Meta-Analysis of Pharmacological Treatments in HFmrEF and HFpEF

Quick Takes

  • In a network meta-analysis, a combination of ARNI, BB, MRA, and SGLT-2i was most effective in reducing CV death and HF hospitalizations in patients with HF with EF >40%.
  • BB had the smallest benefit in combination therapy for HF with EF >40% and digoxin and had no benefit.
  • Efficacy of combination therapy with ARNI, SGLT-2i, and MRA declined as EF increased.

Study Questions:

What is the additive efficacy of quadruple drug therapy for patients who have heart failure with mildly reduced ejection fraction (HFmrEF) and HF with preserved ejection fraction (HFpEF)?


This was a systematic review and network meta-analysis of randomized controlled trials assessing efficacy of angiotensin antagonists (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers [ARB], angiotensin receptor neprilysin inhibitors [ARNI]), beta-blockers (BB), mineralocorticoid antagonists (MRA), sodium glucose co-transporter 2 inhibitors (SGLT2i), vericiguat, and digoxin in adults with HF with EF >40%. The primary outcome included a composite of time to cardiovascular (CV) death and first HF hospitalization. HFmrEF was classified as EF 40-49% and HFpEF as EF >50%.


This meta-analysis included 13 main studies enrolling 29,875 adults with mean follow-up of 33 months and mean left ventricular EF 56%. When assessed individually, the composite primary endpoint was lower only with SGLT2i, MRA, and ARNI. The quadruple combination of ARNI, BB, MRA, and SGLT2i resulted in the largest improvement but with marginal benefit due to BB. CV death was lowered with MRA only when assessed individually. The quadruple combination of ARNI, BB, MRA, and SGLT-2i lowered CV death and this was largely driven by MRA. SGLT-2i and ARNI reduced HF hospitalizations with the largest decline in HF hospitalizations with combination therapy of ARNI, BB, MRA, and SGLT2i.

In subgroup analyses, for HFmrEF, ARNI, MRA, and SGLT2i individually reduced the composite primary endpoint and a combination of these three agents was most effective in reducing the primary endpoint, CV death, and HF hospitalizations. For EF of >50%, only SGLT2i were effective individually. The combination of ARNI, MRA, and SGLT2i was less effective in reducing the composite primary endpoint for HFpEF and ineffective in reducing CV death. HF hospitalizations were only decreased with EF 50-59% but not EF >60% with this triple therapy.


In a network meta-analysis, a quadruple combination of ARNI, BB, MRA, and SGLT-2i was most effective in reducing CV death and HF hospitalizations. BB had the smallest benefit in this combination therapy. However, efficacy of combination therapy declined as EF increased.


Although HFpEF is as prevalent as HF with reduced EF, therapeutics for HFpEF have lagged. While SGLT2i have shown the largest benefit for HF irrespective of EF, current guidelines moderately recommend MRA and ARB/ARNI for HFpEF and there are little data assessing combination therapy for HFpEF. Findings from this meta-analysis suggest that standard quadruple therapy should be used in patients with HFmrEF. However, for patients with HFpEF and EF of 50-60% triple therapy with ARNI, MRA, and SGLT2i had the best outcomes with no additive benefit of BB. Lack of benefit with combination therapy in HFpEF likely suggests different pathways and perhaps a larger focus needs to be placed on management of co-existing morbidities such as obesity, hypertension, and kidney disease in this group.

Clinical Topics: Heart Failure and Cardiomyopathies

Keywords: Heart Failure, Preserved Ejection Fraction, Mineralocorticoid Receptor Antagonists, Sodium-Glucose Transporter 2 Inhibitors

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