Eptifibatide has long-term benefit, cost-efficiency

ESPRIT trial changed coronary-stent practices

Several months have passed since the release of the six-month results of the ESPRIT (Enhanced Suppression of the Platelet Receptor glycoprotein IIb/IIIa using Integrilin Therapy) trial. During this time, many physicians have switched from abciximab (ReoPro) to eptifibatide (Integrilin) as their primary GP IIb/IIIa inhibitor in the setting of coronary intervention during stenting, says one of the trial’s principal investigators. And more are considering it, he suggests.

A look at the trial

ESPRIT was a randomized, placebo-controlled trial designed to assess whether a novel, double-bolus dose of eptifibatide could improve the outcomes of patients undergoing coronary stenting. The trial involved 2,064 patients undergoing stent implantation in a native coronary artery.

The trial was stopped prematurely in February 2000 when results showed a highly significant 37% reduction in the endpoint complications by 48 hours between the placebo group and the eptifibatide group. The 30-day secondary endpoint, which was a composite of death, myocardial infarction (MI), or urgent target vessel revascularization (TVR), also was reduced significantly.

By six months, the composite endpoint of death or MI had occurred in 7.5% of eptifibatide-treated patients and in 11.5% of placebo-treated patients, a difference of 35%. The composite of death, MI, or TVR was 14.2% in eptifibatide-treated patients vs. 18.3% in placebo-treated patients. Most of this benefit accrued early (less than 48 hours after initiation of therapy) and was maintained through six months. Six-month mortality in the eptifibatide group was 0.8% vs. 1.4% in the placebo group, and TVR occurred in 8.6% of the eptifibatide group vs. 9.4% of the placebo group.

"The fact that we have a durable result that is very highly statistically significant reinforces the result of using this class of drugs, in particular eptifibatide, in the setting of coronary intervention during stenting," says James E. Tcheng, MD, FACC, FSCAI, associate professor of medicine at the Duke Clinical Research Institute at Duke University Medical Center in Durham, NC.

The ESPRIT investigators were hoping that the absolute risk reduction would stay the same between 30 days and six months, Tcheng says. "We saw the absolute risk reduction increase between 30 days and six months. That means that there is not only a durable benefit, but that the benefit continues to increase with time."

The implication of these results is profound, he continues. "This means that something we are doing for a very short period of time — the drug is only given for 18-24 hours — is having long-lasting effects that continue to make a difference with the passage of time."

Eptifibatide vs. abciximab

The ESPRIT results are basically the same as the results that have been seen in trials of other IIb/IIIa inhibitors, in particular ReoPro, given the same type of study design, Tcheng says. "The relative risk reduction and the absolute risk reduction are what we had predicted, what we had expected, and are entirely consistent with those that have been seen with the others."

However, some researchers have questioned whether ReoPro has more benefit to diabetics than Integrilin. The discussion stems from one analysis of one trial of ReoPro — EPISTENT (Evaluation of IIb/IIIa Platelet Inhibitor for Stenting trial), Tcheng says. EPISTENT evaluated three strategies in reducing the primary endpoint of death, heart attack, and urgent repeat procedures at 30 days (coronary stenting alone, coronary stent with ReoPro, and conventional angioplasty plus ReoPro). Compared with patients receiving a stent alone, those receiving angioplasty and ReoPro had a 36% reduction in the primary endpoint, while those receiving both a stent and ReoPro had a 51% reduction.

The EPISTENT trial showed a greater than 50% relative reduction in the rate of restenosis at six months after the procedure in the diabetic subgroup. From that, the conclusion has been reached that ReoPro has magical benefits in the setting of diabetes, Tcheng says. He disagrees with this conclusion for several reasons.

"In the ESPRIT trial, the risk reduction wasn’t 50%; it was about 11% with regard to restenosis," he says. "But we would have expected that the rate reduction in the diabetics was the same as that in the nondiabetics." This is what the researchers found. "So from a statistical standpoint, the results we saw in the ESPRIT trial make more sense. It’s not that there isn’t a benefit. It’s just that the benefit is basically the same between the diabetics and the nondiabetics."

Tcheng also is concerned that this result has not been duplicated in other trials. "There is actually an increase in restenosis in the diabetic population in other trials of ReoPro. There is no statistical consistency from one trial to the next, which makes you think that it may have been a play of chance."

He says the rate of restenosis in the diabetics who received ReoPro in the TARGET trial (Do Tirofiban and ReoPro Give Similar Efficacy Trial) was higher than in the group that did not receive ReoPro. TARGET compared two GP IIb/IIIa inhibitors, tirofiban (Aggrastat) and ReoPro; it
randomized 4,809 patients who were undergoing percutaneous coronary revascularization with stenting to either ReoPro or Aggrastat. The 30-day results showed a significant benefit with ReoPro. The six-month results, however, show that the benefit of ReoPro has become much smaller over time, and at six months there was no significant difference for TVR or mortality between the two drugs. Most importantly, the reduction in MI seen with abciximab at 30 days has not translated into a reduction in mortality at six months.

Because of the other trials and a myriad of other reasons, Tcheng basically makes no discrimination between the diabetics and the nondiabetics — they should all receive a GP IIb/IIIa inhibitor, he says. "The choice of IIb/IIIa is up to the institution. I would make a strong argument that the diabetics are benefited by both Integrilin and ReoPro."

Duke had primarily been choosing ReoPro during coronary stent implantation until it saw the results of the ESPRIT trial, Tcheng says. "In February/March 2000 before the trial was terminated prematurely, we were using a IIb/IIIa agent in about 85% of our patients, about 90% of which was ReoPro. After the 30-day results were released in April 2000, we switched to about 50/50. After the six-month results were released, we went to the opposite: 90% Integrilin and 10% ReoPro."

He claims that three-quarters or more of institutions have made the switch from ReoPro to Integrilin as their primary IIb/IIIa antagonist, and that many more are considering it. A primary reason for making the switch is the difference in price of the drugs. "[Integrilin] costs about $350 per treatment as opposed to ReoPro, which is about $1,500 per treatment," he says. "The economics so strongly favor the use of Integrilin. That’s one of the reasons why our lab has switched from using ReoPro to Integrilin in our angioplasty procedures. Another is that the drug works.

"If you think about [these savings] across the whole health care economy of the United States, you are talking about hundreds of millions of dollars," he continues. "At the same time, it is not only saving money, but it also is saving lives and creating better outcomes."