European Heart Journal Advance Access published November 17, 2015
European Heart Journal
doi:10.1093/eurheartj/ehv565
Improving outcomes in heart failure: a personal
perspective†
John J.J.V. McMurray*
British Heart Foundation Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, G12 8QQ, UK
Received 16 June 2015; revised 18 September 2015; accepted 4 October 2015
Improving outcomes in heart
failure: a personal perspective
When I was a medical student and junior doctor in the early 1980s I
saw many patients on the wards in hospital with this terrible illness
for which we could do little. When the heart fails as a pump one of
the main manifestations is accumulation of fluid due to retention of
sodium and water by the kidneys which also malfunction as a result
of reduced blood flow and other mechanisms. Fluid accumulation in
the legs and lungs leads to swelling (peripheral oedema) and breath-
lessness. Reduced blood flow to the muscles also causes intense fa-
tigue. Back in these early days diuretics which caused the kidneys to
produce more urine and relieve fluid intention) and digoxin, a 200
year old plant-extract thought to stimulate contraction of the failing
heart, were the only two treatments we had, except for the rare,
young, patient who was lucky enough to get a transplant. Otherwise,
I knew that around 7 out of 10 of those men and women I saw would
be dead within a year. Even worse the last months of their lives were
characterized by disabling symptoms and exercise intolerance mak-
ing even ordinary everyday activities a struggle, if not impossible. Of-
ten patients were also readmitted to hospital because of acute
worsening of their symptoms. Around the time I graduated from
medical school USA and European investigators such as Jay Cohn,
Gary Francis, Peter Harris, and Philip Pool-Wilson were beginning
to unravel the pathophysiology—the disease mechanisms—of heart
failure and starting to explore the possibility of finding new treat-
ments for this condition.1,2 The picture that emerged was remark-
able. Although the primary problem was of course weakness and
failing of the contraction of the heart muscle, it was the secondary
responses (and their effects on the blood vessels, kidneys, and failing
heart) that were key to the understanding of why heart failure pro-
gressively worsened over time and to effective new treatments. It
was realized that inappropriate activation of a key hormonal path-
way, the renin-angiotensin-aldosterone system (RAAS), occurs in
patients with heart failure, contributing to the progressive worsen-
ing I have mentioned and, ultimately, death. One of my most forma-
tive experiences as a young Cardiology trainee was seeing Dr Karl
Swedberg, as he was then, from Gothenburg University present
* Corresponding author. Tel: +44 141 3303479, Fax: +44 141 3306955, Email: john.mcmurray@glasgow.ac.uk
†
This article is based on the acceptance speech for the Ricordati prize on 13 June 2015.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com.
SPECIAL ARTICLE
the results of the first trial (CONSENSUS) in heart failure to
show that we could reduce the risk of death in this terrible illness.3
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That trial, conducted in around 250 people with very advanced
heart failure, showed that a drug which blocked the RAAS, enalapril,
had a dramatic and early effect on mortality. Later another, larger,
trial showed that the same drug also improved survival in patients
with less severe symptoms; one of the leaders of that trial was Salim
Yusuf (Figure 1).4 Another less well publicized discovery around that
time was that the heart was not just a mechanical pump but also an
endocrine organ that secreted peptide hormones which stimulated
the kidneys to excrete sodium and water.5 I was fascinated by this
discovery and in 1986 went to work with one of the pioneers study-
ing these newly described hormones in humans, Professor Allan
Struthers at the University of Dundee in Scotland. We showed
that these natriuretic peptides, as well as promoting urine produc-
tion by the kidneys, also inhibited the RAAS.6 – 8 We also hypothe-
sized that because of these actions, boosting natriuretic peptide
levels might be a useful way to treat patients with heart failure.8
While working in Dundee I heard that Dr Henry Dargie in Glasgow
was working with a new drug that blocked an enzyme (neutral endo-
peptidase or neprilysin) which breaks down natriuretic peptides
(thereby increasing natriuretic peptide levels).9 – 11 Because of that
I moved to Glasgow in 1988 in the hope of becoming involved in
the further development of this exciting new compound. Unfortu-
nately, for reasons we did not understand at the time, the effect of
this agent was not sustained over time and it was abandoned. How-
ever, that story did not end there, as I will come back to. I pursued
additional lines of research, finding that angiotensin II could be pro-
duced in human tissues by non-angiotensin-converting enzyme
(ACE) pathways.12,13 This provided some of the rationale to add a
new type of RAAS antagonist, an angiotensin receptor blocker, to an
ACE inhibitor and that an ARB might be as good as or even better
than an ACE inhibitor. With Karl Swedberg, Marc Pfeffer (Brigham
and Women’s Hospital, Boston), Christopher Granger (Duke Uni-
versity), and Salim Yusuf I conducted a series of trials in patients with
chronic heart failure (CHARM) and a large trial in patients with
heart failure after myocardial infarction (VALIANT, where I became
friends with Rob Califf, Lars Køber, Aldo Maggioni, Eric Velazquez,
Page 2 of 4
Faiez Zannad, among others) using two of these new drugs.14 – 17
Together we showed that ARBs were an effective alternative to
ACE inhibitors (important because some patients cannot tolerate
an ACE inhibitor) and that in heart failure adding an ARB to an
ACE inhibitor further reduced the risk of death and hospital admis-
sion. With ACE inhibitors and b-blockers which had also been
shown to be of benefit in heart failure, we now had three drugs
that used together led to much better outcomes for our patients
with heart failure than could have been dreamt of twenty years
early. I had also been interested in a different type of RAAS blocker
spironolactone, which is a mineralocorticoid receptor antagonist
(MRA) blocking the actions of aldosterone rather than angiotensin
II. Spironolactone had been shown by Bert Pitt (Ann Arbor Mich-
igan) and Faiez Zannad (Nancy, France) to reduce the risk of death
in patients with severe heart failure when added to an ACE inhibitor
but this was before we had learnt about the value of b-blockers and
Figure 1 Heart failure-reduced ejection fraction: thirty years of progress - positivedrug trials 1986 –2001.
Figure 2 Heart failure-reduced ejection fraction: thirty years of progress - positive drug, device and other trials 2001 – 2014.
J.J.J.V. McMurray
ARBs (the famous RALES trial).18 I and others showed that MRAs
also seemed to have beneficial actions in patients with milder
symptoms and was lucky enough to team up with Drs Pitt, Zannad,
Swedberg, and Henry Krum from Melbourne in Australia among
others, to lead a new mortality/morbidity trial with the MRA epler-
enone in patients with heart failure and mild symptoms, by this stage
adding the MRA not only to an ACE inhibitor but also a
b-blocker.19,20 We were delighted to be able to show that this
treatment led to a striking improvement in outcome with both
an improvement in survival and decrease in hospital admissions.
Now we had a treatment that was even better than an ARB when
added to an ACE inhibitor and b-blocker and a triad of treatments
capable of transforming the lives of all patients with this type of
heart failure (Figure 2).
More recently I had another opportunity to pursue the hypoth-
esis that enhancing the actions of natriuretic peptides might
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Improving outcomes in heart failure
Figure 3 Heart failure trials: the disappointments: 1987– 2013.
be beneficial in heart failure. By the late 1990s we had learnt that
neprilysin inhibition had to be combined with an RAAS blocker to
express its full therapeutic potential and that the better RAAS
blocker might be an ARB rather than an ACE inhibitor.21 With an-
other friend and colleague of many years standing, Milton Packer,
I went on to lead a trial using the new strategy of using a combined
angiotensin receptor neprilysin inhibitor (ARNI), comparing this
head-to-head with the now “standard-of-care” ACE inhibitor enala-
pril.22 – 25 We were fortunate to work again with Karl Swedberg and
other friends including Jean Rouleau (Montréal), Scott Solomon (Bos-
ton, MA), and Mike Zile (Charleston, SC) and colleagues from Novar-
tis. Could we beat and replace a current gold-standard treatment that
had revolutionized the management of heart failure 20 years earlier
and had not been bettered since? Last year we showed that this novel
approach lowered the risk of death and hospital admission even
further, in fact effectively doubling the mortality benefit of enalapril
the drug that had opened up a new era of hope for patients with heart
failure back in 1987 at the start of my career in Cardiology (Figure 2).
Now we are on the cusp of having available just three drugs that
can make a fundamental difference to the lives our patients with
heart failure and their loved ones. Treatment with b-blocker, an
MRA and an ARNI together will reduce the risk of premature death
to around a third to a quarter of what it was when I qualified from
medical school, as well as reduce the crippling symptoms and fre-
quent hospital admissions suffered by patients with heart failure. It
has taken us 30 years to reach this point and there have been
many failures along the way (Figure 3). However, we have got to
where we are because of the massive collaborative effort between
doctors, governments, and industry across the world. The world
community of clinical trialists is a remarkable one that has changed
the way we practice medicine for the better. But, of course, funda-
mentally key to this venture has been our patients who have trusted
Page 3 of 4
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us, literally with their lives, in agreeing to participate in clinical trials.
We still face challenges. Implementation of effective treatments is
still suboptimal for reasons that we do not always understand.26
In some countries it is because the drugs are still not affordable
by many but in others it is because of lack of knowledge, education,
or other factors. Here guidelines, organization and audit of care have
the potential to make a huge difference and I am a passionate advo-
cate of promoting the uptake of evidence-based medicines through
these approaches.27 – 29 Another important finding I and others, in-
cluding my good friend Simon Stewart from Melbourne, demon-
strated many years ago in a randomized trial is that specialist
nurses can improve outcomes for patients with heart failure in
part through careful implementation of effective therapies.30,31
Finally, there is another less common but still important type of
heart failure—heart failure with preserved ejection fraction where
the problem is with the relaxation and filling of the heart and not
its contraction and emptying. Sadly, to date all our efforts to help
patient with this problem have failed, although we have not given
up and continue to look for a breakthrough.16,32 – 34
Authors’ contributions
J.M.M.: drafted the manuscript.
Acknowledgements
I thank the Recordati Foundation and judges’ panel for this presti-
gious award. I am delighted and honoured to share this with my
friend and colleague professor Salim Yusuf from McMaster Univer-
sity who I have worked with for over 15 years and I also wish to rec-
ognize the many other investigators I have worked with and who
have helped and encouraged me over so many years. I am also espe-
cially pleased that the Recordati foundation has highlighted the
Page 4 of 4
importance of heart failure as one of the increasingly common med-
ical problems world-wide today.
Conflict of interest: none declared.
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