Peripheral arterial disease (PAD)


Refers to vascular diseases caused by atherosclerosis of the abdominal aorta, iliac and lower extremity arteries.

PAD currently affects more than 8.5 million people in the US.

Affects more than 230 million individuals worldwide.

Lifetime risk estimation of PAD is 30% in black men, 27.6% in black women, approximately 22% in Hispanic men and women, and 19% white men and women.

Due to obstructing plaques caused by atheroslerotic occlusive disease and commonly occurs in the infrarenal aorta and iliac arteries.

The number of people living with PAD is increasing worldwide, as people are living longer with chronic diseases.

With an aging population and increasing rates of diabetes, the prevalence of PAD is expected to increase.

Plaques may induce symptoms either by obstructing blood flow directly or by embolizing atheroslerotic or thrombotic material to more distal blood vessels.

The plaque occludes the arterial lumen and leads to reduction in peripheral blood flow to the extremities.

Lower extremity PAD is associated with all major atherosclerotic risk factors.

The ankle-brachial index (ABI) is a simple, inexpensive, and reasonably accurate noninvasive diagnostic test for PAD.

The ratio of systolic pressure measured at the brachial artery and at the ankle arteries has been adopted to diagnosed peripheral arterial disease.

ABI consists of sequential measurement of Doppler system pressures in the brachial, dorsalis pedis, and posterior tibial arteries in each extremity.

Definition is a resting ankle-brachial index (ABI) of less than 0.90. with a 95% sensitivity in detecting angiogram positive disease.

Lower ABI values are associated with increased cardiovascular mortality.

19-31% of patients with PAD have a normal borderline rest and ABI.
Exercise treadmill ABI testing increases the sensitivity of the ABI to detect PAD in patients with symptoms or signs of PAD with normal or borderline resting ABI.
A post exercise ABI decline of more than 20% or a post exercise ankle pressure decrease of more than 30 mmHg can establish diagnosis of PAD.

When the ankle brachial index value is used to define the presence of peripheral artery disease in the US it is found to be low in people 50 years and younger.

Peripheral arterial disease increases sharply with age, reaching approximately 20% in octogenarians.

Only approximately 10-15% of people with peripheral arterial disease will develop chronic limb threatening ischemia, the most severe form of PAD, or require amputation.

Approximately 11% of people with PAD develop chronic limb threatening ischemia, consisting of at rest, gangrene, or ischemic foot ulcers.

Acute limb ischemia, defined as sudden loss of limb perfusion that threatens limb viability with pain, paresthesias, weakness of the foot and is characterized by foot pallor, weakness, coolness, and absent pulses and lower extremity pressure less than 50 mmHg.

Chronic kidney disease, prior lower extremity revascularization, atrial fibrillation, and lower baseline ABI values are associated with higher rates of acute limb ischemia.

It is associated with high risk of coronary artery disease or cerebrovascular disease.
The most common cause of death in patients with PAD or coronary and cerebral vascular disease accounting for 40-60%, and for 10-20% of occurrences.

The rates of myocardial infarction, ischemic stroke, and vascular death in patients with peripheral artery disease without critical limb ischemia is estimated at 5-7% per year

The rates of peripheral artery disease reported to be twice is high in African-Americans.

It is recommended that the patients over age 50 stand those under 50 with risk factors such as hypertension, hyperlipidemia, smoking, or a greater than 10 year history of diabetes be screened for PAD using an ABI.

Clinical manifestations include: impaired walking, intermittent claudication, critical limb ischemia, and associated adverse cardiovascular events and limb outcomes.

Compared with patients with known coronary artery disease they are 30-50% less likely to receive antiplatelet drugs, statins for smoking cessation interventions.
The risk of PAD persists 20-30 years after smoking cessation.
Individuals with diabetes have a two-four fold higher risk of PAD.

The majority of patients with PAD do not present with classical intermittent claudication.

70-90% of people with PAD report no exertional leg symptoms doing daily life, and others report leg symptoms that begin during walking good or not otherwise consistent with intermittent claudication search his leg symptoms that do not involve calf or that resolve during walking.

In the Edinburgh artery study patients with an ankle brachial index of less than or equal 0.9, only 15% have classic intermittent claudication, while 35% report no exertional leg symptoms.

Affects 12% of community-dwelling people and 18% of people over the age of 55 in general medical practices.

Is an estimated 1 in 16 Americans 40 years of age or older has PAD.

Similar to coronary artery disease in that both conditions are caused by atherosclerosis that narrows and blocks arteries.

Atherosclerosis affects up to 10% of the Western population older than 65 years.

Involves the narrowing of peripheral arteries in the arms, legs, stomach, and head.

Individuals with PAD have a higher risk for coronary artery disease and stroke.

If left untreated,may result in complications such as gangrene and subsequent amputation.

It is uncommon before age 50 and fix 20% of people aged 80 and older in the US.

An early sign of major adverse cardiovascular events.

Cigarette smoking is associated with a 2-4 fold increase risk of peripheral artery disease.

Cigarette smoking is one of the strongest risk factors: more than 1/3 of patients with PAD are current smokers.
Smoking cessation is the most important modifiable risk factor in the management of patients with PAD.

Diabetes is associated with approximately 2-4 fold increase in risk.

The risk associated with hypertension has an odds ratio of increased risk from 1.5 to 2.2.

CHADS2 also a good predictor ischemic stroke in patients without atrial fibrillation.

Higher total cholesterol is associated with an increased risk, where is high density lipoprotein cholesterol is associated with decreased risk.

In patients with PAD CHADS2 scores provide a prediction accuracy 92% for ischemic stroke.

Large-vessel PAD increases mortality from cardiovascular disease significantly.

Under diagnosed, often undertreated, and more common then previously thought.

29% of individuals older than the age of 70, or older than the age of 50 with a history of smoking or diabetes are reported to have PAD.

PAD carries a greater than 20% risk of a coronary event in 10 years.

In patients with critical limb ischemia, the rate of risk of death at one year is as high as 25%.

PAD associated with increased risk for major adverse cardiac events, myocardial infarction, ischemic stroke, and cardiovascular death and major adverse limb events including amputation and acute limb ischemia.

With symptomatic PAD the annual rates of major adverse cardiac events or 4-5%, and rates of major adverse limb events are 1-2%.

Low risk that a patient with claudication will develop severe ischemia and require amputation.

The risk of death from coronary events is three to four times higher than matched controls without claudication.

About 7& of patients with Intermittent claudication undergo lower extremity bypass surgery, 4% require amputations, and 16% will have worsening of symptoms.

Major amputations in patients with intermittent claudication are reported at 1-3% of patients over a five-year period.

The risk of major amputation at one year is approximately 50% for patients with critical limb ischemia.

Low risk that a patient with claudication will develop severe ischemia and require amputation.

The risk of death from coronary events is three to four times higher than matched controls without claudication.

About 7% of patients with Intermittent claudication undergo lower extremity bypass surgery, 4% require amputations, and 16% will have worsening of symptoms.

5-year mortality rate is estimated to be 30%.

The prevalence of peripheral vascular disease in the general population is 12–14%, affecting up to 20% of those over 70.

The incidence 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.

70%–80% of affected individuals are asymptomatic and only a minority ever require revascularisation or amputation.

With severe claudication, critical limb-threatening ischemia occurs and is treated with revascularization to prevent or limit tissue loss.

Following revascularization patients are at high risk for subsequent vascular complications and particularly for acute limb ischemia, with a risk approximately four times as high as that among persons who have never undergone revascularization.

Acute limb ischemia is associated with long hospitalizations and high incidence of limb loss, disability, and death.
Following revascularization the use of rivaroxaban plus aspirin is associated with a significant lower incidence of acute limb ischemia, major amputations for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular disease causes than aspirin alone.
Controlled randomized trials of coated stents with antiproliferative drugs in patients with femoropopliteal PAD reveals significantly reduced repeat revascularization rates compared with uncoated devices.
In a randomized trial of patients with PAD treated with paclitaxel coded or uncoated endovascular devices resulted in in all cause mortality without difference during 1-4 years of follow up.
Studies revealed an increased risk of death among patients with femoral popliteal PAD treated with percutaneous coated revascularization devices by approximately 7% at five years.

The increased mortality from percutaneous coated devices appeared to be late phenomenon, emerging 2-3  years after the device use or implantation.

Affects 1 in 3 diabetics over the age of 50.

Affects 12–20 percent of Americans age 65 and older, that is approximately 10 million Americans have PVD.

Only 25 percent of PAD patients are undergoing treatment.

The incidence 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.

Affects approximately 20% individuals over the age of 55 years with half of patients being asymptomatic.

Prevalence increases with age, presence of hypertension, diabetes and smoking abuse.

Framingham study indicated a 2 fold higher incidence rate in men, 3.6% vs 1.8%.

First ever acute peripheral arterial events requiring hospitalization in Oxfordshire, England 2002-2005 estimated to be 0.52 per 1000 population per year.

In most developed countries severe limb ischemic associated with pain, ulceration and gangrene estimated to be 50-100 per 100,000 per year.

Increased fibrinogen levels correlate with severity of disease and likelihood of death.

Classically associated with intermittent claudication but most patients describe other types of symptoms or have no symptoms at all.

About a fifth of patients have typical intermittent claudication, rest pain, ulcerations or gangrene, while another third have exertional leg symptoms

Patients have muscle atrophy and fewer muscle fibers than patients without peripheral arterial disease.

With PAD a spectrum of lower extremity symptoms and functional impairment result from blood flow limitation during exercise and progressive male site damage with muscle remodeling.

Patients with PAD have poorer walking endurance, slower cadence, and shorter walking step length with slower walking velocity than non-PAD patients.

Functional limitations associated with PAD are associated with poor quality of life, increase hospitalization rates, increased mortality, and increased medical costs.

Among at risk individuals regular vigorous physical activities are associated with decreased PAD and all-cause mortality (Chang P et al).

Walking related impairment due to a decline in walking velocity.

Among patients with claudication 25% experience increasing pain, 5% require a revascularization procedure and 1-2% need amputation.

Among patients who have asymptomatic PAD 5-10% develop symptoms over 5 years.

Patients with intermittent claudication develop pain at rest and skin ulceration with an incidence of 0.25-0.45 per 1000 people per year.

The development of critical leg ischemia much more frequent in diabetics.

Critical limb ischemia is defined as a condition by greater than two week history of ischemic rest pain, nonhealing wound/ulcers, or gangrene in one or both legs attributable to arterial occlusive disease.

Critical limb ischemia is associated with a high risk for actual tissue loss, amputation, and cardiovascular events.

Patients with critical limb ischemia present with an ankle brachial index of less than .4 and toe systolic pressure <30 mmh Hg.

At rest, the presence of hemodynamically significant stenosis, vascular resistance decreases to maintain calfmuscle perfusion despite a decrease in systolic pressure.

In the exercised muscle, this mechanism fails to sufficiently increase blood flow to match metabolic needs, with ensuing muscle ischemia.

Repetitive cycles of exercise induced ischemia followed by reperfusion triggers the formation of reactive oxygen species, leading to abnormal myocyte metabolism and impaired contractile performance.

Differential diagnosis includes: spinal stenosis, osteoarthritis, chronic venous insufficiency, and neuropathy.

Bypass surgery and balloon angioplasty are primary treatments available.

Surgical treatment has long term patency and clinical durability but high morbidity, mortality and the necessity for frequent imaging of graft, re-interventions and need for quality veins.

Daily rivaroxaban and aspirin significantly reduced major limb and cardiovascular events among patients with PAD who had undergone lower extremity revascularization.

Vascular repair of large caliber vessels such as the aorta and iliac arteries are best done with prosthetic vascular grafts with high ten-year patency while vessels of small caliber below inguinal ligament are best replaced with autologous veins with five-year patency of 63-80%.Among patients with intermittent claudication after one year of follow up, the combination of endovascular revascularization and supervised exercise resulted in greater improvement in walking distance and health-related quality-of-life compared with supervised exercise only (Fakhry F et al).

Statins lead to a reduction in progression of claudication, critical limb ischemia, need for a revascularozation,  or amputation in PAD.
All patients with PAD should receive statins.

Prevalence rate of 6%-25% among women older than 55 years and sharply increase with age.

Mortality rates among patients with PAD are approximately 5-6% a year, with approximately 30% of patients dying from coronary artery or other cardiovascular disease within 5 years of their initial diagnosis.

Stroke and myocardial infarction 3 times more common than in individuals without PAD, even if no vascular symptoms are present.

After 5-10 years of follow-up 70-80% of patients with peripheral arterial disease are clinically stable and 20-30% require interventions.

In the Walking and Leg Circulation Study (WALCS) a longitudinal observational studies of men and women with a mean age of 71 years with and without PAD, those with severe PAD with an ankle brachial index of less than 0.5. were 12 times more likely to become unable to walk continuously for six minutes at 2 year follow-up, compared with those with a normal ankle brachial index at baseline (MDermott MM et al).

If the above study at five years of follow-up participants with severe PAD had a fourfold increase risk of mobility loss compared with participants without PAD at baseline, while individuals with moderate and mild PAD, respectively, had a 3.82 fold and a 3.2 fold increased risk of mobility loss at 5 five year follow-up, compared with participants without PAD at baseline.

Most frequent in the femoropopliteal-tibial distribution, followed by the aortoiliac, carotid and vertebral arteries.

Ankle-brachial index (ABI) has a 95% sensitivity and 99% specificity for diagnosing peripheral arterial disease.

Smoking is the single most important risk factor.

Aortoiliac occlusive arteriosclerosis produces pain in the hip, buttocks or thigh.

Femoropopliteal occlusive disease typically causes pain in the muscles of the calf.

Crossing the legs does not decrease Doppler pressures.

The prevalence of peripheral arterial disease in patients undergoing percutaneous coronary intervention is 18%.

In hospital mortality rate for patients undergoing percutaneous coronary revascularization is three times higher than in patients without peripheral arterial disease.

Antiplatelet therapy should be considered with aspirin or clopidrogrel.

Combination of aspirin and clopidrogrel should be utilized if the patient experiences a recurrent vascular event while receiving monotherapy.

The rate of stroke as a complication of percutaneous coronary intervention is 0.6% in patients with peripheral arterial disease, twice as high as patients without such disease.

Patients with percutaneous coronary intervention and peripheral arterial disease have a higher rate of bleeding than patients without such disease.

Treatment includes: smoking cessation, diabetic management, hypertension, lipid management, use of antiplatelet drugs, aspirin, anti-thrombotic drugs to reduce disease progression and reduce other cardiovascular risks.

Treatment with percutaneous transluminal angioplasty is effective initially in restoring bloodflow, restenosis with vessel recoil and neo intimal hyperplasia occur in more than 60% of patients within one year of the procedure.

Among patients with symptomatic femoral popliteal peripheral arterial disease percutaneous transluminal angioplasty with the paclitaxel coated balloon has a higher patency at 12 months then with angioplasty with standard balloon dilation (Rosenfield K et al),

Exercise programs in patients with claudication helps to open collateral blood flow and can increase walking endurance.

Treadmill exercise is associated with an increased maximal treadmill walking distance.

Treadmill exercises increase maximal treadmill walking distance by 50-200%.

Home based walking exercise programs can improve walking endurance, physical activity, and patient perceived walking endurance and speed in patients with and without classic claudication symptoms (McDermott MM et al).

Cilostazol or pentoxifylline treatment relieve symptoms of claudication.

Pentoxifylline is a methylxanthine derivative that increases red blood cells deformed ability potentially increasing arterial and micro circulatory flow and tissue oxygen concentration.

A systematic review concluded that the benefits of pentoxifylline for intermittent claudication symptoms is uncertain.

Cilostazol promotes vasodilation, particularly in femoral arteries and his antiplatelet and anti-thrombotic activities.

In a metanalysis cillstazol was associated with a 43 m improvement in treadmill walking distance compared with placebo.

Cilostazol a phoshodiesterase type 3 inhibitor increases walking distance from baseline by approximately 50% over placebo.
Cilostazol improvements are moderate compared with benefits of supervised exercise.
Up to 30% of patients with Cilostazol experience:  headache, diarrhea, abdominal stools, dizziness, and heart palpitations.
Supervised walking exercise is the first line therapy to improve walking in PAD.

After a trial of medical treatments vascular or endovascular surgery are considered.

Endovascular revascularization of the lower extremity often results in rapid improvement in walking distance and quality of life.

No convincing evidence supports the use of percutaneous balloon angioplasty or stenting in patients with intermittent claudication.

Angioplasty can be done on solitary lesions in large arteries, but angioplasty may not have sustained benefit.

Plaque excision, is also a condiseration.

Bypass grafting may be needed to circumvent a stenosed area of the arterial vasculature by the saphenous vein, although artificial material is often used when the veins are of lesser quality.

Rarely, sympathectomy can lead to vasodilatation.

Patients have 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 the Ankle brachial pressure index (ABPI).

Goals of medical treatment include improvement in symptoms, exercise performance, quality-of-life, and reduction of the risk of adverse cardiovascular events and limb events.

The most effective approaches include:  training, and endovascular revascularization.

Supervised walking/treadmill activity improves walking distances.

supervised walking exercise therapy is associated with an improvement in maximal treadmill walking distance when compared with the control group that did not exercise.

Home based walking exercise for peripheral artery disease is efficacious, and  should be first line therapy for a PAD.

Treatment with drugs have limited efficacy with an increase in walking distance between 12-60%.

Pentoxifylline treatment increases walking distance by 15%, and cilostazol by 25% (Stevens JW et al).

Rampiril, an ACE inhibitor, results in increased pain- free and maximum treadmill walking times compared with placebo (Ahimatos AA et al).

For patients with intermittent claudication antiplatelet therapy is associated with lower all-cause and cardiovascular disease mortality compared with placebo.

A type III phosphodiesterase inhibitor that inhibits platelet aggregation and increases vasodilation and is effective for treatment of intermittent claudication.

Comparing all platelet antiplatelet therapies, the strongest evidence exists for thienopyridines, such as clopidogrel.

The benefit of antiplatelet drugs in PAD is not universal.

Aspirin is a single agent in asymptomatic PAD is not better than placebo.
In patients with symptomatic PAD aspirin mono therapy can reduce the risk of systemic atherothrombotic events.
Clopidogrel among patients with PAD was associated with an almost 24% relative risk reduction of the combined risk of myocardial infarction, ischemic stroke, or vascular death compared with 325 mg of aspirin.
COMPASS Trial found a the combination of anti-platelets and low-dose anticoagulant therapy promises to be the best treatment for peripheral atherosclerotic cardiovascular disease.
In the COMPASS trial, the combination of a low-dose rivaroxaban plus aspirin was associated with a risk of major adverse limb events including acute limb ischemia, chronic limb ischemia treated with revascularization, and major limb amputation that was approximately 45% lower and  a risk of major adverse cardiovascular events that was approximately 30% lower than with aspirin alone.
Clinical outcomes for revascularization procedures in nursing home patients are poor (Oresanya L et al) as 82% of individuals died or were non-ambulatory within the first year.

In the above study lower extremity revascularization procedures were relatively ineffective in preserving or enhancing the functional state or the ability to walk in nursing home residents and was associated with a high likelihood of death within 1 year.

Patients with PAD who have a major adverse limb event, including those who undergo peripheral revascularization, are at even greater risk for subsequent limb events.
In the Premier healthcare database patients who have undergone peripheral revascularization, the cumulative incidence of repeat peripheral revascularization procedure or amputation after a median of 2.7 years was approximately 42%, many of these procedures were performed within one year.
In the VOYAGER PAD study similar findings were noted.
Among patients with PAD Telmisartan did not improve six minute walk distance at six month follow-up compared with placebo.

Among patients with chronic limb threatening ischemia who had adequate great saphenous vein for surgical revascularization, the incidence of major adverse limb event or death was significantly lower in a surgical group than in an endovascular group (Farber A).

About 20% of patients with chronic limb threatening ischemia have no revascularization options, leading to above ankle amputation.

Transcatheter arterialization of the deep veins is a percutaneous approach, creating an artery to vein connection to deliver oxygenated blood by means of the venous system to the ischemic foot to prevent amputation.

Transcatheter arterializaation of the deep veins is safe and successful in patients with chronic limb, threatening ischemia and no conventional surgical or endovascular revascularization treatment options (ShishrhborMH).


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