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> Common sense is genius dressed in its working clothes. Ralph Waldo Emerson, American essayist (1803–1882) Modulation of the renin–angiotensin–aldosterone system (RAAS) has revolutionized the management of patients with heart failure and reduced ejection fraction (HFrEF) (Figure).1 Before clinical trials with angiotensin-converting enzyme (ACE) inhibitors, there were no therapies proven to improve survival in patients with HFrEF, barring cardiac transplantation in a small, select group of patients with advanced HF. Subsequent studies with both ACE inhibitors and angiotensin receptor blockers (ARB), as well as β-blockers and mineralocorticoid receptor antagonists (MRA), have shown significant reduction in morbidity and mortality in patients with HFrEF across the spectrum of pathogenesis (ischemic and nonischemic) and functional class.Figure. Pathophysiology of the renin–angiotensin–aldosterone system and therapeutic targets in heart failure. Modified from Ref. 1. AT1 indicates angiotensin type 1; ACE, angiotensin-converting enzyme; EDHF, endothelium-derived hyperpolarizing factor; and SNS, sympathetic nervous system. Asterisk indicates investigational.Despite impressive benefits across multiple trials, the use of RAAS antagonists in clinical practice poses multiple challenges, as eloquently stated in this issue’s Challenges for the Basis of Practice by Sexton.2 In particular, most pivotal studies did not include patients with moderate or severe chronic kidney disease (CKD), who now may comprise ≤50% of patients with ambulatory HF and two thirds of patients hospitalized with acute HF. Similarly, although evidence supports the use of ACE inhibitors or ARBs to slow progression of renal dysfunction in patients with diabetes mellitus and CKD, these studies excluded patients with HF in general. The interactive effect of RAAS antagonists on populations of patients with HF and CKD may be elucidated, in part, from post hoc analyses of pivotal studies (Table3–9), but ultimately individual patient decisions must be made by clinicians. Furthermore, these decisions are often made against a demographic …

Response to Sexton: Inhibiting the Renin–Angiotensin–Aldosterone System in Patients With Heart Failure and Renal Dysfunction