Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Tenecteplase plus enoxaparin or abciximab was better than tenecteplase plus unfractionated heparin for acute MI

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ACP J Club. 2002 Mar-Apr;136:43. doi:10.7326/ACPJC-2002-136-2-043

Related Content in this Issue
• Companion Abstract and Commentary: Reteplase plus abciximab and reteplase alone led to similar 30-day mortality rates in acute MI


Source Citation

The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (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 Aug 25;358:605-13. [PubMed ID: 11530146]


Abstract

Question

In patients with acute myocardial infarction (MI), what is the efficacy and safety of tenecteplase (TNK) plus enoxaparin, TNK plus unfractionated heparin (UFH), or half-dose TNK plus abciximab?

Design

Randomized (allocation concealed*), blinded (assessors of stroke outcomes),* controlled trial with 30-day follow-up.

Setting

575 hospitals in 26 countries.

Patients

6095 patients who were ≥ 18 years of age (mean age 61 y, 76% men) and had acute MI of < 6 hours, ST-segment elevation ≥ 0.1 mV in ≥ 2 limb leads or ≥ 0.2 mV in ≥ 2 contiguous precordial leads, or left bundle-branch block. Exclusion criteria included elevated blood pressure, recent glycoprotein IIb or IIIa inhibitor use, and various other diseases and conditions. Follow-up was 99.9%.

Intervention

Patients were allocated to receive full-dose TNK plus enoxaparin (enoxaparin was given intravenously as a 30-mg bolus and subcutaneously at 1 mg/kg of body weight every 12 h for up to 7 d) (enoxaparin group, n = 2040); half-dose TNK plus weight-adjusted low-dose UFH plus abciximab (abciximab was given as a 0.25 mg/kg bolus and 0.125 µg/kg per min infusion for 12 h) (abciximab group, n = 2017); or full-dose TNK plus UFH (UFH was given as a 60 U/kg bolus and 12 U/kg per h infusion for 48 h) (UFH group, n = 2038). Full TNK doses ranged between 30 and 50 mg, and half doses ranged between 15 and 25 mg, according to body weight.

Main outcome measures

Main outcomes were the composite end point of 30-day mortality, in-hospital reinfarction, or in-hospital refractory ischemia (composite efficacy end point) and the composite end point that included the composite efficacy end point plus in-hospital intracranial hemorrhage or in-hospital major bleeding (composite efficacy plus safety end point).

Main results

Analysis was by intention to treat. Lower rates of the composite efficacy end point were seen in the enoxaparin (P < 0.001) and abciximab groups (P < 0.001) than in the UFH group. Similarly, lower rates of the composite efficacy plus safety end point were seen in the enoxaparin (P = 0.003) and abciximab groups (P = 0.014) than in the UFH group.

Conclusion

In patients with acute myocardial infarction, tenecteplase plus enoxaparin and half-dose tenecteplase plus abciximab and unfractionated heparin were more effective and safe than tenecteplase plus unfractionated heparin.

*See Glossary.

Sources of funding: Boehringer Ingelheim; Genentech; Aventis.

For correspondence: Professor F.J. Van de Werf, Gasthuisberg University Hospital, Leuven, Belgium. E-mail Frans.VandeWerf@uz.kuleuven.ac.be.


Table. Tenecteplase plus enoxaparin or abciximab vs unfractionated heparin (UFH) for acute myocardial infarction at 30 days†

Outcomes Comparisons Event rates RRR (95% CI) NNT (CI)
Composite efficacy end point Enoxaparin vs UFH 11% vs 15% 26% (13 to 37) 25 (16 to 53)
Abciximab vs UFH 11% vs 15% 28% (16 to 39) 23 (16 to 44)
Composite efficacy plus safety end point Enoxaparin vs UFH 14% vs 17% 19% (7 to 30) 30 (18 to 92)
Abciximab vs UFH 14% vs 17% 16% (4 to 28) 36 (20 to 175)

†Composite efficacy end point = mortality, in-hospital reinfarction, or in-hospital refractory ischemia; composite efficacy plus safety end point = composite efficacy end point plus in-hospital intracranial hemorrhage or in-hospital major bleeding. Other abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

The 2 latest large thrombolytic trials, GUSTO V and ASSENT-3, have used combination antithrombotic regimens to further reduce death caused by MI by more rapidly restoring coronary patency.

2 previous pilot studies (1, 2) suggested that a half-dose thrombolytic plus platelet inhibition with full-dose abciximab, in addition to aspirin and reduced-dose heparin, was associated with greater early patency than the prototype full-dose thrombolytic. The GUSTO V and ASSENT-3 studies tested this combination therapy to verify that enhanced early patency improved survival and reduced reinfarction without increasing bleeding.

Surprisingly, GUSTO V failed to show reduced mortality with combination therapy. However, it showed a reduced incidence of reinfarction, which provides some support for the concept. The combination was associated with a modest, but significant, increase in bleeding but fortunately not with an increase in brain hemorrhage.

ASSENT-3 was a smaller and less ambitious trial than GUSTO V and used a composite primary end point. ASSENT-3 showed more positive results than did GUSTO V; reduced-dose TNK plus abciximab was more beneficial than TNK alone, with a slight increase in bleeding (not cerebral bleeding). However, the effects on mortality alone were not evaluated. The biggest surprise was that the enoxaparin-plus-TNK combination showed the best results.

Several questions remain. Although it seems that TNK is better than reteplase for combined therapy with abciximab, this has not been proved in a head-to-head comparison study. Ongoing trials are testing other platelet inhibitors (e.g., eptifibatide and tirofiban) with half-dose TNK to see whether these small molecules show better results than does abciximab (3). The paradox is that with more data clinicians face greater decision-making challenges and need to consider greater ranges of available choices, diminishing returns, high cost, and formulary restrictions.

How should patients with ST-elevation MI be treated if primary angioplasty is not immediately available? Aspirin, TNK, and enoxaparin seem to offer the best combination of favorable results, safety, and simplicity. However, combination half-dose lytic and abciximab therapy may be advantageous in patients who are < 75 years of age because of reduced reinfarction and less bleeding than in the elderly.

Eptifibatide and tirofiban should not be substituted for abciximab until more comparison studies become available. Most important, clinicians making changes in their thrombolytic formulations should not neglect the basic treatment methods of aspirin, β-blockers, angiotensin-converting enzyme inhibitors, statins, and smoking cessation.

Steven Borzak, MD
Florida Cardiology Group and Florida Cardiovascular Research
Atlantis, Florida, USA

Steven Borzak, MD
Florida Cardiology Group and Florida Cardiovascular Research
Atlantis, Florida, USA


References

1. Antman EM, Giugliano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 trial. Circulation. 1999;99:2720-32.

2. Strategies for Patency Enhancement in the Emergency Department (SPEED) Group. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation. 2000;101:2788-94.

3. Simoons ML. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet. 2001;357:1915-24.