The LIDO study: intravenous levosimendan is superior
for severe heart failure
Article
Follath F, Cleveland JGF, Just H, et al.
Efficacy and safety of intravenous levosimendan compared with dobutamine
in severe low-output heart failure (the LIDO study): a randomised double-blind
trial.
Lancet. 2002;360:196-202.
Background
Levosimendan is a new agent with a dual mechanism of action. In myocytes,
levosimendan sensitises troponin C to calcium in myocytes, thus promoting
actin-myosin interaction for enhancement of systolic contraction. Levosimendan
also promotes vasodilation by opening ATP-sensitive potassium channels.
By these inotropic and vasodilatory actions, levosimendan increases cardiac
output without increasing myocardial oxygen demand.
Objective
The purpose of this study was to compare the effects of levosimendan and
dobutamine on haemodynamic performance and on clinical outcome in patients
with low-output heart failure.
Study design
Hospitalised patients (n=203) were randomised for therapy in a multicentre,
double-blind, parallel-group study. With continuous haemodynamic monitoring,
levosimendan was infused over 10 min as a loading dose (24 mcg/kg), followed
by a 24 h maintenance infusion (0.1 mcg/kg). Dobutamine was infused for
24 h at a dose of 5 mcg/kg without a loading dose; the infusion rate was
doubled if the response at 2 h was inadequate. The primary endpoint was
the proportion of patients with haemodynamic improvement (defined as >
30% increase in cardiac output and > 25% decrease in pulmonary
capillary wedge pressure) at 24 h.
Results
Of the patients assigned to receive levosimendan (n=103) and dobutamine
(n=100), haemodynamic improvement was achieved in 29 (28%) levosimendan
patients compared to 15 (15%) in the dobutamine group (p=0.022). At one
month, the mortality rate was halved among patients treated with levosimendan
compared to those treated with dobutamine (8% versus 17%; p=0.049; hazard
ratio 0.43 with 95% CI of 0.18-1.00). After 180 days, the levosimendan
group had 26% deaths (n=26), while the dobutamine group had 38% (n=37);
the difference was statistically significant (p=0.029; hazard ratio 0.57
with 95% CI 0.34-0.95).
Conclusions
For improving haemodynamic performance in patients with heart failure,
the new intravenous drug levosimendan was significantly more effective
than standard dobutamine therapy. This haemodynamic benefit was accompanied
by halved mortality rates at one month—an effect that was maintained
at 6 months.
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The OPTIME-CHF study: routine use of intravenous
milrinone is not supported
Article
Cuffe MS, Calif RM, Adams KF Jr, et al.
Short-term intravenous milrinone for acute exacerbation of chronic heart
failure: a randomized controlled trial.
JAMA. 2002;287:1541-1547.
Background
When it comes to in-hospital management of patients with an acute exacerbation
of chronic heart failure, there is little evidence to guide therapy. Although
positive inotropes usually produce beneficial haemodynamic effects, the
effect of such therapy on patients’ intermediate-term outcomes is
unclear. This OPTIME-CHF study (Outcomes of a Prospective Trial of Intravenous
Milrinone for Exacerbation of Chronic Heart Failure) was designed to test
whether short-term treatment with milrinone (in addition to standard therapy)
can improve clinical outcomes of patients hospitalised with acutely decompensated
chronic heart failure.
Study design
Patients were randomly assigned to receive a 48-hour infusion of either
milrinone (0.5 mg/kg per minute initially; n=477) or saline placebo (n=472).
Results
The median number of days hospitalised for cardiovascular causes (within
60 days of randomisation into the study) was not significantly different
between patients given milrinone (6 days) and placebo (7 days; p=0.71).
Complications occurred more frequently in patients who received milrinone,
including sustained hypotension requiring intervention (10.7% vs 3.2%;
p<0.001) and new atrial arrhythmias (4.6% vs 1.5%; p=0.004).
The milrinone and placebo groups did not differ significantly for in-hospital
mortality, for 60-day mortality, or for the composite incidence of death
and readmission.
Conclusion
Results of this study do not support use of milrinone (in addition to
standard therapy) for treatment of patients hospitalised with exacerbation
of chronic heart failure.
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VMAC study: intravenous nesiritide improves haemodynamic
function
Article
Publication Committee for the Vasodilation in the Management of Acute
Congestive Heart Failure (VMAC) Investigators. Intravenous nesiritide
vs nitroglycerin for treatment of decompensated congestive heart failure:
a randomized controlled trial.
JAMA. 2002;287:1531-1540.
Background
In the United States, the leading hospital discharge diagnosis for older
patients (> 65 years) is decompensated congestive heart failure (CHF).
This randomised, double-blind study was designed to compare the efficacy
of nesiritide, nitroglycerin, and placebo as intravenous treatment in
patients hospitalised for acutely decompensated CHF.
Study design
In addition to standard medications, study patients received intravenous
nesiritide (n=204), intravenous nitroglycerin (n= 143), or placebo (n=142)
for 3 hours, followed by nesiritide (n=278) or nitroglycerin (n=216) added
to standard medications for 24 hours.
Results
At 3 hours, the mean decrease for pulmonary capillary wedge pressure (PCWP)
from baseline was
-5.8 mmHg for nesiritide (vs placebo, p<0.001; vs nitroglycerin, p=0.03),
-3.8 mmHg for nitroglycerin (vs placebo, p=0.09), and -2 mmHg for placebo.
At 3 hours, dyspnoea was significantly reduced in patients on nesiritide
compared to those on placebo, but not compared to patients on nitroglycerin.
At 24 hours, a reduction in pulmonary capillary wedge pressure was greater
in the nesiritide group (-8.2 mmHg) than in the nitroglycerin group (-6.3
mmHg), while global clinical status was only modestly improved, and dyspnoea
was not significantly different.
Conclusion
When added to standard care for patients hospitalised with acutely
decompensated CHF, nesiritide improves haemodynamic function and treats
some patient symptoms more effectively than intravenous nitroglycerin
or placebo.
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Treatment of acute heart failure: changing tides
Article
Poole-Wilson PA.
Treatment of acute heart failure: out with the old, in with the new.
JAMA. 2002;287:1578-1580.
Comments from an expert
In an accompanying JAMA editorial, Dr. P. Poole-Wilson comments
on the results of the milrinone OPTIME trial by Cuffe et al and the nesiritide
trial by the VMAC investigators. He recognises that, until now, little
or no progress has been made in management of acute heart failure and
treatment of those who have it. However, these latest trial results indicate
that it may be time to dismiss older therapeutic approaches (milrinone)
and embrace newer strategies (nesiritide).
In the opinion of Poole-Wilson, “the report by Cuffe et al is an
example of a clinical trial with an important neutral (possibly negative)
result that should affect clinical care.” In addition to the observations
for patients with acute heart failure, Dr. Poole-Wilson also questions
the use of milrinone for circulatory support in other similar conditions.
In the study reported by the VMAC investigators, effects of nesiritide
(a recombinant natriuretic peptide) were at least equivalent to nitroglycerin
and were arguably superior for the treatment of acute heart failure.
In addition, Dr. Poole-Wilson mentions other therapies newly introduced
to the therapeutic scene for acute heart failure. These include levosimendan
(a calcium sensitiser), tezosentan (an endothelin inhibitor), and therapeutic
pyruvate (an alternate substrate for the failing heart).
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Short-term endothelin receptor blockade with
tezosentan has immediate and long-term benefits
Article
Clozel M, Qiu C, Qiu CS, Hess P, Clozel JP.
Short-term endothelin receptor blockade with tezosentan has both immediate
and long-term beneficial effects in rats with myocardial infarction.
J Am Coll Cardiol. 2002;39:142-147.
Background
Endothelin (ET) appears to play a major role in progression from myocardial
infarction to heart failure. Tezosentan, a dual ETA/ETB
inhibitor, may be useful for blocking this harmful sequence. This study
was designed to investigate the short-term effects of tezosentan on cardiac
function, pulmonary oedema, and the long-term effects on evolution of
heart failure in a rat model of myocardial infarction (MI).
Study design
Rats were subjected to coronary artery ligation and then treated with
tezosentan (10 mg/kg intravenous bolus) or placebo at 1 hour and 24 hours
after MI. Haemodynamics and lung weight were measured
48 hours after MI, and survival was assessed over a 5-month interval.
Results
Placebo-treated rats developed heart failure 48 hours after ligation,
as evidenced by an increase in left ventricular end-diastolic pressure
(LVEDP), reduction in the maximal rate of rise of LV pressure (dP/dtmax)
and in the mean arterial pressure, and development of pulmonary oedema.
By contrast, tezosentan therapy lessened the increase in LVEDP and in
lung weight, and slightly reduced mean arterial pressure. While tezosentan
was only administered within the first 24 hours of MI, benefit persisted
over 5 months—with reduced cardiac hypertrophy (22%) and markedly
decreased survival (50% survival vs. 19% survival in placebo-treated rats,
p<0.001).
Conclusion
When given during the first day after MI in rats, tezosentan improved
acute haemodynamic conditions and markedly increased survival. Tezosentan
thus offers potential for prevention and treatment of ischaemic heart
failure.
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The MOXSE study: reduction of cardiac remodelling
by lowering sympathetic activation
Article
Swedberg K, Bristow MR, Cohn JN, et al.
Effects of sustained-release moxonidine, an imidazoline agonist, on plasma
epinephrine in patients with chronic heart failure.
Circulation. 2002;105:1797-1803.
Background
Sympathetic activation is increased in chronic heart failure. Moxonidine
acts via central nervous system receptors to decrease sympathetic activation.
This study was designed to investigate effects of sustained-release moxonidine
on plasma norepinephrine levels and on echocardiographic features of the
heart in patients with heart failure.
Study design
Patients with chronic heart failure (n=268; NYHA II-IV) on optimal standard
therapy were randomised to receive either placebo or one of 5 doses of
sustained-release (SR) moxonidine (0.3, 0.6, 0.9, 1.2, or 1.5 mg b.i.d.).
After a 7-week dose-titration phase, patients were followed at their maximally-tolerated
dose for another 12 weeks. After the active phase of the study, plasma
norepinephrine was evaluated over another 3 days.
Results
A marked, statistically significant dose-related decrease in plasma norepinephrine
was observed at weeks 7 and 19. At the highest dose (1.5 mg b.i.d.), the
reduction of norepinephrine was 52%. A modest increase in left ventricular
ejection fraction (LVEF) and a modest decrease in heart rate (HR) accompanied
these reductions. However, there was a dose-related increase in adverse
events.
Conclusions
Plasma norepinephrine was reduced in a dose-related manner by moxonidine.
This reduction was accompanied by evidence of reverse remodelling, but
also by an increase in adverse events. Related beneficial effects have
been reported for beta-blocker therapy (increased LVEF and decreased HR).
However, the increase in adverse events associated with moxonidine treatment
may mean that there are fundamental differences between anti-adrenergic
treatment that is delivered by sympatholysis or delivered by beta-receptor
blockade.
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