Transcript Trial Overview - Clinical Trial Results

Direct renin inhibition with aliskiren alone,
and in combination with enalapril,
compared with enalapril, in heart failure:
Aliskiren Trial to Minimize OutcomeS in
Patients with HEart failuRE (ATMOSPHERE)
JJV McMurray1, WT Abraham2, K Dickstein3, LV Køber4, MA Ali5,
Y Chiang5, AS Desai6, C Gimpelewicz5, Q Sho5, SD Solomon6, G
Tarnesby5, BM Massie7, H Krum8 on behalf of the ATMOSPHERE
committees and investigators.
1University
of Glasgow, UK; 2Ohio State University, USA; 3Stavanger University
Hospital, Stavanger, Norway; 4Copenhagen University Hospital, Denmark; 6Brigham
and Women's Hospital, Boston, USA; 5Novartis Pharma AG, Basel, Switzerland;
7University of California, San Francisco, USA; 8Monash University, Australia.
Background: Renin inhibition in heart failure
with reduced ejection fraction (HF-REF)
 ACE inhibitors reduce mortality and reduce heart failure
hospitalization rates in patients with HF-REF, across
the spectrum of symptom severity (CONSENSUS,
SOLVD).
 ARBs are an alternative in patients unable to tolerate an
ACE inibitor because of cough (CHARM-Alternative).
 ARBs futher reduce cardiovascular mortality (CHARMAdded) and heart failure hospitalization (CHARMAdded, Val-HeFT) when added to an ACE inhibitor.
 Might a direct renin inhibitor (aliskiren) add to the
benefit of an ACE inhibitor or be a better alternative to
an ACE inhibitor?
Aliskiren Trial to Minimize OutcomeS in
Patients with HEart failuRE (ATMOSPHERE)
In reducing the risk of the primary composite outcome of
cardiovascular death or heart failure hospitalization
• Aliskiren added to enalapril is
Superiority
hypotheses
superior to enalapril
• Aliskiren monotherapy is
superior to enalapril
Non-inferiority
hypothesis
• Aliskiren monotherapy is noninferior to enalapril
https://clinicaltrials.gov NCT00853658
ATMOSPHERE: Entry criteria
• Age ≥18 years. NYHA class II-IV. LVEF ≤0.35
• BNP ≥150 pg/ml (NTpro-BNP ≥600 pg/ml) or if HF hosp.
within12 mo. BNP ≥100 pg/ml (NTpro-BNP ≥400 pg/ml)
• Background ACEi therapy equivalent to enalapril ≥10 mg/d
• Beta-blocker unless contraindicated/not tolerated
• SBP ≥95 mmHg run-in/ ≥90 mmHg at randomization
• eGFR ≥35 ml/min/1.73m2 at randomization /no decrease
>25% during run in
• Potassium <5.0 mmol/l run-in/ <5.2 mmol/l at randomization
ATMOSPHERE: Trial design
Primary outcome: CV death or heart failure hospitalization
(event driven: target 2318 patients [2369 accrued])
Randomization
*89% 10mg bid
†Target dose (titrated from 150mg qd)
Enalapril 5-10mg bid* (n=2336)
Enalapril
Enalapril +
5-10mg bid Aliskiren150mg qd
Aliskiren 300mg qd† (n=2340)
Enalapril 5-10mg bid + Aliskiren300mg qd (n=2340)
Open-label run-in
4-12 weeks
Prior ACEi use discontinued
Double-blind
Median follow-up = 36.6 months
ATMOSPHERE: Baseline characteristics
Aliskiren+Enalapril
(n=2340)
Aliskiren
(n=2340)
Enalapril
(n=2336)
Age (years)
Women (%)
Ischemic etiology (%)
LVEF (%)
NYHA class II / III (%)
63.2 ± 11.7
21.1%
57.1%
28.5 ± 5.7
64.0% / 33.7%
63.3 ± 12.1
22.7%
55.3%
28.4 ± 5.7
64.0% / 34.3%
63.3 ± 11.7
21.4%
55.7%
28.3 ± 5.7
61.7% / 36.3%
Systolic BP (mm Hg)
124 ± 19
124 ± 18
123 ± 18
Heart rate (beats/min)
72 ± 13
72 ± 12
72 ± 13
NT pro-BNP (pg/ml)
1193 (640-2351)
History of diabetes
Digitalis
Beta-blocker
MRA
CRT-P/CRT-D
ICD/CRT-D
28.4%
32.7%
92.0%
36.6%
6.1%
15.0%
1167 (627-2173) 1223 (634-2194)
26.8%
32.0%
91.2%
36.9%
5.1%
15.5%
27.9%
31.2%
91.9%
37.8%
5.6%
14.4%
ATMOSPHERE: Censoring of
patients with diabetes*
• Following the results of ALTITUDE (aliskiren added to an
ACE-I/ARB in patients with diabetes and CKD/CVD) and
ASTRONAUT (aliskiren added to an ACE-I/ARB in patients
hospitalized with HF), the Clinical Trials Facilitation Group of
the Heads of Medicines Agencies in Europe requested that
patients with diabetes have study drug discontinued.
• Follow-up for the efficacy analyses in patients with diabetes
(and some others) who had treatment discontinued because
of a regulatory request was censored at the date of
implementation of these requests. Patients off study drug
were still followed to end of the trial.
• Median follow-up for analysis of efficacy in patients with
diabetes was 24.1 months and in patients without diabetes
was 46.0 months.
*and some others
ATMOSPHERE: Trial conduct
Completeness of follow-up for vital status (at end of trial or
regulatory censoring date).
• Combination therapy: 31/2340 (1.3%) had unknown vital
status.
• Aliskiren: 19/2340 (0.8%) had unknown vital status.
• Enalapril: 19/2336 (0.8%) had unknown vital status.
Study drug dose (mean ±SD)
• Combination group:19.0 (3.0) mg of enalapril and 272 (58)
mg of aliskiren; Aliskiren group: 276 (55) mg; Enalapril
group 18.6 (3.5) mg.
Study drug discontinuation
• Non-diabetics: Combination 44%, aliskiren 40%; enalapril
42%. Proportion of possible treatment time patients took
study drug was 77%, 81% and 80%, respectively.
• Diabetics: 31%, 28% and 32%; 80%, 84 and 82%,
respectively.
Aliskiren Trial to Minimize OutcomeS in
Patients with HEart failuRE (ATMOSPHERE)
In reducing the risk of the primary composite outcome of
cardiovascular death or heart failure hospitalization
• Aliskiren added to enalapril is
Superiority
hypotheses
superior to enalapril
• Aliskiren monotherapy is
superior to enalapril
Non-inferiority
hypothesis
• Aliskiren monotherapy is noninferior to enalapril
https://clinicaltrials.gov NCT00853658
ATMOSPHERE: Primary outcome
ATMOSPHERE: Components of the
primary composite outcome
CV death
HF hospitalization
ATMOSPHERE: Effect of combination
therapy in patients with and without diabetes
Effect of combination therapy on the primary outcome in patients
without diabetes
(*additional superiority hypothesis in revised statistical analysis plan)
Patients without diabetes
n (%)*
Patients with diabetes
n (%)
Aliskiren+
Enalapril
Enalapril
HR
(95% CI)
P value
574/1675
(34.3%)
592/1684
(35.2%)
0.96
(0.85-1.07)
0.46
196/665
(29.5%)
216/652
(33.1%)
0.86
(0.71-1.04)
0.13
Interaction P-value = 0.35
Aliskiren Trial to Minimize OutcomeS in
Patients with HEart failuRE (ATMOSPHERE)
In reducing the risk of the primary composite outcome of
cardiovascular death or heart failure hospitalization
• Aliskiren added to enalapril is
Superiority
hypotheses
superior to enalapril
• Aliskiren monotherapy is
superior to enalapril
Non-inferiority
hypothesis
• Aliskiren monotherapy is noninferior to enalapril
https://clinicaltrials.gov NCT00853658
ATMOSPHERE: Comparison of enalapril
and aliskiren monotherapy (non-inferiority)
Pre-specified criterion for declaring non-inferiority
was a P-value ≤0.0123 (one-sided)
All patients
n (%)
Aliskiren
(n=2340)
Enalapril
(n=2336)
HR
(95% CI)
P value
791
(33.8%)
808
(34.6%)
0.99
(0.90-1.10)
0.0184*
*Did not meet the pre-specified P-value for significance
ATMOSPHERE:
Secondary and exploratory outcomes
Secondary outcome:
• Kansas City Cardiomyopathy Questionnaire (KCCQ) Change in the clinical summary score (CSS) from
baseline to 12 months
Exploratory outcomes (selected):
• Composite CV outcome: CV death, HF hospitalization,
MI, stroke or resuscitated cardiac arrest
• Composite renal outcome: renal death, ESRD (initiation
of dialysis, renal transplantation, or a serum Cr above 6.0
mg/dl [530 μmol/l]), or doubling of serum Cr from baseline
(to >upper limit of normal) sustained for at least 1 month
ATMOSPHERE: Pre-specified secondary outcome
KCCQ: change in CSS
from baseline to 12
months, points (95% CI)
Aliskiren+
Enalapril
Aliskiren
-5.04
(±0.56)
-6.03
(±0.57)
Enalapril
Difference
(95% CI)
(1)
Difference
(95% CI)
(2)
P
value
(1)
P
value
(2)
-5.01
(±0.55)
-0.03
(-1.56-1.50)
-1.02
(-2.56-0.52)
0.97
0.20
(1)= Comparison of enalapril plus aliskiren versus enalapril; (2)= Comparison of aliskiren versus enalapril
ATMOSPHERE: Pre-specified exploratory outcomes†
CV death, HF
hospitalization, MI,
stroke or resuscitated
cardiac arrest n (%)
Composite renal
outcome* n (%)
Aliskiren+
Enalapril
(n=2340)
Aliskiren
(n=2340)
Enalapril
(n=2336)
HR
(95% CI)
(1)
HR
(95% CI)
(2)
P
value
(1)
P
value
(2)
841
(35.9)
874
(37.4)
877
(37.5)
0.94
(0.86-1.04)
1.01
(0.92-1.11)
0.23
0.81
39
(1.7)
26
(1.1)
18
(0.8)
2.17
(1.24-3.79)
1.50
(0.82-2.74)
0.007
0.18
† Selected pre-specified outcomes
(1)= Comparison of enalapril plus aliskiren versus enalapril; (2)= Comparison of aliskiren versus enalapril
* renal death, ESRD (initiation of dialysis, renal transplantation, or a serum Cr above 6.0 mg/dl [530 μmol/l]), or
doubling of serum Cr from baseline (to >upper limit of normal) sustained for at least 1 month
ATMOSPHERE: All-cause mortality
ATMOSPHERE: Pre-specified subgroups
Combination Enalapril
n/N (%)
n/N (%)
Favors combination
Interaction
P-value
Favors enalapril
Aliskiren Enalapril
n/N (%)
n/N (%)
Favors aliskiren
Interaction
P-value
Favors enalapril
ATMOSPHERE: Safety outcomes
Aliskiren+
Enalapril
(n=2340)
Aliskiren
(n=2340)
Enalapril
(n=2336)
P value
(1)
P value
(2)
322 (13.8%)
87 (3.7%)
249 (10.6%)
31 (1.3%)
258 (11.0%)
55 (2.4%)
0.005
0.008
0.67
0.009
95 (4.1%)
46 (2.0%)
63 (2.7%)
35 (1.5%)
62 (2.7%)
29 (1.2%)
0.009
0.06
1.00
0.53
Hyperkalemia n (%)
K+ >5.5mmol/l
K+ >6.0mmol/l
401 (17.1%)
116 (5.0%)
255 (10.9%)
70 (3.0%)
291 (12.5%)
83 (3.6%)
<0.0001
0.02
0.10
0.29
Cough n (%)
290 (12.4%)
241 (10.3%)
284 (12.2%)
0.83
<0.05
Hypotension n (%)
Symptoms
Symptoms and SBP <90mmHg
Renal impairment n (%)
Cr ≥2.5mg/dl
Cr ≥3.0mg/dl
(1) = Comparison of enalapril plus aliskiren versus enalapril; (2)= Comparison of aliskiren versus enalapril
Summary and conclusions
Combination therapy
 The addition of aliskiren to an evidence-based dose of
enalapril led to more adverse events without an increase
in benefit.
 This finding differs from the prior ARB “add-on” trials and
may reflect a difference in study design (the previous
trials did not require an evidence-based dose of
background ACE inhibitor).
 There is probably a ceiling to RAS blockade in heart
failure, above which there is no further benefit
Aliskiren monotherapy
 Non-inferiority was not demonstrated for aliskiren
compared with enalapril.
In memory of our colleague and friend
Henry Krum, 1958-2015
Henry Krum, 1958-2015
ATMOSPHERE
43 countries, 844 Sites, 7064 Patients
Thank You