Hello, and welcome to Clot Chronicles, which today is focused on lower-extremity peripheral artery disease (PAD). This presentation is based on a recent review published in JAMA that covers the epidemiology, diagnosis, and treatment of PAD. I’m Mary McDermott, Jeremiah Stamler Professor of Medicine at Northwestern University Feinberg School of Medicine. 

Lower-extremity PAD affects about 8.5 million people in the United States and about 230 million people worldwide. Risk factors for PAD are cardiovascular (CV) disease risk factors, in general, and include smoking, diabetes, hypertension, and high cholesterol, in addition to some genetic markers and increased levels of inflammation. PAD is uncommon before the age of 50 but increases in prevalence with age such that as many as 20% of people over the age of 80 have PAD. Diabetes and smoking are particularly strong risk factors for PAD and are even stronger risk factors for PAD than they are for coronary artery disease.

PAD is characterized by lack of sufficient oxygen supply during walking activity. And so, when people go to walk with PAD, they typically will have weakness or discomfort in their legs. The most classic symptom of PAD is intermittent claudication, which is defined as pain in the calves with walking that resolves within 10 minutes of rest. However, most people with PAD don’t have this classic symptom; many will report no exertion or leg symptoms at all, and this is because many people with PAD have either reduced their physical activity to avoid ischemic leg symptoms or have slowed their walking speed to avoid symptoms. 

PAD can be objectively measured and identified using the ankle-brachial index (ABI). The ABI is a Doppler-recorded ratio of systolic pressures at the ankle compared to systolic pressures at the arm, the brachial artery. A normal ABI is about 1.1 to 1.3 because normally pressures at the ankle are higher than pressures at the brachial artery. An ABI <0.9 is about 85% sensitive and nearly 100% specific for the presence of PAD. 

PAD is important because it’s associated with difficulty walking and disability, and it’s also associated with increased rates of CV events. Therefore, management of PAD focuses on prescribing treatments to reduce rates of CV events, improving walking performance, and preventing disability. Regarding prevention of CV events, American Heart Association and American College of Cardiology guidelines recommend statin therapy, antiplatelet therapy with or without antithrombotic therapy, and treatment of hypertension to reduce CV events in people with PAD. 

Regarding cholesterol lowering, guidelines recommend the highest dose of a potent statin to reduce the LDL cholesterol by at least 50% and to attain an LDL cholesterol of <70. European Society of Cardiology guidelines have similar recommendations but recommend that the LDL cholesterol be reduced to <55. If a high-dose, potent statin is not sufficient to meet these targets, then ezetimibe or a PCSK9 inhibitor should be prescribed. 

Regarding antithrombotic or antiplatelet therapy, current guidelines recommend either clopidogrel or aspirin to prevent CV events in people with PAD. However, some evidence suggests that clopidogrel may be better than aspirin. The recently published COMPASS trial showed that rivaroxaban 2.5 mg twice daily combined with aspirin 100 mg significantly reduced CV event rates in more than 27,000 people who had CV disease. In the subset of about 6,400 patients with PAD, the combination of rivaroxaban twice daily with 100 mg of aspirin similarly reduced rates of CV events, and also reduced rates of lower-extremity revascularization and rates of amputation. Similar findings were recently reported in the VOYAGER trial of patients with PAD who had undergone lower-extremity revascularization.

Regarding antihypertensive therapy, guidelines recommend angiotensin receptor blockers (ARBs) or an angiotensin-converting enzyme (ACE) inhibitor to treat hypertension to <130/80 in people with PAD. With regard to improving functioning in PAD, there are only two FDA-approved therapies – pentoxifylline and cilostazol. However, recent evidence regarding pentoxifylline show that it’s really not much better than placebo. Cilostazol, the second FDA-approved medication for PAD, has modest benefits for improving walking in people with PAD and is frequently stopped due to side effects. Walking exercise is, by far, the most effective therapy to improve walking performance in people with PAD – that is, by far, the most effective medical therapy. 

Six months of supervised treadmill exercise improves 6-minute walk distance (6MWD) by 30 to 35 meters when compared to a control group that did not exercise. Since 2017, the Center for Medicare and Medicaid Services has covered supervised treadmill exercise for PAD and will cover an initial therapy of 36 supervised exercise sessions 3 times weekly over 12 weeks as prescribed by a physician. If symptoms persist, a second 36-session prescription can be provided. However, most people with PAD don’t actually participate in supervised exercise therapy, either because the services are not available to them, particularly in rural areas, or because of the inconvenience of having to travel to a center for regular exercise participation. 

Home-based walking exercise also significantly improves walking performance in people with PAD. Several randomized trials have shown that home-based walking exercise improved 6MWD by about 45 to 55 meters compared to a control group that did not exercise. However, not all home-based exercise interventions have been effective – and those that were effective used a coach to monitor the patient’s progress along with other behavioral methods to achieve benefit. 

A randomized trial of 305 participants, the LITE trial recently published in JAMA, demonstrated that home-based exercise that induced ischemic leg symptoms while walking significantly improved 6MWD and treadmill walking distance compared to a control group. Home-based walking exercise conducted at a comfortable pace without ischemic leg symptoms was not effective. 

In summary, PAD now affects about 230 million people worldwide and is associated with increased rates of cardiovascular events, walking impairment, and disability. People with PAD should be treated with the highest dose of potent statin tolerated, with antiplatelet therapy with or without antithrombotic therapy, and all should be prescribed walking exercise. Thank you for your attention.