JAMA Clinical Guidelines Synopsis
September 15, 2022
Management of Heart Failure
Mark N. Belkin, Adam S. Cifu, Sean Pinney
JAMA. 2022;328(13):1346-1347. doi:10.1001/jama.2022.16667
Guideline title 2022 American College of Cardiology (ACC)/American Heart Association AHA)/Heart Failure Society of America (HFSA) Guidelines for the Management of Heart Failure
Release date April 1, 2022
Prior versions 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure and 2013 ACCF/AHA Guideline for the Management of Heart Failure
Developer and Funding Source ACC/AHA Joint Committee on Clinical Practice Guidelines
Target population Adult patients with a diagnosis of or at risk for heart failure (HF)
Major recommendations
- Classifications for HF are separated into 4 categories based on ejection fraction (EF) and disease history: HF with reduced EF (EF ≤40%), HF with mildly reduced EF (EF 41%-49%), HF with preserved EF (EF ≥50%), and HF with improved EF (EF previously ≤40% with improvement to >40%).
- In patients with chronic HF with reduced EF, angiotensin receptor–neprilysin inhibitors (ARNIs) are preferred over angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). If ARNI use is not feasible, ACEIs are preferred over ARBs, unless there is significant cough or angioedema (class 1, level of evidence [LOE] A).
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors should be included across all HF categories (symptomatic HF with reduced EF [class 1, LOE A]; HF with mildly reduced EF and HF with preserved EF [class 2a, LOE B-R]).
- Patients with HF with improved EF should continue to receive medical therapy originally indicated for HF with reduced EF (class 1, LOE B-R).
- Evidence-based treatment of HF with preserved EF includes blood pressure control (class 1, LOE C-LD), SGLT2 inhibitors (class 2a, LOE B-R), mineralocorticoid antagonists, ARBs, and ARNIs (class 2b, LOE B-R).
Summary of the Clinical Problem
Since the 2017 publication of the ACC/AHA/HFSA focused update of HF guidelines, multiple clinical trials have demonstrated the significant benefits of novel medical therapies for patients with HF across the spectrum of EF.1-4 The emergence of these therapies adds nuance and complexity to the care of patients with HF.
Characteristics of the Guideline Source
The guideline was written by the ACC/AHA Joint Committee on Clinical Practice Guidelines (Table).5 The committee comprised advanced HF cardiologists, general cardiologists, internists, interventional cardiologists, surgeons, pharmacists, an electrophysiologist, an advanced nurse practitioner, and 2 patient representatives. Representatives were included from the ACC, AHA, and HFSA. Six official reviewers were nominated from the AHA, ACC, HFSA, and Joint Committee on Clinical Practice Guidelines, in addition to 32 content reviewers. All relationships with industry of external reviewers and writing committee members were tracked and listed in the supplementary material. Detailed criteria on relationships with industry for ACC/AHA guideline documents were linked within the article, and the disclosures of all writing committee members were listed in the appendix. As specified, the writing committee chair and at least half the writing committee did not have any relationship with industry. Criteria used to establish class/strength of recommendation and level/quality of evidence were listed in the document.
Evidence Base
The guideline incorporates the updated 2021 universal definition of HF for classification. The updated classification differentiates into HF with reduced EF (EF ≤40%), HF with mildly reduced EF (EF 41%-49%), HF with preserved EF (EF ≥50%), and HF with improved EF (EF previously ≤40% with improvement to >40%). This allows for more nuanced recommendations with incorporation of new data in the HF with mildly reduced EF, HF with preserved EF, and HF with improved EF populations.
In chronic HF with reduced EF, the 2017 update to the guidelines recommended transition to an ARNI after a patient was shown to tolerate an ACEI or ARB. This recommendation was based on the results of trials such as the PARADIGM-HF randomized clinical trial (RCT) that included 8442 patients and showed significant improvement in mortality with sacubitril-valsartan over enalapril, including a 2.8% absolute risk reduction (ARR) in all-cause mortality.4 Additional RCTs have since indicated that use of ARNIs, without a trial of ACEIs or ARBs, results in positive cardiac remodeling and a reduction in cardiac biomarkers, without excess adverse events.5
The guideline recommends that SGLT2 inhibitors be initiated in patients with symptomatic, chronic HF with reduced EF. This recommendation (class 1, LOE A) is based on 2 large RCTs that compared dapagliflozin or empagliflozin with placebo in patients with chronic HF with reduced EF (4744 patients in the dapagliflozin trial and 3730 in the empagliflozin trial) and showed improvement in HF hospitalization and cardiovascular death.1,2 Dapagliflozin resulted in a 3.7% ARR in HF hospitalization and a 1.9% ARR in cardiovascular death, both of which were statistically significant improvements.6 Empagliflozin resulted in a significant 5.1% ARR in HF hospitalization but no significant reduction in cardiovascular death.1
Notably, the guideline now includes a recommendation (class 1, LOE B-R) to continue guideline-directed medical therapy instituted for HF with reduced EF even after improvement in EF (ie, HF with improved EF). This is based on the TRED-HF RCT in which 51 patients with dilated cardiomyopathy with improved EF who were randomized to withdrawal of medication had a 44% relapse of HF, compared with 0% relapse in the medication continuation group.7
The EMPEROR-Preserved trial, an RCT comparing empagliflozin with placebo in 5988 patients with left ventricular EF greater than 40% and chronic HF symptoms, demonstrated a 3.2% reduction in HF hospitalization and cardiovascular mortality.1SGLT2 inhibitors are thus recommended (class 2a, LOE A) for patients with chronic HF with mildly reduced EF and HF with preserved EF. Mineralocorticoid antagonists and ARBs or ARNIs are also recommended for patients with HF with preserved EF (class 2b, LOE B-R) to reduce HF hospitalization.5
Benefits and Harms
The substitution of ARNIs for ACEIs and ARBs and the addition of SGLT2 inhibitor therapy to evidence-based β-blockers and mineralocorticoid antagonists are expected to reduce all-cause mortality. This guideline emphasizes the additive benefit of SGLT2 inhibitors and ARNIs. In an effort to avoid harm and add nuance to the guidelines, “value statements” were included for HF therapeutics for which cost-effectiveness studies were available. Despite the class 1 recommendation regarding in-hospital initiation of foundational HF therapeutics, for which there is strong evidence of mortality benefit, there are limited details regarding initiation and titration strategies, which may constrain robust clinical uptake.8,9
Discussion
The new guidelines provide updated recommendations of medical therapy for patients with HF across the spectrum of EF. Importantly, the guidelines emphasize differences in treatment regimens, and their associated levels of evidence, within the context of the new universal definition of HF. These recommendations are based predominantly on strong RCT data and serve as a needed update due to the large amount of robust evidence published in HF therapeutics since the 2017 update to the 2013 HF guidelines.10
Areas in Need of Future Study or Ongoing Research
While the addition of ARNIs and SGLT2 inhibitors to established medications is now known to be effective for HF, there is a need for implementation science research to determine how best to initiate, escalate, and switch between various agents now endorsed as guideline-directed medical therapy (GDMT). This is particularly important for HF with reduced EF due to the numerous and growing evidence-based therapies. More robust data on the efficacy of ARNIs in heart failure of various etiologies, as well as additional studies regarding magnetic resonance angiography use in HF with mildly reduced EF and HF with preserved EF, will almost certainly affect how these drugs are used in the future. Furthermore, research into the role of SGLT2 inhibitors for primary prevention of HF and in the management of HF with improved EF would be beneficial. More data regarding novel therapies such as vericiguat (a soluble guanylyl-cyclase stimulator) and omecamtiv mecarbil (a cardiac-specific myosin activator) are needed. These drugs have been shown to benefit patients with HF with reduced EF, but the trials were conducted without optimal incorporation of updated GDMT (ie, ARNIs or SGLT2 inhibitors).
