DURHAM, N.C. -- In the first demonstration of the therapeutic benefit of an agent that stimulates blood vessel growth, a group of cardiologists have improved the functional abilities of patients with painful blockages in the blood vessels in their legs.
The phase II randomized double-blind placebo controlled trial aimed to test whether an "angiogenic growth factor" could increase the duration of walking by patients with intermittent claudication -- a condition marked by clogged blood vessels in the legs -- which leads to severe and often debilitating pain during walking. This pain is similar to the pain of angina caused by clogged coronary arteries.
The results of the trial, led by Duke University Medical Center cardiologist Brian Annex, M.D., and Robert Lederman, M.D., then with the University of Michigan and now with the National Heart Lung Blood Institute, were published in the June 15, 2002 issue of the journal Lancet.
While the researchers are not certain that the agent, known as recombinant fibroblast growth factor-2 (rFGF-2), actually triggered the creation of new blood vessels, they found that treated patients could significantly increase their peak walking times compared to similar patients who did not receive the agent.
"This is the third large multi-center randomized placebo-controlled trial looking at the therapeutic use of an angiogenic agent and the first to show a positive result in its primary endpoint," said Annex. "This study provides the strongest and most convincing data to date that an angiogenic agent can have a positive effect in humans."
For nearly a decade, researchers have been testing different angiogenic agents for the treatment of heart disease. Researchers hope that these agents can stimulate new blood vessel growth into damaged heart muscle, or around arterial blockages. But so far, the results of recent studies in humans have not been encouraging, Annex said.
"Angiogenesis is an extremely exciting area with a great deal of potential. It is also one that has been in need of positive randomized, placebo-controlled data to accelerate further research," Annex said. "This study is an important step in that direction."
Patients with clogged blood vessels in their legs suffer from a general condition known as peripheral artery disease. This chronic, progressive condition is similar to heart disease in that arteries become clogged with the buildup of plaque. This clogging results in a shortage of oxygen to leg muscles, which causes pain, or "claudication" -- the same process by which oxygen-starved heart muscle produces angina.
Walking increases the demand by leg muscles for oxygen, so patients with his condition typically can only walk short distances before the pain forces them to stop. The pain diminishes with rest. Since such pain is the main symptom limiting the quality of life of these patients, the researchers wanted to test rFGF-2's ability to allow patients to walk longer distances.
The researchers enrolled 190 patients at 22 centers across the U.S. and divided them into three groups: one group received one dose of rFGF-2, another group received two doses 30 days apart, and the last group received a placebo. The researchers then measured peak walking times 90 and 180 days later.
Interestingly, said the researchers, they found that the patients who received two doses did not do as well as those receiving one dose.
"Specifically, the placebo group saw a 14 percent increase in peak walking time, while those who received one dose improved 34 percent," Annex said. "And those who received two doses increased their peak walking time 20 percent. Why this difference appeared is unclear, but we'll probably find with further studies what types of patients respond better to rFGF-2--if someone didn't respond to one dose, they probably wouldn't respond to the second dose."
Not only did the patients' peak walking times increase, but they also showed improved scores in the ankle-brachial pressure index (ABI), which measures blood pressures at the ankle and is a key test used in diagnosing peripheral artery disease.
"Increases in both peak walking times and the ABI support the hypothesis that perfusion, or blood flow, was improved in these patients," Annex said.
While the mechanism of the beneficial effect is not clear, Annex speculates that the rFGF-2 might have caused new vessels to grow around blocked arteries, or may have somehow made the vessels in the area of the blockage work better.
rFGF-2, a recombinant protein made in bacteria, is nearly identical to the protein produced naturally in humans. Chiron Corp., Emeryville, Calif, produces rFGF-2 and funded the trial, which was dubbed TRAFFIC - Therapeutic Angiogenesis with FGF for Intermittent Claudication.
Annex has no financial interest in Chiron or the agent. The Duke Clinical Research Institute was the coordinating center for the trial.
Other members of the team, most of whom are members of the Peripheral Atherosclerosis Research Consortium (PARC), included Farrell Mendelsohn, M.D., a cardiologist in Birmingham, Ala.; R. David Anderson, M.D., Sarasota Memorial Hospital, Fla.; Jorge Saucedo, M.D., University of Arkansas for Medical Sciences, Little Rock; Alan Tenaglia, M.D., Tulane University Medical Center, New Orleans; James Hermiller, M.D., Nasser, Smith and Pinckerton, Indianapolis; William Hillegass, University of Alabama, Birmingham; Krishna Rocha-Singh, M.D., Prairie Cardiovascular Consultants, Springfield, Ill.; and Thomas Moon, M.D. and M.J. Whitehouse, M.D., of Chiron. The full list of investigators can be found at the PARC website, http://www.arterial.org.
Journal
The Lancet