Study of carotid disease in patients with peripheral artery disease

OBJECTIVE
To study the stenosis of the carotid arteries in patients with symptomatic peripheral arterial disease.


METHODS
we assessed 100 consecutive patients with symptomatic peripheral arterial disease in stages of intermittent claudication, rest pain or ulceration. Carotid stenosis was studied by echo-color-doppler, and considered significant when greater than or equal to 50%. We used univariate analysis to select potential predictors of carotid stenosis, later taken to multivariate analysis.


RESULTS
The prevalence of carotid stenosis was 84%, being significant in 40% and severe in 17%. The age range was 43-89 years (mean 69.78). Regarding gender, 61% were male and 39% female. Half of the patients had claudication and half had critical ischemia. Regarding risk factors, 86% of patients had hypertension, 66% exposure to smoke, 47% diabetes, 65% dyslipidemia, 24% coronary artery disease, 16% renal failure and 60% had family history of cardiovascular disease. In seven patients, there was a history of ischemic cerebrovascular symptoms in the carotid territory. The presence of cerebrovascular symptoms was statistically significant in influencing the degree of stenosis in the carotid arteries (p = 0.02 at overall assessment and p = 0.05 in the subgroups of significant and non-significant stenoses).


CONCLUSION
the study of the carotid arteries by duplex scan examination is of paramount importance in the evaluation of patients with symptomatic peripheral arterial disease, and should be systematically conducted in the study of such patients.


INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION
A therosclerosis is the disease of the modern world, directly related to lifestyle, such as physical inactivity, smoking, stress and diet.As a systemic disease, it affects many arteries simultaneously, such as coronary, carotid and lower limb arteries.
It is important to study the whole patient, evaluating the various arterial vessels 1 .Therefore, the diagnosis of atherosclerosis in patients still in the early or subclinical stages enables earlier and more appropriate treatment and prevents possible complications 2 .
Complications of atherosclerosis, such as acute myocardial infarction and stroke, are now among the leading causes of morbidity and mortality worldwide.The stroke is now the leading cause of death in Brazil [3][4][5] .
Peripheral artery disease is responsible for 42,000 cases of amputation per year in Brazil in accordance with the 2005-2011 Data/SUS 6 .It is associated with the same risk factors of coronary artery disease and carotid artery stenosis.
Peripheral artery disease is an important marker of atherosclerosis and is also a predictor of cardiac and cerebrovascular events.Patients with peripheral artery disease have a higher chance of morbidity and mortality from ischemic heart and cerebrovascular diseases, such as acute myocardial infarction and stroke.These patients have a mortality of approximately 30% in five years and 50% in ten years 7 , and have a higher incidence of atherosclerosis in the carotid territory 8 .Some studies have estimated that approximately 25% to 35% of these patients show significant stenosis in the carotid arteries 9 .The identification of these patients has the potential to prevent stroke, since it may establish the correct medical or surgical treatment.
About 15% to 48% of strokes are caused by atherosclerosis of the carotid arteries 10 .The treatment of stroke has low success rates, with 30% of patients who remain hospitalized for long periods and 30% requiring permanent care in the long term.
The incidence of stroke could be reduced by up to 50% with the modification and control of risk factors such as smoking, diabetes, hyperlipidemia, hypertension, among others.Identifying patients with stenosis of the carotid arteries would allow early clinically or surgical treatment (endarterectomy or angioplasty) 11   The diagnosis of significant carotid disease can be made by ultrasound with color-Doppler, called "duplex scan", which is a non-invasive and inexpensive test.Prospective, randomized studies have shown the benefits of treatment of carotid stenosis in reducing the incidence of cerebral ischemia, both in symptomatic and in asymptomatic patients [12][13][14][15][16][17] .
The aim of this study was to study the stenosis of the carotid arteries in patients with symptomatic peripheral arterial disease, assessing the prevalence of carotid artery disease, the severity of peripheral arterial disease, the severity of involvement of extracranial carotid arteries and the associated risk factors.

METHODS METHODS METHODS METHODS
We prospectively evaluated 100 patients with symptomatic peripheral arterial disease treated in the Governador Felicio Rocho and Israel Pinheiro (IPSEMG) hospitals from June 2011 to April 2012.
The study was approved by the Ethics Committee of the Felicio Rocho Hospital in May 2011, and recorded with the protocol number 365/2011, and also approved by the Ethics Committee of the Universidade Federal de Minas Gerais (CAAE 403541112.2.0000.5149).Patients were invited to participate in the study and enrolled after signing the Informed Consent Form (ICF).
After the diagnosis of carotid stenosis, all patients received clinical treatment with antiplatelet agents, statins and control of risk factors and associated diseases.
We consecutively included in the study patients with symptomatic peripheral arterial disease in stages of intermittent claudication (rank 1, 2 or 3 of Rutherford), rest pain (Rutherford classification 4) or ulceration (Rutherford 5 or 6).We excluded patients who disagreed to participate and those at risk of imminent death or severe systemic disease.
The evaluation of carotid stenosis was performed by eco-color-doppler.Significant stenosis of the carotid arteries was defined as equal to or greater than 50%.The carotid arteries were examined bilaterally, the stenosis degree being considered the one on the side with more pronounced involvement.To measure the degree of stenosis, we used the consensus document that correlates criteria of flow speed and anatomical data 18 .
For evaluation of peripheral arterial disease, patients underwent anamnesis and physical examination, with assessment of various risk factors for atherosclerosis, measurement of ankle-brachial index (ABI) and Rutherford classification.
The risk factors assessed were age, gender, smoking, diabetes, dyslipidemia, hypertension, medications used to control hypertension, coronary artery disease, renal failure, family history of atherosclerosis, previous history of lower limb revascularization, myocardial revascularization , aortic aneurysm, intervention in the carotid arteries, renal artery intervention, amputation, history of ischemic cerebrovascular symptoms related to the carotid artery territory and arterial territory affected in lower limb (aortoiliac, femoropopliteal or infrapopliteal).The presence of some motor limitation regarding ambulation was evaluated and deemed reduced in patients using wheelchairs or restricted to bed.We considered patients symptomatic as for the carotid territory those with a history of focal neurological symptoms directly related to this territory, such as amaurosis fugax, hemiparesis or hemiplegia.
For ABI measurement, we used a sphygmomanometer with 10-12 cm wide cuff positioned just above the ankle and measured systolic pressure with portable doppler in posterior tibial and fibular dorsalis pedis arteries.The ABI is obtained by the ratio of the highest systolic pressure in the arteries at the ankle level and the highest systolic pressure in the brachial artery (left or right).
This study is characterized as a cros-sectional, prospective epidemiological one.We used univariate analysis to select potential predictors of severity of carotid artery stenosis by evaluating: the degree of carotid artery stenosis on a scale ranging from 0% (no stenosis) to 100% (occlusion), not accounting for the subgroups of stenosis degrees.For these calculations we employed the Mann-Whitney test and Spearman coefficient, used to evaluate the influence of ABI and classification of clinical severity (Rutherford classification).
We used the chi-square and Mann-Whitney tests and, where necessary, the Chi-Square was replaced by Fisher's exact test to assess carotid stenosis.Patients were separated into two subgroups of stenosis degrees, one less than 50% (not significant stenosis) and another above 50% (significant stenosis).To select among the potential predictors in multiple regression, we used the backward algorithm.For the evaluation of the carotid treated in its original scale, without subdivision into groups of grades of stenosis, we employed the method of Quasi-Likelihood.We used logistic regression for the carotid evaluation in subgroups.
Since the objective of the study was to test the correlation between carotid stenosis and peripheral artery disease, and given a significance level of 0.05 for a twotailed test with a medium effect size and a power of 80%, the sample should be composed of approximately 85 individuals (Figure 1).

RESULTS RESULTS
The age of patients ranged from 43 to 89 years, with a mean of 69.78 (standard deviation 10.01).Sixtyone patients were male.Nineteen patients had reduced motor activity.The distribution of patients according to the degree of stenosis of the carotid arteries is found in Table 1.The prevalence of carotid stenosis was 84%, being significant in 40% of patients and severe in 17%.Absence of plaque in the carotid arteries was found in 16%.Two patients had unilateral internal carotid occlusion; one had a history of stroke two years before and the other was asymptomatic.
Regarding the classification of Rutherford, 50% of patients had grades 1, 2 or 3 (claudicating) and 50% of patients had grades 4, 5 or 6 (patients with rest pain or ulceration, i.e., critical ischemia).The ABI measurement showed an average of 0.58, with 50% of the patients with less than 0.56.
We note that 86% of the patients had hypertension, 66% exposure to smoke, 47% diabetes, 65% dyslipidemia, 24% coronary artery disease, 16% renal failure and 60% had family history of cardiovascular disease (Table 2).A history of vascular surgery was found in 48% of the patients, with a predominance of lower limb revascularization, performed in 34 patients (34%), and coronary artery bypass grafting (CABG) in ten (10% ).
Seven patients (7%) had a history of some prior ischemic cerebrovascular symptoms in the carotid territory, two of them (2%) TIA and five patients (5%) stroke.In all these patients, this story had occurred more than two years before.
Patients were classified according to the arterial territory affecting the lower limbs, with findings of femoropopliteal disease in 63%, Infrapopliteal in 43% and aortoiliac in 26%.
After the diagnosis of carotid stenosis we evaluated the approach to to this finding.In 76% of patients observation was chosen, and 24% held some additional procedure.Of the latter, 15 were submitted only to more exams (new duplex-scan, angiography or magnetic resonance angiography) and nine patients underwent intervention in the carotid arteries, of which three were carotid endarterectomies and six were carotid angioplasties.All patients undergoing carotid endarterectomy or angioplasty had carotid stenosis higher or equal to 70% (severe stenosis).These patients had no complications postoperatively.Variables that significantly influenced the degree of stenosis of the carotid arteries showed a pd"0.25,being selected for multivariate analysis: prior symptomatic cerebrovascular disease, dyslipidemia, reduced motor activity, age, coronary artery disease, renal failure (Table 3) .
There was a negative correlation, although not significant (p = 0.073) between the ABI and the overall evaluation of carotid stenosis.The correlation between the assessment of carotid and the classification of Rutherford, on its turn, is positive, but also not significant (p = 0.110) (Figure 2).
The following variables were selected as potential predictors of significant carotid stenosis (pd"0.25):reduced motor activity, history of previous symptomatic cerebrovascular disease, gender, age, diabetes, dyslipidemia and coronary artery disease (Table 4).
In multivariate analysis with the previously selected variables, only the variable previous symptomatic cerebrovascular disease remained in the final regression to globally explain the variation of carotid stenosis.The presence of prior symptomatic cerebrovascular disease increases in 30.98 the average value of carotid stenosis, with p = 0.0231.
In the assessment of carotid stenosis in groups of significant injuries and non-significant ones, only the variables prior symptomatic cerebrovascular disease and gender were retained in the final regression to explain the    Figure 1 -Figure 1 -Figure 1 -Figure 1 -Figure 1 -Curve of sample and effect sizes, fixing 80% power and a significance level of 5% for the correlation coefficient (r = 0.30).
variation in evaluation of carotid stenosis.The results show that the chance of a female patient have an assessment of significant carotid stenosis is 2.28 (0.92 to 5.68) times the odds of male patients, but not statistically significant (p = 0.0766).The odds of a patient with prior symptomatic cerebrovascular disease present with a carotid stenosis considered significant is approximately 12.This is an unprecedented work in Brazil, since similar studies have not been found after research conducted in the SciELO and LILACS databases.The study of carotid artery disease and peripheral arterial disease are topics of great relevance, since stroke is currently the leading cause of death in Brazil and peripheral arterial disease is responsible for thousands of amputations [3][4][5] .
Our results show a 84% prevalence of carotid stenosis in the sample, being significant in 40% of patients.Previous studies reported a prevalence of significant carotid stenosis ranging from 14.3% to 37.2%, but the samples of patients with peripheral arterial disease are different between the works, and in many of them there are only asymptomatic and claudicating patients 8,9,19,20 .The higher  prevalence of carotid stenosis found in our sample can be explained by the severity of the patients' peripheral arterial disease, since half of the them had critical ischemia of the lower limbs, indicating greater arterial involvement.
As for the studied risk factors for atherosclerosis, the results are consistent with published data, indicating an association with hypertension, smoking, diabetes, dyslipidemia, coronary artery disease, positive family history and chronic renal failure2 .Dyslipidemia was statistically significant for the presence of carotid stenosis in univariate analysis (p = 0.0497).None of these factors, however, was statistically significant for the severity of carotid stenosis after multivariate analysis and logistic regression.This may be explained by the fact that both factors have a high prevalence both in patients with peripheral arterial disease and in patients with carotid stenosis, indicating that these are potential markers of systemic atherosclerosis.The identification of modifiable risk factors configures an important part of treatment.In all study patients, once risk factors and associated comorbidities were identified, medical therapy was initiated.The use of antiplatelet agents, statins, smoking cessation and controlling blood pressure and diabetes are essential to prevent stroke 21 .
The average age of patients was 69.78 years, also indicating a direct relationship of arterial involvement with the elder population, in accordance to previously published work 22 .Distribution by age groups also revealed a predominance of older patients, with 80% of individuals in the series with greater than or equal to 60 years of age.
There was a predominance of male patients in our study, the proportion of about three men to two women, also compatible with the publications found in the literature, in which it is evident that atherosclerosis predominates in males 2 .Our results show, however , an interesting finding after multivariate analysis logistic regression.The females showed a trend (p = 0.0759) for significant carotid stenosis.A previous publication has shown the female gender as a risk factor for the progression of carotid stenosis in patients with peripheral arterial disease 9 .Other studies have shown that the female sex is also an independent risk factor for significant carotid stenosis, but in a population of coronary patients in preoperative of surgical myocardial revascularization 23 .The female gender appears to be a risk factor for neurological complications after carotid angioplasty and restenosis after carotid endarterectomy [24][25][26] .
The study of the variables ankle-brachial index (ABI) and classification of Rutherford showed a relationship between severity of peripheral artery disease and severity of carotid stenosis.Despite the non-significant values found in the statistical analysis, there was a tendency towards lower measures of ABI and higher values in the classification of Rutherford, featuring a more severe peripheral arterial disease, and findings of more pronounced carotid stenosis.These findings are consistent with published data indicating that there is direct association between the severity of peripheral arterial disease and degree of carotid stenosis 19,27 .
Patients were studied regarding the arterial territory of the affected lower limb.There was a predominance of the femoropopliteal segment, almost two thirds of patients, followed by the aortoiliac and infrapopliteal territory.However, there was no statistically significant relationship between these variables and the involvement of the carotid arteries.
An important point to be emphasized concerns the approach to the patient after the duplex scan examination of the carotid.There was change in the conduct, which initially would be expectant without the prior diagnosis of carotid stenosis, in 24% of the patients.In these, the finding of stenosis was considered so relevant as to requested a more detailed study of the degree of stenosis.In 15% of patients, only additional exams were performed, without intervention.In 9%, carotid intervention was held according to the indication criteria established in large randomized studies 10,15,17,28 .These intervention patients showed carotid stenosis greater than 70%, and were indicated a treatment with level 1 scientific evidence for prevention of cerebrovascular accident.It should be noted that the required number of patients to be operated to prevent a single stroke accident in five years is high, about six endarterectomies in symptomatic patients and 17 in asymptomatic ones 29,30 , in services with low rates of postoperative neurological complications.Even for the non-operated patients we initiated the appropriate clinical treatment, currently considered the first option for treatment of asymptomatic patients by some authors 21 .Both the diagnosis and the indicated treatment would not have been carried if the examination of the carotid arteries was not requested.Early diagnosis and treatment of carotid stenosis are of utmost importance for the prevention of stroke, as already emphasized 11 .
The presence of prior neurological symptoms related to the carotid territory was also statistically significant for the presence of carotid stenosis after logistic regression and multivariate analysis.It should be emphasized, however, that the patients in this sample classified as having a history of neurological symptoms had presented with these at least more than two years before, ie, they had no recent history of neurological symptoms, which might not motivate the request of a carotid echo-color-doppler study.In the NASCET study 30 patients were considered symptomatic only if they had neurological symptoms in the carotid territory in the past six months.
Patients with symptomatic peripheral arterial disease display a high prevalence of significant carotid stenosis (40%).There was a trend in the association between severity of peripheral artery disease and severity of carotid stenosis, although not significant.Previous history of neurological symptoms was statistically significant in explaining the severity of carotid stenosis.In conclusion, the study of the carotid arteries by duplex scan examination is of paramount importance in the evaluation of patients with symptomatic peripheral arterial disease and should be systematically indicated to such patients.
34 (1.47 to 125.0) times the chance of patients with asymptomatic disease, with a p value of 0.05.DISCUSSION DISCUSSION DISCUSSION DISCUSSION DISCUSSION This study sought to describe the clinical characteristics, risk factors and the association with carotid stenosis in a sample of patients with symptomatic peripheral arterial disease treated by a reference service in Angiology and Vascular Surgery.

Figure 2 Figure 2 Figure 2 Figure 2 Figure 2 -
Figure 2 Figure 2 Figure 2 Figure 2 Figure 2 -Scatter Plot of the ankle-brachial index (ABI) and the Rutherford classification according to the degree of carotid stenosis.

Table 1 Table 1 -
Distribution of patients according to the degree of carotid artery stenosis.

Table 2 Table 2 Table 2 Table 2 Table 2 -
Distribution of the number of patients about the risk factors and associated diseases

Table 3 Table 3 Table 3 Table 3 Table 3 -
Descriptive measures and Mann-Whitney test for carotid stenosis and the variables studied.

Table 4 Table 4 Table 4 Table 4 Table 4 -
Distribution of patients into two groups according to the degree of carotid stenosis and the variables studied.