Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction

doi:10.1016/S0140-6736(01)05775-0

The Lancet

Volume 358, Issue 9282, 25 August 2001, Pages 605-613

https://doi.org/10.1016/S0140-6736(01)05775-0 Get rights and content

Summary

Background

Current fibrinolytic therapies fail to achieve optimum reperfusion in many patients. Low-molecular-weight heparins and platelet glycoprotein IIb/IIIa inhibitors have shown the potential to improve pharmacological reperfusion therapy. We did a randomised, open-label trial to compare the efficacy and safety of tenecteplase plus enoxaparin or abciximab, with that of tenecteplase plus weight-adjusted unfractionated heparin in patients with acute myocardial infarction.

Methods

6095 patients with acute myocardial infarction of less than 6 h were randomly assigned one of three regimens: full-dose tenecteplase and enoxaparin for a maximum of 7 days (enoxaparin group; n=2040), half-dose tenecteplase with weight-adjusted low-dose unfractionated heparin and a 12-h infusion of abciximab (abciximab group; n=2017), or full-dose tenecteplase with weight-adjusted unfractionated heparin for 48 h (unfractionated heparin group; n=2038). The primary endpoints were the composites of 30-day mortality, in-hospital reinfarction, or in-hospital refractory ischaemia (efficacy endpoint), and the above endpoint plus in-hospital intracranial haemorrhage or in-hospital major bleeding complications (efficacy plus safety endpoint). Analysis was by intention to treat.

Findings

There were significantly fewer efficacy endpoints in the enoxaparin and abciximab groups than in the unfractionated heparin group: 233/2037 (11·4%) versus 315/2038 (15·4%; relative risk 0·74 [95% CI 0·63–0·87], p=0·0002) for enoxaparin, and 223/2017 (11·1%) versus 315/2038 (15·4%; 0·72 [0·61–0·84], p<0·0001) for abciximab. The same was true for the efficacy plus safety endpoint: 280/2037 (13·7%) versus 347/2036 (17·0%; 0·81 [0·70–0·93], p=0·0037) for enoxaparin, and 287/2016 (14·2%) versus 347/2036 (17·0%; 0·84 [0·72–0·96], p=0·01416) for abciximab.

Interpretation

The tenecteplase plus enoxaparin or abciximab regimens studied here reduce the frequency of ischaemic complications of an acute myocardial infarction. In light of its ease of administration, tenecteplase plus enoxaparin seems to be an attractive alternative reperfusion regimen that warrants further study.

Introduction

Tenecteplase—a genetically engineered variant of alteplase—has provided a new standard of fibrinolytic therapy by virtue of its equivalent efficacy with regard to 30-day mortality, its reduced propensity for systemic bleeding complications, and its simple administration as a bolus.¹ Despite these advantages, however, there are still substantial challenges, including suboptimal macroperfusion and microperfusion, recurrent ischaemia, and reinfarction and intracranial haemorrhage, in the optimum care of patients with acute myocardial infarction.2, 3

Antithrombotic agents are an important component of pharmacological reperfusion therapy for acute myocardial infarction. At present, unfractionated heparin and aspirin are routinely given to most patients. Low-molecular-weight heparins have only recently been studied with fibrinolytics. Unlike unfractionated heparin, low-molecular-weight heparins have more predictable kinetics, are less protein-bound, have less potential for platelet activation, and require no monitoring, providing a strong rationale for potentially better outcomes when given in combination with fibrinolytics.⁴ Most studies have shown either less reocclusion, enhanced late patency of the infarct-related vessel, or a reduction in reinfarction rate when compared with unfractionated heparin.5, 6, 7, 8 Largescale studies with low-molecular-weight heparins have not previously been done.

Pilot studies with platelet glycoprotein IIb/IIIa inhibitors and reduced-dose fibrinolytic agents have shown better patency of the epicardial infarct-related artery, and signs of improved tissue reperfusion.9, 10, 11 The phase III Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-V trial showed a reduction in ischaemic complications of acute myocardial infarction with half-dose reteplase and abciximab compared with full-dose reteplase.¹² That trial, however, failed to show a significant reduction in 30-day mortality and there was a significant increase in non-cerebral bleeding complications.

The treatment of acute myocardial infarction requires combination of several therapies. We therefore did a large exploratory trial to develop evidence about whether specific combinations might provide clinical benefit. The aim of the study was to compare the efficacy and safety of three antithrombotic conjunctive therapies with tenecteplase: the first was the low-molecular-weight heparin enoxaparin given up to discharge or revascularisation for a maximum of 7 days; the second was the platelet glycoprotein IIb/IIIa inhibitor abciximab for 12 h; and the third was weight-adjusted unfractionated heparin for 48 h according to the guidelines of the American College of Cardiology and the American Heart Association (ACC/AHA).¹³

Section snippets

Patients

We recruited patients in 575 hospitals in 26 countries. Inclusion criteria were identical to those of the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-2 trial:¹ age 18 years or older, onset of symptoms less than 6 h before randomisation, ST-segment elevation of at least 0·1 mV in two or more limb leads or at least 0·2 mV in two or more contiguous precordial leads, or left bundle-branch block. Exclusion criteria on admission were: systolic blood pressure of more

Results

6095 patients were enrolled between May, 2000, and April, 2001, of whom 5989 received study medication (figure 1). The baseline characteristics were similar in the three groups (table 1). Overall, the study populations were similar to those of previous trials on thrombolytics. As expected, the time from randomisation to bolus tenecteplase was significantly longer in the abciximab group because of the complexity of the treatments and the need to give the boluses of heparin and abciximab before

Discussion

The results of the group treated with full-dose tenecteplase and weight-adjusted unfractionated heparin in this trial were very similar to those of ASSENT-2. In ASSENT-2, a higher and not fully weight-adjusted dose of unfractionated heparin was given and the first partial thromboplastin time was measured 6 h after start of treatment. Nonetheless, total mortality, reinfarction, total stroke, and intracranial haemorrhage rates were almost identical in both trials. However, there were fewer major

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Cited by (803)

A bibliometric analysis of tenecteplase research utilizing a commonly used citation index
2024, Clinical Neurology and Neurosurgery
Tenecteplase is increasingly being used as a first-line treatment for acute ischemic stroke after several randomized studies demonstrated its safety and efficacy, resulting in a massive increase in the number of published studies on this topic. Our aim was to investigate the most impactful authors and relevant journals that have been instrumental in validating this treatment, in hopes of identifying objective research trends that may assist scientists, health organizations, and funding agencies to collaborate and plan future avenues of research.
Using the search terms “Tenecteplase” and “Tenecteplase” AND “Stroke,” 2683 and 1150 references were queried, respectively, using the abstract and citation database, Scopus. Scopus Citation Analysis was used to categorize the countries and authors who produced the most research. Metadata was retrieved and transferred to bibliographic visualization software, VOSviewer, for co-authorship and co-occurrence analyses to identify trends in tenecteplase research.
Data visualization software identified three tenecteplase research clusters – myocardial infarction, pulmonary embolism, and acute ischemic stroke. Our bibliographic analysis graphically identified that ischemic stroke currently leads both myocardial infarction and pulmonary embolism in annual publications pertaining to tenecteplase therapy, and further pinpointed perfusion imaging and wake-up strokes as the most relevant areas of study. The United States led all countries in tenecteplase publications, including exclusively stroke studies. The European Heart Journal led all journals in overall publications, while Stroke led all journals in stroke-related studies.
Through the use of bibliographic analysis and data visualization, we identified major articles and journals that reflected and shaped the current landscape of tenecteplase; recognized authors who engaged in tenecteplase research as it progressed from cardiopulmonary disease to stroke; and postulated future avenues of research.
Biosimilarity. Do not confuse biosimilar and biocopy. Example of tenecteplase
2023, Annales Pharmaceutiques Francaises
Non-innovator biological products (NIBPs) or ‘biocopies’ are available in several countries at lower prices than biosimilars. These drugs, sometimes so-called ‘biosimilars’, may not meet all of the quality criteria expected of clinically equivalent products. NIBPs can exhibit major differences in physicochemical and pharmacological properties compared with their reference biological but may be presented to prescribers based on clinical trial data and claimed clinical equivalence. Tenecteplase (TNK-tpA) is a recombinant derivative of tissue plasminogen activator, used as a third-generation thrombolytic agent for treatment of acute myocardial infarction. A TNK-tPA presented as biosimilar to the originator (Metalyse®, Boehringer Ingelheim; TNKase®, Roche/Genentech) is now available for use in India (Elaxim®, Gennova Pharmaceuticals). Elaxim® is not approved in Europe or the USA but has been proposed in several countries as a replacement for the originator. Based on available literature, we discuss why this biocopy cannot be considered biosimilar to the originator tenecteplase. We describe clear differences in physicochemical and pharmacological properties. For example, the biocopy demonstrates clot lysis activity that is substantially lower than the originator and contains high concentrations of foreign proteins that confer potential for immunological reactions. Clinical data on the biocopy are limited; randomized trials to demonstrate the absence of difference in efficacy and safety between the biocopy and originator have not been conducted. This example demonstrates that confirmation of similarity, by close examination of pharmaceutical quality attributes, and preclinical and clinical data, is mandatory before presenting to prescribers a biological product as clinically equivalent.
Des produits biologiques non innovants (MIBP) ou « biocopies » sont disponibles dans plusieurs pays à des prix inférieurs à ceux des biosimilaires. Ces soi-disant « biosimilaires », autorisés dans les pays à faible revenu, peuvent ne pas répondre à tous les critères de qualité attendus pour des produits cliniquement équivalents. Les MIBP peuvent ainsi présenter des différences majeures des propriétés physicochimiques et pharmacologiques par rapport à leur produit de référence, mais peuvent n’être présentés aux prescripteurs essentiellement que sur la base d’essais cliniques cherchant à prouver l’équivalence clinique revendiquée. La ténectéplase (TNK-tpA) est un dérivé recombinant de l’activateur tissulaire du plasminogène, utilisé comme agent thrombolytique de troisième génération pour le traitement de l’infarctus aigu du myocarde. Un TNK-tPA présenté comme biosimilaire au princeps (Metalyse®, Boehringer Ingelheim; TNKase®, Roche/Genentech) est désormais disponible en Inde (Elaxim®, Gennova Pharmaceuticals). Elaxim® n’est pas homologué en Europe ni aux États-Unis mais a été proposé dans plusieurs pays en remplacement du princeps. Sur la base de la littérature disponible, nous discutons des raisons pour lesquelles cette biocopie ne peut pas être considérée comme biosimilaire à la ténectéplase d’origine. Nous décrivons des différences notables dans les propriétés physicochimiques et pharmacologiques. Par exemple, la biocopie démontre une activité de lyse du caillot qui est sensiblement inférieure à celle de l’original et contient des concentrations élevées de protéines étrangères qui confèrent un potentiel de réactions immunologiques. Les données cliniques sur la biocopie sont limitées; des essais randomisés pour démontrer l’absence de différence d’efficacité et de sécurité entre la biocopie et le princeps n’ont pas été menés. Cet exemple démontre que la confirmation de la similarité, par un examen attentif des attributs de qualité pharmaceutique et des données précliniques et cliniques, est obligatoire avant de présenter aux prescripteurs un produit biologique comme cliniquement équivalent.
Rationale and design of the RIGHT trial: A multicenter, randomized, double-blind, placebo-controlled trial of anticoagulation prolongation versus no anticoagulation after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction
2020, American Heart Journal
Current guidelines recommend anticoagulation therapy during primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI). However, whether anticoagulation should be continued after pPCI has not been well investigated.
The RIGHT trial is a prospective, multicenter, randomized, double-blind, placebo-controlled trial in STEMI patients treated with pPCI evaluating the prolongation of anticoagulation after the procedure. Patients are randomized in a 1:1 fashion to receive either prolonged anticoagulant or matching placebo (no anticoagulation) for at least 48 hours after the procedure. When randomized to anticoagulation prolongation, the patient is assigned to intravenous unfractionated heparin (UFH) or subcutaneous enoxaparin or intravenous bivalirudin (same drug and same regimen at each center). The primary efficacy endpoint is the composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, stent thrombosis (definite) or urgent revascularization (any vessel) at 30 days. The primary safety endpoint is major bleeding (BARC 3-5) at 30 days. Based on a superiority design and assuming a 35% relative risk reduction (from 7% to 4.5%), 2856 patients will be enrolled, accounting for a 5% drop-out rate (α = 0.05 and power = 80%).
The RIGHT trial tests the hypothesis that post-procedural anticoagulation is superior to no anticoagulation in reducing ischemic events in STEMI patients undergoing pPCI.
The Second Strategic Reperfusion Early After Myocardial Infarction (STREAM-2) study optimizing pharmacoinvasive reperfusion strategy in older ST-elevation myocardial infarction patients
2020, American Heart Journal
The STREAM study demonstrated that a pharmaco-invasive strategy was at least as effective as primary PCI (pPCI) in patients presenting early with ST-elevation myocardial infarction (STEMI). The current trial is a response to the finding that reduced intracranial hemorrhage (ICH) in patients ≥75 years occurred after halving the dose of tenecteplase. Additionally, a subsequent analysis of full dose tenecteplase or alteplase in the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT) trials demonstrated a steep increase in bleeding events beginning around the age of 60 years.
STREAM-2 will compare the efficacy and safety of a novel pharmaco-invasive strategy as compared to routine pPCI in STEMI patients ≥60 years presenting within 3 hours from symptom onset. In the pharmaco-invasive arm patients will receive half-dose tenecteplase, as soon as possible before transport to a PCI center. In the pPCI arm, patients will be treated according to optimal standard of care defined by local practice. The key criteria for efficacy will be the number of patients achieving ≥50% ST-segment resolution before and after PCI in lead with maximal ST elevation at baseline and the clinical endpoints of death, congestive heart failure, shock or re-infarction, rescue PCI and aborted myocardial infarction, both singularly and as a composite at 30 days. Key safety criteria are total stroke, ICH and major non-intracranial bleeds. Approximately 600 patients will be randomized (400 to pharmaco-invasive treatment and 200 to pPCI). An interim analysis is planned after 300 patients are enrolled to consider adapting the trial to include a larger sample size aimed at undertaking a formal confirmatory trial.
The study will provide new insights aimed at establishing an effective and safer pharmaco-invasive treatment for the growing population of older STEMI patients who cannot undergo timely pPCI.
αIIbβ3 (GPIIb-IIIa) antagonists
2019, Platelets
Platelets play a key role in thrombosis and hemostasis, especially during an acute coronary syndrome and in patients undergoing percutaneous coronary intervention. Associated adverse cardiovascular events from normal platelet function can be mitigated via adequate platelet inhibition. Glycoprotein IIb-IIIa (αIIbβ3) antagonists were first introduced to the market with the intent of being potent, intravenous, antiplatelet agents with a quick onset of action. These agents have been the centerpiece of multiple well conducted investigations over the last several decades. In this chapter, we briefly discuss the pharmacological mechanism and subtle differences between the three currently available intravenous glycoprotein IIb-IIIa antagonists: abciximab, eptifibatide, and tirofiban. Furthermore, we present data from landmark clinical trials highlighting the efficacy and safety of these agents in various clinical scenarios. Lastly, we present a comparison between these agents and other antiplatelet drugs as well as the role of these agents in our modern-day clinical practice.
Comparative efficacy and safety of reperfusion therapy with fibrinolytic agents in patients with ST-segment elevation myocardial infarction: a systematic review and network meta-analysis
2017, The Lancet
Fibrinolytic therapy offers an alternative to mechanical reperfusion for ST-segment elevation myocardial infarction (STEMI) in settings where health-care resources are scarce. Comprehensive evidence comparing different agents is still unavailable. In this study, we examined the effects of various fibrinolytic drugs on clinical outcomes.
We did a network meta-analysis based on a systematic review of randomised controlled trials comparing fibrinolytic drugs in patients with STEMI. Several databases were searched from inception up to Feb 28, 2017. We included only randomised controlled trials that compared fibrinolytic agents as a reperfusion therapy in adult patients with STEMI, whether given alone or in combination with adjunctive antithrombotic therapy, against other fibrinolytic agents, a placebo, or no treatment. Only trials investigating agents with an approved indication of reperfusion therapy in STEMI (streptokinase, tenecteplase, alteplase, and reteplase) were included. The primary efficacy outcome was all-cause mortality within 30–35 days and the primary safety outcome was major bleeding. This study is registered with PROSPERO (CRD42016042131).
A total of 40 eligible studies involving 128 071 patients treated with 12 different fibrinolytic regimens were assessed. Compared with accelerated infusion of alteplase with parenteral anticoagulants as background therapy, streptokinase and non-accelerated infusion of alteplase were significantly associated with an increased risk of all-cause mortality (risk ratio [RR] 1·14 [95% CI 1·05–1·24] for streptokinase plus parenteral anticoagulants; RR 1·26 [1·10–1·45] for non-accelerated alteplase plus parenteral anticoagulants). No significant difference in mortality risk was recorded between accelerated infusion of alteplase, tenecteplase, and reteplase with parenteral anticoagulants as background therapy. For major bleeding, a tenecteplase-based regimen tended to be associated with lower risk of bleeding compared with other regimens (RR 0·79 [95% CI 0·63–1·00]). The addition of glycoprotein IIb or IIIa inhibitors to fibrinolytic therapy increased the risk of major bleeding by 1·27–8·82-times compared with accelerated infusion alteplase plus parenteral anticoagulants (RR 1·47 [95% CI 1·10–1·98] for tenecteplase plus parenteral anticoagulants plus glycoprotein inhibitors; RR 1·88 [1·24–2·86] for reteplase plus parenteral anticoagulants plus glycoprotein inhibitors).
Significant differences exist among various fibrinolytic regimens as reperfusion therapy in STEMI and alteplase (accelerated infusion), tenecteplase, and reteplase should be considered over streptokinase and non-accelerated infusion of alteplase. The addition of glycoprotein IIb or IIIa inhibitors to fibrinolytic therapy should be discouraged.
None.

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Fast track — ArticlesEfficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

Am Heart J

Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial

Lancet

Thrombolysis for acute myocardial infarction

Circulation

Fibrinolysis for acute myocardial infarction. Current status and new horizons for pharmacological reperfusion, part I

Circulation

Low molecular weight heparins in the treatment of acute coronary syndromes

Arch Intern Med

A randomized comparison of low-molecular-weight heparin enoxaparin and unfractionated heparin adjunctive to t-PA thrombolysis and aspirin (HART II)

Circulation

Fast track — Articles
Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction