Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers in Heart Failure With Chronic Kidney Disease　― Propensity Score Matching Analysis ―

Hyun-Jin Kim; Min-Ho Lee; Sang-Ho Jo; Won-Woo Seo; Sung Eun Kim; Kyung-Jin Kim; Jin-Oh Choi; Hyo-Suk Ahn; Dong-Ju Choi; Kyu-Hyung Ryu

doi:10.1253/circj.CJ-19-0782

Abstract

Background: Whether angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) exert beneficial effects in patients with concomitant heart failure (HF) and chronic kidney disease (CKD) remains uncertain. In this study, the effects of ACEI and ARB on long-term clinical outcomes in such patients were investigated.

Methods and Results: Study data were obtained from a multicenter cohort that included patients hospitalized for HF. A total of 1,601 patients with both HF and CKD were classified according to prescription of ACEI or ARB at discharge. The mortality rate was 19.0% in the ACEI/ARB treatment group (n=943) and 33.6% in the no ACEI/ARB treatment group (n=658) during follow-up. The ACEI/ARB treatment group had a significantly higher cumulative death-free survival rate than the no ACEI/ARB treatment group. Cox regression analysis showed that using ACEI or ARB was independently associated with reduced risk of all-cause death after adjusting for confounding factors. The beneficial effects of ACEI or ARB were retained after propensity score matching.

Conclusions: Prescription of an ACEI or ARB at discharge was associated with reduction in all-cause mortality in patients with acute HF and CKD. Clinicians need to be aware of the prognostic value and consider prescribing ACEI or ARB to high-risk patients.

The prevalence of heart failure (HF) is increasing and the 5-year survival rate after the onset of HF is approximately 50%.¹ Patients with HF and concomitant chronic kidney disease (CKD) have a higher rate of poor clinical outcomes than patients with HF alone, and the prevalence of patients with both diseases is increasing.²^–⁶ Bidirectional negative effects of heart and kidney dysfunction cause a potential vicious cycle such as cardiorenal syndrome. Renal dysfunction contributes to exacerbation of HF by reducing sodium excretion and volume expansion, upregulating neurohormonal pathways as well as inflammatory and other potential mechanisms,⁷^–⁹ while HF aggravates CKD by reducing renal perfusion and activating the sympathetic nervous and renin-angiotensin-aldosterone systems.⁸^,⁹ Therefore, the association between CKD and HF is multifactorial and causal in nature, and meticulous treatment is needed. However, the treatment strategies for HF patients with CKD are unclear because evidence that supports recommendations for these patients is minimal.¹⁰ Direct application of HF management guidelines for the general population to CKD patients is difficult because these patients are often excluded from most of the clinical trials on which guidelines are based.¹⁰^,¹¹ Similarly, although the effects of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-receptor blocker (ARB) therapies on mortality and morbidity have been proven in patients with HF,¹²^–¹⁵ how these drugs affect the prognosis of HF patients with CKD remains uncertain. The use of an ACEI or ARB at discharge was shown in several observational cohort studies to only reduce all-cause death in HF patients with reduced ejection fraction combined with CKD.¹⁶^,¹⁷ However, because the study populations in those studies were restricted to patients with severe renal insufficiency who had CKD stage 4 or 5, clinical application to HF patients with the full range of CKD is limited. In addition, the effects of ACEIs or ARBs on clinical outcomes, including rehospitalization, in HF patients with CKD, have been evaluated in only a few studies. Therefore, in the present study, the effects of these drugs on long-term clinical outcomes, including all-cause death and rehospitalization for HF, in patients with both HF and moderate to severe CKD, were investigated using data from a prospective multicenter registry.

Methods

Study Design and Setting

Study data were obtained from a nationwide Korean Heart Failure (KorHF) registry, a prospective multicenter cohort that included patients hospitalized for acute HF. From June 2004 to April 2009, 24 hospitals in Korea entered 3,200 patients diagnosed with HF at the time of admission according to the Framingham criteria.¹⁸ The study design and the primary results of the KorHF registry have been published.¹⁹ The diagnosis of HF was confirmed again at hospital discharge. Treatment and drug administration was at the discretion of the physicians and it was recommended for contraindicated drugs to be abolished. At least 1 year of follow-up was strongly recommended for all patients, and follow-up outcome data were prospectively collected from medical records and telephone correspondence, including deaths and rehospitalizations for HF. Among the 3,200 patients with HF initially enrolled, 3,150 had data available regarding estimated glomerular filtration rate (eGFR) based on serum creatinine and using the Modification of Diet in Renal Disease (MDRD) equation.²⁰ Among the patients with an identified eGFR, 1,613 had moderate to severe CKD with eGFR <60 mL/min/1.73 m² based on the definition of CKD.²⁰ The final analysis included data from 1,601 patients classified into 2 groups based on whether they were or were not prescribed an ACEI or ARB at discharge: the ACEI/ARB treatment group and no ACEI/ARB treatment group. The study protocol complied with the Declaration of Helsinki and was reviewed and approved by the institutional review boards of Hallym University Sacred Heart hospital and each participating hospital. All patients provided written informed consent prior to participation in the study.

Data Collection

The data were collected from the KorHF registry database using a web-based electronic data capture system that included electronic case report forms.¹⁹ The following demographic and clinical characteristics were extracted: age, sex, body mass index (BMI, kg/m²), systolic blood pressure (BP), diastolic BP, heart rate, and traditional cardiovascular risk factors. The causes of HF and key laboratory data considered as prognostic markers of HF were also collected. Left ventricular EF (LVEF) was extracted from echocardiographic data to assess LV systolic function. The LVEF was calculated from 4 apical 4- and 2-chamber views using the modified Simpson’s biplane method. If this method could not be applied, the LVEF was calculated using the M-mode. The discharge medications and medications at admission, such as β-blockers, ACEIs, ARBs, and aldosterone antagonists, were also identified.

Study Outcomes

The primary outcome was all-cause death during follow-up (median, 426.5 days, mean duration 521.0 days). The composite clinical event of all-cause death and HF readmission during follow-up was also obtained. HF readmission was defined as rehospitalization because of worsening of HF. Death and its timing were confirmed through medical records review or from telephone interview; HF readmission and its timing were collected from the discharge charts of medical records.

Statistical Analysis

All categorical data are shown as frequencies and percentages, and the statistics for continuous variables are expressed as mean and standard deviation. Pearson’s chi-square test was used to compare categorical variables. Student’s t-test was used to compare continuous variables with normal distribution and the Mann-Whitney U test was used to compare continuous variables with non-normal distribution. Kaplan-Meier survival analyses and log-rank tests were used to compare death-free survival rate and clinical event-free survival rate depending on whether the patient was prescribed ACEI or ARB at discharge. In addition, univariate followed by multivariate Cox proportional hazards regression analyses were performed to assess the risk factors of all-cause death after adjusting for individual risk factors. Factors found to have predictive significance (P<0.05) in the univariate analysis were included in the regression model. Moreover, a propensity score-matched population was selected to adjust for uneven distribution of baseline characteristics using a propensity score and 1:1 matched analysis was performed. Multiple logistic regression analysis was conducted to represent the propensity score, which was the probability of prescribing an ACEI or ARB at discharge. The adjusted variables were as follows: age, sex, BMI, history of HF, hypertension, diabetes, myocardial infarction, hemoglobin, eGFR, serum sodium, NT-proBNP, LV end-diastolic dimension, LVEF, and use of β-blockers or aldosterone antagonists at discharge. The 291 patients in the ACEI/ARB treatment group were matched to 291 patients in the no ACEI/ARB treatment group. Kaplan-Meier survival analyses and log-rank tests were also used to compare death-free survival rate in the propensity score-matched patient groups. P<0.05 was considered statistically significant. All analyses were performed using SPSS 21.0 software (IBM Corp., Armonk, NY, USA).

Results

Baseline Characteristics

Of the 1,601 patients with HF and CKD, 943 patients were included in the ACEI/ARB treatment group and 658 in the no ACEI/ARB treatment group in the present study. The patients’ baseline characteristics are presented in Table 1. Briefly, the mean age of the total study population was 71.5±11.9 years. Systolic BP tended to be higher in the ACEI/ARB treatment group and diastolic BP was significantly higher in the ACEI/ARB treatment group than in the no ACEI/ARB treatment group. The hemoglobin level and MRDR eGFR were significantly lower and the NT-proBNP level was significantly higher in the no ACEI/ARB treatment group. LVEF was significantly decreased in the ACEI/ARB treatment group compared with the no ACEI/ARB treatment group. The patients in the ACEI/ARB treatment group were significantly more likely to use β-blockers and aldosterone antagonists at discharge than patients in the no ACEI/ARB treatment group. In addition, 21.1% of patients in the no ACEI/ARB treatment group used an ACEI and 8.4% of patients in the no ACEI/ARB treatment group used an ARB during admission, but were not prescribed these medications at discharge.

Table 1. Baseline Characteristics of the Study Patients

	All (n=1,601)	ACEI/ARB treatment group (n=943)	No ACEI/ARB treatment group (n=658)	P value
Age, years	71.5±11.9	71.0±12.1	72.1±11.6	0.059
Male, n (%)	683 (42.7%)	399 (42.3%)	284 (43.2%)	0.735
BMI (>23 kg/m²)	661 (47.5%)	416 (48.8%)	245 (45.5%)	0.220
SBP, mmHg	132.5±32.2	133.8±31.4	130.6±33.2	0.054
DBP, mmHg	77.5±19.1	78.7±19.1	75.9±19.0	0.005
Heart rate, beats/min	90.7±25.4	90.1±24.7	91.6±26.4	0.265
Previous medical history, n (%)
Heart failure	514 (34.7%)	274 (33.1%)	240 (36.6%)	0.154
Hypertension	908 (56.7%)	544 (57.7%)	364 (55.3%)	0.347
Diabetes	631 (39.4%)	385 (40.8%)	246 (37.4%)	0.166
Myocardial infarction	293 (18.3%)	171 (18.1%)	122 (18.5%)	0.836
Cause of HF, n (%)
Ischemic heart disease	666 (43.1%)	404 (43.3%)	262 (42.8%)	0.849
Valvular heart disease	195 (12.6%)	113 (12.1%)	82 (13.4%)	0.456
Laboratory data
Hemoglobin, g/dL	11.7±2.4	12.0±2.4	11.4±2.4	<0.001
Creatinine, mg/dL	2.1±1.6	2.0±1.7	2.1±1.6	0.071
MDRD eGFR, mL/min/1.73 m²	38.7±14.6	39.9±14.4	36.9±14.6	<0.001
Serum sodium, mEq/L	137.6±5.3	137.8±5.3	137.3±5.3	0.063
CRP, mg/dL	3.3±5.5	3.2±5.2	3.6±5.8	0.239
NT-proBNP, pg/mL	12,244.4±11,567.2	11,378.9±10,966.0	13,547.8±12,316.2	0.002
Echocardiographic data
LVEDD, mm	56.3±9.9	57.0±9.8	55.3±10.1	0.002
LVESD, mm	44.0±11.8	44.9±11.7	42.5±11.7	<0.001
LVEF, %	38.8±15.5	37.7±15.4	40.4±15.6	0.001
Medications at admission, n (%)
β-blocker	645 (40.3%)	431 (45.7%)	214 (32.5%)	<0.001
ACEI	726 (45.3%)	587 (62.2%)	139 (21.1%)	<0.001
ARB	381 (23.8%)	326 (34.6%)	55 (8.4%)	<0.001
Medications at discharge, n (%)
β-blocker	631 (39.5%)	484 (51.3%)	147 (22.5%)	<0.001
ACEI	611 (38.2%)	611 (64.8%)	–	–
ARB	365 (22.9%)	365 (38.7%)	–	–
Aldosterone antagonist	512 (32.1%)	404 (42.8%)	108 (16.5%)	<0.001

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BMI, body mass index; CRP, C-reactive protein; DBP, diastolic blood pressure; HF, heart failure; LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end-systolic dimension; LVEF, left ventricular ejection fraction; NT-proBNP, NT-pro-B-type natriuretic peptide; SBP, systolic blood pressure.

Clinical Outcomes

A total of 400 patients (25.0%) died during follow-up (median, 426.5 days; interquartile range, 122.0–898.8 days). The all-cause death rate was significantly lower in patients in the ACEI/ARB treatment group than in the no ACEI/ARB treatment group (19.0% vs. 33.6%, P<0.001; Table 2). The patients in the ACEI/ARB treatment group developed significantly less composite clinical events of HF readmission and all-cause death than patients in the no ACEI/ARB treatment group (45.1% vs. 50.5%, P=0.031).

Table 2. Study Outcomes

	All (n=1,601)	ACEI/ARB treatment group (n=943)	No ACEI/ARB treatment group (n=658)	P value
All-cause death, n (%)	400 (25.0%)	179 (19.0%)	221 (33.6%)	<0.001
Composite events of HF readmission or all-cause death, n (%)	757 (47.3%)	425 (45.1%)	332 (50.5%)	0.031

Abbreviations as in Table 1.

Supplementary Table 1 shows the clinical outcomes between the 2 groups based on CKD stage according to the guidelines;²⁰ in HF patients with CKD stage 3 or 4 (eGFR 30–59 mL/min/1.73 m² and 15–29 mL/min/1.73 m², respectively), the all-cause death rate was significantly lower in patients in the ACEI/ARB treatment group than in the no ACEI/ARB treatment group. Significant difference in all-cause death was not observed between patients with HF and CKD stage 5 in the ACEI/ARB and no ACEI/ARB treatment groups.

Clinical Outcomes in Propensity Score-Matched Population

After propensity score matching, 291 of 943 patients in the ACEI/ARB treatment group were successfully matched to an equal number of patients in the no ACEI/ARB treatment group. Baseline characteristics were not significantly different between groups after propensity score matching (Supplementary Table 2). The clinical outcomes of the matched population showed significantly lower rate of all-cause death in the ACEI/ARB treatment group (17.5% vs. 31.3%, P<0.001; Supplementary Table 3).

Effects of ACEI or ARB on Long-Term Clinical Outcomes in HF Patients With CKD

Based on whether the HF patients with CKD received an ACEI or ARB at discharge, the cumulative death-free survival rate and cumulative composite clinical event-free survival rate were analyzed and the results are shown in Figure 1. Patients in the ACEI/ARB treatment group had a significantly higher cumulative death-free survival rate than patients in the no ACEI/ARB treatment group at long-term follow-up (67.3% vs. 52.9%, log-rank P<0.001, Figure 1A). Patients in the ACEI/ARB treatment group also had a significantly higher cumulative composite clinical event-free survival rate (37.2% vs. 28.6%, log-rank P=0.001, Figure 1B). In addition, the cumulative death-free survival rate was significantly higher in the ACEI/ARB treatment group than in the no ACEI/ARB treatment group after propensity score matching (65.3% vs. 56.2%, log-rank P<0.001; Figure 1C).

Figure 1.

Kaplan-Meier analysis survival curves for heart failure (HF) patients with chronic kidney disease. (A) Cumulative death-free survival rate based on the use of ACEI or ARB at discharge, (B) cumulative composite clinical event-free survival rate based on the use of ACEI or ARB at discharge and (C) cumulative death-free survival rate in HF patients with CKD after propensity score matching based on the use of ACEI or ARB at discharge. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker.

Based on the univariate analysis (Table 3), the following factors were associated with all-cause death in HF patients with CKD: use of ACEI/ARB at discharge (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.386–0.572, P<0.001), use of β-blocker or aldosterone antagonist, age, BMI >23 kg/m², history of HF, hemoglobin, serum sodium, and CRP. After adjusting for confounding factors, the Cox regression analysis showed the use of ACEI/ARB at discharge was independently associated with 48% reduced risk of all-cause death in patients with HF and CKD (OR 0.52, 95% CI 0.400–0.675, P<0.001). Older age and low sodium level were also significant independent predictors of all-cause death, and obesity was an independent negative predictor. However, the use of β-blockers at discharge was not an independent predictor of all-cause death in HF patients with CKD.

Table 3. Independent Predictors for Long-Term Death in HF Patients With CKD

	Univariate			Multivariate
	OR	95% CI	P value	OR	95% CI	P value
ACEI/ARB at discharge	0.47	0.386–0.572	<0.001	0.52	0.400–0.675	<0.001
β-blocker at discharge	0.56	0.449–0.693	<0.001	0.76	0.575–1.010	0.058
Aldosterone antagonist at discharge	0.72	0.578–0.901	0.004	0.83	0.604–1.130	0.231
Age, years	1.03	1.019–1.038	<0.001	1.03	1.017–1.044	<0.001
BMI >23 kg/m²	0.57	0.455–0.708	<0.001	0.69	0.530–0.989	0.008
History of HF	1.33	1.082–1.628	0.007	1.26	0.968–1.631	0.086
Hemoglobin, g/dL	0.89	0.855–0.929	<0.001	0.97	0.909–1.026	0.257
Serum sodium, mEq/L	0.96	0.945–0.979	<0.001	0.97	0.946–0.989	0.003
CRP, mg/dL	1.03	1.009–1.044	0.003	1.01	0.993–1.034	0.216

CI, confidence interval; CKD, chronic kidney disease; OR, odds ratio. Other abbreviations as in Table 1.

Subgroup analysis of all-cause death in the propensity score-matched population was performed based on older age (≥70 years), sex, BMI (>23 kg/m²), history of hypertension, diabetes, myocardial infarction, HF, CKD stage, LVEF (≤40%), and use of β-blockers or aldosterone antagonists at discharge. Use of ACEI/ARB at discharge significantly reduced all-cause death in HF patients with CKD across all subgroups except in the younger age (<70 years) and CKD stage 5 subgroups, without statistical significance (Figure 2).

Figure 2.

Subgroup analysis of all-cause death in the propensity score-matched population based on long-term follow-up. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; LVEF, left ventricular ejection fraction, OR, odds ratio.

Discussion

Based on the results from this nationwide, prospective, large-scale registry, 50% of patients with HF had concomitant moderate to severe CKD with eGFR <60 mL/min/1.73 m² and 58.9% of them received ACEI or ARB treatment at discharge. Although ACEI and ARB are proven therapies for reducing the mortality rate in HF patients, whether their use confers a benefit in HF patients with CKD is questionable. However, the use of an ACEI or ARB was associated with significant reduction in all-cause death (as much as 48%) and decreased the composite of all-cause death and HF readmission in patients with HF and CKD in the present study. In addition, the efficacy of ACEI and ARB therapy was consistent in various subgroups and the benefit remained after propensity score matching. Notably, HF patients with CKD stage 5, eGFR <15 mL/min/1.73 m², and who had severe renal impairment, did not benefit from ACEI or ARB use. This negative result was possibly because either the ACEI or ARB did not affect patients with severely depressed renal function or the dosing of the ACEI or ARB was insufficient to exert beneficial effects, as well as the fact that this was a small group.

Interaction Between Heart and Kidney

Patients with HF have many comorbidities that can aggravate their HF status.²¹ CKD is common, and reportedly, approximately 30–60% of HF patients experience moderate to severe renal insufficiency.²²^,²³ The present study results showed that 50% of patients hospitalized for acute HF also had CKD. Both CKD and HF have the same characteristics that indicate disease progression, and interactions in both directions promote disease progression. As the stage of both CKD and HF progresses, the clinical and pathophysiological connection further expands and severely worsens each disease.²⁴ One of the pathophysiological mechanisms is pro-inflammatory factors that can cause both HF and CKD patients to be in a chronic inflammatory state with increased levels of circulating inflammatory mediators.⁸^,²⁵ Another important factor is activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, which is also associated with chronic inflammation.⁹ Multiple mechanisms may lead to a vicious cycle of negative impact such as salt and fluid retention and decreased perfusion of the kidneys.

Necessity for ACEI or ARB in HF Patients With CKD

Angiotensin II is a major bioactive peptide of the renin-angiotensin-aldosterone system (RAAS) that acts via the angiotensin type 1 receptor.²⁶ In addition, angiotensin II increases the level of circulating inflammatory markers in animal and in vitro studies.²⁷^,²⁸ Use of an ACEI or ARB in previous studies decreased plasma levels of inflammatory markers, including tumor necrosis factor α, nuclear factor-κB, interleukin-6, and soluble vascular cell adhesion molecule-1, in subjects with various cardiovascular diseases.²⁹^–³² This finding indicates that regulation of the RAAS, including blockage of angiotensin II, may be a key treatment to prevent the inflammatory process that leads to the vicious cycle in patients with HF and CKD. However, most clinical studies on RAAS blockade have not included HF patients with CKD. Thus, evidence for treatment using a RAAS inhibitor in the high-risk subset of HF patients with CKD is lacking.⁶^,³³

Although observational cohort studies or subgroup analyses have been conducted, the use of ACEI or ARB in patients with concomitant HF and CKD has been evaluated in only a few studies.¹⁶^,¹⁷^,³⁴ Berger et al¹⁷ showed that the use of an ACEI or ARB during hospitalization reduced the 30-day mortality rate in patients with HF exacerbation and CKD; however, they showed 1-year mortality data of ACEI and ARB users only in the CKD stage 5 subgroup (eGFR <15 mL/min/1.73 m²) after adjusting only 2 parameters (age and sex) in patients with concomitant HF. Positive data were shown only for patients not on dialysis. Moreover, this was a retrospective observational study performed in only one location in the USA. In that study, prescription status and mortality based on renal function status in HF patients were assessed instead of the contribution of the ACEI or ARB to the prognosis in HF patients with CKD. In another study, Edner et al¹⁶ showed beneficial effects of an ACEI or ARB on 1-year survival in HF patients with reduced LVEF and CKD stage 4 or 5 after propensity score matching based on the use of ACEI or ARB. The results from a similar study also showed benefits in patients with reduced LVEF coexisting with CKD stage 3 or 4 after propensity score matching.³⁴ Compared with these studies, a wider range of CKD stage and LVEF status was included in the present study, and a higher degree of relative mortality reduction (48%) was observed after adjusting for all relevant risk factors in a prospective nationwide registry. The results from the present study can be applied to acute HF patients regardless of LVEF status and to a wider range of eGFR in HF patients with CKD.

Use of Aldosterone Antagonists in Patients With HF and CKD

Aldosterone is also a significant contributor to inflammation and fibrosis in both kidney disease and HF.³⁵ Among the HF patients with CKD in the present study, 32.1% used an aldosterone antagonist at discharge. Aldosterone antagonists have been contraindicated in CKD patients and overall use in other patients has been limited because of concerns regarding adverse effects of hyperkalemia or deterioration of renal function. However, in the present study, the overall prescription rate of an aldosterone antagonist at discharge was 32.1%, which was higher in the ACEI/ARB treatment group than in the no ACEI/ARB treatment group (42.8% vs. 16.5%, respectively; Table 1). Although a systematic review and meta-analysis have been published showing that aldosterone antagonists had a beneficial effect on all-cause death and cardiovascular events with no prevalence of severe hyperkalemia in CKD patients,³⁶ use of an aldosterone antagonist was not an independent predictor of all-cause death in HF patients with CKD in the present study.

The results from this study provide evidence that ACEIs and ARBs are associated with improved long-term clinical outcomes in HF patients with CKD. The outcomes not only included the all-cause death rate, but also composite clinical events of HF readmission and death. However, this observation could not be extended to HF patients with severe renal impairment (CKD stage 5). A plausible explanation is the small number of patients using an ACEI or ARB in the subset analysis (mainly because these drugs are contraindicated in patients with severe renal impairment) and the possibility of insufficient dosing to exert clinically significant outcomes.

Study Limitations

First, the study was not a randomized controlled clinical trial, but a prospective multicenter cohort study, Thus, the inevitable bias that may have affected the results could not be avoided. Nonetheless, this drawback was addressed with the use of propensity-matching statistical analysis and subgroup analysis and consistent results were obtained. Second, although this study included HF patients with CKD, data were lacking regarding albuminuria, which was included in the CKD definition. In the present study, only CKD stages with eGFR level were considered. Third, the number of patients in the CKD stage 5 subgroup was small and the effects of an ACEI or ARB in this group remain uncertain based on the study results. Finally, diastolic HF patients with preserved LVEF were included, but detailed echocardiographic data about diastolic dysfunction were not available and so it was difficult to distinguish them.

Despite these limitations, this study is important because the possible benefits of therapy in patients with both HF and CKD from a large-scale nationwide prospective registry are presented, despite very limited evidence on using ACEI or ARB being available. In addition, the results from present study may be helpful in providing evidence to prescribe an ACEI or ARB to HF patients regardless of concomitant moderate to severe CKD, because this patient subset is at the highest risk of death and cardiovascular events.

Conclusions

Prescription of an ACEI or ARB at discharge was associated with reduced 1-year mortality rate and reduced composite endpoint of death and HF readmission in patients with concomitant HF and CKD. Clinicians need to be aware of the prognostic value and consider prescribing an ACEI or ARB to patients with renal insufficiency above moderate but excluding endstage renal disease.

Disclosures / Funding Sources

None.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-19-0782

References

1. Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al. Heart Disease and Stroke Statistics – 2019 update: A report from the American Heart Association. Circulation 2019; 139: e56–e528.
2. Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Johansen K, et al. United States Renal Data System 2011 Annual Data Report: Atlas of chronic kidney disease & end-stage renal disease in the United States. Am J Kidney Dis 2012; 59: A7, e1–e420.
3. Bock JS, Gottlieb SS. Cardiorenal syndrome: New perspectives. Circulation 2010; 121: 2592–2600.
4. Lofman I, Szummer K, Dahlstrom U, Jernberg T, Lund LH. Associations with and prognostic impact of chronic kidney disease in heart failure with preserved, mid-range, and reduced ejection fraction. Eur J Heart Fail 2017; 19: 1606–1614.
5. Damman K, Valente MA, Voors AA, O’Connor CM, van Veldhuisen DJ, Hillege HL. Renal impairment, worsening renal function, and outcome in patients with heart failure: An updated meta-analysis. Eur Heart J 2014; 35: 455–469.
6. Hein AM, Scialla JJ, Edmonston D, Cooper LB, DeVore AD, Mentz RJ. Medical management of heart failure with reduced ejection fraction in patients with advanced renal disease. JACC Heart Fail 2019; 7: 371–382.
7. Curtis BM, Parfrey PS. Congestive heart failure in chronic kidney disease: Disease-specific mechanisms of systolic and diastolic heart failure and management. Cardiol Clin 2005; 23: 275–284.
8. Colombo PC, Ganda A, Lin J, Onat D, Harxhi A, Iyasere JE, et al. Inflammatory activation: Cardiac, renal, and cardio-renal interactions in patients with the cardiorenal syndrome. Heart Fail Rev 2012; 17: 177–190.
9. Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam B. The severe cardiorenal syndrome: ‘Guyton revisited’. Eur Heart J 2005; 26: 11–17.
10. Segall L, Nistor I, Covic A. Heart failure in patients with chronic kidney disease: A systematic integrative review. Biomed Res Int 2014; 2014: 937398.
11. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA 2006; 296: 1377–1384.
12. Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau JL, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002; 106: 920–926.
13. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303–310.
14. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised trial: The Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355: 1582–1587.
15. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349: 1893–1906.
16. Edner M, Benson L, Dahlstrom U, Lund LH. Association between renin-angiotensin system antagonist use and mortality in heart failure with severe renal insufficiency: A prospective propensity score-matched cohort study. Eur Heart J 2015; 36: 2318–2326.
17. Berger AK, Duval S, Manske C, Vazquez G, Barber C, Miller L, et al. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with congestive heart failure and chronic kidney disease. Am Heart J 2007; 153: 1064–1073.
18. Ho KK, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 1993; 88: 107–115.
19. Kim HL, Kim MA, Choi DJ, Han S, Jeon ES, Cho MC, et al. Gender Difference in the prognostic value of N-terminal pro-B type natriuretic peptide in patients with heart failure: A report from the Korean Heart Failure Registry (KorHF). Circ J 2017; 81: 1329–1336.
20. National Kidney F. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: S1–S266.
21. Kim MS, Lee JH, Cho HJ, Cho JY, Choi JO, Hwang KK, et al. KSHF Guidelines for the Management of Acute Heart Failure. Part III: Specific management of acute heart failure according to the etiology and co-morbidity. Korean Circ J 2019; 49: 46–68.
22. Heywood JT, Fonarow GC, Costanzo MR, Mathur VS, Wigneswaran JR, Wynne J, et al. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: A report from the ADHERE database. J Card Fail 2007; 13: 422–430.
23. Smith GL, Lichtman JH, Bracken MB, Shlipak MG, Phillips CO, DiCapua P, et al. Renal impairment and outcomes in heart failure: Systematic review and meta-analysis. J Am Coll Cardiol 2006; 47: 1987–1996.
24. Shiba N, Shimokawa H. Chronic kidney disease and heart failure: Bidirectional close link and common therapeutic goal. J Cardiol 2011; 57: 8–17.
25. Smith DH, Thorp ML, Gurwitz JH, McManus DD, Goldberg RJ, Allen LA, et al. Chronic kidney disease and outcomes in heart failure with preserved versus reduced ejection fraction: The Cardiovascular Research Network PRESERVE Study. Circ Cardiovasc Qual Outcomes 2013; 6: 333–342.
26. Jugdutt BI. Expanding saga of the renin-angiotensin system: The angiotensin II counter-regulatory AT2 receptor pathway. Circulation 2015; 131: 1380–1383.
27. Kalra D, Sivasubramanian N, Mann DL. Angiotensin II induces tumor necrosis factor biosynthesis in the adult mammalian heart through a protein kinase C-dependent pathway. Circulation 2002; 105: 2198–2205.
28. Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, et al. Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int Suppl 2002; (82): S12–S22.
29. Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Tsutsui T, et al. Angiotensin II type 1 receptor antagonist decreases plasma levels of tumor necrosis factor alpha, interleukin-6 and soluble adhesion molecules in patients with chronic heart failure. J Am Coll Cardiol 2000; 35: 714–721.
30. Neri Serneri GG, Boddi M, Modesti PA, Coppo M, Cecioni I, Toscano T, et al. Cardiac angiotensin II participates in coronary microvessel inflammation of unstable angina and strengthens the immunomediated component. Circ Res 2004; 94: 1630–1637.
31. Koh KK, Ahn JY, Han SH, Kim DS, Jin DK, Kim HS, et al. Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients. J Am Coll Cardiol 2003; 42: 905–910.
32. Lauten WB, Khan QA, Rajagopalan S, Lerakis S, Rahman ST, Parthasarathy S, et al. Usefulness of quinapril and irbesartan to improve the anti-inflammatory response of atorvastatin and aspirin in patients with coronary heart disease. Am J Cardiol 2003; 91: 1116–1119.
33. Damman K, Tang WH, Felker GM, Lassus J, Zannad F, Krum H, et al. Current evidence on treatment of patients with chronic systolic heart failure and renal insufficiency: Practical considerations from published data. J Am Coll Cardiol 2014; 63: 853–871.
34. Ahmed A, Love TE, Sui X, Rich MW. Effects of angiotensin-converting enzyme inhibitors in systolic heart failure patients with chronic kidney disease: A propensity score analysis. J Card Fail 2006; 12: 499–506.
35. Brown NJ. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol 2013; 9: 459–469.
36. Lu R, Zhang Y, Zhu X, Fan Z, Zhu S, Cui M, et al. Effects of mineralocorticoid receptor antagonists on left ventricular mass in chronic kidney disease patients: A systematic review and meta-analysis. Int Urol Nephrol 2016; 48: 1499–1509.

Corresponding author

Register with J-STAGE for free!