Shinshu Med J,64⑶ :135～146,2016 The Optimal Cut-offValue of Ankle Brachial Index for Screening Cardiovascular Disease Risk in Hemodialysis Patients Makoto HARADA, Wataru TSUKADA, Osamu TSUKADA Koji HASHIMOTOand Yuji KAMIJO 1) Department of Nephrology, Shinshu University School of Medicine 2) Department of Nephrology and Urology, Jishyukai Ueda Kidney Clinic Severe atherosclerosis and vascular calcification, causing coronary artery stenosis or peripheral artery diseases (PAD),are frequently detected in hemodialysis (HD)patients.Ankle brachial index (ABI)is a useful marker for detecting PAD,as well as being predictive of the development of cardiovascular diseases (CVD). However,obvious atherosclerotic vascular changes in HD patients might elevate the optimal cut-offvalue of ABI for screening CVD over the conventional ABI cut-offvalue,0.9.Moreover,the ABI cut-offvalue may be altered by the presence of diabetes mellitus (DM)in HD patients.This retrospective cohort study involved 110 patients on maintenance HD. The ABI cut-off value predicting CVD in HD patients was determined by receiver operating curve(ROC)analysis.ABI cut-offvalues were also compared in groups of subjects with and without DM.The ABI cut-offvalue predictive of CVD in all 110 HD patients was 0.960(area under the curve ［AUC］0.761,sensitivity 0.641,specificity 0.803).The cut-offvalue of ABI was 1.045 in the DM group (AUC 0. 735,sensitivity 0.813,specificity 0.606)and 0.960 in the non-DM group (AUC 0.773,sensitivity 0.714,specificity 0.868). Kaplan-Meier analysis showed that patients with ABI below the cut-off values in each group were significantly more likely to develop CVD.The optimal ABI cut-offvalues for screening high-risk HD patients with CVD should be set at higher levels than the conventional cut-offvalue(0.9),and that the optimal cut-off values might differ in HD patients with and without DM,at 1.045 and 0.960,respectively.Shinshu Med J 64 : 135―146, 2016 (Received for publication December 3, 2015;accepted in revised form January 15, 2016) Key words:ankle brachial index (ABI), cardiovascular diseases, hemodialysis Abbreviations:PAD,peripheral artery diseases;HD,hemodialysis;ABI,ankle brachial index ;CVD,cardiovascular diseases;DM,diabetes mellitus;ROC,receiver operating curve;AUC,area under the curve major causes of death in HD patients,their detection Introduction is difficult,because they progress asymptomatically. Severe atherosclerosis and vascular calcification, Fewer HD patients with acute myocardial infarc- which can lead to coronary artery stenosis and/or tion (AMI) had chest pain than non-HD patients. peripheral artery diseases (PAD), are frequently Therefore,evaluation of disease severity of atheros- detected in patients on hemodialysis (HD). clerosis could have prognostic implications in HD Although these cardiovascular diseases (CVD) are patients and has predictive value for CVDs. In general, ankle brachial index (ABI) is a useful Corresponding author:Yuji Kamijo marker for detecting PAD,and for predicting future Department of Nephrology,Shinshu University School of CVDs including myocardial infarction and Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan stroke. Recent reports showed that ABI cut-off E-mail:yujibeat＠shinshu-u.ac.jp values below 0.9 are useful for predicting future CV No.3,2016 135 Harada.Tsukada W .Tsukada O et al. Fig.1 Chart of the study flow events.In HD patients,however,the appropriate agreed to participate in the study were enrolled. ABI cut-offvalue predicting CVD is unknown.We Patients were excluded if clinical data, including hypothesized that it would be higher than that of background clinical information,laboratory values, non-HD patients, since dialysis patients are more measurements of ABI,cardio-ankle vascular index likely to develop severe arterial calcification. (CAVI),and aortic arch calcification score(AoACS), Furthermore, previous reports suggested that were missing.Patients with severe active infectious diabetes mellitus (DM)causes more severe arterial diseases or malignancies at the time of study entry, calcification as well as atherosclerotic lesions than and those who could not be followed up until CVD, other diseases. The difficulties encountered in death,or December 2013,were excluded.Of the 167 compressing calcified arteries lead to increases in patients,57 were excluded.These patients included blood pressure, suggesting that DM alters the ABI 38 in the geriatric medical care facility for the cut-offvalue. elderly who had dementia, were bedridden, and In the HD patients including DM patients, sensi- were in poor physical condition; 17 who lacked tivity of the ABI cut-offvalue below 0.9 for diagnos- sufficient clinical information, such as past compli- ing PAD was only 29.9 %.Thus,sensitivity of the cations or history of CVD ; and two who refused ABI cut-off value below 0.9 for screening CVD is informed consent. Thus, 110 outpatients were expected to be low in HD patients.This study was enrolled (Fig. 1). The study protocol was approved therefore designed to determine the optimal ABI by the institutional review board of the ethics com- cut-off value for screening high risk HD patients mittee of Shinshu University (approval number: with CVD,as well as to assess the effects of DM on 1996)and conformed to the Declaration of Helsinki ABI cut-offvalues. as revised in 2008. Written informed consent was obtained from each patient before study entry. Materials and Methods Baseline examinations Study design and subjects ABI was evaluated in each patient with a Vasera This retrospective cohort study was designed to VS-1500A (Fukuda Denshi, Tokyo, Japan) just determine the ABI cut-offvalue predictive of CVD before the start of an HD session at the beginning of in HD patients. Beginning in January 2010, 167 a week. Briefly, patients were placed in a supine patients were undergoing conventional maintenance position and their systolic blood pressure was mea- HD in Jishyukai Ueda Kidney Clinic,with almost all sured in the brachial artery of the arm without of them screened by ABI. Stable outpatients who vascular access and in the posterior tibial arteries 136 Shinshu Med J Vol.64 ABI in HD patients of both legs. ABI was defined as the ratio of blood result of the hemorrhage,which was not reversible pressure in each leg to the blood pressure in the within 24 hours.Aortic dissection was defined as the upper arm,with the lower of the two values used for acute onset of chest or back pain,and a diagnosis of analysis. CAVI was evaluated by the same auto- dissected aorta on computed tomography (CT) fol- matic oscillometric cuff measurement device. The lowing surgery or medication. An aortic aneurysm cuffs were applied to both upper arms and ankles. was defined by a dilated aorta diagnosed by CT Electrodes were fixed to each wrist and a heart following an operation.The definitions of AP,AMI, sound sensor was placed on the second intercostal CI, and PAD were the same as above. sternum.The methods of measuring and calculating Statistical analysis CAVI have been described. AoACS was calcu- Continuous variables were compared by Mann- lated as the number of sectors with aortic arch Whitney U tests, and categorical variables by Fi- calcification in plain chest X-rays, divided into 16 sher’s exact tests. Factors associated with CVD circumferences. Blood samples obtained before were evaluated by Cox proportional hazard regres- the start of an HD session at the beginning of a sion analysis.Receiver operating curve (ROC)anal- week were analyzed by BML, Inc, Japan. ysis was used to evaluate the ABI cut-off value Endpoint and diagnosis of CVD predictive of CVD in HD patients. To evaluate The study endpoint was the incidence of CVD, whether DM altered the ABI cut-offvalue,subjects including ischemic heart diseases (IHDs),PAD,and were separated into those with and without DM and cerebral infarction (CI). IHDs included angina their cut-offvalues compared.Kaplan-Meier analy- pectoris (AP) and acute myocardial infarction sis was used to determine the cumulative incidence (AMI).AP was defined based on coronary angiogra- of CVD. All statistical analyses were performed phy, followed by percutaneous coronary interven- using SPSS Statis tics version 22.0J (IBM Corp., tion or coronary artery bypass graft surgery. AMI Armonk, NY, USA), with statistical significance was defined as symptoms of myocardial ischemia; defined as a p＜0.05. new or presumed significant ST-segment to T- Results wave (ST-T) changes or new left bundle branch block on electrocardiograms;or an increase in the Baseline clinical characteristics cardiac enzyme marker creatinine kinase MB type. The baseline clinical characteristics of all 110 CI was defined as an acute episode of focal or global patients enrolled in this study are shown in Table 1. neurological dysfunction caused by brain, spinal Of these patients,39 experienced CVD during follow- cord, or retinal vascular injury as a result of the up, and 71 did not. Fifteen patients had IHD, 7 infarction,which was not reversible within 24 hours patients CI,and 17 patients PAD.Median ABI,rate and was symptomatic. PAD was defined based on of chronic glomerulonephritis (CGN) and hemoglo- peripheral angiography, followed by percutaneous bin concentration were significantly lower,while the peripheral artery intervention, an open surgical rates of DM,past history of CVD,and deaths from procedure,or medication.The occurrence of a CVD all causes were significantly higher,in the CVD (＋) for each patient was evaluated by more than two than in the CVD (－)group. The median follow-up researchers. period was 25 months. None of the other demo- Past history of CVD was defined as a previous graphic and clinical characteristics differed occurrence of AP, AMI, CI, cerebral hemorrhage, significantly in the two groups. PAD, aortic dissection, or aortic aneurysm.