American College of Cardiology

Functional testing after angioplasty need not be routine, study finds

(ORLANDO, FLA.)—Heart vessels widened by angioplasty balloons or the tiny metal scaffoldings called stents can narrow again over the next six to nine months. Various indirect tests, often performed during exercise and using nuclear imaging techniques, can reveal such vessel renarrowing, a process called restenosis. It has long been controversial whether those functional tests should be routine after angioplasty or stenting, or rather performed only if the patient develops restenosis symptoms, such as chest pain.

The first randomized, head-to-head comparison of the two strategies suggests that patients fare just as well if they get the functional tests only if symptoms develop. "There should be no major adverse clinical impact to a watchful-waiting strategy," said Dr. Mark J. Eisenberg, of Jewish General Hospital, Montreal, Quebec, Canada. "On the other hand, a routine functional testing strategy is more costly and time consuming and of unclear clinical benefit."

Treatment guidelines suggest that functional testing after stenting be reserved for patients with risk factors for restenosis, including diabetics and those with disease in multiple heart vessels or poor heart function. But the randomized "Aggressive Diagnosis of Restenosis" (ADORE) trial also suggested that such high-risk groups, which account for up to half of cases, don't necessarily benefit from a routine testing strategy. Dr. Eisenberg and his colleagues are currently exploring that specific issue in another trial.

Dr. Eisenberg is scheduled to present the ADORE trial results on Monday, March 19, at 9:15 a.m. at the American College of Cardiology 50th Annual Scientific Session in Orlando, Fla.

**Virus-mediated gene therapy for new heart vessel growth tested in multicenter trial

(ORLANDO, FLA.)—The heart can naturally develop new vessels to supplement the flow of blood carried by the main heart arteries. Various growth factors that control the development of such collateral vessels can be administered, directly or indirectly, as a treatment for heart muscle that isn't getting an adequate supply of blood on its own. A study has tested in patients with heart disease the administration of a virus that has been genetically modified to release one of the major growth factors involved in collateral development, fibroblast growth factor-4 (FGF-4).

In the multicenter "Adenovirus FGF Angiogenic Gene Therapy" (AGENT) trial, 79 patients received injections of the genetically altered virus at five different dosage levels. Patients were evaluated over the next three months to test the treatment's safety and whether it led to improvements in blood flow to the heart—indirectly measured by exercise testing.

Earlier studies of various growth-factor proteins for inducing new vessel growth, a process called angiogenesis, have generally had disappointing results in patients with heart disease. The AGENT trial is among largest of studies of its kind to use a genetically altered virus as a means to deliver angiogenic growth factors.

Dr. Cindy L. Grines, of William Beaumont Hospital in Royal Oak, Mich., is scheduled to present preliminary findings from the AGENT trial on Monday, March 19, at 9:30 a.m. at the American College of Cardiology 50th Annual Scientific Session in Orlando, Fla.

**Vessel-growing protein reduces symptoms of reduced blood flow to the leg muscles

(ORLANDO, FLA.)—A number of studies have tested the administration of proteins that promote the growth of new blood vessels, with mostly disappointing results, in patients with reduced blood flow to the heart muscle. But a large randomized trial of the technique, therapeutic angiogenesis, in patients with reduced leg-muscle blood flow suggests that the novel treatment can work well after all.

The "Therapeutic Angiogenesis With Recombinant Fibroblast Growth Factor-2 for Intermittent Claudication" (TRAFFIC) study "is the first large, phase II protein angiogenesis study in peripheral artery disease," said Dr. Robert J. Lederman. "And it's the first angiogenesis trial in either peripheral vessel or coronary artery disease to show a benefit."

In the placebo-controlled TRAFFIC trial, patients who experienced pain in their leg muscles due to reduced blood flow, a condition called intermittent claudication, received infusions of a bioengineered angiogenic protein, recombinant fibroblast growth factor-2 or rFGF-2. After 180 days, the treatment was associated with improvements in symptom-free walking time and other measures of increased blood flow in the leg muscles.

Dr. Lederman, of the National Heart, Lung, and Blood Institute, Bethesda, Md., took part in the TRAFFIC study as a co-principal investigator while at the University of Michigan, Ann Arbor. He is scheduled to present the trial's results on Monday, March 19, at 9:45 a.m. at the American College of Cardiology 50th Annual Scientific Session in Orlando, Fla.

Novel drug treatment unstiffens arteries, lowers blood pressure

(ORLANDO, FLA.)—Many medications for hypertension lower blood pressure by increasing arterial compliance, allowing the vessels to expand freely to meet the body's variable needs for blood. Usually these drugs, called vasodilators, achieve their effects by influencing the metabolism of the cells forming arterial walls. But one potential vasodilator under investigation as a treatment for hypertension seems to work in an entirely new way: by unstiffening the collagen protein mesh that normally gives artery walls their strength.

Because of its novel mechanism, the new agent, ALT-711, could potentially be added to standard medications to increase the effect of therapy. "There's some suggestion that it may have a synergistic effect with standard hypertension drugs," said Dr. David A. Kass, professor of medicine and biomedical engineering, Johns Hopkins University, Baltimore.

The body continually recycles its collagen and other structural proteins, breaking them down and building them back up as part of normal metabolism. Often, in aging and in some disease states like diabetes, molecular crosslinks made of a glucose-related compound can work their way into the protein meshwork that strengthens such body structures as skin and blood vessels. These so-called advanced glycation crosslinks, Dr. Kass explained, make collagen-rich blood vessels stiffer, less able to dilate as needed. That can lead to hypertension.

A randomized trial has provided indirect evidence that treatment with ALT-711 may reverse the process of advanced glycation crosslinkage in vascular structural proteins. Older patients with systolic hypertension and evidence of increased arterial stiffness who took the drug showed significantly improved blood pressure and vascular compliance.

"This study represents the most advanced clinical testing of ALT-711. The only preceding studies have been in animals or have been safety studies in limited numbers of patients," said Dr. Kass. He will present its results at 10 a.m. on Monday, March 19, at the American College of Cardiology 50th Annual Scientific Session in Orlando, Fla.

**New drug indication will provide major treatment advance for certain type of heart attack

(ORLANDO, Fla.)—The addition of clopidogrel, a drug that helps keep platelets from forming clots, to standard medications can significantly benefit patients with acute coronary syndromes—a limited form of heart attack that is one of the most common disorders seen in emergency rooms—according to a randomized study.

Patients with acute coronary syndromes, or ACS, are typically given aspirin, which is a weak antiplatelet drug, along with blood-thinning agents like heparin to break down clots within heart vessels that are causing symptoms. Some patients with ACS also undergo catheter interventions, such as balloon angioplasty or coronary stenting.

The "Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events" (CURE) trial is the largest study of its kind in patients with ACS. Its finding of an added benefit from clopidogrel "is one of the most significant advances for patients with acute coronary syndromes since aspirin," according to the principal investigator, Dr. Salim Yusuf, Hamilton General Hospital and McMaster University, Hamilton, Ontario, Canada.

Dr. Yusuf is scheduled to present the results of CURE at 10:15 a.m. on Monday, March 19, at the American College of Cardiology 50th Annual Scientific Session in Orlando, Fla.

Patients in CURE who received clopidogrel along with standard ACS medications, with or without catheter procedures, showed significant reductions in serious clinical events over an average of nine months.

"The widespread use of clopidogrel in addition to aspirin in ACS could prevent about 50,000-100,000 heart attacks, strokes, or deaths every year in North America," said Dr. Yusuf.

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