John McMurray (University of Glasgow, United Kingdom)

Presented at ACC 2016

Background

In patients with heart failure with reduced ejection fraction (HF-REF), angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalisation (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. The role of a direct renin inhibitor in such patients is unknown.
The Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) study compared the ACE inhibitor enalapril, the direct renin inhibitor aliskiren, and the combination of the two drugs in 7016 patients with heart failure and a reduced ejection fraction (HF-REF).
After a single-blind run-in period, patients (age ≥18 years, NYHA class II-IV symptoms and a LVEF ≤35%) were assigned 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.

Main results  

• After a median follow-up of 36.6 months, the primary outcome occurred in 32.9% in the combination-therapy group and in 34.6% in the enalapril group (HR 0.93; 95% CI 0.85-1.03; P=0.17).
• The primary outcome occurred in 33.8% in the aliskiren group (HR vs. enalapril, 0.99; 95% CI 0.90- 1.10; P=0.91); the prespecified test for noninferiority was not met.
• Patients in the group that received both drugs were at higher risk for hypotensive compared with those who received enalapril alone (13.8% vs. 11.0%, P=0.005)
• Patients in the combination-therapy group also had a higher risk of an elevated serum creatinine concentration (4.1% vs. 2.7%, P=0.009) and elevated potassium concentration (17.1% vs. 12.5%, P<0.001)
• Adverse event rates with aliskiren alone were generally similar to those seen with enalapril alone.

Conclusion  

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.

Comment from the authors
A notable feature of the ATMOSPHERE trial was the regulatory intervention in which the drug was discontinued in patients with diabetes during the course of the trial. [1] This intervention was based on the findings of possible harm from aliskiren in patients with diabetes in two other trials (ASTRONAUT and ALTITUDE).[2-4]
This trial included a large proportion of patients with diabetes, who had exposure to aliskiren for a median of 24 months despite truncated follow-up. No worse outcomes were identified 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. A statement of the data and safety monitoring board of ATMOSPHERE concerning this regulatory intervention has now been published [5], with subsequent correspondence.

Source

Press release ACC 2016, 4 April 2016

References

1. Krum H, McMurray JJ, Abraham WT, et al. The Aliskiren Trial to Minimize OutcomeS in Patients with HEart failure trial (ATMOSPHERE): revised statistical analysis plan and baseline characteristics. Eur J Heart Fail 2015; 17: 1075-83.
2. Parving H-H, Brenner BM, McMurray JJV, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012; 367: 2204-13.
3. Gheorghiade M, Bohm M, Greene SJ, et al. Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. JAMA 2013; 309: 1125-35. 
4. Maggioni AP, Greene SJ, Fonarow GC, et al. Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial. Eur Heart J 2013; 34: 3117-27.
5. Swedberg K, Borer JS, Pitt B, Pocock S, Rouleau J. Challenges to data monitoring committees when regulatory authorities intervene. N Engl J Med. DOI: 10.1056/NEJMsb1601674.

This study was published simultaneously in NEJM