CDU

Claudication – muscular leg pain when walking – is a hallmark of peripheral artery disease. It's akin to coronary artery disease but involves limbs, not heart. "Peripheral artery disease," said interventional cardiologist Robert Lederman, "is another manifestation of atherosclerosis – the coronary artery disease that brings on cardiovascular disorders like angina or myocardial infarction, and cerebrovascular disease leading to stroke." He added that coronary and peripheral arterial disease "are the same in different locations in the body." Peripheral atherosclerotic disease, he said, "affects 15% of adult Americans over the age of 55." At least a third of them, Lederman added, "have classical symptoms of intermittent claudication. It may be under-recognized or under-reported, because many adults consider exertional muscular leg pain – namely claudication – to be yet another of the indignities of aging."

Lederman, an investigator at the National Heart, Lung and Blood Institute (Bethesda, Maryland), is lead author of a paper in the June 15 issue of The Lancet on "Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomized trial."

"TRAFFIC is the first large-scale trial of therapeutic angiogenesis to show efficacy in its primary endpoint," Lederman said. "For the first time, we rigorously conducted clinical trials in which we showed that therapeutic angiogenesis actually worked. We now have proof of principle that angiogenic agents – drugs intended to grow new arteries – may be able to improve symptoms in patients with cardiac as well as peripheral artery disease. For such patients with intermittent claudication we've shown improved treadmill performance after administration of recombinant fibroblast growth factor-2 [rFGF-2] compared to placebo."

He added, "This could conceivably also apply to myocardial disease, although this very same drug has been tested in a similar Phase II trial, after intercoronary artery administration, and there was no compelling evidence of efficacy."

TRAFFIC is the acronym for Therapeutic Angiogenesis With Recombinant FGF For Intermittent Claudication. It was sponsored by Chiron (Emeryville, California), manufacturer of FGF, and conducted by a group of physicians called PARC, the Peripheral Atherosclerosis Research Consortium. It was a multicenter trial involving 190 patients at 23 sites. Lederman was a co-founder of PARC in 1997.

"The clinical impairment in intermittent claudication is the inability to walk free of pain," Lederman said. "We used a standardized treadmill protocol in which patients were encouraged to walk until they absolutely had to stop, which defined peak walking time. Secondary measurements included blood pressure in the ankles. These tended to remain the same in placebo patients, but showed a small but significant increase in patients receiving fibroblast growth factor."

"As we report in The Lancet, at 90 days, for the primary endpoint, the patients who received rFGF-2 were able to walk farther than those who received placebo. Neither the participating subjects nor the investigators knew which patients received drug and which placebo. The average baseline – peak walking time – was 5.5 minutes, which is considered a moderate to severe impairment.

"Basic fibroblast growth factor is a protein, a peptide that we injected directly into the arteries of both legs of all patients. And we tested three different dosing regimens: placebo, injected at day zero and at day 30; a single dose of the drug injected at day zero followed by placebo at day 30; and the same dose of FGF given twice – on days zero and 30. The overall outcome: Patients who received FGF were able to walk farther than patients who received placebo. The single-dose group had significantly more improvement compared with placebo. We assumed and expected a double dose to be better than single, but it was not. It did not appear to be worse but was certainly no better, which we had hypothesized."

"FGF is not approved by FDA," Lederman pointed out. He said there's only one existing FDA-approved drug for treating intermittent claudication that actually works. "It's called Pletal, or cilostazol, made by Otsuka America (Rockville, Maryland)." Basic fibroblast growth factor causes proliferation of endothelial blood vessel cells in vitro, and angiogenesis in vivo. Therapeutic angiogenesis attempts to apply this occurrence to ameliorate disorders of inadequate tissue perfusion in human patients.

Lederman said the PARC consortium is conducting clinical studies of other approaches – for example, gene transfer with vascular endothelial growth factor, another related factor. One study is for intermittent claudication and the other for critical limb ischemia, beyond claudication, where patients are in danger of losing their limbs because of more severe peripheral artery disease. The three manifestations of critical ischemias are pain, even at rest, an ulcer that won't heal or shrink and gangrene. It's a more morbid manifestation of the same claudication problem.