Washington, DC - Now published in the March 17, 2007 issue of the Lancet, results from the ACUITY-PCI substudy suggest bivalirudin alone can safely replace heparin and GP IIb/IIIa inhibitors in ACS patients undergoing contemporary PCI with similar rates of ischemia and less bleeding at 30 days [1]. As previously reported by heartwire when the study was presented at the TCT 2006 meeting, the findings largely mirror those of the broader ACUITY study but also hint at particular subsets in whom the choice of thrombin inhibitor may prove more complicated.

"Substitution of unfractionated heparin or enoxaparin with bivalirudin results in comparable clinical outcomes in patients with moderate- or high-risk acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors in whom percutaneous coronary intervention is done," Dr Gregg Stone (Columbia University, New York, NY) and colleagues write. "Anticoagulation with bivalirudin alone suppresses adverse ischemic events to a similar extent as . . . heparin plus glycoprotein IIb/IIIa inhibitors, while significantly lowering the risk of major hemorrhagic complications."

As previously reported by heartwire, ACUITY-PCI was made up of the 7789 patients from the ACUITY trial who underwent PCI during the trial. Drug-eluting-stent use in these patients was roughly 60% in all three groups: those receiving heparin plus GP IIb/IIIa inhibitors; those receiving bivalirudin plus GP IIb/IIIa inhibitors; and those receiving bivalirudin alone, with randomization roughly equal among the three groups. In an intention-to-treat analysis, the 30-day primary end points—composite ischemia (death, MI, or unplanned revascularization for ischemia), major bleeding, or net clinical outcomes (major bleeding or composite ischemia) were not significantly different between the groups receiving bivalirudin plus GP IIb/IIIa inhibitor or heparin plus GP IIb/IIIa inhibitors. Composite ischemia rates were similar between the two groups; however, major bleeding was significantly lower in the bivalirudin-only group at 30 days, as compared with the group receiving heparin plus GP IIb/IIIa inhibitors. Unlike the main ACUITY trial, the net clinical benefit—combining ischemic and bleeding events—was no different between the heparin-plus-GP-IIb/IIIa-inhibitor and the bivalirudin-only groups.

Two subgroups, both identified in a post hoc analysis, have fueled lingering concerns of a bleeding/ischemia trade-off with bivalirudin: troponin-positive patients and patients without thienopyridine (clopidogrel) pretreatment. In troponin-positive patients—a group also singled out in the main trial—ischemic complications were not significantly different between the heparin-plus-GP-IIb/IIIa-inhibitor and bivalirudin-only group, but there was a 1% absolute increase in ischemic composite events. At the same time, however, the incidence of major bleeding was significantly reduced in this subgroup.

In patients who were pretreated with clopidogrel before PCI, rates of 30-day composite ischemic events were the same in the bivalirudin-monotherapy and heparin-plus-GP-IIb/IIIa-inhibitor groups; however, rates of composite ischemic events tended to be higher in the bivalirudin-only group vs the heparin-plus-GP-IIb/IIIa-inhibitor group if they received clopidogrel only postprocedure or not at all.

Bleeding was significantly reduced in the bivalirudin-only arm, regardless of clopidogrel treatment status.

"As a pharmacological adjunct in patients with ACS undergoing PCI using contemporary drugs and devices, bivalirudin monotherapy is comparable to the combination of heparin plus GP IIb/IIIa inhibitors in the prevention of periprocedural ischemic complications, while significantly lowering the risk of major and minor bleeding as well as the need for blood transfusions," Stone et al conclude.

In an accompanying Comment, however, Dr Ron Waksman (Washington Hospital Center, DC) argues that ACUITY PCI "has deficiencies that preclude it from being definitive" [2].

He points to the fact that randomization was not stratified by treatment assignment, since it was done before angiography; different types of GP IIb/IIIa inhibitors and heparin drugs were permitted in the control arm of the trial; the trial enrolled lower-risk patients (as compared with the recent SYNERGY and OASIS 5 trials); and STEMI patients were excluded from the study. Finally, he argues, the analysis was not powered for noninferiority testing, and "therefore the comparability or noninferiority status of bivalirudin remains a question."

In an interview with heartwire, Waksman highlighted some of his other concerns. "My main criticism is that this is not a definitive study because it was a subset of the main ACUITY study. It was not powered to give conclusive results," he said.

Waksman says he does use bivalirudin for PCI and for ACS patients, "but we don't use it as the sole drug." In particular, Waksman says he still has misgivings about troponin-positive patients as well as patients who are not taking clopidogrel.

"We don't yet have the studies to confirm that we don't need GP IIb/IIIa inhibitors in patients who are not preloaded with clopidogrel," he told heartwire. "If ACS patients are loaded with clopidogrel on the table, they have their antiplatelet therapy in their stomach, but not in their bloodstream. Then postprocedure, if you've just treated them with bivalirudin, the short half-life time of the bivalirudin can wear off and the clopidogrel has not yet kicked in, so postprocedure they may not be covered by antiplatelet therapy or antithrombin therapy. In those patients we may need to add GP IIb/IIIa inhibitors or another potent antiplatelet therapy."

But adding GP IIb/IIIa inhibitors negates the benefits of bivalirudin, he notes.

"If you add IIb/IIIas to bivalirudin because you're worried about either troponin-positive patients or patients who are not on clopidogrel, you're not getting any of the benefit of reduced bleeding and no reduced cost. So you might as well stick to heparin and IIb/IIIas rather than switch to bivalirudin. . . . "If you have to pay for IIb/IIIas as well as bivalirudin, you have to ask yourself, what benefit am I getting for similar costs?"