Dr Gregg Stone (Columbia University, New York, NY) presented the results of ACUITY-PCI here at the TCT 2006 meeting earlier this week, emphasizing their congruence with the overall ACUITY findings, as well as those of REPLACE-2 in low- to moderate-risk patients undergoing PCI.

"The conclusions and clinical implications from the ACUITY-PCI trial are clear," Stone said. "In patients with moderate- and high-risk ACS undergoing PCI, replacing upstream heparin with bivalirudin in patients treated with GP IIb/IIIa inhibitors provides similar clinical and angiographic outcomes; however, replacing heparin and GP IIb/IIIa blockers with bivalirudin alone with provisional GP IIb/IIIa inhibitor use in less than 10% of patients results in similar rates of ischemia, with markedly reduced hemorrhagic complication, thereby improving overall event-free survival."

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: heparin plus GP IIb/IIIa inhibitors, bivalirudin plus GP IIb/IIIa inhibitors, and bivalirudin alone, with randomization roughly equal between the three groups. At 30 days, the primary end point of ACUITY-PCI, non-CABG major bleeding, was significantly lower in the bivalirudin-only group at 30 days, with no significant differences in ischemic events, in composite or analyzed independently. 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 group and the bivalirudin-only group.

An expert panel discussing the results following the presentation appeared on the whole to agree with Stone's conclusions, but several pointed to the two subgroups, both identified in a post hoc analysis, in whom lingering concerns of a bleeding/ischemia trade-off with bivalirudin have dogged this drug since the beginning. 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 groups, 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 a press conference, Dr Harvey White (Auckland City Hospital, New Zealand), a member of the ACUITY trial steering committee, emphasized that the increase in the ischemic composite was nonsignificant and made up of "enzyme leaks."

"An enzyme leak is associated with a 2.5 times mortality increase at 12 months, whereas the risk from bleeding is 3.6 times for mortality at one year," White said. "Interventionalists are certainly going to look at this [increase in ischemic events], but I think the most important thing is that this wasn't statistically significant, and bleeding was."

Also attracting attention in ACUITY-PCI, as in the main ACUITY trial, were patients not on clopidogrel, roughly one third of the ACUITY-PCI population. Among patients not on clopidogrel, bleeding was significantly reduced, as in the PCI cohort as a whole, but ischemic events were significantly increased, by almost 3%.

The clopidogrel observations "make physiological sense," Dr James Ferguson (Texas Heart Institute, Houston) told heartwire. "The simple reason is that bivalirudin has a relatively short half-life, and in higher-risk individuals you need more antiplatelet therapy for a longer period of time. . . . So if you are not pretreated and you get your thienopyradine in the procedure, it's going to take a while for it to kick in. What you see in the times when the bivalirudin is wearing off and the patient may not yet be covered by the thienopyradine already on board, that's when there would be difficulties."

Ferguson cautioned that the clopidogrel results should be taken with a grain of salt, since the analysis was not specified in the trial protocol. "Does this mean that you have to load with clopidogrel and if someone has not been loaded with clopidogrel that you shouldn't use bivalirudin alone? I would not go to that conclusion right now, but it's a concern, and it's something you need to think about."

Also commenting on the study for heartwire, Dr Eric Topol (Case Western Reserve University, Cleveland, OH) said the substudy results were "interesting."

It looks like certain subgroups, including troponin-negative patients and patients who have taken prior clopidogrel, do well on bivalirudin monotherapy, he said. "But of course this is post hoc type of analysis, and nothing is definitive here."

One-year data will be even more informative, he suggested, and will likely have a greater impact on the question of whether a bivalirudin strategy could replace standard practice in ACS patients undergoing PCI. "In the meantime, a case can be made that there is no 'trade-off' in certain groups of patients—just pronounced less bleeding and no numerical excess in MI."

Another ACUITY paper focusing on the diabetic subset, also presented at TCT 2006, suggests that diabetics might also be well suited to bivalirudin monotherapy, Topol noted.

Other experts tried to predict if and how the ACUITY-PCI results might influence their practice. White stated that he believed bivalirudin should be "the drug of choice," although for cost reasons it currently is used in only 15% of cases in his hospital, primarily in patients believed to be at higher bleeding risk.

But Dr David Faxon (Brigham and Women's Hospital, Boston, MA) pointed to the wide range of patients included in ACUITY PCI, ranging from moderate- to high-risk ACS patients. "There's unstable angina and there's unstable angina," he said. For very high-risk patients, "I must say, I'm hanging on to the GP IIb/IIIas."

Likewise, Dr Deepak Bhatt (Cleveland Clinic, OH) pointed out that ACUITY-PCI speaks to non-ST-elevation ACS patients and specifically applies to patients treated in the same way as those in the trial, with relatively quick door-to-balloon times. Questions remain, however, regarding the STEMI population. "Intuitively I think that GP IIb/IIIa inhibitors would add value there, in patients with STEMI and visible thrombus, and there are ongoing studies addressing the use of bivalirudin in those settings," Bhatt said.

Ferguson made the point that noninferiority studies like ACUITY tend to reinforce practice patterns, not change them. "If you were a believer in bivalirudin before ACUITY, then the glass is half full; if you were a skeptic before, then the glass is half empty. But what this trial does is reinforce that bivalirudin is an option once you make a decision to go to the cath lab."

Ferguson does not believe bivalirudin will eliminate a role for GP IIb/IIIa inhibition. "I'm not sure that the results of ACUITY mean that we should be using less GP IIb/IIIa blockers, but it solidified the position of bivalirudin in the invasively managed patients. Now we have more data for people who choose to pursue that option: there are concerns that one has to consider in high-risk individuals, including troponin-positive patients and those who do not have thienopyradine pretreatment, but one size doesn't fit all, and you need to use the therapies that fit best within your institution."