Download Levosimendan vs Dobutamine for Patients With Acute

ORIGINAL CONTRIBUTION
Levosimendan vs Dobutamine for Patients
With Acute Decompensated Heart Failure
The SURVIVE Randomized Trial
Alexandre Mebazaa, MD, PhD
Markku S. Nieminen, MD, PhD
Milton Packer, MD
Alain Cohen-Solal, MD, PhD
Franz X. Kleber, MD
Stuart J. Pocock, PhD
Roopal Thakkar, MD
Robert J. Padley, MD
Pentti Põder, MD, PhD
Matti Kivikko, MD, PhD
for the SURVIVE Investigators
Context Because acute decompensated heart failure causes substantial morbidity and
mortality, there is a need for agents that at least improve hemodynamics and relieve
symptoms without adversely affecting survival.
Objective To assess the effect of a short-term intravenous infusion of levosimendan or dobutamine on long-term survival.
Design, Setting, and Patients The Survival of Patients With Acute Heart Failure
in Need of Intravenous Inotropic Support (SURVIVE) study was a randomized, doubleblind trial comparing the efficacy and safety of intravenous levosimendan or dobutamine in 1327 patients hospitalized with acute decompensated heart failure who required inotropic support. The trial was conducted at 75 centers in 9 countries and patients
were randomized between March 2003 and December 2004.
Interventions Intravenous levosimendan (n = 664) or intravenous dobutamine
(n = 663).
Main Outcome Measure All-cause mortality at 180 days.
A
CUTE DECOMPENSATED HEART
failure (ADHF) remains a
common cause of hospitalization worldwide but it is not
clear how patients admitted for clinical deterioration should be managed.
Patients are generally treated with diuretics and vasodilators, while patients with evidence of peripheral hypoperfusion also may receive positive
inotropes, usually dobutamine or milrinone. These positive inotropic agents
improve hemodynamics and symptoms by increasing intracellular cyclic
adenosine monophosphate within the
failing heart but have been associated
with an increased risk of death and
other cardiovascular events.1,2
Levosimendan is a pharmacological
agent that exerts positive inotropic effects by binding to cardiac troponin C in
a calcium-dependent manner, sensitizing myofilaments to calcium.3,4 Levosimendan also has vasodilatory proper-
Results All-cause mortality at 180 days occurred in 173 (26%) patients in the levosimendan group and 185 (28%) patients in the dobutamine group (hazard ratio, 0.91;
95% confidence interval, 0.74-1.13; P=.40). The levosimendan group had greater decreases in B-type natriuretic peptide level at 24 hours that persisted through 5 days
compared with the dobutamine group (P⬍.001 for all time points). There were no
statistical differences between treatment groups for the other secondary end points
(all-cause mortality at 31 days, number of days alive and out of the hospital, patient
global assessment, patient assessment of dyspnea at 24 hours, and cardiovascular mortality at 180 days). There was a higher incidence of cardiac failure in the dobutamine
group. There were higher incidences of atrial fibrillation, hypokalemia, and headache
in the levosimendan group.
Conclusion Despite an initial reduction in plasma B-type natriuretic peptide level in
patients in the levosimendan group compared with patients in the dobutamine group,
levosimendan did not significantly reduce all-cause mortality at 180 days or affect any
secondary clinical outcomes.
Trial Registration clinicaltrials.gov Identifier: NCT00348504
www.jama.com
JAMA. 2007;297:1883-1891
Author Affiliations: Departments of Anesthesiology (Dr
Mebazaa), Critical Care Medicine (Dr Mebazaa), and
Cardiology (Dr Cohen-Solal), Université Paris Diderot
and Hospital Lariboisière AP-HP, Paris, France; Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland (Dr Nieminen); Department of Clinical Sciences, University of Texas Southwestern Medical
School, Dallas (Dr Packer); Department of Internal Medicine, Charité Medical School, Berlin, Germany (Dr Kleber); Medical Statistics Unit, London School of Hygiene
©2007 American Medical Association. All rights reserved.
and Tropical Medicine, London, England (Dr Pocock);
Cardiovascular Clinical Research, Abbott Laboratories, Abbott Park, Ill (Drs Thakkar and Padley); and Cardiology Unit, Clinical Research and Development, Orion
Pharma, Espoo, Finland (Drs Põder and Kivikko).
The SURVIVE Investigatiors are listed at the end of
this article.
Corresponding Author: Alexandre Mebazaa, MD, PhD,
Hospital Lariboisière, 2 Rue A Paré, Paris, France 75475
Cedex 10 ([email protected]).
(Reprinted) JAMA, May 2, 2007—Vol 297, No. 17
Downloaded from www.jama.com at Medical Library of the PLA, on August 19, 2007
1883
LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE
Exclusion criteria included severe
ventricular outflow obstruction; systolic blood pressure persistently lower
than 85 mm Hg or heart rate persistently at 130/min or higher; intravenous inotrope use during the index hospitalization (except dopamine ⱕ2 µg/kg
per minute or digitalis); history of torsade de pointes; and serum creatinine
level higher than 5.1 mg/dL (450
µmol/L) or dialysis.
Figure 1. Participant Flow Through the Study
1337 Assessed for Eligibility
10 Excluded (Did Not Meet Inclusion
or Met Exclusion Criteria)
1327 Randomized
664 Randomized to Receive Levosimendan
660 Received Levosimendan
as Assigned
663 Randomized to Receive Dobutamine
660 Received Dobutamine
as Assigned
3 Lost to Follow-up
30 Discontinued Intervention
10 Major Cardiovascular Event
9 Serious Adverse Event
9 Event Judged by Investigator
to Warrant Withdrawal
2 Other
8 Lost to Follow-up
41 Discontinued Intervention
15 Major Cardiovascular Event
9 Serious Adverse Event
14 Event Judged by Investigator
to Warrant Withdrawal
3 Other
Study Plan
664 Included in Primary Efficacy Analysis
663 Included in Primary Efficacy Analysis
660 Included in Safety Analysis
4 Excluded (Did Not Receive Study Drug)
660 Included in Safety Analysis
3 Excluded (Did Not Receive Study Drug)
ties due to its facilitation of an adenosine
triphosphate–dependent potassium
channel opening5 and anti-ischemic effects.6 In clinical studies, levosimendan
increased cardiac output and lowered
cardiac filling pressures and was associated with reducing cardiac symptoms,
risk of death, and hospitalization.7-9 Unlike other positive inotropic agents, the
primary actions of levosimendan are independent of interactions with ␤-adrenergic receptors.10,11 Compared with the
␤-adrenergic agonist dobutamine in the
Levosimendan Infusion versus Dobutamine (LIDO) trial,12 levosimendan exerted superior hemodynamic effects and
in secondary and post hoc analyses was
associated with a lower risk of death after 31 and 180 days.
Survival of Patients With Acute Heart
Failure in Need of Intravenous Inotropic Support (SURVIVE) was the first
survival trial performed in patients
with ADHF, to our knowledge. The
SURVIVE trial assessed the effect of
short-term intravenous infusions of levosimendan or dobutamine on longterm survival.
METHODS
The SURVIVE trial was conducted at 75
centers in Austria, Finland, France, Ger-
many, Israel, Latvia, Poland, Russia, and
the United Kingdom. The study protocol was approved by independent ethics committees and was conducted in
accordance with the Declaration of Helsinki13 and applicable regulatory requirements. This trial was designed,
implemented, executed, and overseen
by the study sponsor and steering committee. An independent data and safety
monitoring board had access to unblinded data and periodically reviewed the safety results.
Study Patients
The study enrolled patients aged 18
years or older who provided written
informed consent and were hospitalized with ADHF. All patients had an
ejection fraction of 30% or less
within the previous 12 months and
required intravenous inotropic support, as evidenced by an insufficient
response to intravenous diuretics
and/or vasodilators, and at least 1 of
the following at screening: (1) dyspnea at rest or mechanical ventilation for ADHF; (2) oliguria not as a
result of hypovolemia; or (3) pulmonary capillary wedge pressure of 18
mm Hg or higher and/or cardiac
index of 2.2 L/min per m2 or less.
1884 JAMA, May 2, 2007—Vol 297, No. 17 (Reprinted)
SURVIVE was a randomized, doubleblind, multicenter, parallel-group study.
Randomization was performed by a
2-step procedure (FIGURE 1). First, vials containing study drug were assigned a number using randomly permuted blocks. Second, patients were
randomized centrally, using an interactive voice response system, to receive levosimendan or dobutamine at
a ratio of 1:1. Randomization was stratified using a biased coin algorithm with
previous ADHF and country as factors.
During the treatment period,
patients were randomized to receive
2 double-blind intravenous infusions: levosimendan and placebo for
dobutamine in the levosimendan
group or dobutamine and placebo for
levosimendan in the dobutamine
group. A loading dose of levosimendan (12 µg/kg) or placebo for levosimendan was administered over 10
minutes, followed by an infusion
(0.1 µg/kg per minute) for 50 minutes; the rate was increased to 0.2
µg/kg per minute for an additional
23 hours as tolerated. The infusion of
dobutamine or placebo for dobutamine was initiated at a rate of 5 µg/kg
per minute and could be increased at
the discretion of the investigator to a
maximum rate of 40 µg/kg per
minute. The infusion was maintained
as long as clinically appropriate
(minimum of 24 hours) and was
tapered according to each patient’s
clinical status.
Plasma B-type natriuretic peptide
(BNP) levels were measured after 1, 3,
and 5 days. Hospitalization or death was
noted for the 180-day period. If pa-
©2007 American Medical Association. All rights reserved.
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LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE
Study End Points
The primary end point of the study was
all-cause mortality during the 180 days
following randomization. Secondary
end points included all-cause mortality during 31 days, change in BNP level
from baseline to 24 hours, number of
days alive and out of the hospital during the 180 days, change in patientassessed dyspnea at 24 hours, patientassessed global assessment at 24 hours,
and cardiovascular mortality through
180 days.
To monitor safety, adverse events
were collected for 31 days following initial study drug administration and during all blinded drug readministrations.
Statistical Analyses
The sample size was based on the objective of assessing differences in allcause mortality between the levosimendan and dobutamine groups at 180
days. The trial was event-rate driven until 330 deaths had occurred, providing
85% power (␣ = .05) to detect a 25%
relative risk reduction in mortality rates
between the treatment groups, assuming the 180-day mortality rate was
25.3%. The originally targeted number of patients, based on LIDO,12 was
700 but was increased to 1320 following a blinded review of mortality after
131 deaths to achieve the target number of 330 deaths.
To control the type I error due to 2
interim analyses, the Haybittle-Peto
boundary was used and differences in
risk between the 2 treatments at the end
of the trial were considered significant
at a P value of less than .05.
Table 1. Baseline Patient Demographics and Characteristics*
Levosimendan
(n = 664)
493 (74)
Male sex
White race
Age, mean (SD), y
Weight, mean (SD), kg
Vital signs, mean (SD)
Systolic BP, mm Hg
Diastolic BP, mm Hg
Heart rate, beats/min
Cardiovascular history
History of heart failure
Myocardial infarction
Mitral insufficiency
Hypertension
Atrial fibrillation/flutter
Tricuspid insufficiency
Stable angina pectoris
Type 2 diabetes
Initial hospitalization characteristics
Ischemic etiology for acute heart failure
NYHA class IV
LVEF, mean (SD), %†
BNP level, pg/mL‡
Mean (SD)
Median (range)
Cardiovascular medications prior to infusion
␤-Blocking agents
ACE inhibitor or ARB
Aldosterone antagonists
Dobutamine
(n = 663)
463 (70)
627 (94)
67 (12)
79 (18)
625 (94)
66 (12)
79 (16)
116 (18)
70 (12)
84 (17)
116 (19)
70 (12)
83 (17)
586 (88)
453 (68)
412 (62)
405 (61)
324 (49)
317 (48)
310 (47)
205 (31)
585 (88)
455 (69)
419 (63)
429 (65)
308 (46)
308 (46)
318 (48)
223 (34)
503 (76)
572 (86)
24 (5)
502 (76)
562 (85)
24 (5)
1581 (1490)
1178 (573-2066)
Intravenous diuretics
Intravenous nitrates
Intravenous dopamine§
1667 (1670)
1231 (583-2084)
336 (51)
463 (70)
336 (51)
333 (50)
451 (68)
366 (55)
523 (79)
241 (36)
50 (8)
523 (79)
252 (38)
34 (5)
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; BNP, B-type natriuretic peptide; BP, blood pressure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.
*Values are expressed as number (percentage) unless otherwise indicated.
†Most recent within 12 months preceding randomization.
‡The Axsym BNP assay (Abbott Laboratories, Abbott Park, Ill) was used. The normal level for BNP was less than 135
pg/mL in individuals who did not have heart failure.
§A dose of 2 µg/kg per minute or less.
Figure 2. Effect of Dobutamine and Levosimendan Treatment on All-Cause Mortality During
180 Days Following the Start of Study Drug Infusion
©2007 American Medical Association. All rights reserved.
1.0
Probability of Survival
tients required additional inotropic support during the study period, the intention was to maintain the blind by
readministering the patient’s original assigned study drug and dosing regimen. However, this was not mandated
so failure to do so was not considered
a protocol violation. If readministration occurred within 7 days of initial
infusion, levosimendan was administered without a loading dose and at 0.1
µg/kg per minute.
0.8
0.6
Cox Proportional Hazards P = .40
0.4
Levosimendan
Dobutamine
0.2
0
0
30
60
90
120
150
180
Time Since Start of Study Drug Infusion, d
No. at Risk
Levosimendan
Dobutamine
664 608 586
663 596 568
525
519
462
454
(Reprinted) JAMA, May 2, 2007—Vol 297, No. 17
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1885
LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE
Table 2. Primary, Secondary, and Post Hoc All-Cause Mortality End Points*
No. (%) of Patients†
Levosimendan Dobutamine
(n = 664)
(n = 663)
Primary end point
All-cause mortality at 180 d
Secondary end point
All-cause mortality at 31 d
Mean change in BNP at 24 h
from baseline, pg/mL
Mean No. of days alive and
out of the hospital during 180 d
Dyspnea assessed at 24 h;
ⱖmild improvement¶
Global assessment at 24 h;
ⱖmild improvement¶
Cardiovascular mortality during 180 d
Post hoc all-cause mortality
5d
14 d
90 d
HR (95% CI)
P
Value
173 (26)
185 (28)
0.91 (0.74-1.13)
.40‡
79 (12)
(n = 628)
−631
120.2
91 (14)
(n = 611)
−397
116.6
0.85 (0.63-1.15)
.29‡
⬍.001§
544 (82)
550 (83)
531 (80)
537 (81)
157 (24)
171 (26)
0.90 (0.72-1.12)
.33‡
29 (4)
59 (9)
139 (21)
40 (6)
69 (10)
138 (21)
0.72 (0.44-1.16)
0.84 (0.59-1.19)
0.99 (0.78-1.25)
.17‡
.33‡
.91‡
.30 㛳
.96 㛳
⬎.99
Abbreviations: BNP, B-type natriuretic peptide; CI, confidence interval; HR, hazard ratio.
*Survival differences were tested for significance by the Cox proportional hazard regression model with treatment as the
only covariate. Comparison of categorical variables such as dyspnea assessment, patients’ global assessment, and days
alive and out of the hospital were performed by the Cochran-Mantel-Haenszel test with effect for treatment only. Changes
in BNP levels were analyzed using the Kruskal-Wallis test.
†Unless otherwise indicated.
‡Cox proportional hazards model was used for treatment effect only.
§Analysis of covariance model used with baseline value as covariate and treatment for main effect.
㛳Cochran-Mantel-Haenszel mean score test with effect for treatment only.
¶Distribution from markedly improved to markedly worse.
Figure 3. Mean Change From Baseline in
B-Type Natriuretic Peptide Levels at 1, 3, and
5 Days by Treatment Group
Mean Change From
Baseline, pg/mL
0
–200
Dobutamine
–400
–600
Levosimendan
–800
0
1
2
3
4
5
Time Since Start of
Study Drug Infusion, d
There was a significantly greater mean (SE) change
from baseline in plasma B-type natriuretic peptide levels in the levosimendan group compared with the
dobutamine group at 1, 3, and 5 days after initiation
of study drug infusion. P⬍.001 at all 3 time points.
Statistical significance was determined using KruskalWallis test with treatment effect.
Analysis of survival was based on a
patient’s randomization in accordance with the intention-to-treat
principle. Cumulative survival curves
were constructed as time-to-event
plots by Kaplan-Meier methods and
differences were tested for signifi-
cance by the Cox proportional hazard regression model, with treatment
as the only covariate. The Cox model
also was used to examine potential
treatment ⫻ subgroup interactions
using treatment, subgroup, and
treatment ⫻ subgroup interaction as
covariates. Prespecified subgroup
analyses included the baseline variables of sex, age, previous ADHF,
acute myocardial infarction at initial
hospitalization, serum creatinine
level, oliguria, ␤-blocker use,
angiotensin-converting enzyme
inhibitor or angiotensin II receptor
blocker use, systolic blood pressure,
heart rate, dyspnea at rest, and
mechanical ventilation for ADHF.
The Cox model within subgroups
was further considered if the interaction P value was .10 or less.
Comparison of categorical variables such as dyspnea assessment, patients’ global assessment, and number
of days alive and out of the hospital was
performed using the Cochran-MantelHaenszel test with effect for treatment
only. Changes in BNP levels were ana-
1886 JAMA, May 2, 2007—Vol 297, No. 17 (Reprinted)
lyzed using the Kruskal-Wallis test.
Comparisons between treatment groups
for the incidence rates of adverse events
were performed using a Fisher exact test
and mean change from baseline of other
variables were performed by analysis of
covariance with baseline as a covariate. Treatment differences in mean
change from baseline in electrocardiogram and vital signs were tested by
analysis of covariance with baseline as
a covariate. Statistical analyses were performed using SAS version 8.2 (SAS Institute Inc, Cary, NC) and significance was reported at a P value of .05
or less.
RESULTS
Patient Population
A total of 1327 patients hospitalized
with ADHF were randomized between March 2003 and December 2004
to either the levosimendan group
(n = 664) or the dobutamine group
(n = 663). Of this intention-to-treat
population, 1320 patients (660 in each
group) received study drug and were
included in the safety population
(Figure 1).
Patients randomized to levosimendan or dobutamine were similar with
respect to pretreatment characteristics (TABLE 1) and concomitant medications. Patients had increased BNP levels and the large majority (n = 1171;
88%) had previous ADHF.
After the initial hour that includes
loading dose, levosimendan was continuously infused at a mean (SD) rate
of 0.2 (0.02) µg/kg per minute for 23.4
(2.9) hours; dobutamine was infused
at a rate of 5.9 (2.6) µg/kg per minute
for 39.3 (44.4) hours. During the 180day period, 102 (⬍8%) patients (48 in
the levosimendan group and 54 in the
dobutamine group) received blinded readministration of study drug. Also, during the study period, 75 (11%) patients in levosimendan group received
open-label dobutamine (n=72) or levosimendan (n=3) while 79 (12%) patients in the dobutamine group received open-label dobutamine (n=74)
or levosimendan (n=5).
©2007 American Medical Association. All rights reserved.
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LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE
Primary and Secondary End Points
During the 180 days after study drug
infusion, there were 173 deaths (26%)
in the levosimendan group and 185
deaths in the dobutamine group (28%)
(hazard ratio, 0.91 [95% confidence interval, 0.74-1.13] P = .40; FIGURE 2).
Analysis of all-cause mortality at 31 days
and cardiovascular mortality at 180 days
also showed no difference between the
treatment groups (TABLE 2).
Plasma BNP levels decreased more in
the levosimendan group than in the
dobutamine group at 24 hours and at
3 and 5 days (all P⬍.001) (FIGURE 3).
Other secondary variables were similar between the treatment groups
(Table 2).
Subgroup analyses were performed
to assess the influence of prespecified
baseline characteristics on the difference in survival between patients in the
levosimendan and dobutamine groups
(TABLE 3 and TABLE 4). Most of the prespecified subgroup analyses showed no
interactions. However, a prior history
of heart failure at baseline did influence the between-group difference at
31 days (treatment ⫻ prior heart failure interaction, P= .05) but not at 180
days. At 31 days, in the 88% of patients with a prior history of heart failure, there was a trend for lower risk of
death in the levosimendan group compared with the dobutamine group.
However, in the subgroup of patients
without a prior history of heart failure
(12%), there was a numerical increase
in the levosimendan group.
Safety and Tolerability
Systolic and diastolic blood pressure initially declined more in the levosimendan group than in the dobutamine
group. Following cessation of the study
drug infusions, these differences subsided (FIGURE 4). Heart rate increased
more in the levosimendan group than
in the dobutamine group (Figure 4) and
remained elevated through 5 days.
Compared with dobutamine-treated
patients, levosimendan-treated patients were less likely to experience cardiac failure (P=.02) and more likely to
experience atrial fibrillation (P=.05), hy-
pokalemia (P = .02), and headache
(P=.01) during the initial 31 days following study drug administration
(TABLE 5). The treatment groups were
similar with respect to frequency of hypotension, renal insufficiency, ventricular arrhythmias, or history of torsade de
pointes. The QTc interval did not increase with levosimendan and did not
differ between the 2 groups.
COMMENT
Patients hospitalized for ADHF carry a
high risk of death and rehospitalization in the months following admission.14,15 Available evidence suggests
that the short-term risk may be influenced by treatment16 because several
therapeutic agents including dobutamine, milrinone, and nesiritide have
been associated with an early increase
Table 3. Influence of Prespecified Baseline Characteristics on the Difference in Survival at
31 Days*
Sex
Female
Male
Age, y
⬍65
ⱖ65
History of CHF
Yes
No
Prior use of ␤-blocker
Yes
No
Prior use of ACE
inhibitor or ARB
Yes
No
AMI as primary cause
of hospitalization
Yes
No
Serum creatinine level,
mg/dL (µmol/L)
ⱕ2.5 (ⱕ221)
⬎2.5 (⬎221)
Oliguria
Yes
No
Dyspnea at rest
Yes
No
Mechanical ventilation
for heart failure
Yes
No
Heart rate, beats/min
⬍83
ⱖ83
Systolic blood
pressure, mm Hg
⬍100
ⱖ100
Total
No. of
Patients
Levosimendan
Dobutamine
371
956
20/171 (12)
59/493 (12)
30/200 (15)
61/463 (13)
0.77 (0.43-1.35)
0.89 (0.62-1.28)
.65
501
826
20/237 (8)
59/427 (14)
22/264 (8)
69/399 (17)
1.01 (0.55-1.84)
0.77 (0.55-1.10)
.47
1171
156
59/586 (10)
20/78 (26)
78/585 (13)
13/78 (17)
0.73 (0.52-1.03)
1.61 (0.80-3.25)
.05
669
658
24/336 (7)
55/328 (17)
31/333 (9)
60/330 (18)
0.75 (0.44-1.28)
0.91 (0.63-1.32)
.55
914
413
41/463 (9)
38/201 (19)
38/451 (8)
53/212 (25)
1.05 (0.67-1.63)
0.72 (0.47-1.09)
.22
178
1149
23/83 (28)
56/581 (10)
30/95 (32)
61/568 (11)
0.83 (0.48-1.43)
0.89 (0.62-1.28)
.82
1237
87
63/620 (10)
16/44 (36)
75/617 (12)
16/43 (37)
0.82 (0.59-1.15)
0.97 (0.48-1.95)
.68
101
1226
13/49 (27)
66/615 (11)
19/52 (37)
72/611 (12)
0.67 (0.33-1.38)
0.90 (0.64-1.26)
.44
1184
133
67/595 (11)
11/64 (17)
76/589 (13)
13/69 (19)
0.86 (0.62-1.20)
0.88 (0.39-1.97)
.96
24
1302
3/12 (25)
75/651 (12)
5/12 (42)
86/651 (13)
0.52 (0.12-2.20)
0.86 (0.63-1.17)
.49
705
622
25/339 (7)
54/325 (17)
35/366 (10)
56/297 (19)
0.75 (0.45-1.26)
0.87 (0.59-1.26)
.66
271
1051
23/135 (17)
55/527 (10)
32/136 (24)
58/524 (11)
0.69 (0.40-1.19)
0.93 (0.64-1.35)
.37
Mortality Rate, No./Total (%)
HR (95% CI)
P Value for
Interaction
Abbreviations: ACE, angiotensin-converting enzyme; AMI, acute myocardial infarction; ARB, angiotensin II receptor blocker;
CHF, congestive heart failure; CI, confidence interval; HR, hazard ratio.
*The Cox model was used to examine potential treatment ⫻ subgroup interactions using treatment ⫻ subgroup interaction as covariates.
©2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, May 2, 2007—Vol 297, No. 17
Downloaded from www.jama.com at Medical Library of the PLA, on August 19, 2007
1887
LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE
Table 4. Influence of Prespecified Baseline Characteristics on Survival at 180 Days*
Total
No. of
Patients
Levosimendan
Dobutamine
HR (95%CI)
371
956
45/171 (26)
128/493 (26)
58/200 (29)
127/463 (27)
0.89 (0.60-1.32)
0.93 (0.73-1.19)
.86
501
826
54/237 (23)
119/427 (28)
56/264 (21)
129/399 (32)
1.08 (0.74-1.57)
0.83 (0.65-1.06)
.25
1171
156
148/586 (25)
25/78 (32)
165/585 (28)
20/78 (26)
0.87 (0.70-1.09)
1.31 (0.73-2.37)
.19
669
658
65/336 (19)
108/328 (33)
72/333 (22)
113/330 (34)
0.87 (0.62-1.22)
0.95 (0.73-1.24)
.69
914
413
104/463 (23)
69/201 (34)
98/451 (22)
87/212 (41)
1.04 (0.79-1.38)
0.77 (0.56-1.06)
.15
178
1149
27/83 (33)
146/581 (25)
40/95 (42)
145/568 (26)
0.72 (0.44-1.17)
0.98 (0.78-1.23)
.23
1237
87
149/620 (24)
24/44 (55)
164/617 (27)
21/43 (49)
0.88 (0.71-1.10)
1.10 (0.61-1.99)
.48
101
1226
20/49 (41)
153/615 (25)
27/52 (52)
158/611 (26)
0.69 (0.39-1.24)
0.95 (0.76-1.19)
.26
1184
133
151/595 (25)
21/64 (33)
161/589 (27)
22/69 (32)
0.92 (0.73-1.14)
0.99 (0.54-1.80)
.80
24
1302
6/12 (50)
166/651 (26)
5/12 (42)
180/651 (28)
1.05 (0.32-3.49)
0.90 (0.73-1.12)
.75
705
622
78/339 (23)
95/325 (29)
88/366 (24)
97/297 (33)
0.93 (0.69-1.26)
0.88 (0.66-1.17)
.80
271
1051
53/135 (39)
129/527 (23)
62/136 (46)
121/524 (23)
0.80 (0.55-1.15)
0.97 (0.76-1.25)
.39
Sex
Female
Male
Age, y
⬍65
ⱖ65
History of CHF
Yes
No
Prior use of ␤-blocker
Yes
No
Prior use of ACE
inhibitor or ARB
Yes
No
AMI as primary cause
of hospitalization
Yes
No
Serum creatinine level,
mg/dL (µmol/L)
ⱕ2.5 (ⱕ221)
⬎2.5 (⬎221)
Oliguria
Yes
No
Dyspnea at rest
Yes
No
Mechanical ventilation
for heart failure
Yes
No
Heart rate, beats/min
⬍83
ⱖ83
Systolic blood
pressure, mm Hg
⬍100
ⱖ100
Mortality Rate, No./Total (%)
P Value for
Interaction
Abbreviations: ACE, angiotensin-converting enzyme; AMI, acute myocardial infarction; ARB, angiotensin II receptor blocker;
CHF, congestive heart failure; CI, confidence interval; HR, hazard ratio.
*The Cox model was used to examine potential treatment ⫻ subgroup interactions using treatment ⫻ subgroup interaction as covariates.
in the risk of death.1,17,18 In this study,
we compared levosimendan, which sensitizes the cardiac myofilament response to calcium and facilitates the opening of adenosine triphosphate–
dependent potassium channels with
minimal effect on intracellular cyclic
adenosine monophosphate, to dobutamine, the most widely used therapy for
ADHF, which predominately acts by increasing intracellular cyclic adenosine
monophosphate. In the LIDO trial,12
those assigned to levosimendan had a
lower risk of death than those assigned to dobutamine but this benefit
was not the primary end point of the
study.
The SURVIVE study is the first prospective, randomized trial to monitor
long-term survival in patients with
ADHF. The results revealed no significant difference between levosimendan and dobutamine in all-cause mortality at 31 and 180 days after study
drug infusion.
The SURVIVE study demonstrated
that levosimendan-treated patients had
marked decreases in BNP level compared with dobutamine-treated patients through 5 days. The contrast in
the effects of levosimendan over dobutamine is congruent with the pharmacokinetics of both drugs; the active metabolite of levosimendan peaks
approximately 3 days after the start of
the infusion and has a half-life of 80
hours.19 In contrast, dobutamine has a
shorter half-life and no known active
metabolite. Therefore, it is noteworthy that in the SURVIVE trial numerical differences in survival between the
Figure 4. Mean Change From Baseline in Systolic Blood Pressure, Diastolic Blood Pressure, and Heart Rate Through 5 Days by Treatment Group
Systolic Blood Pressure
Diastolic Blood Pressure
Dobutamine
–2
–3
Levosimendan
–4
–5
–6
8
–1
Dobutamine
–2
–3
Levosimendan
–4
–5
–6
0 6
24
48
72
96
120
Study Assessment, h
Mean Change From
Baseline, Beats/min
0
–1
Mean Change From
Baseline, mm Hg
Mean Change From
Baseline, mm Hg
Heart Rate
0
1
Levosimendan
6
4
2
0
–2
–4
Dobutamine
–6
0 6
24
48
72
96
120
0 6
24
Study Assessment, h
48
72
96
120
Study Assessment, h
Error bars indicate SEs.
1888 JAMA, May 2, 2007—Vol 297, No. 17 (Reprinted)
©2007 American Medical Association. All rights reserved.
Downloaded from www.jama.com at Medical Library of the PLA, on August 19, 2007
LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE
2 drugs were seen early in the trial immediately following the cessation of
treatment (ie, hazard ratio, 0.72 [95%
confidence interval, 0.44-1.16] at 5 days
post hoc analysis) but these hazard ratio differences dissipated in the absence of continued therapy during longterm follow-up.
A second explanation for the lack of
mortality difference between the treatment groups during long-term therapy
is that levosimendan and dobutamine
may differ in their survival effects only
in a subgroup of ADHF patients. In
SURVIVE, randomization was stratified by previous heart failure based on
earlier evidence that it might influence ADHF mortality20 and treatment
differences. Therefore, it is noteworthy that a history of heart failure
influenced the treatment differences we
observed. Specifically, treatment differences in favor of levosimendan at 31
days were more apparent in patients
with a prior history of heart failure than
in those with recent-onset heart failure, possibly because of the greater use
of ␤-blockers in patients with chronic
heart failure. ␤-Receptor antagonists
may interfere with the hemodynamic
benefits of dobutamine21,22 or potentiate the circulatory actions of levosimendan12,23 or both.
A third explanation may be that a different dobutamine dosing strategy in the
SURVIVE study prohibited the replication of the 180-day mortality in the LIDO
study,12 a hemodynamic study in which
all patients had a pulmonary artery catheter inserted. In SURVIVE, the tailored
approach was different from the dobutamine dosing regimen used in the LIDO
study in which patients in the dobutamine group initially received 5 µg/kg per
minute and were up-titrated to 10 µg/kg
per minute if hemodynamic goals were
not achieved. In the SURVIVE trial, the
dobutamine dose could have been increased up to 40 µg/kg per minute to
achieve clinical goals, however it was administered at a relatively low dose of 6
µg/kg per minute and for an average of
39 hours. The dobutamine dosing regimen was determined by the treating physician in a blinded fashion and accord-
ing to the patient’s needs. Additionally,
the dobutamine infusion was discontinued after 24 hours in the LIDO study.
The individualized dosing strategy
adopted for dobutamine in the SURVIVE
trial may have produced the 180-day
mortality of 28% compared with 38% in
the LIDO study. By contrast, levosimendan was given in a fixed manner in both
the SURVIVE and LIDO studies with the
Table 5. Treatment-Emergent Adverse Events*
No. (%) of Patients
Levosimedan
(n = 660)
518 (78.5)
Dobutamine
(n = 660)
502 (76.1)
195 (29.5)
102 (15.5)
217 (32.9)
92 (13.9)
.21
.48
Cardiac failure§
Hypokalemia
Atrial fibrillation
Headache
81 (12.3)
62 (9.4)
60 (9.1)
55 (8.3)
112 (17.0)
39 (5.9)
40 (6.1)
31 (4.7)
.02
.02
.05
.01
Ventricular tachycardia
Nausea
Ventricular extrasystoles
Insomnia
Tachycardia
52 (7.9)
45 (6.8)
40 (6.1)
37 (5.6)
33 (5.0)
48 (7.3)
49 (7.4)
24 (3.6)
29 (4.4)
33 (5.0)
.76
.75
.05
.38
⬎.99
Chest pain
Diarrhea
Pneumonia
Congestive cardiac failure
Constipation
Renal failure
Vomiting
Pyrexia
Urinary tract infection
Cardiac arrest
Anxiety
Pulmonary edema
Dizziness
Cough
Pain in extremity
Pruritus
Cardiogenic shock
Ventricular fibrillation
32 (4.8)
30 (4.5)
30 (4.5)
26 (3.9)
26 (3.9)
24 (3.6)
22 (3.3)
22 (3.3)
21 (3.2)
20 (3.0)
20 (3.0)
20 (3.0)
19 (2.9)
19 (2.9)
18 (2.7)
16 (2.4)
15 (2.3)
15 (2.3)
47 (7.1)
21 (3.2)
24 (3.6)
22 (3.3)
28 (4.2)
22 (3.3)
24 (3.6)
19 (2.9)
30 (4.5)
26 (3.9)
19 (2.9)
18 (2.7)
16 (2.4)
21 (3.2)
10 (1.5)
7 (1.1)
23 (3.5)
19 (2.9)
.10
.25
.49
.66
.89
.88
.88
.75
.25
.45
⬎.99
.87
.73
.87
.18
.09
.25
.60
Any adverse event
Any serious adverse event‡
Hypotension
P
Value†
.32
Anemia
15 (2.3)
17 (2.6)
.86
Hyperkalemia
Epistaxis
Back pain
Muscle spasms
15 (2.3)
14 (2.1)
13 (2.0)
12 (1.8)
16 (2.4)
7 (1.1)
18 (2.7)
13 (2.0)
⬎.99
.19
.47
⬎.99
Angina pectoris
Dyspnea
12 (1.8)
9 (1.4)
18 (2.7)
17 (2.6)
.36
.16
8 (1.2)
9 (1.4)
7 (1.1)
7 (1.1)
17 (2.6)
15 (2.3)
14 (2.1)
0
.10
.30
.19
.02
Bradycardia
Hypertension
Cataract
Agitation
*Safety population includes any patient who received study drug.
†Calculated using the Fisher exact test.
‡A serious adverse event was defined as any event in a study patient that was fatal, life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or relevant disability or incapacity, was a congenital anomaly/
birth defect, or any other medically significant event (eg, an intervention to prevent one of the listed outcomes).
§Term based on investigator reporting and may or may not represent similar type of event as congestive cardiac failure (below).
©2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, May 2, 2007—Vol 297, No. 17
Downloaded from www.jama.com at Medical Library of the PLA, on August 19, 2007
1889
LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE
same 180-day all-cause mortality rate of
26%. Accordingly, future trials should
consider allowing the dose of levosimendan to also be individualized.
Compared with dobutamine-treated
patients, levosimendan-treated patients were more likely to experience an
initial decrease in systolic and diastolic
blood pressure (Figure 4). The latter,
likely related to the mode of administration of levosimendan and especially
to the bolus dose, might be responsible
for the occurrence of atrial fibrillation
and possibly to other detrimental effects such as death. Accordingly, future trials should investigate the optimal mode of administration of
levosimendan. Hypokalemia was consistently observed in SURVIVE as in
other trials.7,12 Mechanism of hypokalemia remains to be elucidated.
In conclusion, the SURVIVE trial
demonstrated no survival difference between levosimendan and dobutamine
during long-term follow-up despite evidence for an early reduction of plasma
BNP level for levosimendan. These findings may be related to the short duration of treatment in the trial, a selective effect of levosimendan in specific
subgroups, or the lack of a true difference between the 2 drugs. Further studies are needed to distinguish between
these possibilities.
Author Contributions: Drs Mebazaa and Nieminen had
full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Mebazaa, Nieminen, Packer,
Cohen-Solal, Kleber, Pocock, Põder, Kivikko.
Acquisition of data: Nieminen, Padley, Põder, Kivikko.
Analysis and interpretation of data: Mebazaa,
Nieminen, Packer, Cohen-Solal, Kleber, Pocock,
Thakkar, Padley, Põder.
Drafting of the manuscript: Mebazaa, Nieminen,
Packer, Cohen-Solal, Kleber, Pocock, Thakkar, Padley.
Critical revision of the manuscript for important intellectual content: Mebazaa, Nieminen, Packer,
Cohen-Solal, Kleber, Pocock, Thakkar, Padley, Põder,
Kivikko.
Statistical analysis: Pocock, Padley.
Obtained funding: Padley, Põder.
Administrative, technical, or material support: Thakkar,
Padley, Põder, Kivikko.
Study supervision: Mebazaa, Nieminen, Packer,
Cohen-Solal, Kleber, Thakkar, Padley.
Financial Disclosures: Dr Mebazaa reported being a
consultant for Abbott, Orion Pharma, Protein Design
Biopharma, and Sigma-Tau and receiving honoraria
from Abbott, Guidant, and Edwards Life Sciences. Dr
Nieminen reported being a consultant for Abbott, Orion
Pharma, Scios, Medtronic, and Pfizer. Dr CohenSolal reported being a consultant for and receiving
honoraria from Abbott, Orion Pharma, Protein Design Biopharma, AstraZeneca, Amgen, Takeda, and
Menarini. Dr Kleber reported receiving research grants
from Orion Pharma and being a consultant for Abbott and Orion Pharma. Dr Pocock reported being a
consultant for Abbott, Orion Pharma, and Scios. Dr
Packer reported being a consultant for Abbott and
Orion Pharma. Drs Thakkar and Padley are Abbott employees. Drs Põder and Kivikko are Orion Pharma employees.
Funding/Support: Abbott and Orion Pharma funded
the SURVIVE trial and data analysis activities.
Role of the Sponsor: Analyses of study results were
performed, with supervision from the sponsor, by ICON
Clinical Research (Dublin, Ireland, and North Wales,
Pa). The sponsor was involved in the management,
analysis, and interpretation of the data. Abbott and
Orion Pharma reviewed the manuscript prior to submission.
Independent Statistical Review: Raphaël Porcher, PhD
(Department of Biostatistics, Université Paris Diderot
and University Hospital Saint-Louis, Paris, France), received full access to the study protocol, amendments, statistical analysis plan, and raw database. In
his opinion, the statistical analysis plan is appropriate
to the study as is the way that the results are presented in the manuscript. From the raw database, Dr
Porcher recomputed the time to death during the 180
days following the start of the study drug (primary end
point) of all 1327 patients randomized in the study
and checked the ones used by Abbott (Abbott Park,
Ill) for analysis. Dr Porcher then performed the main
analysis on an intent-to-treat basis as well as by subgroup analyses for the presence of previous chronic
heart failure, which were prespecified in the statistical analysis plan. The results of these analyses are in
complete agreement with that reported in this article. Dr Porcher additionally performed several sensitivity analyses specified in the statistical analysis plan
or potentially relevant, which confirmed the results.
Compensation for Dr Porcher’s work was paid to the
Université Paris Diderot by Abbott.
Steering Committee: Alexandre Mebazaa (chair), Department of Anesthesiology and Critical Care Medicine, Université Paris Diderot and Hospital Lariboisière, Paris, France; Markku S. Nieminen, Division
of Cardiology, Helsinki University Central Hospital, Helsinki, Finland; Milton Packer, Department of Clinical
Sciences, University of Texas Southwestern Medical
School, Dallas; Alain Cohen-Solal, Department of Cardiology, Université Paris Diderot and Hospital Lariboisière, Paris, France; Franz X. Kleber, Department
of Internal Medicine, Charité Medical School, Berlin,
Germany; Stuart J. Pocock, Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, England.
Data and Safety Monitoring Board: John Cleland
(chair), Castle Hill Hospital, Cottingham, England; Dan
Langrois, CHU Brabois, Vandoeuvre-les-Nancy, France;
Viatcheslav Mareev, Cardiology Research Center, Moscow, Russia; Richard Kay, PAREXEL International, South
Yorkshire, England.
SURVIVE Trial Investigators: Austria: Alexander Geppert (Wilhelminenspital der Stadt Wien, Wien); Thomas
Martys (Kaiserin-Elisabeth-Spital der Stadt Wien, Wien);
Johannes Mlczoch (Krankenhaus der Stadt Wien Lainz,
Wien); Jörg Slany (Krankenanstalt Rudolfstiftung,
Wien). Finland: Juhani Airaksinen (Turku University
Central Hospital, Turku); Veli-Pekka Harjola (Helsinki University Central Hospital); Heikki Huikuri (University of Oulu, Oulu); Pirjo Mäntylä (Central Hospital of North Karelia, Joensuu); John Melin (Central
Hospital of Central Finland, Jyväskylä); Keijo Peuhkurinen (Kuopio University Hospital, Kuopio). France:
Philippe Asseman (CHU Lille, Lille); Jean-François Aupetit (CH Saint-Joseph et Saint-Luc, Lyon); Michel Barboteu (Centre Médical d’Evecquemont, Meulan); Marc
Benacerraf (Centre Cardiologique du Nord, Saint De-
1890 JAMA, May 2, 2007—Vol 297, No. 17 (Reprinted)
nis); Jean-Marc Boulenc (Clinique Saint Joseph, Colmar); Alain Cariou (Hôpital Cochin Port Royal, Paris);
Alain Cohen-Solal (Hôpital Beaujon, Clichy); Pierre
Coste (Hôpital Cardiologique Haut Leveque, Pessac); Jean Luc Dubois-Rande (Hôpital Henri Mondor,
Creteil); Olivier Dubourg (Hôpital Ambroise Paré, Boulogne Billancourt); Marc Feissel (Centre Hospitalier Belfort/Montbeliard, Belfort); François Funck (Centre Hospitalier René Dubos, Pontoise); Michel Galinier (Hôpital
Rangueil, Toulouse); Pierre Gibelin (Hôpital Pasteur,
Nice); Yannick Gottwalles (Clinique Saint Joseph, Colmar); Louis Guize (Hôpital Européen Georges Pompidou, Paris); Gilbert Habib (CHU de la Timone, Marseille); Ivan Laurent (Institut Hospitalier Jacques Cartier,
Massy); Hervé Le Marec (Hôpital Nord Laennec,
Nantes-Saint-Herblain); Bruno Levy (Hôpital Central
Nancy, Nancy); Alexandre Mebazaa (Hôpital Lariboisière, Paris); Gilles Montalescot (Hôpital PitiéSalpêtrière, Paris); Gérald Roul (Hôpital de Hautepierre, Strasbourg); Rémi Sabatier (CHU Côte de Nacre,
Caen); Pierre Squara (Clinique Ambroise Paré, Neuilly sur Seine); Gabriel Steg (Hôpital Bichat-Claude Bernard, Paris); Jean-Louis Teboul (CHU Bicêtre, Le Kremlin-Bicetre); Paul Touboul (Hôpital Cardiologique Louis
Pradel, Bron); Philippe Vignon (Hôpital Dupuytren,
Limoges); Simon Weber (Hôpital Cochin Port Royal,
Paris); Faies Zannad (CHU de Nancy, Vandoeuvre
les Nancy); Robin Zelinsky (Clinique Saint-Sauveur,
Mulhouse). Germany: Gerhard Bauriedel (Universitätsklinikum Bonn, Bonn); Michael Böhm (Universitätskliniken des Saarlandes, Homburg/Saar); Michael
Buerke (Klinikum der Medizinischen Fakultät der Martin-Luther-Universität Halle-Wittenberg, Halle [Saale]);
Angelika Costard-Jäckle (AK St Georg, Hamburg); Aly
El-Banayosy (Herz-u Diabeteszentrum NordrheinWestfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen); Gerd Hasenfub (Universitätsklinikum Göttingen, Göttingen); Franz Xaver Kleber
(Unfallkrankenhaus Berlin, Berlin); Veselin Mitrovic
(Kerckhoff Klinik GmbH, Bad Nauheim); Thomas Münzel (Universitätsklinikum Hamburg-Eppendorf, Hamburg); Klaus Pethig (Klinik für Innere Medizin III der
Friedrich Schiller Universität Jena, Jena); Andrew Remppis (Medizinische Universitätsklinik und Poliklinik,
Heidelberg); Peter Schuster (St Marien Krankenhaus
Siegen, Siegen); Robert Schwinger (Universität zu Köln,
Köln [Lindenthal]); Ruth Strasser (Medizinische Klinik
II/Kardiologie, Dresden). Israel: Jonathan Balkin (Shaare
Zedek Medical Center, Jerusalem); Tuvia Ben Gal (Rabin
Medical Center, Beilinson Campus, Petah Tikva); Daniel
David (Meir Hospital, Sapir Medical Center, Kfar Saba);
Dov Freimark (Sheba Medical Center, Tel Hashomer);
Andre Keren (Bikur Holim Hospital, Jerusalem); Tiberiu
Rosenfeld (Haemek Medical Center, Afula); Yoseph
Rozenman (Wolfson Medical Center, Holon). Latvia:
Galina Dormidontova (Daugavpils Central Regional
Hospital, Daugavpils); Maija Keisa (Valmiera Hospital, Valmiera); Janis Lacis (P. Stradina Clinical University Hospital, Riga); Alfreds Libins (Liepaja Hospital,
Liepaja); Dace Meldere (Riga Clinical Hospital Gailezers,
Riga); Jurijs Verbovenko (Riga First Hospital, Riga). Poland: Jerzy Adamus (Central Military Hospital,
Warszawa); Marek Dabrowski (Szpital Bielanski,
Warszawa); Robert Gil (Department of Invasive Cardiology, Warszawa); Jerzy Korewicki (Institute of Cardiology, Warszawa); Maria Krzeminska-Pakula (Bieganski Hospital, Lodz); Grzegorz Opolski (Medical
University ul Banacha 1a, Warszawa); Wieslawa Piwowarska ( Jagiellonian University School of Medicine, Cracow); Lech Polonski (Silesian Centre of Heart
Diseases, Zabrze). Russia: Igor N. Bokarev (Moscow
Medical Academy, Moscow); Nikolai A. Gratsiansky
(Hospital No. 29, Moscow); Victor A. Lyusov (Russian Medical University, Moscow); Valentin S. Moiseyev (Russian People’s Friendship University, Moscow); Mikhail Y. Ruda (Russian Cardiology Research
Centre, Moscow); Raisa I. Stryuk, Sergey N. Tereschenko, and Vladimir S. Zadionchenko (Moscow
©2007 American Medical Association. All rights reserved.
Downloaded from www.jama.com at Medical Library of the PLA, on August 19, 2007
LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE
State Medico-Stomatological University, Moscow);
Dmitry A. Zateyshchikov (Central Clinical Hospital of
Russian Government Medical Centre, Moscow). United
Kingdom: Sanjay Arya (Royal Albert Edward Infirmary, Wigan); Craig Barr (Russells Hall Hospital, West
Midlands); John Berridge (Leeds General Infirmary,
Leeds); Henry Dargie (Clinical Research Institute,
Glasgow); Gregory Lip (University Department of
Medicine, Birmingham); Bernard Prendergast (Wythenshawe Hospital, Manchester); Andrew Rhodes (St
George’s Hospital, London); Roxy Senior (Northwick
Park Hospital, Harrow); Mervyn Singer (Middlesex Hospital, London).
Acknowledgment: We are grateful to Thea Nieminen,
RN, Toni Sarapohja, MSc (Orion Pharma, Espoo, Finland), and Nancy Chou, MS, RD, Leticia DelgadoHerrera RPh, MS, Stefan Hergenroeder, PhD, Bidan
Huang, PhD, Brigitte Kalsch, MD, Udo Legler, MD,
Michael Marshall, PharmD, and Greg Schulz (Abbott, Abbott Park, Ill) for their role in coordinating the
efforts of ICON Clinical Research, the 2 sponsors, and
the steering committee. All persons acknowledged did
not receive compensation for their involvement with
this work.
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