J Am Soc Nephrol 14: 1591–1598, 2003 Ankle-Brachial Blood Pressure Index Predicts All-Cause and Cardiovascular Mortality in Hemodialysis Patients KUMEO ONO,* AKIYASU TSUCHIDA,† HIRONOBU KAWAI,ʈ HIDENORI MATSUO,‡ RYOUJI WAKAMATSU,§ AKIRA MAEZAWA,¶ SHINTAROU YANO,¶¶ TOMOYUKI KAWADA,# and YOSHIHISA NOJIMA@ for the GUNMA Dialysis and ASO Study Group *Kan-etsu Chuo Hospital, †Toho Hospital, ʈMaebashi Saiseikai Hospital, ‡Hidaka Hospital, §Nishikatakai Clinic, ¶Wakaba Hospital, ¶¶ Hirosegawa Clinic, #Department of Public Health, Gunma University School of Medicine, and @Third Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan. Abstract. A reduction in ankle-brachial BP index (ABPI) is icantly higher in patients with lower ABPI than those with associated with generalized atherosclerotic diseases and pre- ABPI Ն 1.1 to Ͻ1.3. During the study period, 77 cardiovas- dicts cardiovascular mortality and morbidity in several patient cular and 41 noncardiovascular fatal events occurred. On the populations. However, a large-scale analysis of ABPI is lack- basis of Cox proportional hazards regression analysis, ABPI ing for hemodialysis (HD) patients, and its use in this popula- emerged as a strong independent predictor of all-cause and tion is not fully validated. A cohort of 1010 Japanese patients cardiovascular mortality. After adjustment for confounding undergoing chronic hemodialysis was studied between Novem- variables, the hazard ratio (HR) for ABPI Ͻ 0.9 was 4.04 (95% ber 1999 and May 2002. Mean age at entry was 60.6 Ϯ 12.5 yr, confidence interval, 2.38 to 6.95) for all-cause mortality and and duration of follow-up was 22.3 Ϯ 5.6 mo. Patients were 5.90 (2.83 to 12.29) for cardiovascular mortality. Even those stratified into five groups (Ͻ 0.9, Ն 0.9 to Ͻ 1.0, Ն 1.0 to Ͻ with modest reductions in the ABPI (Ն 0.9 to Ͻ1.1) appeared 1.1, Ն 1.1 to Ͻ 1.3, and Ն 1.3) by ABPI measured at entry by to be at increased risk. Patients having abnormally high ABPI an oscillometric method. The frequency distribution of ABPI (Ն 1.3) also had poor prognosis (HR, 2.33 [1.11 to 4.89] and was 16.5% of patients Ͻ 0.9, 8.6% of patients Ն 0.9 to Ͻ 1.0, 3.04 [1.14 to 8.12] for all-cause and cardiovascular mortality, 16.9% of patients 1.0 Ն to Ͻ 1.1, and 47.0% of patients Ն 1.1 respectively). Thus, the present findings validate ABPI as a to Ͻ 1.3, whereas 10.9% of patients had an abnormally high powerful and independent predictor for all-cause and cardio- ABPI (Ն 1.3). The relative risk of a history of diabetes mellitus vascular mortality among hemodialysis patients. (DM), cardiovascular, and cerebrovascular disease was signif- Growing numbers of patients are now on hemodialysis as a strategies should ultimately improve their survival and quality result of end-stage renal disease (ESRD). ESRD is associated of life. with a substantially reduced life expectancy, of which cardio- Peripheral arterial occlusive disease (PAOD) has recently vascular disease (CVD) is the leading cause (1–3). Several attracted much attention as a risk factor for adverse outcomes. cardiovascular risk factors are applicable to both the general Epidemiological and clinical studies of the general population and the hemodialysis population. In contrast, some cardiovas- have clearly shown that PAOD is a strong predictor for sub- cular risk factors are present to a greater extent in the hemo- sequent cardiovascular and overall mortality (5–8). Limited dialysis population than in the general population, while others available data also suggest that PAOD is prevalent in hemo- appear irrelevant in hemodialysis patients (4). Therefore, it is dialysis patients (4,9–11) and is associated with poor outcomes important to define risk factors critical for overall and cardio- (9,10). However, evaluation of PAOD receives relatively little vascular mortality in this patient population. Identification of attention among hemodialysis patients. Hence they are less patients who require aggressive preventive and interventional likely to receive appropriate treatment than are those, for example, with coronary artery disease. Ankle-brachial BP index (ABPI; the ratio of ankle to bra- chial systolic BP) is a simple, non-invasive, and reliable Received September 25, 2002. Accepted February 10, 2003. method to access PAOD. Not only useful in diagnosing PAOD, Correspondence to Dr. Yoshihisa Nojima, Third Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan. Phone: large-scale studies showed that ABPI is a strong predictor for 81-27-220-8161; Fax: 81-27-220-8173; E-mail: [email protected] CVD and mortality (5–8). However, the measurement of ABPI 1046-6673/1406-1591 has not been fully validated in the ESRD population. There- Journal of the American Society of Nephrology fore, we sought in the current study to clarify the diagnostic Copyright © 2003 by the American Society of Nephrology and prognostic value of ABPI in hemodialysis patients. The DOI: 10.1097/01.ASN.0000065547.98258.3D ABPI was measured at the baseline in a cohort of Japanese 1592 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 1591–1598, 2003 patients undergoing chronic hemodialysis. All subjects had ABPI Measurement detailed assessment of other risk factors and were followed-up ABPI was determined in all participants and control individuals for 2 yr on average. We found that there is a graded inverse using ABI-form (Colin, Japan), which simultaneously measures bi- relationship between the ABPI and both cardiovascular and lateral arm and ankle (brachial and posterior tibial arteries, respec- all-cause mortality. Multivariate analysis indicated that ABPI tively) BP by an oscillometric method. Before this study, the agree- is independent from other risk factors, including advanced age, ment was assessed between the oscillometric and the conventional Doppler methods in measuring ankle BP in 238 volunteers, including hypertension, and diabetes mellitus. Thus, the measurement of healthy subjects and patients with PAOD (unpublished observations, ABPI effectively identifies high-risk hemodialysis patients, a Mano N. et al.). The variables determined by the two methods were target population requiring intensive follow-up. highly correlated with one another (R ϭ 0.985; P Ͻ 0.001) even in the range of systolic pressure Ͻ 100 mmHg. The mean Ϯ SD of differ- ences was Ϫ0.69 Ϯ 6.47 mmHg, and the limits of agreement were Materials and Methods 12.2 and Ϫ13.6 mmHg, respectively. The BP was measured after Study Design and Patients completion of the dialysis treatment and after allowing patients at rest This prospective cohort study was conducted at 15 dialysis centers in supine position at least for 5 min. Some patients needed more than in the Gunma and Saitama districts of Japan. To be eligible for this 15 min for the BP to stabilize. ABPI was calculated by the ratio of the study, patients had to have received regular hemodialysis at least for ankle systolic pressure divided by the arm systolic pressure. The 3 mo just before entry. Moreover, patients had to be clinically stable systolic pressure of the arm without dialysis access and the lower for 3 mo before entry and specifically lack acute cardiovascular, value of the ankle pressure were used for the calculation. The ABPI cerebrovascular, infectious, or other active diseases. A total of 1010 measurement was done once in each patient. patients were recruited from November 1999 to July 2001. All of them agreed to participate in the follow-up study. The mean Ϯ SD age of Outcome Data Collection the cohort was 60.6 Ϯ 12.5 yr. The observation ended in May 2002. At the end of the follow-up, the status of all patients was assessed During the follow-up period, one patient received a renal transplant. and data on mortality were obtained for the entire cohort. We recorded This patient was followed until the date of transplantation and then 118 deaths, including 77 fatal cardiovascular events, 36 of which were censored. Twenty-eight patients moved away from the study dialysis attributed to heart failure, 14 to cerebral infarction, 11 to the myocar- centers. Among these, outcome data from ten patients could be dial infarction, 8 to cerebral hemorrhage, 2 to pulmonary embolism, obtained. The remaining 18 patients were censored at departure to and 2 to ruptured aneurysms. Other cardiovascular events included another dialysis unit. The mean patient follow-up was 22.3 Ϯ 5.6 mo. aortic valve stenosis, ventricular fibrillation, ischemic gangrene of the Demographic and medical data were obtained from medical foot, and sudden cardiac arrest of unknown cause. The 41 fatal records and interviews with patients and/or the patient’s primary noncardiovascular causes were infectious disease (n ϭ 16), cancer (n nephrologists at study entry. These include age, gender, smoking ϭ 13), gastrointestinal bleeding (n ϭ 3), traffic accident (n ϭ 2), and ϭ history (ever versus never), body mass index (BMI, weight/height2), other (n 7). comorbid conditions, serum creatinine, albumin, cholesterol, and KT/V. Comorbid conditions were defined as follows. Coronary artery Statistical Analyses disease: a history of exertional angina, a history of ischemic electro- Data are expressed as mean Ϯ SD. The ␹2 test for trend was used cardiogram change followed by medication of vasodilator, previous to test for a dose-response relation of variables between ABPI cate- angiogram showing significant occlusive disease, a history of a past gories. Differences between mean values were assessed by ANOVA. myocardial infarction, or a history of coronary artery bypass surgery Bivariate associations between the ABPI and discrete variables were or angioplasty.