This study was a double-blind, randomised equivalency trial with 16,949 STEMI patients in 29 countries to receive either
- 100 mg alteplase infused over 90 minutes or
- 30-50 mg tenecteplase administered as a single bolus over 5-10 seconds, dosed according to body weight (0.50-0.55 mg/kg ), which is identical to the recommendation in the current licence for Metalyse®.
The efficacy results from TIMI 10B and the safety data from ASSENT-1 suggested that a tenecteplase dose of 0.53 mg/kg represented the inflection point between continuous reperfusion benefit with increasing dose and the plateau of no further benefit with further increasing doses. Therefore, this dose was selected for testing against front-loaded alteplase in the ASSENT-2 phase III mortality trial.
Additionally all patients received:
- aspirin, 150-325 mg as soon as possible, followed by 15-325 mg daily, and
- heparin, bolus of 4000 U and infusion of 800 U/h for patients who weighted 67 kg or less or 5000 U bolus and infusion of 1000 U/h for patients who weighted more, adjusted to maintain an activated partial thromboplastin time of 50-75 seconds for 48-72 hours.
The primary endpoint of the study was all-cause mortality at 30 days, secondary endpoints included net clinical benefit (absence of death or non-fatal stroke at 30 days), major non-fatal cardiac events in hospital, and stroke.
ASSENT-2: Study design
Overall, 30-day mortalities for treated patients were almost identical:
- 6.18% in the tenecteplase group and
- 6.15% in the alteplase group.
The one-sided 95% CI of the absolute and relative differences in 30-day mortality fulfilled the pre-specified criteria of equivalence. There was no subgroup of patients with significant differences between tenecteplase and alteplase, with the exception of patients treated after 4-6 hours from symptom onset. This group benefits from a statistically significant absolute difference of 2.2% in 30-day mortality (7.0% for tenecteplase versus 9.2% for alteplase, p=0.018). The higher fibrin specificity of tenecteplase compared to alteplase probably leads to better dissolution of older thrombi.
ASSENT-2: 30-day mortality confirms equivalence of tenecteplase and alteplase
ASSENT-2: 30-day mortality in patient subgroups
In the tenecteplase group significantly fewer major bleeding complications occurred, resulting in a significantly lower need for blood transfusions, probably because of the higher fibrin specificity of tenecteplase.
Rates of total stroke were comparable in both treatment groups:
- 1.78% for tenecteplase and
- 1.66% for alteplase.
Rates of intracranial haemorrhage (ICH) were similar, too. Overall, the stroke rates seen in ASSENT-2 were similar to those seen in earlier trials such as GUSTO-III.
ASSENT-2: Frequency of non-intracranial bleeding complications
ASSENT-2: Frequency of strokes
Increasing age, low body weight, history of hypertension and systolic blood pressure >140 mm/Hg on admission were independent risk factors identified by multivariate analysis, similar to those reported in other trials. Patients that are generally considered to be at high risk of ICH did not have particularly high rates of ICH when treated with tenecteplase. In fact, patients with the composite risk profile of being female, age >75 years and weight <67 kg tended to have lower rates of ICH when treated with tenecteplase (3/264, 1.14%) than with alteplase (8/265, 3.02%). Such observations confirm the safety of tenecteplase in high-risk patients.
ASSENT-2: Risk factors for intracranial haemorrhage
The total mortality rate of 9.2% with single-bolus tenecteplase and 9.1% of front-loaded alteplase remain equivalent after one year. The lower 30-day mortality rate in patients treated 4-6 hours after onset of symptoms persisted at one year follow-up, but was no longer statistically significant.
The results of ASSENT-2 confirm that tenecteplase is equivalent to alteplase in treatment of AMI with respect to the 30-day and one year outcomes for mortality and the combined outcomes for mortality and non-fatal stroke.
ASSENT-2: One year follow-up