Download Clinical trials update from the American Heart Association

The European Journal of Heart Failure 8 (2006) 105 – 110
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Clinical trials update from the American Heart Association:
REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II,
SURVIVE, and PROACTIVE
a
b
Department of Cardiology, University of Hull, Castle Hill Hospital, Cottingham, Kingston-upon-Hull, HU15 5JQ, UK
Department of Primary Care and General Practice, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
Received 1 December 2005; accepted 7 December 2005
Abstract
This article provides information and a commentary on trials presented at the American Heart Association meeting held in November
2005, relevant to the pathophysiology, prevention and treatment of heart failure. All reports should be considered as preliminary data, as
analyses may change in the final publication. In REPAIR-AMI an improvement in ejection fraction was observed in post-MI patients
following infusion of bone marrow stem cells. However, the ASTAMI study showed no benefit of stem cell implantation in a similar patient
cohort. The JELIS study reported a reduction in major coronary events in patients receiving statins plus fish oil compared to statins alone.
MEGA showed that low dose statins in a low risk population reduce the incidence of major cardiovascular events. Two studies of
levosimendan in acute heart failure gave conflicting results, in the REVIVE-II study levosimendan was reported to have a superior effect on
the composite primary outcome compared to placebo, however, in SURVIVE despite a trend to early benefit with levosimendan, there was no
difference in effect on long-term outcome versus dobutamine. The PROACTIVE study showed encouraging results for the use of
pioglitazone in post-myocardial infarction patients with concomitant type 2 diabetes.
D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: American Heart Association; REPAIR-AMI; ASTAMI; JELIS; MEGA; REVIVE-II; SURVIVE; PROACTIVE
1. REPAIR-AMI (Reinfusion of Enriched Progenitor
cells And Infarct Remodelling in Acute Heart Failure)
and ASTAMI (Autologous Stem cell Transplantation in
Acute Myocardial Infarction)
Results of REPAIR-AMI were presented by Volker
Schachinger, JW Goethe University, Germany. Results of
ASTAMI were presented by Ketil Lunde, Rikhospitalet
University Hospital, Norway.
Replacing lost cardiac myocytes could make a valuable
contribution to the management or prevention of heart
failure. Over the last decade attempts have been made to
* Corresponding author. Tel.: +44 1482 624086; fax: +44 1482 624085.
E-mail address: [email protected] (A.P. Coletta).
implant skeletal muscle myoblasts or pluripotential stem
cells into damaged or failing myocardium. Currently, it is
not clear whether such interventions are safe or effective.
Also, the mechanism of effect is uncertain [1]. Stem cell
implantation could encourage new vessel growth, alter the
function of existing myocardium, or cells may evolve into
functional cardiac myocytes. Accordingly, two welldesigned randomised controlled trials reported at the AHA
are welcome. Both studies targeted post myocardial
infarction patients. The emerging strategy is to repopulate
damaged myocardium. Intervention that is too early may fail
due to inadequate perfusion or high oxidative and inflammatory stress and if too late may prove ineffective due to the
presence of dense organized myocardial scar. However, up
to two thirds of dysfunctional segments after a myocardial
infarction will reflect stunned, hibernating or partial
thickness myocardium and it is possible that intervention
1388-9842/$ - see front matter D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejheart.2005.12.003
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John G.F. Cleland a, Nick Freemantle b, Alison P. Coletta a,*, Andrew L. Clark a
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J.G.F. Cleland et al. / The European Journal of Heart Failure 8 (2006) 105 – 110
have the capacity to form muscle cells. Furthermore,
BOOST-II randomizing 200 patients with large myocardial
infarction and significantly depressed LV function will
assess the impact of bone marrow derived cell transfer on
long term regional and global LV function and outcome
over 3 years.
2. JELIS ( Japan EPA Lipid Intervention Study) and
MEGA (Management of Elevated cholesterol in the
primary prevention Group of Adult Japanese)
Results of JELIS were presented by Mitsuhiro Yokoyama,
Kobe University Graduate School of Medicine, Japan.
Results from MEGA were presented by Haruo Nakamura,
National Defence Medical College, Saitama, Japan.
The first two large multicentre outcome trials in
cardiovascular disease in Japan were presented at this
meeting.
The JELIS study included 18,645 hypercholesterolaemic
patients, of these, 3664 patients had a previous history of
coronary artery disease (CAD) and were classified as
‘‘secondary prevention’’ the remaining 14,981 patients had
no history of CAD and were classified as ‘‘primary
prevention’’ All patients were receiving low-dose statins
and half were randomised to additional treatment with 1800
mg of highly purified eicosapentenoic acid (EPA) daily. The
mean duration of follow-up was 4.5 years.
The addition of fish oil to low dose statin therapy
significantly reduced the incidence of the primary endpoint
(primary endpoint outcomes included sudden cardiac death,
myocardial infarction, unstable angina, or any procedures to
reopen blocked arteries). The beneficial effects of fish oil
plus statins were greater in patients in the secondary
prevention group. There was no effect on sudden death
(Table 1).
Previous studies of fish oil supplementation have shown
conflicting results [3,4]. It is possible that the results of this
study may have been influenced by the high level of fish
consumption in the Japanese population compared to
western countries. These data continue the fish oil story,
however, whether there is a beneficial effect on sudden
death in heart failure patients and whether this is due to
decreased vascular events or arrhythmias, remains to be
established [5].
The MEGA study showed that low dose statins in a low
risk population still reduce the incidence of major cardiovascular events. However, the safety and efficacy of statins
Table 1
Percentage of patients with endpoint events in the JELIS trial
Primary endpoint
Sudden cardiac death
Statin,
n = 9319
Statin plus
fish oil, n = 9326
Hazard ratio
3.5%
0.2%
2.8%
0.2%
0.81 (0.69 – 0.95)
1.06 (0.55 – 2.07)
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with stem cells could influence the function of such
segments.
The REPAIR-AMI study, from Germany and Switzerland, randomly assigned 204 patients to infusion of bone
marrow stem cells (estimated 236 million cells) or cell-free
supernatant an average of 4 days after a myocardial
infarction. Cells were obtained by aspirating, in both
groups, 50 ml of bone marrow from the iliac crest. By four
months left ventricular ejection fraction had improved in
both groups (92% of patients completed follow-up) but the
improvement was significantly greater in patients who
received stem cells 48% to 54%, compared with 47% to
50% in the placebo group ( p = 0.021). Benefits were most
obvious in patients who received the intervention more than
5 days after their myocardial infarction. Clinical events were
rare, there were 2 deaths in each group, in the placebo group
two patients developed heart failure and 5 patients had a
recurrent myocardial infarction, none of these events
occurred in the stem-cell group. More patients required
revascularisation in the placebo group (28 versus 19). These
small differences in the rate of recurrent infarction and
revascularisation may have occurred by chance and could
have influenced the outcome in terms of ventricular
function.
In contrast, the ASTAMI study from Norway randomly
assigned 100 patients with an anterior myocardial infarction
to stem cell implant or not, 5– 8 days after the acute event
[2]. Patients were thoroughly investigated including nuclear
myocardial perfusion scan, echocardiogram and cardiac
magnetic resonance imaging. The investigators observed no
benefit and indeed CMR suggested that at 6 months, left
ventricular ejection fraction had increased more in the
control group (+ 1.2% versus + 4.3%; p = 0.05).
A recent update of the BOOST study suggested that the
beneficial bone marrow transfer post MI is sustained at 18
months, however, there was a further improvement of global
LV function in the control group and therefore, the intergroup comparison was no longer significant.
Other observational data suggest that cell transplantation
may improve left ventricular function even in patients with
long-standing heart failure. Whether or not the extent of
myocardial scar is an important determinant of this response
is uncertain.
These trials should mark the end of small, single centre
studies. Clearly, the technique is feasible, is not dramatically
effective, but does not expose patients to very high risk.
Larger (several hundred patients per group), longer-term
(3 – 5 years follow-up), multicentre trials looking for
evidence of modest benefit and risk are now required.
One such trial (MAGIC) is underway using autologous
skeletal muscle myoblasts in patients with chronic heart
failure who are undergoing coronary bypass and defibrillator implantation, the latter due to the possible increase in
risk of sudden arrhythmic death associated with this form of
stem cell therapy. Whereas bone marrow stem cells may
evolve into many different cells, myoblasts appear only to
J.G.F. Cleland et al. / The European Journal of Heart Failure 8 (2006) 105 – 110
in very high risk populations, such as those with heart
failure, require further investigation [5,6].
3. REVIVE-II (Randomised multicentre evaluation of
intravenous levosimendan efficacy versus placebo in the
short term treatment of decompensated heart failure)
and SURVIVE (Survival of patients with acute heart
failure in need of intravenous inotropic support trial)
deemed improved and 7% fewer worse with levosimendan. Of those assigned to levosimendan 15% required
intravenous rescue therapy, mostly diuretics, versus 26%
of those assigned to placebo. Plasma concentrations of
BNP fell by about 250 pg/ml and duration of hospitalisation was shortened by about 2 days ( p = 0.001), but
this was not accompanied by a reduction in mortality. By
90 days, there were 35 deaths on placebo and 45 in the
levosimendan group (Fig. 1). There were more reports of
hypotension (50% versus 36%) and atrial fibrillation (8%
versus 2%) in the levosimendan group compared with the
placebo group.
Overall these data are promising but not conclusive. The
effect on symptoms was modest. The most impressive
finding is the reduction in bed-days. Despite a reduction in
BNP, usually considered a good prognostic sign, there was a
trend to higher mortality, which contrasts with previous
studies of levosimendan. Whether reduction of already low
arterial pressure, exacerbated by the use of a loading dose,
was associated with the trend to increased mortality awaits
analysis as does the clinical effect in relation to the use of
beta-blockers.
The SURVIVE study compared levosimendan and
dobutamine in patients who had been admitted to hospital
with acute heart failure and a LVEF <30%, who remained
breathless at rest despite intravenous diuretics and vasodilators, if they had features of a low cardiac output
including oliguria, cool peripheries and low arterial pressure. Patients had to have a systolic blood pressure in the
range of 80– 130 mm Hg and serum creatinine < 450 Amol/
L. This was one of the highest risk populations ever enrolled
in a study of heart failure. More than one in four patients
had died within 6 months despite modern medical therapy,
which is higher than in any other study of acute heart failure
and similar to the 5-month rate in the CONSENSUS study
[11]. Clearly, the needs of patients remain unmet, even by
modern therapy. However, potentially many of these deaths
were in patients verging on or with cardiogenic shock and
therefore beyond rescue with either agent. The primary
outcome was all-cause mortality at 180 days, a time far
beyond the haemodynamic effects of either agent. This
endpoint was based on the concept that a short-term
intervention could have long-term effects, rather like
thrombolysis or aspirin after a myocardial infarction or
antibiotics for pneumonia, and is supported by observations
from previous trials, although these had only shown a shortterm mortality gain without long-term catch-up rather than
continuing divergence in survival.
The design was of a conventional randomised controlled
trial, comparing short-term administration of levosimendan
and dobutamine using a double-dummy technique. Altogether, 1327 patients were randomised. The mean age was
67 years, 72% were men, 88% had a past history of heart
failure, LVEF was 24%, 76% had ischaemic heart disease,
mean systolic blood pressure was 116 mm Hg and plasma
concentrations of BNP were grossly elevated.
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Results of REVIVE-II were presented by Milton Packer,
University of Texas Southwestern Medical Center, Texas,
USA. Results of SURVIVE were presented by Alexandre
Mebazza, Hopital Lariboisiere, Paris, France.
Levosimendan has inotropic and vasodilator properties
mediated by calcium-concentration dependent (i.e. operates
mainly in systole) calcium sensitisation and opening
potassium channels [7,8]. Three modest sized trials have
suggested that short-term (6– 24 h) infusion of levosimendan might improve symptoms and reduce subsequent
mortality over the following 180 days [7– 9]. REVIVE
and SURVIVE were designed to confirm these findings in
large prospectively designed studies.
The REVIVE-II study compared levosimendan and
placebo in patients who had been admitted to hospital with
a primary or secondary diagnosis of heart failure and LVEF
< 35% if they remained breathless at rest after use of
diuretics and vasodilators. The protocol suggested that
patients should be enrolled within 48 h of admission but
did permit patients to be enrolled after this time. Thus, this
was predominantly a study of severe heart failure patients
unresponsive to standard therapy, whose needs are obviously not met by current therapy. Patients requiring
ventilatory support, with systolic blood pressure <90 mm
Hg or serum creatinine > 450 umol/L were excluded. The
primary endpoint was a complex composite outcome.
Patients who rated themselves as moderately or markedly
improved at 6 h, 24 h and 5 days were considered to have
improved provided they met no criteria for worsening. This
endpoint reflects the desire to obtain prompt and sustained
benefit. Worsening included death, patient self reported
moderate or severe deterioration at any time-point or
worsening symptoms at any time or persistent severe
symptoms after 24 h requiring rescue therapy for instance
with intravenous diuretic, vasodilator or inotropic agents.
Other patients were considered unchanged. These criteria
had been modified in light of a previous pilot trial
(REVIVE-I).
The mean age of the 600 patients randomised was 63
years and 72% were men. Mean LVEF was 23%, over 70%
were oedematous, 68% had rales and mean systolic blood
pressure was 116 mm Hg. ACE inhibitors, beta-blockers,
digoxin and spironolactone were prescribed to 85%, 78%,
60% and 41% of patients, respectively.The primary endpoint was achieved ( p = 0.015). However, the net benefit in
absolute terms was modest, as about 6% more patients were
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J.G.F. Cleland et al. / The European Journal of Heart Failure 8 (2006) 105 – 110
a
0.455 (0.254, 0.834)
CASINO*
0.734 (0.202, 2.524)
REVIVE-1
0.225 (0.004, 2.416)
REVIVE-II
1.726 (0.786, 3.948)
Exact Fixed Effects
0.721 (0.469, 1.113)
Random Effects
0.718 (0.315, 1.637)
0.001
0.01
0.1
0.2
0.5
1
2
5
Heterogeneity = 9.579502 (df = 3) P = 0.0225
b
RUSSLAN
0.54 (0.32, 0.90)
CASINO*
0.53 (0.24, 1.14)
REVIVE-1
0.75 (0.14, 3.74)
REVIVE-II
1.35 (0.82, 2.23)
Exact Fixed Effects
0.79 (0.58, 1.08)
Random Effects
0.75 (0.43, 1.30)
0.1
0.2
0.5
1
2
5
Heterogeneity = 9.868768 (df = 3) P = 0.0197
Fig. 1. (a) Meta-analysis (odds ratio and 95% confidence intervals) of levosimendan versus placebo on short term mortality—pooled fixed and random effects
[9 – 11]. *Numbers recalculated from percentages, data not verified. (b) Meta-analysis (odds ratio and 95% confidence intervals) of levosimendan versus
placebo on long-term mortality—pooled fixed and random effects [9 – 11]. *Numbers recalculated from percentages, data not verified.
There was a trend to early benefit with levosimendan that
was not sustained beyond the period of haemodynamic
efficacy of the drug (Table 2). Levosimendan reduced
plasma concentrations of BNP to a greater extent than
dobutamine and this effect was sustained for 5 days.
Subgroup analysis showed heterogeneity in outcome between countries. Levosimendan was associated with a
substantial reduction in the relative (and modest reduction
in absolute) risk of death during the first 30 days compared
to dobutamine. Patients were more likely to experience
atrial fibrillation (9.1% versus 6.1%; p < 0.05) and less likely
to experience worsening heart failure (12.3% versus 17%;
p < 0.02) on levosimendan compared to dobutamine. There
were no differences in mean serum creatinine or total
hypotensive episodes but these outcomes require more
detailed analysis.
Previous studies comparing levosimendan and dobutamine recruited mainly patients with severe chronic heart
failure and this group appeared to gain greater benefit in
SURVIVE, possibly because they were more likely to be
receiving a beta-blocker, which interacted favourably with
levosimendan compared to dobutamine in a previous study
of subacute heart failure [12] (Fig. 2).
Most studies of chronic heart failure require a standard
background therapy. Trials of acute heart failure are
conducted on top of very variable background therapy for
which there is little evidence of benefit for many components. SURVIVE showed evidence of regional heterogene-
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RUSSLAN
J.G.F. Cleland et al. / The European Journal of Heart Failure 8 (2006) 105 – 110
a
LIDO
0.41 (0.15, 1.07)
CASINO*
0.43 (0.13, 1.27)
SURVIVE
0.81 (0.51, 1.26)
Exact Fixed Effects
0.66 (0.45, 0.96)
Random Effects
0.62 (0.39, 0.99)
0.2
0.5
1
2
Heterogeneity = 2.669791 (df = 2) P = 0.2632
b
LIDO
0.58 (0.30, 1.10)
CASINO*
0.26 (0.12, 0.55)
SURVIVE
0.91 (0.71, 1.17)
Exact Fixed Effects
0.75 (0.60, 0.93)
Random Effects
0.55 (0.27, 1.11)
0.1
0.2
0.5
1
2
Heterogeneity = 12.570649 (df = 2) P = 0.0019
Fig. 2. (a) Meta-analysis (odds ratio and 95% confidence intervals) of levosimendan versus dobutamine on short-term mortality—pooled fixed and random
effects [9,13]. *Numbers recalculated from percentages, data not verified. (b) Meta-analysis (odds ratio and 95% confidence intervals) of levosimendan versus
dobutamine on long-term mortality—pooled fixed and random effects [9,13]. *Numbers recalculated from percentages, data not verified.
ity in effect suggesting that differences in clinical practice
may have influenced outcome. Only including patients and
centres that adhere to an agreed evidence-based care
pathway will improve the ability of new interventions and
new trials to show benefit. Clearly, some patients are so sick
that no intervention can save them, whilst others will
survive without any intervention. Identifying patients at
Table 2
Outcome data from SURVIVE
Intervention
Levosimendan (n = 664)
Dobutamine (n = 663)
Hazard ratio
Deaths
0–5
days
6 – 30
days
30 – 180
days
Total
29
40
0.72
(0.55 – 1.16)
50
41
94
94
173
185
0.91
(0.74 – 1.13)
high but modifiable risk is one of the most important tasks
of medicine and medical research.
Levosimendan is a vasodilator. Patients with a baseline
systolic arterial pressure of 80 mm Hg or lower could be
enrolled in REVIVE/SURVIVE. This agent is not suitable
for the treatment of hypotension or cardiogenic shock on the
basis of current evidence. Recruitment of patients with
inappropriately low arterial pressure that fell further on
levosimendan resulting in problems with vital organ
perfusion may well have led to a loss of any advantage
from levosimendan compared to dobutamine and a neutral
outcome. Also, it should be noted that studies of dobutamine indicating an excess mortality are derived mainly
from repetitive dosing in patients with chronic severe heart
failure and not from studies of acute heart failure [13].
The clinical significance of a short-term mortality gain,
assuming the observed subgroup analysis is real, that cannot
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0.1
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J.G.F. Cleland et al. / The European Journal of Heart Failure 8 (2006) 105 – 110
4. PROACTIVE: (PROspective pioglitAzone Clinical
Trial In macro Vascular Events)
Results presented by Erland Erdmann, University of
Koeln, Germany.
Glitazones are contra-indicated in patients with heart
failure. There is considerable uncertainty about how to
manage diabetes in patients with heart failure or in the postinfarction setting. The PROACTIVE study randomised
5238 patients with type 2 diabetes (mean duration 8 years
in the post-myocardial infarction cohort) and macrovascular
disease to placebo or pioglitazone (target dose 45 mg/day).
Patients were followed for 2.85 years [14]. Patients with a
previous (> 6 months) myocardial infarction (n = 2445; 47%
of total) constituted a large subgroup of patients at increased
risk of LVSD and heart failure. Piogiltazone improved the
cardiovascular risk profile by reducing triglycerides and
LDL cholesterol and increasing in HDL cholesterol. This
was associated with a reduced risk of recurrent coronary
vascular events and a trend to lower cardiac mortality (about
1.5% absolute risk per year reduced by about 17% in
relative terms). There was a slight increase in the risk of
worsening oedema and a diagnosis of heart failure (2.7%
absolute increase) but this did not lead to an increase in
mortality for heart failure or all-cause. These data are
encouraging and the cardiovascular benefit similar in
relative terms to that from statins. Data investigating safety,
efficacy and tolerability both in the acute post-infarction
setting and in heart failure would be welcome.
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be retained is uncertain. Are these data sufficient to warrant
the widespread use of levosimendan? This depends on your
clinical practice. If you do not use intravenous inotropic or
vasodilator agents for the management of heart failure then
there is insufficient evidence, as yet, to suggest that you
should use levosimendan. However, there is as much or
more evidence for the safety and efficacy of levosimendan
for acute on chronic heart failure than for any other
intravenous inotropic or vasodilator agent, including nitrates
or nesiritide. Therefore, if you do use such intravenous
agents for the treatment of such patients you might consider
levosimendan, even perhaps as the agent of first choice
provided cost is not an issue. Clearly, more clinical trial data
are desirable and will probably be required by regulators.
Further clinical trials comparing levosimendan against
placebo, dobutamine or intravenous nitrates would be of
great interest. However, short-term treatment with any agent
without the potential for long-term reinforcement may have
limited long-term success. Studies of pulsed inotropic
therapy and of oral levosimendan are planned or are
underway.