Peripheral artery disease
|Peripheral artery disease|
|Other names||Peripheral vascular disease (PVD), peripheral artery occlusive disease, peripheral obliterative arteriopathy|
|An arterial insufficiency ulcer in a person with severe peripheral artery disease|
|Specialty||Interventional radiology, vascular surgery|
|Symptoms||Leg pain when walking which resolves with rest, skin ulcers, bluish skin, cold skin|
|Causes||Atherosclerosis, artery spasm|
|Risk factors||Cigarette smoking, diabetes, high blood pressure, high blood cholesterol.|
|Diagnostic method||Ankle-brachial index < 0.90, duplex ultrasonography, angiography|
|Treatment||Stopping smoking, supervised exercise therapy, surgery|
|Medication||Statins, ACE inhibitors, cilostazol|
|Frequency||155 million (2015)|
Peripheral artery disease (PAD) is an abnormal narrowing of arteries other than those that supply the heart or brain. When narrowing occurs in the heart, it is called coronary artery disease, and in the brain, it is called cerebrovascular disease. Peripheral artery disease most commonly affects the legs, but other arteries may also be involved – such as those of the arms, neck, or kidneys. The classic symptom is leg pain when walking which resolves with rest, known as intermittent claudication. Other symptoms include skin ulcers, bluish skin, cold skin, or abnormal nail and hair growth in the affected leg. Complications may include an infection or tissue death which may require amputation; coronary artery disease, or stroke. Up to 50% of people with PAD do not have symptoms.
The greatest risk factor for PAD is cigarette smoking. Other risk factors include diabetes, high blood pressure, kidney problems, and high blood cholesterol. The most common underlying mechanism of peripheral artery disease is atherosclerosis, especially in individuals over 40 years old. Other mechanisms include artery spasm, blood clots, trauma, fibromuscular dysplasia, and vasculitis. PAD is typically diagnosed by finding an ankle-brachial index (ABI) less than 0.90, which is the systolic blood pressure at the ankle divided by the systolic blood pressure of the arm. Duplex ultrasonography and angiography may also be used. Angiography is more accurate and allows for treatment at the same time; however, it is associated with greater risks.
It is unclear if screening for peripheral artery disease in people without symptoms is useful as it has not been properly studied. In those with intermittent claudication from PAD, stopping smoking and supervised exercise therapy improve outcomes. Medications, including statins, ACE inhibitors, and cilostazol may also help. Aspirin does not appear to help those with mild disease but is usually recommended in those with more significant disease due to the increased risk of heart attacks. Anticoagulants such as warfarin are not typically of benefit. Procedures used to treat the disease include bypass grafting, angioplasty, and atherectomy.
In 2015, about 155 million people had PAD worldwide. It becomes more common with age. In the developed world, it affects about 5.3% of 45- to 50-year-olds and 18.6% of 85- to 90-year-olds. In the developing world, it affects 4.6% of people between the ages of 45 and 50 and 15% of people between the ages of 85 and 90. PAD in the developed world is equally common among men and women, though in the developing world, women are more commonly affected. In 2015 PAD resulted in about 52,500 deaths, which is an increase from the 16,000 deaths in 1990.
Signs and symptoms
The signs and symptoms of peripheral artery disease are based on the part of the body that is affected. About 66% of patients affected by PAD either do not have symptoms or have atypical symptoms. The most common presenting symptom is intermittent claudication, which causes pain and severe cramping when walking or exercising. The pain is usually located in the calf muscles of the affected leg and relieved by rest. This occurs because during exercise the muscles of the leg need more oxygen and in an unaffected leg, the arteries would be able to increase the amount of blood and therefore oxygen going to the exercised leg. However, when there is a narrowing, the artery is unable to meet the increased demand for oxygen by the muscles.
In individuals with severe PAD, complications may arise, including critical limb ischemia and gangrene. Critical limb ischemia occurs when the obstruction to blood flow in the artery is compromised to the point where the blood is unable to maintain oxygenation of tissue at rest. This can lead to pain at rest, feeling of cold, or numbness in the affected foot and toes. Other complications of severe PAD include lower limb tissue loss, arterial insufficiency ulcers, erectile dysfunction, and gangrene. People with diabetes are affected by gangrene of the feet at a rate that is 30 times higher than the unaffected population. Many of these severe complications are irreversible.
Factors contributing to increased risk of PAD are the same as those for atherosclerosis. These include age, sex, and ethnicity. PAD is two times as common in males as females. In terms of ethnicity, PAD is more common in people of color compared to the white population in a 2:1 ratio.
- Smoking – tobacco use in any form is the single greatest risk factor of peripheral artery disease internationally. Smokers have up to a 10-fold increase in risk of PAD in a dose-response relationship. Exposure to second-hand smoke has also been shown to promote changes in the lining of blood vessels (endothelium), which can lead to atherosclerosis. Smokers are 2–3 times more likely to have lower extremity PAD than coronary artery disease. Greater than 80%-90% of patients with lower extremity peripheral arterial disease are current or former smokers. The risk of PAD increases with the number of cigarettes smoked per day and the number of years smoked.
- High blood sugar – Diabetes mellitus is shown to increase risk of PAD by 2–4 fold. It does this by causing endothelial and smooth-muscle cell dysfunction in peripheral arteries. The risk of developing lower extremity peripheral arterial disease is proportional to the severity and duration of diabetes.
- High blood cholesterol – Dyslipidemia, which is an abnormally high level of cholesterol or fat in the blood. Dyslipidemia is caused by a high level of a protein called low-density lipoprotein (LDL cholesterol), low levels of high-density lipoprotein (HDL cholesterol), elevation of total cholesterol, and/or high triglyceride levels. This abnormality in blood cholesterol levels have been correlated with accelerated peripheral artery disease. Management of Dyslipidemia by diet, exercise, and/or medication is associated with a major reduction in rates of heart attack and stroke.
- High blood pressure – Hypertension or elevated blood pressure can increase a person's risk of developing PAD. Similarly to PAD, there is a known association between high blood pressure and heart attacks, strokes and abdominal aortic aneurysms. High blood pressure increases the risk of intermittent claudication, the most common symptom of PAD, by 2.5- to 4-fold in men and women, respectively.
- Other risk factors which are being studied include levels of various inflammatory mediators such as C-reactive protein, fibrinogen, homocysteine, and lipoprotein A. Individuals with increased levels of homocysteine in their blood have a 2-fold risk of peripheral artery disease. While there are genetics leading to risk factors for peripheral artery disease, including diabetes and high blood pressure; there have been no specific genes or gene mutations directly associated with the development of peripheral artery disease.
High risk populations
- All people who have leg symptoms with exertion (suggestive of claudication) or ischemic rest pain
- All people aged 65 years and over regardless of risk factor status
- All people between 50 and 69 and who have a cardiovascular risk factor (particularly diabetes or smoking)
- Age less than 50 years, with diabetes and one other atherosclerosis risk factor (smoking, dyslipidemia, hypertension, or hyperhomocysteinemia)
- Individuals with an abnormal lower extremity pulse examination
- Those with known atherosclerotic coronary, carotid, or renal artery disease
- All people with a Framingham risk score of 10%–20%
- All people who have previously experienced chest pain
As previously mentioned, the most common cause of peripheral artery disease, especially in patients over 40 years old, is atherosclerosis. Atherosclerosis is a narrowing of the arteries caused by lipid or fat build up and calcium deposition in the wall of the affected arteries. The most commonly affected site occurs at arterial branch points, because there is an increase in turbulence and stress on the artery at these areas where the artery branches to supply distant structures. Disease of distant structures, including feet and toes, are usually caused by diabetes and seen in the elderly population.
Additional mechanisms of peripheral artery disease including arterial spasm, thrombosis, and fibromuscular dysplasia. The mechanism of arterial spasm is still being studied, but it can occur secondary to trauma. The symptoms of claudication ensue when the artery spasms, or clamps down on itself, creating an obstruction. Similar to atherosclerosis, this leads to decreased blood flow to the tissue downstream of the obstruction. Thrombosis, or the formation of a blood clot, occurs usually due stasis or trauma. Damage to the lining of the blood vessel begins the process of clot formation. The blood clot ultimately creates a narrowing in the artery preventing adequate blood flow and oxygen to the tissue further down.
Diagnosing or identifying peripheral artery disease requires history of symptoms and a physical exam followed by confirmatory testing. In the setting of symptoms consistent with peripheral artery disease a physician will then examine an individual for specific exam findings. Abnormal physical exam findings can lead a health care provider to consider a specific diagnosis. However, in order to confirm a diagnosis, confirmatory testing is required.
These findings are associated with peripheral artery disease:
- Decreased or absent pulses
- Muscle atrophy or wasting
- Noticeable blueness of the affected limb
- Decreased temperature (coolness) in affected limb when compared to the other
- Thickened nails
- Smooth or shiny skin and hair loss
- Buerger's test can check for pallor when the affected limb is in an elevated position. The limb is then moved from elevated to sitting position and is checked for redness, which is called reactive hyperemia. Buerger's test is an assessment of arterial sufficiency, which is the ability of the artery to supply oxygenated blood to the tissue that it goes to.
If peripheral artery disease is suspected, the initial study is the ankle–brachial index (ABI). The ABI is a simple, non-invasive test, which measures the ratio of systolic blood pressure in the ankle to the systolic blood pressure in the upper arm. This is based on the idea that if blood pressure readings in the ankle are lower than those in the arm, a blockage in the arteries that provide blood from the heart to the ankle is suspected.
An ABI range of 0.90 to 1.40 is considered normal. A person is considered to have PAD when the ABI is ≤ 0.90. However, PAD can be further graded as mild to moderate if the ABI is between 0.41 and 0.90, and severe if an ABI is less than 0.40. These categories can provide insight into the disease course. Furthermore, ABI values of 0.91 to 0.99 are considered borderline and values >1.40 indicate noncompressible arteries. If an ABI >1.40 is calculated, this could indicate vessel wall stiffness caused by calcification, which can occur in people with uncontrolled diabetes. Abnormally high ABIs (>1.40) are usually considered false negatives and thus, such results merit further investigation and higher-level studies. Individuals with noncompressible arteries have an increased risk of cardiovascular mortality within a two-year period.
In individuals with suspected PAD with normal ABIs can undergo exercise testing of ABI. A baseline ABI is obtained prior to exercise. The patient is then asked to exercise (usually patients are made to walk on a treadmill at a constant speed) until claudication pain occurs (for a maximum of 5 minutes), after which the ankle pressure is again measured. A decrease in ABI of 15%–20% would be diagnostic of PAD.
If ABIs are abnormal, the next step is generally a lower limb Doppler ultrasound to look at the site of obstruction and extent of atherosclerosis. Other imaging can be performed by angiography, where a catheter is inserted into the common femoral artery and selectively guided to the artery in question. While injecting a radio-dense contrast agent, an X-ray is taken. Any blood flow-limiting blockage found in the X-ray can be identified and treated by procedures including atherectomy, angioplasty, or stenting. Contrast angiography is the most readily available and widely used imaging technique. Modern computerized tomography (CT) scanners provide direct imaging of the arterial system as an alternative to angiography.
Magnetic resonance angiography (MRA) is a noninvasive diagnostic procedure that uses a combination of a large magnet, radio frequencies, and a computer to produce detailed images of blood vessels inside the body. The advantages of MRA include its safety and ability to provide high-resolution, three-dimensional imaging of the entire abdomen, pelvis and lower extremities in one sitting.
The two most commonly used methods to classify peripheral artery disease are the Fontaine and the Rutherford systems of classification. The Fontaine stages, were introduced by René Fontaine in 1954 to define severity of chronic limb ischemia:
- Stage I: asymptomatic
- Stage IIa: intermittent claudication after walking a distance of more than 200 meters
- Stage IIb: intermittent claudication after walking a distance of less than 200 meters
- Stage III: rest pain
- Stage IV: ulcers or gangrene of the limb
The Rutherford classification was created by the Society for Vascular Surgery and International Society of Cardiovascular Surgery, introduced in 1986 and revised in 1997 (and known as the Rutherford classification after the lead author, Robert B. Rutherford). This classification system consists of four grades and seven categories (categories 0–6):
- Grade 0, Category 0: asymptomatic
- Grade I, Category 1: mild claudication
- Grade I, Category 2: moderate claudication
- Grade I, Category 3: severe claudication
- Grade II, Category 4: rest pain
- Grade III, Category 5: minor tissue loss; ischemic ulceration not exceeding ulcer of the digits of the foot
- Grade IV, Category 6: major tissue loss; severe ischemic ulcers or frank gangrene
Recently, the Society for Vascular Surgery came out with a classification system based on "wound, ischemia and foot Infection" (WIfI). This classification system, published in 2013 was created to account for the demographic changes that have occurred over the past forty years including increased incidence of high blood sugar and evolving techniques and ability for revascularization. This system was created on the basis of ischemia and angiographic disease patterns not being the sole determinants of amputation risk. The WIfI classification system is broken up into two parts: wounds and ischemia. Wounds are graded 0 through 3 on the presence of ulceration and/or gangrene and ischemia.
- Grade 0: no ulcer, no gangrene
- Grade 1: small, shallow ulcer; no gangrene
- Grade 2: deep ulcer with exposed tendon or bone, gangrene limited to toes
- Grade 3: extensive, full-thickness ulcer; gangrene extending to forefoot or midfoot
Ischemia is graded 0 through 3 based on ABI, ankle systolic pressure, and toe pressure.
- Grade 0: ABI 0.8 or higher, ankle
- Grade 1: arterial brachial index 0.6 to 0.79, ankle pressure 70 to 100 mm Hg, toe pressure 40 to 59 mm Hg
- Grade 2: ABI 0.4–0.59, ankle pressure 50 to 70 mm Hg, toe pressure 30 to 39 mm Hg
Testing for coronary artery disease or carotid artery disease is of unclear benefit. While PAD is a risk factor for abdominal aortic aneurysms (AAA), there is no data on screening individuals with asymptomatic PAD for abdominal aortic aneurysms. In people with symptomatic PAD screening by ultrasound for AAA is not unreasonable.
Depending on the severity of the disease, these steps can be taken, according to these guidelines:
- Stopping smoking (cigarettes promote PAD and are a risk factor for cardiovascular disease)
- Regular exercise for those with claudication helps open up alternative small vessels (collateral flow) and the limitation in walking often improves. Treadmill exercise (35 to 50 minutes, three or four times per week) has been reviewed as another treatment with a number of positive outcomes, including reduction in cardiovascular events and improved quality of life. Supervised exercise programs increase pain-free walking time and the maximum walking distance in people with PAD.
- Management of diabetes
- Management of hypertension
- Management of high cholesterol, and antiplatelet drugs such as aspirin and clopidogrel. Statins reduce clot formation and cholesterol levels, respectively, can help with disease progression, and address the other cardiovascular risks that the affected person is likely to have.
According to guidelines, taking aspirin or clopidogrel is recommended to reduce MI, stroke, and other causes of vascular death in people with symptomatic peripheral artery disease. The effectiveness of both aspirin and clopidogrel, to reduce risk of cardiovascular ischemic events in people with symptomatic PAD is not well established.
Cilostazol can improve symptoms in some. Pentoxifylline is of unclear benefit.[needs update] Cilostazol may improve walking distance for people who experience claudication due to peripheral artery disease, but no strong evidence suggests that it improves the quality of life, decreases mortality, or decreases the risk of cardiovascular events.
Treatment with other drugs or vitamins are unsupported by clinical evidence, "but trials evaluating the effect of folate and vitamin B12 on hyperhomocysteinemia, a putative vascular risk factor, are near completion".
After a trial of the best medical treatment outline above, if symptoms persist, patients may be referred to a vascular or endovascular surgeon. The benefit of revascularization is thought to correspond to the severity of ischemia and the presence of other risk factors for limb loss such as wound and infection severity.
- Angioplasty (or percutaneous transluminal angioplasty) can be done on solitary lesions in large arteries, such as the femoral artery, but may not have sustained benefits. Patency rates following angioplasty are highest for iliac arteries, and decrease with arteries towards the toes. Other criteria that affect outcome following revascularization are length of lesion and number of lesions. There does not appear to be long term advantages or sustained benefit to placing a stent following angioplasty in order to hold the narrowing of the subsartorial artery open.
- Atherectomy, in which the plaque is scraped off of the inside of the vessel wall (albeit with no better results than angioplasty).
- Vascular bypass grafting can be performed to circumvent a diseased area of the arterial vasculature. The great saphenous vein is used as a conduit if available, although artificial (Gore-Tex or PTFE) material is often used for long grafts when adequate venous conduit is unavailable.
- When gangrene has set in, amputation may be required to prevent infected tissues from causing sepsis, a life-threatening illness.
- Thrombolysis and thrombectomy are used in cases of arterial thrombosis or embolism.
A guideline from the American College of Cardiology and American Heart Association for the diagnosis and treatment of lower extremity, renal, mesenteric, and abdominal aortic PAD was compiled in 2013, combining the 2005 and 2011 guidelines. For chronic limb threatening ischemia the ACCF/AHA guidelines recommend balloon angioplasty only for people with a life expectancy of 2 years or less or those who do not have an autogenous vein available. For those with a life expectancy greater than 2 years, or who have an autogenous vein, bypass surgery is recommended.
Individuals with PAD have an "exceptionally elevated risk for cardiovascular events and the majority will eventually die of a cardiac or cerebrovascular etiology"; prognosis is correlated with the severity of the PAD as measured by an ABI. Large-vessel PAD increases mortality from cardiovascular disease significantly. PAD carries a greater than "20% risk of a coronary event in 10 years".
The risk is low that an individual with claudication will develop severe ischemia and require amputation, but the risk of death from coronary events is three to four times higher than matched controls without claudication. Of patients with intermittent claudication, only "7% will undergo lower-extremity bypass surgery, 4% major amputations, and 16% worsening claudication", but stroke and heart attack events are elevated, and the "5-year mortality rate is estimated to be 30% (versus 10% in controls)".
The prevalence of PAD in the general population is 12–14%, affecting up to 20% of those over 70; 70%–80% of affected individuals are asymptomatic; only a minority ever require revascularisation or amputation. Peripheral artery disease affects one in three diabetics over the age of 50. In the US, it affects 12–20 percent of Americans age 65 and older. Around 10 million Americans have PAD. Despite its prevalence and cardiovascular risk implications, only 25% of PAD patients are undergoing treatment.
In people aged 40 years and older in the United States in 2000, rates of PAD was 4.3%. Rates were 14.5% people aged 70 years or over. Within age groups, rates were generally higher in women than men. Non-Hispanic blacks had a rates of 7.9% compared to 4.4% in Non-Hispanic whites and 3.0% (1.4%–4.6%)in Mexican Americans.
The incidence of symptomatic PAD increases with age, from about 0.3% per year for men aged 40–55 years to about 1% per year for men aged over 75 years. The prevalence of PAD varies considerably depending on how PAD is defined, and the age of the population being studied. Diagnosis is critical, as people with PAD have a four- to five-fold higher risk of heart attack or stroke.
The Diabetes Control and Complications Trial, and the U.K. Prospective Diabetes Study trials, in people with type 1 and type 2 diabetes, respectively, demonstrated that glycemic control is more strongly associated with microvascular disease than macrovascular disease. Pathologic changes occurring in small vessels may be more sensitive to chronically elevated glucose levels than is atherosclerosis occurring in larger arteries.
Research is being done on therapies to prevent progression of PAD. In those who have developed critically poor blood flow to the legs, the benefit of autotransplantation of autologous mononuclear cells is unclear.
Only one randomized controlled trial has been conducted comparing vascular bypass to angioplasty for the treatment of severe PAD. The trial found no difference in amputation-free survival between vascular bypass and angioplasty at the planned clinical endpoint, but the trial has been criticized as being underpowered, limiting endovascular options, and comparing inappropriate endpoints. As of 2017, two randomized clinical trials are being conducted to better understand the optimal revascularization technique for severe PAD and critical limb ischemia (CLI), the BEST-CLI (Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia) Trial, and the BASIL-2 (Bypass Versus Angioplasty in Severe Ischaemia of the Leg – 2 )Trial.
- Moore, Jonathan (September 1, 2008). "Creating the Ideal Microcosm for Rapid Incorporation of Bioengineered Alternative Tissues Using An Advanced Hydrogel Impregnated Gauze Dressing: A Case Series". The Foot & Ankle Journal. doi:10.3827/faoj.2008.0109.0002.
- Violi, F; Basili, S; Berger, JS; Hiatt, WR (2012). Antiplatelet therapy in peripheral artery disease. Handbook of Experimental Pharmacology. 210. pp. 547–63. doi:10.1007/978-3-642-29423-5_22. ISBN 978-3-642-29422-8. PMID 22918746.
- "What Are the Signs and Symptoms of Peripheral Arterial Disease?". nhlbi.nih.gov. August 2, 2011. Archived from the original on February 25, 2015. Retrieved February 26, 2015.
- "What Is Peripheral Arterial Disease?". nhlbi.nih.gov. August 2, 2011. Archived from the original on February 25, 2015. Retrieved February 25, 2015.
- "What Is Peripheral Vascular Disease?" (PDF). American Heart Association (heart.org). 2012. Archived (PDF) from the original on April 12, 2015. Retrieved February 26, 2015.
Peripheral artery disease (PAD) is the narrowing of the arteries to the legs, stomach, arms and head.
- "What Causes Peripheral Arterial Disease?". nhlbi.nih.gov. August 2, 2011. Archived from the original on February 25, 2015. Retrieved February 26, 2015.
- Fowkes, FG; Rudan, D; Rudan, I; Aboyans, V; Denenberg, JO; McDermott, MM; Norman, PE; Sampson, UK; Williams, LJ; Mensah, GA; Criqui, MH (October 19, 2013). "Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis". Lancet. 382 (9901): 1329–40. doi:10.1016/s0140-6736(13)61249-0. PMID 23915883. S2CID 38652734.
- "How Is Peripheral Arterial Disease Diagnosed?". August 2, 2011. Archived from the original on April 7, 2015. Retrieved March 27, 2015.
- Ruiz-Canela, M; Martínez-González, MA (2014). "Lifestyle and dietary risk factors for peripheral artery disease". Circulation Journal. 78 (3): 553–9. doi:10.1253/circj.cj-14-0062. PMID 24492064.
- "How Is Peripheral Arterial Disease Treated?". nhlbi.nih.gov. August 2, 2011. Archived from the original on February 25, 2015. Retrieved February 26, 2015.
- Hageman, D; Fokkenrood, HJ; Gommans, LN; van den Houten, MM; Teijink, JA (April 6, 2018). "Supervised exercise therapy versus home-based exercise therapy versus walking advice for intermittent claudication". The Cochrane Database of Systematic Reviews. 4: CD005263. doi:10.1002/14651858.CD005263.pub4. PMC 6513337. PMID 29627967.
- Hankey, GJ; Norman, PE; Eikelboom, JW (February 1, 2006). "Medical treatment of peripheral arterial disease". JAMA. 295 (5): 547–53. doi:10.1001/jama.295.5.547. PMID 16449620.
- GBD 2015 Disease and Injury Incidence and Prevalence, Collaborators. (October 8, 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–1602. doi:10.1016/S0140-6736(16)31678-6. PMC 5055577. PMID 27733282.
- GBD 2015 Mortality and Causes of Death, Collaborators. (October 8, 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1459–1544. doi:10.1016/s0140-6736(16)31012-1. PMC 5388903. PMID 27733281.
- "Overview of Peripheral Arterial Disease – Heart and Blood Vessel Disorders". Merck Manuals Consumer Version. Retrieved April 30, 2019.
Disorders of arteries that supply the brain with blood are considered separately as cerebrovascular disease.
- Shantulli, Shu (2018). "Update on peripheral arterial disease: Epidemiology and evidence-based facts". Atherosclerosis.
- Harrison's principles of internal medicine (20 ed.). McGraw-Hill Education / Medical. 2018. ISBN 9781259644047.
- Gerhard-Herman, MD; Gornik, HL; Barrett, C; Barshes, NR; Corriere, MA; Drachman, DE; Fleisher, LA; Fowkes, FG; Hamburg, NM; Kinlay, S; Lookstein, R; Misra, S; Mureebe, L; Olin, JW; Patel, RA; Regensteiner, JG; Schanzer, A; Shishehbor, MH; Stewart, KJ; Treat-Jacobson, D; Walsh, ME (March 21, 2017). "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". Journal of the American College of Cardiology. 69 (11): 1465–1508. doi:10.1016/j.jacc.2016.11.008. PMID 27851991.
- Andras, A; Ferket, B (April 7, 2014). "Screening for peripheral arterial disease". The Cochrane Database of Systematic Reviews. 4 (4): CD010835. doi:10.1002/14651858.CD010835.pub2. PMID 24711093.
- U.S. Preventive Services Task Force (December 15, 2014). "Peripheral artery disease screening and cardiovascular disease risk assessment with the ankle-brachial index in adults: recommendation statement". Am Fam Physician. 90 (12): 858A–858D. Archived from the original on March 31, 2017.
- Bedenis, R; Stewart, M; Cleanthis, M; Robless, P; Mikhailidis, DP; Stansby, G (October 31, 2014). "Cilostazol for intermittent claudication". The Cochrane Database of Systematic Reviews. 10 (10): CD003748. doi:10.1002/14651858.CD003748.pub4. PMC 7173701. PMID 25358850.
- Lin, JS; Olson, CM; Johnson, ES; Whitlock, EP (September 3, 2013). "The ankle-brachial index for peripheral artery disease screening and cardiovascular disease prediction among asymptomatic adults: a systematic evidence review for the U.S. Preventive Services Task Force". Annals of Internal Medicine. 159 (5): 333–41. doi:10.7326/0003-4819-159-5-201309030-00007. PMID 24026319.
- Poredos, P; Jezovnik, MK (March 2013). "Is aspirin still the drug of choice for management of patients with peripheral arterial disease?". VASA. Zeitschrift für Gefässkrankheiten. 42 (2): 88–95. doi:10.1024/0301-1526/a000251. PMID 23485835.
- Hauk, L (May 15, 2012). "ACCF/AHA update peripheral artery disease management guideline". American Family Physician. 85 (10): 1000–1. PMID 22612053.
- Vascular medicine : a companion to Braunwald's heart disease. Creager, Mark A., Beckman, Joshua A., Loscalzo, Joseph. (2nd ed.). Philadelphia, PA: Elsevier/Saunders. 2013. ISBN 9781455737369. OCLC 810335904.CS1 maint: others (link)
- GBD 2013 Mortality and Causes of Death, Collaborators (December 17, 2014). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 385 (9963): 117–71. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604. PMID 25530442.
- Münter, KC (2016). "Education in wound care: Curricula for doctors and nurses, and experiences from the German wound healing society ICW". Military Medical Research. 3 (1): 29. doi:10.1186/s40779-016-0094-1. PMC 5011891. PMID 27602234.
- Rabow, Michael W.; McPhee, Stephen J.; Papadakis, Maxine A. (September 7, 2018). Current medical diagnosis & treatment 2019. Papadakis, Maxine A.,, McPhee, Stephen J.,, Rabow, Michael W. (Fifty-eighth ed.). New York, N.Y. ISBN 9781260117431. OCLC 1048597590.
- Peripheral Arterial Disease at Merck Manual of Diagnosis and Therapy Professional Edition. Retrieved August 9, 2010.
- Joosten MM, Pai JK, Bertoia ML, Rimm EB, Spiegelman D, Mittleman MA, Mukamal KJ (October 2012). "Associations between conventional cardiovascular risk factors and risk of peripheral artery disease in men". JAMA. 308 (16): 1660–7. doi:10.1001/jama.2012.13415. PMC 3733106. PMID 23093164.
- Elsevier Point of Care (December 11, 2018). "Atherosclerotic peripheral artery disease". Clinical Key. Retrieved December 14, 2018.
- Price J, Mowbray P, Lee A, Rumley A, Lowe G, Fowkes F (1999). "Relationship between smoking and cardiovascular risk factors in the development of peripheral arterial disease and coronary artery disease; Edinburgh Artery Study Edinburgh Artery Study". European Heart Journal. 20 (5): 344–353. doi:10.1053/euhj.1998.1194. PMID 10206381.
- Smith GD, Shipley M, Rose G (1990). "Intermittent claudication, heart disease risk factors, and mortality. The Whitehall Study". Circulation. 82 (6): 1925–1931. doi:10.1161/01.cir.82.6.1925. PMID 2242518.
- Cole C, Hill G, Farzad E, Bouchard A, Moher D, Rody K, Shea B (1993). "Cigarette smoking and peripheral arterial occlusive disease". Surgery. 114 (4): 753–6, discussion 756–7. PMID 8211690.
- Rooke, TW; Hirsch, AT; Misra, S; Sidawy, AN; Beckman, JA; Findeiss, L; Golzarian, J; Gornik, HL; Jaff, MR; Moneta, GL; Olin, JW; Stanley, JC; White, CJ; White, JV; Zierler, RE; American College of Cardiology Foundation Task, Force; American Heart Association Task, Force (April 9, 2013). "Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA Guideline Recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". Journal of the American College of Cardiology. 61 (14): 1555–70. doi:10.1016/j.jacc.2013.01.004. PMC 4492473. PMID 23473760.
- Kannel WB, McGee D (1979). "Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study". Diabetes Care. 2 (2): 120–126. doi:10.2337/diacare.2.2.120. PMID 520114. S2CID 39307266.
- Creager MA, Lüscher TF, Cosentino F, Beckman JA (2003). "Diabetes and vascular disease pathophysiology, clinical consequences, and medical therapy: part I." Circulation. 108 (12): 1527–1532. doi:10.1161/01.cir.0000091257.27563.32. PMID 14504252.
- Lüscher TF, Creager MA, Beckman JA, Cosentino F (2003). "Diabetes and vascular disease pathophysiology, clinical consequences, and medical therapy: Part II". Circulation. 108 (13): 1655–1661. doi:10.1161/01.cir.0000089189.70578.e2. PMID 14517152.
- Beks P, Mackaay A, De Neeling J, De Vries H, Bouter L, Heine R (1995). "Peripheral arterial disease in relation to glycaemic level in an elderly Caucasian population: the Hoorn study". Diabetologia. 38 (1): 86–96. doi:10.1007/s001250050257. PMID 7744233.
- Unit ES (2005). "Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins". Lancet. 366 (9493): 1267–1278. doi:10.1016/s0140-6736(05)67394-1. PMID 16214597.
- Kannel W, McGee D (1985). "Update on some epidemiologic features of intermittent claudication: the Framingham Study". Journal of the American Geriatrics Society. 33 (1): 13–8. doi:10.1111/j.1532-5415.1985.tb02853.x. PMID 3965550. S2CID 13543458.
- Ridker PM, Stampfer MJ, Rifai N (2001). "Novel risk factors for systemic atherosclerosis". JAMA: The Journal of the American Medical Association. 285 (19): 2481–2485. doi:10.1001/jama.285.19.2481. PMID 11368701.
- TASC II Guidelines
* Norgren L, Hiatt WR, Dormandy JA; Hiatt; et al. (2007). "Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II)". Eur J Vasc Endovasc Surg. 33 (Suppl 1): S1–75. doi:10.1016/j.ejvs.2006.09.024. PMID 17140820.CS1 maint: multiple names: authors list (link)
* Norgren L, Hiatt WR, Dormandy JA, TASC II Working Group, et al. (2007). "Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II)". J Vasc Surg. 45 (Suppl S): S5–67. doi:10.1016/j.jvs.2006.12.037. PMID 17223489.
* Norgren L, Hiatt WR, Dormandy JA (2007). "Inter-Society Consensus for the Management of Peripheral Arterial Disease". Int Angiol. 26 (2): 81–157. PMID 17489079.
- Ron Walls, MD, Robert Hockberger, MD and Marianne Gausche-Hill, MD, FACEP, FAAP (May 18, 2017). Rosen's Emergency Medicine: Concepts and Clinical Practice 9th Edition. Elsevier, Inc. pp. Chapter 41, pgs 435–444. ISBN 9780323354790.CS1 maint: multiple names: authors list (link)
- Vowden P, Vowden K (March 2001). "Doppler assessment and ABPI: Interpretation in the management of leg ulceration". Worldwide Wounds. Archived from the original on May 9, 2008. – describes ABI procedure, interpretation of results, and notes the somewhat arbitrary selection of "ABI of 0.8 has become the accepted endpoint for high-compression therapy, the trigger for referral for a vascular surgical opinion and the defining upper marker for an ulcer of mixed aetiology.
- Amini, Arya; Gordon, Ian; Wilson, Samuel; Williams, Russell A. (October 2013). "Noncompressible arteries correlate with increased cardiovascular mortality at 2 years". Annals of Vascular Surgery. 27 (7): 918–923. doi:10.1016/j.avsg.2013.01.006. ISSN 1615-5947. PMID 23993108.
- Leiner T, Kessels AG, Nelemans PJ, Vasbinder GB, de Haan MW, Kitslaar PE, Ho KY, Tordoir JH, van Engelshoven JM699-708; Kessels; Nelemans; Vasbinder; De Haan; Kitslaar; Ho; Tordoir; Van Engelshoven (May 2005). "Peripheral arterial disease: comparison of color duplex US and contrast-enhanced MR angiography for diagnosis". Radiology. 235 (2): 699–708. doi:10.1148/radiol.2352040089. PMID 15858107.CS1 maint: multiple names: authors list (link)
- Leiner, T (February 2005). "Magnetic resonance angiography of abdominal and lower extremity vasculature". Top Magn Reson Imaging. 16 (1): 21–66. doi:10.1097/01.rmr.0000185431.50535.d7. PMID 16314696. S2CID 8026674.
- Norgren, L.; Hiatt, W. R.; Dormandy, J. A.; Nehler, M. R.; Harris, K. A.; Fowkes, F. G. R.; TASC II Working Group; Bell, Kevin; Caporusso, Joseph (2007). "Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II)". European Journal of Vascular and Endovascular Surgery. 33 Suppl 1: S1–75. doi:10.1016/j.ejvs.2006.09.024. ISSN 1078-5884. PMID 17140820.
- Fontaine R, Kim M, Kieny R; Kim; Kieny (1954). "Die chirugische Behandlung der peripheren Durchblutungsstörungen. (Surgical treatment of peripheral circulation disorders)". Helvetica Chirurgica Acta (in German). 21 (5/6): 499–533. PMID 14366554.CS1 maint: multiple names: authors list (link)
- Rutherford, Robert B.; Baker, J. Dennis; Ernst, Calvin; Johnston, K. Wayne; Porter, John M.; Ahn, Sam; Jones, Darrell N. (September 1997). "Recommended standards for reports dealing with lower extremity ischemia: Revised version". Journal of Vascular Surgery. 26 (3): 517–538. doi:10.1016/S0741-5214(97)70045-4. PMID 9308598.
- Teraa, M; et al. (2016), "Critical limb ischemia: current trends and future directions", J Am Heart Assoc, 5 (2): e002938, doi:10.1161/JAHA.115.002938, PMC 4802465, PMID 26908409.
- Mills, Joseph L.; Conte, Michael S.; Armstrong, David G.; Pomposelli, Frank B.; Schanzer, Andres; Sidawy, Anton N.; Andros, George; Society for Vascular Surgery Lower Extremity Guidelines Committee (January 2014). "The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: risk stratification based on wound, ischemia, and foot infection (WIfI)". Journal of Vascular Surgery. 59 (1): 220–234.e1–2. doi:10.1016/j.jvs.2013.08.003. ISSN 1097-6809. PMID 24126108.
- Mills JL, Sr; Conte, MS; Armstrong, DG; Pomposelli, FB; Schanzer, A; Sidawy, AN; Andros, G; Society for Vascular Surgery Lower Extremity Guidelines, Committee (January 2014). "The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: risk stratification based on wound, ischemia, and foot infection (WIfI)". Journal of Vascular Surgery. 59 (1): 220–34.e1–2. doi:10.1016/j.jvs.2013.08.003. PMID 24126108.
- US Preventive Services Task, Force.; Curry, SJ; Krist, AH; Owens, DK; Barry, MJ; Caughey, AB; Davidson, KW; Doubeni, CA; Epling JW, Jr; Kemper, AR; Kubik, M; Landefeld, CS; Mangione, CM; Silverstein, M; Simon, MA; Tseng, CW; Wong, JB (July 10, 2018). "Screening for Peripheral Artery Disease and Cardiovascular Disease Risk Assessment With the Ankle-Brachial Index: US Preventive Services Task Force Recommendation Statement". JAMA. 320 (2): 177–183. doi:10.1001/jama.2018.8357. PMID 29998344.
- Burns P, Gough S, Bradbury AW; Gough; Bradbury (March 2003). "Management of peripheral arterial disease in primary care". BMJ. 326 (7389): 584–8. doi:10.1136/bmj.326.7389.584. PMC 1125476. PMID 12637405.CS1 maint: multiple names: authors list (link)
- Salhiyyah, K; Forster, R; Senanayake, E; Abdel-Hadi, M; Booth, A; Michaels, JA (September 29, 2015). "Pentoxifylline for intermittent claudication". The Cochrane Database of Systematic Reviews. 9: CD005262. doi:10.1002/14651858.CD005262.pub3. PMC 6513423. PMID 26417854.
- Fowkes FG, Gillespie IN; Gillespie (2000). Fowkes, Gerry (ed.). "Angioplasty (versus non surgical management) for intermittent claudication". Cochrane Database Syst Rev (2): CD000017. doi:10.1002/14651858.CD000017. PMID 10796469.
- Johnston KW, Rae M, Hogg-Johnston SA, Colapinto RF, Walker PM, Baird RJ, Sniderman KW, Kalman P (1987). "5-year results of a prospective study of percutaneous transluminal angioplasty". Annals of Surgery. 206 (4): 403–413. doi:10.1097/00000658-198710000-00002. PMC 1493220. PMID 2959214.
- Emmerich J (2005). "Current state and perspective on medical treatment of critical leg ischemia: gene and cell therapy". The International Journal of Lower Extremity Wounds. 4 (4): 234–241. doi:10.1177/1534734605283538. PMID 16286375. S2CID 18384741.
- Chowdhury, Mohammed M.; McLain, Alexander D.; Twine, Christopher P. (June 24, 2014). "Angioplasty versus bare metal stenting for superficial femoral artery lesions". The Cochrane Database of Systematic Reviews (6): CD006767. doi:10.1002/14651858.CD006767.pub3. ISSN 1469-493X. PMC 6544814. PMID 24959692.
- Wardle, Bethany G.; Ambler, Graeme K.; Radwan, Rami W.; Hinchliffe, Robert J.; Twine, Christopher P. (September 29, 2020). "Atherectomy for peripheral arterial disease". The Cochrane Database of Systematic Reviews. 9: CD006680. doi:10.1002/14651858.CD006680.pub3. ISSN 1469-493X. PMID 32990327.
- Tw, Rooke; At, Hirsch; S, Misra; An, Sidawy; Ja, Beckman; Lk, Findeiss; J, Golzarian; Hl, Gornik; Jl, Halperin (November 1, 2011). "2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (Updating the 2005 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". Journal of the American College of Cardiology. 58 (19): 2020–45. doi:10.1016/j.jacc.2011.08.023. PMC 4714326. PMID 21963765.
- Shammas NW (2007). "Epidemiology, classification, and modifiable risk factors of peripheral arterial disease". Vasc Health Risk Manag. 3 (2): 229–34. doi:10.2147/vhrm.2007.3.2.229. PMC 1994028. PMID 17580733.
- Selvin, Elizabeth; Erlinger, Thomas P. (August 10, 2004). "Prevalence of and Risk Factors for Peripheral Arterial Disease in the United States Results From the National Health and Nutrition Examination Survey, 1999–2000". Circulation. 110 (6): 738–743. doi:10.1161/01.CIR.0000137913.26087.F0. PMID 15262830.
- Selvin E, Wattanakit K, Steffes MW, Coresh J, Sharrett AR; Wattanakit; Steffes; Coresh; Sharrett (April 2006). "HbA1c and peripheral arterial disease in diabetes: the Atherosclerosis Risk in Communities study". Diabetes Care. 29 (4): 877–82. doi:10.2337/diacare.29.04.06.dc05-2018. PMID 16567831. Archived from the original on March 4, 2012.CS1 maint: multiple names: authors list (link)
- Suzuki, Jun-Ichi; Shimamura, Munehisa; Suda, Hiroyuki; Wakayama, Kouji; Kumagai, Hidetoshi; Ikeda, Yuichi; Akazawa, Hiroshi; Isobe, Mitsuaki; Komuro, Issei (April 2016). "Current therapies and investigational drugs for peripheral arterial disease". Hypertension Research. 39 (4): 183–191. doi:10.1038/hr.2015.134. ISSN 1348-4214. PMID 26631852. S2CID 3070349.
- Moazzami, K; Moazzami, B; Roohi, A; Nedjat, S; Dolmatova, E (December 19, 2014). "Local intramuscular transplantation of autologous mononuclear cells for critical lower limb ischaemia". The Cochrane Database of Systematic Reviews. 12 (12): CD008347. doi:10.1002/14651858.CD008347.pub3. PMC 7175832. PMID 25525690.
- Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, Fowkes FG, Gillepsie I, Ruckley CV, Raab G, Storkey H (December 2005). "Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial". Lancet. 366 (9501): 1925–34. doi:10.1016/S0140-6736(05)67704-5. PMID 16325694. S2CID 54229954.
- Conte, MS (May 2010). "Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) and the (hoped for) dawn of evidence-based treatment for advanced limb ischemia". Journal of Vascular Surgery. 51 (5 Suppl): 69S–75S. doi:10.1016/j.jvs.2010.02.001. PMID 20435263.
- Menard MT, Farber A, Assmann SF, et al. (2016). "Design and Rationale of the Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial". J Am Heart Assoc. 5 (7): e003219. doi:10.1161/JAHA.116.003219. PMC 5015366. PMID 27402237.
- Popplewell A, Davies H, Jarrett H, et al. (2016). "Bypass versus angio plasty in severe ischaemia of the leg - 2 (BASIL-2) trial: study protocol for a randomised controlled trial". Trials. 17: 11. doi:10.1186/s13063-015-1114-2. PMC 4704263. PMID 26739146.
- "Gene Therapy for PAD Approved". December 6, 2011. Archived from the original on September 3, 2015. Retrieved August 5, 2015.
- Deev, R.; Bozo, I.; Mzhavanadze, N.; Voronov, D.; Gavrilenko, A.; Chervyakov, Yu.; Staroverov, I.; Kalinin, R.; Shvalb, P.; Isaev, A. (March 13, 2015). "pCMV-vegf165 Intramuscular Gene Transfer is an Effective Method of Treatment for Patients With Chronic Lower Limb Ischemia". Journal of Cardiovascular Pharmacology and Therapeutics. 20 (5): 473–82. doi:10.1177/1074248415574336. PMID 25770117. S2CID 13443907.
- "Peripheral Arterial Disease" at the National Heart, Lung and Blood Institute
- Peripheral Arterial Disease (P.A.D.) at the American College of Foot and Ankle Surgeons
- Gerhard-Herman, Marie D.; Gornik, Heather L.; Barrett, Coletta; Barshes, Neal R.; Corriere, Matthew A.; et al. (November 13, 2016). "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary". Circulation. 135 (12): e686–e725. doi:10.1161/CIR.0000000000000470. PMC 5479414. PMID 27840332.