Contemporary Drug Development in Heart Failure

Abstract

Until now, successful drug development in chronic heart failure (HF) with reduced ejection (HFrEF) has followed a conceptual model of targeting the secondary consequences of HF and its associated peripheral maladaptive processes leading to cardiovascular adverse remodeling. Step-wise modulation of angiotensin-II, the adrenergic system, and aldosterone have contributed to reductions in mortality in chronic HFrEF. Moreover, other vasodilators, such as hydralazine and nitrates, have improved outcomes in African American patients with HFrEF. Similarly, the combination of a neprilysin inhibitor and an angiotensin-II receptor blocker (ARB) provided incremental improvement in cardiovascular outcomes albeit at the cost of a higher risk of hypotension. The introduction of many other novel HFrEF agents beyond these therapies has largely failed, and the outcomes for these patients, especially after hospital discharge, have remained relatively stagnant and exceedingly high.1 To date, almost all disease-modifying therapies in HFrEF cause blood pressure lowering as an intended or unintended consequence. Low systolic blood pressure (SBP), which may reflect the extent of myocardial reserve, is one of the strongest determinants of clinical course in ambulatory and hospitalized patients with HFrEF.2–4 Hypotension, especially in high-risk or susceptible patients, presents a major hurdle to the contemporary HFrEF drug development paradigm and will likely pose an even greater obstacle once sacubitril/valsartan achieves widespread clinical application. The continued addition of hemodynamically active novel agents does not seem to be a practical or sustainable approach to further optimize HFrEF outcomes. Herein, we critically explore recent trends in the HFrEF drug development pipeline and discuss the importance of shifting to a strategy of developing therapies that directly target primary cardiac abnormalities without significantly influencing blood pressure or heart rates. Optimal blood pressure is critical for maintaining adequate coronary and renal perfusion pressures, especially in patients with overt or subclinical vascular disease. Patients with …