Peripheral Arterial Disease and Stroke Risk: Understanding the Association

Did you know that at least 370 million people worldwide have Peripheral Arterial Disease? The research paper falls within the scope of the World Health Organisation’s definition of health, namely ‘a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity’ (WHO, 1948). This paper assesses the risk factors for stroke in patients with peripheral artery disease (PAD). The decision to choose the stroke implications of PAD as a topic arises from several factors. Stroke is a major cause of death and disability, and cardiovascular diseases are identified as key risk factors for death and disability from non-communicable diseases in the WHO global burden of disease initiative. Thus, the ramifications of PAD can be considered in terms of death and disability from stroke. Second, the stroke implications of PAD are often overlooked, overshadowed by the study of cerebrovascular disease with an assumption that stroke in these patients is atherothrombotic in nature. This paper will argue that patients with PAD have a significantly increased risk and introduce some of the mechanisms by which this occurs. Third, the stroke implications of PAD lead to increased healthcare expenditure from an already austere NHS budget. Our findings will be valuable in identifying high-risk groups for whom preventative therapies may be most beneficial.

Overview of Peripheral Arterial Disease (PAD)

Non-invasive testing methods, such as the ankle-brachial index (ABI), are helpful in making the diagnosis and assessing the severity of PAD. Color duplex ultrasonography provides a non-invasive method for defining the anatomy of lower extremity arterial lesions. High-quality contrast arteriography is the most accurate test for defining the location and nature of arterial lesions, and is most useful when considering interventions such as angioplasty or vascular surgery.

Peripheral arterial disease (PAD) is a common condition in which atherosclerotic plaques affect the arterial circulation to the lower extremities. The prevalence of PAD increases with age and is most common in persons older than 50 years, affecting 5% of persons in this age group, and as many as 15-20% of persons older than 70 years. Diabetes is a particularly strong risk factor for PAD. The Framingham Heart Study showed a 2-4 fold increase in relative risk for intermittent claudication and new onset claudication in persons with diabetes.

Overview of Stroke Risk

Stroke, a diverse and heterogeneous abnormality of cerebral function, is a major cause of severe disability and public health problems, as well as a significant drain on healthcare resources. Stroke is broadly categorized into two types: ischemic and hemorrhagic, with the former more common but lower in terms of case fatality. Ischemic stroke occurs when there is a blockage in the cerebral blood vessel, depriving the brain of adequate blood flow and ultimately resulting in brain infarction. Hemorrhagic stroke occurs when a blood vessel bursts, also leading to brain infarction and is more severe with higher mortality. Although PAD is intrinsically a disease of the peripheral arteries, it does raise the risk of both ischemic and hemorrhagic stroke, but the discussion here will be on the former, as published evidence of the association between PAD and hemorrhagic stroke is scarce. While it is easily comprehensible how PAD raises the risk of cerebral ischemia in patients with carotid stenosis, it is less clear how it raises the risk in patients without carotid stenosis and those without PAD. Understanding both the shared and differing risk factors for PAD and cerebral infarction can only strengthen awareness of how PAD raises stroke risk and can perhaps lead to ways to prevent stroke in patients with PAD.

The Link between Peripheral Arterial Disease and Stroke

An important element of describing the association between PAD and stroke is an understanding of the underlying mechanisms, although these are not fully understood. The concept that PAD is a marker for systemic atherothrombosis, which is strongly associated with an increased risk of stroke, has been supported by studies reporting stroke rates in patients with intermittent claudication (the classic symptom of PAD due to atherosclerosis) to be 1.5 to 2 times higher than the general population. Furthermore, the finding following acute myocardial infarction or unstable angina, that PAD patients have higher than expected rates of cardiovascular events, suggests that the increased risk of stroke in this group may in part be due to continued progression of atherothrombotic disease rather than embolization of atheroma from limb arteries. It has also been suggested that patients with critical limb ischemia could be at high risk of cerebral infarction due to the often coexisting cerebrovascular atherosclerotic disease changes in these patients; however, no definite evidence has been provided.

Various factors suggest that PAD could lead to an increased risk of stroke. Patients with PAD and those with a history of cerebrovascular disease share common vascular risk factors. The FHS and other studies found smoking, diabetes, and hypertension to be significant risk factors for both PAD and stroke. In addition, asymptomatic carriers of carotid artery atherosclerosis, as detected by ultrasound, were found to have an increased prevalence of symptomatic PAD when compared to those without carotid disease. This finding suggests that a systemic atherothrombotic process affects multiple vascular beds, which in turn would increase the risk of stroke in PAD patients. High cholesterol has been shown to be a significant risk factor for intermittent claudication, a manifestation of PAD, and is also a significant risk factor for stroke. Hyperhomocysteinemia has also been implicated in the pathogenesis of atherosclerosis and atherothrombosis, and has been found to be a significant risk factor for peripheral arterial disease and stroke. These shared risk factors support the concept that PAD and stroke are linked by a common atherothrombotic process. An article in the New England Journal of Medicine defined atherosclerosis as a systemic disease that reduces life expectancy and impairs quality of life, with the potential to cause critical ischemia in the limbs, mesenteric ischemia, renal failure, and stroke. With advances in modern medicine, the article stated that the objectives in preventing atherosclerotic disease are to reduce cardiovascular events and to lower the progression rate of the underlying disease. Whether targeting prevention of atherothrombosis will effectively reduce the incidence of stroke in PAD patients remains to be proven.

Shared Risk Factors

Hypertension is the most widely recognized risk factor for stroke. It has consistently been shown to double the risk of future stroke in both men and women. Hypertension is also very common in patients with PAD. In a study of 5560 patients with symptomatic PAD, 77% had a history of hypertension. The relationship between hypertension and stroke in this population was recently explored with a post hoc analysis of the chariot study. This was a randomized trial comparing clopidogrel and aspirin in patients with symptomatic PAD.

Despite overlap in risk factors for symptomatic peripheral arterial disease (PAD) and stroke, many studies have failed to unequivocally characterize these risk factors as increasing stroke risk in patients with PAD. A likely explanation for this is the high prevalence of comorbid conditions such as hypertension, hyperlipidemia, and diabetes in patients with atherosclerosis. However, three risk factors have been shown to have a strong independent association with stroke in patients with PAD.

Mechanisms of Association

There is some evidence that patients with symptomatic PAD might have increased platelet activity compared with those without PAD. The only direct data about platelet function and stroke risk in patients with PAD come from the results of the recent Aspirin for Asymptomatic Atherosclerosis trial. In this trial, patients with asymptomatic atherosclerosis identified by abnormal ankle brachial pressure indices and who had no history of stroke were at increased risk of stroke, but the effects of allocation to antiplatelet therapy were not significantly different from there in patients in whom the atherosclerosis was manifest as IC. Further evidence of increased platelet aggregation and fibrin deposition within lower limb arteries comes from studies of antiplatelet therapy in patients with intermittent claudication.

Ischaemic limb or stroke events caused by PAD may represent varied expressions of atherosclerosis at different sites. In some patients, the first event is a stroke. High blood pressure, diabetes, and cigarette smoking are known to be major risk factors for both ischaemic heart disease and stroke. Certainly, these risk factors could explain much of the association between PAD and cerebrovascular events. However, there are a number of other factors that might be especially pertinent to stroke risk in patients with PAD. Retrospective analyses have shown that intermittent claudication is associated with an increased risk of subsequent stroke. Among patients with IC, those who have concomitant coronary disease are more likely to die from heart disease than from stroke. This suggests that the presence of multisite atherosclerosis might amplify the normal risk of cerebrovascular events that accompanies ageing. An alternative explanation is that patients with PAD have an increased vulnerability to certain types of stroke that is unrelated to classic risk factors for atherothrombotic disease.

Clinical Evidence

Noninvasive tests to diagnose PAD have also been related to cerebrovascular events in a number of studies. In a case-control study of patients who had carotid endarterectomy, a group of subjects with prior or asymptomatic PAD, defined by an ABI of ≤0.95, had a 2- to 3-fold increase in risk of previous ipsilateral ischemic symptoms and positive findings on cerebral CT scan compared with those without PAD. This association holds true for both symptomatic and asymptomatic PAD when using a number of different markers of cerebrovascular disease, showing a consistent pattern of increased stroke risk in the setting of PAD. Unfortunately, many of these studies have not controlled for confounding risk factors that are common to both PAD and cerebrovascular disease, and results have been inconsistent regarding the independent effect of PAD on the risk of stroke. Measures to improve case-ascertainment and appropriate control for confounding risk factors, as well as clarifying the effect of PAD on stroke subtypes, will allow for a clearer understanding of the cerebrovascular implications of PAD.

Clinical evidence of an association between PAD and stroke is based on multiple types of epidemiologic studies in different populations. In a study on 1345 Japanese individuals 65 years and older, history of intermittent claudication and confirmed PAD by ABI were associated with a 3-fold and 4-fold increase in relative risk of ischemic stroke over 4 years, respectively, after adjusting for other risk factors. A 2-fold increase in risk of stroke was also reported in a community-based cohort of older adults in the United States due to symptomatic PAD. Data from the Edinburgh Artery Study demonstrated that claudication was associated with a 2- to 3-fold increase in risk of both fatal and nonfatal stroke in men, and a 7-fold increase in risk of nonfatal stroke alone. Up to a 6-fold increase in the relative risk for stroke has been associated with asymptomatic PAD as determined by low ABI, in men only, in the Framingham Cardiovascular Disease Risk in Men and Women: Pooled Cohort Study. Collectively, these findings provide consistent evidence for an increased risk of stroke in those with PAD, with some indication of a dose-response effect between severity of PAD and risk of stroke. The establishment of the strength of association between a PAD diagnosis and risk of stroke has been clarified in several recent case-control studies, PET and MRI studies, and randomized trials.

Managing the Association between Peripheral Arterial Disease and Stroke

The association between PAD and stroke and the potential benefit of aggressive cardiovascular risk reduction underlines the importance of providing care that is focused upon the patient’s global cardiovascular risk, often through a multidisciplinary approach. Epidemiological data from several well-known studies prove that cardiovascular complications of atherosclerosis represent the major cause of morbidity and mortality for patients with PAD, and by reducing these cardiovascular complications, it will also reduce the risk of stroke. Multidisciplinary care should involve cooperation between primary care physicians, vascular medicine specialists, neurologists, and general internists. The key to this approach is to develop cost-effective strategies to educate both physicians and patients about the extent of the global atherosclerotic disease and the potential benefit of risk-reducing strategic therapies.

Treatment approaches for PAD range from lifestyle modifications and risk factor reduction to revascularization procedures. The Walking and Leg Circulation Study showed that cilostazol, a phosphodiesterase inhibitor, can reduce the risk of ischemic stroke in patients with intermittent claudication. This effect was independent of the medication’s effect on reducing cardiovascular events. And several surgeries to relieve lower extremity ischemia have also shown to reduce the risk of stroke, although they may not be the best option to reduce the risk of stroke alone.

Prevention strategies address modifiable risk factors for stroke and PAD, including hypertension, hyperlipidemia, and diabetes. In addition, antiplatelet agents have been shown to reduce the risk of stroke in patients with PAD. Hypertension is an important and modifiable risk factor for both ischemic stroke and PAD. The use of antiplatelet agents for primary prevention of stroke in patients without a history of TIA or stroke and with asymptomatic PAD requires work, particularly given the known risk of bleeding with these agents. Even though low dose aspirin might reduce the risk of ischemic stroke in mostly healthy individuals, it is not indicated for use in patients with PAD to reduce the risk of stroke.

Prevention Strategies

In this context, the recent American Heart Association/American College of Cardiology guidelines on management of patients with peripheral arterial disease provide clear direction for evidence-based management of associated cardiovascular risk factors in PAD patients.

In the medical community, a recent shift has occurred from use of lipid tests to identify patients with PAD who may benefit from lipid-lowering therapy, to a focus on using lipid-lowering therapy to reduce cardiovascular risk in all patients with PAD. This is consistent with a general trend in PAD management, moving away from mere treatment of leg symptoms, to management of PAD as a systemic atherosclerotic disease with increased risk of cardiovascular events.

One recent study reported that hypertension is an important and potentially modifiable risk factor for progression of lower extremity arterial disease to symptomatic PAD. Because well-controlled blood pressure is also effective in preventing stroke, this is another area where intervention may have an impact on reduction of major cardiovascular events in PAD patients. Similarly, lipid-lowering therapy has been shown to slow progression of intermittent claudication and improve cardiovascular event-free survival in patients with PAD.

Specifically in the area of stroke prevention, several studies have now shown that antiplatelet therapy reduces the risk of fatal and nonfatal stroke in patients with a history of transient ischemic attack or stroke, as well as in patients with multiple risk factors for stroke. Although the efficacy of antiplatelet therapy specifically in PAD patients has not been studied, the high risk of cardiovascular events in those with PAD makes this a logical recommendation.

Based on the well-established association between PAD and stroke, individuals with PAD, especially those with intermittent claudication, should be considered candidates for aggressive primary and secondary prevention of cardiovascular events. Because individuals with PAD have a high prevalence of asymptomatic coronary and carotid artery disease, and because the prognosis of those with symptomatic cardiovascular disease is poor, medical management should not be focused exclusively on claudication symptoms. Instead, the goal should be to reduce the risk of myocardial infarction, stroke, and cardiovascular-related death.

Treatment Approaches

Surgical revascularization may be indicated in PAD patients with severe stenosis of the carotid arteries and certain patients with symptomatic cerebrovascular disease. High surgical risk patients with carotid artery stenosis and symptomatic PAD, who would be poor candidates for carotid endarterectomy, may benefit from carotid artery stenting. A randomized controlled trial found that in patients with PAD and intermittent claudication, surgical revascularization was not effective in primary and secondary prevention of cardiovascular and cerebrovascular events compared with medical management.

Data from a small group of patients with PAD and intracranial arterial stenosis showed that the use of cilostazol was associated with a decreased risk of stroke or death compared with those taking aspirin. Although the difference was not statistically significant, the authors suggest that a prospective randomized study be conducted to assess the efficacy of cilostazol in preventing stroke in this population.

When considering treatment options for PAD patients with risk factors for stroke, it is evident that the best possible pathway is the modification of cardiovascular risk factors. This will often mean the use of antiplatelet agents like aspirin, which can be very effective in the prevention of stroke. Cholesterol-lowering medications, such as statins, have a beneficial effect in reducing the risk of stroke and are indicated in patients with PAD to lower the risk of cardiovascular events. Aggressive blood pressure control is important and may involve the use of ACE inhibitors. For PAD patients with hypertension and a history of cerebrovascular disease, the management of blood pressure with an ACE inhibitor was found to be more protective against cardiovascular events than with an alternative antihypertensive agent.

Multidisciplinary Care

In the contemporary healthcare environment, there is an increasing trend towards sub-specialization amongst medical practitioners and a health system that is rapidly becoming more complex. This has made a team approach to healthcare professional involvement in disease management more difficult. PAD is a complex disease associated with multiple comorbidities, especially in the aged population which it predominantly affects. The strong association with cerebrovascular disease and stroke makes effective prevention strategies and treatment approaches to stroke pertinent to the management of patients with PAD. Stimulating collaboration between healthcare professionals in the management of the PAD patient has never been more important, and innovative methods to promoting multidisciplinary care are required. Future research into health systems and healthcare professional behavior is needed to determine the optimal methods of implementation of multidisciplinary strategies in the prevention of stroke in patients with PAD.

Multidisciplinary care takes disease management a step further than that of treatment approaches and involves coordinated participation from a diverse range of healthcare professionals in the area of vascular medicine and those in the primary and secondary prevention of stroke. The majority of clinical trials examining various prevention strategies and treatment approaches to cerebrovascular disease in patients with PAD now recommend a multidisciplinary ‘treat to target’ approach that involves the combined efforts of general practitioners, vascular specialists, neurologists, and other medical specialists, alongside input from nursing and other paramedical professionals. The shared goal between these differing healthcare professionals is the reduction of the risk of stroke and other cardiovascular events in patients with PAD.

Future Directions and Research Opportunities

Advancements in ultrasound and other imaging techniques have greatly improved our ability to diagnose PAD, but studies aiming to enhance early detection of PAD in the community and in high-risk patients are needed. Earlier studies focused on intermittent claudication as the primary manifestation of PAD. With recognition of the diverse clinical presentations and multiple manifestations of PAD, a variety of symptom and health-related quality of life (HRQOL) measures have been developed and validated as primary and secondary outcomes. These tools have been, and can further be, utilized to enhance the assessment of patients with PAD in clinical studies. Outcome measures particularly relevant to patients with mild PAD or with predominant leg symptoms include functional status and objective measures of physical performance. Studies that utilize a core set of outcome measures can enhance comparability of results across studies and can focus on the unique aspects of the disease process in different patient populations. Outcomes research continues to be done to determine the broad impact of PAD on public health. Understanding the epidemiology of PAD in specific populations, as well as its economic impact, increases awareness and allocation of resources to address this prevalent and morbid disease state.

Advancements in Diagnosis and Screening

It is generally accepted that identifying the presence of PAD, even when not clinically evident, is essential to address this often systemic and progressive disease. Interestingly, carotid artery intima-media thickness, atherosclerotic plaque, and increased carotid artery wall thickness are now each associated with increased risk of stroke, providing rationale to assess if similar subclinical markers in the cerebral circulation can identify patients at risk for adverse neurologic outcomes. Ankle-brachial index (ABI) is a simple, noninvasive, and reproducible physiologic test to assess for the presence of lower extremity atherosclerosis. Although ABI has already proven a useful tool to diagnose PAD and stratify cardiovascular risk, recent work suggests that measures of arterial stiffness and lower extremity pulse wave velocity may provide incremental information in determining cardiovascular risk and the presence of adverse cardiovascular events. Similarly, newer noninvasive imaging techniques such as MRI and computed tomography angiography have shown promise in providing detail of the anatomic distribution and plaque morphology in peripheral arteries and may prove useful in predicting adverse cardiovascular outcomes. The availability of such a broad armamentarium of diagnostic tools and established surrogate markers for adverse cardiovascular events provide a compelling opportunity to evaluate these same cardiovascular endpoints in patients with PAD. Whether these tests will become standard of care and demonstrate improvement in patient outcomes, however, remains to be determined.

Novel Therapeutic Interventions

The high morbidity and mortality associated with symptomatic intracranial stenoses makes this an attractive target for aggressive treatment, but the failure of several studies to show benefit from aspirin and anticoagulation has led to the investigation of percutaneous transluminal angioplasty and stenting. Early results have been promising and a large randomised trial comparing it to medical treatment is currently ongoing. However, while cerebral revascularisation is a therapeutic option in patients with PAD who have concomitant intracranial disease, it cannot be considered a method of preventing stroke.

An alternative approach is through revascularisation of the cerebral circulation. Limitations of our current understanding of extracranial cerebrovascular disease and absence of effective treatment may indicate that such patients have potential to benefit from advances in this field over the next few decades, but this method would be irrelevant in patients with asymptomatic carotid disease. Randomised studies have shown that surgery is more effective than medical treatment in preventing stroke in patients with severe carotid stenosis, and recent trials using carotid stenting as an alternative to endarterectomy have demonstrated technical feasibility and safety. However, enthusiasm has been tempered by the disappointing results of the SAPPHIRE trial that showed that stenting was not as good as surgery in patients with symptomatic carotid disease, and the high restenosis rate seen in a multicentre trial of stenting in symptomatic and high risk asymptomatic patients.

The preferable associations between PAD and stroke raise the important question of whether treating PAD might actually prevent stroke. While identifying and controlling vascular risk factors should be useful, we conclude that for many patients this approach may have come too late, therefore alternative interventions need to be established. Blocking the atherosclerotic process is a logical approach, but to impact on the incidence of stroke such treatment needs to be started early, and it is difficult to establish when initiation of antiplatelet or lipid lowering therapy might be appropriate. Furthermore, recent data from the HOPE trial shows that an ACE inhibitor was effective in reducing stroke in patients with evidence of other macrovascular disease, but had no benefit in those with isolated peripheral vascular disease. This implies that different mechanisms may be involved in the pathogenesis of stroke in PAD compared to other forms of atherosclerosis. Although data is limited, the concept of neuroprotection is relevant, and by identifying patients at high risk of stroke it may be feasible to study drugs specifically in this group.

Addressing Gaps in Knowledge

An entirely novel area of research is the potential association between PAD and cognitive dysfunction. Emerging evidence suggests that atherosclerosis is a risk factor for Alzheimer’s disease and all cause dementia. Furthermore, several studies have indicated an association between peripheral atherosclerosis and cognitive impairment. Given the global burden of cognitive dysfunction in the elderly and its impact on quality of life and disability, this area represents an important potential avenue for research with respect to PAD and atherothrombotic disease. High quality primary data in these areas will enhance our understanding of the impact of PAD on atherothrombotic disease at its various sites and provide valuable insights into the potential mechanisms underlying the observed increased risk of atherothrombotic events in PAD.

Despite the burgeoning literature examining PAD as an independent risk factor for CHD or simply as a marker for atherosclerosis, there are few data addressing the relationship between peripheral atherothrombotic events and stroke. In addition, prior studies investigating PAD and stroke have potentially conflated differing etiological subtypes of stroke. Given that large artery atherothrombosis and small vessel disease represent the principal mechanisms underlying the majority of ischemic strokes, it is imperative to elucidate the association between PAD and specific stroke subtypes. This will require large, prospective studies with systematic ascertainment of both asymptomatic and symptomatic PAD, utilization of sensitive and specific measures to identify stroke events and classification of stroke subtypes using neuroimaging or autopsy.

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