Clinical trials in acute heart failure: simpler
solutions to complex problems. Consensus
document arising from a European Society
of Cardiology cardiovascular round-table think
tank on acute heart failure, 12 May 2009†
Theresa A. McDonagh1*, Michel Komajda2, Aldo P. Maggioni3, Faiez Zannad4,
Mihai Gheorghiade5, Marco Metra6, and Henry J. Dargie7
Cardiology Department, King’s College Hospital, Denmark Hill, London SE5 9RS, UK; 2
CHU Pitie´-Salpeˆtrie`re, Institut de Cardiologie, Paris, France; 3
ANMCO Research Center,
Florence, Italy; 4
Department of Cardiology, Nancy University, Nancy, France; 5
Center for Cardiovascular Innovation, Northwestern University Chicago, IL, USA; 6
Cardiovascular Diseases, University of Brescia, Italy; and 7
Western Inﬁrmary, Glasgow, UK
Received 30 January 2011; revised 30 June 2011; accepted 8 July 2011; online publish-ahead-of-print 29 September 2011
This European consensus document aims to identify the main reasons for the apparent lack of progress in the introduction of new medicines
for acute heart failure. Relevant issues include not only the heterogeneity of the patient group but also the pharmacology of the medicines
themselves and the design of the trials. Above all, this document attempts to provide some pragmatic solutions to this complex syndrome to
simplify the execution of meaningful therapeutic endeavours in this area of undoubted unmet clinical need in the future.
Keywords Acute heart failure † Clinical trials
Acute heart failure (AHF), often deﬁned as the rapid onset of
symptoms and/or signs of heart failure, occurring for the ﬁrst
time (de novo) or recurring in a patient with known heart failure
(acute decompensated chronic heart failure) continues to be a
serious public health problem in both Europe and the USA.1,2
Within the European Union during 2010, there were 15 million
patients with heart failure, we can expect there to be 3.6 million
emergency admissions to hospital for AHF of which the substantial
majority will be for worsening symptoms of chronic heart failure
The in-hospital mortality rate in Europe, according to
the EuroHeart Failure Study, is 8.1% for de novo heart failure,
9.1% for those presenting with pulmonary oedema, and 40%
for cardiogenic shock3
(Figure 1). A more recent pilot study
showed some improvements, quoting a 5.6% mortality rate for
pulmonary oedema and 22% for cardiogenic shock.4
the combined event rate for death or rehospitalization after an
admission with AHF at about 50% at 6 months.5 –8
It has become fashionable when reviewing the treatment of
AHF, to lament the disappointing lack of progress compared
with CHF. In clinical trials, the annualized mortality in patients
with CHF has fallen remarkably from 50% in the placebo arm of
CONSENSUS to 10% in the treatment arm of CARE-HF follow-
ing the sequential addition to baseline diuretics, of angiotensin-
converting enzyme inhibitors (ACEI), beta-blockers, aldosterone
and angiotensin receptor blockers, and cardiac resynchronization
In clinical trials of AHF, however, there has been no
such cause for celebration. Indeed, there is yet to be published a
single trial in which unequivocal beneﬁt can be reasonably
claimed for any of the several putative candidate therapies which
have been proposed for its treatment. Similarly, our therapeutic
armamentarium for AHF has not progressed in this time, consisting
of diuretics, vasodilators, and inotropes. Underpinning the
impression of lack of progress is a large number of ‘failed clinical
trials’ of new drugs which have resulted in a sense of futility in
the scientiﬁc community for advancing new developments in this
Other members of the think tank are listed in the Appendix.
* Corresponding author. Tel: +44 203 299 4257, Fax: +44 207 351 8634, Email: firstname.lastname@example.org
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: email@example.com.
European Journal of Heart Failure (2011) 13, 1253–1260
This document aims to identify the main reasons for the appar-
ent lack of progress in the introduction of new medicines for AHF.
Relevant issues include not only the heterogeneity of the patient
group but also the pharmacology of the medicines themselves
and the design of the trials. Above all, this paper attempts to
provide some pragmatic solutions to this complex syndrome to
simplify the execution of meaningful therapeutic endeavours in
this area of undoubted unmet clinical need in the future.
‘Seeing the trees from the wood’
A fundamental problem in performing AHF trials is the hetero-
geneous nature of the patients presenting with AHF. The latest
European Society of Cardiology (ESC) Guidelines categorize
AHF into six different clinical presentations, which also have con-
(Figure 2). Clearly, AHF is not a distinct diagnosis
but rather a collection of syndromes with different causes and
varying clinical features which fall under the heart failure umbrella
and require urgent medical intervention. Treating these AHF syn-
dromes as a single entity and attempting to evaluate the beneﬁts
of a single new agent would appear to be futile. Moreover, patients
with certain clinical presentations, especially those with ‘de novo’
heart failure, are more difﬁcult to study in clinical trials. First, a diag-
nosis of the underlying cause of the clinical presentation is
required. Second, due to the potential instability of the underlying
disease processes involved such as acute valve malfunction or
acute myocardial diseases such as myocarditis, baseline stability
of clinical, or haemodynamic status cannot be assumed or even
expected. For these reasons clinical trials in AHF have been
conﬁned mainly to patients with acutely decompensated CHF.
However, even within this group there is a large amount of hetero-
geneity within the trials, even when they have tested similar groups
of AHF drugs. (Table 1) The one important exception to this are
the heart failure trials in acute myocardial infarction (AMI), in
Table 1 Drug failures in acute heart failure
Trial name Drug tested Patients enrolled
VMAC Nesiritide Decompensated CHF
Excluded SBP , 90 mmHg
Mean SBP . 124 mmHg
No LVEF cut point
OPTIME Milrinone Decompensated systolic heart failure,
not requiring inotropes
Excluded SBP , 80 mmHg
Mean SBP ¼ 120 mmHg
Mean LVEF ¼ 23%
VERITAS Tezosentan Acute heart failure
Two out of four- BNP, pulmonary
oedema, CXR congestion,
LVEF , 40%
Mean LVEF ¼ 20% in VERITAS I and
28% in VERITAS II
Mean SBP ¼ 131 in VERITAS I and
132 in VERITAS II
SURVIVE Levosimendan Acute decompensated HF requiring
LVEF , 30%
Mean LVEF ¼ 24$
Mean SBP-116 mmHg
REVIVE -2 Levosimendan Acute decompensated HF
Symptomatic despite i.v. diuretic
LVEF , 35%
Excluded SBP , 90 mmHg
EVEREST Tolvaptan Hospitalized for decompensated CHF
LVEF ≤ 40%
Excluded SBP , 120 mmHg
Mean LVEF ¼ 27.5%
Mean SBP ¼ 120 mmHg
Rolofylline Acute heart failure
Impaired renal function
ASCEND-HF Nesiritide Acute decompensated heart failure
Recent drug trials in acute heart failure showing the heterogeneity of patients
LVEF, left ventricular ejection fraction; SBP, systolic blood pressure; BNP, B-type
natriuretic peptide; CXR, chest X-ray; CHF, chronic heart failure.
Figure 2 The heterogeneity of acute heart failure syndromes
according to the recent European Society of Cardiology
Figure 1 Mortality of acute heart failure syndromes. In-hospital
mortality in EuroHeart Failure Survey II by history of heart failure
and clinical class. EHFS II, EuroHeart Failure Survey II.
T.A. McDonagh et al.1254
which ACEI and beta-blockers have been successfully evaluated
with positive results.19,20
What can we learn from the success stories in cardiovascular
therapeutics in the two major disease areas where there has
been spectacular success, CHF and AMI? The advances in myocar-
dial infarction (MI) care have been achieved by studying distinct
clinical presentations of the pathology, ST Segment Elevation MI
(STEMI) and Non-ST Elevation MI (NSTEMI). Similarly, the
achievements in CHF therapeutics have stemmed from
investigation of a speciﬁc subgroup of patients, i.e. those with left
ventricular systolic dysfunction (LVSD).
The differences are, however, fairly major since AMI has a
precise mechanistic cause which is plaque rupture leading to occlu-
sive or non-occlusive thrombus formation and the typical clinical
and electrocardiographic signs of STEMI or NSTEMI. The treat-
ment for STEMI is to reperfuse the artery either by the use of
lysis or more recently by percutaneous coronary intervention.
For NSTEMI the aim is to prevent total or subtotal occlusion by
using anti-thrombotic therapy.
No such simple approach works for AHF as the causes are more
diverse and, in some cases, not speciﬁcally cardiac since they
include lack of adherence to proven21
heart failure medicines
and lifestyle advice together with intercurrent chest or other infec-
tions or anaemia, and other precipitating factors.3,6
include situations not remediable by conventional medical treat-
ments, such as acute mechanical problems including valve incom-
petence, cardiac tamponade, or even ruptured papillary muscles.
As in CHF, most AHF trials have been performed in patients
with LVSD. Thus, a potential problem may be that many patients
in AHF trials are already on standard therapy for LVSD and, as
with CHF trials, we are therefore treating an already-well-treated
group of patients whose baseline medications have been shown
to markedly reduce symptoms and improve outcomes.13
It is possible to simplify this crucial step of more accurate patient
characterization. There are three main areas to be considered
namely the clinical presentation, the underlying cardiac phenotype,
and ﬁnally the underlying aetiology of the AHF episode. Ideally,
these three areas should be clearly deﬁned before randomization
to a new therapy. An obvious example is the patient presenting
with pulmonary oedema associated with LVSD due to ischaemic
heart disease who might beneﬁt from a very different type of medi-
cine than one presenting with pulmonary oedema associated with
preserved systolic function and left ventricular (LV) hypertrophy
due to hypertension.
For the two main types of presentation, breathlessness and
oedema, simple diuretic therapy, especially when given intrave-
nously (i.v.), is very effective in relieving symptoms rapidly.
However, we do not know what impact this has on short-,
medium- or long-term outcome.
Acute heart failure occurs most frequently as an acute decompen-
sation of CHF, while in about one-third of patients it presents ‘de
novo’. Both of these may present as one of the recognized ‘AHF
syndromes’ which include pulmonary oedema, cardiogenic shock,
and severe peripheral oedema.22
This characterization of the
mode of presentation is important as it links the pathophysiology
to the pharmacology of potential new therapeutic agents.23
It is also crucial to categorize patients according to some simple
clinical biometrics because clinicians in the AHF setting must
initiate treatment as quickly as possible while identifying suitability
for entry into a clinical trial. The most important variables are heart
rate, systolic blood pressure (which can be low, normal, or high),
and the presence or absence of renal impairment.24,25
has become simpler due to the adoption of the National Kidney
Foundation Classiﬁcation, where simple clinical formulae such as
the modiﬁcation of diet in renal disease (MDRD, which has been
validated in heart failure) can be used to calculate the estimated
glomerular ﬁltration rate (eGFR).26
For the future we will undoubtedly need to consider biomarkers
to classify the AHF population further. Many new candidates will
emerge but at the present time we should have a measure of
B-type natriuretic peptide, a raised plasma concentration of
which conﬁrms that the patients are very likely to have cardiac
dysfunction underlying their symptoms while excluding those
with normal levels who are extremely unlikely to have heart
Similarly, the measurement of troponin at baseline
will also be useful, not only to help deﬁne those presenting with
overt myocardial ischaemia and heart failure but as a baseline for
future monitoring of myocardial injury.29 – 31
It is of paramount importance to classify AHF patients according to
the type of cardiac dysfunction underlying the presentation. At
present, patients should be divided into those predominantly
with LVSD and those whose heart failure occurs in the presence
of preserved left ventricular ejection fraction. Of note, for the
latter group of patients there must be some evidence of cardiac
dysfunction before the heart failure diagnosis can be made, the
most useful indicators being the presence of a large left atrial
size/volume or the presence of LV hypertrophy32
as well as trans-
mitral Doppler ﬂow indices suggestive of increased pulmonary
Finally, it is mandatory to match the patient subgroups according to
the underlying cardiac pathology which has caused the cardiac
dysfunction. Of particular relevance is ischaemic heart disease, by
far the most common cause of heart failure.33
should be categorized at presentation into those with heart
failure due to ischaemic heart disease stratiﬁed as acute MI or
chronic coronary artery disease (CAD); and those whose heart
failure is non-ischaemic the most common causes being hyperten-
sion, arrhythmias, and dilated cardiomyopathy.
Using this simple classiﬁcation it is easier to envisage a clinical
trial population at which a speciﬁc drug can be targeted, e.g.
patients in known CHF presenting with pulmonary oedema, with
a low blood pressure, evidence of renal impairment, systolic
dysfunction, and known ischaemic heart disease represent a very
different group to those presenting de novo, in cardiogenic shock
with systolic dysfunction and acute MI or those with ﬂash pulmon-
ary oedema in the context of uncontrolled hypertension.
Clinical trials in AHF 1255
‘Horses for courses’
Matching drugs to subpopulations
After patients have been appropriately characterized, speciﬁc novel
therapies can be usefully targeted.
Of the novel therapies currently being studied or those in the
pipeline, we can divide the drugs broadly into ﬁve groups which
have obvious clinical targets (Table 2). These are: vasodilator
agents (for use in those with normal or high systolic blood
pressure), inotropes (for those in cardiogenic shock or pulmonary
oedema/ﬂuid retention, and low blood pressure), renal preser-
vation agents (for those with worsening renal function), diuretics
(for patients with ﬂuid overload), and myocardial protection
agents (for those with CAD or ongoing ischaemia).
Novel vasodilator drugs currently being studied include cinaciguat
However, some new drugs have more than one
mode of action, for example, chimeric natriuretic peptides such as
CD-NP have both venodilatory and natriuretic effects.36,37
some novel inotropes also have other properties. Istaroxime is a
Na-K/ATPase inhibitor which increases SERCA 2a activity and is
both inotropic and lusitropic38
and the cardiac myosin activators,
while being thought of as inotropes actually prolong stroke volume
by an improved energy efﬁciency of the contractile apparatus
rather than increasing dP/dt and increasing myocardial oxygen
demand like conventional inotropes.17
Urocortins also exhibit
powerful inotropic and lusitropic effects.39
Novel myocardial pro-
tection agents include adenosine regulators such as acadesine,
which has anti-ischaemic effects and ameliorates glucose uptake
and free fatty acid oxidation hence increasing ATP synthesis.40
Novel classes of drugs which are in the advanced stages of
development in CHF may also have a role in AHF, e.g. direct
macronutrients such as omega-3 fatty acids,42
and micronutrients such as thiamine, amino acids, L-carnitine, and
It is also important to consider device therapies here. In particu-
lar, ultraﬁltration devices for those with ﬂuid overload and renal
impairment, mechanical assist devices for cardiogenic shock and
conventional heart failure devices, cardiac resynchronization
therapy, and deﬁbrillators, the latter of which are as yet untested
in the acute setting.44 –46
Careful matching of drugs and devices is needed not just with
regard to the subgroup being studied but also bearing in mind
the mechanism of action of the drug. Speciﬁc mechanistic targets
should be addressed in deﬁned patient subgroups.
For this area to be addressed more satisfactorily we need to
know much more about the underlying pathophysiology of AHF
syndromes. It is insufﬁcient just to know that the condition has
high short-term mortality—it is much more important to know
when and how people are dying with AHF to meaningfully target
new drug/device therapies. Future studies should also focus on
aspects of care which may be unrelated to speciﬁc agents being
given in AHF studies, e.g. the attention to detail in pre-discharge
care such as electrolyte balance, optimization of CHF treatment,
and stability prior to discharge, which can also impact on short-
and long-term outcomes.
‘Turning tribulations into trials’
Clinical trials in acute heart failure
After careful consideration of the patient subgroups and the drug
mechanisms, we need to give some attention to the design of AHF
trials themselves. Timing of interventions is also important, as an
intervention given very early in the presentation may have a very
different effect to the same intervention given later—an obvious
lesson from AMI reperfusion studies.47,48
We have to consider three important areas namely, design, size,
This will depend greatly on the stage of investigation of the agent in
question which is conventionally divided into three phases. In
Phases 1 and 2 the new agent is being characterized in terms of
its pharmacodynamic and pharmacokinetic characteristics while
in Phase 3, the deﬁnitive trials of efﬁcacy and safety, are often
much larger. Of late, these trials have become very large, expens-
ive, and time consuming leading to delays in reaching patient care
and with a high price of the new drugs for the health systems of
even economically well-developed countries to sustain. A detailed
account of clinical trial design is beyond the scope of this paper but
general principles can be summarized.
The ﬁrst consideration in conducting AHF trials is whether to
use a placebo or an active control. This is a key issue as many
trials to date have been conducted using a comparator of ‘standard
usual care’ which has been ill-deﬁned, is often non-evidence based,
and is therefore subject to extreme variation especially in large
multicentre and multinational trials.49
(1) We recommend an active comparator if the new medicinal
product belongs to an existing therapeutic class, for example:
(a) New vasodilator: nitroglycerine.
(b) New diuretic: furosemide/other ‘loop’ diuretic.
(c) New inotrope: dobutamine.
(2) For new classes of drugs (e.g. congestion management, vaso-
pressin inhibitors, relaxin, etc.), the study treatment should
be tested against placebo as add-on to the existing therapies
Table 2 Some new therapeutic agents for acute heart
failure and their potential targets
Agent For patients with these
Diuretics, vasopressin antagonists,
Patients with signs of ﬂuid
overload, high BNP
Vasodilators Normal to high SBP, high BNP
Inotropes Low SBP, signs of
Renal preservation agents Renal dysfunction
Myocardial protection agents CAD, or ongoing ischaemia
BNP, B-type natriuretic peptide; SBP, systolic blood pressure; CAD, coronary
T.A. McDonagh et al.1256
as there are no reliable comparators. It is extremely important
here to deﬁne standard existing practice and background
medical therapy in trials of decompensated CHF.50
(3) If the purpose of the trial is an improvement in outcome, then
there are no reliable comparators (no evidence-based treat-
ments have been shown to improve patient outcomes in
AHF), a placebo group should be used as the comparator.
(1) For superiority trials with morbidity and mortality endpoints,
the usual methods for calculating sample size should be
(2) For deﬁning the absence of a detrimental effect in trials with
signs and/or symptoms as the primary endpoint, a non-
inferiority approach vs. placebo (e.g. EVEREST) should be
used; the boundary margins should be ﬁxed depending on
the type of drug and the patient proﬁle.49
In such cases, the
effect on symptoms and signs should be clearly demonstrable
especially for regulatory purposes.
Selection of endpoints in AHF trials is challenging. No single
endpoint can be uniformly applied to trials across such a hetero-
Mortality trials have been the benchmark in CHF; however,
there is underlying doubt as to whether applying this approach
in AHF trials is appropriate. The fundamental question is
whether it is possible to improve post-discharge long-term mor-
tality or indeed morbidity with a drug that is given i.v. for only a
few hours or days in hospital?
Because of this unanswered concern, it is not current thinking
that a trial in AHF can be conducted with mortality as the sole
primary endpoint, because unlike in AMI, in AHF we have no
speciﬁc pathophysiological target. Theoretically, this could be poss-
ible in the future if a speciﬁc pathophysiological target could be
identiﬁed. Current thinking in the testing of AHF drugs is that
they should improve symptoms without increasing mortality.49
Against this background, composite mortality/morbidity end-
points have to be employed based on combinations of mortality
and readmission to hospital for heart failure or days alive and
out of hospital with heart failure.
Composite endpoints including morbidity and mortality
These are necessary where the mechanism of action of the drug
may have an impact on future mortality or morbidity. Consider-
ation should be given to the following components of the compo-
(1) Mortality should be all cause and not just cardiovascular.
(2) The timing should be 30–60 days, as measurement of the end-
point should occur shortly after symptom onset. Kaplan–
Meier curves show that the timing of events in AHF is
similar to that for ACS, i.e. they occur early: there is an
impressive slope over the ﬁrst 30–40 days (Figure 3), after
which events mirror those in CHF. Therefore, we should ﬁx
the timing to that at which most events occur.
(3) Readmissions should be included in the endpoint in some way,
as they are relevant both clinically and in terms of cost. Stricter
deﬁnitions of readmission (e.g. within 24 h, necessitating i.v.
treatment for heart failure, etc.) are needed to minimize
issues of heterogeneity in medical care between centres,
countries, and geographical areas. There is also a need for
Figure 3 Kaplan–Meier curves for survival from acute heart failure, acute coronary syndromes, and chronic heart failure. AHF, acute heart
failure; ACS, acute coronary syndromes; CHF, chronic heart failure. Reproduced with permission from AP Maggioni.
Clinical trials in AHF 1257
clinical trial protocols to try to standardize in-hospital care and
to minimize differences in length of stay which can affect read-
mission times and rates.
(4) The composite end point should vary according to the
mechanism of action of the drug, e.g. the endpoint could be
a composite of all-cause death or readmission for heart
failure (and may include other cause speciﬁc admissions
depending on the potential side effect proﬁle of the drug
under study, e.g. seizures for adenosine antagonists).
(5) Post-marketing surveys are desirable (but not necessary) to
conﬁrm the drug approval.
Primary endpoints based on symptoms and/or signs
These can be consideredfor short-term interventions. This is an area
where a lot of controversy has arisen in previous AHF trials. First,
standard therapy in many clinical trials, is very good atrelieving symp-
toms such as dyspnoea—it is therefore difﬁcult to prove that a new
drug is superior in that regard.51
Second, methods of quantifying
symptoms in clinical trials have been poorly validated. In future
trials, validated scales such as Likert or Visual Analogue Scales
should be employed and the timing of their measurement carefully
It is now agreed that haemodynamic endpoints are
not appropriate in Phase III randomized controlled trials.
Some general points about the inclusion of symptoms in end-
(1) We do not recommend the inclusion of an endpoint based on
signs/symptoms in a composite endpoint that also includes a
(a) How and when signs/symptoms should be evaluated
depends largely on the patients’ clinical proﬁle.
(b) To push the bar to a higher level: we need to demonstrate
evidence of superiority in terms of signs and symptom
relief with a new drug but without evidence of deterio-
ration in renal function or of cardiac damage. This is
where newer surrogate endpoints should be considered,
e.g. troponin rise or measures of renal impairment such
as eGFR, cystatin C,53
or neutrophil gelatinase-associated
(c) For interventions which improve symptoms there must be
evidence of absence of a detrimental effect in terms of 6–
12 month mortality.
(d) For drugs aimed at improving symptoms, a post-marketing
survey is necessary to conﬁrm the drug approval.
It may be useful to consider the domains proposed by the
Federal Drug Administration (FDA) Study Group as a general
guide for choosing the components of the endpoints to be
included when testing different types of drugs in different patient
subgroups, although not all of them would be necessary in a
single trial (45). These domains are:
(1) Symptom relief.
(2) Measures of congestion relief (i.e. improvement in clinical
(3) Index hospitalization data (e.g. length of stay).
(4) Prevention of end-organ damage (heart and kidney).
(5) Post-discharge: death and rehospitalization data.
Information about all of the domains studied could then be pre-
sented in the ‘package’ of documentation submitted to the regulat-
ory authorities for drug approval, but still using as the primary
endpoint morbidity/mortality (if possible) or improvement of
symptoms. The other domains tested should offer supportive data.
The different approaches used by the two main regulatory auth-
orities, the FDA and European Medicines Authority, have led to
differences in the licensing of drugs for AHF between the USA
and Europe (for example, nesiritide is available in the USA and
levosimendan in parts of Europe). The adoption of a more
uniﬁed strategy, as proposed above, for patient selection, targeting
of drugs to patient subgroups according to the mechanism and
careful choice of appropriate endpoints should lead to a more
rational presentation of data to the regulatory authorities. This
should result in more consistent decisions between the different
Acute heart failure remains an area of great unmet clinical need. It
is possible to do meaningful clinical trials in AHF if we adopt a
more coherent strategy of tighter patient selection for more tar-
geted drug therapy within appropriate and well thought out clinical
trial designs. The European approach outlined above is very much
in line with current US thinking on AHF trials. This more harmo-
nized approach will hopefully deliver better outcomes for patients
with AHF in the future.
Conﬂict of interest: none declared.
Other contributors to the Think Tank
Gerasimos Filippatos, University of Athens, Athens, Greece.
Alexandre Mebazaa, Department of Anesthesiology and Intensive
Care, Lariboisie`re University Hospital, Paris, France.
Piotr Ponikowski, Wroclaw Military Hospital, Wroclaw, Poland.
Neville C Jackson, Pﬁzer, New London, CT, USA.
Krishna Prasad, The MHRA, 1 Nine Elms Lane, London.
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