Inhibition of the Renin-Angiotensin System and Cardiovascular Mortality in Chronic Hemodialysis Patients

Kiyotsugu Omae, Tetsuya Ogawa, Masao Yoshikawa, Michihiro Mitobe, Kosaku Nitta

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DOI: 10.4236/ijcm.2011.22011                

Abstract

INTRODUCTION: Since the outcomes associated with the use of renin-angiotensin-system inhibitors (RASi) by hemodialysis (HD) patients are not fully known, we investigated their effect on the cardiovascular mortality of chronic HD patients. METHODS: Data from 388 HD patients (237 men and 151 women) who were routinely treated for at least 6 months were analyzed. Treatment with a RASi was the major predictor variable. The main outcome measure was cardiovascular mortality. Cox regression analysis was used to assess for the use of RASi and risk of death. RESULTS: Hypertension was diagnosed in 320 patients (82.5%), and 197 (50.8%) of them were treated with a RASi (treated group) and 191 (49.2%) were not (untreated group). The treated group had a higher prevalence of hypertension, history of congestive heart failure, and presence of ST-T changes. Kaplan-Meier analysis revealed a reduction in risk of cardiovascular death in the treated group during the follow-up period (fig. 2; log-rank: p=0.0379). The multivariate analysis showed that treatment with a RASi was also independently associated with reduced cardiovascular mortality (hazard ratio= 0.184; p=0.0161). CONCLUSIONS: The results of this study suggest a possible association between the treatment with RASi and reduced risk of cardiovascular mortality, independent of their effect of lowering blood pressure.

Keywords

Renin-Angiotensin-System Inhibitors, Cardiovascular Outcomes, Hypertension, Hemodialysis

1. Introduction

The high mortality rate of dialysis patients has been well documented by previous studies [1-2]. Cardiovascular diseases are responsible for about half of the deaths of patients with end-stage renal disease (ESRD) and are a major cause of mortality [3]. Hypertension may be the underlying cause of cardiovascular morbidity in hemodialysis (HD) patients [4]. Epidemiological studies in HD patients have suggested that low blood pressure (BP), not high is associated with all-cause mortality of dialysis patients [5-8]. Based on this paradoxical epidemiological finding, some have cautioned against lowering the BP of hypertensive patients on long-term HD therapy [9].

Several randomized trials have investigated whether antihypertensive therapy, including with angiotensinconverting enzyme (ACE) inhibitors [10], angiotensin receptor blockers (ARBs) [11-12], and β-blockers [13]as well as calcium channel blockers (CCBs) [14] can prevent cardiovascular events in dialysis patients. However, there is evidence that a large proportion of dialysis patients with cardiac disease do not receive appropriate treatment with antihypertensive agents, including with renin-angiotensin system inhibitors (RASi), at least in part because of nephrologist’s concerns regarding the possibility of adverse reactions [15-16].

This study was designed to investigate the effects of RASi, such as ACE inhibitors and ARBs, on all-cause and cardiovascular mortality in patients who are undergoing long-term HD therapy.

2. Methods

Patients were recruited from among those who had been routinely treated for at least 6 months in the dialysis unit of the Yoshikawa Hospital and Saiseikai-Kurihashi Hospital in March 2006. The criteria for inclusion in the cohort were absence of congestive heart failure, diagnosed based on the presence of dyspnea in addition to two of the following conditions: raised jugular pressure, bibasilar crackles, pulmonary venous hypertension, and interstitial edema on a chest X-ray that required hospitalization or extra ultrafiltration [17]. The original cohort consisted of 457 patients, but 69 patients were excluded because of inappropriate prescriptions, transfer to another dialysis facility, or death in a traffic accident, and the remaining 388 patients (237 men and 151 women) who agreed to enroll this study were included in the final cohort.

Every HD patients underwent a monthly standard 12-lead ECG., and ST-T changes were evaluated by two investigators based on the Minesota code (MC) for ST-T segment depression (MC 4-1 to 4-4) or for a negative or flat T wave (MC 5-1 to 5-3) [18]. Exclusion criteria were: malignancy, active infection, pericardial effusion, and evidence of major valvular heart disease. The Institutional Research Ethics Committee of both hospitals approved the study protocol, and all patients gave written informed consent.

HD was performed three times weekly (4 hrs/day) with a standard technique. The potassium concentration of the dialysate was 2.0 mEq/L, and the calcium concentration was 3.0 mEq/L. Dry-weight estimates are performed routinely in our institution based on clinical signs of hydration, BP behaviors during the HD session. BP was recorded three times with a brachial sphygmomanometer after the subject had rested in the supine position for at least 10 min, and the average value of the three measurements was recorded. Hypertension was defined as systolic blood pressure (SBP) was ≥140 mmHg and/or diastolic blood pressure (DBP) was ≥90 mmHg, or the use of antihypertensive agents. Diabetes mellitus (DM) was defined o the basis of the World Health Organization (WHO) criteria [19]. Medical records were carefully checked for prescriptions of antihypertensive agents, including ACE inhibitors, ARBs, CCBs, and alphaor beta-blockers (α/β-Bs). Parameters measured at the time of baseline examination included SBP, DBP, heart rate, and intradialysis weight gain (△BW). This study was conducted in compliance with the Declaration of Helsinki.

In order to measure routine laboratory markers, including the hematocrit and serum levels of urea nitrogen, uric acid, albumin, potassium (K), calcium (Ca), phosphorus (P), and total cholesterol, blood sampling was performed every month during the follow-up period. The mean values of each parameter during the follow-up period were used for statistical analyses.

Continuous variables are presented as means ± standard deviation. Categorical variables are reported as numbers and percentages. Differences between mean values were tested for significance by the paired t test (continuous variables) or chi-square test (categorical variables), as appropriate. The main outcome measures were all-cause and cardiovascular mortality. Their association between treatment with RASi and mortality was analyzed. A survival curve was estimated by the Kaplan-Meier product limit method, and a log-rank test was used to examine the difference in survival curves between the treated group and untreated group for significance. A multivariate analysis was performed using a Cox regression model. Adjusted hazard ratios (HRs) and their 95% confidence intervals are reported. A p value less than 0.05 was considered significant. The statistical analyses were performed with SPSS 9.0 software program (SPSS Inc., Chicago, IL, USA).

3. Results

Table 1 shows the subjects’ clinical and demographic characteristics and whether they were treated or untreated with a RASi. A total of 388 HD patients (237 men and 151 women) met all of the eligibility criteria and consented to participate. Their mean age was 65.5 ± 6.5 years, and their mean duration of HD therapy (dialysis vintage) at the time of enrollment was 5.9 ± 3.2 years. There were 127 patients (53.6%) with diabetes and 102 (26.3%) with ST-T changes. Hypertension was diagnosed in 320 patients (82.5%), and 197 patients (50.8%) were treated with a RASi (treated group) and 191 patients (49.2%) were not (untreated group). The treated group had a higher prevalence of hypertension, history of congestive heart failure, and presence of ST-T changes. The serum levels of albumin, K, and P were higher in the treated group than in the untreated group. A higher proportion of the patients in the treated group also received CCBs and beta-blockers than in the untreated group. There were no statistically significant differences in age, gender, DM, presence of atrial fibrillation, hematocrit, or serum levels of urea nitrogen, uric acid, or total cholesterol between the treated group and the untreated group.

During the mean follow-up period of 2.74 ± 0.49 years, 62 patients (16.0%) died, and 40 of the deaths were due to cardiovascular disease (Table 2). The all-cause mortality rate was lower in the treated group (p = 0.0088). The time course of the relationship between RASi prescription and survival is shown by Kaplan-Meier survival curves (Figure 1 and Figure 2). The survival rate was higher in the treated group, and treatment with a RASi did significantly affect all-cause mortality risk (Figure 1; log-rank: p = 0.0009). A reduction in risk of cardiovascular death in the treated group was also observed during the follow-up period (Figure 2; log-rank: p = 0.0379).

Table 1. Baseline demographic characteristics of eligible patients.

Table 2. Cause of death.

Figure 1. Kaplan-Meier curve showing the relationship between the all-cause mortality of chronic hemodialysis patients and treatment with renin-angiotensin system inhibitors (RASi).

Figure 2. Kaplan-Meier survival analysis of cardiovascular mortality among chronic HD patients according to whether they were treated with a renin-angiotensin system inhibitor (RASi).

The multivariate analysis showed that treatment with a RASi was independently associated with lower all-cause mortality (HR = 0.204; p = 0.0051) based on the Cox proportional hazards regression model (Table 3). Age, comorbidity of DM, serum levels of albumin and K were also prognostic factors for all-cause mortality. Treatment with a RASi was also independently associated with lower cardiovascular mortality (HR = 0.184; p = 0.0161) based on the Cox proportional hazards regression model (Table 4). Age, serum levels of albumin and K and prescription of a CCB were also extracted as prognostic factors for cardiovascular mortality.

Table 2 shows the causes of death of the 62 patients. Cardiovascular disease accounted for 40 of the deaths (64.5%), and the causes of the other 22 deaths (35.5%) included infection, hepatic failure, cancer, and respiratory failure. The proportion of cause of cardiovascular death in the treated group and untreated group did not reach statistical significance.

Conflicts of Interest

The authors declare no conflicts of interest.

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