Washington, DC - ACUITY investigators have now published one-year results for the subset of ACS patients in the trial who subsequently underwent PCI [1]. This latest ACUITY paper suggests that there were no differences in composite ischemia or mortality at 12 months between the three study groups in the trial, even when limited to patients who went on to have a coronary intervention.

The paper appears online August 25, 2008 in the Journal of the American College of Cardiology.

The overall ACUITY trial evaluated the optimum upstream treatment of patients with moderate- to high-risk non-ST-elevation ACS heading to the cath lab, with patients randomized to one of three arms: unfractionated heparin (UFH) or enoxaparin plus routine GP IIb/IIIa inhibition; bivalirudin plus routine GP IIb/IIIa inhibition; or bivalirudin alone. Results for the PCI subset—7789 out of 13 819 in the overall ACUITY study—were first presented by Dr Harvey White (Green Lane Hospital, Auckland, New Zealand), lead author on the published study, during the 2007 European Society of Cardiology (ESC) meeting, as reported by heartwire.

As with the overall trial, the ACUITY PCI subset suggested that there were no significant differences between the three antithrombotic regimens being tested, at least in terms of rates of composite ischemia or mortality, despite the fact that the 30-day results had suggested that bivalirudin monotherapy might be the preferable regimen, with "noninferior" rates of ischemic events and reduced rates of major bleeding compared with the other two arms.

In their paper, White et al point to the fact that the trial was powered to look at a 30-day composite end point, and as such, it is "not surprising" that the reduction in bleeding with bivalirudin monotherapy did not translate into reduced mortality at one year.

"Although mortality was similar in the bivalirudin alone vs heparin plus IIb/IIIa-receptor antagonists, despite the 41% reduction in bleeding seen with bivalirudin and despite the significant association of bleeding with mortality, this can be explained by the fact that ACUITY was powered statistically for 30-day net clinical outcomes of composite ischemia and major bleeding, and a much larger study would be required to look at mortality," White commented to heartwire. That said, he continued, "I would expect the 41% reduction in bleeding to translate to a reduction in long-term mortality."

By the same token, however, ischemic events in PCI-treated patients were numerically higher in the bivalirudin-monotherapy arm but, again, had no impact on one-year mortality differences between treatment groups.

White made the point, however, that there were other benefits of reduced bleeding that did reach statistical significance. For example, patients who had major bleeds spent, on average, an additional two days in the hospital.

As White showed during the ESC, the comparable one-year outcomes were also seen across subgroups of patient risk, including those who switched from a different antithrombin therapy to bivalirudin at the time of randomization. There were no differences in one-year outcomes according to timing of clopidogrel administration, something other studies have hinted at.

"The 12-month data are reassuring for the group of patients in the bivalirudin arm who didn't receive clopidogrel preloading, given the suggested interaction, although not significant at 30 days," White told heartwire. "There was no interaction with mortality and clopidogrel use at 12 months. Patients who switched at randomization to bivalirudin had similar rates of one-year mortality and composite ischemia compared with patients who stayed on UFH or enoxaparin, further supporting this approach."

On balance, the authors conclude, the ACUITY PCI one-year results, on top of the reduction in bleeding seen in the 30-day results, "make bivalirudin rather than UFH or enoxaparin plus a GP IIb/IIIa inhibitor an attractive antithrombotic choice for moderate- and high-risk ACS patients undergoing PCI."

Of note, however, the US FDA earlier this year issued a "not-approvable" letter to the Medicines Company for an additional dosing regimen for bivalirudin in the upstream treatment of acute coronary syndromes (ACS) initiated in the emergency department, based on the results of the ACUITY trial. The drug is already indicated for use in the cath lab during PCI.

In the wake of ACUITY's release, commentators have questioned the noninferiority margins used in the ACUITY trial, set at 25%, meaning that anything up to a 25% worsening in outcome would be classed as noninferior. Some experts have suggested that this margin is far too wide.