The document discusses lessons learned from failed clinical trials of pharmacological therapies for acute heart failure syndromes (AHFS). Several factors contributed to the failures, including heterogeneity among AHFS patients, short duration of treatment effect from drugs, and focus on short-term clinical status rather than long-term outcomes. The authors propose strategies to improve future trials, such as enrolling more narrowly defined patient populations, considering combination therapies, and using composite endpoints of clinical status and hard outcomes.

1. Teerlink, James E. Udelson, Clyde W. Yancy, Faiez Zannad and Mihai Gheorghiade
O'Connell, Christopher M. O'Connor, Ileana L. Pina, Piotr Ponikowski, Hani N. Sabbah, John R.
Maggioni, Barry M. Massie, John J. McMurray, Mandeep Mehra, Marco Metra, John
Hernandez, Sadiya Khan, Michel Komajda, Marvin A. Konstam, Peter P. Liu, Aldo P.
Dickstein, Gerasimos S. Filippatos, Gregg C. Fonarow, Barry H. Greenberg, Adrian F.
G. Michael Felker, Peter S. Pang, Kirkwood F. Adams, John G.F. Cleland, Gad Cotter, Kenneth
Learned and Directions Forward
Clinical Trials of Pharmacological Therapies in Acute Heart Failure Syndromes: Lessons
Print ISSN: 1941-3289. Online ISSN: 1941-3297
Copyright © 2010 American Heart Association, Inc. All rights reserved.
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2. Special Report
Clinical Trials of Pharmacological Therapies in Acute Heart
Failure Syndromes
Lessons Learned and Directions Forward
G. Michael Felker, MD, MHS; Peter S. Pang, MD; Kirkwood F. Adams, MD; John G.F. Cleland, MD;
Gad Cotter, MD; Kenneth Dickstein, MD; Gerasimos S. Filippatos, MD; Gregg C. Fonarow, MD;
Barry H. Greenberg, MD; Adrian F. Hernandez, MD, MHS; Sadiya Khan, MD; Michel Komajda, MD;
Marvin A. Konstam, MD; Peter P. Liu, MD; Aldo P. Maggioni, MD; Barry M. Massie, MD;
John J. McMurray, MD; Mandeep Mehra, MD; Marco Metra, MD; John O’Connell, MD;
Christopher M. O’Connor, MD; Ileana L. Pina, MD; Piotr Ponikowski, MD; Hani N. Sabbah, PhD;
John R. Teerlink, MD; James E. Udelson, MD; Clyde W. Yancy, MD; Faiez Zannad, MD, PhD;
Mihai Gheorghiade, MD; on behalf of the International AHFS Working Group
Acute heart failure syndromes (AHFS) are characterized
by a gradual or rapid onset of new or worsening signs
and/or symptoms of heart failure (HF) requiring urgent
therapy, usually resulting in hospitalization.1,2 The societal
burden of AHFS is substantial, with Ͼ1 million hospitaliza-
tions annually in the United States and similar relative
numbers in Europe.2–6 Ongoing epidemiological trends, such
as the aging population, improved survival after myocardial
infarction, and a decrease in sudden death due to defibrillator
therapy, suggest that the prevalence of chronic HF resulting
in hospitalization will continue to increase during the coming
decades.7 The prognosis after hospitalization for AHFS re-
mains bleak, with rates of death or recurrent hospitalization at
6 months approaching 50%,8–10 outcomes that have changed
little in recent years despite improvements in the management
of chronic HF.11 Hidden within these oft-cited statistics is a
notable paradox—signs and symptoms of AHFS (dyspnea,
edema, etc) are successfully treated in the majority of patients,
but postdischarge outcomes remain dismal, and attempts to
develop new short-term therapies for AHFS have largely been
unsuccessful. Since our initial publication in 2005,1 4 large,
international phase III development programs—tezosentan,12
levosimendan,13 tolvaptan,14 and rolofylline15—have failed to
convincingly demonstrate the safety and efficacy of these agents
in AHFS. Even for drugs approved for AHFS treatment (milri-
none and nesiritide in the United States and levosimendan in
parts of Europe), there have been persistent concerns about
safety.16–18 Broadly speaking, the pharmacological armamentar-
ium for AHFS—loop diuretics, vasodilators, and inotropes—is
largely unchanged from the 1970s.19
Although substantial efforts in the last decade to develop
improved AHFS therapies have yielded disappointing results,
we believe that as a scientific community, we are now better
equipped to conduct future studies. Hospitalization for AHFS
is now recognized as a critical clinical problem in both the US
and European guidelines.2,6 This consensus document arose
From the Duke Clinical Research Institute Durham, NC (G.M.F.); Department of Emergency Medicine, Center for Cardiovascular Quality and
Outcomes, Northwestern University, Feinberg School of Medicine, Chicago, Ill (P.S.P.); Departments of Medicine and Radiology, School of Medicine,
University of North Carolina at Chapel Hill, NC (K.F.A.); Department of Cardiology, Castle Hill Hospital, University of Hull, Kingston-upon-Hull, UK
(J.G.F.C.); Momentum Research Inc, Durham, NC (G.C.); Stavanger University Hospital, Stavanger, Norway; Institute of Internal Medicine, University
of Bergen, Bergen, Norway (K.D.); Athens University Hospital Attikon, Athens, Greece (G.S.F.); Ahmanson-UCLA Cardiomyopathy Center, David
Geffen UCLA Medical Center, Los Angeles, Calif (G.C.F.); University of California, San Diego, San Diego, Calif (B.G.); Department of Medicine,
Feinberg School of Medicine, Northwestern University, Chicago, Ill (S.K.); Duke Clinical Research Institute, Duke University School of Medicine,
Durham, NC (A.F.H.); University Pierre et Marie Curie Paris, Assistance Publique Hopitaux de Paris, Paris, France (M.K.); Cardiovascular Center, Tufts
Medical Center, and Tufts University School of Medicine, Boston, Mass (M.A.K.); Institute of Circulatory and Respiratory Health, Canadian Institutes
of Health, Toronto General Hospital, University of Toronto (P.P.L.); ANMCO Research Center, Firenze, Italy (A.P.M.); University of California, San
Francisco, Calif, Cardiology Division, San Francisco Veterans Affairs Medical Center, San Francisco, Calif (B.M.M.); BHF Cardiovascular Research
Centre, University of Glasgow, Glasgow, Scotland (J.J.M.); University of Maryland School of Medicine, Baltimore, Md (M.M.); Department of
Experimental and Applied Medicine, University and Civil Hospital of Brescia, Brescia, Italy (M.M.); Division of Cardiology, Feinberg School of
Medicine, Chicago, Ill (J.O.C.); Duke Heart Center, Division of Clinical Pharmacology, Duke University Medical Center, Durham, NC (C.M.O.); Case
Western Reserve University, Cleveland, Ohio (I.L.P.); Medical University, Faculty of Health Sciences, Clinical Military Hospital, Poland (P.P.);
Department of Medicine, Henry Ford Hospital, Detroit, Mich (H.N.S.); University of California, San Francisco, and Veterans Affairs Medical Center, San
Francisco, Calif (J.R.T.); Division of Cardiology, Tufts Medical Center, Boston, Mass (J.E.U.); Baylor Heart and Vascular Institute, Dallas, Tex (C.W.Y.);
CHU Cardiology Department, Nancy University, Nancy, France (F.Z.); and Department of Medicine, Center Cardiovascular Quality and Outcomes,
Northwestern University, Feinberg School of Medicine, Chicago, Ill (M.G.).
Guest Editor for this article was Mariell Jessup, MD.
Correspondence to Mihai Gheorghiade, MD, Center for Cardiovascular Quality and Outcomes, Northwestern University Feinberg School of Medicine,
645 N Michigan Ave, Suite 1006, Chicago, IL 60611. E-mail m-gheorghiade@northwestern.edu
© 2010 American Heart Association, Inc.
(Circ Heart Fail. 2010;3:314-325.)
Circ Heart Fail is available at http://circheartfailure.ahajournals.org DOI: 10.1161/CIRCHEARTFAILURE.109.893222
314

3. from the meeting organized by the International Working
Group on Acute Heart Failure Syndromes, which occurred at
the US Food and Drug Administration (FDA) in December
2008, which was attended by representatives from academia,
industry, and regulatory authorities.20 Participants did not
receive any compensation or honoraria, and there was no
industry sponsorship. In this review, we highlight lessons
learned, discuss areas in need of further development, and
propose concrete ways forward to successfully develop new
therapies for this major public health problem.
Why Have We Failed to Develop New
Therapies for AHFS?
Why has there been so little progress in the development of
new treatments for these disorders? Although there are many
possible explanations, a general consensus around several
root causes has emerged.
Patient Heterogeneity
The plural terminology “acute heart failure syndromes” is
evidence that acute HF is not a single disease but rather a
group of related disorders characterized by similar presenting
signs and symptoms. Multiple definitions and varying termi-
nology for these syndromes further highlight this heteroge-
neity, and there continues to be debate as to whether acute HF
represents a distinct entity or is simply part of the natural
progression of chronic HF.2,6 AHFS encompasses patients
with diverse presentations and pathophysiology, ranging from
patients presenting suddenly with severe hypertension and
normal or near-normal ejection fraction (EF) to those with
advanced systolic dysfunction and low output states. In
between these less-common extremes of presentation lie the
majority of patients who present with AHFS due to volume
overload and who are equally likely to present with a
preserved EF or with a low EF. It is unlikely that the same
therapy would be efficacious in such varied patient popula-
tions; thus, it is not surprising that “one size fits all”
approaches for developing new therapies have not met with
success. Only recently has there been a more concerted effort
to develop new agents that are targeted at specific subgroups.
In part, this is because AHFSs have lacked a universally
accepted, clinically useful classification framework for clin-
ical subtypes under the umbrella of AHFS. By analogy, some
of the progress in the development of new acute coronary
syndrome therapies may be attributable to targeting selected
subpopulations (eg, ST segment–elevation myocardial infarc-
tion versus non–ST segment–elevation myocardial infarction
versus unstable angina), and indeed, therapies that are effica-
cious for 1 group (such as thrombolytic therapy for ST segment–
elevation myocardial infarction) are not useful for other (such as
unstable angina). Although consensus proposals for a classifica-
tion framework for AHFS have been developed,1–2,5,21 they have
yet to be universally accepted or integrated into the design of
clinical trials. A simplified classification system focused on
clinical trial design is proposed in Table 1. Whether this
classification or other classification systems will identify patients
who have different therapeutic responses to the same AHFS
therapy remains uncertain.
Table 1. Profiles in Patients With AHFS With Implications for Clinical Trial Design
Clinical Presentation Characteristics Targets and Therapies
AHFS with hypertension Often develops suddenly (hours). Predominantly pulmonary
(radiographic/clinical) with or without systemic congestion.
Preserved EF common. Acute pulmonary edema is an
extreme form of this phenotype
Target: blood pressure and volume management,
oxygenation in acute pulmonary edema
Therapy: vasodilatorsϮloop diuretics, noninvasive
mechanical ventilation for acute pulmonary
edema
AHFS due to volume overload Typically develops gradually (days or weeks) and is
associated with systemic congestion. May or may not be
associated with dietary or medication noncompliance.
Usually on background of chronic HF. Peripheral edema
common, radiographic pulmonary congestion may be
minimal
Target: volume management, end-organ
preservation
Therapy: loop diureticsϮvasodilators, other
volume removal strategies (ultrafiltration,
adenosine antagonists, vasopressin antagonists)
AHFS with hypotension Symptoms related to low cardiac output, typically with
decreased renal function; may have atypical symptoms
(confusion, lethargy, abdominal pain). Typically
accompanied by congestion as well, although may be
subtle. Cardiogenic shock represents an extreme form of
this phenotype
Target: cardiac performance, end-organ
preservation
Therapy: Inotropic drugsϮvolume removal
strategies listed above. Consider mechanical
support such as intra-aortic balloon pump
AHFS due to other conditions Heterogeneous category based on underlying cause. May
precipitate 1 of syndromes above, or presentation may be
primarily related to primary cardiovascular condition (eg,
acute MI with cardiogenic shock)
Target: treat underlying cause and target
Atrial fibrillation Therapy: varied, depending on underlying cause
Acute coronary syndromes
Acute valvular heart disease
(mitral regurgitation, aortic
insufficiency)
Myocarditis
Pulmonary emboli
Infections
AHFS indicates acute heart failure syndromes; EF, ejection fraction; HF, heart failure; MI, myocardial infarction.
Felker et al Clinical Trials in Acute Heart Failure Syndromes 315

4. Poor Understanding of Pathophysiology
A wide variety of mechanisms and triggers have been
implicated in the pathogenesis of AHFS,22 but the relative
contribution of each is uncertain, and potentially important
mechanisms may remain unidentified. Although increased
ventricular filling pressures (and, less frequently, low cardiac
output) are clearly central to the development of AHFS, these
hemodynamic concepts alone fail to capture the complex set
of interactions between the heart, kidney, peripheral vascu-
lature, and a variety of circulating mediators that occur in
AHFS. With AHFS presentation, injury to the myocardium or
other end organs (such as the kidney) may occur, potentially
accelerating the trajectory of disease progression.23,24 Al-
though a detailed review of AHFS pathophysiology is beyond
the scope of this review, greater investment in fundamental
research aimed at improving our understanding of underlying
mechanisms is required to improve the precision of classifi-
cation, the accuracy of therapeutic targeting, the identifica-
tion of organ injury, and the probability of success in
developing new treatments.
Background Therapy and Natural History
Randomized controlled trials in AHFS have traditionally
compared a new intervention with placebo, in addition to
“standard” therapy for AHFS. However, standard therapy has
rarely been explicitly defined and has differed among studies,
although efforts for greater standardization of therapy in
ongoing trials are under way.25 Although intravenous loop
diuretics are the cornerstone of background therapy for
AHFS, the dose and route of administration vary markedly
among providers and institutions, and questions remain about
the safety and efficacy of these drugs in AHFS.26,27 This
variability is even more significant for other therapies, such
as inotropes, vasodilators, and noninvasive ventilation. Fi-
nally, there is large variability in the use and dosing of oral
neurohormonal antagonists (such as angiotensin-converting
enzyme inhibitors, ␤-blockers, and aldosterone antagonists)
in patients hospitalized with AHFS, which may have substan-
tial effect on clinical outcomes.28,29 Taken together, this lack
of standardization may obfuscate the efficacy and safety of
new drugs. Importantly, given the clinical urgency of AHFS,
background therapy is often continuously adjusted during the
course of hospitalization. This complicates the evaluation of
new therapies because the placebo group may receive more
treatments over time, and diminish the observed treatment
effect.
A related issue is whether new treatments must be devel-
oped as “add-ons” to background therapy or alternatively
whether new treatments should be compared directly with
existing therapies (ie, active control trials). Active control
trials would potentially allow a more direct comparison of
new therapies with existing ones (eg, comparing a new drug
for volume management directly against to loop diuretics).
Given the lack of standardization of “standard” therapy for
AHFS, active controlled trials would be feasible and could
potentially allow for the more rapid advancement of AHFS
therapy. In addition to comparing single agents, this paradigm
could be extended to include “strategy” trials, directly com-
paring 1 therapeutic approach in a given patient population
with others. One notable example of this approach was the
UNLOAD [Ultrafiltration versus Intravenous Diuretics for
Patients Hospitalized for Acute Decompensated Heart Fail-
ure] study, which compared mechanical ultrafiltration di-
rectly with loop diuretics in patients hospitalized with AHFS
and volume overload.30 This study showed greater weight
loss in the ultrafiltration group but no difference in dyspnea
improvement between the study groups. Although not the
primary end point of the study, there were significant rehos-
pitalizations for HF in the ultrafiltration group.
Finally, despite greater understanding of AHFS from
international registries, we still lack detailed data on the
“natural history” of these disorders. Comprehensive data on
potential precipitants of AHFS in large cohorts have only
recently been published.9 Preliminary studies demonstrate an
association between the passage of time and symptom reso-
lution; however, much more data are needed. Analysis of the
placebo group from large trials such as EVEREST [Efficacy
of Vasopressin Antagonism in Heart Failure Outcome Study
with Tolvaptan] may help clarify the natural history of AHFS
and better define the goals of therapy and areas for further
research.
Study Design Issues: Inclusion Criteria
The lack of objective criteria for the diagnosis of AHFS has
been a barrier to precise identification of the most relevant
study populations. AHFS is a clinical diagnosis based on
hospitalization for symptoms (usually dyspnea) and signs
(edema, pulmonary congestion by examination or chest
radiograph, increased jugular venous pressure). In general,
these measures are subjective, qualitative, and highly variable
among patients, providers, and institutions. In addition, these
measures are not “static” but “dynamic” and vary over time
and with treatment. Finally, the decision to hospitalize a
patient may be influenced by a variety of social and cultural
factors unrelated to disease severity. The lack of agreed and
objective criteria for enrollment in AHFS clinical trials has
made the identification of a homogeneous clinical trial
population who clearly have the disease of interest a chal-
lenge. Inclusion of patients without AHFS in clinical trials
will dilute any potential treatment effect of a new therapy,
just as inclusion of patients with noncardiac chest pain in
acute coronary syndrome studies would decrease the ob-
served treatment effect in acute coronary syndrome. Simi-
larly, enrolling ST segment–elevation myocardial infarction
patients 12 hours after an event versus within 90 minutes
would also significantly influence results. Thus, there is a
substantial need to use more objective, quantitative criteria
for the diagnosis of AHFS and for enrollment in clinical
trials. As discussed in further detail in the following section,
carefully defining the type or “stage” of the trial, as well as
the emergence of natriuretic peptide (brain natriuretic pep-
tide, or N-terminal pro—B-type natriuretic peptide) measure-
ments as an inclusion criterion, has led to greater homogene-
ity of study populations (ie, fewer patients without AHFS)
and seems to represent a major methodological improvement
in the design and conduct of randomized controlled trials in
AHFS.
316 Circ Heart Fail March 2010

5. Study Design Issues: Timing and Duration
of Intervention
Timing is fundamental to the treatment of acute myocardial
infarction—acute reperfusion therapies that are highly effica-
cious when given within a few hours of presentation show
diminished benefit when used later.31 To date, there has been
surprisingly little investigation of the effect of the timing of
intervention on treatment benefits in AHFS, and whether a
“therapeutic window” exists for AHFS intervention is un-
known. Observational data from ADHERE [Acute Decom-
pensated Heart Failure National Registry] suggest that earlier
natriuretic peptide measurement and earlier implementation
of therapy may lead to improved AHFS outcomes,32 but little
is known about the optimal timing for applying specific
therapies. A previously suggested scheme for dividing the
timing of AHFS interventions into stages may provide a
useful framework for considering the timing of AHFS inter-
ventions and is discussed in detail later in this article.1
In addition to timing, the optimal duration of therapy is not
well understood. To date, most trials have focused on
short-term (hours to days) intravenous therapy, and contro-
versy persists as to whether short-term therapies alter the
underlying pathophysiology to a sufficient degree to reap
long-term benefits. Although the possibility that AHF thera-
pies could be continued after hospital discharge has not been
carefully investigated, the high short-term rehospitalization
rate associated with HF suggests that continuing an effective
treatment into this postdischarge “vulnerable phase” could be
beneficial and should be explored in future studies.33 This
phase might also be used to reintroduce therapy to those who
display high-risk features.
Study Design: End Points
One major impediment to progress in AHFS has been the lack
of consensus on appropriate end points for phase III studies in
AHFS.34 A review of the large phase III randomized con-
trolled trials conducted in AHFS during the past decade
clearly indicates this lack of consensus because no 2 studies
have used the same primary end point (Table 2). Some of the
uncertainty about clinical end points relates to a fundamental
(and as yet unanswered) question about AHFS therapies—
can an acute intervention given for a brief period (hours to
days) at the time of hospitalization be anticipated to improve
postdischarge outcomes at 30, 60, or 180 days? Clearly, there
are examples of this phenomenon in other areas of card-
iology, such as acute reperfusion therapy for myocardial
infarction. For a short-term therapy to improve long-term
outcomes, it would need to (1) fundamentally change the
pathophysiology of the acute disease process in a way that
fundamentally alters the substrate, resulting in improved
performance (“a better heart”) and/or leads to greater perse-
veration of downstream organ function (either cardiac func-
tion or other end organs); (2) markedly affect in-hospital
mortality; (3) enable resolution of congestion without the
potentially harmful effects (such as neurohormonal activation
from diuretics) of current therapies; and/or (4) facilitate the
addition or intensification of lifesaving long-term therapies.
The fact that no short-term therapy for AHFS has done so to
date has resulted in a shift of focus (for efficacy but not for
safety) toward short-term symptom relief and/or shorter-term
outcomes (5 to 7 days). Controversy continues as to whether
such a shift represents an unacceptable “lowering of the bar”
or simply recognition of the limitations of current therapies
and a rational focus on more achievable goals. Given the lack
of robust evidence for most AHFS therapies currently in use,
a substantial improvement in short-term symptoms combined
with demonstrated safety would appear to mark an advance
over the current standard of care.
Regulatory Issues
The lack of consensus from the scientific community in
defining a clinically meaningful benefit has led to a lack of
regulatory consensus. Differences in regulatory requirements
between the FDA in the United States and European Medi-
cines Agency in Europe have led to substantial variability in
the design and conduct of large international clinical trials,
including the use of coprimary end points for some trials to
satisfy the requirements of both agencies.35 This has resulted
in agents such as nesiritide being approved in the United
States but not in Europe, whereas other drugs, such as
levosimendan, are approved in some parts of Europe but not
in the United States. This lack of harmony between regulatory
agencies can be seen as both contributing to a lack of progress
(commercial sponsors are reluctant to invest resources in
areas where the requirements for approval are not clear) and
reflecting a more general lack of consensus about the most
appropriate metrics to measure efficacy and safety in AHFS.
Directions Forward: Roadmap for Phase III
Studies in AHFS
The historical lack of success in developing safe and effective
new therapies and the barriers described earlier have led to a
diminished enthusiasm for pursuing novel compounds and
clinical trials in this area. However, in light of the substantial
and growing effect of AHFS on public health, it is imperative
to continue to develop potential new treatments for AHFS. In
the following sections, we summarize concepts that we
believe will help provide a framework for moving forward
with the development of new therapies for AHFS.
Defining and Targeting Appropriate
Study Populations
As noted earlier, a major limitation of previous clinical trials
in AHFS has been the heterogeneity of the enrolled patient
population. Increasingly, several trends seem to be improving
the ability to identify and target specific patient populations.
Timing: Applying the Right Therapy at the Right
Time to the Right Patient Population
A staging system for considering the distinct phases of the
AHFS presentation has been proposed.1 The right therapy
given at the wrong time may lead to an incorrect conclusion
regarding efficacy. Defining the target, based on a compre-
hensive mechanistic understanding of the drug, will allow for
proper staging of the trial.
Stage A trials target patients during their initial presenta-
tion.36 For stage A, the main goals are hemodynamic stabili-
zation; rapid, meaningful, and sustained improvement in
Felker et al Clinical Trials in Acute Heart Failure Syndromes 317

6. breathlessness; preservation of hemodynamic reserve; and
prevention of downstream harm (ie, organ protection/organ
preservation). Studies targeting patients in stage A should
enroll patients early, although patients are still symptomatic
(eg, emergency department). Repeated assessments of symp-
toms (eg, dyspnea) should occur at multiple time points
during the first 24 hours and then daily to assess the speed and
sustainability of improvement.
Stage B trials include therapies for patients who remain
symptomatic or deteriorate despite initial therapy during
hospitalization (therapies started 24 hours or more after initial
presentation). These patients can be recognized early by the
Table 2. Primary End Points in Large AHFS Studies (Adapted From Allen et al34)
Acronym
Sample
Size Intervention Primary End Point(s)
VMAC 489 Nesiritide infusion 48 h vs nitroglycerine infusion
vs placebo
Coprimary
⌬ Pulmonary capillary wedge pressure at 3 h
⌬ Dyspnea (Likert) at 3 h
OPTIME 951 Milrinone infusion 48 h vs placebo Cumulative days of hospitalization for cardiovascular cause or days
dead within 60 d after randomization
ESCAPE 433 Therapy guided by pulmonary artery catheter
plus clinical assessment vs clinical assessment
alone
Days alive and out of hospital during the first 6 months
VERITAS 1435 Tezosentan infusion 24–72 h vs placebo Coprimary
Change in dyspnea (at 3, 6, and 24 h with VAS 0–100) for 24 h
(area under the curve)
Death or worsening heart failure (pulmonary edema, shock, new
or 1 intravenous therapy, mechanical cardiac or pulmonary
support, renal replacement therapy) at 7 d
SURVIVE 1327 Levosimendan infusion vs dobutamine infusion
as long as clinically indicated in patients with
AHFS requiring inotropic support
All-cause mortality at 180 d
REVIVE-2 600 Levosimendan infusion vs placebo in
hemodynamically stable patients with AHFS
Composite of clinical signs and symptoms of heart failure over 5 d
expressed as 3-stage end point
Better (moderately or markedly improved global assessment at
6 h, 24 h, and 5 d with no worsening)
Same
Worse (death from any cause, persistent or worsening HF
requiring intravenous diuretics, vasodilators, or inotropes at any
time; or moderately or markedly worse patient global
assessment at 6 h, 24 h, or 5 d)
C3PO 1069 Standard oxygen therapy vs noninvasive
intermittent positive-pressure ventilation (NIPPV)
vs continuous positive airway pressure
ventilation (CPAP) in acute pulmonary edema
Death within 7 d (oxygen therapy vs NIPPV) or death or intubation
within 7 d (NIPPV vs CPAP)
EVEREST 4133 Tolvaptan vs placebo up to 112 wk Short-term composite: changes in global clinical status (by VAS)
and body weight at day 7 or discharge
Long-term dual end points
All-cause mortality (superiority and noninferiority)
Cardiovascular death or HF hospitalization (superiority only)
ASCEND-HF Enrolling Nesiritide infusion vs placebo Coprimary
Composite of all-cause mortality and heart failure
rehospitalization through 30 d
Dyspnea at 6 and 24 h
PROTECT I
and II
2033 Rolofylline infusion vs placebo Composite of clinical signs and symptoms of heart failure over 7 d
expressed as 3-stage end point
Better (moderately or markedly improved global assessment at
24 and 48 h with no worsening)
Same
Worse (death from any cause, persistent or worsening heart
failure through day 7, or creatinine increase Ն0.3 mg/dL at 7
and 14 d)
VAS indicates visual analog scale; NIPPV, noninvasive positive-pressure ventilation; CPAP, continuous positive airway pressure.
318 Circ Heart Fail March 2010

7. presence of adverse prognostic markers (low blood pressure,
increased natriuretic peptide levels, increased troponin,
and/or renal dysfunction), failure to respond to diuretic
therapy, or deterioration (hypotension or worsening renal
function) with initial treatment. Such interventions could be
designed to improve cardiac function directly, manage con-
gestion in a safer and/or more effective way, or improve or
preserve renal function.
Stage C trials include interventions targeted at improving
long-term outcomes through improved implementation of
evidence-based therapies or use of long-term pharmacologi-
cal or device therapy. To be successful, interventions for
stage C trials would either have to be continued after
discharge or have a sustained pharmacological or biological
effect.
Stage D trials target patients during the “vulnerable” phase
or early postdischarge phase. For those patients who are
identified during close follow-up to be at higher risk, inter-
vention at this time might mitigate the natural tendency for
patients to worsen to the point of acute decompensation.
Clearly, various interventions may be used at different
times in the AHFS course with differing therapeutic aims. In
addition, although outlined in distinct stages, there is definite
overlap. Creation of a “matrix,” with clinical subgroups and
various interventions, may serve as a useful framework for
more focused clinical trials.
Biomarkers and Patient Selection
The use of more objective inclusion criteria, such as brain
natriuretic peptide or N-terminal pro–B-type natriuretic pep-
tide, in AHFS clinical trials has led to a study population with
a higher event rate, increasing the statistical power of clinical
trials. Recent phase II clinical trials that have required
increases in natriuretic peptide levels for inclusion have
suggested a lesser effect of standard therapy on the resolution
of signs and symptoms.37,38 Although it has been suggested
that further improvements in signs and symptoms are difficult
targets given their rapid improvement with standard therapy,
these more recent observations suggest that a substantial
degree of dyspnea persists in higher-risk patients who could
serve as a potential target for therapy. In addition to natri-
uretic peptides, analyses of both clinical trials and observa-
tional data have consistently identified a number of other
important markers of risk in AHFS, including decreased renal
function, hyponatremia, lower systolic blood pressure, and
troponin release.8,10,39,40
Targeting Selected Subgroups
Rather than using a “one size fits all approach,” clinical trials
of new therapies should target specific subgroups that seem
most likely to respond, based on the mechanism of action of
the proposed agent. Combined with the importance of timing
and use of objective measures for patient inclusion, other
readily available clinical characteristics can be used to rapidly
distinguish various patient subgroups to determine therapy
and selection of patients for trials. At the time of initial
presentation to the emergency department (stage A), severity
of signs and symptoms, systolic blood pressure, degree of
hypoxia, troponin release, and renal function allow for risk
stratification of patients in terms of both disease severity as
well as the need for specific therapies and appropriateness for
specific clinical trials. After initial stabilization, additional
variables such as EF, the presence of coronary artery disease,
the degree of systemic congestion, and any specific triggers
identified (such as atrial fibrillation) provide added discrim-
ination of relevant subgroups (stage B trials). For variables
such as EF, which may be less central to early management
but play a critical role in subsequent care, stratification of
enrollment or prespecified subgroup analysis by EF may be
considered.
Systolic blood pressure has emerged as a critical prognos-
tic factor in AHFS.41 Data from large registries have demon-
strated that the majority of patients with AHFS present with
normal or increased systolic blood pressure, often with
preserved systolic function.41 Clinical observation of these
patients suggests the possibility that they have a unique
pathophysiology, because many such patients have acute
pulmonary edema in the setting of relatively little change in
weight or other measures of volume status.42 This fact has
suggested the hypothesis that vasoconstriction and contrac-
tility-afterload mismatch may play a critical role in these
patients, a mechanism that would be amenable to vasodilator
therapy. However, only recently have trials of novel vasodi-
lators focused specifically on this patient population.38
Another underrecognized covariate in defining appropriate
patient populations for study may be the presence or absence
of coronary artery disease. Data from the OPTIME-CHF
study have suggested that the balance of safety and efficacy
of milrinone may differ on the basis of the underlying
substrate, with potentially beneficial effects in nonischemic
patients and clear evidence of harm in those with underlying
coronary artery disease.16 Hibernating/ischemic myocardium
may be particularly vulnerable to therapies that may increase
oxygen demand and/or lead to myocardial injury.23 This
finding underscores the need to target therapy based on
pathophysiology, and this paradigm may be operative with
other therapies as well. Recent focus on the effects of AHFS
therapies on coronary perfusion has led to the hypothesis that
this may be another critical “mechanism of harm” in patients
with obstructive coronary artery disease.43
Patients with renal dysfunction may represent another
specific substrate for treatment. These patients are a hetero-
geneous group and include patients with a history of chronic
kidney disease due to diabetes, hypertension, and arterioscle-
rosis and/or patients with renal dysfunction secondary to the
AHF-related hemodynamic, neurohormonal, or intrinsic renal
abnormalities (“vasomotor nephropathy”).44 Worsening renal
dysfunction caused by intrinsic renal disease and/or vasomo-
tor nephropathy may be a trigger for decompensation or may
develop during hospitalization. All of these patient subgroups
have a poor prognosis, and specific therapies targeted at renal
preservation are currently under investigation. Although pilot
data on using the renal-protective agent rolofylline were
suggestive of benefit,37 the results from the larger phase III
PROTECT [Placebo-controlled Randomized Study of the
Selective A1 Adenosine Receptor Antagonist Rolofylline for
Patients Hospitalized with Acute Decompensated Heart Fail-
ure and Volume Overload to Assess Treatment Effect on
Felker et al Clinical Trials in Acute Heart Failure Syndromes 319

8. Congestion and Renal Function] did not demonstrate benefits
on either renal function or downstream clinical outcomes.15
Renal protection may still represent a novel target of treat-
ment for patients with AHFS, although the most appropriate
patient population and the best intervention remain uncertain.
Targeting Appropriate Level of Risk
In addition to targeting subgroups with specific agents aimed
at specific mechanisms, it is critical to direct interventions to
patients with appropriate levels of risk. A small number of
variables, including blood pressure, renal function, and natri-
uretic peptide levels, have been shown to provide robust risk
stratification in patients with AHFS.8,10,39 Clinical trials have
often excluded patients with high-risk features, complicating
the extrapolation of results to broader patient populations.
From a clinical perspective, it is important to identify patients
at both extremes of the risk spectrum. For patients at very low
risk of events, additional interventions are unlikely to im-
prove outcomes further. For patients with high risk for future
events (either because of the severity of HF or to the degree
of comorbidities), traditional AHFS interventions may be
unlikely to change the natural history of the disease. Although
such patients make up a small portion of the AHFS popula-
tion, they contribute substantially to the burden of in-hospital
mortality. Clinical profiles defined for the INTERMACS
[Interagency Registry for Mechanically Assisted Circulatory
Support] registry provide guidance for when such patients
should be considered for mechanical support.45 Appropriate
identification and triage of such patients at the time of
hospitalization to either mechanical support (or alternatively
to end-of-life care) is an important goal of AHFS manage-
ment and has been emphasized in recent guidelines.6
Study Design: Methodological Issues in AHFS
Clinical Trials
Essential to the conduct of clinical trials is the use of
established, validated, and reproducible measures to assess
efficacy and safety. Surprisingly, many efficacy measures for
clinical trials in AHFS remain highly subjective and have not
been validated. As an example, recent large clinical trials that
have included assessments of symptoms (often as the primary
end point or a component of the primary end point) have used
widely variable methodology (Likert versus visual analog
scale) and time points, none of which have been carefully
validated in AHFS. Such variability has introduced “random
error” that has resulted in decreased statistical power to detect
real differences in symptomatic benefit and has also precluded
comparison across studies. Recently, several efforts have been
made to evaluate the evolution of symptoms in AHFS, the
relative change in various instruments compared with each
other, and the association of such changes with other out-
comes.46,47 A recent proposal for standardized dyspnea assess-
ment is an important first step toward better application of
patient reported outcomes in clinical trails in AHFS.48
As with breathlessness, the evaluation of congestion is
dependent on relatively qualitative measures (jugular venous
pressure, peripheral edema, rales, congestion on chest radio-
graph) that may not be highly correlated with more objective
measures.49 Although resolution of congestion is clinically
important, current tools for assessing it are too qualitative and
subject to intraobserver variability to be used as a primary end
point in clinical trials.
Moving Beyond Congestion: Preventing
Injury as a Target of Therapy
Given that signs and symptoms of congestion are the major
drivers of hospitalization for AFHS, it is not surprising that
much of drug development in AHFS has viewed congestion
as a major target of therapy. Despite significant clinical
improvement, patients continue to have persistent elevation in
pulmonary capillary wedge pressure, severely abnormal he-
modynamics, and neurohormonal abnormalities that likely
continue into the postdischarge period. Although relief of
congestion remains an important goal, it is clear that effec-
tively addressing congestion only during the initial hospital-
ization does not necessarily correlate with improving post-
discharge outcomes.14,50 There is a major need to identify
alternative or additional targets. Targeting the prevention of
end-organ damage in the myocardium and kidney is a
potential therapeutic goal. Reverse cardiac remodeling may
also be an important end point.
Multiple datasets have demonstrated that detectable levels
of troponin are present in patients with both chronic HF and
AHFS and are associated with adverse long-term out-
comes.40,51–54 The underlying mechanisms of troponin release
in patients with HF remain unclear. It occurs in patients both
with and without coronary artery disease. Whether prevention
of troponin release is a useful surrogate of myocardial
damage during AHFS that improves outcome is unknown but
has been tested in pilot studies.23
As described previously, a large body of recent evidence
supports the concept that worsening renal function is associ-
ated with adverse outcomes, both during the index hospital-
ization and after discharge.55–59 The failure of the adenosine
A1 blocker rolofylline to improve outcomes in the pivotal
PROTECT trial has called into question whether worsening
renal function is a mediator of worse outcome or simply a
marker of poor prognosis. Newer plasma and urinary markers
(such as cystatin C and neutrophil gelatinase-associated
lipocalin [NGAL]) may provide more sensitive or specific
measures of renal injury that could provide mechanistic
evidence of a link between organ damage and outcome and
potentially allow better targeting of renoprotective strategies.
End Points in AHFS Studies
No single end point can capture all elements of the clinical
course of AHFS, and therefore, no single end point will be
appropriate for all interventions or patient populations.34 We
suggest that each of the 4 domains detailed next be assessed and
reported in all phase III AHFS studies, recognizing that various
weights will be given to each domain depending on the mech-
anism of action of specific therapies. This would allow interven-
tions to be compared and contrasted and is similar to the
“consumer reports” approach that has been previously described
for acute myocardial infarction studies.60
320 Circ Heart Fail March 2010

9. Signs and Symptoms
● Symptom relief (visual analog scale, Likert, provocative
dyspnea assessment, other)
● Measures of congestion relief (edema, rales, jugular venous
pressure, weight)
The primary symptom of AHFS is breathlessness, and the
development and validation of accurate and reproducible
metrics for measuring symptom relief would be a major step
forward in AHFS research.48 Controversy remains about both
the rapidity and the degree of resolution of signs and
symptoms in patients with AHFS. Some studies have sug-
gested that breathlessness improves quickly in the majority of
patients,50,61,12 whereas other studies (using stricter inclusion
criteria) have suggested that a clinically important burden of
breathlessness may be unaddressed in AHFS.37,38 Consistent
with the goals of making patients “feel better or live longer,”
breathlessness is an important target for phase III studies in
AHFS. However, given that symptoms of breathlessness are
relatively short-lived (ie, hours to days) in many patients with
standard therapy, dyspnea should be assessed early in the
clinical course. Improvement in dyspnea could be combined
with other measures in a clinical composite primary end
point. For improvement in breathlessness to be considered
clinically important, it should be rapid, substantial, and
sustained beyond a few hours. To quantify this effect,
measurement at multiple time points is required. In addition
to timing, the conditions under which dyspnea is measured
should be standardized.48 Signs of congestion, such as jugular
venous pressure, peripheral edema, rales, and body weight,
are supportive evidence of clinical effect but are probably not
suitable for inclusion in primary end points of phase III
studies.
Index Hospitalization
● In-hospital mortality
● Length of stay
● Worsening HF in hospital
In-hospital events occupy a middle ground between immedi-
ate symptom relief (which may be of questionable long-term
benefit) and postdischarge outcomes (which may be difficult
to improve with short-term therapies). In-hospital mortality is
obviously important but infrequent (Ϸ4%), unless a subset of
sick patients is chosen.39,62 Although length of stay is theo-
retically attractive, it is influenced by a variety of factors
(financial, social, and cultural) that are not directly related to
clinical status and is subject to geographic variation in
international clinical trials.63
Worsening HF has gained increasing acceptance as an
important clinical measure in AHFS and has been a compo-
nent of the primary end point of several recent phase III
studies.13,37,12 Worsening HF is usually defined as either
failure to improve (persistent signs and symptoms of HF
despite therapy) or worsening signs and symptoms of HF
despite therapy. Worsening HF could be considered some-
what analogous to “recurrent ischemia” in studies of acute
coronary syndromes. One frequent component of the wors-
ening HF definition is the requirement for “rescue therapy”—
ie, the need to initiate or intensify intravenous therapy (such
as inotropes or intravenous vasoactive agents) or implement
mechanical cardiac or ventilatory support. Although the need
for such rescue therapy makes intuitive sense, guidance from
European Medicines Agency suggests that they do not con-
sider this an appropriate component of an efficacy end
point.64
Prevention of End-Organ Damage
● Renal dysfunction or injury (blood urea nitrogen, creati-
nine, cystatin C, other markers)
● Myocardial injury (troponin)
As noted earlier, markers of renal dysfunction or myocar-
dial injury are powerful predictors of outcome in AHFS.
Although these markers have previously been considered
primarily as markers of safety, we suggest the hypothesis that
resolution of congestion while avoiding myocardial injury or
worsening of renal function could be considered the major
short-term goal of AHFS therapy. To evaluate this concept,
we propose that serial measures of both renal function
(including novel markers of renal injury, if possible) and
circulating troponin be considered a standard component of
the evaluation of new therapies in AHFS.
Postdischarge Events
● Deathϩrehospitalization at 60 days
● Days hospitalized or dead within 60 days
● Mortality (all-cause or cardiovascular) at 180 days
Poor postdischarge outcomes (ie, high rates of HF rehospi-
talization and death) are the major unmet medical need in
AHFS and, together with the rapid relief of symptoms, are the
most important targets for therapy. Because rates of noncar-
diovascular events are high in AHFS because of the age of the
population and the presence of other comorbid conditions,
formal adjudication of end points is important so that disease-
specific end points can be evaluated. “Days hospitalized or
dead”–type end points are attractive because they integrate
both the index hospitalization and postdischarge events;
however, early death may have a disproportionate influence
on this end point. In addition, this end point is susceptible to
the same cultural variability as length of stay, although these
factors may balance out in the context of a randomized
controlled trial. Longer-term mortality (eg, 180 days) seems
unlikely to be affected by short-term interventions (stage A or
B) alone but should be captured as a safety measure in all
AHFS studies.
Safety in AHFS Studies
Drug safety has become a major focus of drug development
in general and for AHFS therapies in particular. The 2 drugs
approved for AHFS by the FDA in recent decades (milrinone
in 1988 and nesiritide in 2001) have come under substantial
scrutiny because of concerns about the balance of safety and
efficacy.17,18,65 There remains a great deal of uncertainty
about how to quantify the confidence with which a new
Felker et al Clinical Trials in Acute Heart Failure Syndromes 321

10. AHFS therapy can be declared “safe.” Phase III studies
should include formal assessment of the upper boundary of
risk (either relative or absolute) that can be excluded by the
planned sample size.66 This statistical exercise quickly leads
to the recognition that even large studies (eg, Ͼ5000 patients)
cannot exclude an increase in rare events with a high degree
of confidence. The evaluation of drug safety should consider
the totality of data (using the approach suggested earlier), and
the type and degree of observed benefit may have important
implications for acceptable safety boundaries (eg, drugs that
substantially affect worsening HF or length of stay may
require less-stringent evidence of safety than do drugs that
address symptoms alone). In addition, we suggest that a
reduction of end-organ damage supports long-term safety,
and conversely, an increase in markers of end-organ damage
should heighten the need for robust evidence of safety.
Formal regulatory guidance on long-term safety assessments
for AHFS therapies is currently unavailable, but recent FDA
guidance on cardiovascular safety for antidiabetic therapies
may provide a useful model.67
Composite End Points
Given that none of the domains discussed in this article can
individually capture the potential benefits of a new therapy
for AHFS, there is a need to define clinical composite end
points that combine these measures. Although the details of
individual composites may differ, we believe composite end
points that capture each of these domains (symptoms, end-
organ dysfunction or injury, in-hospital events, and postdis-
charge events) are the best option for the primary end point in
future AHFS studies. The inclusion of measures of organ
function (such as creatinine) or injury (such as troponin) as a
component of the primary end point is controversial.68 The-
oretically, we suggest that such measures could provide
supportive evidence of efficacy as part of a primary end point,
so long as they were combined with evidence of benefit on
more traditional clinical outcomes (symptoms, events). The
various components of the composite and their relative
weighting may differ, depending on the nature of the therapy,
the pathophysiological target, the patient subgroup being
targeted, and the timing of intervention. Regardless of the
composite used, any evaluation of new therapies must also
include a careful evaluation of longer-term safety to exclude
the risk of significant harm. A variety of composite ap-
proaches have been used in previous studies, including the
use of coprimary end points (eg, symptoms and postdischarge
outcomes with dividing of the acceptable type I error12) or
creating trichotomous composites (better/same/worse) that
capture various domains within their definition.37 Another
similar but alternative approach is the use of a “global rank”
method, in which patients participating in a clinical trial are
ranked on the basis of a prespecified hierarchy of events (eg,
deaths are given the worst rank, rehospitalizations next worst,
etc). Although these end points may be complex to interpret,
1 advantage of the global rank approach is that it “weighs” the
components of the clinical experience in a way that might be
congruent with clinical judgment, assuming that a consensus
can be reached.69
Conclusions and Next Steps
Innovation in trial design for AHFS remains a high priority.
Greater consensus within the scientific community about the
current challenges and the best ways forward is a critical step
in this process, and we believe that many aspects of this
consensus are now in place. In this document, we have
identified current barriers and potential solutions for moving
forward. Greater standardization and validation across the
field of AHFS research—in clinical classification, inclusion-
exclusion criteria, metrics for gauging clinical response to
treatment, end points, and regulatory requirements—are crit-
ical for moving the field forward. Such standardization will
require greater degrees of cooperation and consensus among
the scientific community, industry, and regulatory agencies to
achieve demonstrable progress.
Acknowledgments
We thank Norman Stockbridge, MD, PhD, for his role in organizing
the initial FDA conference in December 2008 and his thoughtful
review of this manuscript.
Disclosures
Dr Felker is a consultant to and has received research grants from
Amgen, Cytokinetics, Corthera, Roche, Diagnostics Geron, XDX,
and BG Medicine. Dr Pang is a consultant for Astellas, Bayer, EKR
Therapeutics, Johnson & Johnson, the Medicines Company, Otsuka,
Palatin Technologies, PDL BioPharma, and Pericor Therapeutics;
has received Solvay Pharmaceuticals Honoraria from BiogenIdec,
Corthera, Ikaria, and Nile Therapeutics; and has received research
support from Merck and PDL BioPharma. Dr Adams is a consultant
for Amgen, Otsuka, Merck, Roche, Nile, and Johnson & Johnson. He
is on the speaker’s bureau of Roche, Novartis, Astra-Zeneca, CVT,
Lilly, and Sanofi-Aventis. He has received research support from
Amgen, Johnson & Johnson, Merck, Medtronic, Boston Scientific,
Otsuka, Corthera, and Roche. Dr Cleland is a consultant for GSK,
Medtronic, Servier, and Amgen and has received MSD research
grants from Takeda, Medtronic, and Amgen. Dr Cotter is an
employee of Momentum Research, Inc, which received research fees
from Merck, Corthera Inc, Nile Therapeutics Inc, and Celadon, Inc.
Dr Filippatos has received research grant support from Roche
Diagnostics, Brahms, Otsuka, and SigmaTau. Dr Fonarow reports
receiving research grants from the National Institutes of Health,
receiving honoraria from AstraZeneca, GlaxoSmithKline,
Medtronic, Merck, Novartis, and Pfizer, and serving as a consultant
for GlaxoSmithKline, Medtronic, Merck, Novartis, St Jude Medical,
Pfizer, Sanofi, and Scios. Dr Greenberg is a consultant for Novartis,
Cytokinetics, and Sanofi-Aventis. He is on the speakers’ bureau of
Merck, Sanofi-Aventis, Novartis, and Gilead. Dr Hernandez has
received research funding from Johnson & Johnson/Scios,
Medtronic, and Merck and honoraria from Novartis, AstraZeneca,
and Medtronic. Dr Komajda is a consultant for Servier and Biogen.
He is a speaker for Servier, BMS, AstraZeneca, GSK, Sanofi-
Aventis, and Boehringer Ingelheim. Dr Konstam is an investigator
and/or has a consulting agreement with Otsuka, Cardiokine, Bio-
genIdec, Merck, Cytokinetics, and Trevena. Dr Liu has received
honoraria from Pfizer, Novartis, Merck, and Schering. He is a
consultant for Amgen, Novartis, Roche, Medtronic, and Merck. Dr
Maggioni has received research grants from Novartis and received
honoraria for lectures from Novartis. He is a steering committee
member in studies sponsored by Novartis, Johnson & Johnson, and
Bayer. Dr Massie is a consultant for Merck, Corthera, Nile Thera-
peutics, and DCRI for the ASCEND Trial sponsored by Johnson &
Johnson. Dr McMurray has received a grant to run an end point
committee for the ASCEND HF study from Duke University and a
trial sponsored by Scios/Johnson & Johnson. Dr Mehra has received
active research grants from the National Institutes of Health, Mary-
land Industrial Partnerships, and the State of Maryland Cigarette
322 Circ Heart Fail March 2010

11. Restitution Fund, and has consulting relationships with St Jude
Medical, Medtronic, Solvay, Johnson & Johnson, and PeriCor. Dr
Metra has received honoraria from Cardiokine, Corthera, Merck,
Nile Therapeutics, and Otsuka. Dr O’Connell is an advisory board
member and consultant for CardioKinetix. Dr O’Connor is a con-
sultant for Forest, Medtronic, Amgen, Medpace, Impulse Dynamics,
Actelion, Cytokinetics, Roche, and Trevena. Dr Pina is on the
speakers bureaus of AZ, Merck, Solvay, and Novartis, received
grant/research from the National Institutes of Health, and is a
consultant to the FDA and Sanofi-Aventis. Dr Ponikowski received
honoraria from Biogen, Corthera, Merck, and Debiopharm. Dr
Teerlink is a consultant to and has received research support and
honoraria from Abbott, Actelion, Astellas, AstraZeneca, BAS Med-
ical/Corthera, BiogenIdec, BMS, Cardio-Dynamics, CHF Solutions,
CoGeneSys/Teva, Cytokinetics, Essential Pharma, Geron, GSK,
Medtronic, Momentum Research, National Institutes of Health, NovaC-
ardia/Merck, Novartis, Protein Design Labs, Sanofi-Aventis, Scios/
Johnson & Johnson, Veterans Administration, Wyeth, and Zealand
Pharma. Other conflicts include serving as a former member of the
FDA Cardiovascular and Renal Drug Advisory Committee. Dr
Udelson has done prior consulting work for Otsuka and served as a
nonvoting steering committee member of a trial sponsored by Pericor
and editor of Circulation: Heart Failure. Dr Zannad has relation-
ships with AstraZeneca, Servier, Pfizer, Novartis, Abbott, Boeh-
ringer Ingelheim, Rilypsa, Rosted, Merck, Daiicmi Sankyo, Takeda,
Boston Scientific, Medtronic, and Otsuka. Dr Gheorghiade is a
consultant for Abbott Labs, Astellas, AstraZeneca, Bayer Schering
Pharma AG, CorThera Inc, Cytokinetics Inc, DebioPharm SA,
Errekappa Terapeutici (Milan, Italy), GlaxoSmithKline, Johnson &
Johnson, Medtronic, Merck, Novartis Pharma AG, Otsuka Pharma-
ceuticals, Pericor Therapeutics, Protein Design Laboratories, Sanofi
Aventis, Sigma Tau, and Solvay Pharmaceuticals. He receives
funding from DebioPharm SA, Medtronic, Novartis Pharma AG,
Otsuka Pharmaceuticals, Sigma Tau, and Solvay Pharmaceuticals,
on behalf of the International AHFS Working Group.
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KEY WORDS: heart failure Ⅲ patients Ⅲ trials Ⅲ acute heart failure
Felker et al Clinical Trials in Acute Heart Failure Syndromes 325