Building the Foundation for a New Era of Quadruple Therapy in Heart Failure
Authors: G. Michael Felker
Journal: Circulation (2019)

Building the Foundation for a New Era of Quadruple Therapy in Heart FailureArticles, see p 90 and 100 T he serial development of treatments that improve morbidity and mortality in patients with chronic heart failure with reduced ejection fraction (HFrEF) is one of the great success stories of cardiovascular therapeutics.Until recently, the combination of β-blockers, renin-angiotensin system inhibitors (angiotensinconverting enzyme inhibitors or angiotensin receptor blockers), and mineralocorticoid receptor antagonists formed the foundation of triple therapy for heart failure (HF).These agents, each of which provides clear benefits on mortality and morbidity in patients with HFrEF, collectively came to be termed guideline-directed medical therapy (GDMT).This stable foundation of HF therapeutics was upended in 2014 by the stunning results of the PARADIGM-HF study (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), demonstrating substantial improvements in outcomes with the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan above and beyond the benefits provided by the angiotensin-converting enzyme inhibitor enalapril. 1Now, only a few years later, a remarkable data set has emerged with the sodium-glucose cotransporter-2 inhibitors (SGLT2is) in HF.Initially, the diabetes cardiovascular outcome trials provided evidence of the role of these agents in preventing incident HF in patients with type 2 diabetes mellitus.Last, the recent publication of the primary results of the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) demonstrated substantial benefits in outcomes on top of triple therapy for patients with chronic HFrEF, benefits that are remarkably similar in patients with and without diabetes mellitus. 2So is it now time for triple therapy to evolve to quadruple therapy in patients with HFrEF?The field of HF must now grapple with a number of questions in light of these new data in patients with established HFrEF.Is this a class effect of SGLT2is in general or specific to dapagliflozin?What about other benefits beyond morbidity and mortality?What are the specific mechanisms underlying the observed effects?And last, how should this new class of drugs be implemented, especially in groups of patients (eg, the elderly) where aggressive uptitration of triple therapy has often been a challenge?In that context, the articles by Kosiborod et al 3 and Martinez et al 4 in this issue of Circulation expand the dapagliflozin in HF story and provide greater insights into some of these critical questions.First, Kosiborod et al 3 present a detailed analysis of the effects of dapagliflozin on health-related quality of life in the DAPA-HF study.These data are of critical importance, because improving patient-reported outcomes in HF, especially in highly symptomatic patients, is an important goal in drug development.The reported analysis from DAPA-HF shows a clinically important benefit on health-related quality of life (as measured by the well-validated Kansas City Cardiomyopathy