reported within 30 days of administration of the investigational product. Of these, 4 (5.71%) deaths were reported in biosimilar TNK arm compared to 2 (5.71%) deaths in reference arm (all-cause mortality rate at 30 days' post dosing). As shown in [Table 4], the difference between the all-cause mortality rate at 30 days' post dosing between the two arms was statistically not significant (P = 1.00).
Table 4: All-cause mortality rate at 30 days post dosing (ITT population)

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In terms of secondary endpoints, resolution of elevated ST segment was evaluated at 90 min ECG compared to baseline. In biosimilar TNK arm, 30 (42.86%) individuals achieved 50% resolution of elevated ST segment at 90 min compared to 14 (40.00%) individuals in reference arm. The difference in the two arms was statistically not significant (P = 0.7748). Myocardial re-infarction was monitored at each ECG evaluation time point till day 30. A total of 3 events of myocardial re-infarction (2 events at 90 min and 1 event at 24 h) were reported in biosimilar TNK arm compared to 1 event (at 60 min) reported in reference arm. Change in the left ventricular ejection fraction was assessed by echocardiography performed at baseline (within 48 h after admission) to day 30. The mean change from baseline the in left ventricular ejection fraction was 12.2% in biosimilar TNK arm and 14.4% in reference arm. The difference between the two arms was statistically not significant (P = 0.6715). The incidence of ventricular tachyarrhythmias was comparable in biosimilar TNK and reference arm at each ECG evaluation time point from baseline to day 30. The change in serum levels of all cardiac enzymes (CPK, CPK MB, Troponin T, and Troponin I) was comparable between the two arms at all evaluation time points. The descriptive statistics of baseline and end of the study for left ventricular ejection fraction did not show any statistically significant difference between both the groups.

For pharmacokinetic analysis, ratio analysis was performed for Ln-transformed pharmacokinetic parameters Cmax, AUC0-8, and AUC0-∞. Ln-transformed pharmacokinetic parameters Cmax, AUC0-8, and AUC0-∞ were evaluated considering the 90% confidence interval [Table 5]. For biosimilar TNK and reference product, mean Cmax was 12440 and 10916 ng/mL, AUC0-8 was 10815 and 8771 (ng × h/mL), and AUC0-∞ was 10953 and 9023 (ng × h/mL), respectively. The median tmax observed for both biosimilar TNK and reference product was 5 min. The median t1/2 observed for biosimilar TNK, and reference product was 0.84 and 1.123 h, respectively. The difference could be attributed to the less number of patients in the control group. The inter-individual variability of biosimilar TNK was much lower for Cmax compared to the reference. The inter-individual variability, whereas it was comparable for AUC0-8 and AUC0-∞ between both the arms. The ratios of the mean of Ln-transformed data (T/R ratio) for lnCmax, lnAUC0-8, and lnAUC0-∞ were 124.88, 124.50, and 121.94, respectively. The descriptive pharmacokinetics is given in [Table 5]. TNK being fibrin specific binds to fibrin in thrombus in the coronary artery/arteries depending on the extent of pathological thrombosis. Hence, serum concentration of TNK is likely to be variable because of its preferential distribution depending on the pathological thrombus and its extent.[6]
Table 5: Descriptive Pharmacokinetic Parameters

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Safety results

In this study, a total of 103 adverse events were reported out of which 66 were reported in the biosimilar TNK arm and 37 were reported in the reference arm. There were 37 (52.86%) individuals in biosimilar TNK arm and 17 (51.43%) individuals in the reference arm who had at least one treatment-emergent adverse event (TEAE). There were 1 (1.43%) individual in biosimilar TNK arm and 2 (5.71%) individuals in the reference arm with at least one TEAE related to study medication. There were 6 (8.57%) individuals in the biosimilar TNK arm and 2 (5.71%) individuals in the reference arm with at least one serious adverse event (SAE). A total of 9 SAEs were reported during this study. SAE term of one event was split into two separate terms for the medical dictionary of regulatory affairs (MedDRA) coding. Therefore, 9 SAEs were coded into 10 SAE terms (of which, 8 were reported in the biosimilar TNK arm and 2 were reported in the reference arm). Out of these, 3 SAEs were assessed as related (1 definitely related and 2 possibly related) to the investigational product, and 7 SAEs were unrelated to study medication. No individuals from biosimilar TNK or reference arm were discontinued from the study due to the adverse event. All adverse events were classified according to MedDRA version 19.1. The percentage of individuals with adverse events in each arm was compared, and the difference between the two arms was statistically nonsignificant (P > 0.05). The summary of all adverse events is presented in [Table 6].
Table 6: Overall summary of adverse events (ITT)

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According to system organ class in the biosimilar TNK arm, the most commonly reported (incidence ≥5%) TEAEs were related to General disorders and administration site conditions 11 (15.71%), respiratory, thoracic and mediastinal disorders 11 (15.71%), investigations 8 (11.43%), cardiac disorders 7 (10.00%), gastrointestinal disorders 4 (5.71%), nervous system disorders 4 (5.71%), and vascular disorders 4 (5.71%). In the reference arm, the most commonly reported (incidence ≥5%) TEAEs were related to general disorders and administration site conditions 10 (28.57%), gastrointestinal disorders 5 (14.29%), respiratory, thoracic and mediastinal disorders 3 (8.57%), cardiac disorders 2 (5.71%), infections and infestations 2 (5.71%), musculoskeletal and connective tissue disorders 2 (5.71%), and nervous system disorders 2 (5.71%). In biosimilar TNK arm, the reported cardiovascular adverse events included bradycardia 1 (1.43%), cardiac tamponade 1 (1.43%), cardiogenic shock 2 (2.86%), sinus tachycardia 1 (1.43%), ventricular fibrillation 1 (1.43%), and ventricular tachycardia 3 (4.29%). In reference arm, the reported cardiovascular adverse events included sinus tachycardia 1 (2.86%) and ventricular tachycardia 1 (2.86%).

In this study, a total of 8 deaths were reported, i.e., 06 (8.02%) in biosimilar TNK arm and 2 (5.71%) in reference arm. Of these 8 reported deaths, 6 deaths were reported within 30 days of administration of the investigational product. Of these, 4 (5.71%) deaths were reported in biosimilar TNK arm compared to 2 (5.71%) deaths in reference arm (all-cause mortality rate at 30 days' post dosing). The difference between the all-cause mortality rate at 30 days' post dosing between biosimilar TNK and reference arms was statistically not significant (P = 1.00). Overall, out of eight reported deaths, five were cardiorespiratory and three were noncardiac.


  Discussion Top


Following ST-segment elevation myocardial infarction (STEMI), early and complete epicardial reperfusion is associated with improved survival.[7] TNK is a third generation thrombolytic, a mutant of t-PA, modified in such a way that it has decreased plasma clearance, increased fibrin specificity and reduced sensitivity to plasminogen activator inhibitor-1.[8] The apparent improvement in side effects coupled with the ease of the administration of TNK t-PA makes it an attractive option in multiple settings.[8] The American College of Chest Physicians recognizes TNKase as a Class 1A recommendation in the treatment of STEMI patients within 12 h from the onset of symptoms.[9]

Ease of administration, rapid action (three times faster than tPA), potency (13.5-fold more potent in lysing platelet-rich clotsin vivo than tPA), weight-adjusted dosing - 0.53 mg/kg, highest fibrin specificity, reduced plasma clearance, high PAI-1 resistance (80-fold more than tPA), and less ICH make TNK a favored thrombolytic or best amongst the equals[10] and is preferred to be used in high risk subset of diabetics.[11]

Following the U.S. and EU guidelines, biosimilarity to a reference product has been demonstrated through analytical data, animal testing and one or more clinical studies, including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics. Further to the detailed characterization with physicochemical and biological orthogonal testing, the present study was designed to establish the clinical biosimilarity of TenecteRel™ (TNK) with that of innovator reference TNK in patients with ST-segment elevation myocardial infarction (STEMI). This was a prospective, multi-center, randomized, two-arm, parallel group, active-control, and comparative clinical study. The demographic characteristics of the individuals enrolled in biosimilar and reference TNK arms were comparable for age, height, and weight. The primary endpoints of the study, i.e., TIMI Grade 3-flow rate and 30 days' mortality were comparable in both treatments arms. Overall, TIMI Grade 3-flow rate was comparable between both the arms. Biosimilar TNK was also comparable to the reference product with respect to other efficacy parameters including 50% resolution of elevated ST segment at 90 min, change in left ventricular ejection fraction, changes in cardiac enzyme levels, myocardial re-infarction, and ventricular tachyarrhythmias. These findings support the comparable efficacy profile of biosimilar and reference TNK. Pharmacokinetics was assessed in the light of efficacy and safety profile of the two arms and the observed results have no bearing on the safety and efficacy profile of the drug as evident from its their comparable efficacy and safety profile. Further, the lower variability of biosimilar TNK for Cmax compared to reference, indicates a favorable pharmacokinetic profile of the Test formulation. As per the available literature, the safety observations are consistent with the known safety profile of TNK. Several studies have reported the similar adverse events observed during this study and therefore, considering the disease condition and the safety profile of the study medication, the SAEs in this study do not raise any new safety concern. Immunogenicity samples from all individuals were negative for antidrug antibodies against TNK. There were no apparent immunologically mediated safety or efficacy concerns reported in this study, and the results were consistent with the available literature on TNK.[11]


  Conclusion Top


TenecteRel™ (biosimilar TNK) has comparable efficacy profile to that of reference innovator TNK as evident from the efficacy variables analyzed between the treatment arms. The comparable adverse events support the similar safety profile. Overall, both drugs were well tolerated. The observed safety profile is in line with a known safety profile of TNK. No major safety concerns were noted during this study with biosimilar or reference TNK. Therefore, based on this comparability, TenecteRel™ (biosimilar TNK) may be considered as a suitable alternative to reference TNK in patients with ST-segment elevation myocardial infarction (STEMI).

Acknowledgment

We would like to acknowledge the investigators who participated in the study across the country and were instrumental in conducting and completion of the trial to generate data. Any opinions, findings, and conclusions expressed in this material are those of the authors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Melandri G, Vagnarelli F, Calabrese D, Semprini F, Nanni S, Branzi A. Review of tenecteplase (TNKase) in the treatment of acute myocardial infarction. Vasc Health Risk Manag 2009;5:249-56.  Back to cited text no. 1
    
2.
Iyengar SS, Nair T, Hiremath JS, Jadhav U, Katyal VK, Kumbla D, et al. Pharmacologic reperfusion therapy with indigenous tenecteplase in 15,222 patients with ST elevation myocardial infarction – The Indian registry. Indian Heart J 2013;65:436-41.  Back to cited text no. 2
    
3.
Shavadia HJ, Bainey K, Tyrrell B, Brass N, Paterson C, Knapp D, Wels RC. half-dose tenecteplase compared to conventional stsegment myocardial infarction (stemi) reperfusion strategies in the elderly: An observational analysis. Can J Cardiol 2015;31:S20-1.  Back to cited text no. 3
    
4.
Guillermin A, Yan DJ, Perrier A, Marti C. Safety and efficacy of tenecteplase versus alteplase in acute coronary syndrome: A systematic review and meta-analysis of randomized trials. Arch Med Sci 2016;12:1181-7.  Back to cited text no. 4
    
5.
Morrow DA, Antman EM, Charlesworth A, Cairns R, Murphy SA, de Lemos JA, et al. TIMI risk score for ST-elevation myocardial infarction: A convenient, bedside, clinical score for risk assessment at presentation: An intravenous nPA for treatment of infarcting myocardium early II trial substudy. Circulation 2000;102:2031-7.  Back to cited text no. 5
    
6.
Reliance Life Sciences. TenecteRelTM (Tenecteplase) Clinical Study Report. Ver. 1. Reliance Life Sciences; 2017. p. 1-45.  Back to cited text no. 6
    
7.
Yuri B, Pride C, Michael Gibson. Efficacy and safety of single-bolus tenecteplase compared with front-loaded alteplase in Chinese patients with acute myocardial infarction. J Geriatr Cardiol 2007;4:142-3.  Back to cited text no. 7
    
8.
Iyengar SS, Godbole GS. Thrombolysis in the era of intervention. J Assoc Physicians India Suppl 2011;59:26-30.  Back to cited text no. 8
    
9.
Iyengar SS, Nair T, Hiremath J, Dutta AL, Jadhav U, Katyal VK, et al. Pharmacological reperfusion therapy with tenecteplase in 7,668 Indian patients with ST elevation myocardial infarction – A real world Indian experience. J Assoc Physicians India 2017;65:43-7.  Back to cited text no. 9
    
10.
Saran RK, Sethi R, Nagori M. Tenecteplase – The best among the equals. Indian Heart J 2009;61:4454-8.  Back to cited text no. 10
    
11.
Sathyamurthy I, Jayanthi K, Iyengar SS, Hiremath JS, Kumbla D, Ramesh B. Efficacy and safety of tenecteplase in diabetic and non-diabetic patients of STEMI – Indian registry data. J Assoc Physicians India 2010;58:229-30.  Back to cited text no. 11
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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