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The Lancet

Volume 354, Issue 9180, 28 August 1999, Pages 716-722
The Lancet

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

https://doi.org/10.1016/S0140-6736(99)07403-6Get rights and content

Summary

Background

Bolus fibrinolytic therapy facilitates early efficient institution of reperfusion therapy. Tenecteplase is a genetically engineered variant of alteplase with slower plasma clearance, better fibrin specificity, and high resistance to plasminogen-activator inhibitor-1. We did a double-blind, randomised, controlled trial to assess the efficacy and safety of tenecteplase compared with alteplase.

Methods

In 1021 hospitals, we randomly assigned 16 949 patients with acute myocardial infarction of less than 6 h duration rapid infusion of alteplase (≥100 mg) or single-bolus injection of tenecteplase (30–50 mg according to bodyweight). All patients received aspirin and heparin (target activated partial thromboplastin time 50–75 s). The primary outcome was equivalence in all-cause mortality at 30 days.

Findings

Covariate-adjusted 30-day mortality rates were almost identical for the two groups—6·18% for tenecteplase and 6·15% for alteplase. The 95% one-sided upper boundaries of the absolute and relative differences in 30-day mortality were 0·61% and 10·00%, respectively, which met the prespecified criteria of equivalence (1% absolute or 14% relative difference in 30-day mortality, whichever difference proved smaller). Rates of intracranial haemorrhage were similar (0·93% for tenecteplase and 0·94% for alteplase), but fewer non-cerebral bleeding complications (26·43 vs 28·95%, p=0·0003) and less need for blood transfusion (4·25 vs 5·49%, p=0·0002) were seen with tenecteplase. The rate of death or non-fatal stroke at 30 days was 7·11% with tenecteplase and 7·04% with alteplase (relative risk 1·01 [95% Cl 0·91–1·13]).

Interpretation

Tenecteplase and alteplase were equivalent for 30-day mortality. The ease of administration of tenecteplase may facilitate more rapid treatment in and out of hospital.

Introduction

Rapid infusion of the tissue-plasminogen activator alteplase in association with aspirin and heparin, is the gold standard for pharmacological reperfusion in acute myocardial infarction. No other fibrinolytic regimen has been shown to be superior or equivalent to the administration of 100 mg alteplase given initially as a bolus followed by a step-down infusion over a period of 90 min (front-loaded approach) to lower 30-day mortality.1

Because of the ease of administration, bolus fibrinolysis facilitates rapid administration, including treatment before admission to hospital, and may ensure complete administration of the fibrinolytic agent, as well as a low rate of medication errors. Double-bolus administration of reteplase, a deletion mutant of alteplase with slower plasma clearance, was the first third-generation fibrinolytic. Apart from its ease of administration, the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-III) trial2 showed no efficacy or safety advantage for reteplase over front-loaded alteplase.2

Tenecteplase is a triple-combination mutant of alteplase developed to circumvent some of the limitations of current fibrinolytic therapies. Tenecteplase has a longer plasma half-life (20 vs 4 min), better fibrin specificity, and higher resistance to inhibition by plasminogen-activator inhibitor-1 than alteplase.3 Efficacy for clot lysis of single-bolus administration of tenecteplase was studied in the Thrombolysis in Myocardial Infarction (TIMI) 10A and TIMI 10B trials,4, 5 and safety was assessed in the Assessment of the Safety of a New Thrombolytic (ASSENT-1) study.6 The results of these studies suggested that a bodyweight-adjusted single bolus of 0·50–0·55 mg/kg tenecteplase would be equivalent to a 90 min regimen of alteplase for efficacy and safety. In this double-blind, randomised, controlled study, we formally tested this hypothesis.

Section snippets

Study population

We recruited patients from October, 1997, to November, 1998, in 1021 hospitals in 29 countries. To be eligible, patients had to: be aged 18 years or older; have onset of symptoms of acute myocardial infarction within 6 h before randomisation; have ST-segment elevations of 0·1 mV or more in two or more limb leads, or 0·2 mV or more in two or more contiguous precordial leads; or have left bundle-branch block. Exclusion criteria on admission were: hypertension, defined as systolic blood pressure

Randomisation and study treatments

After giving informed consent, patients were randomly assigned, through a central computerised telephone system, a bodyweight-adjusted bolus of tenecteplase plus bolus and infusion of placebo, or a bolus and infusion of alteplase plus bolus of placebo. We gave each patient a unique study number that corresponded with the number of a treatment kit.

Tenecteplase (or placebo) was administered over 5–10 s in a dose according to bodyweight: 30 mg to patients who weighed less than 60·0 kg, 35 mg to

Statistical analysis

We aimed to show therapeutic equivalence of single-bolus tenecteplase compared with front-loaded alteplase. To show equivalence or non-inferiority in all-cause mortality is judged to be an appropriate study approach to establish that a variant of a standard treatment achieves a clinical benefit similar to that of the standard treatment, provided that appropriate criteria of equivalence are prespecified.7, 8, 9 We adopted a stringent definition of equivalence and developed the null hypothesis

Results

16 949 patients were randomised between October, 1997, and November, 1998, of whom 16 504 received study medication (figure 1). In 445 patients (209 assigned tenecteplase, 236 assigned alteplase), no study medication was administered because of: detection of exclusion criteria after randomisation (135 patients), technical reasons, such as broken vials (49), death or adverse event immediately after randomisation (23), or other reasons (238), of which primary angioplasty (46), administration of

Discussion

Single-bolus tenecteplase was equivalent to front-loaded alteplase in the effect on 30-day mortality. The upper boundaries (0·61% and 10·00%) were well below the prespecified upper confidence limits of equivalence of 1% or 14%.

There was no particular subgroup of patients in whom tenecteplase or alteplase was significantly better, with the exception of patients treated after 4 h; this group had a better outcome with tenecteplase, with a significant absolute 2% difference in 30-day mortality. As

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