Stockholm, Sweden, 30 August: Results from ATOLL, a phase 3 randomised trial comparing two anticoagulants in primary PCI for ST elevation MI, show that the low molecular weight heparin enoxaparin may provide better outcomes in such cases than the traditionally used unfractionated heparin.
The former, explained principal investigator Professor Gilles Montalescot from the Cardiology Department of Pitié-Salpêtrière University Hospital, Paris, has already been associated with a 57% relative risk reduction of major bleeding when compared with unfractionated heparin (UFH) in a large randomised study performed in elective PCI. But so far, primary PCI for STEMI has traditionally been supported by unfractionated heparin. The aim of the ATOLL study was to compare head-to-head intravenous enoxaparin with UFH in patients undergoing PCI for STEMI. "The time has come to acknowledege that there is better anticoagulation than UFH in PCI, primary PCI included" said Professor Montalescot.
ATOLL was a 43-site multicentre randomised trial in STEMI patients scheduled for primary PCI. Randomisation mostly occurred before hospital admission. The primary endpoint was the composite of death, complications of MI, procedure failure or non-CABG major bleeding at 30 days. The main secondary endpoint was the ischaemic composite endpoint of death, recurrent MI/ACS or urgent revascularisation. Death or complications of MI was also examined, while the main safety endpoint was major bleeding (according to the STEEPLE definition) during hospital stay. The net clinical benefit combined death, complications of MI or major bleeding.
At 43 sites in four countries (Austria, France, Germany, USA), 910 patients were randomised to receive IV enoxaparin (0.5mg/kg, same dose with or without glycoprotein IIb/IIIa inhibitors as antiplatelet therapy, and no coagulation monitoring) or IV UFH (50-70IU/kg with GPIIb/IIIa inhibitors, 70-100IU without GPIIb/IIIa inhibitors, and dose adjusted to anti-coagulation monitoring) before coronary angiography. Patients were excluded if they had received any anticoagulant before randomisation, so that patients were uniformly treated with one or the other anticoagulant. The technical aspects of the PCI - including type of arterial access, stenting, choice of stents as well as use of intra-aortic balloon pumps - were left to the discretion of the investigators, said Professor Montalescot.
Results from the study showed that a high risk population was recruited, 18% of them elderly (over 75 years) and 5% in shock or cardiac arrest. Primary PCI was performed through a radial access in 68% of cases, with 75% of patients receiving GPIIb/IIIa inhibitors and two-thirds of patients receiving high dose clopidogrel.
The primary endpoint was reduced with enoxaparin from 34% to 28% (RR 17%), but did not reach statistical significance (p=0.07). The main secondary endpoint was significantly reduced by 41%, from 11.3% to 6.7% (p=0.02). The classic triple ischaemic endpoint of death, reinfarction or urgent revascularisation was also reduced from 8.5% to 5.1% (p=0.04). Enoxaparin reduced the endpoint of death or complications of MI from 12.4% to 7.8% (RR 37%, p=0.02). Death (any cause) decreased from 6.3% to 3.8% (p=0.08) and death or resuscitated cardiac arrest decreased from 7% to 4% with enoxaparin (p=0.05).
The main safety endpoint occurred in 4.9% of patient on enoxaparin and 4.5% of patients on UFH (non-significant), translating into a superiority of enoxaparin over UFH for a net clinical benefit (of death, complication of MI or major bleeding) of 15% vs 10.2% (p=0.03).
Commenting on the results, Professor Montalescot said: "We have performed the first pure head-to-head comparison between two anticoagulants in primary PCI, with all antiplatelet agents being even. In this comparison, IV enoxaparin did not reduce procedural failure, in particular low TIMI flow and non ST-resolution, which had a direct impact on the primary endpoint. However, harder ischaemic endpoints were all reduced with IV enoxaparin on top of intense antiplatelet therapy.
"Enoxaparin also showed a good safety profile with a superior net clinical benefit. Our data demonstrate that this strategy, which is easier to use, is also more effective at reducing the most serious ischaemic complications of STEMI treated with primary PCI.”