Heart failure drug treatment: the fantastic four
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Why the study?
Does combined treatment with an ARNI, beta-blocker, MRA, and SGLT2 inhibitor improve outcomes in patients with HFrEF compared to conventional therapy?
Key Points
- To evaluate the efficacy and safety of combining SGLT2 inhibitors with sacubitril/valsartan and other guideline-directed medical therapies in patients with heart failure with reduced ejection fraction.
- Reviewed findings from the EMPEROR-Reduced trial evaluating empagliflozin, specifically analyzing outcomes among the 19.5% of participants who were receiving sacubitril/valsartan at baseline.
- Synthesized supporting evidence and meta-analyses across clinical trials, including DAPA-HF (10.7% baseline sacubitril/valsartan use), PIONEER-HF, and SOLOIST-WHF.
- In EMPEROR-Reduced, empagliflozin demonstrated consistent reductions in the primary composite endpoint of cardiovascular death or first heart failure hospitalization, total heart failure hospitalizations, and renal decline regardless of baseline ARNI use.
- In DAPA-HF, dapagliflozin produced a hazard ratio of 0.70 for the primary endpoint in patients receiving a beta-blocker, MRA, and ARNI compared with 0.74 in those not taking an ARNI.
- A comprehensive four-drug regimen in a 55-year-old patient with HFrEF provides an estimated 8.3 additional years free from cardiovascular death or heart failure hospitalization and 6.3 additional years of overall survival compared with conventional dual therapy.
Structured PICO
Does combined treatment with an ARNI, beta-blocker, MRA, and SGLT2 inhibitor improve outcomes in patients with HFrEF compared to conventional therapy?
P
Population
Patients with chronic heart failure and a reduced ejection fraction (HFrEF)
I
Intervention
Combination therapy with an ARNI, a beta-blocker, an MRA, and an SGLT2 inhibitor (dapagliflozin or empagliflozin)
C
Comparator
Conventional therapy (e.g., ACE inhibitor and beta-blocker) or standard therapy without an ARNI
O
Outcome
Composite of cardiovascular death or first heart failure hospitalizationcomposite
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Physicians caring for patients with HFrEF should not consider prescribing either an ARNI or an SGLT2 inhibitor, but rather both therapeutic principles in combination as default strategy. Thus, in clinical practice, patients without contraindications appear to gain most benefit from combined treatment with the 'fantastic four': an ARNI, a beta-blocker, an MRA, and an SGLT2 inhibitor.”
“The detailed analyses from two large outcome trials in HFrEF with SGLT2 inhibitors now substantiate the first crude data already reported in the original publications as well as in the meta-analysis of DAPA-HF and EMPEROR-Reduced showing that patients treated with an ARNI derive at least the same benefit from additional SGLT2 inhibitor treatment as patients not on an ARNI.”
GCGregg C. FonarowChief of cardiology, University of California Los Angeles
“Start all four pillars simultaneously. Most patients can tolerate, and will benefit from, a simultaneous start.”
Implication
The totality of evidence supports early initiation of a four-drug regimen (ARNI, beta-blocker, MRA, and SGLT2 inhibitor) as the default strategy for patients with HFrEF.
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Cite This Study
Johann Bauersachs (2020) studied this question.