SGLT2i+ARNi+BB+MRA Most Effective Novel Combination Therapy for HFrEF

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Using a meta-analysis of randomized controlled trials, researchers assessed which combination therapy for HFrEF would best reduce CV outcomes.

The following article is a part of conference coverage from the American College of Cardiology’s 71st Annual Scientific Session & Expo being held in Washington, DC, from April 2 to 4, 2022. The team at Cardiology Advisor will be reporting on the latest news and research conducted by clinicians and scientists in the field. Check back for more from the ACC 2022 .


Combinatorial therapy of sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitors (ARNi), beta-blockers (BB), and mineralocorticoid receptor antagonists (MRA) was the most effective intervention for the reduction of cardiovascular (CV) outcomes among patients with heart failure with reduced ejection fraction (HFrEF), according to study results presented at the American College of Cardiology 71st Annual Scientific Session & Expo, from April 2 to 4, 2022, in Washington, DC.

Although novel combinatorial therapy approaches have been found to reduce heart failure (HF) hospitalization and CV death, no comprehensive analysis of drug combinatorial efficacy has been performed.

In order to evaluate the most effective approaches, investigators at the University of Hawaii performed a network meta-analysis using data from 43 randomized clinical trials comprising 91 pairwise and 18 direct comparisons of drug therapies.

During the 121,947 patient-year follow-up, the 5 best therapeutic approaches for reducing risk for CV death were SGLT2i, ARNi, BB, and MRA (hazard ratio [HR], 0.24; 95% CI, 0.14-0.42); ARNi, BB, and MRA (HR, 0.34; 95% CI, 0.22-0.53); SGLT2i, angiotensin-converting enzyme inhibitors (ACEis), BB, and MRA (HR, 0.37; 95% CI, 0.24-0.57); ivabradine (IVA), ACEi, BB, and MRA (HR, 0.39; 95% CI, 0.25-0.63); and soluble guanylate cyclase (sGC), ACEi, BB, and MRA (HR, 0.41; 95% CI, 0.26-0.65).

For the reduction of the risk for HF hospitalization, the top 5 therapy combinations were SGLT2i, ACEi, BB, and MRA (HR, 0.23; 95% CI, 0.16-0.34); SGLT2i, ARNi, BB, and MRA (HR, 0.24; 95% CI, 0.16-0.38); IVA, ACEi, BB, and MRA (HR, 0.25; 95% CI, 0.16-0.39); sGC, ACEi, BB, and MRA (HR, 0.31; 95% CI, 0.20-0.47); and ARNi, BB, and MRA (HR, 0.32; 95% CI, 0.22-0.47).

Contrasting the probabilities of being the best therapy for either endpoint found that overall, SGLT2i+ARNi+BB+MRA was most effective at reducing both CV death and HF hospitalization.


Diaz Acevedo J, Castro A, Pino Moreno J. Hierarchical ranking of novel therapies combinations in heart failure with reduced ejection fraction: Network meta-analysis. Presented at: American College of Cardiology 71st Annual Scientific Session & Expo; April 2-4, 2022. Abstract 1157-010/10

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