Chicago, IL - In moderate- to high-risk ACS patients, deferring GP IIb/IIIa-blocker use until they are actually in the cath lab and then treating just those undergoing PCI may increase the risk of ischemic events but reduces the risk of major bleeding, according to the results of the ACUITY Timing trial [1]. But experts who did not participate in the trial say the results apply only to patients in whom the time from treatment initiation to PCI is similar to that of ACUITY Timing trial: a median of four to five hours.

"They really didn't test the question. . . . The type of sites they chose to be in the study and the approach they wanted was for everyone to go to the cath lab and for people to go there pretty quickly after randomization," Dr Robert Harrington (Duke Clinical Research Institute, Durham NC) explained to heartwire. "That's not going to test the question of upstream vs delayed use, there's insufficient time to do so."

The ACUITY Timing results, first reported by heartwire from the ACC 2006 Scientific Sessions, have now been published in the February 14, 2007 issue of the Journal of the American Medical Association. In an accompanying editorial [2], Harrington, with Dr Kenneth W Mahaffey (Duke Clinical Research Institute) write that the results from ACUITY Timing "should not fundamentally change the use of GP IIb/IIIa inhibitors in clinical practice" but praise the investigators for attempting to answer an important question within the context of a larger trial. ACUITY Timing was conducted among two of the three arms—the GP IIb/IIIa-inhibitor arms—in the main ACUITY trial.

As lead investigator Dr Gregg Stone (Columbia University, New York, NY) and colleagues note in their paper, GP IIb/IIIa blockers have a class I indication for use in ACS patients undergoing an early invasive strategy, but it is unclear whether it is preferable to give them up front to everyone or to defer treatment until the patient is in the cath lab and then give a IIb/IIIa blocker just to those patients who will definitely undergo PCI.

"It is not known whether the reduction in hemorrhagic complications by deferring GP IIb/IIIa-inhibitor administration (for selective use during PCI only) is sufficient to warrant the potential increase in adverse ischemic events by not treating all patients with GP IIb/IIIa inhibitors upstream (prior to angiography)," Stone et al write.

In ACUITY Timing, 9207 patients undergoing cardiac catheterization followed by revascularization where appropriate were randomized to either early or deferred GP IIb/IIIa-inhibitor treatment. As previously reported by heartwire, the ACUITY Timing results showed that deferred use of IIb/IIIa blockers was associated with a slightly higher rate of ischemic events, which was accounted for mainly by unplanned revascularizations and did not meet the criterion for noninferiority. At the same time, however, the deferred approach was associated with a significantly lower incidence of major bleeding, and as a result, there was no difference in the net clinical outcome at 30 days (a composite of death/MI/unplanned revascularization/major bleeding) between the two approaches.

Stone noted that overall, 98% of the patients in the upstream group received a IIb/IIIa blocker vs 55.7% in the deferred group. Median time from hospital admission to randomization was approximately six hours in each group, time from randomization to the start of GP IIb/IIIa-blocker treatment was 0.6 hours in the upstream group and 4.5 hours in the deferred group, while time from randomization to PCI was 4.7 hours in the early-GP IIb/IIIa-inhibitor group and 5.1 hours in the deferred-GP IIb/IIIa-inhibitor group.

But, in their accompanying editorial, Mahaffey and Harrington point out that "real-world" treatment delays are often longer than those reported in ACUITY Timing. For example, the median time from hospital admission to PCI in the CRUSADE registry for ACS patients was 23.4 hours during weekdays and 46.3 hours on weekends, substantially longer than the roughly five-hour window in ACUITY Timing trial.

"This important and perhaps unanticipated limitation influences how these results might apply to typical clinical practice outside of the ACUITY sites," the editorialists write.

To heartwire, Harrington emphasized that the ACUITY Timing results really apply only to patients admitted to centers that have median delay times of four to five hours from treatment initiation to coronary angiography.

"Even in that short period of time, there is at least a suggestion of fewer ischemic events in the upstream treated group vs the delayed group, and there's more bleeding in the upstream group, that's the trade-off. And I would say that ACUITY Timing sets up the hypothesis for the large trial that we already have under way, the EARLY-ACS trial."

When he presented the ACUITY Timing results last year, Stone argued that IIb/IIIa blockers may not be needed at all if bivalirudin is used as the antithrombotic agent. As he previously commented to heartwire: "From all the results together, I would recommend that bivalirudin monotherapy be the preferred option for ACS undergoing an early invasive strategy and suggest that IIb/IIIa blockers are not needed at all, apart from for bailout use. But there will still be some interventionalists who will want to use IIb/IIIa blockers routinely, and in that situation the ACUITY Timing trial supports the ability to defer starting these agents until the patient is in the cath lab and then treating only those who are undergoing PCI."

Indeed, Harrington suggests the question may not be which drug is better, but which drug is best suited to any given practice.

Everyone is out there bashing one another, saying 'my drug is better than your drug,' and that's the nature of the marketplace, but clinicians need to be a bit more circumspect.

"We now have data supporting the use of unfractionated heparin, enoxaparin, fondaparinux, and bivalirudin, all as anticoagulants in the setting of acute coronary disease. All of them are supported by a body of clinical-trials work, but there are some differences among the trials, including the strategies that we use in the trials, whether it's early invasive therapy or delayed invasive therapy or a mixture thereof. My sense is that they all work to varying degrees, they all have benefits and risks associated with them, and largely what you pick is probably as dependent on the style of practice that you employ as anything else. It is probably worthwhile for your healthcare system to reduce the risk of medical errors, etc, that you essentially pick one or two strategies that best fit your local practice."

For example, he says, for centers that typically employ a day or two of antithrombotic therapy, only cathing patients who fall into a certain risk category, enoxaparin or fondaparinux are "fine" choices. Likewise, bivalirudin is a "very reasonable choice" at centers where patients head directly from the emergency room to the cath lab.

"Everyone is out there bashing one another, saying 'my drug is better than your drug,' and that's the nature of the marketplace, but clinicians need to be a bit more circumspect and say, many of these agents work, let me figure out the one that fits best into my local practice environment and let's make sure I can get everyone on board from the emergency department up through the operating room to all sing the same tune."