This document summarizes the ATMOSPHERE trial which tested whether combining the renin inhibitor aliskiren with the ACE inhibitor enalapril was superior to enalapril alone in patients with heart failure. The trial found no benefit to adding aliskiren to enalapril and aliskiren alone was not proven to be no worse than enalapril alone. The combination led to more adverse effects without additional clinical benefits. The results do not support using aliskiren in addition to or as an alternative to ACE inhibitors for heart failure patients.

2. AIM
• To test 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

4. RAAS INHIBITORS IN HF
ACE Inhibitors
• CONSENSUS
• SOLVED
ARBS
• CHARM ALTERNATIVE
• ELITE-II
ACEI vs ARBS vs COMBINATION
• VALIANT
ALISKIREN
• ALTITUDE
• ASTROUNAUT
• ATMOSPHERE

5. ACE Inhibitors and ARBs
• incomplete RAAS blockade
• reduced feedback inhibition of renin release, triggering a reactive rise in PRA
ACE Inhibitor
• reactive rise in PRA causes a compensatory increase in Ang I which partially
restores Ang II production by ACE-dependent and ACE-independent pathways
• Causes dry cough and angioedema
ARB
• reactive rise in plasma renin activity causes compensatory increases in both Ang I
and Ang II
• latter may partially restore AT II type 1 receptor stimulation and stimulate
profibrotic AT type 2 receptors and prothrombotic AT type 4 receptor

6. ACE INHIBITORS IN HF

7. ACE INHIBITORS IN HF

8. ARBS IN HF

9. ARBS vs ACE INHIBITORS IN HF

10. ARBS vs ACE INHIBITORS IN HF

11. ARBS vs ACE INHIBITORS vs COMBINATION

12. ARBS vs ACE INHIBITORS vs COMBINATION

13. ARBS vs ACE INHIBITORS vs COMBINATION

14. ALISKIREN IN HF-PREVIOUS TRIALS

16. ALTITUDE Trial
• Aliskiren increases the risk of adverse events and stroke without any
cardiovascular or renal improvements in patients with Type 2
Diabetes
• trial was stopped prematurely

18. ASTRONAUT trial
aliskiren to standard HHF therapy in non-diabetic patients
• well-tolerated and improves post-discharge outcomes and biomarker
profiles.
diabetic patients receiving aliskiren
• worse post-discharge outcomes.

19. The Aliskiren Trial to Minimize Outcomes in
Patients with Heart Failure (ATMOSPHERE)
• randomized trial comparing enalapril alone with aliskiren alone and
with the combination of aliskiren and enalapril in patients with heart
failure
• March 13, 2009, to December 26, 2013
• median follow-up was 36.6 months

20. ELIGIBLE PATIENTS
1. chronic heart failure with NYHA class II to IV symptoms and an EF
≤35%
2. plasma BNP ≥ 150 pg /ml (or NT-proBNP≥600 pg /ml)
3. if they had been hospitalized for heart failure within the previous 12
months, a BNP ≥ 100 pg /ml (or an NT-proBNP ≥400 pg /ml).
4. 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.

21. EXCLUSION CRITERIA
1. symptomatic hypotension
2. SBP <95 mm Hg at screening (or <90 mm Hg at randomization),
3. eGFR < 40 ml / minute / 1.73 m2 at screening (or <35 ml / minute / 1.73 m2 at
randomization or a decline of >25% in eGFR between screening and randomization)
4. serum potassium ≥ 5.0 mmol / liter at screening (or ≥5.2 mmol /liter at randomization)
5. history of inability to take ACE inhibitors

22. • 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

23. OUTCOMES
primary outcome
• composite of death from
cardiovascular causes or a first
hospitalization for heart failure
secondary outcomes
• change from baseline to 12
months in the Kansas City
Cardiomyopathy Questionnaire
(KCCQ) clinical summary score
• change in the NT-proBNP
concentration from baseline to
4 months

24. • ALTITUDE &ASTRONAUT Trials -led 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

31. DISCUSSION
 patients with heart failure in which the addition of an ARB to an ACE
inhibitor was of some benefit in previous trials
 more likely explanation is that neither earlier trial required an
evidence-based dose of ACE inhibitor, whereas our trial did
 absence of additional benefit with combination therapy in our study
was not due to a lack of incremental inhibition of RAAS, because the
addition of aliskiren to enalapril led to more adverse effects that are
indicative of greater blockade of this system.

32.  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 MI
 there is a therapeutic ceiling for blockade of RAAS beyond which there is
little or no additional efficacy and only more adverse effects.
 despite the high rate of discontinuation of the randomly assigned therapy
by the end of the trial, overall exposure to the treatment was satisfactory
 We did not identify worse outcomes in the patients with diabetes who
were treated with combination therapy than in those who were treated
with enalapril alone.
 Patients with diabetes who were treated with aliskiren monotherapy had
outcomes similar to those of patients treated with enalapril.

33. CARRY HOME MESSAGE
no benefit from the addition of a renin inhibitor to an
evidence-based dose of enalapril
not support the use of a renin inhibitor as an
alternative to an ACE inhibitor, because the
prespecified criterion for noninferiority was not met.