Auckland, New Zealand - In patients with moderate- and high-risk non-ST-elevation ACS, switching from either unfractionated heparin or enoxaparin to bivalirudin before angiography results in a net clinical benefit (similar ischemic outcomes and reduced bleeding), according to further results from the ACUITY trial [1]. These results are consistent with the overall trial findings.

However, in patients naive to antithrombin therapy at randomization, although bivalirudin was still associated with less bleeding than unfractionated heparin or enoxaparin, this did not translate into a significant net clinical benefit.

The current ACUITY analysis, published in the May 6, 2008 issue of the Journal of the American College of Cardiology, was conducted by a group led by Dr Harvey White (Green Lane Hospital, Auckland, New Zealand).

They say the current results are clinically relevant, since moderate- and high-risk NSTE-ACS patients are often treated with either unfractionated heparin or enoxaparin in the emergency department or at a transferring hospital before treatment with bivalirudin.

They also point out that the recent European Society of Cardiology guidelines for the diagnosis and treatment of NSTE-ACS recommend that, for PCI procedures, the initial anticoagulant should be maintained during the procedure regardless of whether this treatment is unfractionated heparin, enoxaparin, or bivalirudin. This recommendation is based on the results of the SYNERGY trial, which showed that crossing over between unfractionated heparin and enoxaparin was associated with increased bleeding. But White et al point out that the current analysis has not shown the same results when patients are switched from unfractionated heparin or enoxaparin to bivalirudin, which might be explained by the different mechanism of action of bivalirudin compared with the other antithrombin agents.

They suggest that the increase in bleeding when switching between unfractionated heparin and enoxaparin in SYNERGY may have been due to the stacking of two antithrombin therapies with prolonged anti-Xa activity on top of one another without a sufficient washout period. But they point out that adding bivalirudin, with its lack of Xa activity, to unfractionated heparin or enoxaparin would not increase the existing anti-Xa activity, and any incremental anti-IIa effect would be temporary, given the short half-life and rapid clearance of bivalirudin.

In the ACUITY trial, 13 819 patients with moderate- and high-risk NSTE-ACS were randomized to one of three groups: unfractionated heparin or enoxaparin plus GP IIb/IIIa inhibitors; bivalirudin plus IIb/IIIa inhibitors; or bivalirudin monotherapy with provisional use of GP IIb/IIIa inhibitors for ischemic complications. Results of the overall study showed the best outcomes in the bivalirudin monotherapy group, which had a similar rate of ischemic complications but a reduced rate of bleeding.

The current analysis focused on major outcomes at 30 days in patients receiving consistent unfractionated heparin/enoxaparin and in those switched at randomization from pretreatment with unfractionated heparin or enoxaparin to bivalirudin monotherapy. It also compared outcomes in patients naive to antithrombin therapy who were randomized to unfractionated heparin/enoxaparin or bivalirudin monotherapy.

In the trial, 2137 patients received consistent unfractionated heparin (1294) or enoxaparin (843), and 2 078 patients pretreated with unfractionated heparin or enoxaparin were switched to bivalirudin. Results showed that those switching to bivalirudin had similar rates of ischemia as those on consistent unfractionated heparin or enoxaparin plus a GP IIb/IIIa inhibitor, with less major bleeding and improved net clinical outcomes.

The patients naive to antithrombin therapy who were administered bivalirudin had similar rates of ischemia, less major bleeding, and similar net clinical outcomes compared with the naive patients administered unfractionated heparin or enoxaparin plus a GP IIb/IIIa inhibitor.

Commenting on this observation for heartwire, White said that these results "need to be interpreted in the light of the overall ACUITY results, which showed an approximated 50% reduction in major bleeding with bivalirudin and no increase in ischemia in all groups." He noted that the naive patients were an underpowered subgroup comparison and, even so, net clinical outcome still showed a trend toward benefit with bivalirudin. "Furthermore, the naive patients were a selected group of lower-risk patients with lower event rates, making the discernment of a difference even more unlikely," he added.

But others have not been quite so quick to completely dismiss these results. Dr Paul Armstrong (University of Alberta, Edmonton) commented to heartwire: "In naive patients, all the benefit is 'less bleeding,' and there is a cost, which is more death/MI (81 vs 63 events, p=0.09), so there is a trend toward more ischemic events that I would not be prepared to pay." He added that the antithrombin-naive patients do not appear to be at lower risk than crossovers, as they have similar rates of death and MI, but he said he would hesitate in making any firm recommendations on these data, as this was a post hoc subgroup analysis and so should be thought of as hypothesis-generating only, and "extreme caution is appropriate."

Dr Dan Simon (University Hospitals Case Medical Center, Cleveland, OH) suggested that the lack of a significant net benefit with bivalirudin in antithrombin-naive patients may be tied up with the issue of clopidogrel pretreatment. "Naïve patients are lower risk and so treated less aggressively prior to being enrolled in the trial. While these patients may have received clopidogrel after angiography, they probably were not adequately pretreated. Hence, you are seeing higher ischemic events in bivalirudin monotherapy," he speculated.

Lead investigator of the overall ACUITY trial, Dr Gregg Stone (Cardiovascular Research Foundation, New York), also stressed the need for caution when interpreting the clinical results of subgroups. "The trial was powered for three end points: MACE, major bleeding, and net adverse clinical events. Thus, for the end points the trial was powered for, bivalirudin had comparable ischemia, less bleeding, and greater event-free survival. Importantly, there were no significant interactions between the effects of bivalirudin and switching vs not switching on any of these end points. Therefore, this means that the results of the overall trial apply to the switched subgroups, meaning that in the patients naive to antithrombin therapy, bivalirudin had comparable ischemia, less bleeding, and greater event-free survival—this is the appropriate interpretation of the manuscript. This is the only correct statistical interpretation. The trial was underpowered for mortality even with 13 819 patients (the entire study), let alone subgroups, and no conclusions should even be considered from this," he commented to heartwire.