Peripheral Arterial Disease in Women: an Overview of Risk Factor Profile, Clinical Features, and Outcomes

Purpose of Review Peripheral arterial disease (PAD) is the third most common manifestation of cardiovascular disease (CVD), following coronary artery disease (CAD) and stroke. PAD remains underdiagnosed and under-treated in women. Recent Findings Women with PAD experience more atypical symptoms and poorer overall health status. The prevalence of PAD in women increases with age, such that more women than men have PAD after the age of 40 years. There is under-representation of PAD patients in clinical trials in general and women in particular. In this article, we address the lack of women participants in PAD trials. We then present a comprehensive overview of the epidemiology/risk factor profile, clinical features, treatment, and outcomes. Summary PAD is prevalent in women and its global burden is on the rise despite a decline in global age-standardized death rate from CVD. The importance of this issue has been underlined by the American Heart Association’s (AHA) “Call to Action” scientific statement on PAD in women. Large-scale campaigns are needed to increase awareness among physicians and the general public. Furthermore, effective treatment strategies must be implemented.


Background
Peripheral arterial disease (PAD) remains a significant health concern across the globe. As of 2010, more than 200 million people worldwide are living with PAD, representing a 29% increased prevalence in low-middle income countries and 13% increase in high income countries [1,2]. In the USA alone, PAD affects 8 million Americans aged > 40 years [3]. In the Reduction of Atherothrombosis for Continued Health (REACH) Registry, the cumulative end point of major cardiovascular events, vascular interventions, and hospitalization was significantly higher in patients with PAD than patients with coronary artery disease (CAD) [4]. PAD is associated with equal morbidity and mortality and economic costs as CAD and ischemic stroke [5,6]. In a scientific statement on Women and PAD from the AHA in 2012 [7], Hirsch et al. noted the increased prevalence of PAD in adults ≥ 40 years of age, and highlighted the need for raising clinical awareness, focused treatment plans, and expanding research on PAD in women. Women have higher rates of asymptomatic/ subclinical disease and the majority have atypical symptoms. They also have a poorer overall health status. Women with PAD suffer more from depression compared to women without PAD [8-15, 16•].
Overall, there is limited recruitment of patients with PAD in cardiovascular trials, especially women, minorities, and the elderly [17•]. For the purpose of this review, we will focus on the different aspects of PAD in women including data on representation in research studies, epidemiology, clinical features, and outcomes.

Representation of Women in PAD Studies
Sex differences in PAD have been reported not only in prevalence, diagnosis, and clinical presentation but also in outcomes. Women continue to have variable enrollment in studies on PAD (Table 1 and Fig. 1). In more than half of these studies, women comprise < 35% of the whole study population. In the Nation Wide inpatient sample of patients with PAD, women comprised 41% of the study population. However, in randomized control trials (RCT) of vascular surgery, women represented only 22% [18]. In a systematic review of cardiovascular trials, which collectively enrolled 412,048 patients, only 27% of the total population were women [17•]. While enrollment of women has increased overall in clinical trials, it continues to lag behind their overall representation in this disease [19•].

Epidemiology and Risk Factors
Women with PAD present on average 10-20 years later than men [20]. Around 20-30% of women aged 70 years or older are affected by PAD [21,22]. This is hypothesized to be secondary to the loss of the vascular protective effects of estrogen which promotes vasodilation and has anti-oxidative effects. In a study of > 370,000 surgical inpatients with PAD, Vouyouka et al. found that women were more likely to be older, obese, and black [23•]. Overall risk factors for PAD remain similar among men and women, including smoking, age, diabetes mellitus, hypertension, and dyslipidemia [3]. Diabetes and hyperlipidemia have been shown to increase the risk of intermittent claudication by fourfold in women [24,25]. Importantly, ethnic differences have been shown to affect the prevalence of PAD as well, with the highest prevalence of PAD among non-Hispanic black women over the age of 70 (25%) [26•]. Other studies have shown association between obesity [27], levels of C-reactive protein (CRP) [28,29], osteopenia/osteoporosis [30,31], hypothyroidism, and PAD. In the Multiethnic Study of Atherosclerosis (MESA) [29], women had higher levels of CRP than men, after adjustment for comorbidities, hormonal status, and age. Conflicting data has emerged for the association between hormone replacement therapy and PAD in women. In the Women Health Initiative (WHI) and Heart and Estrogen/Progestin replacement (HERS) studies, no benefit was observed from HRT use for PAD or CAD. Conversely, the Rotterdam study showed a 52% decreased risk of PAD in women who used HRT for > 1 year [32][33][34]. Interestingly, vascular complications associated with pregnancy have also been associated with an increased risk of PAD. The Cardiovascular Health After Maternal Placental Syndrome (CHAMPS) study showed a threefold increased risk of PAD and twofold increased risk of coronary artery and cerebrovascular disease in patients with maternal placental syndromes, including pre-eclampsia, gestational hypertension, placental abruption, and placental infarction [35]. The mechanisms for this association are unclear, although one likely hypothesis is underlying endothelial dysfunction.
The treatment of risk factors varies by gender. In the REACH registry [4], consisting of > 68,000 outpatients, risk factor control was less frequently observed in patients with diagnosis of PAD. Optimal risk factor control was twice as likely for men than women despite a higher incidence of diabetes, hypertension, and elevated total cholesterol in women.

Symptoms
Both men and women present with typical, atypical, or asymptomatic PAD. Studies have shown that the majority of PAD patients do not have typical claudication [11,36]. Asymptomatic disease is defined as absence of exertional leg symptoms in the presence of an ankle-brachial index (ABI) < 0.90, while atypical symptoms are defined by leg symptoms present at rest and exercise [37,38]. In the Women Health and Aging study (WHAS), of the 933 women enrolled, 35% (n = 328) had an ABI of 0.90; of these, 328 patients (63%) had no exertional leg symptoms [39]. Importantly, asymptomatic PAD has been shown to be more common in women than in men (13 vs 9%; p < 0.03) [40]. When symptomatic, women seek medical attention with more complex (multilevel) and severe disease including critical limb ischemia (CLI) [16•, 40, 41]. In patients with CLI, women had a twofold higher incidence of femoropopliteal disease compared to men [42]. This finding was reproduced in another patient cohort undergoing angioplasty that showed pronounced femoropopliteal disease in women while men had more below-the-knee disease [43]. Additionally, women have greater lower extremity functional impairment [8], with shorter treadmill distance to intermittent claudication [44], shorter maximal treadmill walking distance [8,44], and poorer quality of life scores compared to men [45]. Other studies have demonstrated a higher prevalence of asymptomatic disease in women, which may lead to a late presentation, thus contributing to severe disease or CLI [41].

Treatment
The principle components of PAD treatment consist of supervised exercise therapy, pharmacological treatment, and lower extremity revascularization. Patients with PAD are less likely to receive guideline-directed medical therapy (GDMT) than are patients with other forms of cardiovascular disease, including CAD [46][47][48]. For example, in one study on secondary prevention of PAD, statin use was reported in only 31%, angiotensin- converting enzyme inhibitor use in 25%, and aspirin use in 36% [48]. Data also exists on suboptimal use of systemic vascular treatment or lack of adherence to standard therapy. In the NHANES study, only 24-34% adherence to preventive therapy was reported [48]. CHAMPS study cited similar suboptimal use of GDMT but was particularly notable for lower rates in women and older patients [31]. In terms of intensity of treatment with standard pharmacologic agents, men were more likely to receive all agents (antiplatelets, statins, and angiotensin enzyme inhibitors) than women (22.4 vs 18.2%) [31]. This finding was reproduced in another study from Quebec which showed that men were more likely to receive statins, antiplatelet agents, and angiotensin-converting enzyme inhibitors than women (22.4 vs 18.2%, p < 0.001) [31]. Patients with PAD experience a profound limitation in exercise performance. There is evidence of a well-established benefit following a typical 12-week exercise training program [49,50]. Lower extremity exercise training has been shown to increase time to claudication, increase distance before claudication, and increase overall walking distance [51]. Unfortunately, women with PAD have been shown to be less responsive to exercise rehabilitation programs [52], particularly diabetic women. This may partly be due to a greater impairment in calf muscle oxygen saturation during and following exercise [53]. Gardner et al. reported that improvements in absolute walking distance were significantly less for women than men after 1 year of standard exercise therapy. Women also reported less subjective improvement on walking impairment questionnaire domains [54]. These differences have been attributed to lower hemoglobin saturation during ambulation [53], poorer leg strength [55], higher inflammation, higher level of oxidative stress, and insulin resistance [53].
Endovascular revascularization and open bypass surgery are two strategies for disabling claudication after failure of medical therapy or for those with CLI. Although the choice of procedure depends on many lesion characteristics including lesion site [56,57], the 2016 AHA/ACC Guidelines recommend an endovascular approach first for both lifestyle limiting claudication and CLI. While data has been equivocal, sex differences have also been reported in lower extremity endovascular versus bypass treatment. Using 69 million discharge records from the Nationwide Inpatient Sample from 1998 to 2006, Roe et al. reported discrepancies in the proportion of endovascular procedures being performed in women compared to men. Women were less likely to undergo amputation or open vascular surgery than men. Women, however, were more likely to undergo an endovascular procedure during hospitalization [58,59]. Several possible reasons have been cited for lower bypass rates, including the observation that women with PAD are generally older with more advanced disease, comorbidities, and may have smaller vessel size precluding bypass.

Carotid Artery Stenosis and Management
Women have a greater risk of disabling stroke (58 vs 48%) and stroke-related mortality (20 vs 14%) [60]. Strokerelated mortality has not changed over the past 50 years in women and is attributed to older age at onset of stroke among women [60]. Multiple trials have demonstrated a reduction in the risk of stroke in select patients with symptomatic internal carotid artery disease and to a lesser extent, in those with asymptomatic carotid artery disease [61][62][63]. However, it is noteworthy that women comprised only 28-34% of enrolled patients in these trials. In an analysis of the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and ACAS trial, 30-day risk for death was higher in women than in men (2.3 vs 0.8%, p = 0.002), owing to higher risk of fatal stroke [64]. Both men and women benefited from carotid endarterectomy (CEA) for stroke prevention. However, in another study, the risk of stroke or death within 30 days after CEA in symptomatic patients was greater in women (8.7%) vs men (6.8%) [65], a finding which was reproduced in a systematic review of 36 studies [66]. However, other studies have shown no significant difference in complications and mortality following CEA [67,68]. Regarding carotid artery stenting, women have worse outcomes, including higher rates of in-hospital mortality and stroke [69]. Risk of stroke or mortality was 1.7-fold higher in symptomatic women and 3.4-fold higher in asymptomatic women with carotid artery stenosis (CAS) compared to CEA. Asymptomatic women experienced worse outcomes compared to men, with higher stroke rates after CEA and higher myocardial infarction rates after both CEA and CAS [70].

Quality of Life
Quality of life scores have become an important tool to assess treatment effectiveness in the general population. Multiple studies have shown worse health status and health-related quality of life in women when compared with men suffering from PAD [10,12,13]. In addition, functional status has been determined to be significantly lower for women [45]. This was associated with greater mood disturbances [12]. Female gender has been adversely associated with durability of the revascularization or the quality of life following revascularization for claudication or CLI [71]. In a longitudinal study of a large PAD population, women with PAD were found to have compromised health status both at diagnosis and 12 months after follow-up. The mechanism for poor health status in these women was thought to be associated with lower education and lack of social support (women were less likely to have a partner) [72].

Outcomes/Prognosis
Outcome trials of endovascular or surgical revascularization in men and women have reported conflicting results. Several studies have reported an unfavorable impact of sex on outcomes after peripheral revascularization procedures Women tend to have higher perioperative mortality whether undergoing surgical or endovascular procedures [73,74]. Furthermore, they have inferior patency rates after surgical revascularization [75][76][77], higher risk of stent thrombosis with endovascular revascularization [77], wound complications [78], and bleeding events [23•]. On the other hand, multiple other studies, including some systematic reviews, have found no sex difference in patency rates and amputation-free survival [79][80][81].
PAD is associated with increased risk of CVD mortality and morbidity. A low ABI (≤ 0.9) is associated with a threefold increased risk of all-cause mortality and cardiovascular mortality in both men and women [82]. Women with PAD have a two-to fourfold increased risk of cardiovascular mortality and morbidity compared to women without PAD [15].
Compared to men, women are more likely to be admitted for acute myocardial infarction [83], more likely to be admitted emergently with longer hospital stays and more likely to require rehabilitation or nursing home care [16•, 59, 84]. Similarly, women with CLI have higher in-hospital mortality after both endovascular treatments and open surgery [85].

Conclusions
PAD remains a major healthcare problem. It remains underdiagnosed and understudied in women. The major challenge in PAD treatment in women is their late presentation and the higher prevalence of asymptomatic disease which may lead to more advanced disease at presentation and a higher risk of adverse events and mortality. Concerted research efforts should be carried out to further determine the effects of sex on different aspects of PAD including risk factors, clinical burden, treatment, and outcomes. In addition, campaigns to raise awareness among clinicians and the general public should be undertaken. Efforts along the lines of the "National Wear Red Day" campaign by the AHA should be pursued aggressively to increase awareness.

Compliance with Ethical Standards
Conflict of Interest Qurat-ul-ain Jelani, Mikhail Petrov, Sara C. Martinez, Lene Holmvang, Khaled Al-Shaibi, and Mirvat Alasnag declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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