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Associations Between Peripheral Artery Disease and Ischemic Stroke

Implications for Primary and Secondary Prevention
Originally published5 Aug 2010https://doi.org/10.1161/STROKEAHA.110.582627Stroke. 2010;41:2102–2107

Abstract

Background and Purpose—Although peripheral artery disease (PAD) has a particularly poor prognosis compared with vascular disease in other territories, little attention is paid to its epidemiology, treatment, and prevention. Despite the high prevalence of PAD in patients with stroke, and of stroke in patients with PAD, PAD is omitted from all guidelines for treatment, prevention, and rehabilitation of stroke, although coronary artery disease risk is considered. Therefore, routine PAD screening is seldom undertaken and so disease is probably often missed.

Summary of Review—This review evaluates epidemiology of PAD in patients with stroke and of stroke in patients with PAD. The role of the ankle–brachial pressure index; imaging and novel markers in risk prediction of PAD in patients with stroke; and treatment and prevention of PAD are reviewed.

Conclusions—In both primary and secondary prevention settings, PAD indicates a high risk of future events. Data on which additional preventive measures are beneficial in this patient group are lacking, but the presence of PAD does have implications for current management in both primary and secondary prevention of stroke.

Vascular disease is the leading cause of death globally.1 Vascular disease in 1 arterial territory strongly predicts disease in other territories,2 and disease in other territories increases risk of vascular events in patients with prior stroke/transient ischemic attack (TIA), particularly the long-term risk of events due to coronary artery disease (CAD).3 Of the 3 major vascular beds (coronary, cerebral, and peripheral), the epidemiology, prognosis, pathophysiology, treatment, and prevention of peripheral artery disease (PAD) are least studied.

Despite the high risk of PAD in patients with stroke,4 and of stroke in patients with PAD,5 consideration of PAD is omitted from guidelines for treatment, prevention, and rehabilitation of stroke, and there is also scant mention of CAD.6,7 Routine PAD screening is seldom undertaken and disease is probably often missed. This review evaluates the epidemiology of PAD in patients with stroke and of stroke in patients with PAD. The role of the ankle–brachial index (ABI) and imaging in PAD risk prediction in patients with stroke and treatment and prevention of PAD are reviewed. Although this review is restricted to PAD in the lower limbs, the conclusions may well be pertinent to atherosclerosis of the aorta.

Comparative Epidemiology of PAD Versus Other Arterial Territories

PAD includes asymptomatic disease (defined by an ABI ≤0.9), intermittent claudication, and acute PAD events (acute limb ischemia and critical limb ischemia). Acute limb ischemia can be viable, threatened, or irreversible.8 Critical limb ischemia includes rest pain and ulceration.9

In a survey of Scottish men and women aged 55 to 74 years, 4.5% had claudication and 9.0% had a low ABI (defined as ≤0.9).10 In a similar survey of individuals free of clinical cardiovascular disease, 10.9% had a low ABI, increasing with age, deprivation, and female sex.11 Previous studies have tended to concentrate on prevalence of asymptomatic PAD, claudication, and stable PAD.10,11–13 Unlike acute CAD and acute stroke/TIA, there are few population-based data on incidence or outcome of acute PAD events. In the Oxford Vascular Study (OXVASC), which provides reliable data on epidemiology of different acute PAD events within the same population over the same period,14 9% of all acute vascular deaths were due to acute PAD (compared with 45%, 42%, and 4% due to cerebrovascular, coronary, and unclassifiable deaths, respectively). Incidence of acute PAD events was therefore lower than for CAD and stroke/TIA (0.52, 1.91, and 2.27 per 1000 population per year, respectively), but case fatality was higher14 (Figures 1 and 2).

Figure 1. Thirty-day case-fatality rates for acute vascular events in a population-based study (OXVASC).13

Figure 2. Age-specific event rates for nonfatal acute vascular events in a population-based study (OXVASC).13

The profile of both traditional (Table) and novel15 risk factors is generally more aggressive in patients with PAD than in patients with CAD or stroke. Factors that predict PAD progression (decreasing ABI over time) include age, smoking, diabetes,16 and C-reactive protein.15 It is unclear whether the number or severity of risk factors is more important in PAD pathogenesis. Smoking increases PAD risk more than CAD or stroke/TIA risk,17 whereas diabetes has no differential effect.18

Table. Cardiovascular Risk Factors in Patients With Stroke/TIA From the OXVASC Population by the Presence of a History of PAD (Unpublished Data)
Presence of a History of PAD (n=111) Absence of a History of PAD (n=1741) P* OR (PAD Versus No PAD†; 95% CI; P)
*χ2 test.
†Adjusted for age and sex.
Hypertension 77 (69.4%) 956 (54.9%) 0.002 1.80, 1.39–2.22; P=0.006
Diabetes mellitus 30 (27.0%) 194 (11.1%) <0.0001 3.13, 2.70–3.56; P<0.0001
Hyperlipidemia 43 (38.7%) 436 (25.0%) 0.001 1.95, 1.56–2.34; P=0.001
Former smoking 58 (52.3%) 639 (37.9%) 0.001 1.70, 1.31–2.09; P=0.008
Current smoking 19 (17.1%) 220 (13.0%) 0.001 1.72, 1.19–2.25; P=0.04
Atrial fibrillation 28 (25.2%) 306 (17.6%) 0.03 1.39, 0.94–1.84; P=0.15
Cardiac failure 23 (20.7%) 153 (8.8%) <0.0001 2.49, 2.00–2.96; P<0.0001

Additional Risks Associated With PAD in Patients With Stroke

The REduction of Atherothrombosis for Continued Health (REACH) registry included 2-year follow-up of subjects with multiple risk factors and/or existing vascular disease. Forty-one percent of patients with stroke/TIA had disease in other territories (30% CAD, 5% PAD, and 6% both CAD and PAD).6 Overall, event rates for stroke, myocardial infarction and cardiovascular death were higher for patients with stroke/TIA and PAD than for patients with stroke/TIA and CAD.19 Twenty-two percent of patients with stroke/TIA with symptomatic PAD had a vascular event or hospitalization at 1 year versus 13% of patients with stroke/TIA without symptomatic PAD.20

However, the REACH registry underestimated stroke/TIA with concomitant PAD, because it only included symptomatic disease.21 Among patients with stroke/TIA, 51% in the Systemic Risk Score Evaluation in Ischemic Stroke Patients (SCALA) study and 33.5% in the Polyvascular ATHerothrombosis Observational Study (PATHOS) had a low ABI, whereas only 10% had PAD symptoms.22,23 Asymptomatic PAD has similar comorbidity, risk factor profile, and mortality as symptomatic PAD.5,24

Risk of Stroke in Patients With PAD

Asymptomatic and symptomatic patients with PAD have increased stroke/TIA risk compared with patients without PAD25 and compared with patients with CAD and patients with stroke/TIA in some studies19 independent of traditional risk factors. Moreover, progressive PAD (decline in ABI ≥0.15 over 5 years) is associated with increased stroke risk26 compared with stable PAD.

In asymptomatic individuals in the REACH registry, prior stroke, prior PAD, hyperglycemia, and hypercholesterolemia were significant stroke predictors at 1 year.27 In a Chinese study, 25% of patients with PAD had ≥70% asymptomatic carotid stenosis compared with 11% of patients with CAD,28 suggesting PAD as a stronger predictor of concurrent stroke risk than CAD. In addition, carotid stenosis is more prevalent in asymptomatic patients with PAD than patients with a normal ABI.29 Compared with symptomatic unilateral carotid stenosis, symptomatic bilateral carotid stenosis was associated with nonstroke vascular death (hazard ratio=2.0; 1.5 to 2.6) and prior PAD (OR=1.5; 1.2 to 2.0) in the European Carotid Surgery Trial, again reflecting systemic disease burden.30 Therefore, asymptomatic and symptomatic PAD increase stroke/TIA risk is associated with asymptomatic carotid stenosis.

In addition, data from OXVASC show that the presence of PAD is associated with increasing severity of cerebrovascular events with a history of PAD being reported in 29 of 492 (5.9%) patients with TIA, 44 of 492 (8.9%) patients with minor ischemic stroke, and 28 of 194 (14.4%) patients with major ischemic stroke (OXVASC, unpublished data).

Clinical Implications of PAD in Primary Prevention of Stroke

ABI is used clinically in PAD screening. A systematic review of 7 population cohort studies of 28 679 individuals showed that sensitivity and specificity of low ABI to predict CAD, stroke, and cardiovascular mortality were 16.5% and 92.7%; 16.0% and 92.2%; and 41.0% and 87.9%, respectively.31Figure 3 shows a meta-analysis of studies reporting the association between ABI and risk of cardiovascular events in prospective cohort studies (Supplemental Table I; available at http://stroke.ahajournals.org). Other than PATHOS,23 all studies were in the primary prevention setting. All-cause mortality was 4 times higher in patients with low ABI versus normal ABI (OR 3.99; 95% CI 3.70 to 4.30), and the pooled ORs for total cardiovascular events, stroke/TIA, and CAD were 2.84 (2.62 to 3.08), 2.33 (2.02 to 2.68), and 2.38 (2.13 to 2.66), respectively (Figure 3).

Figure 3. Meta-analysis of the association of ABI with all-cause mortality, total cardiovascular events, stroke/TIA, and coronary heart disease (see Supplemental Table I and supplemental references).

Inclusion of ABI may therefore improve existing cardiovascular risk prediction tools. In 1 cohort study, low ABI doubled 10-year mortality and risk of myocardial infarction across all Framingham risk categories.32 In 10-year CAD risk prediction, inclusion of the ABI led to 1 in 5 men and 1 in 3 women changing their risk category from that predicted by Framingham risk score alone,32 which may affect preventive strategies. Although similar analyses are lacking for prediction of stroke/PAD in primary prevention, consideration of ABI is likely to similarly improve risk prediction.

Prevalence of asymptomatic carotid stenosis increases with decreasing ABI.33 Therefore, there may be a role for screening for asymptomatic carotid stenosis in patients with PAD, although the benefit of carotid endarterectomy in such patients is low.34

Compared with disease in other territories, there is less patient and physician awareness about PAD.35 There is therefore a role for patient education regarding PAD and lifestyle measures (including weight loss, smoking cessation, and exercise) are likely to be as important in PAD as in other vascular disease.

Data on the effectiveness of primary prevention of PAD itself are limited because the outcome has been neglected in randomized controlled trials of antithrombotics, antihypertensives, and statins, which have concentrated on composite measures of coronary events, stroke, and coronary revascularization36 or have included only certain acute PAD events.37,38 Recent trial data have not demonstrated a role for aspirin in primary prevention in asymptomatic PAD patients (ABI <0.9).39,40

High ABI (>1.40) could be related to poor arterial compressibility resulting from stiffness and calcification, which may occur more commonly in diabetics, perhaps explaining the increased vascular risk associated with ABI >1.40.33 PAD is associated with increased blood pressure variability, which increases risk of stroke.41 Therefore, antihypertensives that reduce variability (eg, calcium channel blockers) may be particularly useful in patients with PAD.

Clinical Implications of PAD in Secondary Prevention of Stroke

There are several implications of PAD in patients with stroke/TIA. First, the prognostic value of ABI in the secondary prevention setting means that ABI should be checked in patients presenting with stroke/TIA. The PATHOS study included patients with acute coronary syndromes, stroke, and TIA and followed them for 1 year after measuring ABI showing that low ABI is associated with a 2-fold increased all-cause mortality and risk of cardiovascular events (Figure 3).23

Second, systemic vascular disease on imaging may predict cerebrovascular disease and disease in other territories. In patients with acute stroke, arterial stiffness, measured by brachial–ankle pulse wave velocity, was associated with cerebral arterial calcification on CT angiography, suggesting correlation between cerebral arterial calcification and systemic arterial stiffness.42 Patients with TIA and those with stroke with PAD may therefore need more detailed imaging of the cerebral circulation and extracranial circulation, although in the OXVASC study, prevalence of symptomatic carotid stenosis was associated with a history of PAD, whereas vertebrobasilar stenosis was not.43 More studies of intracranial arterial stenosis and PAD are required.

Third, more aggressive treatment and prevention of PAD in patients with stroke/TIA may be cost-effective given that PAD doubled 1-year costs associated with hospitalization for vascular events in a cohort with prior TIA or stroke.44 Despite high prevalence of multiterritory vascular disease in patients with stroke/TIA, and the associated increase in cardiovascular risk, current treatment guidelines omit management of multiterritory vascular disease.6,7 No routine PAD screening is recommended in guidelines, and PAD is likely to frequently go undetected. Even recommendations for management of CAD in patients with stroke are currently limited to antiplatelet therapy. Once diagnosed, PAD is undertreated with antihypertensives, antiplatelets, and statins compared with patients with CAD and those with stroke.38,45,46

Fourth, trial data on the effectiveness of secondary prevention are lacking in patients with stroke/TIA with PAD. In primary prevention in patients with PAD, aspirin alone or in combination with dipyrimidine was associated with reduction in stroke (relative risk 0.66; 0.47 to 0.94) and cardiovascular events (relative risk 0.75; 0.48 to 1.18) but was not associated with reduction in mortality, myocardial infarction, or major bleeding.46 In patients with PAD, like in patients with CAD or stroke/TIA, major bleeding was independently associated with a 3-fold increased risk of ischemic vascular events (hazard ratio 3.0; 1.9 to 4.7).47 In patients with stroke/TIA, clopidogrel was as effective as aspirin in reduction of vascular death (including PAD).48 A systematic review found no evidence that β-blockers should be avoided in patients with PAD,49 but they should be avoided in secondary prevention after TIA/stroke because they increase blood pressure variability.41

Fifth, asymptomatic PAD is associated with worse limb function, possibly hampering poststroke recovery. The proper management of PAD can improve stroke rehabilitation.50

Conclusions and Future Research

Patients with stroke with disease in other territories have increased risk of recurrent cardiovascular events, leading to higher hospital readmission rates and costs. Although CAD and PAD prevalence in patients with stroke is high, multiterritory vascular disease is often undetected, potentially resulting in suboptimal management. Despite the clinical need to manage high-risk patients with stroke more effectively, current guidelines omit detection and treatment of PAD.

PAD (either development of symptomatic claudication or acute events) must also be measured as an outcome event in intervention trials to assess treatment effects. In prevention trials, patients with PAD should be a defined subgroup to ascertain how much of the association with cardiovascular events is potentially reversible. There is a need for population-based data on the incidence, risk factors, and outcome of acute PAD events, and stroke complicated by multiterritory disease, to enable health service planning, monitor the effectiveness of prevention, inform patients about risks and prognosis, plan clinical trials, and allow comparisons between populations and over time.

Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.

Sources of Funding

The Oxford Vascular Study is funded by the UK Medical Research Council, the Dunhill Medical Trust, the Stroke Association, the BUPA Foundation, the National Institute for Health Research (NIHR), the Thames Valley Primary Care Research Partnership, and the NIHR Biomedical Research Centre, Oxford.

Disclosures

None.

Footnotes

Correspondence to Peter M. Rothwell, MD, PhD, FRCP, FMedSci, Stroke Prevention Research Unit, Department of Clinical Neurology, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford, UK OX3 9DU. E-mail

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