Association between modified CHA2DS2-VASc Score with Ankle-Brachial index < 0.9

The ankle-brachial index (ABI) is a reliable diagnostic examination for peripheral arterial occlusive disease (PAOD). We previously reported CHADS2 score was significantly correlated with PAOD. However, the association between CHA2DS2-VASc score and ABI < 0.9 is not evaluated in the literature. The aim of the present study was to investigate whether CHA2DS2-VASc score has a strong association with PAOD. We enrolled 1482 patients in this study. PAOD was defined as ABI < 0.9 in either leg. Vascular disease in CHA2DS2-VASc score was modified as vascular disease except PAOD. Of the 1482 subjects, the prevalence of ABI < 0.9 was 5.6%. Multivariate analysis showed that the increased age, decreased estimated glomerular filtration rate and increased modified CHA2DS2-VASc score (OR, 1.764; p < 0.001) were independent associated with ABI < 0.9. In addition, the percentage of ABI < 0.9 in patients with modified CHA2DS2-VASc score of 0, 1, and <2 were 0%, 0.9%, and 0.7%, respectively (All < 1%). Our study demonstrated modified CHA2DS2-VASc score was significantly associated with ABI < 0.9. Calculation of modified CHA2DS2-VASc score might be useful in identifying patients with PAOD and in stratifying the risk of PAOD in non-AF patients.


Results
The prevalence of ABI < 0.9 was 5.6%. Table 1 shows the comparison of clinical characteristics between patients with and without ABI < 0.9. The mean age of the 1482 patients was 61.4 ± 13.6 years. Compared with patients with ABI ≥ 0.9, patients with ABI < 0.9 were found to have an older age, higher prevalence of heart failure, hypertension, diabetes, cerebrovascular disease, and CAD, higher CHADS 2 score, higher modified CHA 2 DS 2 -VASc score, lower BMI, lower eGFR, higher uric acid level, and higher percentage of using of aspirin, ARBs, diuretics, and statins. Table 2 shows the determinants of ABI < 0.9 in all study patients. In the univariate analysis, ABI < 0.9 was found to be significantly associated with increased age, a history of heart failure, hypertension, diabetes, cerebrovascular disease, and coronary artery disease, low BMI, high CHADS 2 score, high modified CHA 2 DS 2 -VASc score, low eGFR, high uric acid level, and high percentage of using aspirin, ARBs, diuretics, and statins. In the forward multivariate logistic analysis, increased age (odds ratio [OR], 1.058; 95% confidence interval [CI], 1.017-1.101; p = 0.005), lower eGFR (OR, 0.977; 95% CI, 0.960-0.994; p = 0.01), and high modified CHA 2 DS 2 -VASc score (OR, 1.764; 95% CI, 1.338-2.325; p < 0.001) were associated with ABI < 0.9.

Discussion
In this study, we evaluated the association of ABI < 0.9 with modified CHA 2 DS 2 -VASc score. We found that advanced age, lower eGFR, and modified CHA 2 DS 2 -VASc score was independently associated with ABI < 0.9. In Characteristics All patients (n = 1482) ABI < 0.9 (n = 83) ABI ≥ 0.9 (n = 1399) P value Age ( addition, the percentage of ABI < 0.9 in patients with modified CHA 2 DS 2 -VASc score of 0, 1, and <2 were 0%, 0.9%, and 0.7%, respectively (All < 1%). CHA 2 DS 2 -VASc score is a validated clinical prediction tool, which outperforms the CHADS 2 score in predicting stroke and systemic embolism of AF patients 22 . Several recent studies extended the usage of CHA 2 DS 2 -VASc score to non-AF population [30][31][32] . Mustafa Cetin et al. reported that CHA 2 DS 2 -VASc score was increased in patients with mild and severe CAD, and it was correlated significantly with the number of diseased vessels and Gensini score. Therefore, their findings suggested that CHA 2 DS 2 -VASc score might be useful in prediction of the risk of severe CAD 30 . Modi R et al. also found that CHADS 2 score and CHA 2 DS 2 -VASc score correlated significantly with CAD severity and suggested these scores might play an important role in predicting the severity of CAD 31 . In addition, Hoshino T et al. reported that CHADS 2 score > 2 and CHA 2 DS 2 -VASc score > 4 are associated with 3-month functional outcome of stroke in patients with prior coronary artery disease 32 .
Patients with PAOD have significantly increased cardiovascular morbidity and mortality. The 5-year mortality of patients with asymptomatic and symptomatic PAOD is 19% and 24% 8 . However, in patients with critical limb ischemia, mortality rates could be as high as 20% within 6 months from diagnosis and exceeding 50% at 5 years 9 . Therefore, how to identify high risk and low risk patients become extremely important during initial diagnosis. Risk factors of PAOD include advanced age, diabetes, hypertension, stroke, heart failure, and so on 6,10-14 . Advanced age, diabetes, and hypertension were considered as traditional risk factors of PAOD. Because PAOD was a systemic atherosclerotic process and shares similar risk factors to atherosclerosis in the coronary and carotid arteries, there was also a strong association of PAOD with stroke and CAD [11][12][13]16,17 . Coexistent CAD and stroke were highly prevalent in patients with PAOD particularly in the elderly population 7,17 . Adesunloye BA et al. also showed patients with heart failure were over 3 times more likely to have PAOD compared to the general population 14 .
PAOD was more prevalent in women than generally appreciated. The estimates of PAOD varied greatly according to the different diagnostic criteria. PAOD was also be affected by different race 15 . According to a systemic review of global estimates of prevalence and risk factors for PAOD in 2000 and 2010, the association of sex with PAOD had an inconsistent result in the two setting. For all countries, female overall had a significantly higher risk than male, but in high income countries, male had an increased risk of PAOD than females 18 . In our previous nationwide cohort study of PAOD in Taiwan, female gender was found to be a significant predictor of new-onset POAD after multivariate analysis 20 . Because the components of modified CHA 2 DS 2 -VASc score were significantly correlated with PAOD, modified CHA 2 DS 2 -VASc score itself should have a strong correlation with PAOD. In the present study, we consistently demonstrated that modified CHA 2 DS 2 -VASc score was significantly associated with ABI < 0.9 not only in the univariate analysis but also in the multivariate analysis. In addition, although CHADS 2 score was significantly associated with ABI < 0.9 in the univariate analysis, the association disappeared in the multivariate analysis. Hence, modified CHA 2 DS 2 -VASc score might be more useful in identifying patients with PAOD than CHADS 2 score.  Although CHADS 2 score was a useful and simple tool to estimate the risk of PAOD in our previous study 19,20 , it still had the limitation to identify low-risk patients which is similar to its usage in AF patients for stroke and systemic embolism prediction. In our study, the percentage of ABI < 0.9 in patients with CHADS 2 score of 0 and 1 were 0.7% and 1.7%; however; the percentage of ABI < 0.9 in patients with CHA 2 DS 2 -VASc score of 0 and 1 were 0% and 0.9% which were both <1%. These results suggest that CHA 2 DS 2 -VASc score might be a more useful clinical tool for new-onset PAOD prediction and help physicians to further stratify the risk of PAOD than CHADS 2 score in non-AF patients.
The prevalence of ABI < 0.9 was 5.6% in our study. According to the previous literature, the prevalence of PAOD in Asia was less than 5% in the general population 33 . In addition, Chen et al. also reported that overall prevalence of ABI < 0.9 in 1915 Taiwanese patients was 5.4%, which was also similar to our study 34 .
Although there are several similar risk factors such as age, hypertension, diabetes, and heart failure between CHA 2 DS 2 -VASc score and stroke, CAD, and even PAOD, there still exists many dissimilarities between them. For example, when the predicted outcome is stroke, the definition of vascular disease of CHA 2 DS 2 -VASc score is prior myocardial infarction, PAOD, or aortic plaque. However, when the predicted outcomes is CAD, some studies define the vascular disease as the one used in stroke prediction 35 , but some studies define the vascular disease as PAOD only 30,31 . In the present study, we evaluated the association between PAOD and modified CHA 2 DS 2 -VASc score, so we defined the vascular disease as CAD only.
There were several limitations to our study. First, because our study was a cross-sectional one, we could only confirm the significant association of modified CHA 2 DS 2 -VASc score with ABI < 0.9. We could not elucidate the true cause-effect relationship between them. Second, since the subjects of this study were already being evaluated for heart disease, it was susceptible to selection bias and making findings potentially less generalized. Third, the majority of our patients were treated chronically with antihypertensive medications. For ethical reasons, we did not withdraw these medications and could not exclude the influence of antihypertensive agents on our findings. However, we had adjusted these parameters during multivariate analysis in our study.
In conclusion, our study demonstrated modified CHA 2 DS 2 -VASc score was significantly associated with ABI < 0.9. Calculation of modified CHA 2 DS 2 -VASc score might be useful in identifying patients with PAOD and in stratifying the risk of PAOD in non-AF patients. Future prospective study is needed to examine the ability of modified CHA 2 DS 2 -VASc score in prediction of newly-onset of PAOD.

Study subjects.
Our study was a cross-sectional study. Study subjects were consecutively included from a group of patients who were arranged for echocardiographic examinations at Kaohsiung Municipal Hsiao-Kang Hospital. We excluded patients with significant aortic or mitral valve diseases, AF, and inadequate image visualization. Finally, a total of 1482 patients were included. ABI assessment. The values of ABI were measured by an ABI-form device (VP1000; Colin Co. Ltd., Komaki, Japan), which simultaneously and automatically measured blood pressures in both arms and ankles using an oscillometric method 36,37 . The ABI was calculated by the ratio of the ankle systolic blood pressure divided by the higher systolic blood pressure of the arms. After obtaining bilateral ABI values, the lower one was used for later analysis. The ABI measurement was done once in each patient.
Collection of demographic, medical, and laboratory data. Demographic and medical data including age, gender, smoking history, and comorbid conditions were obtained from interviews or medical records of patients. The body mass index (BMI) was calculated as the ratio of weight in kilograms divided by square of height in meters. Laboratory data such as triglyceride, total cholesterol, and uric acid were measured from fasting blood samples. The value of estimated glomerular filtration rate (eGFR) was calculated using the equation in the Modification of Diet in Renal Disease (MDRD) study 38 . In addition, medications of patients including aspirin, β-blockers, calcium channel blockers, angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), diuretics, and statins during the study period were obtained from medical records.
Assessment of CHADS 2 score and modified CHA 2 DS 2 -VASc score. The CHADS 2 score is derived from the sum of point values of individual risk factors: congestive heart failure, hypertension, age ≥ 75 years, diabetes (1 point each), and prior stroke (2 points). The modified CHA 2 DS 2 -VASc score is derived from the sum of point values of individual risk factors: congestive heart failure, hypertension, age between 65 and 74 years, diabetes, female sex, vascular disease except PAOD (1 point each), age ≥ 75 years (2 points), and prior stroke (2 points). Because the aim of current study was to evaluate the risk of PAOD, vascular disease in this study was modified as vascular disease except PAOD. Congestive heart failure was defined as left ventricular systolic dysfunction with left ventricular ejection fraction ≦40% or having a known history of congestive heart failure. Hypertension was defined as systolic blood pressure ≧140 mmHg or diastolic blood pressure ≧90 mmHg or anti-hypertensive drugs were prescribed. Diabetes was defined as fasting blood glucose level greater than 126 mg/dL or hypoglycemic agents were used to control blood glucose levels. Prior stroke was defined as history of cerebrovascular disease including cerebral bleeding and infarction.
Statistical analysis. The SPSS 18.0 (SPSS, Inc., Chicago, IL, USA) was used for statistical analysis. Data are expressed as percentages or mean ± standard deviation. Categorical and continuous variables between groups were compared by independent Chi-square test and samples t-test, respectively. The relationship between variables and ABI < 0.9 was assessed by univariate regression analysis. Subsequently, significant variables in the univariate analysis were further analyzed by forward multiple logistic regression analysis to identify the parameters associated with ABI < 0.9. All tests were 2-sided, and the level of significance was established as p < 0.05.