Spironolactone as a Treatment to extend life in Heart Failure Patients
Submitting InstitutionUniversity of Dundee
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences, Medical Physiology
Summary of the impact
Our research with spironolactone has advanced treatment in heart failure.
We conducted the first "proof of concept" study to show that
spironolactone had beneficial cardiac effects in man. In patients with
heart failure, we demonstrated that it reduced cardiac sympathetic
activity and arrhythmias. Spironolactone was pioneered in Dundee as a
treatment to reduce deaths in chronic heart failure. This treatment is now
recommended (Level A evidence; Class I recommendation) for the treatment
of symptomatic heart failure in all guidelines including the 2010 NICE
guidelines. It is also now a standard in the 2010 NHS Quality Improvement
A major advance in the treatment of heart failure was the development in
the 1980s of the neurohormonal hypothesis of heart failure (i.e. heart
failure develops and progresses because endogenous neurohormonal systems
such as the renin-angiotensin-aldosterone system that are activated by the
initial injury to the heart exert a deleterious effect on the
circulation). The success of angiotensin converting enzyme inhibitors (ACE
inhibitors), which were shown in 1987 to reduce deaths in heart failure,
provided support for this hypothesis. The expectation thereafter was that
ACE inhibitors would suppress aldosterone to such an extent that adding
spironolactone to an ACE inhibitor would not add therapeutic value and
could be hazardous.
The underpinning research and development work that challenged this
contention was funded by the British Heart Foundation and Scottish
Hospital Endowments Research Trust and carried out at the University of
Dundee under the leadership of Prof Allan Struthers (Division of
Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical
School, Dundee) with assistance from Dr (now Prof) Chim Lang (at
the time a Lecturer in the Department) in collaboration with Michael
Arnott and Norman Kennedy (Department of Medical Physics). The original
impetus for our work was that corticosterone was a known inhibitor of
uptake for noradrenaline in non-cardiac tissue. This made us wonder
whether aldosterone (a related steroid hormone) would alter noradrenaline
kinetics in a different tissue, the myocardium.
We began by showing this was indeed the case in animals and went on to
confirm the same effect in man [i]. This was a major finding since cardiac
noradrenergic/sympathetic activity is well known to produce arrhythmias
and hasten death in patients with heart failure. In 1995 we published
seminal work showing that spironolactone not only reduced cardiac
adrenergic activity but also reduced ventricular arrhythmias when added to
ACE inhibitors in patients with heart failure [i]. This was the first
demonstration of a beneficial cardiac effect of spironolactone in man.
Hitherto, spironolactone was thought of only as a diuretic and our work
changed thinking about this familiar drug. These encouraging results,
along with data from others showing that spironolactone might reduce
myocardial fibrosis in rats, were a major factor in persuading Searle to
launch the large, multicentre Randomized ALdactone Evaluation Study
(RALES) trial. An important contribution of the Dundee paper was based on
the fact that cardiac arrhythmias are the main cause of sudden cardiac
death in man; our observation that spironolactone reduced cardiac
arrhythmias and adrenergic activity suggested for the first time that
spironolactone might indeed reduce sudden cardiac deaths [i-iv]. This
hypothesis was subsequently confirmed by the 1999 RALES study and then by
the 2003 Eplerenone Post-Acute Myocardial Infarction Heart Failure
Efficacy and Survival Study (EPHESUS).
The findings of EPHESUS raised the question of whether spironolactone
would be beneficial in patients with mild or asymptomatic heart failure.
Our subsequent publication in Heart [v] was the first study to
show beneficial effects in mild to asymptomatic congestive heart failure
on a key mechanism underlying its benefits—that is, endothelial function.
Spironolactone also improved other markers of prognosis (including
brain/B-type naturietic peptide) in patients with asymptomatic or mild
congestive heart failure when added to optimal treatment including 03b2
References to the research
i. Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers
AD (1995) Effects of adding spironolactone to an angiotensin-converting
enzyme inhibitor in chronic congestive heart failure secondary to coronary
artery disease. Am. J Cardiol. 76, 1259-1265 (DOI:
ii. MacFadyen RJ, Barr CS, Struthers AD (1997) Aldosterone
blockade reduces vascular collagen turnover, improves heart rate
variability and reduces early morning rise in heart rate in heart failure
patients. Cardiovasc. Res. 35, 30-34
iii. MacFadyen RJ, Lee AFC, Morton JJ, Pringle SD, Struthers AD
(1999) How often are angiotensin II and aldosterone concentrations raised
during chronic ACE inhibitor treatment in cardiac failure? Heart 82,
v. Macdonald JE, Kennedy N, Struthers AD (2004) Effects of
spironolactone on endothelial function, vascular angiotensin converting
enzyme activity, and other prognostic markers in patients with mild heart
failure already taking optimal treatment. Heart 90,
The research underpinning this case study was funded by research grants
from SHERT, British Heart Foundation and the Scottish Office:
• Struthers AD, Barr CS: Does spironolactone produce beneficial
effects over and above an ACE inhibitor in chronic heart failure?;
Scottish Hospitals Endowment Research Trust (1992-1993) £23,190.
• Struthers AD, Fraser C: Does aldosterone blockade produce
beneficial effects over and above an ACE inhibitor in chronic heart
failure?; British Heart Foundation (1992-1994) £21,210.
• Struthers AD, Pringle S, Morton JJ: The Identification of
Angiotensin II Reactivation in Heart Failure patients taking ACE
Inhibitors; Scottish Home & Health Department (1995-1996) £41,526.
• Struthers AD, MacFadyen RJ, Pringle S: Spironolactone induced
bradycardia at dawn: what is the mechanism and does it reduce ischaemia?;
Scottish Home & Health Department (1996-1998) £120,140.
• Struthers AD, Kennedy N: Will spironolactone reduce cardiac
deaths in mild chronic heart failure?; Tenovus/Northwood Trust (2000-2002)
• Struthers AD, Pringle S, Donnan P: Does Aldosterone Blockade
improve endothelial dysfunction in patients with coronary artery disease
but without heart failure?; British Heart Foundation (2004-2006) £104,071.
Details of the impact
Our underpinning research addressed the challenge of heart failure, which
is a global health issue. It led to the recognition that aldosterone
antagonists such as spironolactone have beneficial effects in individuals
with various kinds of heart failure. It is now widely recognised that
aldosterone antagonists improve survival among patients with chronic,
severe systolic heart failure and heart failure after myocardial
infarction. Consequently, current guidelines recommend the use of an
aldosterone-receptor antagonist in these patients. This has led to
significant patient benefit.
Aldosterone antagonist treatment is now recommended in National Institute
for Health and Case Excellence (NICE) guidelines, specifically those on
chronic heart failure (; issued in 2010). In preparing this Guideline,
NICE gave detailed consideration to our previous work, as follows:
"....studies were identified comparing aldosterone antagonists plus
optimal medical management with placebo plus optimal medical management in
patients with chronic heart failure. Barr (1995) [i] compared
spironolactone with placebo in a population with chronic heart failure
(CHF) secondary to coronary heart disease. Macdonald (2004) [v] compared
spironolactone with placebo in a population with mild heart failure,
defined as patients whose CHF had been at least [New York Heart
Association] NYHA class II at diagnosis, but optimising their treatment
had improved the patients' condition substantially into a stable and less
symptomatic one....." (Section 184.108.40.206, p96; tabulated on p103). This
contributed to the following recommendation (R29) for second-line
treatments: "....consider adding one of the following if a patient remains
symptomatic despite optimal therapy with an ACE inhibitor and a
beta-blocker: an aldosterone antagonist licensed for heart failure
(especially if the patient has moderate to severe heart failure [NYHA14
class III-IV], or has had a myocardial infarct within the past
In recognition of the influence of his work on heart failure, Prof Struthers
was appointed as a member of the Steering Group of the NHS Quality
Improvement Scotland Heart Disease project, which led in 2010 to the
publication of Clinical Standards for Heart Disease . These apply
throughout the NHS in Scotland and recommend (Standard Statement 15, p28)
that "Patients with heart failure are commenced on medication to reduce
symptoms and improve prognosis, unless contraindicated....15.5 Patients
with left ventricular systolic dysfunction and persistent New York Heart
Association class III heart failure and who have been New York Heart
Association class IV in the last 6 months receive spironolactone except
In a further recent development , the Eplerenone in Mild Patients
Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)
randomised, double-blind trial evaluated the effects of another
aldosterone antagonist, eplerenone, in patients with chronic systolic
heart failure and mild symptoms. The decision to undertake this study was
based upon the outcomes of the RALES and EPHESUS studies, both of which
were influenced by our work [i-iv]. The results of this Pfizer-funded
study indicated that eplerenone, as compared with placebo, reduced both
the risk of death and the risk of hospitalization among patients with
systolic heart failure and mild symptoms.
An aldosterone antagonist is now recommended (Level 1 recommendation) for
use in all patients with systolic heart failure including patients with
mild NYHA II heart failure. Clinical practice guidelines making this
recommendation include the 2012 European Society of Cardiology guidelines
[4,5] and the 2011 National Heart Foundation of Australia and Cardiac
Society of Australia and New Zealand guidelines [6,7].
Aldosterone antagonist treatment has been shown to be cost effective: the
incremental cost-effectiveness ratio for aldosterone antagonist therapy
when added to standard therapy (ACE inhibitor plus 03b2-blocker) in
patients with heart failure has been calculated to be ~US$500 per life
year gained .
Finally, the most recent development (April 2013) has been the addition
of the use of spironolactone for heart failure to the World Health
Organization Model List of Essential Medicines, which is updated every two
years using a transparent evidence-based process endorsed by the WHO
Expert Committee on Selection and Use and serves as a guide for the
development of national and institutional essential medicine lists
throughout the world .
Sources to corroborate the impact
- National Clinical Guideline Centre (2010) Chronic heart failure: the
management of chronic heart failure in adults in primary and secondary
care London: National Clinical Guideline Centre. Available from: http://guidance.nice.org.uk/CG108/Guidance/pdf/English.
- NHS Quality Improvement Scotland (2010) Clinical Standards on Heart
Disease (ISBN 1-84404-590-0).
- Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H,
Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group (2011). Eplerenone
in patients with systolic heart failure and mild symptoms. N. Engl.
J. Med. 364, 11-21 (DOI: 10.1056/NEJMoa1009492).
- McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein
K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber
L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik
PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors
AA, Zannad F and Zeiher A; ESC Committee for Practice Guidelines (2012)
ESC Guidelines for the diagnosis and treatment of acute and chronic
heart failure 2012: The Task Force for the Diagnosis and Treatment of
Acute and Chronic Heart Failure 2012 of the European Society of
Cardiology. Developed in collaboration with the Heart Failure
Association (HFA) of the ESC. Eur. Heart J. 33,
- Letter of Corroboration from the Chairman of the 2012 European Society
of Cardiology Guideline on Heart Failure.
- Krum, H, Jelinek MV, Stewart S, Sindone A, Atherton JJ. (2011) 2011
update to National Heart Foundation of Australia and Cardiac Society of
Australia and New Zealand Guidelines for the prevention, detection and
management of chronic heart failure in Australia, 2006 Med. J. Aust.
194, 405-409 (https://www.mja.com.au/journal/2011/194/8/2011-update-national-heart-
- Letter of Corroboration from the Chair, National Heart Foundation of
Australia, Cardiac Society of Australia and New Zealand, Chronic Heart
Failure Guidelines Expert Writing Panel.
- Banka G, Heidenreich PA, Fonarow GC (2013) Incremental
cost-effectiveness of guideline-directed medical therapies for heart
Am. Coll. Cardiol. 61, 1440-6. (DOI: 10.1016/j.jacc.2012.12.022).
- WHO Model Lists of Essential Medicines; available at: