ATOLL: An international, randomized trial comparing i.v. enoxaparin with i.v. unfractionated heparin in primary PCI for ST-elevation myocardial infarction 

---

	Presenter
	Presenter | see Discussant report
Montalescot, Gilles (France)	ACCESS THE PRESENTATION SLIDES

List of Authors:
Montalescot, Gilles; Zeymer, Uwe; Cohen, Marc; Goldstein, Patrick; Huber, Kurt; Pollack, Charles; Gallula, Philippe; Vicaut, Eric

Abstract:

Background:
Intravenous (i.v.) low molecular weight heparin enoxaparin (0.5mg/kg) has been associated with a 57% relative risk reduction of major bleeding when compared with unfractionated heparin (UFH) in a large randomized study performed in elective PCI. So far, primary PCI (pPCI) for ST elevation has traditionally been supported by UFH. Intravenous enoxaparin may provide better outcomes when used for pPCI.

Objectives:
The aim of this study was to compare head-to-head, enoxaparin and UFH in patients undergoing pPCI for STEMI, patients being selected at first medical contact, randomization and treatment occurring mostly before hospital admission.

Methods:
Patients, more than 18 years old without upper age limit, presenting for primary PCI of STEMI within 12hrs of symptom onset were eligible for randomization. Patients that received any anticoagulant before randomization were excluded. Exclusion criteria included also the administration of thrombolytic agents for the current episode, a recent stroke, oral anticoagulant therapy, a limited life expectancy, childbearing potential, and known contraindications to therapy with aspirin, thienopyridines, or heparins. Written informed consent was required. In both groups, the use of concomitant drugs, including glycoprotein IIbIIIa inhibitors, was left to the discretion of the investigators.
The primary endpoint is the net clinical benefit as evaluated by the composite of death, complications of MI, procedure failure and non-CABG major bleeding, at 30 days. The main safety endpoint is major bleeding during hospitalization (STEEPLE definitions). The main ischemic end-point (secondary) is the composite of death, recurrent ACS or urgent revascularization.

Results:
In 43 active sites of four countries (Austria, France, Germany, USA), 911 patients were randomized to receive i.v. enoxaparin (0.5mg/kg; same dose with or without GPIIb/IIIa inhibitors) or i.v. UFH (50-70IU/kg with GPIIb/IIIa inhibitors; 70-100IU without GPIIb/IIIa inhibitors), before coronary angiography. Technical aspects of PCI including type of arterial access, thrombectomy, stenting, choice of stents as well as use of intraaortic balloon pumps or other devices were left to the discretion of the investigators. To date, enrolment is complete and results will be presented at the ESC congress.

Conclusions:
ATOLL is the first randomized study in primary PCI that compares two different anticoagulants in STEMI patients naive of anticoagulation at the time of randomization and receiving similar antiplatelet therapy. ATOLL: Acute STEMI Treated with primary angioplasty and intravenous enoxaparin Or UFH to Lower ischemic and bleeding events at short- and Long-term follow-up.

---

	Discussant
	Discussant | see Presenter abstract
White, Harvey (New Zealand)	ACCESS THE PRESENTATION SLIDES

Report:

The ATOLL (Acute STEMI Treated with primary angioplasty and intravenous enoxaparin Or UFH to Lower ischemic and bleeding events at short- and Long-term follow-up) trial was presented in a Hot Line at the European Society of Cardiology Meeting in Stockholm by Gilles Montalescot.

This is the first randomized study evaluating enoxaparin in primary percutaneous coronary intervention (PCI). In this trial 910 patients were randomized to either unfractionated heparin 50-70IU with a target ACT of 300-350 sec and if IIb/IIIa inhibitors were planned to be given, an ACT of 200-300 sec or to IV enoxaparin 0.5mg/kg regardless of whether IIb/IIIa inhibitors were to be given or not. Subcutaneous enoxaparin was recommended to be given to discharge. Of note 70% of patients were randomized pre-hospital.

The trial was statistically underpowered for a realistic 20% effect size and the primary endpoint was negative. At 30 days the primary endpoint of death, myocardial infarction, procedural failure or non-coronary artery bypass grafting major bleeding occurred in 28% of patients randomized to enoxaparin and 33.7% of patients randomized to unfractionated heparin RR 0.83; 95% CI 0.68 - 1.01; p=0.07. The main prespecified ischemia endpoint of death, recurrent myocardial infarction, acute coronary syndromes or urgent revascularization was reduced from 11.3% to 6.7%; p=0.01 with enoxaparin. The non-prespecified endpoint of death, myocardial infarction and revascularization was also decreased; p=0.04. This endpoint is not comparable to the ischemic endpoint of cardiovascular death, myocardial infarction and stroke in other contemporary trials and no statistical adjustment was made for multiple analyses of secondary endpoints. There was no effect on TIMI 3 flow or ST resolution.

Major bleeding according to TIMI non- coronary artery bypass grafting criteria was similar in both groups; 2.9% enoxaparin vs 2.4% unfractionated heparin. The multiple subcutaneous injections of enoxaparin following PCI may explain the increased bleeding compared with single bolus administration and over anticoagulation may have occurred if renal impairment was not recognised, whereas a single bolus regardless of renal function is safe. On the other hand the radial approach (67.5%) would be expected to have reduced bleeding by 70%.

There was a trend for the relatively high 30 day mortality to be reduced; 6.3% unfractionated heparin vs 3.8% enoxaparin; p=0.08. This compares to the 3.1% 30 day mortality in patients randomized to unfractionated heparin plus IIb/IIIa antagonists and 2.1% in patients randomized to bivalirudin in the HORIZONS trial. There are no data to show that enoxaparin reduces infarct size or improves TIMI flow and bleeding was not reduced. In the absence of a plausible mechanism, it is likely that the lower mortality with enoxaparin occurred by chance.

Further analysis in respect of the radial approach, use of IIb/IIIa antagonists (73.6%) where the effectiveness is unclear in the presence of intensive P2Y12 inhibition, thrombectomy (39.2%), clopidogrel dose and stent thrombosis are awaited.

Conclusion:
Patients undergoing primary PCI require an effective anticoagulant that acts quickly and reduces ischemic complications of myocardial infarction and death. As bleeding is also related to long term mortality, it is desirable to have an agent that does not increase bleeding. The ability to give an agent that does not require monitoring is an advantage and cost is an important consideration.

The ATOLL trial investigators have shown that enoxaparin is safe for patients undergoing primary PCI and likely has a clinically relevant effect in reducing ischemic complications compared with unfractionated heparin. They have moved us closer to the goal of further improving the outcomes of patients suffering an ST elevation myocardial infarction.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.