But soon, a revolutionary new stent coated with a compound called rapamycin or sirolimus, may be coming to America and could practically eliminate re-clogging, or restenosis. European regulators approved the drug-coated stent for use in European Union countries in April. Now, U.S. doctors and patients are awaiting Food and Drug Administration approval of the device, which is undergoing clinical trials. Based on European data, though, they are hailing the drug-coated stent as a major breakthrough in the treatment of patients with heart disease.
Few know, however, that the scientists responsible for the discoveries that led to the development of the coated stent are members of the Center for Molecular Cardiology at P&S.
Dr. Andrew Marks, Wu Professor of Molecular Cardiology, and director of the Center for Molecular Cardiology, first started studying rapamycin 15 years ago when he discovered the compound's receptor was part of the ryanodine receptor, a calcium channel he studies that regulates muscle contraction. Although the ryanodine receptor studies were unrelated to restenosis, Dr. Marks started a new project in his laboratory when he read rapamycin could inhibit T cell proliferation. (The drug originally had been isolated from a bacterium found on Rapa Nui, the indigenous name for Easter Island.)
"I thought rapamycin might prevent proliferation of other cell types and could prevent cell growth contributing to restenosis," Dr. Marks says. "But everyone told us we were crazy."
At the time, most researchers blamed restenosis on blood clotting. However, Dr. Marks knew smooth muscle cells in artery walls can proliferate and migrate into the interior of the vessel when the vessel is injured by the angioplasty and reasoned this process could contribute to restenosis. Dr. Marks recruited Dr. Steven Marx, now assistant professor of medicine/cardiology (in the Center for Molecular Cardiology), to help determine how the drug worked. In 1993, the researchers, then working at Mount Sinai, tested rapamycin's effect on cultured smooth muscle cells and found the drug directly prevented cell growth and migration by inhibiting regulators of cell cycle progression.
In the same year, Dr. Marks approached the drug's owner, Wyeth-Ayerst Research, now called Wyeth, about its potential for preventing restenosis. The company was developing rapamycinwhich was approved in 1999to prevent kidney transplant rejection based on the drug's immunosuppressive properties. However, Dr. Marks says the development of new anti-clotting drugs and intracoronary stents, which were anticipated to dramatically reduce restenosis, convinced the drug firm not to pursue rapamycin for restenosis prevention after angioplasty.
Unexpectedly, though, despite the new anti-clotting therapies and stents, the restenosis rate remained high, at approximately 20 percent to 30 percent, and many researchers started pursuing how to limit smooth muscle cell proliferation.
By this time, in 1998, Drs. Marks and Marx already had compelling evidence from pigs that rapamycin prevented restenosis, backing up their in vitro findings. Arteries from animals injected with rapamycin after a balloon angioplasty showed 50 percent less clogging than control animals. Dr. Marks, now at Columbia, showed the data to Cordis, a Johnson & Johnson company. Cordis quickly signed a licensing agreement with Wyeth-Ayerst and started the development of a rapamycin-coated stent, which delivers the drug precisely to the spot of injury.
Recently, in European and South American trials of 238 patients, the rapamycin-coated stent made by Cordis, named CYPHER, performed extremely well. Angiograms of the stented artery showed zero restenosis in all patients at 12 months compared with 26 percent with the standard stent. Based on the findings, European regulators in April approved CYPHER for use in the European Union.
"We knew from a decade of work that rapamycin inhibits smooth muscle cell growth, so we expected a reduction in restenosis," Dr. Marks says. "To go from 26 percent to zero percent is fantastic, but I expect when stents are used in a wider population with more severe disease the number will increase slightly but will still be low, probably less than 5 percent."
Preliminary results from a larger U.S.-based trial, called SIRIUS, of CYPHER show a 2 percent rate of restenosis. Full results are expected this fall, and Cordis anticipates FDA approval in 2003. Longer studies will be needed to see if restenosis remains low after several years.
"There's never been a drug like this before," Dr. Marks says. "All cardiologists will want to use these stents in their patients. Patients will do better and it will reduce the number of people needing bypass surgery."
However, the stent is expensive. In Europe, CYPHER sells for approximately three times that of uncoated stents. Dr. Marks says the high cost may drive some hospitals into bankruptcy unless Medicare and private insurers quickly start reimbursing health care providers for the entire cost of the stent.
"Developing and bringing other types of coated stents into the clinic will bring prices down, which will be a very important thing for the healthcare system and patients," Dr. Marks says. "We've discovered another naturally occurring molecule similar to rapamycin and we are starting animal studies to see if it prevents restenosis as well."
The American Heart Association supported this research.