Abstract
Background/Aims
Spironolactone may be hazardous in heart failure (HF) patients with renal dysfunction due to risk of hyperkalemia and worsened renal function. We aimed to evaluate the effect of spironolactone on all-cause mortality in HF outpatients with renal dysfunction in a propensity-score-matched study.
Methods
A total of 2,077 patients from the Norwegian Heart Failure Registry with renal dysfunction (eGFR <60 mL/min/1.73 m2) not treated with spironolactone at the first visit at the HF clinic were eligible for the study. Patients started on spironolactone at the outpatient HF clinics (n = 206) were propensity-score-matched 1:1 with patients not started on spironolactone, based on 16 measured baseline characteristics. Kaplan-Meier and Cox regression analyses were used to investigate the independent effect of spironolactone on 2-year all-cause mortality.
Results
Propensity score matching identified 170 pairs of patients, one group receiving spironolactone and the other not. The two groups were well matched (mean age 76.7 ± 8.1 years, 66.4% males, and eGFR 46.2 ± 10.2 mL/min/1.73 m2). Treatment with spironolactone was associated with increased potassium (delta potassium 0.31 ± 0.55 vs. 0.05 ± 0.41 mmol/L, p < 0.001) and decreased eGFR (delta eGFR −4.12 ± 12.2 vs. −0.98 ± 7.88 mL/min/1.73 m2, p = 0.006) compared to the non-spironolactone group. After 2 years, 84% of patients were alive in the spironolactone group and 73% of patients in the non-spironolactone group (HR 0.59, 95% CI 0.37-0.92, p = 0.020).
Conclusion
In HF outpatients with renal dysfunction, treatment with spironolactone was associated with improved 2-year survival compared to well-matched patients not treated with spironolactone. Favorable survival was observed despite worsened renal function and increased potassium in the spironolactone group.
Key Words: Heart failure, Reduced renal function, Spironolactone, Prognosis
Introduction
Reduced renal function is common in outpatients with chronic heart failure (HF) and an independent predictor of all-cause mortality [1,2,3]. While the prevalence in the general population is about 4.7% [4], nearly 50% of patients with chronic HF have glomerular filtration rate (GFR) <60 mL/min/1.73 m2 [1,2]. Still, patients with kidney disease are underrepresented in randomized controlled trials (RCTs) of cardiovascular interventions [5]. Although RCTs are considered as gold standard when evaluating the effectiveness of therapeutic agents, well-designed observational studies may provide important information in subgroups not addressed in RCTs [6].
The use of spironolactone in addition to ACE inhibitor (ACEi) and β-blocker is recommended in symptomatic patients with reduced left ventricular ejection fraction (LVEF) [7,8]. Caution is necessary in patients with renal dysfunction, as use of spironolactone may cause hyperkalemia and worsening renal function [9,10]. Worsening renal function is a strong predictor of increased mortality in HF patients, and the safety of spironolactone in patients with reduced renal function is still a matter of uncertainty [11,12,13,14]. Yet, spironolactone is used extensively in HF outpatients with renal dysfunction [2].
The aim of our study was to evaluate the effect of spironolactone on all-cause mortality in chronic HF patients with reduced renal function using a propensity-score-matched model on Norwegian HF outpatients.
Material and Methods
The Norwegian Heart Failure Registry
Since the year 2000, the Norwegian Heart Failure Registry has collected data on outpatients referred to HF clinics in Norwegian hospitals. In 2012, recruitment of patients occurred in 25 HF clinics in the different Norwegian regions with a catchment area representing about half of Norway's population. The recruiting HF clinics are run by cardiologists and specialized nurses. The patients were enrolled successively after being diagnosed with chronic HF of any etiology according to the guidelines of the European Society of Cardiology (ESC) [7,15], and three visits were recorded. At the first visit (baseline), medical history, physical examination, echocardiography, New York Heart Association (NYHA) functional class, laboratory results, and the medical management of HF were registered. The second visit was registered after the cardiologists had optimized the medical treatment and the patient had participated in an educational program. The third visit, arranged 6 months after visit 2, served as an assessment of the patient's health condition, medication, and laboratory results after intervention at the HF clinic. Mortality data are retrieved yearly from Statistics Norway. A total of 6,779 patients were included by February 2012. HF outpatients with reduced renal function (estimated GFR [eGFR] <60 mL/min/1.73 m2) not using spironolactone at the first visit were enrolled in the study (n = 2,077).
Definitions
Renal function was expressed as eGFR and calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [16].
eGFR = 141 × min(Scr/κ,1)α × max(Scr/κ,1)-1.209 × 0.993Age × 1.018 (if female) × 1.159 (if black).
Scr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males and α is −0.329 for females and −0.411 for males. Renal dysfunction was defined as eGFR <60 mL/min/1.73 m2.
Based on ESC guidelines on HF [7], LVEF was defined as reduced at ≤35% and as preserved at ≥50%.
Daily doses of ACEi were converted to enalapril equivalent doses (enalapril 20 mg = lisinopril 20 mg = ramipril 10 mg = captopril 100 mg), and then expressed as percent of enalapril target dose. Target dose of enalapril was defined as 20 mg per day. Daily doses of loop diuretics were converted to furosemide equivalent doses (furosemide 40 mg = bumetanide 1 mg). Daily doses of β-blockers were converted to metoprolol equivalent doses (metoprolol 200 mg = bisoprolol 10 mg = carvedilol 50 mg = atenolol 100 mg).
The follow-up time was set to 2 years as data on persistent use of spironolactone after the last registered visit were not available.
Statistical Analysis
Baseline characteristics were presented as mean ± standard deviation for continuous variables and as frequency (percentage) for categorical data. Student t test was used when comparing continuous variables. Similarly, χ2 test was used when comparing categorical variables.
A multivariate logistic regression model was built to calculate the individual propensity score for being started on spironolactone at the outpatient HF clinic. Spironolactone use at the last visit at the outpatient HF clinic was entered as the dependent variable in the model. Baseline variables associated with spironolactone treatment (p < 0.20) were entered as independent variables, together with important potential confounding variables associated with mortality in HF patients. As complete data sets are required for the propensity score matching procedure, variables with many missing values (serum cholesterol and LVEF) were excluded from the analyses. The independent variables in the propensity matching procedure were then: age, gender, BMI, ischemic heart disease, claudication and/or previous stroke, percutaneous coronary intervention and/or coronary artery bypass graft, systolic blood pressure, NYHA functional class 3 and 4, use of RAS-blocking agents, percent of ACEi daily target dose, diuretics dose, use of acetylsalicylic acid, use of statin, eGFR, serum potassium, and serum sodium.
Patients whose optimized HF treatment at the last visit included spironolactone were propensity-score-matched 1:1 with patients not using spironolactone in a randomized case order with match tolerance 0.1 and a priority to exact match.
Kaplan-Meier statistics was used to investigate differences in survival between HF outpatients with reduced renal function that were prescribed spironolactone during HF treatment optimization at HF clinics and patients not on spironolactone. Univariate Cox regression model was utilized to calculate hazard ratio (HR) for spironolactone use on all-cause mortality in HF outpatients with reduced renal function.
Student t test was used to assess changes in eGFR and serum potassium from the first to the last visit between the two treatment groups, and paired t test was used to assess changes within each treatment group.
Statistical analyses were carried out using SPSS for Windows version 22 (IBM SPSS Statistics, New York, NY, USA). Level of significance was set as p value ≤0.05.
Results
Baseline characteristics of 2,077 HF outpatients with reduced renal function and no prior use of spironolactone at the first visit to HF clinics are presented in Table 1. The mean age was 76.1 ± 8.8 years, 65.3% were males, and the mean eGFR was 43.7 ± 11.6 mL/min/1.73 m2. Ten percent (n = 206) were registered as using spironolactone at the last visit. Compared to HF outpatients whose optimized medical treatment remained without spironolactone, the future spironolactone users had higher BMI and NYHA class, higher eGFR, and lower serum potassium, and they used higher doses of ACEi (Table 1).
Table 1.
Baseline characteristics of 2,077 heart failure outpatients with renal dysfunction and no previous use of spironolactone
| Patients with valid data | Total (n = 2,077) | Started on spironolactone (n = 206) | Not started on spironolactone (n = 1,871) | p value | |
|---|---|---|---|---|---|
| Age, years | 2,077 (100) | 76.1±8.8 | 76.1±8.2 | 76.1±8.9 | 0.982 |
| Male gender | 2,077 (100) | 1,356 (65.3) | 139 (67.5) | 1,217 (65.0) | 0.487 |
| Body mass index | 1,765 (85.0) | 25.8±4.8 | 27.2±5.3 | 25.7±4.7 | <0.001 |
| Smoking | 2,068 (99.6) | 225 (10.9) | 14 (6.8) | 211 (11.3) | 0.050 |
| Medical history | |||||
| Ischemic heart disease | 2,000 (96.3) | 1,277 (63.9) | 126 (63.3) | 1,151 (63.9) | 0.869 |
| Hypertension | 1,938 (93.3) | 750 (38.7) | 80 (40.4) | 670 (38.5) | 0.603 |
| Claudication and/or previous stroke | 1,938 (93.3) | 386 (19.9) | 36 (18.2) | 350 (20.1) | 0.519 |
| PCI/CABG | 1,931 (93.0) | 692 (35.8) | 67 (34.0) | 625 (36.0) | 0.573 |
| Physical findings | |||||
| Heart rate, beats/min | 2,073 (99.8) | 71.2±14.9 | 71.7±14.7 | 71.1±15.0 | 0.595 |
| SBP, mm Hg | 2,076 (100) | 128.0±22.9 | 128.0±23.6 | 128.0±22.9 | 0.979 |
| LVEF groups | 0.078 | ||||
| LVEF ≤35% | 1,152 (65.5) | 102 (58.6) | 1,050 (66.3) | ||
| 35% < LVEF < 50% | 408 (23.2) | 45 (25.9) | 363 (22.9) | ||
| LVEF ≥50% | 198 (11.3) | 27 (15.5) | 171 (10.8) | ||
| NYHA class III/IV | 2,037 (98.1) | 1,199 (58.9) | 144 (70.9) | 1,055 (57.5) | <0.001 |
| Medication | |||||
| RAS blockade | 2,074 (99.9) | 1,780 (85.8) | 171 (83.0) | 1,609 (86.1) | 0.222 |
| ACEi dose/day, % of target dose | 2,065 (99.4) | 40.0±38.8 | 47.9±44.0 | 39.1±38.1 | 0.002 |
| β-Blocker dose/day, mg | 2,044 (98.4) | 70.0±66.3 | 69.2±67.1 | 70.1±66.2 | 0.859 |
| Loop diuretics dose/day, mg | 2,076 (100) | 69.4±65.3 | 70.7±47.8 | 69.2±67.0 | 0.750 |
| RAS + β-blocker use | 2,070 (99.7) | 1,476 (71.3) | 136 (66.3) | 1,340 (71.8) | 0.098 |
| Acetylsalicylic acid use | 2,076 (100) | 991 (47.7) | 78 (37.9) | 913 (48.8) | 0.003 |
| Statin use | 2,077 (100) | 1,108 (53.3) | 102 (49.5) | 1,006 (53.8) | 0.245 |
| Laboratory values | |||||
| eGFR, mL/min/1.73 m2 | 2,077 (100) | 43.7±11.6 | 45.7±9.9 | 43.5±11.8 | 0.010 |
| Serum potassium, mmol/L | 2,071 (99.7) | 4.39±0.50 | 4.25±0.48 | 4.40±0.49 | <0.001 |
| Serum sodium, mmol/L | 2,075 (99.9) | 140.3±3.3 | 140.1±4.0 | 140.3±3.3 | 0.387 |
Values are expressed as n (%) or mean ± SD. ACEi dose/day, percent of daily enalapril equivalent target dose; β-blocker dose/day, daily metoprolol equivalent dose; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PCI/CABG, percutaneous coronary intervention and/or coronary artery bypass graft; SBP, systolic blood pressure.
Of a total of 1,814 HF outpatients with no prior use of spironolactone and complete datasets, 170 patients treated with spironolactone at the last visit were propensity-score-matched 1:1 with 169 HF outpatients not treated with spironolactone. Baseline characteristics were well balanced in the two examined groups (Table 2). Two-year mortality rate was 22%. After 48 months, 84% patients were alive in the spironolactone group and 73% patients in the non-spironolactone group. The use of spironolactone was an independent predictor of improved survival in HF outpatients with reduced eGFR (2-year mortality HR 0.59, 95% CI 0.37-0.92, p = 0.020; Fig. 1).
Table 2.
Characteristics of 170 pairs of propensity-matched heart failure outpatients with renal dysfunction and no previous use of spironolactone
| Total (n = 339) | Started on spironolactone (n = 170) | Not started on spironolactone (n = 169) | p value | |
|---|---|---|---|---|
| Age, years | 76.7±8.1 | 76.4±8.0 | 77.1±8.1 | 0.445 |
| Male gender | 225 (66.4) | 113 (66.5) | 112 (66.3) | 0.969 |
| Body mass index | 26.8±5.0 | 27.0±5.1 | 26.7±4.9 | 0.510 |
| Smoking | 27 (8.0) | 12 (7.1) | 15 (8.9) | 0.537 |
| Medical history | ||||
| Ischemic heart disease | 220 (64.9) | 107 (62.9) | 113 (66.9) | 0.449 |
| Hypertension | 143 (42.2) | 68 (40.0) | 75 (44.4) | 0.414 |
| Claudication and/or previous stroke | 71 (20.9) | 35 (20.6) | 36 (21.3) | 0.872 |
| PCI/CABG | 115 (33.9) | 58 (34.1) | 57 (33.7) | 0.940 |
| Physical findings | ||||
| Heart rate, beats/min | 71.8±15.1 | 71.4±13.7 | 72.3±16.4 | 0.610 |
| SBP, mm Hg | 130.4±22.4 | 129.6±22.7 | 131.2±22.1 | 0.502 |
| LVEF groups | ||||
| LVEF ≤35% | 183 (60.6) | 82 (55.0) | 101 (66.0) | 0.084 |
| 35% < LVEF < 50% | 76 (25.2) | 40 (26.8) | 36 (23.5) | |
| LVEF ≥50% | 43 (14.2) | 27 (18.1) | 16 (10.5) | |
| NYHA class III/IV | 231 (68.1) | 118 (69.4) | 113 (66.9) | 0.615 |
| Medication first visit | ||||
| RAS blockade | 284 (83.8) | 141 (82.9) | 143 (84.6) | 0.676 |
| ACEi dose/day, % of target dose | 46.9±42.6 | 47.5±44.0 | 46.3±41.3 | 0.791 |
| β-Blocker dose/day, mg | 69.1±65.0 | 67.5±65.1 | 70.7±65.1 | 0.657 |
| RAS+β-blocker use | 224 (66.3) | 109 (64.5) | 115 (68.0) | 0.490 |
| Loop diuretics dose/day, mg | 68.1±54.7 | 71.8±49.1 | 64.4±60.0 | 0.215 |
| Acetylsalicylic acid use | 142 (41.9) | 66 (38.8) | 76 (45.0) | 0.251 |
| Statin use | 173 (51.0) | 89 (52.4) | 84 (49.7) | 0.626 |
| Medication last visit | ||||
| RAS blockade | 287 (82.5) | 137 (78.7) | 150 (86.2) | 0.067 |
| ACEi dose/day, % of target dose | 48.8±44.0 | 47.8±44.3 | 49.8±43.9 | 0.661 |
| β-Blocker dose/day, mg | 93.9±75.4 | 96.4±79.4 | 91.4±71.3 | 0.526 |
| RAS + β-blocker use | 241 (69.1) | 114 (65.1) | 127 (73.0) | 0.113 |
| Loop diuretics dose/day, mg | 65.1±56.1 | 66.1±53.9 | 64.0±58.3 | 0.715 |
| Acetylsalicylic acid use | 146 (40.3) | 67 (37.0) | 79 (43.6) | 0.199 |
| Statin use | 193 (53.3) | 92 (50.8) | 101 (55.8) | 0.343 |
| Laboratory values | ||||
| eGFR, mL/min/1.73 m2 | 46.2±10.2 | 45.6±10.2 | 46.8±10.2 | 0.282 |
| Serum potassium, mmol/L | 4.27±0.46 | 4.23±0.47 | 4.30±0.45 | 0.164 |
| Serum sodium, mmol/L | 140.2±3.7 | 140.1±4.0 | 140.3±3.4 | 0.713 |
Values are expressed as n (%) or mean ± SD. ACEi dose/day, percent of daily enalapril equivalent target dose; β-blocker dose/day, daily metoprolol equivalent dose; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PCI/CABG, percutaneous coronary intervention and/or coronary artery bypass graft; SBP, systolic blood pressure.
Fig. 1.
Kaplan-Meier survival plot of heart failure outpatients with renal dysfunction propensity-matched by spironolactone treatment at the last visit at the heart failure clinic.
During a mean time of 8.0 ± 6.3 months from the first visit to the last visit, there was a significant change in both eGFR and serum potassium in the spironolactone group compared to the non-spironolactone group (Table 3). Patients treated with spironolactone experienced an increase in serum potassium from 4.24 ± 0.47 to 4.52 ± 0.51 mmol/L (p < 0.001) and a decrease in eGFR from 45.5 ± 10.2 to 41.4 ± 14.6 mL/min/1.73 m2 (p < 0.001), while there was no significant change in neither serum potassium nor eGFR in patients not using spironolactone.
Table 3.
Change in eGFR and serum potassium in heart failure outpatients with renal dysfunction during follow-up at the heart failure clinic (no spironolactone use at baseline)
| Patients with valid data | Total (n = 339) | Started on spironolactone (n = 170) | Not started on spironolactone (n = 169) | p value | |
|---|---|---|---|---|---|
| eGFR change | 330 (97.3) | –2.57±10.4 | –4.12±12.2 | –0.98±7.9 | 0.006 |
| Serum potassium change | 327 (96.5) | 0.18±0.51 | 0.31±0.55 | 0.05±0.41 | <0.001 |
Values are expressed as n (%) or mean ± SD. eGFR, estimated glomerular filtration rate.
Discussion
In the present study of Norwegian HF outpatients with renal dysfunction, patients treated with spironolactone had improved 2-year survival compared to the propensity-matched patients not treated with spironolactone. The survival benefit was observed despite decrease in renal function and increase in serum potassium levels in patients treated with spironolactone.
Mineralocorticoid receptor antagonists have been shown to improve survival in patients with advanced HF with reduced ejection fraction [17,18,19]. A recent study from the Swedish Heart Failure Registry reported an interaction between spironolactone use and renal function concerning all-cause mortality, indicating a relatively more favorable effect of spironolactone in patients with reduced renal function compared to patients with preserved GFR [20]. In a subgroup analysis of RALES (Randomized Aldactone Evaluation Study), individuals with reduced eGFR had similar reduction in relative risk of all-cause mortality as individuals with eGFR >60 mL/min/1.73 m2[21]. However, study populations in RCTs are highly selected and patients with reduced renal function are underrepresented. Coca et al. [5] found that individuals with renal disease were excluded in 56% of cardiovascular RCTs. Furthermore, only 13-25% of individuals from observational studies were estimated to be eligible for HF RCTs [22]. Patients included in our study were unselected patients treated in Norwegian outpatient HF clinics. Compared to the subgroup of RALES patients with reduced kidney function [21], patients in the present study were older and had lower eGFR and higher serum potassium.
The use of mineralocorticoid receptor antagonists in HF patients with reduced renal function has been debated due to safety concerns. Extended use of spironolactone after publication of RALES resulted in increased rate of hospitalization for hyperkalemia [7,8,9]. In our study, the beneficial effect of spironolactone on survival was observed despite decrease in renal function and increase in serum potassium during follow-up at the outpatient HF clinics. It is well accepted that worsening renal function has a negative impact on survival in HF patients [11,12,23]. However, the prognostic effect of worsening renal function might depend on the HF medication used. A meta-analysis showed that improved survival associated with use of RAAS inhibitors was greatest in patients with worsening renal function [11]. Likewise, Vardeny et al. [21] demonstrated a favorable effect of spironolactone on survival in HF patients with reduced eGFR despite worsening renal function. On the other hand, worsening renal function following the use of high-dose loop diuretics was associated with increased mortality [24]. Given the beneficial effect of spironolactone on survival in HF patients despite decreased eGFR, one could hypothesize that some reduction in renal function with spironolactone should be accepted and should not lead to discontinuation of treatment. However, the degree of worsening renal function and hyperkalemia that should be tolerated needs to be further investigated.
We used propensity-score-matched analysis to correct for differences between baseline characteristics of patients treated and not treated with spironolactone. Propensity score matching makes it possible to design an observational study so that it mimics some of the characteristics of RCTs by balancing the baseline differences between the study and control group. It is an increasingly used method that might be superior to multivariate Cox regression when correcting for confounding variables in observational studies [25]. Based on 16 predefined measured variables in the present study, patients prescribed spironolactone were matched 1:1 with patients not prescribed spironolactone. However, neither propensity score matching nor multivariate Cox regression can correct for unmeasured confounding variables. Yet, the large number of variables used for the estimation of propensity score may back the reliability of our findings.
There are some important limitations. Although the study population consists of unselected outpatients attending HF clinics, some degree of selection might be present. The patients that were prescribed spironolactone were not selected at random, but rather after careful evaluation by the cardiologist. Therefore, we cannot conclude that spironolactone use would be beneficial for all patients with reduced kidney function. Furthermore, the majority of the included individuals had moderately reduced kidney function with eGFR 30-59 mL/min/1.73 m2 and only 10% had eGFR <30 mL/min/1.73 m2. It is likely to assume that patients with severely reduced kidney function would most probably be treated by nephrologists rather than cardiologists, and therefore would not be included in the Heart Failure Registry.
Only mortality data were available after the last registered visit at the outpatient HF clinic. Data on doses of spironolactone and other medication, hospital admissions for decompensated HF, or adverse events would have strengthened the study. Such data were not available. The follow-up time was restricted to 2 years because of lack of data on persistent use of spironolactone.
In conclusion, spironolactone improved the 2-year survival in HF outpatients with reduced renal function compared to propensity-score-matched patients not treated with spironolactone. Favorable survival was observed despite the fact that patients treated with spironolactone experienced a decrease in renal function and an increase in serum potassium. Reluctance to prescribe spironolactone owing to fear for adverse renal events may deprive HF patients with reduced renal function of possibly lifesaving treatment.
Statement of Ethics
All enrolled patients had given written informed consent prior to inclusion in the database. The study was approved by the National Data Inspectorate and the Regional Committee of Medical Research Ethics.
Disclosure Statement
B.W.-G. reports personal fees from Novartis Pharma, outside the submitted work. M.G. reports personal fees from Novartis Pharma and Vifor Pharma, outside the submitted work. D.A. reports personal fees from Novartis Pharma, St. Jude Medical, and Vifor Pharma, outside the submitted work. The other authors have no conflict of interest related to the work to disclose.
Acknowledgements
We gratefully acknowledge all contributors to the Norwegian Heart Failure Registry as the registry is critically dependent on high-quality data from the participating heart failure clinics. The first author is a research fellow and funded by the South-Eastern Norway Regional Health Authority.
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