Wednesday, July 21, 2004

A to Z, SYNERGY Trials: Enoxaparin a Safe, Effective Alternative to Heparin
By Pat French

The results of two international DCRI trials, the Aggrastat (tirofiban) to Zocor (simvastatin), or A to Z trial, and the Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors, or SYNERGY study, have been published in the July 7 issue of the Journal of the American Medical Association.

The trials tested different strategies to prevent excess blood clotting in patients with an acute coronary syndrome (ACS) — unstable angina, or a heart attack without ST-segment elevation — who are also receiving tirofiban and aspirin (A to Z) or who are to have angiography with angioplasty and/or stenting (SYNERGY). Together, the trials show that the anticoagulant enoxaparin, a small-molecule heparin, is not inferior to standard heparin in these patients.

The A to Z trial, led by Dr. Mike Blazing and an international Steering Committee, randomly assigned 3987 patients with ACS to receive enoxaparin or heparin, plus tirofiban and aspirin, for a median ~48 hours. Almost half of the patients in both groups went on to have an angiogram and/or percutaneous coronary intervention, or PCI, which includes angioplasty and/or stenting. The primary endpoint — death, heart attack, or persistent ischemia at 7 days — occurred in 8.4% of the enoxaparin group and 9.4% of the heparin group, which met the study’s criteria for considering enoxaparin not inferior to heparin.

In the SYNERGY study, led by Dr. Ken Mahaffey and an international Steering Committee, 10,027 high-risk patients with ACS who were to have angiography and early PCI, if appropriate, were randomized to receive enoxaparin or standard heparin at least until after the PCI (which took place a median 22 hours after enrollment). In all, 14% of the enoxaparin group died or had a heart attack by 30 days (the primary endpoint), as did 14.5% of the standard heparin group. This difference, although not statistically significant, did meet the protocol’s criteria for considering enoxaparin not inferior to heparin.

With any anticoagulant, the main concern relates to excessive bleeding. In both trials, the rates of major bleeding were somewhat increased with enoxaparin versus heparin, significantly so in SYNERGY when using the bleeding scale from the TIMI trials. The rates of transfusions, and of bleeding events when using the scale from the GUSTO-I trial, did not differ significantly by treatment.

One reason for the overall higher bleeding rates in SYNERGY, in both treatment arms, was that many of these high-risk patients had received an antithrombin drug, which also prevents clotting, before enrollment. About 10%-12% of the patients also had switched to the other treatment after they had entered the study. This latter group had much higher rates of both the primary endpoint (18.5%) and transfusions (31.5%), although the authors state that more work is needed to understand how these “crossover” patients might have affected the study results.

Enoxaparin offers several practical advantages over heparin. First, it can be given subcutaneously every 12 hours, whereas heparin sometimes must be given as a continuous intravenous infusion. Second, enoxaparin treatment does not require the intensive monitoring and dose adjustments that heparin treatment does. Finally, enoxaparin is also less likely to cause a potentially life-threatening reaction, heparin-induced thrombocytopenia, in which the number of platelets, the blood cells involved in clotting, becomes severely reduced.

On balance, then, both studies indicate that enoxaparin is a safe, effective alternative to heparin. Its many advantages should be weighed against the modestly increased risk of bleeding.