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European Journal of Heart Failure 2007 9(4):429-434; doi:10.1016/j.ejheart.2006.10.005
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© 2007 European Society of Cardiology

Effects of aldosterone receptor blockade in patients with mild–moderate heart failure taking a beta-blocker

Colin Berrya, Niamh Murphya, Giuseppe De Vitob, Stuart Gallowayc, Alison Seeda, Carol Fishera, Naveed Sattard, Patrick Vallancee, W. Sewart Hillisa and John McMurraya,*

a Department of Cardiology, Western Infirmary Glasgow, UK
b Department of Applied Physiology, University of Strathclyde Glasgow, UK
c Institute for Sports Research, University of Stirling Stirling, UK
d Department of Metabolic Medicine, Queen Elizabeth Building, Royal Infirmary Glasgow, UK
e Department of Clinical Pharmacology, University College Hospital London, UK

* Corresponding author. Department of Cardiology, Western Infirmary, Glasgow, G11 6NT, UK. Tel.: +44 141 3303479; fax: +44 141 3306955. E-mail address: j.mcmurray{at}bio.gla.ac.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 References
 
Aims: Spironolactone improves prognosis in severe heart failure (HF). We investigated its effects in patients with mild–moderate HF treated with an ACE inhibitor and beta-blocker.

Methods and results: Randomised, double-blind, parallel-group, 3-month comparison of placebo and spironolactone (25 mg daily) in 40 patients in New York Heart Association (NYHA) class I (20%), II (70%) or III (10%), with a left ventricular ejection fraction of <40%.

The mean (standard error) changes from baseline in the spironolactone and placebo groups were, respectively: i) B-type natriuretic peptide (BNP) –53.4(22.2) pg/mL and +3.3(12.1) pg/mL, P=0.04, ii) pro-collagen type III N-terminal amino peptide (PIIINP) –0.6(0.2) µmol/L and +0.02(0.2) µmol/L, P=0.02 and iii) creatinine +10.7(3.2) µmol/L and –0.3(2.6) µmol/L, P=0.01.

Compared with placebo, spironolactone therapy was associated with a reduction in self-reported health-related quality of life: change in visual analog score: –6 (3) vs. +6 (4); P=0.01.

No differences were observed on other biochemical, neurohumoral, exercise and autonomic function assessments.

Conclusion: In patients with mild–moderate HF, spironolactone reduced neurohumoral activation (BNP) and a marker of collagen turnover (PIIINP) but impaired renal function and quality of life. The benefit–risk ratio of aldosterone blockade in mild HF is uncertain and requires clarification in a large randomised trial.

Key Words: Aldosterone • Spironolactone • Heart failure

Received May 30, 2006; Revised August 21, 2006; Accepted October 5, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 References
 
In the Randomized Aldactone Evaluation Study (RALES), the aldosterone receptor blocker, spironolactone, reduced morbidity and mortality in patients with severe heart failure when added to an ACE inhibitor [1]. The results of this trial led to spironolactone becoming a recommended therapy for patients with advanced heart failure [2]. In RALES, however, only 11% of patients randomised to spironolactone were taking a beta-blocker and the mean dose of angiotensin converting enzyme (ACE) inhibitor was relatively low. ACE inhibitors and beta-blockers have similar effects on the autonomic nervous system and other neuroendocrine pathways [3,4]. Their combination leads to greater neurohumoral inhibition [5] and a greater reduction in morbidity and mortality. Neuroendocrine activation is related to the severity of heart failure [6,7]. The addition of an aldosterone receptor antagonist may only be beneficial in those with pronounced neuroendocrine activation i.e. those with severe heart failure and when that activation has not been optimally suppressed.

The aim of the present study was, therefore, to investigate whether the beneficial effects of spironolactone in advanced heart failure are also obtained in patients with mild heart failure taking optimal doses of beta-blockers and ACE inhibitors.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 References
 
2.1. Patients
Forty ambulant patients with mild-moderate heart failure (New York Heart Association functional class I-III) and a left ventricular ejection fraction of <40% were invited to participate in this study. An optimal maintenance dose of both a beta-blocker and either an ACE inhibitor or an angiotensin receptor blocker for at least 30 days was also an inclusion criterion. Criteria for exclusion included use of potassium-sparing diuretics, a serum creatinine concentration of >220 µmol/L and a serum potassium concentration of >5 mmol/L before randomisation.

2.2. Study treatment
Patients were randomised to three months treatment with 25 mg spironolactone daily or matching placebo. The randomisation procedure was performed by the hospital pharmacy Clinical Trials Unit, which also provided the study drugs. Investigators and patients were blinded to the allocated treatment. Follow-up visits after randomisation took place during weeks 1, 3, 6 and 12. A blood test was performed on each of these visits in order to check renal function and blood chemistry. Compliance was confirmed by pill counts. Concomitant heart failure drug therapies were kept constant during the study period.

2.3. Procedures
Study procedures were performed over a 4-day period at baseline and then again after 12 weeks of treatment.

2.3.1. Blood and urine assays
Blood was collected at baseline and after 12 weeks for measurement of plasma neurohormones including arginine vasopressin (AVP), B-type natriuretic peptide (BNP), [8] and norepinephrine (NE), using previously described assays. A marker of collagen turnover, pro-collagen type III N-terminal amino peptide [PIIINP]), [9] an endogenous inhibitor of nitric oxide synthase, asymmetrical dimethylarginine [ADMA], [10] and high-sensitivity C-reactive protein (HS-CRP) were also measured, using established methods [11].

An automated analyser was used for haematological measurements (Sysmex, SE9500, Japan). Twenty four hour urine collections were undertaken for measurement of creatinine clearance and electrolyte excretion.

Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease (MDRD) equation: GFR (mL/min per 1.73m2)=186x[serum creatinine]–1.154x[age]–0.203x[0.742, if the patient is female]x[1.121 if the patient is African-American], [12] where serum creatinine concentration is in mg/dL and age is in years.

2.3.2. Heart rate variability
Twenty four hour ambulatory ECG recordings were used for analysis of HRV. A selection of time domain measures were analysed according to the guidelines of the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996) [13]. Measures of parasympathetic activity included the percentage of adjacent RR differences >50 ms (pNN50), the root-mean-square of successive differences (RMSSD) and the standard deviation of all normal-to-normal R-R intervals (SDNN).

2.3.3. QT interval dispersion (QTd)
QT interval analysis was performed on 12-lead electrocardiograms (ECGs) recorded with a Hewlett-Packard 4700A electrocardiogram machine (Palo Alto, California). All QT intervals and dispersion were analysed blindly using digital software (Summagraphics). QT intervals were corrected with Bazett's formula (QTc=QT/{surd}(RR)).

2.3.4. Cardiopulmonary exercise testing
Bicycle cardiopulmonary exercise tests were carried out on the first and fourth day of the baseline and during the 12 week follow-up assessments. Heart rate and blood pressure were measured at 3 min intervals and each subject was requested to assess his/her rate of perceived exertion (RPE) at the start of each test and during the last minute of exercise. On day 1 an increase in load was applied at 1 min intervals, until the ventilatory threshold (Tvent) was reached. The intensity was verified on-line using breath-by-breath analysis of the expired gas composition and the pulmonary ventilation. The workload corresponding to the individual Tvent was then used to calculate the load for the second test conducted on day 4. This calibration process was performed both at baseline and again at the 12 week assessment.

The calibrated exercise test on day 4 of the baseline and 12 week assessments began with a 3 min period of collection of cardiopulmonary parameters, during which the subject was stationary. The patient then cycled with the bike unloaded for an additional 3 min, at a cadence of 50 rpm. After this, the resistance was set at the submaximal intensity predetermined in the first test (90% Tvent workload), and the subject exercised at this load for an additional 6 min. At the end of this period, the load was removed and the patient was invited to continue pedalling until the cardiopulmonary parameters returned to pre-exercise conditions.

2.3.5. Other measures
A global health visual analogue scale (www.euroqol.org) was completed in order to quantify health-related quality of life. Each subject was asked to draw a line from a point marked ‘your health state today’ onto a 0-100 point 20 cm vertical scale, where 100 at the top of the scale represented ‘best imaginable health’ and 0 at the bottom of the scale represented ‘worst imaginable health’. Daily activity was quantified by calimetry. Each subject wore a digital calimeter for 24 h at baseline and after 12 weeks in order to quantify daily body movement.

2.3.6. Safety
Given the possibility of adverse events, such as hyperkalaemia and renal dysfunction, patients attended the research unit for clinical review and tests of blood chemistry, weekly for the first 3 weeks, then at weeks 4, 8 and 12.

2.4. Statistical analyses
The null hypothesis was that treatment with spironolactone or placebo would have similar effects on autonomic and cardiorespiratory function in patients with mild-moderate heart failure treated with a beta-blocker. A projected sample size was calculated using data from earlier studies undertaken in similar populations [9]. We estimated that 40 patients would be required for a study with 80% power to reject the null hypothesis at a probability level of P<0.05. Our calculation was based on a mean (SD) {Delta}SDNN(i) 3.6(7.9) ms in placebo-treated patients and a mean (SD) {Delta}SDNN(i) of 4.1(9) ms in spironolactone-treated patients [9]. Our pre-specified secondary hypothesis was that BNP would be reduced by spironolactone treatment. Results were analysed on an intention-to-treat basis.

Clinical characteristics between placebo and spironolactone treated patients were compared using a Students t test (mean (standard deviation [SD]) or Fisher's exact test for continuous or categorical variables, respectively. Comparisons of differences between mean (standard error [SE]) change in variables in placebo and spironolactone treated groups were compared with t tests for normally distributed data and Mann-Whitney tests for non-normally distributed data.

2.5. Ethics
The study was conducted in accordance with the Declaration of Helsinki and was approved by the hospital's Ethics Committee. All patients gave written informed consent.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
References
 
Forty heart failure patients with New York Heart Association functional class I (20%); II (70%); III (10%), were randomised (Table 1). All patients were in sinus rhythm. The two treatment groups were generally well matched in terms of sex, co-morbidity and blood chemistry, though there were slight imbalances in age, ischaemic aetiology and aspirin usage. Two placebo-treated patients did not complete the study. One patient had a change of mind after randomisation during the baseline assessment and one other patient withdrew because of headaches attributed to the study medication. Compliance was confirmed by pill counts.


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  		Table 1 Clinical characteristics of the study population

 
Compared to placebo, spironolactone reduced both BNP (P=0.04) and PIIINP (P=0.02) (Fig. 1). The mean changes in serum creatinine, GFR and potassium in each treatment group are illustrated in Fig. 2. Compared to placebo, spironolactone increased mean serum creatinine concentration (P=0.01) and reduced GFR (P=0.01). No statistically significant between group differences were observed for changes in the concentrations of sodium, magnesium, calcium, creatinine clearance, ADMA, AVP, NE or CRP.


Figure 01
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  		Fig. 1 Mean (standard error) change from baseline in plasma concentrations of a) B-type natriuretic peptide (BNP; pg/mL); b) procollagen type III N-terminal amino peptide (PIIINP; µmol/L).

 


Figure 02
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  		Fig. 2 Mean (standard error) change from baseline in a) serum creatinine concentration (µmol/L); b) glomerular filtration rate (mL/min per 1.73 m2); c) serum potassium concentration (mmol/L).

 
The mean (SEM) visual analogue scores for self-reported health-related quality of life in the placebo and spironolactone-treated patients were 66 (15) and 69 (18), respectively (P=0.6). Compared with placebo, spironolactone therapy was associated with a reduction in health-related quality of life: the mean (SEM) change in visual analogue score was –6 (3) vs. 6 (4); P=0.01.

No between group differences were observed for change in QTd, HRV, daily activity, or cardiopulmonary function at rest or in response to exercise.

3.1. Discussion
Treatment with an aldosterone receptor blocker resulted in potentially beneficial changes in plasma BNP and PIIINP concentrations. That spironolactone led to a reduction in plasma BNP concentration may be prognostically important. Plasma BNP concentrations are predictive of morbidity and mortality in patients with heart failure, even in those treated with a beta-blocker [14]. Our finding that spironolactone reduces BNP supports earlier studies in patients with more severe heart failure and less intensive background treatment [15-17]. Furthermore, MacDonald et al. recently reported a placebo-controlled, crossover, study of spironolactone at a dose of 12.5-50 mg daily, given for 12 weeks. Forty-three patients with mild-moderate heart failure were randomised, of which 31 (72%) were taking a beta-blocker [18]. In that study, spironolactone therapy, compared with placebo-treatment, was also associated with a reduction in the plasma concentration of BNP.

Elevated PIIINP concentrations predict an adverse prognosis in HF [19]. Compared with placebo-treated patients, PIIINP concentrations decreased in spironolactone-treated patients. In a prior study, treatment with spironolactone reduced left ventricular remodelling after myocardial infarction and that effect was associated with a reduction in plasma PIIINP concentration [20]. Similarly, reduction in left ventricular mass with spironolactone treatment in hypertensive patients is associated with a fall in PIIINP [21].

Taken together, these observations suggest that aldosterone receptor blockade can reduce cardiac collagen turnover and attenuate cardiac remodelling in patients with mild heart failure treated with a beta-blocker. This too may be important, prognostically, because in RALES reduction in PIIINP was associated with an improvement in clinical outcomes [17].

In the present study, spironolactone therapy was not associated with any improvement in HRV, QTd or cardiorespiratory function. Furthermore, spironolactone treatment had no detectable effect on the plasma concentrations of NE, ADMA, AVP or CRP. MacDonald et al. [18] also found that spironolactone therapy was not associated with any improvement in HRV or myocardial norepinephrine uptake, supporting our findings. They did find a favourable effect of spironolactone on QT dispersion, though a smaller proportion of their patients (72%) were treated with a beta-blocker.

Self-reported health-related quality of life in our patients was lower than the age-matched mean values for a UK population sample (range 75.5-84.4), [22] but higher than the mean (95% CI) baseline value (60 (58-62)) of patients with severe HF randomised in the CArdiac REsynchronisation in Heart Failure (CARE-HF) trial [23]. Surprisingly, in the present study, treatment with spironolactone was associated with a modest reduction in self-perceived health-related quality of life, compared to placebo. This observation is also consistent with that of MacDonald et al. [18] who observed that spironolactone therapy (target dose 50 mg daily) reduced quality of life, as assessed by the Minnesota Living With Heart Failure questionnaire.

Our results, obtained in patients with mild-moderate heart failure, complement what is already known about aldosterone receptor blockade in severe heart failure. Notably, the patients in the present study differed from the patients who participated in RALES, [1] which enrolled patients who had NYHA functional class IV heart failure within 6 months of enrolment and NYHA class III (70%) or IV (30%) heart failure at the time of enrolment. Our findings also complement those of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), in which aldosterone receptor blockade improved cardiac morbidity and mortality in patients with heart failure and left ventricular dysfunction post-MI (75% treated with a beta-blocker) [24].

Some of our findings contrast with those from earlier studies of spironolactone in heart failure, which may be in part due to differences in experimental design.[1,9,25-33] For example, the patients included in earlier spironolactone heart failure studies were sicker (and thus probably had more pronounced neuroendocrine activation), [1] the dose of spironolactone was usually higher (50-100 mg) than in our own study, [29] and fewer patients in these studies received a beta-blocker [1,9,25-33]. Furthermore, the small sample size and limited power of our own study may have contributed to some of our neutral findings [30]. MacDonald et al. [18] also reported favourable changes in forearm endothelial-dependent vasodilatation with spironolactone treatment.

The propensity of spironolactone to cause renal dysfunction and hyperkalaemia, is well recognised and these problems seem to occur more often in ordinary clinical practice than observed in RALES. No adverse events related to renal dysfunction occurred in our study. Nevertheless, we observed typical changes in serum potassium and creatinine concentrations in patients treated with low-dose spironolactone, indicating that the risk of renal-related adverse events with spironolactone may be no less common in patients with mild-moderate heart failure than in those with severe heart failure [34,35]. Renal biochemistry may need to be monitored as assiduously in patients with mild heart failure as in those with a more advanced syndrome.

Spironolactone reduced both BNP and eGFR, as has been noted before [15-18,34,35]. Both changes are likely to be due to volume depletion caused by spironolactone. This would be expected to lead to a reduction in left ventricular filling pressure, probably the major stimulus for the release of BNP, as well as a decline in glomerular filtration.

In conclusion, in this study treatment with an aldosterone receptor blocker resulted in potentially beneficial changes in BNP and collagen turnover in patients with mild-moderate heart failure receiving otherwise optimal drug therapy, including a beta-blocker. Although renal function and self-reported health-related quality of life declined, spironolactone was well tolerated. These findings suggest that the balance between risk and benefit of spironolactone in mild heart failure is uncertain and can only be clarified in a large prospective randomised trial.


   Acknowledgements
 
This study was supported by a British Heart Foundation Project Grant (no. 32659/1). We thank Professor Allan Struthers whose laboratory performed the PIIINP analyses.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 References
 

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