When most people think of atherosclerosis, coronary artery disease (CAD) and stroke come to mind, but a strong third player on the atherosclerotic landscape is peripheral artery disease (PAD).

This highly morbid condition, expected to triple in prevalence by 2030, involves the plaque-related ischemia of arteries carrying blood beyond the heart. The most common type of PAD affects the legs and feet. An estimated 8-12 million Americans over age 40 years, mostly 65 years or older, have lower-body disease, but it can strike other extracardiac organs as well, including the head, arms, stomach, pelvis, and kidneys.

Because it causes tissue damage and tissue death in the legs, feet, and toes, PAD is implicated in 150,000 lower-limb amputations in the US each year. PAD increases the risk for heart attack and stroke and carries a twofold to fourfold increased risk of death. It’s also associated with cognitive impairment and dementia.

Approximately one third of patients with PAD will die within 5 years of diagnosis.

“The tremendous burden of PAD has historically been under-recognized and underdiagnosed relative to heart attack and stroke,” said Marc P. Bonaca, MD, MPH, professor of medicine-cardiology and director of vascular research at the University of Colorado Anschutz School of Medicine in Aurora, Colorado. He estimates the number of affected Americans at 12-15 million — about the same number as those with atrial fibrillation. “But most people on the street have never heard of PAD.”

Not only are cases increasing overall, added Anahita Dua, MD, MBA, MSc, vascular surgeon at Massachusetts General Hospital and associate professor of surgery at Harvard Medical School in Boston, but “we’re also seeing more people come in with the most advanced type, critical limb-threatening ischemia, or CLTI, and microvascular disease, which can lead to revascularization or amputation.”

Approximately 11% of people with PAD have CLTI, said Mary M. McDermott, MD, professor of internal and preventive medicine at Northwestern Feinberg School of Medicine in Chicago. “What is particularly surprising is that approximately 50% of people who present with CLTI have not been previously diagnosed with PAD.” McDermott noted that many patients may think their heterogenous leg symptoms and impaired walking are due to age-related hip osteoarthritis or lumbar disc deterioration because they’re unaware of PAD as a condition.

Because public awareness is so low, said Dua, “A significant number of these patients are presenting to the ER at 2:00 in the morning with a wet gangrenous toe and ultimately end up needing amputation.” Their long-standing PAD hadn’t been diagnosed.

“I also think people tend to prioritize the heart over walking difficulty, perhaps because people perceive that heart damage can kill you, while walking difficulty may be considered less of a health problem,” McDermott said.

This disease process therefore needs to be top of clinicians’ minds, especially when they see patients with the three main risk factors: diabetes, high blood pressure, and smoking, Dua said. Those patients really need to be screened for PAD so that it can be caught early, she said.

The urgency of the PAD epidemic has led the American Heart Association (AHA) to release a comprehensive national action plan to raise awareness and foster timely detection and treatment.

Demographics

According to the AHA, an estimated 19 million people will have PAD by 2025, 16 million of whom will be 65 years or older. PAD is more common in men and smokers, and rates are twice as high in Black Americans. Lifetime risk for PAD for men and women is about 30% in the Black population and about 20% for non-Hispanic White and Hispanic individuals. Additionally, regardless of race, there’s a more than twofold increased risk for PAD in adults with low household incomes, low education levels, and high neighborhood deprivation.

The AHA national action plan urges greater professional and public awareness, as well as targeted measures to improve detection and patient care, especially in the most affected communities and demographic groups.

The Clinical Picture

“Historically, the attitude has been that PAD was the patient’s fault and there wasn’t much you could do about it. And since it isn’t a heart attack or stroke, we’ll just keep an eye on it.” Bonaca said. Few patients got early care with lifestyle modification, pharmacotherapy, and appropriate exercise.

Some organizations recommend screening high-risk groups — those aged 70 years or older or 50-69 years with a history of smoking or diabetes, said McDermott. “Clinicians should take a careful history about walking difficulty in their older patients and have a low threshold for testing people with walking difficulty, symptoms that might be PAD, and risk factors for PAD.”

All three physicians urge clinicians to make a point of asking older patients how well they are walking and to perform the cheap, easy, noninvasive but underutilized ankle-brachial index test on older patients. “Get them to take off their shoes and socks and measure the ankle systolic blood pressure [SBP], which should be about the same as in the arm,” Bonaca said. People without PAD should have a Doppler-recorded SBP ratio value of 1.10-1.30, said McDermott. If the ratio in the ankle to the arm is less than 0.9, then PAD is likely present. Angiographic plaque imaging is also a detection option.

Clinicians should also be alert to these signs and symptoms:

• Aching, heaviness, cramping, weakness, or numbness in the legs
• Pins and needles sensation in legs or feet
• Lack of toenail and leg-hair growth
• Pale, discolored, or blue legs or feet
• Slow-healing sores or wounds on toes, feet, or legs

Management Options

The outlook is positive if steps are taken early. Smoking cessation, supervised exercise, and weight, cholesterol, and glycemic control may stop the progression of the disease. “And we now have multiple medical treatments that can prevent progression and amputations and help people to walk better,” said Bonaca.

Standard PAD medications are similar to those for CAD: agents that lower plaque-forming cholesterol and prevent blood clots, as well as those that control blood pressure and blood glucose levels. These include statins, antiplatelet agents such as clopidogrel and aspirin, and anticoagulants such as heparin and rivaroxaban.

The STRIDE study showed that semaglutide dramatically improved walking capacity in PAD. The novel oral anticoagulant rivaroxaban, the first in its class approved for ischemia prevention, showed positive post-revascularization results when coupled with aspirin in the VOYAGER trial, according to Bonaca.

Vasodilators — cilostazol and pentoxifylline, for example — may improve blood flow and walking capacity.

Other new vascular drugs are under development, as well as stem cell, gene, and cryotherapies, which may promise a brighter future for patients with PAD.

It is thought that walking improves muscle function and blood flow and may stimulate the growth of collateral blood vessels. If possible, people with claudication should walk 30-60 minutes a day at least three times a week.

Patients with PAD are advised to avoid exposing the lower limbs to cold and steer clear of medications causing vasoconstriction, including migraine drugs and over-the-counter cold and sinus remedies containing ephedrine, pseudoephedrine, and phenylephrine. Vasoconstricting recreational drugs such as cocaine and amphetamines also should not be used.

Invasive options to restore blood flow include balloon angioplasty, stenting, and surgery to mitigate or bypass the lower-limb blockage. Amputation is a last resort if limb tissue has died.

Bonaca reported receiving research support from Novo Nordisk and Bayer, the respective makers of drugs used in the STRIDE and VOYAGER trials, in which he was principal investigator. Dua reported having no relevant conflicts of interest. McDermott reported serving on a steering committee for an Eli Lilly study and research support from Mars, Incorporated, and ACI Medical.