Heart failure with reduced ejection fraction (HFrEF) is associated with significant
morbidity and mortality, particularly in patients with New York Heart Association
(NYHA) functional class IV symptoms. Decades of discovery have heralded significant
advancements in the pharmacologic management of HFrEF. However, patients with NYHA
IV symptoms remain an under-represented population in almost every clinical trial
to date, leaving clinicians with limited evidence with which to guide drug treatment
decisions in this patient group with severe heart failure. Randomized controlled trials
of adult patients with NYHA IV symptoms of HFrEF randomized to current guideline-recommended
medical therapy were included in this systematic review and meta-analysis. The outcomes
of interest included the rate of all-cause mortality, cardiovascular mortality, and
heart failure hospitalization. A total of 39 randomized controlled trials were included.
A total of 6 studies examined angiotensin converting enzyme inhibitors, with meta-analyses
of 2 demonstrating a reduced risk of all-cause mortality (relative risk (RR) 0.76,
95% confidence interval 0.59 to 0.97, p = 0.03). A total of 11 studies examined β
blockers, with meta-analysis of 6 demonstrating a reduced risk of all-cause mortality
(risk ratio 0.74, 95% confidence interval 0.60 to 0.92, p = 0.008). A study examined
the mineralocorticoid antagonist spironolactone, reporting a reduced risk of all-cause
mortality in the NYHA IV subgroup. A total of 6 studies examined device therapy, demonstrating
the benefit of cardiac resynchronization therapy with or without an implantable cardiac
defibrillator in reducing hospitalization in the NYHA IV subgroup. Although trial
evidence exists for angiotensin converting enzyme inhibitors, β-blockers, and mineralocorticoid
antagonist therapy in the NYHA IV population, the role of angiotensin receptor blockers
is unclear. Ivabradine, angiotensin receptor neprilysin inhibitors, and sodium-glucose
transport protein 2 inhibitors remain underinvestigated and have not been proved to
provide any benefit above standard heart failure therapy in patients with HFrEF and
NYHA IV symptoms.
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Article info
Publication history
Published online: December 03, 2022
Received in revised form:
October 28,
2022
Received:
August 18,
2022
Footnotes
Drs. Riley J Batchelor& Emilia Nan Tie contributed equally as first authors.
Funding: None.
Identification
Copyright
Crown Copyright © 2022 Published by Elsevier Inc. All rights reserved.
