Targeting the renin-angiotensin-aldosterone system in heart failure

The renin-angiotensin-aldosterone system is a well-established therapeutic target in the treatment of heart failure (HF). Substantial advances have been made with existing agents-angiotensin-converting enzyme (ACE) inhibitors, angiotensin II-receptor blockers (ARBs), and mineralocorticoid-receptor antagonists (MRAs)-and new data continue to emerge. The indication for the use of MRAs has been broadened to include potentially all patients who have HF with reduced ejection fraction (HFrEF), and ACE inhibitors might have a novel application in patients who are at risk of left ventricular dysfunction (those with aortic valvular disease or pacing-induced heart disease). ARBs have been shown to be a beneficial alternative to ACE inhibitors in HFrEF, but their value when added to ACE inhibitors has been questioned. Upstream, direct renin blockade with aliskiren is being pursued in two large trials of HF, despite the premature halting of a third study. A substantial, unmet need remains in patients who have HF with preserved ejection fraction (HFpEF). New data on spironolactone and LCZ696 (a combined ARB and neprilysin inhibitor) show promise for these patients. Results of the TOPCAT study of spironolactone in patients with HFpEF are awaited, and LCZ696 is now being tested in a large trial in patients with HFrEF.