Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure

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n e w e ng l a n d j o u r na l
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Original Article
Aliskiren, Enalapril, or Aliskiren and

Enalapril in Heart Failure
JohnJ.V. McMurray, M.D., Henry Krum, M.B., B.S., Ph.D.,* WilliamT. Abraham, M.D.,
Kenneth Dickstein, M.D., Ph.D., LarsV. Kber, M.D., D.M.Sc.,
AkshayS. Desai, M.D., M.P.H., ScottD. Solomon, M.D., Nicola Greenlaw, M.Sc.,
M.Atif Ali, B.A., Yanntong Chiang, Ph.D., Qing Shao, Ph.D.,
Georgia Tarnesby, M.B., B.Chir., and BarryM. Massie, M.D.,
for the ATMOSPHERE Committees Investigators
A BS T R AC T
BACKGROUND
Among patients with chronic heart failure, angiotensin-convertingenzyme (ACE)

inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in
such patients is unknown. We compared the ACE inhibitor enalapril with the renin
inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure
and a reduced ejection fraction.
METHODS
After a single-blind run-in period, we assigned patients, in a double-blind fashion,

to one of three groups: 2336 patients were assigned to receive enalapril at a dose
of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once
daily, and 2340 to receive both treatments (combination therapy). The primary
composite outcome was death from cardiovascular causes or hospitalization for
heart failure.
RESULTS
After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard
ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as
well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009)
and an elevated potassium level (17.1% vs. 12.5%, P<0.001).
CONCLUSIONS
In patients with chronic heart failure, the addition of aliskiren to enalapril led to
more adverse events without an increase in benefit. Noninferiority was not shown
for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE
ClinicalTrials.gov number, NCT00853658.)
From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.)

and the Robertson Centre for Biostatistics (N.G.), University of Glasgow,
Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in
Therapeutics, School of Public Health
and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.);
the Division of Cardiovascular Medicine,
Davis Heart and Lung Research Institute,
Ohio State University, Columbus (W.T.A.);
Stavanger University Hospital, Stavanger,
and the Institute of Internal Medicine,
University of Bergen, Bergen both in
Norway (K.D.); Rigshospitalet Copenhagen
University Hospital, Copenhagen (L.V.K.);
the Cardiovascular Division, Brigham and
Womens Hospital, Boston (A.S.D., S.D.S.);
Novartis Pharma, Basel, Switzerland
(M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San
Francisco (B.M.M.). Address reprint requests to Dr. McMurray at the British
Heart Foundation Cardiovascular Research
Centre, University of Glasgow, Glasgow
G12 8TA, United Kingdom, or at john
[email protected].
*Deceased.
A list of participating centers and investigators in the Aliskiren Trial to Minimize Outcomes in Patients with Heart
Failure (ATMOSPHERE) is provided in
the Supplementary Appendix, available
at NEJM.org.
This article was published on April 4,
2016, at NEJM.org.
DOI: 10.1056/NEJMoa1514859
Copyright 2016 Massachusetts Medical Society.
n engl j mednejm.org
The New England Journal of Medicine

Downloaded from nejm.org by R LOPEZ MATA on April 5, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
The
ngiotensin-convertingenzyme
(ACE) inhibitors are effective in lowering
the risks of death and hospitalization
among patients with chronic heart failure and
reduced ejection fraction.1,2 As a consequence,
there has been interest in other approaches to
interruption of the reninangiotensin system in
patients with heart failure. Angiotensin-receptor
blockers (ARBs) were the first alternative tested,
and in one placebo-controlled trial, candesartan
was associated with lower risks of death from
cardiovascular causes and hospitalization for
heart failure among patients who could not take
ACE inhibitors.3 However, in a head-to-head comparison, losartan was not as effective as captopril.4
The combination of an ARB and an ACE inhibitor has also been examined in two trials involving patients with heart failure.5,6 In both trials,
the addition of an ARB to standard therapy with
an ACE inhibitor was associated with a lower
risk of hospitalization for heart failure than was
standard therapy alone and, in one trial, with a
lower risk of death from cardiovascular causes.
Neither trial, however, mandated an evidencebased dose of ACE inhibitor, and subsequent trials
that did so showed that the addition of an ARB
was ineffective in patients with myocardial infarction and in other patients at high cardiovascular risk.7,8
Renin inhibition offers another approach to
interruption of the reninangiotensin system.9-11
We tested whether combining the renin inhibitor
aliskiren with the ACE inhibitor enalapril was
superior to enalapril alone and whether aliskiren
was at least noninferior to enalapril in patients
with heart failure.12,13
Me thods
Trial Oversight
The Aliskiren Trial to Minimize Outcomes in

Patients with Heart Failure (ATMOSPHERE) was
a randomized trial comparing enalapril alone
with aliskiren alone and with the combination
of aliskiren and enalapril in patients with heart
failure. The design of the trial and the characteristics of the patients at baseline have been published previously.12,13 The executive committee
(see the Supplementary Appendix, available with
the full text of this article at NEJM.org) designed
and oversaw the conduct of the trial in collaboration with the sponsor (Novartis). The trial
protocol, which is available at NEJM.org, was
2
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approved by the ethics committee at each center.

Data were collected and analyzed by the sponsor
according to a prespecified statistical analysis
plan; the analyses were replicated by an independent statistician, who is one of the authors. The
initial draft of the manuscript was prepared by
the first author and edited by all the authors,
who had unrestricted access to the data and agreed
to submit the manuscript for publication. The authors assume responsibility for the accuracy and
completeness of the data and analyses as well as
for the fidelity of this report to the trial protocol.
Patients
Eligible patients had chronic heart failure with

New York Heart Association (NYHA) class II to
IV symptoms and an ejection fraction of 35% or
less. Participants were also required to have a
plasma B-type natriuretic peptide (BNP) concentration of 150 pg or more per milliliter (or an
N-terminal pro-BNP [NT-proBNP] concentration
of 600 pg per milliliter) or, if they had been
hospitalized for heart failure within the previous
12 months, a BNP concentration of 100 pg or
more per milliliter (or an NT-proBNP concentration of 400 pg per milliliter). Participants must
have been receiving stable doses of an ACE inhibitor (equivalent to at least 10 mg of enalapril daily)
and of a beta-blocker at the time of enrollment.
Exclusion criteria included symptomatic hypotension, a systolic blood pressure of less than
95 mm Hg at screening (or <90 mm Hg at randomization), an estimated glomerular filtration rate
(GFR) of less than 40 ml per minute per 1.73 m2
of body-surface area at screening (or <35 ml per
minute per 1.73 m2 at randomization or a decline of >25% in the estimated GFR between
screening and randomization), a serum potassium concentration of 5.0 mmol or more per liter
at screening (or 5.2 mmol per liter at randomization), and a history of inability to take ACE
inhibitors. Detailed inclusion and exclusion criteria are provided in the Supplementary Appendix. All the participants provided written informed consent.
Procedures
The trial included a two-part run-in phase. After

switching from their existing ACE inhibitor, eligible patients entered the first part of the run-in
phase, during which they received 1 to 4 weeks
of enalapril at a dose of 5 mg twice daily, in a
single-blind fashion, followed (if the level of ad-

Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure
verse events was not unacceptable) by 2 to 4 weeks

of enalapril at a dose of 10 mg twice daily; patients who had been taking a dose of ACE inhibitor that was equivalent to 20 mg of enalapril
daily before the trial could start at the second
step directly. At the end of this period, patients
were stratified according to the dose of enalapril
that could be taken without unacceptable adverse
events: 5 mg twice daily (low-dose stratum) or
10 mg twice daily (high-dose stratum). Patients
then entered the second part of the run-in
phase, during which they received aliskiren at a
dose of 150 mg once daily, in a single-blind fashion, in addition to enalapril.
Patients who could take both treatments were
randomly assigned, in a 1:1:1 ratio, to doubleblind, double-dummy treatment in one of three
groups with the use of a voice-based computerized randomization system involving concealed
trial-group assignments. Patients were assigned
to the combination of enalapril at a dose of 5 or
10 mg twice daily and aliskiren at a dose of 150 mg
once daily, aliskiren at a dose of 150 mg once
daily, or enalapril at a dose of 5 or 10 mg twice
daily. Two weeks after randomization, the dose
of aliskiren was increased to 300 mg once daily
in the combination-therapy group and the aliskiren group, with sham adjustment in the enalapril
group. Patients were evaluated every 2 to 8 weeks
during the first 4 months and every 4 months
thereafter. The dose could be decreased in patients who could not take the target doses.
Outcomes
The primary outcome was a composite of death

from cardiovascular causes or a first hospitalization for heart failure. The secondary outcomes
were the change from baseline to 12 months in
the Kansas City Cardiomyopathy Questionnaire
(KCCQ) clinical summary score and the change
in the NT-proBNP concentration from baseline
to 4 months (this outcome was removed after the
protocol was amended, as explained below).12-14
Additional prespecified exploratory outcomes
are listed in Table S1 in the Supplementary Appendix. A clinical-event committee adjudicated
deaths and major cardiovascular outcomes in a
blinded fashion, using prespecified criteria (see
the Supplementary Appendix).
Statistical Analysis
The original coprimary objectives were, first, to

test whether the combination of aliskiren and
enalapril was superior to enalapril for the primary outcome and, second, to test whether aliskiren alone was superior, or at least noninferior, to
enalapril with respect to the same outcome. On
the basis of our initial power calculation (see the
Supplementary Appendix), we estimated that 7041
patients would need to undergo randomization
and that 2318 primary-outcome events would
need to occur.
While the trial was ongoing, premature termination of the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Disease Endpoints
(ALTITUDE) because of futility and safety concerns, and the subsequent finding in the Aliskiren Trial on Acute Heart Failure Outcomes
(ASTRONAUT) of worse outcomes in patients
with diabetes treated with aliskiren than in those
who received placebo, led the Clinical Trial Facilitation Group of the Heads of Medicines Agencies in Europe to mandate that persons with diabetes at baseline and those in whom diabetes
developed during the present trial discontinue
the treatment and be switched to conventional
therapy and that no further patients with diabetes be enrolled. This decision was executed
worldwide in a protocol amendment issued in
April 2013.13,15,16
This decision led to amendment of the statistical analysis plan. In patients with diabetes, follow-up for trial outcomes was censored on the
date of the enactment of the protocol amendment
(or on the date of other country-specific requests
mandating the stopping of the trial treatment).
Comparison of the combination therapy with
enalapril in patients without diabetes became an
additional superiority hypothesis. The change in
the NT-proBNP concentration was removed as a
secondary outcome.13 The power for the primary
analyses was preserved, as described in the Supplementary Appendix.
Analyses included all the patients who underwent randomization validly, according to the
intention-to-treat principle. Time-to-event data
were evaluated with the use of Cox proportionalhazards models, as described in the statistical
analysis plan (see the protocol). Consistency of
treatment effects was assessed among 25 prespecified subgroups by inclusion of an interaction term for each subgroup. The change in the
KCCQ score was evaluated with a repeatedmeasures analysis. Adverse events were compared with the use of Fishers exact test; prospectively defined adverse events of interest

The
included hypotension, renal impairment, hyperkalemia, and cough.

All P values are two-sided (except for noninferiority). A gatekeeping procedure that combined
hierarchical and simultaneous testing based on
Bonferroni adjustment was used to ensure control
of the type I error rate for the primary and secondary outcomes (see the Supplementary Appendix). On the basis of this procedure, the prespecified one-sided alpha level for the declaration
of noninferiority (for aliskiren vs. enalapril) was
0.0123.
R e sult s
Patients
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The number of patients who had data censored

because of diabetes was 665 (28.4%) in the combination-therapy group, 627 (26.8%) in the aliskiren group, and 652 (27.9%) in the enalapril
group. An additional 20, 25, and 18 patients in
each group, respectively, had data censored because of other country-specific requests (Fig.1).
In persons without diabetes, the median followup was 46.0 months (interquartile range, 28.0 to
56.1); the median follow-up in patients with diabetes was 24.1 months (interquartile range, 15.1
to 33.2).
Treatment Administration
In persons without diabetes, the trial treatment

was discontinued in 741 of 1675 patients (44.2%)
in the combination-therapy group, in 693 of 1713
(40.5%) in the aliskiren group, and in 706 of
1684 (41.9%) in the enalapril group for reasons
other than death or an administrative reason.
The mean percentage of possible treatment time
that patients took the trial medication was 77%
in the combination-therapy group, 81% in the
aliskiren group, and 80% in the enalapril group.
Among patients with diabetes, 211 of 665
patients (31.7%) in the combination-therapy
group, 175 of 627 (27.9%) in the aliskiren group,
and 209 of 652 (32.1%) in the enalapril group
discontinued treatment for reasons other than
death or an administrative reason. The mean percentage of possible treatment time that patients
took the trial medication was 80%, 84%, and
82%, respectively. (The mean doses of the drugs,
according to status with respect to diabetes, are
presented in Table S4 in the Supplementary Appendix.)
From March 13, 2009, to December 26, 2013, a

total of 8835 patients at 789 centers in 43 countries entered the run-in period (Fig.1). Of these,
1771 patients did not fulfill the criteria for randomization, and 48 underwent randomization
erroneously or were enrolled at sites that were
subsequently closed owing to serious violations
of Good Clinical Practice guidelines; these patients
were prospectively omitted from all analyses. Accordingly, for the intention-to-treat analysis,
2340 patients were randomly assigned to the
combination therapy of enalapril plus aliskiren,
2340 to aliskiren alone, and 2336 to enalapril
alone. The percentage of patients in the highdose stratum for enalapril was 89% in each
treatment group. Overall, the treatment groups
were balanced with respect to the characteristics
at baseline (Table1). Participants with diabetes
at baseline were older and more likely to have
ischemic heart disease than were those without
diabetes. (For further information, see Tables S2
Outcomes
and S3 in the Supplementary Appendix.)
Overall, death from cardiovascular causes or hosFollow-up
pitalization for heart failure (the primary outcome)
Overall, the median follow-up was 36.6 months occurred in 770 patients (32.9%) in the combina(interquartile range 22.4 to 52.2), with no signifi- tion-therapy group (11.7 events per 100 personcant difference among the three groups. The num- years), in 791 patients (33.8%) in the aliskiren
ber of patients who were lost to follow-up for vital group (12.1 events per 100 person-years), and in
status before the completion of the trial (or owing 808 patients (34.6%) in the enalapril group (12.4
to regulatory censoring with regard to patients events per 100 person-years) (Fig.2A and Table2).
with diabetes) was 31 (1.3%) in the combination- The hazard ratio in the combination-therapy
therapy group, 19 (0.8%) in the aliskiren group, group, as compared with the enalapril group,
and 19 (0.8%) in the enalapril group. For patients was 0.93 (95% confidence interval [CI], 0.85 to
who did not have data censored for a regulatory 1.03; P=0.17); the hazard ratio in the aliskiren
reason, follow-up ended on July 31, 2015.
group, as compared with the enalapril group,

8835 Patients entered enalapril run-in phase

(median duration, 28 days; IQR, 1639)
1047 Discontinued run-in phase
370 Had adverse event
20 Had abnormal laboratory or other
test result
290 Withdrew consent
201 Had protocol deviation, had
administrative problem, or were
lost to follow-up
73 Died
93 Had other reasons
7784 Entered enalapril+aliskiren run-in phase

(median duration, 18 days; IQR, 1424)
724 Discontinued run-in phase
428 Had adverse event
47 Had abnormal laboratory or other
test result
92 Withdrew consent
65 Had protocol deviation, had
administrative problem, or were
lost to follow-up
23 Died
69 Had other reasons
7064 Underwent randomization
48 Were excluded
22 Did not undergo valid randomization
26 Were from two trial sites prematurely
closed because of GCP violations
2340 Were assigned to receive

combination therapy

aliskiren

enalapril
685 Had data censored because of

diabetes or other regulatory
reasons
680 Had known vital status
at censoring
5 Had unknown vital status
at censoring
1655 Did not have data censored
1629 Had known final vital status
26 Had unknown final vital status

reasons
at censoring
at censoring

reasons
at censoring
at censoring
Figure 1. Disposition of Patients Who Fulfilled Screening Criteria, Entered the Run-in Periods, and Underwent
Randomization.
The rate of withdrawal because of an adverse event was higher during the first (enalapril only) run-in period than
during the second (enalapril plus aliskiren) run-in period. Four patients underwent randomization directly after the
first run-in period and did not participate in the second run-in period. GCP denotes Good Clinical Practice, and IQR
interquartile range.

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Table 1. Characteristics of the Patients at Baseline, According to Treatment Group.*

Characteristic
Age yr
Female sex no. (%)
Combination Therapy
(N=2340)
Aliskiren
(N=2340)
Enalapril
(N=2336)
63.211.65
63.312.06
63.311.71
494 (21.1)
532 (22.7)
499 (21.4)
1547 (66.1)
1519 (64.9)
1526 (65.3)
Race no. (%)

White
Black
32 (1.4)
37 (1.6)
40 (1.7)
Asian
587 (25.1)
591 (25.3)
586 (25.1)
Other race or missing data
174 (7.4)
193 (8.2)
184 (7.9)
Geographic region no. (%)

North America
60 (2.6)
58 (2.5)
59 (2.5)
Latin America
371 (15.9)
377 (16.1)
371 (15.9)
Western Europe
616 (26.3)
620 (26.5)
615 (26.3)
Central Europe
649 (27.7)
646 (27.6)
649 (27.8)
Asia or Pacific region
644 (27.5)
639 (27.3)
642 (27.5)
Ischemic cardiomyopathy
1335 (57.1)
1295 (55.3)
1300 (55.7)
Nonischemic cardiomyopathy
1005 (42.9)
1045 (44.7)
1036 (44.3)
Left ventricular ejection fraction %
28.55.7
28.45.7
28.35.7
II
1498 (64.0)
1497 (64.0)
1441 (61.7)
III
789 (33.7)
803 (34.3)
849 (36.3)
IV
53 (2.3)
38 (1.6)
46 (2.0)
12419
12418
12318
Cause of heart failure no. (%)
NYHA functional class no. (%)
Physiological measure
Systolic blood pressure mm Hg
Heart rate beats/min
7213
7212
7213
27.35.3
27.45.4
27.35.3
1193 (6402351)
1167 (6272173)
1223 (6342194)
7427
7423
7422
1447 (61.8)
1460 (62.4)
1425 (61.0)
Diabetes
665 (28.4)
627 (26.8)
652 (27.9)
Atrial fibrillation
801 (34.2)
788 (33.7)
801 (34.3)
Body-mass index
Laboratory measure
NT-proBNP pg/ml
Estimated GFR ml/min/1.73 m2
Medical history no. (%)
Hypertension
1408 (60.2)
1382 (59.1)
1398 (59.8)
Myocardial infarction
Hospitalization for heart failure
975 (41.7)
929 (39.7)
943 (40.4)
Stroke
169 (7.2)
165 (7.1)
158 (6.8)
Medication at randomization no. (%)

Digitalis
765 (32.7)
748 (32.0)
729 (31.2)
Diuretic
1869 (79.9)
1852 (79.1)
1877 (80.4)
Beta-adrenergic blocker
2152 (92.0)
2133 (91.2)
2147 (91.9)
856 (36.6)
864 (36.9)
882 (37.8)
Mineralocorticoid antagonist

Table 1. (Continued.)
Combination Therapy
(N=2340)
Aliskiren
(N=2340)
Enalapril
(N=2336)
Defibrillating device
350 (15.0)
362 (15.5)
336 (14.4)
Cardiac-resynchronization therapy
142 (6.1)
120 (5.1)
131 (5.6)
Characteristic
Device for treating heart failure at screening
visit no. (%)
* Plusminus values are means SD. Combination therapy included both aliskiren and enalapril. There were no significant differences among the three groups with respect to any of the characteristics listed. Percentages may not total 100
because of rounding. The body-mass index is the weight in kilograms divided by the square of the height in meters.
GFR denotes glomerular filtration rate.
Race was determined by the investigators.
Data for the New York Heart Association (NYHA) class reflect the status of patients at screening; although all patients
were required to have at least class II symptoms at screening, one patient in the aliskiren group was in NYHA class I
(protocol deviation) and another patient in this group did not have the NYHA class recorded at baseline.
Values for the N-terminal proB-type natriuretic peptide (NT-proBNP) concentration were available for 2120 patients in
the combination-therapy group, for 2097 in the aliskiren group, and for 2134 patients in the enalapril group.
Defibrillating devices included an implantable cardioverterdefibrillator and implantable cardioverterdefibrillator with
cardiac resynchronization.
was 0.99 (95% CI, 0.90 to 1.10; P=0.91 for superiority). Although the noninferiority margin of
1.104 was met with the use of the 95% confidence interval, the one-sided P value of 0.0184
did not fulfill the prespecified requirement of a
P value of 0.0123 or less. A sensitivity analysis
that included only patients who received the assigned trial regimen gave consistent results, as
did an analysis in which data that were collected
after regulatory censoring were included (Tables
S5 and S6 in the Supplementary Appendix).
There were no significant between-group differences in the secondary outcome (change in
the KCCQ clinical summary score at 12 months)
or in selected prespecified exploratory outcomes
(Table2 and Fig.2). The exploratory composite
renal outcome (the composite of death from renal causes, end-stage renal disease, or doubling
of the serum creatinine level) occurred significantly more frequently in the combination-therapy group than in the enalapril group (Table2).
At 4 months, 8 months, and 12 months, the decrease from baseline in the NT-proBNP concentration was greater in the combination-therapy
group than in the enalapril group. (See also Tables S7 and S8 in the Supplementary Appendix.)
In persons without diabetes, the primary outcome occurred in 574 of 1675 patients (34.3%) in
the combination-therapy group (10.6 events per
100 person-years) and in 592 of 1684 patients
(35.2%) in the enalapril group (11.1 events per
100 person-years; hazard ratio, 0.96; 95% CI,
0.85 to 1.07; P=0.46). In persons with diabetes,
the primary outcome occurred in 196 of 665 patients (29.5%) in the combination-therapy group
(16.3 events per 100 person years) and in 216 of
652 patients (33.1%) in the enalapril group (18.8
events per 100 person-years; hazard ratio, 0.86;
95% CI, 0.71 to 1.04; P=0.13; P=0.35 for interaction). The effect of combination therapy as
compared with enalapril was consistent for the
primary outcome across the prespecified subgroups, as was the effect of aliskiren as compared
with enalapril. A similar consistency according to
subgroup was seen for the outcome of death
from any cause. (See also Figs. S1 and S2 in the
Supplementary Appendix.)
Safety
Hypotension, renal dysfunction, and hyperkalemia occurred more commonly with combination
therapy than with enalapril. The rates of these
adverse effects were similar in the aliskiren
group and the enalapril group, except for hypotension, which was more common with enalapril than with aliskiren (Table3). The increase in
the rates of renal dysfunction and hyperkalemia
with combination therapy was greater among
patients who were being treated with an aldosterone antagonist at baseline than among those
who were not (Table S9 in the Supplementary
Appendix). The most frequent adverse events and
serious adverse events are summarized in Tables
S10 and S11 in the Supplementary Appendix.
As compared with the value at randomization,
the mean systolic blood pressure at 4 months

The
Combination
Aliskiren
100
Combination vs. enalapril

Hazard ratio, 0.93 (95% CI, 0.851.03)
P=0.17
Aliskiren vs. enalapril
Hazard ratio, 0.99 (95% CI, 0.901.10)
P=0.91
90
80
70
60
50
40
30
20
10
0
360
m e dic i n e
Enalapril
B Death from Cardiovascular Causes

Cumulative Event Rate (% of patients)
A Primary Composite End Point
of
720
1080
1440
100

Hazard ratio, 0.93 (95% CI, 0.821.05)
P=0.23
Hazard ratio, 1.06 (95% CI, 0.941.19)
P=0.34
90
80
70
60
50
40
30
20
10
0
1800
360
Days since Randomization
720
1080
1440
1800
No. at Risk
No. at Risk
Combination 2340 2137 1959 1809 1562 1307 1085 895 689 456 273
Aliskiren
2340 2127 1934 1761 1510 1288 1064 888 681 474 282
Enalapril
2336 2128 1947 1766 1513 1268 1044 866 679 452 281
Combination 2340 2214 2080 1956 1725 1468 1235 1032 805 548 335
Aliskiren
2340 2214 2073 1918 1690 1454 1211 1015 788 564 338
Enalapril
2336 2222 2093 1950 1711 1454 1208 1010 794 539 336
100
D Death from Any Cause

C First Heart FailureRelated Hospitalization

Hazard ratio, 0.93 (95% CI, 0.821.06)
P=0.29
Hazard ratio, 0.99 (95% CI, 0.871.13)
P=0.91
90
80
70
60
50
40
30
20
10
0
360
720
1080
1440
100

Hazard ratio, 0.91 (95% CI, 0.821.02)
P=0.12
Hazard ratio, 1.04 (95% CI, 0.931.16)
P=0.46
90
80
70
60
50
40
30
20
10
0
1800
360
720
1080
1440
1800
No. at Risk
No. at Risk
Combination 2340 2137 1959 1809 1562 1307 1085 895 689 456 273
Aliskiren
2340 2127 1934 1761 1510 1288 1064 888 681 474 282
Enalapril
2336 2128 1947 1766 1513 1268 1044 866 679 452 281
Combination 2340 2214 2080 1956 1725 1468 1235 1032 805 548 335
Aliskiren
2340 2214 2073 1918 1690 1454 1211 1015 788 564 338
Enalapril
2336 2222 2093 1950 1711 1454 1208 1010 794 539 336
Figure 2. KaplanMeier Estimates of the Cumulative Rate of the Prespecified Primary Composite Outcome, Its Components, and Death
from Any Cause.
Hazard ratios in the time-to-event analyses for the comparison of combination therapy (enalapril plus aliskiren) with enalapril alone and
the comparison of aliskiren alone with enalapril alone are shown for the primary composite outcome of death from cardiovascular
causes or first hospitalization for heart failure (Panel A), for the primary-outcome components (Panels B and C), and for death from any
cause (Panel D). CI denotes confidence interval. The comparison of aliskiren with enalapril for the primary end point was a test for superiority; the test for noninferiority is described in the Results section.
was significantly lower with combination therapy than with enalapril (difference vs. enalapril, 1.84 mm Hg; 95% CI, 2.70 to 0.98;
P<0.001). The difference between the mean
values in the aliskiren group and the enalapril
group was 0.53 mm Hg (95% CI, 0.31 to 1.37;
P=0.22).
8
Discussion
We found that the addition of the renin inhibitor
aliskiren to enalapril did not result in a lower
risk of death from cardiovascular causes or hospitalization due to heart failure, as compared
with enalapril alone, but did cause more hypo-

87 (3.7)
31 (1.3)
595 (25.4)
Fatal or nonfatal stroke
First resuscitated cardiac arrest
Death from any cause
26 (1.1)
654 (27.9)
35 (1.5)
103 (4.4)
84 (3.6)
874 (37.4)
6.030.57
442 (18.9)
562 (24.0)
791 (33.8)
Aliskiren
(N=2340)
18 (0.8)
646 (27.7)
32 (1.4)
93 (4.0)
100 (4.3)
877 (37.5)
5.010.55
452 (19.3)
547 (23.4)
808 (34.6)
Enalapril
(N=2336)
2.17
(1.24 to 3.79)
0.91
(0.82 to 1.02)
0.96
(0.58 to 1.57)
0.93
(0.70 to 1.25)
0.87
(0.66 to 1.16)
0.94
(0.86 to 1.04)
0.03
(1.56 to 1.50)
0.93
(0.82 to 1.06)
0.93
(0.82 to 1.05)
0.93
(0.85 to 1.03)
Hazard Ratio or
Difference
(95% CI)
0.007
0.12
0.86
0.65
0.36
0.23
0.97
0.29
0.23
0.17
P Value
Combination Therapy vs.

Enalapril
1.50
(0.82 to 2.74)
1.04
(0.93 to 1.16)
1.10
(0.68 to 1.78)
1.12
(0.85 to 1.49)
0.85
(0.64 to 1.14)
1.01
(0.92 to 1.11)
1.02
(2.56 to 0.52)
0.99
(0.87 to 1.13)
1.06
(0.94 to 1.19)
0.99
(0.90 to 1.10)
Hazard Ratio or
Difference
(95% CI)
0.18
0.46
0.69
0.42
0.28
0.80
0.20
0.91
0.34
0.91
P Value
Aliskiren vs. Enalapril
* The comparison of aliskiren with enalapril was a test for superiority. For noninferiority, the one-sided P value was 0.0184, which did not fulfill the prespecified requirement of a P value
of 0.0123 or less. For all outcomes other than the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (on a scale from 0 to 100, with higher scores indicating
better health-related quality of life), the data are shown as number of patients with an event as a fraction of the number of patients at risk, and the treatment effect is shown as the hazard ratio and the 95% confidence interval (CI), which were calculated with the use of Cox regression models with treatment, dose stratum, and NYHA class (I or II vs. III or IV) as fixedeffect factors and the log-transformed NT-proBNP value at baseline as a covariate. P values are two-sided and were not adjusted for multiple comparisons.
The KCCQ score was evaluated with the use of a repeated-measures analysis with the baseline value as a covariate and treatment, dose stratum, NYHA class, and visit as factors and a
visit-by-treatment interaction; a score of 0 was used in patients who died. The results are shown as the least-square mean change from baseline SE, and the treatment effect is shown
as the least-square mean of the difference with the 95% confidence interval. Scores were available at 12 months for 1811 patients in the combination-therapy group, for 1796 in the
aliskiren group, and for 1804 in the enalapril group.
The full list of prespecified exploratory outcomes is provided in Table S1 in the Supplementary Appendix.
The composite renal outcome consisted of death from renal causes, end-stage renal disease (initiation of dialysis, renal transplantation, or a serum creatinine concentration of >6.0 mg
per deciliter [530 mol per liter]), or a doubling of serum creatinine from baseline (to more than the upper limit of the normal range) that was sustained for at least 1 month.
39 (1.7)
88 (3.8)
Fatal or nonfatal myocardial infarction
Composite renal outcome no. (%)
841 (35.9)
Death from cardiovascular causes, hospitalization for heart

failure, nonfatal myocardial infarction, nonfatal stroke, or
resuscitated cardiac arrest
Other prespecified exploratory outcomes no. (%)
5.040.56
430 (18.4)
First hospitalization for worsening heart failure
Secondary outcome: change in KCCQ clinical summary score at

12 mo
512 (21.9)
770 (32.9)
Combination
Therapy
(N=2340)
Death from cardiovascular causes
Primary composite outcome: death from cardiovascular causes or

first hospitalization for worsening heart failure no. (%)
Outcome
Table 2. Protocol-Specified Primary and Secondary Outcomes.*

The
of
m e dic i n e
Table 3. Prospectively Collected Safety Outcomes during Double-Blind Treatment.*

Combination
Therapy
(N=2340)
Variable
Aliskiren
(N=2340)
Enalapril
(N=2336)
P Value
Combination
Therapy vs.
Enalapril
Aliskiren vs.
Enalapril
no. of patients (%)

Hypotension
Symptomatic hypotension
Symptomatic hypotension with systolic
blood pressure <90 mm Hg
322 (13.8)
249 (10.6)
258 (11.0)
0.005
0.67
87 (3.7)
31 (1.3)
55 (2.4)
0.008
0.009
389 (16.6)
279 (11.9)
306 (13.1)
<0.001
0.23
Renal impairment
Investigator-reported renal impairment
Serum creatinine
2.5 mg/dl
95 (4.1)
63 (2.7)
62 (2.7)
0.009
1.00
3.0 mg/dl
46 (2.0)
35 (1.5)
29 (1.2)
0.06
0.53
351 (15.0)
192 (8.2)
243 (10.4)
<0.001
0.01
401 (17.1)
255 (10.9)
291 (12.5)
<0.001
0.10
Hyperkalemia
Investigator-reported hyperkalemia
Serum potassium
>5.5 mmol/liter
>6.0 mmol/liter
Cough
116 (5.0)
70 (3.0)
83 (3.6)
0.02
0.29
290 (12.4)
241 (10.3)
284 (12.2)
0.83
0.046
* The table shows the numbers and percentages of patients who had the prespecified safety event at any time after randomization until the
end of the trial, except for patients with diabetes (and other patients whose treatment was discontinued owing to the protocol amendment
or another health-authority request), for whom only data collected up to the censoring date were included. The numbers and percentages of
patients who permanently discontinued treatment owing to hypotension-related adverse events were 83 (3.5%) in the combination-therapy
group, 37 (1.6%) in the aliskiren group, and 50 (2.1%) in the enalapril group (P=0.005 for the comparison of combination therapy with
enalapril; P=0.16 for the comparison of aliskiren with enalapril); for renal impairmentrelated adverse events, the corresponding values
were 143 (6.1%), 97 (4.1%), and 106 (4.5%) (P=0.02 for the comparison of combination therapy with enalapril; P=0.52 for the comparison
of aliskiren with enalapril); and for hyperkalemia-related adverse events, the corresponding values were 70 (3.0%), 29 (1.2%), and 31 (1.3%)
(P<0.001 for the comparison of combination therapy with enalapril; P=0.80 for the comparison of aliskiren with enalapril).
To convert values for creatinine to micromoles per liter, multiply by 88.4.
tension, renal dysfunction, and hyperkalemia,

despite the active run-in period that resulted in
the exclusion of patients who had these problems on initial exposure to the treatments studied. In our trial, patients with diabetes had the
treatment stopped prematurely because of regulatory concern about the safety of aliskiren added
to an ACE inhibitor in such persons.15-19 Because
of this, we revised our statistical analysis plan to
prespecify examination of the effect of combination therapy, as compared with enalapril alone,
in patients without diabetes.13 This analysis
showed the same effect of combination therapy
as in the trial overall.
Our findings regarding combination therapy
contrast with those of earlier trials involving
10
patients with heart failure in which the addition

of an ARB to an ACE inhibitor was of some benefit.5,6 Although renin inhibition is pharmacologically distinct from angiotensin-receptor blockade,
the difference between our trial and the other
trials is unlikely to be explained by differences
in the treatments used.9-11 The more likely explanation is that neither earlier trial required an evidence-based dose of ACE inhibitor, whereas our
trial did.
The absence of additional benefit with combination therapy in our study was not due to a
lack of incremental inhibition of the reninangiotensin system, because the addition of aliskiren
to enalapril led to more adverse effects that are
indicative of greater blockade of this system. A

similar excess of adverse effects was noted when

only half the full dose of valsartan was added to
an evidence-based dose of captopril in patients
after myocardial infarction.7 Collectively, these
findings suggest that there is a therapeutic ceiling for blockade of the reninangiotensin system beyond which there is little or no additional
efficacy and only more adverse effects. These findings also argue against the suggestion that the
benefit of sacubitrilvalsartan over enalapril could
be due to more intense blockade of the renin
angiotensin system.20,21 The lack of benefit of
added aliskiren was not due to inadequate statistical power, despite regulatory censoring of data
from patients with diabetes (and from some others). Our trial was event-driven, and the required
number of patients had a primary outcome.
Also, despite the high rate of discontinuation of
the randomly assigned therapy by the end of the
trial, overall exposure to the treatment was satisfactory.
A notable feature of our trial was the regulatory
intervention in which the drug was discontinued in
patients with diabetes during the course of the
trial.13 This intervention was based on the findings
References
1. The CONSENSUS Trial Study Group.
Effects of enalapril on mortality in severe
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Survival Study (CONSENSUS). N Engl J
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diabetes in two other trials (ASTRONAUT and
ALTITUDE).15,16,19 Our trial included a large proportion of patients with diabetes, who had exposure to aliskiren for a median of 24 months despite truncated follow-up. We did not identify
worse outcomes in the patients with diabetes
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ATMOSPHERE concerning this regulatory intervention has now been published in the Journal.22
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aliskiren in patients with symptomatic
heart failure. Circ Heart Fail 2008;1:17-24.
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al. Direct renin inhibition in addition to
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Minimize OutcomeS in Patients with
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Copyright 2016 Massachusetts Medical Society.


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