Top Ten Things Every Clinician Should Know About the 2022 Heart Failure Guidelines

Authors:
Madison Yates, PharmD
Megan Supple, PharmD, BCACP, CPP

Reviewers:
Dawn Fuke, PharmD, BCPS
Tomasz Jurga, PharmD, BCPS, BCACP, BCCP

Citation:
Heidenreich P, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063 

Heart failure (HF) remains a leading cause of morbidity and mortality globally. In the United States alone, 6.2 million adults live with HF and over 650,000 new cases are diagnosed every year.¹ The total cost of HF care in the United States exceeds $30 billion annually, with over half of these costs spent on hospitalizations. Although survival has improved, the absolute mortality rate for HF remains approximately 50% within five years of diagnosis. An analysis of the CHAMP registry found that less than 1% of patients with HF received target doses of a beta blocker, a renin-angiotensin-aldosterone system (RAAS) inhibitor [either an angiotensin-converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNi)], and a mineralocorticoid receptor antagonist (MRA) concurrently for at least 12-months.² Clearly, there is much room for improvement.

The 2022 AHA/ACC/HFSA Heart Failure Guidelines is a much-needed update and consolidates previously published recommendations.^3-5 Here are the top ten things every clinician should know about the 2022 AHA/ACC/HFSA Heart Failure Guidelines.  This list is not in ranked order of importance and is intended to describe the changes most relevant to ambulatory care practitioners. 

#1. New Lingo for HF Classifications. For individuals with Stage C HF, the new guidelines refine the classifications of HF based on LVEF (left ventricular ejection fraction) with new terminology:

Classification of HF	LVEF
HF with reduced EF (HFrEF)	< 40%
HF with improved EF (HFimpEF)	Previously < 40%, now > 40%
HF with mildly reduced EF (HFmrEF)	41 – 49% and evidence of increased LV filling pressures
HF with preserved EF (HFpEF)	> 50% and evidence of increased LV filling pressures

#2. Fantastic Four in HFrEF. Guideline-directed medical therapy (GDMT) for HFrEF now includes four medication classes, with sodium-glucose cotransporter-2 inhibitors (SGLT2i) being the newest addition.

• The SGLT2i empagliflozin and dapagliflozin are recommended as first-line therapy for HFrEF, joining the ranks of evidence-based beta blockers (metoprolol succinate, carvedilol, and bisoprolol), RAAS inhibitors (ARNi, ACEi, or ARB), and MRAs.  All four medication classes have 1A recommendations. Empagliflozin and dapagliflozin have been shown to reduce hospitalizations for HF and cardiovascular (CV) mortality, irrespective of the presence of type 2 diabetes. However, please note that a SGLT2i should not be used in patients with type 1 diabetes. The EMPEROR-REDUCED (empagliflozin) and DAPA-HF (dapagliflozin) trials demonstrated an approximate 25% relative reduction in the composite of CV death or HF hospitalization compared to placebo.^6,7
• Also new to the guidelines is the recommendation to use an ARNi over either an ACEi or ARB (1A recommendation). These recommendations stem from the PARADIGM-HF trial, in which sacubitril-valsartan significantly reduced the composite endpoint of CV death or HF hospitalization by 20% compared to enalapril.⁸ Use of an ACEi or ARB is still beneficial to reduce morbidity and mortality when an ARNi is not feasible, with ARBs recommended for patients unable to tolerate an ACEi because of cough or angioedema. 
• To maximize their benefits, the fantastic four should be titrated to achieve target doses shown to be efficacious in randomized controlled trials. The use of all four drug classes has been estimated to decrease all-cause mortality by 73% when compared with no treatment. 

#3. Add-On Agents. For patients with HFrEF who are receiving optimal (or maximum tolerated) doses of a beta blocker, RAAS inhibitor, MRA, and SGLT2i but continue to have HFrEF symptoms or exacerbations, additional therapies may be warranted. 

• Hydralazine/isosorbide dinitrate continues to be recommended to improve symptoms and reduce morbidity and mortality in African American patients with HFrEF and New York Heart Association (NYHA) class III-IV (Class of Recommendation [COR] 1, Level of Evidence [LOE] A). 
• Ivabradine can be considered in patients with: EF < 35%, NYHA II-III, HR > 70 bpm after maximally tolerated beta-blocker therapy, and in normal sinus rhythm. The SHIFT trial showed a 5% absolute risk reduction (ARR) and 18% relative risk reduction (RRR) in the composite endpoint of HF hospitalizations and CV death, with positive effects driven mainly by a reduction in hospital admissions for worsening HF (COR 2a, LOE B-R).⁹  
• Vericiguat can be considered in patients with LVEF < 45%, NYHA II-IV, recent HF worsening (hospitalization for CHF or need for IV diuresis), and elevated BNP. The VICTORIA trial showed a 3% ARR and 10% RRR in the primary composite endpoint of CV death or HF hospitalization, although neither individual endpoint was statistically significant (COR 2b, LOE B-R).¹⁰  
• Digoxin can be considered in patients who remain symptomatic to improve symptom control/exercise tolerance and reduce hospitalizations (COR 2b, LOE B-R). Target digoxin concentrations should be 0.5 to < 0.9 ng/mL range, although many trials did not appropriately measure digoxin levels. Of note, most of the digoxin clinical trial data preceded the advent of the fantastic four (current GDMT).  

#4. Go With The Flozin in HFmrEF. SGLT2i can be beneficial in decreasing HF hospitalizations and CV mortality in patients with HFmrEF.  

• There are no prospective randomized controlled trials in patients specifically with HFmrEF; all data is derived from post-hoc or sub-group analyses of HF trials that enrolled patients with an LVEF of 41-49%. Nearly 1/3 of patients included in the EMPEROR-Preserved trial had an LVEF of 41-49%. In this subgroup of 1983 patients, empagliflozin reduced the risk of the primary composite endpoint of CV death or hospitalization for HF by 29%.¹¹ SGLT2i are therefore given a stronger recommendation for use in HFmrEF (COR 2a, LOE B-R) than ARNi, ACEi, ARB, MRA, or beta-blocker (COR 2b, LOE B-R). 

#5. Improve It But Don’t Lose It. A new LVEF classification was created for patients with improved LVEF (HFimpEF) and these patients should continue their HFrEF treatments.

• HFimpEF includes all patients with previous HFrEF who now have an LVEF > 40%. The terminology “improved” was used rather than “recovered” since changes in LVEF may not be unidirectional. LVEF could transiently improve but then subsequently decline because the underlying cardiac structural abnormalities often persist. HFimpEF can be thought of as a subgroup of HFrEF.  These patients should continue GDMT to prevent relapse of HF and LV dysfunction, even in asymptomatic patients (COR 1, LOE B-R).  
• TRED-HF was an open-label pilot study of 51 patients whose LVEF had improved from < 40% to > 50% and who became asymptomatic. Patients were randomized to either continue or withdraw their HF medications. Of the patients who withdrew their HF medications, 44% met the primary endpoint of relapse (LVEF decrease of > 10% and to < 50%, increase in LV end-diastolic volume by > 10%, two-fold rise in NT-proBNP and to > 400ng/L, or clinical evidence of HF) within the first six months. Zero patients assigned to treatment continuation experienced a relapse.¹²

#6. More Meds for HFpEF. The 2022 guidelines provide updated recommendations for HFpEF (LVEF ≥ 50%). Until recently, clinical trials showing mortality and hospitalization benefit in the HFpEF population were lacking, and diuresis was the mainstay of therapy to improve symptoms.

• In 2021, the EMPEROR-Preserved study found that empagliflozin reduced the time to HF hospitalization or CV death by 21% — driven primarily by a reduction in time to HF hospitalization. However, there was no benefit in all-cause mortality.¹¹ Of note, this study included patients with LVEF > 40%. As a result, the 2022 guidelines recommend that SGLT2i are beneficial in decreasing HF hospitalizations and CV mortality in patients with HFpEF (COR 2a, LOE B-R). 
• Most recently, dapagliflozin was studied in patients with LVEF > 40% in the DELIVER trial. Dapagliflozin reduced the combined risk of worsening HF or CV death by 16%, primarily driven by a reduction in worsening HF. There were numerically fewer deaths in the dapagliflozin group; however, this did not achieve statistical significance. Similar benefits were seen in patients with LVEF less than or greater than 60%.¹³ 
• MRAs, ARBs, and ARNi may be considered to reduce hospitalizations in select patients with HFpEF, particularly those with LVEF on the lower end of the spectrum (COR 2b, LOE B-R). TOPCAT (investigating spironolactone) and CHARM-Preserved (investigating candesartan) are older trials that both showed reductions in HF hospitalizations.^{14, 15} PARAGON-HF (investigating sacubitril-valsartan) included patients with an LVEF ≥45% and did not find a significant reduction in the primary composite endpoint of CV death or total HF hospitalizations when sacubitril-valsartan was compared with valsartan alone.¹⁶ Secondary outcomes were exploratory and showed a trend toward a reduction in HF hospitalizations with ARNi use. There was also a differential effect in subgroups, with greater benefit seen in women and in those with LVEF between 45-57%.

#7. Show Me the Money! Value statements were added for select recommendations when data from high-quality, cost-effectiveness studies were available.  

• High-value interventions (costs per quality-adjusted life year [QALY] < $60,000) include the treatment of HFrEF with ACEi/ARB/ARNi, beta-blockers, and MRAs.
• Treatment with SGLT2i results in an intermediate economic value (costs per QALY $60,000-$90,000), however a reduction in drug cost (through contract pricing, for example) would improve the cost per QALY and potentially make SGLT2i a high-value therapy, too.

#8. Risky Business. Stages of HF were revised to emphasize the new terminologies of “at risk” for HF for stage A and “pre-HF” for stage B.  Several primary prevention strategies are highlighted in the guidelines.

• At risk for HF (stage A): Primary prevention strategies include controlling hypertension (HTN) with GDMT to prevent symptomatic HF, using SGLT2i in patients with type 2 diabetes (T2DM) and at high CV risk to prevent hospitalizations for HF, and promoting healthy lifestyle habits in the general population (Class 1 recommendations). 
• Pre-HF (stage B): Primary prevention recommendations are similar to those with stage A HF. Emphasis is placed on initiating lifestyle modifications and pharmacological therapies in this population that may prevent or delay the transition to symptomatic HF. Class 1a recommendations in this population include using an ACEi or ARBs and beta-blockers in patients with a history of myocardial infarction (MI) and reduced EF; using statins in patients with MI to prevent HF; and using ACEi and beta blockers in patients with LVEF ≤40%.  

#9. Controlling Comorbidities. Multimorbidity is common in patients with HF. Treating chronic conditions can complicate the management of HF and significantly impact its prognosis.  

• Recommendations are provided for select patients with HF and iron deficiency, anemia, HTN, sleep disorders, T2DM, atrial fibrillation, coronary artery disease, and malignancy. Examples of these recommendations include the use of IV iron replacement to improve functional status and quality of life in patients with HFrEF and iron deficiency with or without anemia (COR 2a). In patients with HF and anemia, erythropoietin-stimulating agents should not be used to improve morbidity and mortality (COR 3: Harm). For patients with comorbidities such as HTN and T2DM, use medications that provide multiple benefits. In patients with HFrEF and HTN, up-titrate GDMT to the maximally tolerated target dose. For patients with both HF and T2DM, use an SGLT2i to manage hyperglycemia and reduce HF-related morbidity and mortality. 

#10. Harm in HFrEF. Although not new to the 2022 guidelines, be aware that there are multiple medications that should be avoided in patients with HFrEF. 

• Nondihydropyridine calcium channel blockers, including diltiazem and verapamil, should be avoided due to their negative inotropic effects, which can decrease cardiac output. 
• Some antihypertensives, including doxazosin and nifedipine, should be avoided in patients with HFrEF as well. 
• Class 1C antiarrhythmics and dronedarone increase mortality risk and should be avoided, as should disopyramide and sotalol in most cases. 
• In patients with concomitant diabetes, thiazolidinediones should be avoided due to an increased risk of HF hospitalizations and fluid retention. Two dipeptidyl peptidase-4 (DPP-4) inhibitors, saxagliptin, and alogliptin, should also be avoided because they increase the risk of HF hospitalizations due to an unknown mechanism.  
• Lastly, NSAIDs worsen HF symptoms and should be avoided when possible. 

---

This commentary and podcast are available for recertification credit through the American Pharmacists Association (APhA) Ambulatory Care Review and Recertification Program.  To learn more, visit APhA BCACP Recertification – Evidence-Based Practice Series.

References