Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial

Summary

Background

Primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction has traditionally been supported by unfractionated heparin, which has never been directly compared with a new anticoagulant using consistent anticoagulation and similar antiplatelet strategies in both groups. We compared traditional heparin treatment with intravenous enoxaparin in primary PCI.

Methods

In a randomised open-label trial, patients presenting with ST-elevation myocardial infarction were randomly assigned (1:1) to receive an intravenous bolus of 0·5 mg/kg of enoxaparin or unfractionated heparin before primary PCI. Wherever possible, medical teams travelling in mobile intensive care units (ambulances) selected, randomly assigned (using an interactive voice response system at the central randomisation centre), and treated patients. Patients who had received any anticoagulant before randomisation were excluded. Patients and caregivers were not masked to treatment allocation. The primary endpoint was 30-day incidence of death, complication of myocardial infarction, procedure failure, or major bleeding. The main secondary endpoint was the composite of death, recurrent acute coronary syndrome, or urgent revascularisation. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00718471.

Findings

910 patients were assigned to treatment with enoxaparin (n=450) or unfractionated heparin (n=460). The primary endpoint occurred in 126 (28%) patients after anticoagulation with enoxaparin versus 155 (34%) patients on unfractionated heparin (relative risk [RR] 0·83, 95% CI 0·68–1·01, p=0·06). The incidence of death (enoxaparin, 17 [4%] vs heparin, 29 [6%] patients; p=0·08), complication of myocardial infarction (20 [4%] vs 29 [6%]; p=0·21), procedure failure (100 [26%] vs 109 [28%]; p=0·61), and major bleeding (20 [5%] vs 22 [5%]; p=0·79) did not differ between groups. Enoxaparin resulted in a significantly reduced rate of the main secondary endpoint (30 [7%] vs 52 [11%] patients; RR 0·59, 95% CI 0·38–0·91, p=0·015). Death, complication of myocardial infarction, or major bleeding (46 [10%] vs 69 [15%] patients; p=0·03), death or complication of myocardial infarction (35 [8%] vs 57 [12%]; p=0·02), and death, recurrent myocardial infarction, or urgent revascularisation (23 [5%] vs 39 [8%]; p=0·04) were all reduced with enoxaparin.

Interpretation

Intravenous enoxaparin compared with unfractionated heparin significantly reduced clinical ischaemic outcomes without differences in bleeding and procedural success. Therefore, enoxaparin provided an improvement in net clinical benefit in patients undergoing primary PCI.

Funding

Direction de la Recherche Clinique, Assistance Publique-Hôpitaux de Paris; Sanofi-Aventis.

Introduction

Anticoagulation during primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) has traditionally been supported by unfractionated heparin, largely on the basis of evidence extrapolated from studies of elective angioplasty. The Joint STEMI/PCI Guidelines Update¹ produced by the American College of Cardiology, American Heart Association, and Society for Cardiovascular Angiography and Interventions as well as guidelines from the Task Force on Myocardial Revascularization of the European Society of Cardiology² continue to afford unfractionated heparin a class 1 recommendation for this indication while recognising that evidence is limited (level of evidence C).

In recent studies with new anticoagulants in primary PCI, such as OASIS-6 (Organization for the Assessment of Strategies for Ischemic Syndromes),³ the subgroup undergoing primary PCI had no clinical benefit with the indirect factor Xa inhibitor fondaparinux and had an excess of catheter thrombosis. In the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial,⁴ the direct thrombin inhibitor bivalirudin alone, as compared with unfractionated heparin plus glycoprotein IIb/IIIa inhibitors, significantly reduced 30-day rates of major bleeding and mortality, but there was increased stent thrombosis within the first 24 h (not at 30 days; class I-B recommendation). Most noteworthy is that in both studies a large proportion of patients received a full dose of unfractionated heparin before randomisation, precluding a real comparison between two anticoagulant drugs. Therefore, there has thus far been no comparison between two anticoagulants in primary PCI that is not confounded by prerandomisation anticoagulation therapy or differing antiplatelet strategy, which can both affect clinical outcomes.2, 3, 5, 6, 7, 8, 9

Subcutaneous enoxaparin provides more predictable anticoagulation than does unfractionated heparin¹⁰ and has an established role in the management of non-ST-elevation acute coronary syndromes and in STEMI treated with thrombolysis.6, 11, 12 The excess bleeding reported in these studies might have been due to the prolonged treatment with therapeutic doses of subcutaneous enoxaparin or the concomitant administration of unfractionated heparin, or both. The clinical usefulness of intravenous enoxaparin has been shown recently in elective PCI at a dose of 0·5 mg/kg, which provides immediately an adequate level of anticoagulation with the short half-life of the drug, adapted to interventional procedures.13, 14, 15, 16, 17 Enoxaparin was also compared with unfractionated heparin in several non-randomised studies that reported significantly better results with enoxaparin in PCI of STEMI,18, 19, 20, 21, 22 but there has been no randomised evaluation of intravenous enoxaparin in primary PCI.

The ATOLL (Acute Myocardial Infarction Treated with Primary Angioplasty and Intravenous Enoxaparin or Unfractionated Heparin to Lower Ischemic and Bleeding Events at Short- and Long-term Follow-up) study is a randomised comparison of intravenous enoxaparin and unfractionated heparin in primary PCI, excluding patients who received any anticoagulation before randomisation and requiring no crossover from one drug to the other during or after the procedure.