Elsevier

The American Journal of Cardiology

Volume 188, 1 February 2023, Pages 52-60
The American Journal of Cardiology

Meta-Analysis on Drug and Device Therapy of New York Heart Association Functional Class IV Heart Failure With Reduced Ejection Fraction

https://doi.org/10.1016/j.amjcard.2022.11.001Get rights and content

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.

Section snippets

Methods

This systematic review and meta-analysis was conducted in accordance to the guidelines outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.23 Systematic searches of the electronic databases MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were conducted, identifying articles from inception to March 2022. A health service librarian with expertise in conducting systematic reviews was engaged in developing the search strategy (LR). The

Results

This systematic search identified 7,988 unique studies, of which 7,570 were excluded based on title or abstract screening. The remaining 418 studies were eligible for full-text review, after which a further 379 studies were excluded, leaving 39 studies included in this systematic review. The most common reason for study exclusion at full-text screen was a study population that did not include patients with NYHA functional class IV symptoms (n = 213 studies). The screening process and all

Discussion

This large systematic review is the only study to compare and pool the results of RCTs examining heart failure therapy in patients with NYHA IV symptoms of HFrEF. A qualitative review of 4 ACEi trials with a meta-analysis of 2 trials found a reduction in all-cause mortality with ACEi therapy versus best medical therapy of the 1,980 to 1,990 seconds (hydralazine, nitrates, digoxin) in the NYHA IV subgroup. A qualitative review of 8 trials randomizing ARB versus placebo or ACEi were inconclusive

Disclosures

The authors have no conflicts of interest to declare.

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  • Drs. Riley J Batchelor& Emilia Nan Tie contributed equally as first authors.

    Funding: None.

    1

    These authors contributed equally.

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