Early GPI More Effective When Paired with Upstream Clopidogrel in NSTE ACS

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In patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) who undergo coronary angiography, early treatment with the glycoprotein IIb/IIIa inhibitor (GPI) eptifibatide lowers the 30-day risk of death and myocardial infarction (MI) when paired with upstream clopidogrel use, according to a subanalysis of the EARLY ACS trial published online February 7, 2011, ahead of print in Circulation.

The benefit from early eptifibatide in this subgroup, although accompanied by increased bleeding, puts a positive spin on the negative overall results of EARLY ACS that were first released nearly 2 years ago at the American College of Cardiology Scientific Sessions/i2 Summit in Orlando, FL, and later published in the May 21, 2009, issue of the New England Journal of Medicine. In those findings, early eptifibatide held no advantage over provisional use of the drug among 9,492 high-risk NSTE ACS patients slated to undergo invasive treatment at 29 centers in North America, Europe, the Middle East, Asia, and Asia-Pacific.

Upstream Clopidogrel + Early GPI

For the current prespecified subanalysis, Tracy Y. Wang, MD, MHS, MSc, of Duke Clinical Research Institute (Durham, NC), and colleagues sought to understand the effects of early vs. delayed, provisional eptifibatide in the context of concurrent upstream clopidogrel use. The researchers looked only at the 9,166 subjects who actually underwent coronary angiography in EARLY ACS. At the time of randomization to either early or provisional eptifibatide, intent to use upstream clopidogrel was declared in 6,895 of these patients (75.2%); three-quarters received a 300-mg loading dose, while others received a loading dose of 600 mg or no loading dose at all.

After adjustment for clinical characteristics, early and delayed, provisional eptifibatide offered similar results regardless of upstream clopidogrel use in terms of the trial’s primary endpoint (composite of death, MI, recurrent ischemia requiring urgent revascularization, or use of thrombotic bailout within 96 hours). At 30-day follow-up, early eptifibatide administration appeared to reduce death/MI risk, but only among those patients intended to receive upstream clopidogrel. Pairing early GPI use with upstream clopidogrel also came at the expense of higher in-hospital TIMI major bleeding (table 1).

Table 1. Upstream Clopidogrel


Early Eptifibatide

Delayed, Provisional Eptifibatide

Adjusted OR
(95% CI)

Primary Composite at 96 Hoursa



0.93 (0.76-1.10)

Death/MI at 30 Days



0.85 (0.73-0.99)

In-Hospital TIMI Major Bleeding



1.54 (1.07-2.24)

In-Hospital GUSTO Severe Bleeding/ Transfusion



1.41 (1.07-1.87)

In-Hospital Transfusion



1.38 (1.04-1.83)

a Death, MI, recurrent ischemia requiring urgent revascularization, or use of thrombotic bailout.

Rates of 30-day death/MI in the cohort not intended for upstream clopidogrel were equivalent between patients receiving early (13.1%) and delayed eptifibatide (12.8%; adjusted OR 1.02; 95% CI 0.80-1.30).

Actual upstream clopidogrel use paralleled closely with the declared intention, so analyzing the data based on actual use did not substantially change the results.

“Platelets play an integral role in the pathophysiology of ACS,” the paper notes. “Among patients undergoing PCI, procedure-related platelet activation poses further risk of thrombotic events, and the extent of platelet hyperreactivity has been correlated with the degree of damage. For this reason, use of thienopyridines and glycoprotein IIb/IIIa inhibitors targets various levels of the hemostatic pathway and can improve short- and long-term outcomes.”

For Some, Two Better Than One

Current American College of Cardiology/American Heart Association guidelines recommend that patients with NSTE ACS treated with an early invasive strategy should receive antiplatelet therapy with either clopidogrel or a GPI upstream before diagnostic angiography. If these patients also have certain high-risk features, such as elevated troponin, the use of both clopidogrel and a GPI together is an option, Dr. Wang told TCTMD in a telephone interview.

Although it appears that using both drugs together may have a synergistic effect, at least in some patients, “clearly we’re also seeing a signal for higher bleeding risk,” she said. “So in my opinion, it ultimately boils down to, who do you select to treat with 2 therapies vs. either 1 alone?”

“Perhaps there’s some benefit to layering on another antiplatelet agent in the acute period when platelets are running amok,” Dr. Wang noted, citing recent literature suggesting that GPIs could help patients who have high on-treatment platelet reactivity with clopidogrel.

“EARLY ACS [as a whole] certainly seems to have shut the door a little bit on eptifibatide use but what we’re seeing in practice is that people still want to be using the drug,” Dr. Wang commented. “I think the [substudy] shows that there may be certain situations where a IIb/IIIa inhibitor is reasonable.”

That being said, it is crucial not to discount bleeding risk when managing patients. “We still need to be very selective about the patients we treat,” she urged.

Strong Backing for GPIs

In a telephone interview, Neal S. Kleiman, MD, of Methodist DeBakey Heart and Vascular Center (Houston, TX), said the subanalysis offered no surprises but might convince some clinicians who have been reluctant to use clopidogrel plus a GPI in this context.

“To me, the story’s pretty clear,” he commented to TCTMD, adding, “It’s going to open people’s eyes a little bit and move them away from the mythology that a thienopyridine makes IIb/IIIa inhibitors unnecessary.”

However, Dr. Kleiman stressed that the subanalysis comes with some caveats. To begin with, it is hard to truly adjust for differences in a nonrandomized comparison and secondly, the 30-day time frame was a secondary endpoint, he added.

Study Details

Patients chosen to receive upstream clopidogrel differed in many respects from their counterparts not selected to receive the thienopyridine. Individuals intended for clopidogrel were slightly younger, were more likely to be male, and were less likely to have diabetes, hypertension, dyslipidemia, prior MI, prior CABG, or renal dysfunction compared with those without planned upstream use. Moreover, there was much geographic heterogeneity: the intent to administer upstream clopidogrel was declared for 51% of patients enrolled at North American sites compared with 86% of those enrolled elsewhere (P < 0.001).


Wang TY, White JA, Tricoci P, et al. Upstream clopidogrel use and the efficacy and safety of early eptifibatide treatment in patients with acute coronary syndrome: An analysis from the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial. Circulation. 2011;123:722-730.



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  • The EARLY ACS trial and the current analysis were funded by research grants from Merck and Schering-Plough.
  • Dr. Wang reports having received research grants from the Bristol-Myers Squibb/Sanofi Partnership, Canyon Pharmaceuticals, Eli Lilly/Daiichi-Sankyo Alliance, Heartscape, Schering-Plough, and The Medicines Company.
  • Dr. Kleiman reports receiving research support from Merck and Schering-Plough. He also served on the steering committee of EARLY ACS.