American Diabetes Association's 69th Scientific Sessions

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While knowledge of peripheral arterial disease has progressed, still much is needed in the way of comparator trials and diagnostics.

PAD – also referred to as peripheral vascular disease or PVD – affects more than 9 million Americans and more than 10 million in Europe, according to Alan T. Hirsch, MD, director of the vascular medicine program at Minneapolis Heart Institute.

“PAD is one of the most prevalent, morbid and mortal cardiovascular diseases,” he said. “The cost of PAD is as high and likely higher than any other CVD.”

PAD is also a marker for atherosclerosis and a predictor of death, myocardial infarction or stroke. Add diabetes into the mix and, “patients with diabetes are at the highest risk,” Hirsch said.

PAD and diabetes

Reena L. Pande, MD, a fellow in vascular medicine, cardiovascular division, at Brigham & Women’s Hospital, said available literature shows that half the people with PAD demonstrate symptoms of metabolic syndrome, which appears in 52% of patients with PAD. Insulin resistance was linked to PAD in NHANES, and Pande said it is no surprise that inflammation – which is linked to insulin resistance – is also related to PAD. The Edinburgh Artery Study shows that patients with diabetes and glucose intolerance have a higher risk for PAD.

“Diabetes increases the risk of amputation and death in patients with PAD,” Pande added.

She said that whether improving insulin resistance would improve outcomes in PAD has not yet been proven, although reducing inflammation with statins has demonstrated a reduction in incidence of claudication, improved walking distance and resulted in more pain-free walking.

“Limitations in nutrient uptake into the exercising skeletal muscle may well impair function and exercise ability in patients with PAD, so theoretically it makes sense that if we can improve insulin sensitivity in the level of the skeletal muscle in the lower extremity that we may be able to get patients walking further and walking with less discomfort. But that data is not yet known,” Pande said.

Biomarkers and diagnostics

In other areas of PAD research, it remains unknown what biomarkers are specific to PAD. There are available biomarkers – like endothelial progenitor cells – but none specifically for PAD.

PAD is diagnosed by ankle brachial index, but John Cooke, MD, PhD, professor of medicine at Stanford University, said that routine screening is not done and one-third of Americans with PAD are undiagnosed.

“Ankle brachial index is the current gold standard, [but] it is not being utilized. If we had a blood test for PAD< there would be much higher throughput,” Cooke said.

He said biomarker research is at an early stage, but researchers are hoping to find biomarkers that will lead to better diagnostic tests, better pathophysiological understanding and potential therapeutic targets.

Research into protein biomarkers has shown promise. Cooke said he and colleagues are working on a bead technique to equalize proteins in plasma to have a better chance at finding the right flags for PAD.

“We’ve got a long way to go; it’s very early in the field right now,” Cooke said. “What we’re looking for is a panel that reflects multiple processes that are occurring locally in skeletal muscle circulating systemically.”

In other areas of PAD diagnostics, Chris M. Kramer, MD, professor of medicine and radiology, director of the CV imaging center at the University of Virginia Health System, and colleagues are developing new MRI-based methods for clinical trials in PAD.

“Instead of just exercise, we’re measuring perfusion reserves, baseline to exercise, that may even be a more accurate assessment of PAD,” Kramer said.

Kramer said one of the methods includes an ergometer attached to an MRI machine that allows moving measurement of the patient limbs. The researchers are addressing the issue of gadolidium intolerance by developing techniques that do not require contrast but are still MRI-based.

Results of a trial using multi-modality MRI to test the efficacy of lipid-lowering therapy on the vessel wall, and atherosclerotic plaque is scheduled to appear in the August issue of the Journal of the American College of Cardiology, Kramer said.

CLEVER trial

Hirsch addressed the need for clinical trials that determine the best course of treatment for PAD. He put out a plea to cardiologists and endocrinologists to consider enrolling patients who have claudication, aortic iliac disease and, if applicable, diabetes into the CLEVER trial. The trial will compare revascularization and exercise in treatment of PAD, but Hirsch said recruitment has not gone well since it started in 2007.

He said patients will receive free cilostazol (Pletal, Otsuka Pharmaceuticals) throughout the study and have access to educational materials on diet, exercise and risk factors. Those who undergo exercise therapy will have supervised exercise for six months.

“This trial is not going that great,” Hirsch said of enrollment. “This is the hardest thing I have ever done in my life … If you live in a city that has a CLEVER investigator and you have a patient with iliac disease, we would like your help.”

Interested physicians can visit the trial’s website for a contact phone number and more information.

“We need PAD trials that are uniquely different from everything that has happened before … multicenter, including all relevant treatment strategies,” Hirsh said. Not just stent vs. no stent, but stent vs. exercise, stent vs. pharmacotherapy, with an effort to include more women and minorities.

“One of the things that strikes me … is how much the disease knowledge base has enhanced,” he said. “I do worry that we may not have transferred this to the bedside.” – by Judith Rusk

For more information:

• Peripheral vascular disease – improving diagnosis and function. Presented at: American Diabetes Association’s 69th Scientific Sessions; June 5-9, 2009; New Orleans.