Her stent studies intrigue doctors, Wall Street

WASHINGTON -- The FedEx packages arrive at Dr. Renu Virmani's laboratory from around the world, a new one every few days. Each contains a plastic container packed with gauze. Inside the gauze is a human heart.

The hearts come from patients who died with stents, tiny metallic-mesh support tubes, implanted in their coronary arteries. Virmani is the world's leading specialist in the art of slicing the arteries and looking directly inside. What she has found has placed her at the center of one of the biggest debates in medicine.

In the three years since they were introduced, drug-coated stents have become one of the world's most widely implanted medical devices. They are also highly profitable, generating about $5 billion a year for their manufacturers and building Boston Scientific Corp. of Natick into the most valuable life-science company in New England.

But in a small number of patients, drug-coated stents appear to trigger blood clots long after they are implanted. The risk of clots has alarmed heart patients and made many doctors rethink their use of the stents. It has hurt Boston Scientific's stock, as Wall Street grows wary of a once-favored product.

It is also making Virmani a celebrity at this week's Cardiovascular Research Foundation conference in Washington, D.C., the world's biggest meeting of the doctors who repair coronary arteries. In a world where most information comes from large-scale statistical studies, Virmani's brightly colored microscope slides offer dramatic evidence of something doctors otherwise never see: how stents affect the human body on the inside.

"What we see is there's delayed healing from all these drugs," she said. "You created a wound in an artery wall. Now you've put in a drug that doesn't allow the wound to heal. You're going to have a problem."

The drug coating on stents is supposed to prevent the arteries from renarrowing after doctors have cleared them out. In 14 of the 23 patients she described in a recent paper, however, Virmani saw blood clots that blocked all or part of an artery. Frequently, the delicate inner lining of the artery had failed to heal around the device.

After years laboring in the obscure field of pathology, studying diseased tissue for the United States military, Virmani has become highly sought-after by doctors and device developers for her expertise. She gave five scientific talks at this week's conference, moderated several more, and quietly met with a group of Wall Street medical-device investors looking for inside information.

The attention is partly a testament to researchers' hunger for concrete information on the long-term effects of drug-coated stents. It is also a vindication for a woman who describes herself as a "blabbermouth" in a field populated by more cautious scientists.

"I am a voice in the wilderness -- I actually don't mind," Virmani said. "I know that there are people who do appreciate what I do, and that keeps me going."

Though often fatal, clotting inside stents is also so rare that it barely registers in clinical trial statistics. The five days of this week's cardiology meeting have featured a steady crossfire of data from stent makers and independent researchers. Boston Scientific, looking at four years of results from its clinical trials, says that compared to those with bare-metal stents, one additional patient in 250 with drug-coated stents is likely to develop a clot one to four years after implantation. Some researchers have found that in real-world practice, the risk appears to be higher, one additional patient in 200 per year.

Of special concern to doctors is that the clot risk does not appear to decrease over time, as it does with the older bare-metal stents. The Food and Drug Administration is convening a special public meeting on the subject in December, and both Boston Scientific and Johnson & Johnson have said they will fund large-scale trials to study the problem.

Still open, however, are the questions of how and why the clots form at all.

To answer it, Virmani and her staff cut the stented artery off each heart they receive, embed it in hard plastic, and use a mechanized steel knife to shave the vessel into thin slices. The slices are doused with a stain and photographed under a powerful microscope, which shows exactly what happened in and around the stent.

In a recent article in the Journal of the American College of Cardiology, she compared autopsies of 23 drug-coated stent patients with those of 25 bare-metal stent patients. Many of the drug-coated stents, she found, left a rough, unhealed inner wall on the artery where they were implanted. By contrast, arteries had healed more smoothly over the bare-metal stents. She said patients with bare-metal stents usually saw smooth artery healing within six months, while drug-coated stent patients could go 40 months without healing.

She notes that her sample of patients is too small to draw any conclusions about the frequency of the problems she sees.

In addition to pointing out the small numbers involved in Virmani's studies, her critics say it's not surprising her findings show troubled arteries, since she can study only patients who have died.

But Dr. Peter Fitzgerald , a Stanford University cardiologist and device inventor, calls Virmani's work "exquisitely important" for understanding the mysterious process of what happens inside human arteries.

"Renu is one of the brightest people I've ever met -- she's passionate, she looks at more of these than anybody," he said.

Virmani started her nonprofit firm, CVPath Institute Inc. , two years ago after leaving the US Armed Forces Institute of Pathology. Today she works in a lab in suburban Maryland, with a staff of 38. Pathologists around the world turn to her when confronted with a particularly vexing problem in the heart, and medical-device makers rely on her to analyze results of early testing on animals.

Although her findings in humans have long made stent companies uncomfortable, her scientific talks this week have consistently been lined with gray-suited industry representatives. One of her slides appeared in a presentation Wednesday afternoon by Boston Scientific's chief medical officer, who was addressing Wall Street's concerns about the stent market.

And though she has been a vocal critic of drug-coated stents, Virmani sees herself as having a broader mission as well: To give autopsy a new prominence in high-tech modern medicine.

"My biggest gripe is that we don't want to learn anything once the patient is dead," she said. "We don't want to call them patients anymore."

Stephen Heuser can be reached at sheuser@globe.com.