Abstract
Peripheral arterial disease is a major cause of morbidity and mortality in Americans. Without aggressive management of the disease as well as comorbidities and risk factors, peripheral arterial disease may progress and place patients at risk for amputation of the affected limb. In addition, patients affected by peripheral arterial disease are at increased risk for death from both cardiovascular and noncardiovascular causes. Although traditionally felt to be a disease of Caucasian men, women compose a significant portion of patients with peripheral arterial disease, especially among the elderly. Increased prevalence of asymptomatic disease in women can lead to delayed diagnosis and treatment. Without the appropriate medical and or surgical intervention, women are at risk of poor procedural outcomes and increased mortality. This review will focus on the differences in peripheral arterial disease based on gender and how these differences can affect the presentation, diagnosis and treatment of peripheral arterial disease in women.
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Learning objectives
Upon completion of this activity, participants should be able to:
Describe the epidemiology of peripheral arterial disease (PAD)
Compare risk factors for PAD among women and men
Identify differences in the diagnosis of PAD among women and men
Treat PAD effectively
Peripheral arterial disease (PAD) affects between 5 and 10 million Americans and is a significant cause of morbidity and mortality [1,2]. Although a majority of patients are asymptomatic at the time of diagnosis, a percentage of patients with PAD will present with intermittent claudication, characterized by cramping pain in the legs with exertion that is relieved with rest, which will worsen in approximately 10–20% and progress to critical limb ischemia (CLI) in 1–2% of patients [3,4]. However, evidence has suggested that PAD does not always progress through the classification stages to CLI, as some patients undergoing amputations for CLI have been found to have no PAD symptoms 6 months prior to the diagnosis of CLI [5]. In addition to the functional impairment caused by PAD, patients with PAD also have a five-to six-fold increase in risk of morbidity and death from other atherosclerotic vascular diseases such as coronary artery disease (CAD) and stroke [6].
Risk factors for PAD are, in general, the same as the risk factors for atherosclerosis and include smoking, diabetes and hypertension as well as advanced age [4,7]. Historically, PAD has also been viewed as a disease of white men. While a majority of older studies report a higher prevalence of PAD in men, more recent studies indicate that the prevalence of PAD in women is approximately equal to that of men, if not greater [7–13]. Perception that women are less likely to have PAD can lead to decreased screening for the disease as well as less aggressive management of risk factors in this patient group. Disparities in time-to-diagnosis and access-to-care may contribute to worse outcomes following treatment. Thus, the purpose of this review is to highlight the differences in PAD based on gender and how these differences can affect the presentation, diagnosis and treatment of PAD in women.
Prevalence of PAD
The overall prevalence of PAD increases with age. In patients younger than 60 years of age, the prevalence is approximately 3%, but can reach up to 15–20% in patients over 70 years of age [14,15]. Male sex is reported as a risk factor for PAD in the 2005 American Heart Association guidelines for the management of PAD [3,11,12,14]. However, the data cited in this publication is from 1985 and several more recent studies have indicated that the prevalence of PAD in women is not only similar to that in men, but is actually higher [6,8–10,16,17]. Reports of PAD prevalence according to gender are conflicting; however, a review of recent population studies yields a mean overall prevalence of 13.4 and 15.6% in men and women respectively (Table 1). There are several factors that may contribute to the disparity in gender-based prevalence across studies.
Prevalence of peripheral arterial disease in population-based studies.
DM: Diabetes mellitus; NHNES: National Health and Nutrition Examination Survey; PAD: Peripheral arterial disease; RECALL: Risk factors, Evaluation of Coronary Calcium and Lifestyle.
Selection bias may play a role in whether differences between genders are accurately reflected in the patient sample. For example, in a study by Vogt et al. of PAD in elderly women over 65 years of age, 6.5% of patients were excluded because they refused ankle blood pressures [18]. In the NHANES study, approximately 20% of patients studied had missing data and patients in this group were more likely to be older and female [13]. Although the authors in this study did not propose an etiology for this finding, it has been postulated that women with PAD may be less likely to leave their homes or community, making them less likely to travel for an examination or participate in a study secondary to increased functional disability [19,20].
Oversampling of patients in a particular demographic group, such as age, may also lead to skewed data. Since prevalence of PAD increases with age, most epidemiologic studies focus on older patient groups (usually >50 years of age). However, the prevalence of PAD among women may vary within subsets of the elderly. In a study of patients with PAD who were referred to a tertiary noninvasive blood flow laboratory for evaluation, demographic data indicated that women were significantly older than men (mean 3.3 years older; p < 0.02) and composed a higher proportion of patients over 65 years of age (69.2% women, 56.8% men) [21]. Alternatively, in several studies that report higher PAD prevalence in women, a significant proportion of patients studied were older than 65 years of age [6,8,22]. In a study by Diehm et al., the overall prevalence of PAD was greater in men than in women (19.8 vs 16.8%). However, the increase in PAD prevalence with age was much greater for women than men. In patients younger than 70 years of age, the prevalence of PAD among women and men was 11.5 and 17.1%, respectively. In patients over 85 years of age, PAD prevalence increased to 39% in women compared with only 27% in men [9].
Reported prevalence may also be influenced by a bias toward increased screening and diagnosis of PAD in male patients. As a result, women may be included less frequently in studies that recruit patients referred from general care practices to vascular laboratories or specialists. A recent survey of female veterans in Texas, USA, indicated that women may be less likely to discuss a diagnosis of PAD with their healthcare provider. Although almost half (47%) of the patients surveyed were classified as high risk for cardiovascular disease (CVD) based on risk factors, approximately two-thirds of patients reported never having discussed circulation problems with a healthcare provider. A comparison survey in male veterans was not included in this study.
Despite some conflicting reports, overall PAD prevalence appears to be higher in men. However, PAD prevalence increases in elderly women and recent studies suggest it may even be higher in women than in men. As such, increased suspicion of PAD in women with appropriate risk factors and associated comorbidities will help to ensure that women with PAD are diagnosed and treated in a timely manner.
Comorbidities & risk factors
Although the etiology of PAD can be thromboembolic, inflammatory or even traumatic, the vast majority of cases result from progressive atherosclerosis. Therefore, the risk factors for PAD are similar to the general risk factors for atherosclerosis and include increased age, tobacco use, diabetes and, to a lesser extent, hypertension and dyslipidemia. Although risk factors such as hypertension, diabetes and smoking may be more prevalent among African-American populations compared with non-Hispanic white patients, for the most part, these risk factors are the same for men and women [8,23–28]. Since patients with PAD also have a high risk of other types of atherosclerotic disease including CAD and cerebrovascular disease, poor management of risk factors leads to progression of PAD as well as increased overall morbidity and mortality.
Cigarette smoking is one of the most significant risk factors for development of PAD with a mean odds ratio of 2.3 for development of symptomatic PAD or critical limb ischemia (CLI) among current smokers [29,30]. The risk of PAD increases with the amount of exposure and may be abrogated by quitting [16,31,32]. In a population study of Chinese patients, He et al. found that risk of PAD in former smokers was maintained if that patient had quit within the past 10 years, but the risk was minimal after 10 years or more [16]. According to the CDC, the overall prevalence of cigarette smoking between 2003 and 2007 has remained stable at approximately 20% of Americans and smoking among women has remained below average with a prevalence between 17 and 19% [33]. Although several studies have noted a decreased prevalence of smoking among women with PAD compared with men, women with PAD are still more likely to be current or former smokers compared with women without PAD [17,18,34–36].
There is an association between levels of C-reactive protein (CRP) and development of PAD [37,38]. Elevated CRP may be an indicator of disease severity and a recent study by Vidula et al. demonstrated that elevated inflammatory markers, including D-dimer and CRP, are predictive of all-cause and cardiovascular mortality within 1 year [39]. Although results from the Multiethnic Study of Atherosclerosis (MESA) demonstrated that women had higher CRP levels compared with men when adjusted for comorbidities, age and hormone status, the decedents in the study by Vidula et al. were more likely to be male [37,40]. Ultimately, the specific role of inflammatory markers in either the diagnosis or prognosis among patients with PAD has yet to be determined.
The prevalence of additional comorbidities that place patients at higher risk for PAD, such as diabetes, hypertension and dyslipidemia, is similar in women and men, but there is some evidence to suggest that non-PAD CVD is more prevalent in men than in women [41]. In the PAD Awareness, Risk and Treatment: New Resources for Survival (PARTNERS) study, 6979 patients older than 50 but younger than 70 years of age with a history of diabetes or smoking were enrolled to determine the relationship between PAD and other CVD classified as a history of angina, myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, abdominal aortic aneurysm, transient ischemic attack or stroke. Among these patients, 53% had a history of either PAD or CVD, but women composed a majority of the PAD-alone group (61%) compared with only 44% of the patients with a history of both PAD and CVD [6]. Since PAD patients with CVD may be more likely to receive aggressive treatment for risk factors such as dyslipidemia and hypertension than patients without associated CVD [6], a decreased recognition of non-CVD disease in women may make them less likely to receive appropriate risk factor modification. Ultimately, men and women with PAD can expect an increased risk of overall and CVD-associated morbidity and mortality [1,14,26,42,43].
Sex hormones, particularly estrogen, have vasoprotective properties that have traditionally been felt to decrease the prevalence of atherosclerotic disease in younger women and contribute to the later presentation of CVD in older women. Estrogen therapy in the postmenopausal period ameliorates unfavorable changes in the lipid profile following menopause, such as an increase in low-density lipoprotein and triglycerides with a concomitant decrease in high-density lipoprotein [44]. In addition, women have a greater endothelial-dependent nitric oxide-mediated vasodilation response than men, which decreases after menopause and is thought to be related to lack of estrogen [45]. Since nitric oxide is a key vasoprotective molecule, estrogen may help reduce the risk of CVD by mediating its local and systemic effect on the vasculature.
Observational studies such as the Rotterdam study indicated that while there may be shortterm increased risk for cardiovascular events, long-term hormone-replacement therapy (HRT) may be beneficial. In their study of 2196 women aged 55–80 years, HRT did not have a protective effect on the risk of PAD if used for less than 1 year; however, women who reported use of HRT for over 1 year had a 52% decreased risk of PAD [46]. However, larger, randomized, controlled trials such as the Women's Health Initiative (WHI) and Heart and Estrogen/Progestin Replacement (HERS) trial have failed to demonstrate a beneficial effect of HRT on risk of cardiovascular events or PAD (Table 2) [47–51]. Both WHI trials (estrogen plus progestin trial and estrogen alone) noted an increase in peripheral vascular events or reintervention, especially at early time points [50,52]. However, no increase in peripheral vascular events was noted in the HERS trial and neither study found an increased incidence of PAD in patients receiving HRT [47,49,50,52].
Randomized, controlled trials for hormone-replacement therapy.
includes carotid disease, lower extremity disease and abdominal aortic aneurysmal disease.
HERS: Heart and Estrogen/Progestin Replacement Study; PAD: Peripheral arterial disease; WHi: Women's Health initiative.
There is also some evidence to support that HRT may increase the risk of poor procedural outcomes in postmenopausal women undergoing revascularization. In a study by Timaran et al., analysis of outcomes in women following angioplasty and stenting at a single institution indicated that HRT significantly reduced 5-year primary patency rates (49 and 74% for HRT vs non-HRT, respectively; p = 0.02) [53]. This effect of HRT on patency was also noted in an analysis of outcomes in women following femoro–popliteal bypass grafting at the same institution [54]. According to the HERS study, patients taking HRT are at increased risk for thromboembolic events, which continues for weeks beyond cessation of drug treatment [47]. This observation may, in part, explain the increased risk of peripheral arterial events noted in the WHI studies [50,52]. Therefore, the authors felt it may not be unreasonable to stop oral HRT 4–6 weeks prior to endovascular or surgical revascularization, particularly in patients with PAD who have additional risk factors for venous thromboembolism [44,47].
In summary, although an association between PAD and CRP has been noted in the literature, use of inflammatory markers as diagnostic or prognostic criteria is not standard of care. Traditional risk factors for PAD such as dyslipidemia, hypertension, diabetes and smoking are similar in prevalence among men and women with PAD. Because women with PAD are more likely to be asymptomatic and less likely to have associated non-PAD atherosclerotic disease, women may be less likely to receive aggressive treatment for these risk factors (see presentation and treatment). Since most women with PAD are postmenopausal, patients should be counseled that HRT is unlikely to provide protection against development of PAD, especially in the short term, and may place patients at risk for poor procedural outcomes.
Presentation of PAD
The prevailing characteristic of PAD is a narrowing or stenosis in one or more arteries in the pelvis or lower extremities, resulting in decreased blood flow and oxygen to the tissues, including the muscles. There is variability in the presentation of PAD depending on the extent of the disease, and severity is commonly categorized using the Fontaine or Rutherford Classification (Tables 3 & 4). Patients typically present with intermittent claudication, which corresponds to Fontaine Class II or Rutherford Grade I (category 1-3). If the narrowing progresses, patients may develop CLI, which is characterized by pain at rest without exertion and/or tissue loss, including nonhealing wounds and ulcers (Figure 1). Patients with CLI are classified as Fontaine Class III or IV or Rutherford Grade II or III (category 4-6).
Fontaine classification of peripheral arterial disease severity.
Rutherford classification of peripheral arterial disease severity.
According to the ACC/AHA 2005 Practice Guidelines for the management of patients with PAD, less than 10% of patients diagnosed with PAD will present with intermittent claudication [3,6]. Approximately 50% of patients will present with pain symptoms that are not typical of PAD and the remaining 40% will be asymptomatic. Some studies have indicated that asymptomatic disease may be even more common in women than in men [6,16,18,22,28,55,56]. There is some variation in the prevalence of symptoms in different populations of women. In a study by McDermott et al. of a population of elderly disabled women, as many as two-thirds of patients were asymptomatic [28]. A Swedish study by Sigvant et al. found that, although women with PAD were more likely to be asymptomatic than men (12.9 vs 9.4% respectively; p = 0.03), a larger proportion of women had symptoms of intermittent claudication when compared with Dutch and American cohorts [8,25,56]. Possibly, the increased prevalence of asymptomatic disease in women is related to activity level. In a recent study by McDermott et al. of lower extremity function in asymptomatic women with PAD, the authors found a linear relationship between presence of exertional leg symptoms and severity of disease as measured by the ankle-brachial index (ABI), but only among patients who walked more than four blocks per week. This linear relationship was not noted among women who were less active and walked less than four blocks per week [37]. In addition, women may present with more atypical symptoms that can be attributed to other comorbidities such as spinal stenosis [19]. Since a large proportion of patients are diagnosed by primary care providers who utilize history more frequently than noninvasive testing with ABI, it is advisable to ask about activity level in screening patients with suspected PAD to determine whether lack of symptoms is a valuable indicator of disease presence.
Decreased detection and subsequent intervention may then result in a higher proportion of women with severe disease and CLI [8,17,22,57–59]. Feinglass et al. found that women who were referred to a noninvasive vascular laboratory with suspected PAD were more likely to have severe disease as measured by ABI compared with men [21]. Although patients with CLI represent a relatively small percentage of all patients with PAD, they require a disproportionate amount of resources for treatment as CLI inevitably requires procedural intervention. In addition, according to Brevetti et al., women referred to a vascular laboratory were less likely to present with intermittent claudication, but more likely to present with Fontaine's stage III or IV disease as compared with men (13.2 vs 4.3%; p = 0.018) [22]. More severe disease also indicates decreased likelihood of revascularization and increased chance the procedural intervention will involve amputation. According to the Factores de Riesgo y Enfermedad Arterial (FRENA) registry, patients who present with Fontaine's Class III and IV have a 12 and 19% incidence of amputation, respectively, and amputation, especially above-the-knee amputation, is associated with increased morbidity and mortality [22,42]
Women may not only be more likely to present with further advanced disease, but may also have worse baseline lower extremity function and quality of life compared with men. In a study by Collins et al. of 403 patients, women with PAD had significantly impaired walking distance and speed compared with women without PAD. This difference was not observed in men with and without PAD [11]. Similar findings were noted in a separate study by McDermott et al. in 2003. In this study, performance measures such as walking speed and distance, measurement of daily physical activity, and a summary performance score were measured in 273 men and women with PAD. Although the disease severity as measured by the ABI was similar in men as compared with women, women had greater impairment in lower extremity function and strength, even when adjusted for potentially confounding comorbidities such as spinal stenosis [19]. The authors suggested that lower extremity impairment may correlate with leg strength and that leg strengthening exercises may be beneficial for patients with PAD. The question remains, however, whether decreased lower extremity function in women with PAD correlates with worse outcomes.
Studies have failed to demonstrate that decreased lower extremity function in patients with PAD is correlated with poor clinical outcomes such as increased risk of fall; however, there does appear to be a correlation between walking ability and decreased quality of life [21,60,61]. The decreased quality of life among patients with PAD may even be more prevalent among women with PAD when compared with men of similar functional status [62,63]. In a study by Oka et al. of men and women with at least Fontaine's Class II PAD, women reported decreased quality of life, which could be attributed to increased reports of bodily pain and mood disturbance as compared with men. The authors asserted that these differences were most likely attributed to gender since the results were found in spite of similar age, disease severity, and an increased prevalence of associated comorbidities in the male patients, all of which can adversely affect quality of life [62]. Exercise in patients with PAD may not only reduce associated risk factors and decrease cardiovascular events; it may also improve quality of life associated with decreased lower extremity function. A recent randomized controlled trial by McDermott et al. demonstrated that supervised exercise training and resistance training not only improved walking and stair climbing ability, but also improved quality of life [64]. Analysis by gender, however, was not performed in this study.
Diagnosis of PAD
Although PAD can be detected by screening questionnaires for the presence of symptoms, since most patients with PAD are asymptomatic, use of more objective noninvasive testing is warranted if patients are considered at risk for PAD based on risk factors and comorbidities. The WHO/Rose Claudication questionnaire has a high specificity of80-90%, but a relatively poor sensitivity of 50–60% for detecting PAD [14,25].
In fact, several studies support the finding that utilizing presence of symptoms alone to diagnose PAD results in a high rate of false-negatives [9,16]. In a study of Chinese patients by He et al., the prevalence of PAD was 11.9% when detected using the Rose Questionnaire alone and 16% when ABI less than 0.9 was utilized. A combination of the two methods increased the prevalence to 20.7% [16]. Therefore, while history and physical assessment are invaluable in assessing overall cardiovascular risk and presence of PAD, objective testing is invaluable to adequate diagnosis.
The most commonly utilized diagnostic screening test is the ABI, which is a ratio of the systolic blood pressure at the ankle as compared with the arm (also known as the arm–ankle index). Standard measurement of the ABI is described in The Inter-Society Consensus for the Management of PAD (TASC II) document [7]. A normal ABI is 1.0-1.29, a borderline (equivocal) ABI is 0.91-0.99, mild-to-moderate PAD is an ABI 0.41-0.9 and severe PAD is an ABI less than 0.4. The TASC II document states that an ABI less than 0.9 has a greater than 90% sensitivity and 95% specificity for detecting angiogram-positive PAD [3]. ABI can be falsely elevated (>1.5) in patients with incompressible arteries, as seen in diabetic patients, and is an indication of medial artery calcification. These patients are typically excluded from most analyses. In patients who have intermittent claudication but a normal resting ABI, addition of exercise testing to the ABI measurement with either a treadmill or heel raises, may improve the sensitivity [65,66]. In a study of 396 patients referred to a vascular laboratory for symptoms of PAD, including intermittent claudication, rest pain and ulceration, 46.2% had an ABI higher than 0.9 at rest. Of these patients who subsequently underwent exercise testing, the ABI fell below 0.9 in 31% after walking 5 min on a treadmill at 12% grade for 2.0 mph [65]. Thus, ABI is an easy and reliable objective tool for PAD diagnosis and significantly improves PAD detection over history and physical alone.
Although an ABI cut-off of 0.9 is typically used to determine presence of PAD in both men and women, some studies have noted that, even in healthy women, the ABI may be lower than in men [2,18]. Based on this observation, the authors in the MESA study recalculated prevalence of PAD in women using a new, lower ABI of 0.88 as a cut-off. With this diagnostic criterion, the PAD prevalence in women decreased from 3.5 to 2.2% and the women/men ratio inverted from 1. 25 to 0.79. Therefore, the authors concluded that the standard PAD definition of 0.9 may overestimate the prevalence of PAD in non-Hispanic white women by 37% and black women by 36% [2]. The decreased ABI in women may be secondary to smaller artery size [67] or to an association between ABI and height [27,68,69]. In the Atherosclerosis Risk in Communities (ARIC) study, when ABI values were adjusted for height, the difference between the average ABI for men and women was reduced and the difference in prevalence between men and women disappeared [27]. However, despite these potential differences and considering the standard error for ABI of 0.1-0.15, a vast majority of studies utilize an ABI of less than 0.9 for diagnosis of PAD [3].
The ABI has been demonstrated to correlate with severity of PAD [6,21]. An ABI less than 0.5 is associated with increased risk of progression to CLI within 6.5 years and an ABI less than 0.4 is associated with the presence of rest pain or tissue loss [3]. A lower ABI is also associated with increased mortality [70]. A recent study by the Prevalence of PAD in Patients with Acute Coronary Syndrome Registry of 1101 patients with acute coronary syndrome demonstrated that an ABI of less than 0.9 was not only associated with increased prevalence of risk factors such as diabetes and stroke, but was also associated with higher mortality and development of heart failure (2.3 vs 0.2% in patients with ABI >0.9; p < 0.01) [71]. A review of epidemiologic studies by McDermott et al. in patients without coronary heart disease indicated that the ABI may be helpful in calculating the risk of cardiovascular events using the Framingham risk score. The Framingham risk score is likely to underestimate risk in women placed in a low-risk category; however, inclusion of the ABI in calculation of the risk score in women increased the Framingham risk score category in approximately one in three individuals if the patient had an abnormal ABI [72]. Therefore, determination of ABI is not only important in determining presence of PAD, but can be a valuable indicator of overall cardiovascular morbidity and mortality.
Use of computed tomography (CT) or magnetic resonance (MR) angiography is usually reserved for patients who have a diagnosis of PAD to determine level and extent of disease and whether patients are candidates for revascularization. MR is sensitive (90-94%) and specific (90-94%), and assists in surgical planning, but it is not practical for screening purposes because MR is expensive, time consuming, requires access to special equipment, and requires exposure to a contrast agent that may not be practical for the patient [6]. Contrast angiography is the gold standard for the diagnosis of PAD and is usually only performed when considering revascularization in a patient as it is invasive and has associated risks of contrast exposure.
Treatment & outcomes
Treatment of PAD includes a combination of risk factor reduction, pharmacologic intervention and revascularization when indicated. Reduction of risk factors should include smoking cessation as well as appropriate treatment of associated comorbidities such as hypertension, diabetes and dyslipidemia since pharmacologic intervention for these conditions has been shown to decrease morbidity and mortality in patients with PAD [44]. For example, antihypertensive therapy, specifically with angiotensinconverting enzyme (ACE) inhibitors, reduces risk of cardiovascular events in patients with PAD [73]. In addition, statin use in women in the HERS trial also lowered overall risk of myocardial infarction and coronary heart disease and appeared to abrogate some of the negative effects of HRT, especially at earlier time points [74]. The role of antiplatelet agents in the prevention of cardiovascular events for PAD is less clear. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) steering committee conducted a randomized trial in 1996 of almost 20,000 patients, including 6452 patients with PAD randomized to clopidogrel or aspirin for almost 2 years. In symptomatic patients with PAD, clopidogrel provided a relative risk reduction from stroke, myocardial infarction or vascular death of 24% over the aspirin-alone group [75]. A more recent meta-analysis by Berger et al. that examined randomized, controlled trials of aspirin use in patients with PAD, found that aspirin alone or in combination with dipyridamole significantly reduced the risk of nonfatal stroke (RR: 0.66; 95% CI: 0.47-0.94) but did not decrease the risk of cardiovascular events, which was the primary outcome measure, or of nonfatal myocardial infarction, cardiovascular mortality or all-cause mortality [76]. The most recent TASC II recommendations indicate that antiplatelet therapy, specifically aspirin, is recommended in PAD patients, but the evidence only supports its use conclusively in patients with concomitant CVD such as CAD and cerebrovascular disease [7]. While the recommendations for prevention and treatment do not vary based on sex, patients with PAD, and in particular women, may be less likely to receive the recommended therapy.
Compared to PAD patients with concomitant CAD, PAD patients without a documented diagnosis of CAD are less likely to receive treatment with either statins, ACE inhibitors or antiplatelet agents [57,77]. In the American Vascular Association Screening Program of 2446 people, 9% of patients were diagnosed with PAD and less than half of these patients (47%) were receiving the appropriate antiplatelet or lipid-lowering agents. Compared to men, women were even less likely to receive the appropriate treatment. Of the women, 40% versus 58% of men were prescribed antiplatelet agents (p = 0.0067) and only 63% of women were taking lipid-lowering agents compared with 87% of men (p = 0.0062) [57]. A recent study by Sigvant et al. in a Swedish population also found that women with PAD were less likely to receive the appropriate pharmacologic risk modification. Compared with women, men had an odds ratio of 1.3 (range: 1. 1–1.5) for lipid-lowering therapy, 1.3 (1.1-1.8) for β-blockers or ACE-inhibitors, and 1.6 (1.3-2.1) for antiplatelet therapy [41]. Poor risk modification can then place patients at risk for disease progression and need for revascularization.
For patients with intermittent claudication, additional treatment should include an exercise program. Studies have demonstrated that adherence to a strict exercise program can increase the pain-free walking distance in patients with PAD [78]. In addition, pharmacologic intervention for symptomatic relief may be prescribed. There is some evidence to suggest that in patients with intermittent claudication, statins such as simvastatin and atorvastatin may provide some symptomatic relief by increasing pain-free walking distance and speed, respectively [79,80]. Additional medications with evidence for treatment of symptomatic PAD include cilostazol, naftidrofuryl and carnitine. Of these three, cilostizol is a phosphodiesterase III inhibitor, is US FDA-approved, and has the most evidence to support its use for treatment of intermittent claudication. It has been studied in multiple, randomized, controlled trials, provides improved peak treadmill performance and quality of life and is recommended as the first-line pharmacologic therapy for intermittent claudication [7,81]. In patients who present with more advanced disease or experience disease progression, revascularization may be indicated.
Indications for procedural intervention include CLI as characterized by rest pain and/or ulceration or symptoms of intermittent claudication that are disabling or lifestyle limiting. An increased prevalence of asymptomatic disease in women or bias towards impairment in activities outside the home may influence whether revascularization is considered in women. In a review of patients referred to a noninvasive vascular laboratory, Feinglass et al. found that, among patients with limb salvage indications, men had a higher procedure rate compared with women (p = 0.03). When controlled for potentially confounding factors, men were still twice as likely to be selected for a procedure than women (p = 0.009) [21]. However, a recent review of patients referred to the noninvasive vascular laboratory at this same institution indicates that this gender bias has been corrected since the previous study [AMARANTO D, NORTHWESTERN UNIVERSITY, IN PRESS].
Women who undergo lower extremity revascularization tend to be older and have more severe disease when compared with men, and these factors could adversely affect procedure outcomes [82,83]. In a review of 5880 procedural outcomes in patients from Albany, Canada, men were more likely to undergo procedures for intermittent claudication (12.6 vs 8.3% for women; p < 0.01) and women were more likely to have limb salvage as an indication for revascularization (89.8 vs 81.0% for men; p < 0.01) [82]. However, graft patency in this study was equivalent between men and women. This is in contrast to findings by Ahchong et al. in an analysis of 211 infrainguinal bypass procedures in Chinese patients. In this study, women were found to have smaller infrapopliteal outflow arteries compared with men (median 2.01 vs 2.45 mm in men; p = 0.03) as well as smaller caliber vein conduits [84]. Accordingly, women had decreased primary graft patency at 3 years compared with men (33 vs 49%; p = 0.03) and the authors postulated that the smaller outflow arterial size and/or conduit may have contributed to the lower patency rates. It may be that small outflow arteries are associated with higher outflow resistance. Ascer et al. reported that 1-year patency and limb salvage rates correlated with outflow resistance [85]. Lastly, mortality was not significantly different between men and women in the studies that have addressed outcomes based on gender, but postoperative wound complications may be higher in women following revascularization [82,86,87].
A recent retrospective review of 1400 patients in the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) undergoing vein bypass grafting for CLI found that 39% of patients presented with wound complications defined as infection, necrosis, hematoma/hemorrhage, or seroma/lymphocele at the surgical incision or harvest site within 30 days [87]. In addition to oral anticoagulation use, female gender was the only other independent risk factor for a wound complication with an odds ratio of 1.376 (95% CI: 1.076-1.757; p = 0.0108). Wound complications were not associated with decreased graft patency but the presence of a wound complication did increase risk of limb loss and mortality. Other authors have suggested that diabetes places women at higher risk for complications when compared with men with diabetes [88,89]. These authors suggested that distribution and amount of body fat or hormonal factors may have attributed to the increased risk in women, although they were unable to quantify these variables [87].
Conclusion
The elderly is the largest growing population subgroup in the USA and far exceeds the growth rate of the population as a whole. Within the elderly, the ratio of women to men is high and continues to increase in the oldest elderly age group (82 males per 100 females in ages 65–69 years and only 26 males per 100 females for persons aged 95–99 years). As a result, morbidity from diseases such as PAD, which are more common in the elderly, will become increasingly common in women. Knowledge of the increased prevalence of PAD among elderly women and the pervasiveness of asymptomatic disease should prompt increased screening using ABI among patients with known risk factors. Improved detection and aggressive risk factor modification, including a discussion of HRT and its potential harmful effects on peripheral vascular events and procedural outcomes, will hopefully reduce the incidence of women who present with more advanced PAD, resulting in decreased morbidity and mortality.
Executive summary
Peripheral arterial disease (PAD) increases with age in both men and women. However, this increase in prevalence may be more significant in women so that, in the oldest elderly, PAD is more common in women than in men.
Bias of healthcare providers or difference in presentation of PAD between men and women may contribute to oversampling of men in PAD studies and affect reports of gender-based prevalence.
Traditional risk factors for PAD are similar to risk factors for atherosclerosis and include hypertension, diabetes, dyslipidemia and smoking.
Women with PAD may be less likely to have associated atherosclerotic disease such as coronary artery and cerebrovascular disease than men. Therefore, emphasis should be placed on screening for PAD among women with nonatherosclerotic comorbidities and general risk factors for cardiovascular disease.
Although hormone-replacement therapy does not appear to increase the incidence of PAD among women, it may contribute to worse procedural outcomes by increasing the inflammatory profile and risk of thrombosis. Some authors recommend discontinuation of HRT for 4–6 weeks prior to revascularization, particularly in patients who are predisposed to thrombosis.
Compared to men, women are more likely to present with asymptomatic PAD.
Increased prevalence of asymptomatic PAD in women may contribute to more advanced disease and critical limb ischemia at the time of diagnosis.
Women with PAD appear to have worse lower extremity function than men, which may contribute to worse quality of life.
Because women are less likely to have typical symptoms of PAD such as claudication, screening for PAD should include measurement of ankle-brachial index (ABI) in addition to history, physical examination and/or questionnaire.
An ABI of less than 0.9 meets diagnostic criteria for PAD and the ABI measurement tends to correlate with severity of disease.
Imaging such as computed tomography or magnetic resonance imaging or invasive tests such as angiography are useful in quantifying the extent of disease and are generally reserved for operative planning.
Treatment of PAD includes both pharmacologic intervention and, when indicated, procedural intervention. In addition, patients with PAD should undergo risk factor modification, including a smoking cessation program if applicable and a supervised exercise program.
Decreased prevalence of associated coronary artery disease in women with PAD may contribute to less aggressive management of risk factors and comorbidities and result in progression of PAD.
Although overall graft patency and mortality are equivalent in men and women following revascularization, decreased artery caliber in women can increase risk of graft failure and women may have a higher incidence of postoperative wound infections.
Footnotes
CME Author
Charles P Vega, MD
Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.
Ashley K Vavra, MD
Division of Vascular Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
Disclosure: Ashley K Vavra, MD, has disclosed no relevant financial relationships.
Melina R Kibbe, MD
Northwestern University, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois Disclosure: Melina R Kibbe, MD, has disclosed no relevant financial relationships.
Women and peripheral arterial disease
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