Peripheral arterial disease (PAD) was once thought to be a disease affecting predominantly men. However, population-based studies have demonstrated that the prevalence of PAD is similar in women and men. Because women in general live longer than men, the overall lifetime risk of developing PAD may be higher for women. Moreover, it is likely that there will be an increasing number of women living with PAD because of the aging of the population and because the prevalence of PAD increases with age. In all age groups, women with PAD have poorer walking performance compared with men. Finally, at present, there is little public awareness of PAD in either women or men. Because there has been negligible attention to sex and gender differences in all aspects of PAD, few data are available on which to base evidence-based recommendations or practice guidelines that are specific for women. This lack of attention to sex and gender differences in clinical research has been noted by others and has been attributed, in part, to the greater prevalence of cardiovascular disease in men, lack of inclusion of an adequate number of women in research protocols, and the historic belief that PAD was a disease of men. This review will outline the differing characteristics of PAD in women and will emphasize the need for future sex-specific research on this topic.
Risk Factors for Peripheral Arterial Disease in Women
Smoking is one of the most important modifiable risk factors for PAD, with the Surgeon General stating that the cessation of smoking is the most effective way to reduce cardiovascular events, and that the risk of stroke and heart attack is significantly reduced within a few years of quitting. Among the U.S. population aged 40 years and older, the prevalence of PAD in never smokers was 3.9%, former smokers was 6.6%, and current smokers was 9.5%. Compared to never smokers, the relative risk of PAD adjusted for age, religion, education, work, hypertension, diabetes, and cholesterol was 1.8 for former smokers and 2.4 for current smokers.
Age is the best established risk factor for PAD in women, and the overall prevalence of PAD increases with aging. In the NHANES study, the prevalence of PAD in women aged 40-49 years was 2.9%. In those aged 50-59 years, it was 3.6%. In those aged 60-69 years, it was 6.2%. In those aged 70-79 years, it was 9.2%. And in those aged 80 years and older, it was 10.8%. Compared to middle-aged adults, elderly PAD patients have more limited functional status and lower extremity functioning, and poorer prognosis with a higher incidence of functional decline, transient ischemic events, myocardial infarction, and cardiovascular events. This gradient relationship between increasing age and PAD prevalence has been found in multiple studies and in different countries, and is independent of other risk factors. In a study of catheterization and angiography, this age-PAD relationship did not appear to be different for women than for men.
Age
The risk of peripheral artery disease (PAD) significantly increases with age. Although PAD can occur in the elderly, it is not a normal part of aging. On average, the first symptoms of claudication, or leg pain on walking, will occur 10 years after the onset of the disease. Claudication is a primary reason to seek medical help for leg PAD. The prevalence of PAD among men and women aged 55-75 years is about 10% to 15%. Ankle-arm index testing demonstrated that 29% of men and 25% of women in this age group had PAD. In both age and gender groups, two-thirds of those with PAD were asymptomatic or had atypical leg symptoms. Thus, the burden of PAD in older adults is quite high and likely underestimated by clinical diagnosis. Among those with established cardiovascular or cerebrovascular disease, symptomatic PAD is even more prevalent, approaching 30% to 40%. In the Framingham Heart Study, the 10-year risk of intermittent claudication as an initial manifestation of CVD was approximately 7%, which was higher than the risk of stroke. Data from the American Heart Association show that the prevalence of intermittent claudication or ischemic leg symptoms is 4.1% to 4.3% for those aged 60-69 years and 5.6% to 5.9% for those aged 70-79 years, with the highest rates among minority populations.
Smoking
The mechanism by which smoking increases PAD is not entirely known, although smoking has been associated with increased oxidative activity and decreased nitric oxide activity. Smoking has been attributed to increased activation of platelets and leukocytes and a decrease in plasma antithrombin and protein S activity. Padberg et al. showed that smoking decreases fibrinolytic potential, leading to increased venous thrombosis and thrombophlebitis. Increased thrombotic activity and inflammation caused by smoking can damage arterial walls and promote atherosclerotic plaque formation. Smokers have higher homocysteine levels, and smoking is an independent risk factor for increased homocysteine levels, which is associated with higher rates of PAD and progression of atherosclerosis.
Smoking is a leading risk factor associated with PAD and is a major contributor to other associated diseases. It is an independent risk factor considering all confounding variables. The Framingham Study showed a two to threefold increase in the relative risk for claudication among male and female smokers. Smoking also increases the hazard of intermittent claudication that requires revascularization. The relative risk is sixfold for men and women who smoke 1+ packs per day. Among intermittent claudicants, progression to severe claudication or limb loss is greatly increased among smokers, with a fourfold increase seen for smokers compared to non-smokers.
Diabetes
Diabetes is a common disorder characterized by its chronic and persistent high levels of blood sugar, which can damage the blood vessels. The peripheral arterial disease and diabetes have a very strong link, with diabetes being a significant risk factor for P.A.D. Patients with diabetes have two to four times the risk of developing P.A.D. and also have more severe disease. The reason for this is likely to be due to the nature of atherosclerosis in diabetes. The process is accelerated and more diffuse, affecting all blood vessels from the aorta down to the smaller leg arteries. The effect of diabetes on the endothelial cells, which line the blood vessels, is detrimental and also accelerates the atherosclerotic process. The role of inflammatory mediators in the atherosclerotic process is also increased in diabetics, which may play a part in why the disease is more severe. An often unrecognized fact is that many diabetics possess P.A.D., but are asymptomatic due to peripheral neuropathy. This is often a reason as to why symptoms of intermittent claudication may go unnoticed. Finally, the prognosis for patients with P.A.D. and diabetes is worse, with a higher incidence of cardiovascular events and also higher rates of amputation. Channeling resources into aggressive preventative measures for diabetics with P.A.D. is of great importance, as this patient group carries the highest burden of disease.
High Blood Pressure
High blood pressure, or hypertension, affects more than 60 million adults in the United States and is a major cause of P.A.D. High blood pressure is a powerful “setup” for P.A.D because it accelerates atherosclerosis and puts an even greater load on the heart to pump blood through the arteries. Both atherosclerosis and the extra work required from the heart increase the likelihood that blood flow to the legs will be impaired. Compared to a normotensive woman, a hypertensive woman is 2 to 4 times as likely to develop symptomatic P.A.D. Controlled clinical data has shown that hypertensive patients with P.A.D can reduce the incidence of heart attack, stroke, and cardiovascular-related death by lowering blood pressure to a more desirable level. This is particularly important for P.A.D patients because they have a very high risk of cardiovascular events. High blood pressure is so detrimental to the vasculature that it increases the risk of amputation for P.A.D patients. The antihypertensive drugs angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may be of particular benefit to P.A.D patients because they also reduce the progression of kidney disease, a common comorbidity.
Symptoms and Diagnosis of Peripheral Arterial Disease in Women
Leg pain is the most characteristic symptom of peripheral arterial disease (P.A.D.) in the lower extremities. The pain from P.A.D. occurs when walking or exercising and goes away after a few minutes of rest. The pain is usually a crampy pain in the calves, thighs or hips. It can also occur in the feet or toes. If P.A.D. becomes severe, the pain can occur during rest and can be intense. Many people with P.A.D. do not experience any symptoms. The leg pain caused by P.A.D. can be mistaken for other conditions, a common reason why P.A.D. is not diagnosed in its early stages. In a recent study, just over half of the participants were aware they had the disease. Part II: What Are the Symptoms of P.A.D. and How Is It Diagnosed? “Many people who have P.A.D. do not experience any symptoms, knowledge of this disease and its typical symptoms is extremely low,” said Robert H. Shalwitz, M.D., of Bethesda Heart Institute in Boynton Beach, Florida. Dr. Shalwitz is a member of the P.A.D. Coalition, a group of leading health organizations and government agencies formed to improve the health and quality of life for those who have, or are at risk for, P.A.D.
Leg Pain and Discomfort
Leg pain and discomfort related to lower limb ischemia is the most common and earliest symptom of peripheral arterial disease. The pain typically occurs in the muscles of the calf, buttock, hip, or thigh and is consistently brought on by the same level of activity and relieved by rest within ten minutes. The clinical diagnosis of intermittent claudication has a high specificity (95%) for peripheral arterial disease, but it has poor sensitivity (20-50%) because patients with early disease or atypical leg pain may not report classic claudication. It is important to ask specifically about the site, character, and radiation of the pain and to differentiate it from neurogenic or musculoskeletal causes of leg discomfort. A recent onset of classic claudication in a smoker or diabetic suggests advanced disease, and claudication that occurs at rest, particularly in a dependent position, indicates severe ischemia. More severe limb-threatening ischemia can cause pain at rest or continuous pain in the foot. In its most severe form, ischemic pain is associated with ulceration or gangrene, and relief of the pain may come only with major limb amputation. It is important to assess the effect of leg pain on functional capacity and quality of life. Eliciting specific activities that precipitate claudication and the distance walked to produce pain can provide an objective measure of disease severity. Quality of life assessments imply that patients with intermittent claudication have a similar functional status to patients with coronary artery disease or congestive cardiac failure.
Numbness or Weakness in the Legs
Numbness or weakness in the legs could be associated with a variety of different medical problems. Why is it associated with PAD? Numbness occurs because of the lack of blood flow to the nerves. If the “communication line” between the brain and the area where the numbness occurs becomes interrupted, there will be weakness in the muscles. How is the lack of blood flow to the nerves more significant than other causes of numbness or weakness in the legs? It is typical for neurogenic weakness (nerves of the brain, spinal cord, and outlying areas) to not affect specific muscle groups. Whereas, if the weakness is in a specific set of muscles, it is more likely attributed to a myopathic origin (problem with the muscles). In the absence of trauma to the area, the affected person and physician can more easily infer that the cause of muscle weakness is more likely systemic in the case of PAD. This is important because the perceived level of tolerable pain or discomfort with activity might prompt a person to avoid certain activities and develop a more sedentary lifestyle. The avoidance of certain activities could then compound the effects of muscle disuse from weakness, which in turn could result in even worse lower extremity function.
Slow Healing Wounds
Wounds need a good blood supply to heal. People with PAD do not have a good blood supply to their legs. This can mean their wounds heal very slowly and they are at risk of developing leg ulcers. These ulcers are painful and if left untreated can become infected and form sores on the skin. This increases the chance of gangrene developing. If gangrene develops and the tissue dies, the person may need an amputation to remove the affected area. Unfortunately, this can lead to further problems. People with diabetes do not heal as well as others even with minor injuries. High blood sugar levels can harden and narrow the arteries, making it difficult for blood to pass through. This only worsens any problem with poor circulation. Around 10% of people with a foot ulcer will need an amputation. 85% of amputations are preceded by a foot ulcer. It is hard to believe that one in four people with PAD and diabetes who have had a minor amputation will die within a year. This risk rises to approximately one in two twelve months after a major amputation. It is thought that this is partly because once the affected limb has been removed, the person is often at risk of developing an ulcer or gangrene in the other limb. This is because they still have PAD and their diabetes has not gone away. This can be a very scary cycle, but it can be broken with the right diagnosis and treatment.
Diagnostic Tests
Finally, a reliable measure of symptoms is the six-minute walk. Patients are instructed to walk as far as possible in six minutes, and the distance walked is then measured. This test can be used to monitor a patient’s progress following treatment.
In sophisticated vascular laboratories, tests can be performed to measure the pressure within the leg arteries and the blood flow through them. These tests, known as hemodynamic studies, are the most accurate way to determine the extent and specific location of a blockage. They are often used to plan the best treatment for a patient.
Angiography is an x-ray examination of the blood vessels to obtain an image. When used with plain x-ray, it can provide detailed information on the location and type of a blockage. More recently, angiography can be done with magnetic resonance imaging (MRA) or computed tomographic scanning (CT), with or without angiography. The needle and catheter required for traditional angiography are omitted in favor of injecting dye into an artery and taking a series of scans. All these forms of angiography are painless and less invasive than the procedure has been in the past.
Another form of ultrasound, duplex imaging, may also be utilized. This is a combination of traditional ultrasound with Doppler ultrasound. It provides pictures of the blood vessels and information on the speed and direction of blood flow. Duplex imaging is useful in locating the exact position of a blockage or narrowing in the blood vessel.
Diagnostic testing of PAD has several aspects. It may begin with a comparison of blood pressure at the arm with blood pressure at the ankle. The difference is an indirect measure of how much blood flow is being hindered in the legs. More specific information can be obtained with Doppler ultrasound, in which special earphones are used to detect the sound of blood flow in the arteries. This test is simple and completely painless.
Treatment and Management of Peripheral Arterial Disease in Women
4.2. Medications The Women’s Health Initiative (WHI) study found that hormone replacement therapy (HRT) in post-menopausal women increased the risk of both cardiovascular events such as myocardial infarction and stroke, and invasive ambulatory treatment or hospitalization for PAD. HRT can also increase the risk of deep vein thrombosis, which is a potential issue for women with both atherosclerotic and thrombotic PAD. Thus, it would seem that there is no advantage for using any form of HRT in terms of treating or preventing progression of PAD in women. Step count is a simple and powerful tool to quantify ambulatory activity, which is diminished in PAD patients compared to healthy age-matched individuals. Step activity in a substudy of the Antithrombotic Trialists Collaboration was found to have predictive value for mortality and cardiovascular events even after adjustment for co-existing disease and multiple other lifestyle variables. The general principle of increasing ambulation for benefits in cardiovascular health can therefore be applied to a specific targeted approach for increasing step activity in PAD patients. Step activity is potentially an outcome measure in trials for PAD for medication treatments with known improving effect on claudication, such as pentoxifylline, cilostazol, and naftidrofuryl.
4.1. Lifestyle Changes Unfortunately, there appears to be a relative lack of data on the efficacy of making lifestyle changes to improve clinical outcomes in women with PAD. Walking “exercise” therapy, while beneficial in terms of functional status in patients with intermittent claudication, appears to be under-utilized in women. Implementing specific exercise regimes for women might be beneficial since women appear to have a greater functional impairment compared to men for any given level of disease severity.
Now for some specific details on how women with PAD are treated. The overarching principle is that established cardiovascular risk factors (blood pressure, lipids, glycaemia) and co-existing cardiovascular disease are treated very similarly to men, with relative benefit being at least as good if not more in women compared to men. However, if we consider each of the therapeutic strategies for PAD, then differences do emerge for men and women.
Lifestyle Changes
Peripheral arterial disease (PAD) is a common cause of morbidity and mortality in the general population. Women need to be placed in a special group. It is now known that the typical symptoms of intermittent claudication and pain on walking affect women more than men. Indeed, in the NHANES 3 dataset, women with PAD were proven to have poorer and more severe lower mobility function than men. When combined with the typical female role of social carer and maintaining the household, PAD can have a significant effect on health-related quality of life. Furthermore, PAD in women is associated with higher levels of depression than in men. The cases of sexual dysfunction in men when suffering from PAD are well-documented. However, it is often overlooked that erectile dysfunction in male partners has been linked with lower levels of physical activity and higher cardiovascular mortality and morbidity in their female counterparts. Erectile dysfunction has also been proven to be an independent risk factor for cerebrovascular and cardiovascular disease in women. Thus, discussing sexual health in females may prove to be an important tool for addressing PAD-related health issues in women.
Medications
Medical therapy is a cornerstone for PAD treatment. There are several medications that can improve symptoms in PAD patients; however, the efficacy of these treatment modalities can vary by gender. Cessation is one of the most beneficial things a patient can do regardless of gender. It has a clear dose-response relationship with the amount smoked and duration of cessation. Unfortunately, it is more difficult for women to quit, and it has been shown that women are more likely to relapse. In women, the cessation of hormone therapy is also important as it can exacerbate intermittent claudication. Supervised exercise therapy has been shown to have differing effects on men and women, with no clear benefit in women to date. The use of antiplatelet agents, specifically aspirin, and statins are of particular importance because these medications help to lower the elevated cardiovascular risk associated with PAD. Although there are no studies to date which evaluate a gender-based difference in the use of these medications, there is strong evidence to suggest their use in all patients with PAD. The use of high-dose antioxidants has been shown to be beneficial in men; however, there are no trials in women to date. The use of ACE inhibitors and angiotensin receptor blockers has been shown to moderately improve walking distance and lower extremity function in both sexes.
Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis in which the legs do not receive enough blood flow to keep up with demand. PAD affects 8-12 million people in the United States and becomes much more common with age. The beclotrial is related to the In Depth Review article, “Peripheral Arterial Disease in Women: Unique Risk and Challenges”. This article will discuss various treatment modalities for PAD and their effectiveness specifically in women. The following manuscripts provide evidence that smoking cessation, cilostazol, and make have particularly beneficial effects in women with PAD. This paper is a great representation of how PAD is a very heterogeneous syndrome and how treatment must be tailored specifically to each patient.
Angioplasty and Stenting
Percutaneous interventions have become the first-line treatment for many peripheral arterial disease (PAD) patients who have severe claudication or limb threat. These procedures are generally less invasive than surgical procedures and involve shorter hospital stays. Angioplasty, with or without stenting, has become a popular treatment modality. Due to advances in technique and technology, it is now possible to successfully treat lesions that, 10 years ago, would have been considered untreatable. Consequently, the indications for endovascular treatment have evolved, and many of these techniques are used in patients with more severe disease than was previously the case. The relative merits of endovascular treatment compared to surgery are still the subject of several trials. Due to the comorbid factors associated with PAD, some patients are not fit for surgery, and a minimally invasive procedure is more suitable. Angioplasty generally has short-term benefits, and measures to prevent restenosis post-procedure are becoming increasingly important. Balloon angioplasty is usually the initial intervention in treating lower extremity arterial disease.
4.4. Bypass Surgery
Bypass surgery is also the treatment of choice for patients with extensive disease affecting the aorto-iliac segment. The potential benefit from bypass surgery compared to angioplasty or medical management may be even greater in women than men. One meta-analysis reported that women younger than 70 years of age treated with bypass surgery had a 59% relative reduction in the risk of amputation and a 48% relative reduction in the risk of death compared to medical management. Bypass surgery has also been associated with lower rates of recurrent amputation in women compared to men.
Bypass surgery may be done to treat pain and wounds that are not relieved by other treatments. This procedure is also used to treat limb-threatening ischemia. Two randomized controlled trials and three meta-analyses comparing angioplasty to bypass surgery for limb-threatening ischemia reported significantly higher rates of limb salvation and overall survival in patients treated with aorto-iliac or aorto-femoral bypass surgery.
Bypass surgery is a procedure that involves using a blood vessel graft to bypass a narrowed or blocked artery. The grafted blood vessel can be a reversed vein from the leg or an artificial graft. This procedure is similar to the detour created when a section of the highway is under construction. The goal of the detour is to re-route traffic so that it can continue to flow smoothly to its destination. Similarly, the goal of the blood vessel graft is to re-route blood around the blockage so that it can be delivered to the extremity.
