ASSENT-3 / -3 PLUS
As current fibrinolytic therapies fail to achieve optimum reperfusion in many patients and low-molecular-weight heparins and platelet glycoprotein IIb/IIIa inhibitors have shown the potential to improve pharmacological reperfusion therapy in the HART II trial, the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 study, compared 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.
The ASSENT-3 Plus trial was a trial of pre-hospital fibrinolysis with tenecteplase randomly assigned to enoxaparin or unfractionated heparin, that involved 106 sites in 12 countries incorporating a wide variation in population density, emergency medical services resources, and physician's interpretation of ECG and administering pre-hospital fibrinolysis. Understanding this diversity will help in evaluating the general applicability and feasibility of pre-hospital fibrinolysis in various health systems, as well as the pre-hospital care of ST elevation myocardial infarction patients regardless of reperfusion strategies.
The ASSENT-3 trial was a randomised, open-label trial designed to compare the efficacy and safety of tenecteplase plus enoxaparin or abciximab, with that of tenecteplase plus weight-adjusted unfractionated heparin. A total of 6095 patients with acute myocardial infarction were randomised to one of three open-label regimens:
- Full-dose tenecteplase and enoxaparin (a low molecular weight heparin) for a maximum of 7 days (n=2040).
- Half-dose tenecteplase with weight-adjusted low-dose unfractionated heparin and a 12-hour infusion of abciximab (n=2017).
- Full-dose tenecteplase with weight-adjusted unfractionated heparin for 48 hours (n=2038). The chart shows the overall trial profile.
ASSENT-3: Study design
At 48 hours, the end of the unfractionated heparin infusion, differences in the primary endpoints among the three groups were already present.
For the primary efficacy endpoint, event rates were:
- 6.1% for full-dose tenecteplase plus enoxaparin,
- 5.2% for half-dose tenecteplase plus abciximab, and
- 8.8% for full-dose tenecteplase plus unfractionated heparin (P<0.0001).
At 30 days, when compared with full-dose tenecteplase and unfractionated heparin, full-dose tenecteplase with enoxaparin and halfdose tenecteplase with abciximab were associated with significant reductions in the primary end points: 15.4% vs 11.4% vs 11.1%, respectively for the efficacy composite endpoint (3 way P<0.0001). The Kaplan-Meier curves for the enoxaparin and abciximab arms start to separate early from that of unfractionated heparin.
The results of the primary efficacy endpoint are shown here in a bar graph after correcting for multiple testing (Bonferroni). Conventional significance was reached for the primary efficacy endpoint when the enoxaparin group was compared to the unfractionated heparin group (p=0.0009) and when the abciximab group was compared to the unfractionated heparin group (p=0.0002).
ASSENT-3: Efficacy endpoints
Kaplan-Meier curves for the primary efficacy and safety composite endpoint show that differences were already apparent between the three groups at 48 hours, the end of the unfractionated heparin infusion. For the primary efficacy and safety endpoint, event rates were 8.1% for full dose tenecteplase plus enoxaparin, 8.2% for half dose tenecteplase plus abciximab, and 10.3% for full-dose tenecteplase plus unfractionated heparin.
At 30 days, when compared with full-dose tenecteplase and unfractionated heparin, full-dose tenecteplase with enoxaparin and half-dose tenecteplase with abciximab were associated with significant reductions in the efficacy plus safety composite end point. Again, the curves for the enoxaparin and abciximab arms start to separate early from that of unfractionated heparin. There does not appear to be any early hazard associated with the therapy. Most of the benefit appeared to accure during the first week of therapy. There did not appear to be any rebound after discontinuation of the enoxaparin after the first week.
ASSENT-3: Efficacy plus safety endpoints
However, just as in GUSTO-V, the benefit of increased patency is achieved at a price in terms of higher rates of thrombocytopenia, major bleeding complications and blood transfusions. It is particularly noteworthy that no benefit and perhaps even harm was observed in patients above 75 years and in diabetics, suggesting a need for caution in both groups.
ASSENT-3: Rates of in-hospital thrombocytopenia and bleeding episodes
The results of the primary efficacy and safety composite endpoint are presented in a graphic format. When compared with full-dose tenecteplase and unfractionated heparin, full-dose tenecteplase with enoxaparin and half-dose tenecteplase with abciximab were associated with significant reductions in the efficacy plus safety composite endpoint (3 way p=0.0062).
For the comparison of full-dose tenecteplase plus enoxaparin vs fulldose tenecteplase plus unfractionated heparin the P value was 0.0037 for the primary efficacy and safety endpoint. For the comparison of half-dose tenecteplase plus abciximab vs full-dose tenecteplase plus unfractionated heparin the P-value was 0.0142 for the primary efficacy and safety endpoint. After correcting for multiple testing (Bonferroni), conventional significance was reached for the primary efficacy and safety endpoint at 30 days in the enoxaparin group (p=0.0146) but not in the abciximab group (p=0.057). A 3 way P value showed no statistically significant difference across the 3 arms in 30-day mortality.
ASSENT-3: 30-day mortality
The ASSENT-3 PLUS satellite study was the first large randomised study to evaluate the feasibility and efficacy of pre-hospital thrombolysis in a multinational environment. It compared tenecteplase administered prior to hospital arrival against the full-dose tenecteplase cohort in the ASSENT-3 trial treated in hospital. A total of 1639 patients with ST elevation myocardial infarction and chest pain of less than 6 hours duration were evaluated at home or in ambulance by an emergency medical team. In each case, a 12-lead ECG was transmitted to the Emergency Department from the ambulance, and patients were randomised to one of two treatment groups, with treatment started during transport:
- tenecteplase plus IV bolus of 30 mg enoxaparin followed by 1 mg/kg subcutaneously BID for up to 7 days (n=818).
- tenecteplase plus weight-adjusted unfractionated heparin for 48 hours (n=821).
ASSENT-3 PLUS: Trial profile
ASSENT-3 PLUS clearly supports the concept that early treatment is beneficial as “Time is Muscle”:
Symptom onset to treatment times were reduced by 47 minutes. 53% of patients were treated within 2 hours, which represents a significant improvement over ASSENT-3, in which only 29% of the 4,000 patients receiving the same regimens in the hospital setting were treated within the same time period.
Earlier treatment was associated with improved 30-day mortality:
- 4.4% among those treated at 0-2 hours,
- 6.2% among those treated at 2-4 hours, and
- 10.4% among those treated at 4-6 hours.
In subgroup analysis, intracranial haemorrhage was found to be greater in the enoxaparin group in patients more than 75 years old (6.7 versus 0.8% p=0.04). Such patients represent a higher-risk population, which may explain the non-statistically significant trend toward increased major bleeding in the enoxaparin group (4.04% vs. 2.80%, p=0.168). Therefore, reduced or weight-adjusted dosing of enoxaparin may be warranted in these patients.
- Ross et al. Randomized comparison of enoxaparin, a low-molecular-weight heparin, with unfractionated heparin adjunctive to recombinant tissue plasminogen activator thrombolysis and aspirin: second trial of Heparin and Aspirin Reperfusion Therapy (HART II). ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001; 358 (9282): 605–613.
- Wallentin et al. Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003; 108 (2): 135–142.