European Journal of Heart Failure (2018) 20, 1323– 1325 EDITORIAL COMMENT doi:10.1002/ejhf.1251 Combination drug therapy in heart failure: greater than the sum of its parts Andrew P. Ambrosy 1,2, * and Ovidiu Chioncel 3 1 Division of Cardiology, Duke University Medical Center, Durham, NC, USA; 2 Duke Clinical Research Institute, Durham, NC, USA; and 3 Institute of Emergency for Cardiovascular Diseases ‘Professor C.C. Iliescu’, University of Medicine and Pharmacy Carol Davila, Bucuresti, Romania This article refers to ‘Incremental beneft of drug ther- apies for chronic heart failure with reduced ejection fraction: a network meta-analysis’ by M. Komajda et al., published in this issue on pages 1315– 1322. Among the countries represented by the European Society of Car- diology (ESC), there are more than 15 million patients living with heart failure (HF). 1,2 The most recent European data suggest that all-cause mortality and hospitalization, respectively, may be as high as 8% and 25% at 1 year. 3,4 Although the prognosis of outpatients with HF with a reduced ejection fraction (HFrEF) has been revolu- tionized by guideline-directed medical therapies (GDMT), there is evidence to suggest patients may not routinely reach target dosing of life-prolonging medications 5,6 and there are a number of novel pharmacotherapies that have been endorsed by the guidelines but not yet widely adopted in clinical practice. 7,8 In this issue of the Journal, Komajda et al. 9 report a network meta-analysis (NMA) of all recommended classes of evidence-based medications for the treatment of HFrEF in order to evaluate the cumulative effcacy and incremental beneft of combination drug therapy. As previously described, the investigators performed a search of the PubMed, EMBASE, and Cochrane CENTRAL databases in order to identify all randomized clinical trials (RCTs) of pharma- cotherapies studied in ambulatory HFrEF patients. 10 Trials were excluded if the entire study population included patients with a concomitant diagnosis (e.g. coronary artery disease, renal failure, etc.) likely to have a major effect on prognosis. Treatments were categorized by class of medication and a threshold of 50% drug uti- lization was selected as the cut-off for combination therapy. NMA was used to evaluate direct (i.e. head-to-head) and indirect (i.e. via one or more imputations) evidence to make pairwise comparisons between a drug (or combination therapy) and putative placebo. A total of 58 RCTs were included in the fnal analytical cohort. However, the network was dominated by 15 cardio- vascular outcomes trials conducted between 1991 to 2014 with at least 1000 patient-years of evidence including landmark The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Heart Failure or of the European Society of Cardiology. doi: 10.1002/ejhf.1234 *Corresponding author. Division of Cardiology, Duke University Medical Center, Duke Clinical Research Institute, 2301 Erwin Road, Durham, NC 27710, USA. Tel: +1 518 598 6117, Email: andrew.ambrosy@dm.duke.edu ............................................................................................................. studies of the following drug classes: angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), beta-blocker (BB), mineralocorticoid receptor antagonist (MRA), I f -channel inhibitor [e.g. ivabradine (IVA)], and angiotensin receptor–neprilysin inhibitor (ARNI) (e.g. sacubitril/valsartan). For all-cause mortality, BB was the only monotherapy found to be superior to placebo [hazard ratio (HR) 0.58, 95% confdence interval (CI) 0.34–0.95]. The most effcacious combinations were ARNI+BB + MRA and ACEI+BB + MRA + IVA, which decreased the relative risk of all-cause mortality, respectively, by 62% and 59% compared to placebo. Notably, among triple therapies, the combination of ACEI+BB + MRA (HR 0.44, 95% CI 0.27–0.67) performed marginally better than ACEI+ARB + BB (HR 0.52, 95% CI 0.32–0.80). Similarly, for all-cause hospitalization, the best outcomes were once again seen for patients receiving ARNI+BB + MRA or ACEI+BB + MRA + IVA with a relative risk reduction of 42% vs. placebo for both combinations. Finally, there was little between-group difference in terms of outcomes when the most effcacious combinations were compared head-to-head as there was a signifcant amount of heterogeneity in the net- work resulting in uncertainty in point estimates (i.e. wide and overlapping CIs). This NMA of RCTs of evidence-based medications clearly sup- ports the role of combination drug therapy in HFrEF and is consis- tent with international guideline recommendations. 7,8 It cannot be overemphasized that the combination of ARNI+BB + MRA led to the greatest overall improvement in survival. This is congruent with the landmark PARADIGM-HF trial, which found that treatment with sacubitril/valsartan resulted in an approximately 3% abso- lute risk reduction and more than 15% relative risk reduction in all-cause mortality. 11,12 In fact, a putative placebo analysis using the control arms of SOLVD-T and CHARM-Alternative, demonstrated that the effects of ARNI therapy on cardiovascular morbidity and mortality were roughly doubled when compared to conventional renin–angiotensin system antagonists (i.e. ACEI and/or ARB). 13 Accordingly, the 2016 ESC HF guidelines recommend switching © 2018 The Authors European Journal of Heart Failure © 2018 European Society of Cardiology