Nephrol Dial Transplant (2008) 23: 3704–3710 doi: 10.1093/ndt/gfn321 Advance Access publication 20 June 2008

Original Article

Use of ACE inhibitors or angiotensin receptor blockers and survival in patients on peritoneal dialysis∗ Wei Fang1,2 , Dimitrios G. Oreopoulos1 and Joanne M. Bargman1 1

Peritoneal Dialysis Program, University Health Network, Toronto, and University of Toronto, Toronto, Ontario, Canada and 2 Renal Division, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Abstract Background. Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve outcome in patients with renal failure not on dialysis therapy and patients on haemodialysis (HD). However, their effect on survival has not been studied in peritoneal dialysis (PD) patients. The present study examined the association between therapy with ACE inhibitor/ARB and mortality in patients undergoing chronic PD. Methods. All patients who commenced PD between 1 January 2000 and 31 December 2005 at the University Health Network were included. Patients were grouped according to whether they had been treated with ACE inhibitor/ARB. They were followed up from the date of PD initiation until death, cessation of PD, transfer to other centres or to the end of the study (31 December 2006). Results. A total of 306 patients were included in the study. One hundred and sixty-five were treated with ACE inhibitors/ARB (treated group) and 141 were not (untreated group). The treated group patients were younger (56.9 ± 16.6 versus 62.3 ± 17.8 years, P < 0.01) and more likely to have a history of hypertension than the untreated group. At the initiation of PD, systolic and diastolic blood pressures were higher in the treated than the untreated group (138.8 ± 21.8 versus 128.6 ± 22.4 mmHg, P < 0.001; 79.8 ± 14.1 versus 74.5 ± 12.5 mmHg, P = 0.001) and remained significantly higher during the follow-up (133.5 ± 16.4 versus 125.1 ± 16.7 mmHg; 77.3 ± 9.8 versus 73.2 ± 9.7 mmHg, both P < 0.001). The treated group had a significantly longer survival compared to the untreated group (log rank 19.191, P < 0.001). After adjusting for age, blood pressure and other demographic and clinical parameters, multivariable Cox proportional hazards modelling showed that the use of ACE inhibitor/ARB was associated with 62% reduced risk for death (HR 0.382, 95% CI 0.232–0.631, P < 0.001). Correspondence and offprint requests to: Joanne M. Bargman, University Health Network, Toronto, and University of Toronto, 200 Elizabeth Street 8N-840, Toronto, Ontario M5G 2C4, Canada. Tel: +1-416-340-4804; Fax: +1-416-340-4999; E-mail: [email protected] ∗ Presented in part at the 40th Congress of the American Society of Nephrology, 2007.

Conclusion. In this retrospective analysis, ACE inhibitor/ ARB therapy was associated with a dramatically reduced mortality in patients on peritoneal dialysis independent of blood pressure and other clinical and demographic variables. Keywords: angiotensin II type 1 receptor blockers (ARB); angiotensin-converting enzyme (ACE) inhibitors; end-stage renal disease (ESRD); peritoneal dialysis (PD); survival

Introduction Cardiovascular disease is a frequent and important cause of morbidity and mortality in patients with end-stage renal disease (ESRD). It is present in as many as 50–60% of ESRD patients and remains the leading cause of mortality [1]. Dialysis patients have a greater than 10- to 20-fold increase in cardiovascular mortality compared with ageand sex-matched populations without renal disease [2,3]. Hypertension is a major risk factor for cardiovascular complications in both the general population and patients with ESRD. An increase in the renin–angiotensin–aldosterone activity is one of the major factors contributing to the hypertension in ESRD patients. Furthermore, epidemiological and experimental data suggest that the activation of the renin–angiotensin–aldosterone system has an important role in increasing the risk of cardiovascular events [4]. In the general population, antihypertensive medications of various groups improve the prognosis of patients with hypertension [5], but the use of angiotensin-converting enzyme (ACE) inhibitors may have additional positive effects on high-risk patients [6]. ACE inhibitors have been shown to improve survival and confer substantial renal benefits in patients with renal failure not on dialysis [7,8]. In haemodialysis (HD) patients, Efrati et al. reported that treatment with ACE inhibitors, independent of their effect on blood pressure, was associated with 52% reduced mortality [9]. However, the effect on survival has not been studied in peritoneal dialysis (PD)

 C The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: [email protected]

Use of ACE inhibitors or angiotensin receptor blockers

patients. The present study examined the association between therapy with ACE inhibitors or angiotensin II type 1 receptor blockers (ACE inhibitor/ARB) and mortality in patients undergoing chronic PD.

Methods All patients who commenced PD between 1 January 2000 and 31 December 2005 at the University Health Network, University of Toronto, Toronto, Canada, were included. Clinical data and details of medical treatment were extracted from charts. Patients with hypertension had been treated with hypertensives as warranted by their clinical status. Patients treated with ACE inhibitor/ARB for at least 6 months were included in the ACE inhibitor/ARB-treated group. At the initiation of PD, the following demographic and comorbidity characteristics were collected: age, gender, underlying cause of ESRD, height, weight, presence of diabetes mellitus (defined either as a comorbid condition or as the aetiology of ESRD), details about transplantation, history of hypertension, previous congestive heart failure (defined as an episode of congestive heart failure during the 6 months before PD commencement) and cardiovascular disease (CVD). CVD was defined as a previous history of coronary artery disease, peripheral vascular disease or cerebrovascular disease. Body mass index (BMI) was calculated as the weight (kg) divided by the square of height (in metres). The following laboratory parameters were collected: haemoglobin, serum albumin, electrolytes, calcium, phosphate, intact parathyroid hormone (iPTH) and lipids. Other clinical data collected at the initiation of PD included the presence of left ventricular hypertrophy (LVH), systolic and diastolic blood pressure, antihypertensive treatment, use of statins, residual renal function (RRF), urine output, PD prescription, peritoneal transport characteristics measured by the dialysate to plasma creatinine ratio (D/Pcr) at 4 h in a standard peritoneal equilibration test and total Kt/V urea. LVH was defined by mass indexed to the body surface area of >131 g/m2 in men and 100 g/m2 in women or by electrocardiographic criteria if echocardiography data were not available. Blood pressure was measured by trained nurses with a standard mercury sphygmomanometer in the supine position in the PD clinic. During the follow-up, data on systolic and diastolic blood pressures were collected serially every 2–3 months. Laboratory measures were collected serially at 6 months, 1 year and annually thereafter. All patients were followed up from the date of PD initiation until death, cessation of PD, transfer to other centres or to the end of the study (31 December 2006). Statistical analyses All results were expressed as mean ± SD for normally distributed data, median and range for skewed data and frequency (%) for categorical data. Differences in patient demographics, clinical and laboratory parameters between the treated group and untreated group were evaluated by Student’s t-test for parametric data and the Mann–Whitney test for nonparametric data. Comparisons of percentages

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between the groups were made with the chi-squared test (χ2 ) or Fisher’s exact test, as appropriate. The outcome event was all-cause mortality. Survival curves were generated by the Kaplan–Meier method and compared by the log-rank test. The association between ACE inhibitor/ARB treatment and mortality was analysed by univariate and then by the multivariate Cox proportional hazards model. The following covariates were used in the modelling process: treatment with ACE inhibitor/ARB, age, sex, diabetes mellitus, CVD, previous congestive heart failure, systolic and diastolic blood pressures, treatment with calcium channel blockers, beta blockers and statins, haemoglobin, serum albumin, calcium, phosphate, lipids, residual renal function and Kt/V urea. Covariates with Pvalue