InTouch Magazine - Spring/Summer 2002

Challenges and New Therapies for Restenosis After Angioplasty

The number-one killer in the United States, coronary artery disease, results from narrowing (stenosis) of the arteries that supply blood to the heart muscle. Over time, substances such as fat and cholesterol can build up in the lining of the artery. If a coronary artery becomes totally blocked for a long enough time, the heart muscle supplied by that artery dies (this is called a myocardial infarction or heart attack). According to the American Heart Association's 2002 Heart and Stroke Statistical Update, more than 1 million Americans will have new or recurrent attacks, and 45% of these will die.

Human coronary artery after coronary atherectomy. The artery has re-narrowed with fibrous tissue in response to the procedure. This is the major cause of restenosis.

Major Advances
Major advances have been made in combating this killer, including coronary artery bypass surgery, angioplasty, and more recently, the use of stents. In 1999, physicians in the United States performed more than 1 million angioplasty procedures, including balloon angioplasty, atherectomy (which shaves away the blockage), and the use of laser catheters that vaporize the plaque. Use of angioplasty has been an effective therapy for widening coronary arteries for many patients with coronary artery disease.

Stents
About 70% to 90% of angioplasty procedures also involve placement of a stent. Stents are like little scaffolds that can be collapsed, placed inside the narrowed segment of artery, and expanded and locked into place to keep the artery open after it has been expanded by angioplasty. The stent remains in the artery permanently to improve blood flow to the heart muscle, which relieves symptoms such as chest pain.

The Problem of Restenosis
Unfortunately, restenosis, or renarrowing, of the artery occurs in about 25% to 45% of patients within about 6 months of an angioplasty procedure, even with the use of a stent. Restenosis usually presents as recurrent angina in most patients but sometimes can be "silent," when delivery of oxygen to the heart muscle is decreased without causing obvious symptoms. Because of restenosis, about 10% to 15% of patients who have undergone angioplasty need another procedure. This has proved to be a major limitation in the fight against coronary artery disease. To meet this challenge, Minneapolis Heart Institute Foundation (MHIF) researchers are leading the way in trying to find solutions to the problem of restenosis.

Mechanisms of Restenosis
To look for ways to prevent restenosis, studies have been done to determine what causes it. Investigators such as Robert S. Schwartz, MD, have found that restenosis following angioplasty results from the body's exaggerated healing response to injury of the vessel when it is stretched with a balloon, scraped with a rotating shaver during atherectomy, or when plaque is vaporized with a laser catheter. When the body is injured, it produces an overgrowth of tissue, resulting in a renarrowing of the vessel. Because specific types of cells are stimulated to grow and divide after angioplasty, the lesions that occur with restenosis differ from atherosclerotic lesions. The lesions in restenosis consist of cells and material resembling normal connective tissue with smooth muscle involvement. Another difference in lesions from restenosis is the time it takes them to develop (usually within six months), which is much shorter than that for atherosclerotic lesions, which evolve over decades. Calcification and thrombus also play a role in restenosis.

Factors that influence the risk of restenosis developing in a patient who has undergone angioplasty include the type of revascularization procedure performed, the site of the lesion, diabetes, male sex, smoking, skill of the operator, method and timing of follow-up, and balloon size. Although some have proposed attempting to limit the amount of injury during revascularization as a means to limit the growth of tissue within the vessel that leads to restenosis, it would be difficult to open the vessel wide enough while also limiting injury.

New Approaches
Researchers at MHIF are studying new approaches to solving the problem of restenosis, and two of these new approaches are showing great promise: radiation therapy (brachytherapy) and drug-eluting stents. With brachytherapy, small doses of gamma or beta radiation are applied to the lesion to reduce tissue overgrowth. Drug-eluting stents are coated with drugs that limit tissue growth.

Brachytherapy
"Radiation therapy is the first and only procedure that the Food and Drug Administration has approved for restenosis," stated Wesley Pedersen, MD, who has been studying the therapy. Clinical trials using brachytherapy to prevent coronary restenosis have demonstrated a clear benefit - restenosis is decreased by 30% to 60%.

"The patient doesn't perceive any difference in the procedure, except that applying the radiation adds a little time (about 2 to 10 minutes for beta radiation and 20 to 40 minutes for gamma radiation)," said Dr. Pedersen. The interventional cardiologist positions the radiation delivery catheter in the lesion, and then the radiation oncologist delivers an appropriate dose of radiation. With longer lesions, it may be necessary to reposition the catheter and deliver the radiation to more than one area. Although beta radiation, with high-energy electrons, can be applied in a shorter time, Dr. Pedersen believes that gamma radiation, with high-energy waves, has an advantage in large vessels, in long blockages, and in aorto-ostial lesions (lesions located at the beginning of the aorta).

Especially encouraging are the results Dr. Pedersen has seen in more complex cases, which include lesions greater than 45 mm in length, bifurcation stenosis (stenosis occurring at a place where vessels branch off), and aorto-ostial lesions. In 103 patients with in-stent restenosis who were studied and treated with gamma brachytherapy (137 lesions), the restenosis rate was as low as 10% or less after 6 months of follow-up. This represents a clear benefit over previous therapies, even in more difficult cases. The study concluded that gamma brachytherapy for coronary in-stent restenosis is "highly efficacious" in a high-volume clinical practice with diverse complex anatomic subsets of patients, or in other words, "real world experience."

This conclusion is in agreement with three randomized studies. The SCRIPPS (Scripps Coronary Radiation to Inhibit Proliferation Post Stenting) and WRIST (Washington Radiation for In-Stent Restenosis Trial) trials were single-center studies, and the GAMMA I trial was a multicenter study, and all demonstrated a clear benefit from brachytherapy. Restenosis decreased by 30% to 60%, and there appeared to be no adverse effects from the therapy. A limitation of brachytherapy is that the procedure can't be repeated if stenosis recurs in a treated lesion because of the concern of toxicity with repeated radiation. However, if an artery becomes renarrowed, procedures such as stenting, balloon angioplasty, or atherectomy can be repeated, or bypass surgery can be done. Also, a drug-eluting stent can be placed in the artery in hopes of a more long-term solution.

High power microscopic view of the fibrous restenosis tissue called neointimal hyperplasia. This shows many cells in a bed of matrix.

Drug-Eluting Stents
"This is the biggest advance I've seen since I've been at the Minneapolis Heart Institute," said Michael Mooney, MD, in discussing drug-eluting stents. "It represents a fundamental change; restenosis has been a major limitation in the treatment of coronary artery disease, and the drug-eluting stent is a major new tool for preventing it."

Along with 55 key centers in the United States, MHIF is the only center in the Twin Cities area that is conducting trials of drug-eluting stents. The SIRIUS study, a large, randomized, double-blinded, placebo-controlled trial, assessed the effectiveness and safety of stents coated with sirolimus, an immunosuppressive agent approved by the US Food and Drug Administration for the prevention of organ rejection following renal transplantation. Sirolimus not only blocks proliferation of cells, but also inhibits inflammation. The study included 1,100 patients and demonstrated excellent results. "None of the treated patients have returned with reblockages," said Dr. Mooney. Follow-up is available up to two years from European studies. "The benefit appears to be real, if we've seen no restenosis at two years," Dr. Mooney said. Other trials are being conducted with another drug called paclitaxel. DELIVER is a multicenter, randomized study that will enroll up to 1,042 patients in approximately 70 centers nationwide. The TAXUS IV clinical trial is the fourth in a series of studies designed to collect clinical information on paclitaxel-eluting stents.