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Advancing care for acute heart failureno time to relax

www.thelancet.com Vol 373 April 25, 2009

proportion of women, of those with preserved systolic function, and of those with hypertensive heart
disease.9
The results of Pre-RELAX-AHF need to be interpreted
in light of its exploratory nature, particularly in view of
the history of small heart-failure trials in which benets
turned out to be the play of chance.1012 The results are
probably too good to be true, in view of the lack of a
dose-dependent eect and the surprising eect of a
short treatment on postdischarge outcomes, including
180-day cardiovascular mortality (particularly with
just 12 cardiovascular deaths). In the nal analysis,
however, the signals that relaxin was reasonably safe
with trends of clinical improvement warrant further
investigation in proper outcomes studies. Beyond
showing the potential therapeutic value of relaxin, the
study highlights the challenge of clinical development
in acute heart failure. Acute heart failure is a
heterogeneous syndrome with distinct presentations,
which range from acute pulmonary congestion to
volume overload to low-output failure. A challenge for
trials in acute heart failure is to identify a population
of patients suited to the therapy against a background
of multiple comorbidities. Success of future trials will

Published Online
March 29, 2009
DOI:10.1016/S01406736(09)60653-X
See Articles page 1429

Science Photo Library

Acute heart failure is a major cardiovascular syndrome


that aects several million people worldwide every
year, and is among the costliest diagnoses for
health-care systems.1 The rate of death and readmission
at 23 months is 3040%.2,3 It has been 7 years since two
of the rst large randomised clinical trials in acute heart
failure were published, trials that assessed milrinone
and nesiritide.4,5 These trials were heralded by the late
Philip Poole-Wilson as breaking new ground in the
management of an all-too-common condition that is
dicult to treat.6 Unfortunately, little progress has been
made since. The only major new treatments approved
for acute heart failure in the past decade are nesiritide
(in the USA) and levosimendan (in Europe), but their
safety and ecacy are often debated.
In The Lancet today, John Teerlink and colleagues
report the results of a randomised phase II trial
(Pre-RELAX-AHF) of a new vasodilator, relaxin, in
patients with normal or high blood pressure admitted
to hospital with heart failure.7 The investigators took
an innovative approach by studying a specic type of
patient with acute heart failure and examining a broad
array of endpoints along the patients journey from
acute dyspnoea, to recovery, and through postdischarge
outcomes. Drawing largely from centres in Russia,
Poland, and Israel, the investigators successfully enrolled
the population. The results showed interesting signals
of benet with relaxin across several domains, including
hard clinical outcomes. Having an acute therapy that
could improve congestive symptoms as well as translate
into improved longer-term clinical outcomes is an
unrealised goal that could fundamentally change the
management of acute heart failure.
By targeting patients with normal or raised blood
pressure (more than 60% of the population with
acute heart failure8), the investigators have focused
on patients for whom this type of therapy might be
most likely to work. This population is more likely to
have preserved left-ventricular systolic function and
has much lower mortality than do patients with lower
blood pressure.8 The population was further dened by
pulmonary congestion on chest radiography, at least
mild renal impairment, and increased brain natriuretic
peptide. The uniqueness of patients in Pre-RELAX-AHF
compared with previous trials is evident by the higher

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Comment

depend on improving the network and infrastructure to


enrol patients eciently and as early as possible in their
presentation, to reect the timing of initiation of acute
therapies for patients in practice.
Pre-RELAX-AHF also underscores the diculty
in selection of endpoints for trials in acute heart
failure, for which there is little consensus. Although
the strategy used in Pre-RELAX-AHF to assess for
patterns or consistency of improvement across seven
sets of measures has appeal, there is a tendency to
focus on chance ndings with this approach. To date,
well validated instruments for improvement are scarce
and no acute therapy has been shown to improve hard
clinical outcomes.
There are exciting prospects for improving the
management of acute heart failure. Moving forward,
what needs to be done in clinical outcome trials of
new therapies for acute heart failure, such as relaxin?
Trials should target types of acute heart failure likely
to respond to the treatment, while at the same time
including populations that represent patients who
will be exposed to the treatment in practice, including
high-risk patients, elderly people, and women (who
tend to be under-represented in clinical trials). Most
importantly, trials should be large enough to clearly
dene the riskbenet ratio. Trials that are powered
to examine important clinical and safety outcomes
beyond dyspnoea relief might then inform patients and
providers of the risks and benets.13

AFH has received research grants from GlaxoSmithKline, Johnson & Johnson
(Scios, Inc), Medtronic, and Merck, and honoraria from AstraZeneca, Geron,
Medtronic, Novartis, Proventys, Thoratec, and ZyCare. CBG has received research
grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb,
GlaxoSmithKline, Novartis, Sano-Aventis, Roche, and The Medicines Company,
and has consulted for or received honoraria from AstraZeneca, deCODE Genetics,
GlaxoSmithKline, Novartis, Sano-Aventis, and The Medicines Company.
1

6
7

10

11

12

*Adrian F Hernandez, Christopher B Granger


Duke Clinical Research Institute, Duke University Medical Center,
Durham, NC 27715, USA
adrian.hernandez@duke.edu

13

Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke


statistics2009 update: a report from the American Heart Association
Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009;
119: 48086.
Curtis LH, Greiner MA, Hammill BG, et al. Early and long-term outcomes of
heart failure in elderly persons, 20012005. Arch Intern Med 2008;
168: 248188.
Fonarow GC, Abraham WT, Albert NM, et al. Association between
performance measures and clinical outcomes for patients hospitalized with
heart failure. JAMA 2007; 297: 6170.
Cue MS, Cali RM, Adams KF Jr, et al. Short-term intravenous milrinone for
acute exacerbation of chronic heart failure: a randomized controlled trial.
JAMA 2002; 287: 154117.
Publication Committee for the VMAC Investigators (Vasodilatation in the
Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for
treatment of decompensated congestive heart failure: a randomized
controlled trial. JAMA 2002; 287: 153140.
Poole-Wilson PA. Treatment of acute heart failure: out with the old, in with
the new. JAMA 2002; 287: 157880.
Teerlink JR, Metra M, Felker GM, et al. Relaxin for the treatment of patients
with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised,
placebo-controlled, parallel-group, dose-nding phase IIb study. Lancet 2009;
published online March 29, 2009. DOI:10.1016/S0140-6736(09)60622-X.
Gheorghiade M, Abraham WT, Albert NM, et al. Systolic blood pressure at
admission, clinical characteristics, and outcomes in patients hospitalized with
acute heart failure. JAMA 2006; 296: 221726.
McMurray JJ, Teerlink JR, Cotter G, et al, for the VERITAS Investigators. Eects
of tezosentan on symptoms and clinical outcomes in patients with acute
heart failure: the VERITAS randomized controlled trials. JAMA 2007;
298: 200919.
Torre-Amione G, Young JB, Colucci WS, et al. Hemodynamic and clinical
eects of tezosentan, an intravenous dual endothelin receptor antagonist, in
patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol
2003; 42: 14047.
Gheorghiade M, Gattis WA, OConnor CM, et al. Eects of tolvaptan,
a vasopressin antagonist, in patients hospitalized with worsening heart
failure: a randomized controlled trial. JAMA 2004; 291: 196371.
Cohn JN, Goldstein SO, Greenberg BH, et al, for The Vesnarinone Trial
Investigators. A dose-dependent increase in mortality with vesnarinone
among patients with severe heart failure. Vesnarinone Trial Investigators.
N Engl J Med 1998; 339: 181016.
Hernandez AF, OConnor CM, Starling RC, et al. Rationale and design of the
Acute Study of Clinical Eectiveness of Nesiritide in Decompensated Heart
Failure Trial (ASCEND-HF). Am Heart J 2009; 157: 27177.

Emergence of clinical vascular tissue engineering


See Articles page 1440

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Since the introduction by Weinberg and Bell in


1986 of the innovative concept of vascular grafts
engineered from living tissue as an alternative to
synthetic vascular prostheses,1 substantial progress
has been made in the development of technologies
for vascular-tissue engineering suitable for clinical
applications.2,3 To ensure a likelihood of clinical success
and long-term patency, tissue-engineered vascular
grafts must be athrombogenic and resistant to intimal

thickening and aneurysm development, as well as having


proper non-linear compliant material properties with
sucient level of suturability and fatigue resistance.
Although animal studies strongly suggest that these
specications are achievable, translation to clinical
practice remains a challenge. In this context, the report
in The Lancet today, by Todd McAllister and co-workers,
on the high level of patency (78% at 1 month and
60% at 6 months) of tissue-engineered blood vessels
www.thelancet.com Vol 373 April 25, 2009

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