By David N. Leff

Something like 1 million heart disease patients worldwide will undergo a relatively simple operation this year to unclog their atherosclerotic coronary arteries.

The procedure, percutaneous angioplasty, involves threading a plastic tube into the plaque-pinched blood vessel, and inflating a balloon that stretches the walls of the artery, thus restoring blood flow to the oxygen-starved heart.

This surgical intervention, sometimes done on an outpatient basis, is effective — while it lasts. One downside is that all too often, in nearly half the cases, the arteries narrow again within a year. This sinister restenosis calls for a repeat angioplasty, or an even more drastic coronary bypass.

Another adverse event in balloon angioplasty is the damage the procedure inflicts on the delicate inner walls of the blood vessel, including the smooth-muscle layer and endothelial cell lining.

No drug therapy exists to prevent the arterial backlash of restenosis, let alone the sudden death and other complications that atherosclerosis often precipitates.

A proprietary monoclonal antibody fragment has changed these no-win odds, as reported in a three-year, randomized, placebo-controlled clinical trial named "EPIC." Today's Journal of the American Medical Association, (JAMA), dated Aug. 13, 1997, describes EPIC's unexpected results under the title: "Long-term protection from myocardial ischemic events in a randomized trial of brief integrinß3 blockade with percutaneous coronary intervention."

Molecular pharmacologist Bob Jordan, who directs clinical pharmacology at Centocor Inc., in Malvern, Pa., explained: "Integrinß3 is the name for a receptor that is particularly rich on the surface of blood platelets. The ReoPro monoclonal antibody fragment is designed to block those platelets from doing their normal job of clumping to form blood clots.

"Starting with the original 160,000-molecular-weight mouse monoclonal," Jordan recounted, "we made a 47,000-molecular-weight chimeric version. It replaced all non-essential parts of the antibody structure with their human equivalent, retaining only the actual murine binding site."

Platelets are not really cells, because they lack a nucleus. But "every cubic centimeter of a normal person's blood contains 300 million platelets, on average," Jordan pointed out. "And every one of those formed elements carries enormous numbers of the integrinß3 receptor."

ReoPro is Centocor's trade name for its humanized, chimeric monoclonal fragment (generic name: abciximab), which was clinically tested in the EPIC trial. ("EPIC" denotes "Evaluation of Platelet IIb/IIIa [integrin receptors] Inhibition for Prevention of Ischemic Complication." (See BioWorld Today, Feb. 20, 1997, p. 1.)

In the early 1990s, that multicenter study enrolled 2,099 high-risk heart patients undergoing angioplasty at 56 academic and community hospitals throughout the U.S.

Those risk factors included acute myocardial infarction and unstable angina, as well as diabetes, high blood pressure, high cholesterol and history of smoking.

During the angioplasty procedure, two-thirds of the patients received a one-shot intravenous bolus of ReoPro, followed in half of these by one 12-hour infusion of the drug. The remaining one-third got placebos.

Three years later, analysis of the trial's outcomes showed that the complication-preventing effects of the ReoPro bolus-plus-infusion had not yet worn off:

* Of the placebo group, 8.6 percent had died, compared to 6.8 percent of the ReoPro contingent.

* Restenosis, requiring repeat angioplasty or coronary bypass, occurred in 40.1 percent of those on placebo, but only 34.8 percent of patients on ReoPro.

* And 13.6 percent of the placebo cohort suffered a subsequent heart attack, compared to 10.7 percent of the ReoPro group.

Cardiologist Eric Topol, who chairs the Cleveland Clinic Foundation's cardiology department, coordinated the EPIC study. He is principal author of the JAMA paper. "The sustained benefit at three years," Topol stated, "was unexpected. We theorized that the outcomes gap between the placebo and ReoPro groups would become narrower beyond the first year. This opens up the possibility of broader uses for ReoPro as a protective agent against atherosclerotic-related events."

"The intriguing question is," said Centocor's Jordan, "How does short-term treatment by blocking the integrin platelets confer such long-term benefit?" He cites two aspects of ReoPro's molecular behavior that deserve attention:

"One, it binds not only to the platelet IIb/IIIa receptor, but also to another receptor present on smooth-muscle cells. So perhaps the long-term benefit may be related to the blockade of smooth-muscle cell migration and proliferation, which certainly occur in balloon injury sites."

How Does Antibody Fragment Block Restenosis?

Jordan emphasized the "perhaps" in this scenario: "Have we proven that? Do we know it for absolute certain? No. It's going to take additional studies to actually establish that ReoPro is blocking restenosis in that way."

A second aspect, in terms of the integrin blockade, he added, is perhaps not as well appreciated about ReoPro. When the monoclonal antibody binds to the platelet — and it really blocks most of the 80,000 to 100,000 integrin receptors on each one — it doesn't fall off right away. Instead, ReoPro dissociates, or reverses slowly, over several hours, and more likely rebinds to another platelet or another receptor.

"So there's a continuous redistribution of ReoPro among all of the receptors that are in circulation. And what that results in is a gradual, tapered restoration of receptors on platelets that occurs — as we've shown in the lab — over two weeks' time." He concluded: "So that with the therapy that we have in the EPIC trial, even though it's only 12 hours, in fact the effects last much longer, but in a tapered and gradual way."

An editorial accompanying the JAMA paper acknowledged that "this is the first trial to demonstrate that an intervention, pharmacological or mechanical, aimed at reducing the incidence of a periprocedural ischemic complication may result in improved long-term survival."

But its authors, cardiologists at the Jefferson College of Medicine, in Philadelphia, raise a key question for the future: "Who should receive this agent when undergoing coronary intervention?"

They make the point that, given "the average cost of abciximab at $1,350 per patient dose, and as long-term survival has only been demonstrated in selected high-risk patients, the issue of cost-effectiveness is vital to understanding [ReoPro's] role in lower-risk patients." *