ACC 2009: EARLY ACS: Delay GP IIb/IIIa Blockers Until in the Cath Lab

March 30, 2009

(March 30, 2009) (Orlando, Florida) — Routine early use of the GP IIb/IIIa blocker eptifibatide was not superior to delayed provisional use in the cath lab in high-risk ACS patients in the EARLY ACS trial [1].

The trial was presented at the American College of Cardiology 2009 Scientific Sessions today and simultaneously published online in the New England Journal of Medicine.

Senior author Dr Kristin Newby (Duke Clinical Research Institute, Durham, NC) explained to heartwire that the EARLY ACS trial addressed the question that has long been debated of whether GP IIb/IIIa blockers were better given upstream to all high-risk ACS patients or to wait until the patient was in the cath lab and the coronary anatomy could be seen, then giving the agent just to those patients who would definitely undergo PCI and were judged to need it most.

"Our study, although not the final word regarding eptifibatide, has helped shed light on how to best use it among high-risk patients," Newby said. "In general, physicians can feel comfortable with a strategy of delayed, provisional administration after a decision to proceed to PCI is made." She added: "Our results are not enough to recommend the routine early administration of IIb/IIIa blockers to all high-risk ACS patients. But, with further analysis, we may be able to tease out some subgroups that may benefit more from such treatment."

On this idea, coinvestigator Dr Robert Giugliano (Brigham & Women's Hospital, Boston, MA) commented: "We need to do a lot more analysis, but our initial results point to those groups where we might be able to look for some benefit of early treatment--and those are the patients with positive troponins, younger patients, and diabetics." But in the paper, the researchers note that patients in the early eptifibatide group had a significantly increased risk of bleeding. "Even if subgroups of patients who might benefit from early eptifibatide treatment could be identified, the risk of bleeding would have to be weighed against potential benefits," they caution.

The ACUITY trial also looked at the question of early vs late treatment with GP IIb/IIIa blockers in ACS patients heading for PCI, with broadly similar results, but it had a few differences compared with EARLY ACS, Newby noted. ACUITY included a slightly lower-risk population, the GP IIb/IIIa blocker used was not specified, and the time interval between early and late treatment was much shorter than in EARLY ACS (five hours vs 21 hours). The short time difference between the two strategies in ACUITY attracted the criticism that it was not a true test of early vs late treatment, and Newby pointed out that the 21-hour time difference in EARLY ACS is much more typical of clinical practice and makes this trial a fairer test of the two approaches.

The EARLY ACS trial enrolled 9492 high risk ACS patients who were assigned to an invasive strategy. They were randomized to either early eptifibatide (two bolus doses of 180 µg/kg 10 minutes apart and standard infusion) or matching placebo infusion with provisional use of eptifibatide after angiography. Of the patients, 97.5% underwent angiography, 59% underwent PCI, 13% received CABG, and 28% were treated medically.

After angiography but before PCI, investigators could request a PCI study drug kit for patients whom they deemed would benefit from eptifibatide on the basis of the angiographic findings. The first bolus of this kit contained eptifibatide for patients who had previously received placebo and placebo for patients who had previously received eptifibatide. Then all these patients received open-label eptifibatide infusion for 18 to 24 hours after the PCI. Of the 5559 patients who underwent PCI, 1434 (25%) were transferred to open-label eptifibatide in this way, 687 from the early-eptifibatide group and 747 from the delayed-eptifibatide group. So 39% of the delayed-eptifibatide group actually received the drug during PCI.

The use of open-label eptifibatide was much more common in North America (56%) than elsewhere (15%). An additional 648 patients (11.7%) received bailout eptifibatide during the PCI procedure (312 from the early-eptifibatide group and 336 from the delayed-eptifibatide group, roughly half in each group).

Results showed a trend toward fewer events but significantly higher rates of bleeding in the routine early-eptifibatide group.

EARLY ACS: Key End Points

End point Routine early eptifibatide (%) Provisional delayed eptifibatide (%) OR (95% CI) p
Death/ MI/ recurrent ischemia requiring urgent revascularization/ thrombotic bailout at 96 h* 9.3 10.0 0.92 (0.80–1.06) 0.23
Death/MI at 30 d 11.2 12.3 0.89 (0.79–1.01) 0.08
TIMI major bleed 2.6 1.8 1.42 (1.07–1.89 0.015
TIMI minor bleed 3.6 1.7 2.14 (1.63–2.81) <0.001
*Primary end point

The authors suggest several reasons for the lack of significant treatment benefit with early routine use of eptifibatide. These include the convergence of use of eptifibatide during PCI in the two study groups, although it would not have been possible to have a strict placebo group as it was believed beneficial to use GP IIb/IIIa blockers in PCI. They also suggest that interventionalists may have simply identified correctly those patients who would have benefited from eptifibatide on angiography and were thus given the drug open label. In addition, adjunctive therapy with aspirin, clopidogrel, heparin, and statins was high, which may have reduced the potential incremental effect of early eptifibatide, and more patients than anticipated were treated with CABG or medical therapy.

Is Use in Cath Lab Justified?

Commenting on the study for heartwire , Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles) said the high rate of bleeding seen with early eptifibatide highlights the risk associated with GP IIb/IIIa blockers, which he believes should lead to questions over their use in the cath lab, too.

"The most rational and evidence-based use of these agents is in the high-risk troponin-positive ACS patient. However, the bleeding risk is also increased, especially when used in conjunction with other antithrombotic agents. In my opinion, the modest benefit does not greatly exceed risk and therefore does not deserve the imprimatur of a class 1A guideline recommendation. I recommend 'bailout' use in the cath lab only in case of procedural complications. In my opinion, the evidence base is not robust for either upstream use or for 'routine' downstream use during PCI."

Newby and Giugliano both disagreed with this statement. Newby commented to heartwire : "This study does not address the question of whether IIb/IIIa blockers should be used in the cath lab. It has been well established in many previous studies that they are beneficial in this setting." Giugliano added: "I don't think you can apply the bleeding results seen in the early group to patients being treated in the cath lab. For one thing, the agent would be much more selectively used in the cath lab, being targeted to those patients who need it most, and it would be used for a much shorter time frame, which would reduce bleeding risk."

EARLY ACS was supported by Schering Plough and Millennium Pharmaceuticals, which market eptifibatide.