Links To And Excerpts From “2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee”

Today, I review, and repost Links To And Excerpts From “2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee”.

Today, I review, link to, and excerpt from 2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Thomas M Maddox, James L Januzzi Jr, Larry A Allen, Khadijah Breathett, Sara Brouse, Javed Butler, Leslie L Davis, Gregg C Fonarow, Nasrien E Ibrahim, JoAnn Lindenfeld, Frederick A Masoudi, Shweta R Motiwala, Estefania Oliveros, Mary Norine Walsh, Alan Wasserman, Clyde W Yancy, Quentin R Youmans. J Am Coll Cardiol. 2024 Apr 16;83(15):1444-1488. doi: 10.1016/j.jacc.2023.12.024. Epub 2024 Mar 8.

All that follows is from the above resource.

1. Introduction

The purpose of this document is to update the 2021 ECDP with further data from recent studies and to provide succinct, practical guidance for managing patients with HFrEF. The format of the 10 Pivotal Issues in the prior versions of this ECDP was preserved, and their associated treatment algorithms and tables have been updated to accommodate the evolving evidence. The Preface and Methods sections are accessible online in the Supplemental Appendix.

Ten Pivotal Issues in HFrEF

1. How to initiate, add, or switch therapies with consideration of newer evidence-based guideline-directed treatments for HFrEF.

2. How to achieve optimal therapy given multiple drugs for HF, including augmented clinical assessment (eg, imaging data, biomarkers, and filling pressures) that may trigger modifications in guideline-directed therapy.

3. When to refer to an HF specialist.

4. How to enhance care coordination.

5. How to improve medication adherence.

6. How to tailor treatment in specific patient cohorts: African-American patients, older adults, and patients with frailty.

7. How to manage patients’ costs and increase access to HF medications.

8. How to manage the increasing complexity of HF.

9. How to manage common comorbidities.

10. How to integrate palliative care and the transition to hospice care.

4. Description and Rationale: Answers to 10 Pivotal Issues in HF

4.1. How to Initiate, Add, or Switch to Evidence-Based Guideline-Directed Therapy for HFrEF

Although loop diuretic agents are an important part of the treatment of congestion in the individual with HFrEF, once approaching or achieving euvolemia, it is critical to add and optimize therapies proven to reduce morbidity and mortality. Established pharmacological therapies for chronic HFrEF include renin-angiotensin inhibitors such as angiotensin II receptor/neprilysin inhibitors (ARNIs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs), along with evidence-based beta-blockers, sodium-glucose cotransporter (SGLT) inhibitors, mineralocorticoid antagonists, loop diuretic agents, hydralazine/isosorbide dinitrate (HYD/ISDN), ivabradine, and vericiguat. With the exception of loop diuretic agents, all of these therapies have been shown in randomized controlled trials to improve symptoms, reduce hospitalizations, and/or prolong survival.^2,7 In contrast, use of digoxin as a treatment for HFrEF lacks contemporary data; most of its use in modern HFrEF management focuses on its role as a rate control agent for atrial fibrillation (AF) in those with low blood pressure.

Since the publication of the 2021 ECDP, more data have emerged to support early and rapid initiation and titration of the “4 pillars” of GDMT to maximize the early benefits of improvement in patient-reported outcomes, reduction in HF hospitalizations, reduction in mortality, and improved adherence to GDMT.8, 9, 10, 11, 12, 13, 14 When using the therapeutic standard of a 4-drug regimen (ARNI, beta-blocker, mineralocorticoid antagonist, SGLT inhibitor), there is an aggregate treatment effect that includes increasing years of survival and years free from cardiovascular (CV) death or HF hospitalizations.¹⁵ As an example, 4-class medication initiation reduced the hazard of CV death or hospital admission for HF significantly (HR: 0.38; 95% CI: 0.3-0.47) compared with therapy with just an ACE inhibitor/ARB plus a beta-blocker.15, 16, 17, 18

Another important development since the publication of the 2021 ECDP is the growing recognition of the safety and urgency of initiating therapies rapidly. As an example, the STRONG-HF (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies) trial showed that among patients admitted to the hospital with acute HF, high-intensity management that included rapid up-titration of GDMT and close follow-up, with a goal of reaching target doses within 6 weeks of discharge after hospitalization, was safe, well-tolerated, and associated with a reduced risk of 180-day all-cause death or HF readmission compared with usual care.^18,19

Finally, the VICTORIA (Vericiguat Global Study in Patients With Heart Failure and Reduced Ejection Fraction) trial showed that in higher-risk patients with HFrEF already on GDMT with worsening symptoms, the oral soluble guanylyl cyclase stimulator vericiguat was superior to placebo in reducing the risk of HF hospitalization and/or CV death.²⁰ Subsequently, vericiguat was given a Class 2b recommendation in the updated 2022 AHA/ACC/HFSA HF guideline.² In light of these developments, an update on when and how to add, switch, and titrate all HFrEF therapies to maximally tolerated and, ideally, target doses (Figure 1, Table 1) was deemed important.

Table 1. Starting and Target Doses of GDMT for HF (Choice and timing of each therapy and who should have them added are discussed in the text)∗

Empty Cell	Starting Dose	Target Dose
Beta-blockers
Bisoprolol	1.25 mg once daily	10 mg once daily
Carvedilol	3.125 mg twice daily	25 mg twice daily for weight <85 kg and 50 mg twice daily for weight ≥85 kg
Metoprolol succinate	12.5-25 mg daily	200 mg daily
ARNI
Sacubitril/valsartan	24/26 mg to 49/51 mg twice daily	97/103 mg twice daily
ACE inhibitors
Captopril	6.25 mg 3× daily	50 mg 3× daily
Enalapril	2.5 mg twice daily	10-20 mg twice daily
Lisinopril	2.5-5 mg daily	20-40 mg daily
Ramipril	1.25 mg daily	10 mg daily
ARBs
Candesartan	4-8 mg daily	32 mg daily
Losartan	25-50 mg daily	150 mg daily
Valsartan	40 mg twice daily	160 mg twice daily
Mineralocorticoid antagonists
Eplerenone	25 mg daily	50 mg daily
Spironolactone	12.5-25 mg daily	25-50 mg daily
SGLT inhibitors
Dapagliflozin	10 mg daily	10 mg daily
Empagliflozin	10 mg daily	10 mg daily
Sotagliflozin	200 mg daily	400 mg daily
Vasodilators
Hydralazine	25 mg 3× daily	75 mg 3× daily
Isosorbide dinitrate†	20 mg 3× daily	40 mg 3× daily
Fixed-dose combination isosorbide dinitrate/hydralazine‡	20 mg/37.5 mg (one tab) 3× daily	2 tabs 3× daily
Ivabradine
Ivabradine	2.5-5 mg twice daily	Titrate to heart rate 50-60 beats/min. Maximum dose 7.5 mg twice daily
Oral soluble guanylyl cyclase stimulator
Vericiguat	2.5 mg daily	10 mg daily

ACC = American College of Cardiology; ACE = angiotensin-converting enzyme; AHA = American Heart Association; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor/neprilysin inhibitor; GDMT = guideline-directed medical therapy; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; HFSA = Heart Failure Society of America; SGLT = sodium-glucose cotransporter; tab = tablet.

HF is a complex clinical syndrome typically associated with multiple comorbidities; most patients are on multiple medications. No clinical trials have specifically evaluated the potential for greater benefit or excessive risk of indicated therapies among patients with multimorbidity. To assess tolerability of medications and best assess the trajectory of HF, it is often necessary for patients to have more frequent follow-ups, especially after initiation or titration of therapy. These follow-ups may be in-person or virtual on a case-by-case basis and depending on patient stability and adjustment(s) made.

4.1.1. Initiating GDMT

Recommendations for starting GDMT in a patient with a new diagnosis of symptomatic HFrEF are detailed in Figure 2.

Figure 2. Treatment Algorithm for Guideline-Directed Medical Therapy

∗ACE inhibitors/ARBs should only be considered in patients with contraindications, intolerance, or inaccessibility to ARNI. In those instances, please consult Figure 3 and the text for guidance on initiation. †Carvedilol, metoprolol succinate, or bisoprolol. Colors correspond to ACC/AHA Class of Recommendation. Green = Class 1 (strong); Yellow = Class 2a (moderate); Orange = Class 2b (weak). ARNI = angiotensin receptor/neprilysin inhibitors; ACC = American College of Cardiology; AHA = American Heart Association; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; NYHA = New York Heart Association; SGLT = sodium-glucose cotransporter.

In a patient with new-onset Stage C HFrEF, a common question is which medication class to initiate first, and a common second question is how rapidly to add additional agents and titrate medication doses. There is no optimal order of initiation and/or titration, so the Writing Committee recommends that clinicians will need to approach each patient in an individual fashion to decide on which agents to titrate and when to do so. The Writing Committee also recommends that regardless of the sequencing of agents, careful initiation and titration of GDMT should be early and as rapid as possible with a goal to use the 4 key medication classes in each patient.

For the person with de novo HFrEF, therapies should be initiated with a goal of reaching target or maximally tolerated doses of the 4 key medication classes as soon as possible, and ideally no longer than 3 months. In many individuals, some GDMT may already be in place, and the Writing Committee recommends initiation and titration of missing key therapies as rapidly as possible, with a goal of reaching target or maximally tolerated doses in an even shorter period. These recommendations are because the STRONG-HF trial showed safety and efficacy of a goal of 50% of target doses by hospital discharge and 100% of target doses by 2 weeks following discharge from the hospital, focusing on an approach that used mostly ACE inhibitors/ARBs, evidence-based beta-blockers, and mineralocorticoid antagonists. Importantly, the STRONG-HF trial had very limited use of ARNI, and SGLT2 inhibitor use was not prioritized. Accordingly, recognizing the challenges introduced by the additional complexity of GDMT and potential hemodynamic impact of the preferred ARNI class, a longer time horizon may be necessary. The Writing Committee affirms potential value from more rapid titration, if safely possible. In some cases, the combination of 4 classes of GDMT can be started at the same time at low doses, and more than 1 titration at a time may be done. In other cases, sequencing of individual medications or various combinations may be necessary.

Recent results from clinical trials examining initiation of ARNI in those without ACE inhibitor or ARB pretreatment suggest that this strategy is well-tolerated and effective, improves health status, and generates considerable reverse cardiac remodeling. Accordingly, the Writing Committee affirms its previous stance of directly initiating ARNI whenever possible to avoid delays in optimizing GDMT.^14,21,22

The initiation and titration of GDMT may require consideration of the individual patient phenotype. For example, initiation of an ARNI (Table 1, Figures 2 and 3) is often better tolerated when the patient is still congested (“wet”), whereas beta-blockers are better tolerated when the patient is less congested (“dry”) with an adequate resting heart rate; beta-blockers should not be newly initiated in patients with decompensated signs or symptoms but can be continued with decompensated HF. Only evidence-based beta-blockers should be used in patients with HFrEF (Table 1, Figures 2 and 3). Titration of ARNI/ACE inhibitor/ARB and beta-blockers is discussed in Section 4.2. When used at guideline-recommended doses, mineralocorticoid antagonists, SGLT inhibitors, and vericiguat have minimal, if any, blood pressure–lowering effect.

Figure 3. GDMT, Including Newer Therapies, in the ECDP for Chronic HF

ARNIs are the preferred renin-angiotensin system inhibitor and should be used as first-line therapy whenever possible. For patients in whom ARNI administration is not possible, an ACE inhibitor/ARB is recommended. ∗Carvedilol, metoprolol succinate, or bisoprolol. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor/neprilysin inhibitors; CBC = complete blood count; eGFR = estimated glomerular filtration rate; SGLT = sodium-glucose cotransporter.

4.1.2. Angiotensin Receptor/Neprilysin Inhibitor

Sacubitril/valsartan is 1 of the “4 pillars” of medical care for HFrEF. The 2022 AHA/ACC/HFSA HF guideline² recommends sacubitril/valsartan as a Class I, Level of Evidence: A therapy to reduce the risk of HF hospitalization and CV mortality in patients with symptomatic chronic HFrEF (Figures 2 and 3, Table 2).

Table 2. Indications for ARNI, Ivabradine, SGLT Inhibitor, and Vericiguat Use

Indications for Use of an ARNI in HFrEF

NYHA functional class II-IV HF Administered in conjunction with a background of GDMT for HF in place of an ACE inhibitor or ARB

Indications for Use of Ivabradine in HFrEF

LVEF ≤35% On maximum tolerated dose of beta-blocker Sinus rhythm with a resting heart rate ≥70 beats/min NYHA functional class II or III HF

Indications for Use of an SGLT Inhibitor in HFrEF

HFrEF (EF ≤40%) with or without diabetes NYHA functional class II-IV HF Administered in conjunction with a background of GDMT for HF

Indications for Use of Vericiguat

HFrEF (LVEF <45%) On maximum tolerated GDMT Worsening HF symptoms

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; EF = ejection fraction; GDMT = guideline-directed medical therapy; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; SGLT = sodium-glucose cotransporter.

Neprilysin, also known as neutral endopeptidase, is a zinc-dependent metalloprotease that inactivates several vasoactive peptides, including the natriuretic peptides, adrenomedullin, bradykinin, and substance P, each of which has an important role in the pathogenesis and progression of HF.²³ Because angiotensin II is also a substrate for neprilysin, neprilysin inhibitors raise angiotensin levels, which explains the rationale for coadministration of an ARB. Neprilysin inhibitors are not combined with an ACE inhibitor due to a higher risk of angioedema.²⁴

Sacubitril/valsartan^17,25 was tested in patients with chronic HFrEF in a randomized controlled trial, PARADIGM HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in HF). The trial enrolled patients with NYHA functional class II to IV symptoms with an ejection fraction (EF) ≤40% (modified to ≤35% 1 year into the trial), stable on doses of ACE inhibitors/ARBs, and on other background GDMT. Patients with a history of angioedema, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m², symptomatic hypotension or systolic blood pressure <100 mm Hg, or current decompensated HF were excluded. The trial began with a sequential run-in period to ensure that every patient who was randomized could tolerate target doses of both sacubitril/valsartan and the comparator enalapril. Of the 10,513 candidates screened, 2,079 were not randomized due to inability to achieve target-dose therapy on enalapril or sacubitril/valsartan. Most patients enrolled in PARADIGM-HF had NYHA functional class II to III symptoms (<100 patients with NYHA functional class IV symptoms).

PARADIGM-HF demonstrated an absolute 4.7% reduction in the primary outcome of CV death or HF hospitalization (HR: 0.80; 95% CI: 0.73-0.87; P < 0.001) in patients treated with sacubitril/valsartan vs enalapril. The number of patients who would need to be treated to prevent 1 primary endpoint over 27 months was 21. These differences in outcomes included a 20% reduction in sudden cardiac death, presumably due to reverse cardiac remodeling and improved EF.

Symptomatic hypotension was more common with sacubitril/valsartan (14.0% vs 9.2%; P < 0.001) but was not associated with worsening of kidney function. Angioedema was numerically higher but not statistically significantly different from enalapril in the sacubitril/valsartan group. The 2022 AHA/ACC/HFSA HF guideline² recommended an ARNI, ACE inhibitor, or ARB to reduce morbidity and mortality in patients with chronic HFrEF and that patients with NYHA functional class II to III symptoms who can tolerate an ACE inhibitor or ARB should transition to an ARNI to further reduce morbidity and mortality (Class I, Level of Evidence: B-R).^2,7,10,11 ARNIs have been associated with improvements in surrogates such as diastolic function, LV function, natriuretic peptide concentrations, burden of ventricular arrhythmias, and hard endpoints, including quality of life, costs, hospital days, and HF hospitalizations.^11,13,14,26, 27, 28, 29, 30 In the PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for HF) study, after 12 months of therapy with sacubitril/valsartan, the median LVEF increased from 28.2% to 37.8% (difference: 9.4%; 95% CI: 8.8%-9.9%; P < 0.001), whereas the median LV end-diastolic volume index decreased from 86.93 mL/m² to 74.15 mL/m² (difference, −12.25 mL/m² [interquartile range: −12.92, −11.58 mL/m²]; P < 0.001) and the median LV end-systolic volume index decreased from 61.68 to 45.46 mL/m² (difference: −15.29 mL/m²; 95% CI: −16.03 to −14.55 mL/m²; P < 0.001). Indexed left atrial volume by body surface area and the E/e′ ratio also decreased significantly.¹⁴ These results were demonstrated in important subgroups not represented in the PARADIGM-HF trial, such as those with de novo HF or naive to ACE inhibitors/ARBs, those with lower NT-proBNP concentrations at enrollment, or those not attaining the target dose during the study. The results from PROVE-HF were further substantiated by evidence from the randomized EVALUATE-HF (Effects of Sacubitril/Valsartan vs Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction) trial, which demonstrated that compared with enalapril, sacubitril/valsartan treatment improved echocardiographic parameters of reverse cardiac remodeling as early as 12 weeks.³¹

Emphasizing the preference for ARNIs over ACE inhibitors or ARBs, the PROVE-HF study demonstrated that improvement in LVEF was accompanied by a reduction in the presence and severity of mitral regurgitation (MR). Given increased use of percutaneous edge-to-edge repair of the mitral valve as an adjunct to GDMT, these results emphasize the importance of optimizing medical therapy, including ARNI, before deciding on such management; in PROVE-HF, 44% of those eligible for mitral valve clipping would no longer qualify after treatment with sacubitril/valsartan.³² In a similar fashion, the PROVE-HF investigators also reported on the potential impact of LVEF increase on eligibility for implantable cardioverter-defibrillator (ICD) placement. Among individuals with an LVEF ≤35% initiated on sacubitril/valsartan, following 12 months of ARNI treatment, 61% had an LVEF >35%.³³

A frequent question is whether use of a mineralocorticoid antagonist is mandatory before initiation of an ARNI. As there are no data to suggest that a mineralocorticoid antagonist is mandatory before ARNI therapy, lack of treatment with a mineralocorticoid antagonist should not delay initiating or switching a patient to an ARNI. Guidance for the transition from an ACE inhibitor or ARB to an ARNI is detailed in Figures 2 and 3 and in Tables 1, 2, 3, and 4.

Table 3. Dose Adjustments of Sacubitril/Valsartan for Specific Patient Populations

Population	Initial Dose
High-dose ACE inhibitor >10-mg total daily dose of enalapril or therapeutically equivalent dose of another ACE inhibitor	49/51 mg twice daily
High-dose ARB >160-mg total daily dose of valsartan or therapeutically equivalent dose of another ARB
De novo initiation of ARNI	24/26 mg twice daily
Low- or medium-dose ACE inhibitor ≤10-mg total daily dose of enalapril or therapeutically equivalent dose of another ACE inhibitor
Low- or medium-dose ARB ≤160-mg total daily dose of valsartan or therapeutically equivalent dose of another ARB
ACE inhibitor/ARB-naive
Severe kidney impairment∗ (eGFR <30 mL/min/1.73 m2)
Moderate hepatic impairment (Child-Pugh class B)
Elderly patients (age ≥75 y)

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor/neprilysin inhibitor; eGFR = estimated glomerular filtration rate; PARADIGM-HF = Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in HF.

∗ This population was not studied in the PARADIGM-HF trial. The statement is consistent with U.S. Food and Drug Administration–approved labeling indications.

Table 4. Contraindications and Cautions for Sacubitril/Valsartan, Ivabradine, SGLT Inhibitors, and Vericiguat

Contraindications	Cautions
A. Sacubitril/Valsartan
Within 36 h of ACE inhibitor use Any history of angioedema Pregnancy Lactation (no data) Severe hepatic impairment (Child-Pugh class C) Concomitant aliskiren use in patients with diabetes Known hypersensitivity to either ARBs or ARNIs	Kidney impairment: Mild-to-moderate (eGFR 30-59 mL/min/1.73 m2): no starting dose adjustment required Severe∗ (eGFR <30 mL/min/1.73 m2): reduce starting dose to 24 mg/26 mg twice daily; double the dose every 2-4 weeks to target maintenance dose of 97 mg/103 mg twice daily, as tolerated Hepatic impairment: Mild (Child-Pugh class A): No starting dose adjustment required Moderate (Child-Pugh class B): Reduce starting dose to 24/26 mg twice daily; double the dose every 2-4 weeks to target maintenance dose of 97/103 mg twice daily, as tolerated Renal artery stenosis Systolic blood pressure <100 mm Hg Volume depletion
B. SGLT Inhibitors
Not approved for use in patients with type 1 diabetes due to increased risk of diabetic ketoacidosis Known hypersensitivity to drug	For HF care, dapagliflozin or sotagliflozin, eGFR <25 mL/min/1.73 m2 Pregnancy Increased risk of mycotic genital infections May contribute to volume depletion. Consider altering diuretic agent dose if applicable Ketoacidosis in patients with diabetes: Temporary discontinuation for at least 3 days before scheduled surgery is recommended to avoid potential risk for ketoacidosis Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level Acute kidney injury and impairment in kidney function: Consider temporarily discontinuing in settings of reduced oral intake or fluid losses Urosepsis and pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated Necrotizing fasciitis* of the perineum (Fournier gangrene): Rare, serious, life-threatening cases have occurred in both female and male patients; assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise *Point of Care Ultrasound in the Diagnosis of Necrotizing Fasciitis. Am J Emerg Med. 2022 Jan:51:397-400. doi: 10.1016/j.ajem.2021.10.033. Epub 2021 Oct 29. “Abstract Background: Necrotizing fasciitis (NF) is a severe, life-threatening soft tissue infection requiring prompt diagnosis and immediate surgical debridement. Imaging, including a computed tomography (CT) scan, can often aid in the diagnosis, though it can prolong time to treatment and diagnosis. Point-of-care ultrasound (POCUS) is often used in the ED to identify soft tissue infections. The objective of this study is to evaluate the use of POCUS to identify NF in patients presenting to the emergency department.  .   . Results: We enrolled 64 patients in this study. Eight were determined to be at high risk of having NF based on CT scan and/or surgical impression. All of these patients also had POCUS images interpreted as concerning for NF. Furthermore, 56 patients were classified as being low risk for having NF based on CT scan and/or surgical impression. All but one of these patients had POCUS images interpreted as not concerning for NF. Conclusions: Our data indicates that POCUS can be used to identify NF with a high sensitivity and specificity.
C. Ivabradine
HFpEF Presence of angina with normal EF Hypersensitivity Severe hepatic impairment (Child-Pugh class C) Acute decompensated HF Blood pressure <90/50 mm Hg Sick sinus syndrome without a pacemaker Sinoatrial node block Second- or third-degree block without a pacemaker Persistent AF or flutter Atrial pacemaker dependence	Sinus node disease Cardiac conduction defects Prolonged QT interval Resting heart rate <60 beats/min
D. Vericiguat
Patients with concomitant use of other soluble guanylate cyclase stimulators Pregnancy	Patients with anemia Patients with symptomatic hypotension Concomitant use with PDE-5 inhibitors is not recommended due to the potential for hypotension

ACE = angiotensin-converting enzyme; AF = atrial fibrillation; ARB = angiotensin receptor blocker; EF = ejection fraction; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; PARADIGM-HF = Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in HF; PDE-5 = phosphodiesterase-5; SGLT = sodium-glucose cotransporter.

∗ This population was not studied in PARADIGM-HF. The statement is consistent with U.S. Food and Drug Administration–approved labeling indications.

In a patient without contraindications to ARNI (eg, no prior angioedema), when making the transition from an ACE inhibitor to an ARNI, a 36-hour washout period should be strictly observed (to avoid angioedema); this delay is not required when switching from an ARB to an ARNI.³⁴

An ideal time to consider GDMT initiation and/or optimization is during hospitalization for HFrEF, and the reader is directed to the 2019 ACC Expert Consensus Decision Pathway on Risk Assessment, Management, and Clinical Trajectory of Patients Hospitalized With Heart Failure.⁶ Although discussion of hospital-based initiation of ARNI is outside of the scope of this document, it is important to prioritize titration of GDMT for patients during the hospital-to-home transition. The PIONEER-HF (Comparison of Sacubitril–Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute HF Episode) trial established that the initiation of ARNI during an acute decompensated HF hospitalization is feasible²² after the patient has been hemodynamically stabilized; in PIONEER-HF, up to 25% of patients developed hypotension when treated with sacubitril/valsartan. Ensuring that patients are not volume-depleted at the time of initiation may help to avoid this issue. Notably, the TRANSITION (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event) study demonstrated that about one-half of patients could achieve the target dose within 10 weeks after in-hospital initiation or soon after discharge.²¹ Accordingly, following the patient’s discharge from the hospital, ongoing efforts toward GDMT optimization (including titration to target doses whenever possible) should continue. And, most recently, the STRONG HF trial demonstrated that for individuals hospitalized with acute HF, intensive and rapid initiation and titration of GDMT supported by in-person follow-up after hospitalization was safe, was tolerated, and resulted in a reduction in 180-day HF hospitalizations and/or CV deaths.³⁵

Clinicians should be advised that ARNIs may exert a greater blood pressure–lowering effect compared with ACE inhibitors/ARBs. Therefore, for patients with lower blood pressure (eg, systolic blood pressure ≤100 mm Hg), careful administration and follow-up are advised. In patients who are not obviously congested and have otherwise stable clinical profiles, decreasing the dose of loop diuretic agents may mitigate the hypotensive effects of sacubitril/valsartan.³⁶ Last, the LIFE trial randomized HFrEF patients with NYHA functional class IV symptoms to ARNI vs ARB and showed no statistically significant difference in NT-proBNP levels with sacubitril/valsartan compared with valsartan alone, no difference in clinical outcomes, and an increase in hyperkalemia events.³⁷ In addition, nearly one-half of the trial participants were unable to tolerate ARNI. Thus, the role of ARNIs may be limited in more advanced HFrEF. Nonetheless, the Writing Committee recommends its use in those who can tolerate it, with careful monitoring for adverse side effects, such as hyperkalemia.

4.1.3. Initiation of an ARNI De Novo Without Prior Exposure to an ACE Inhibitor or ARB

Some patients will meet all criteria for initiation of an ARNI but have not yet been treated with an ACE inhibitor or ARB. Recent data from clinical studies,10, 11, 12 along with aggregate clinical experience, suggest that directly initiating an ARNI, rather than a pretreatment period with an ACE inhibitor or ARB, is a safe and effective strategy. In a prospective study comparing the tolerability of different initiation strategies for sacubitril/valsartan,³⁴ patients with de novo HFrEF or those who were naive to ACE inhibitors/ARBs demonstrated no unexpected adverse effects compared with those already taking an ACE inhibitor/ARB. In a similar fashion, in an open-label prospective study of patients eligible for ARNI therapy, the PROVE-HF study demonstrated tolerability and significant reverse cardiac remodeling among those with de novo HFrEF or those naive to ACE inhibitors/ARBs, who had an average 12% increase in LVEF by 1 year. These results are also supported by data from studies of acute HFrEF that indicate efficacy and tolerability for those not previously treated with an ACE inhibitor/ARB.^12,38 In a prespecified subanalysis from PIONEER-HF, patients with de novo HF who underwent in-hospital initiation of an ARNI had a greater reduction in natriuretic peptide concentrations, a comparable safety profile, and a significant improvement in early clinical outcomes compared with those on enalapril²²; such improvement in early clinical outcomes would be lost in a scenario of ACE inhibitor/ARB pretreatment.

Because of this totality of data, a de novo ARNI approach is now preferred, with close follow-up, serial assessments (blood pressure, electrolytes, and kidney function), and consideration of the risk of angioedema or hypotension (Figures 2 and 3 and Tables 1, 2, 3, and 4). For those with contraindications to even low-dose ARNI (eg, systolic blood pressure <100 mm Hg), consideration should be given for an ACE inhibitor/ARB at very low doses.

When making a recommendation to initiate an ARNI (either as a switch or as de novo treatment), the Writing Committee recommends that the decision occurs within a framework of shared decision-making (https://www.cardiosmart.org/topics/heart-failure/assets/decision-aid/drug-options-for-patients-with-heart-failure). The Writing Committee is aware that an ARNI may not be easily accessible to all patients with HFrEF due to cost and insurance challenges (see the discussion on costs of care in Section 4.7). Although an ARNI is the preferred renin-angiotensin antagonist in HFrEF, an ACE inhibitor/ARB should be used to reduce morbidity and mortality in patients with HFrEF in such cases where the decision is not to use an ARNI. Patients who are initiated on an ARNI and later find it cost-prohibitive should be transitioned to an ACE inhibitor/ARB.

4.1.4. SGLT Inhibitors

SGLT inhibitors (including SGLT1/2 or SGLT2 inhibitors) are a core therapy in the “4 pillars” of medical care for HFrEF. The 2022 AHA/ACC/HFSA HF Guideline² recommends SGLT inhibitors as a Class I, Level of Evidence: A therapy to reduce the risk of HF hospitalization and CV mortality, irrespective of the presence of diabetes, in patients with symptomatic chronic HFrEF (Figures 2 and 3, Table 2). The contraindications to SGLT inhibitors are enumerated in Table 4. Although the mechanism of benefit from these agents in HFrEF remains uncertain, treatment with SGLT inhibitors leads to osmotic diuresis and natriuresis, decreases in arterial pressure and stiffness, and a shift to ketone-based myocardial metabolism.³⁹ Further benefits may be due to reduction of preload and afterload blunting of cardiac stress/injury with less hypertrophy and fibrosis, exerting favorable effects on autophagy and myocardial remodeling.^40,41

Beyond reducing CV events, SGLT inhibitors may have other benefits, including improvement in health status, reduction in loop diuretic agent dosage,⁴⁶ and reduced episodes of hyperuricemia and clinical gout.⁴⁷ Furthermore, SGLT inhibitors have minimal blood pressure–lowering effects^48,49; as such, they may be one of the preferred options for individuals with lower blood pressures who are intolerant to other GDMT choices. Last, the use of SGLT inhibitors reduces risk for hyperkalemia in those treated with mineralocorticoid antagonists and minimizes risk for the latter GDMT being discontinued.⁵⁰

The dosing for SGLT inhibitors is detailed in Table 1, whereas cautions and contraindications for SGLT inhibitors are enumerated in Table 4. Treatment with an SGLT inhibitor may increase diuresis (particularly in those with hyperglycemia); adjustment in loop diuretic agents may be necessary to avoid volume depletion in this setting.

Considerable clinician confusion exists about initiation of SGLT inhibitors in the setting of impaired kidney function. The Writing Committee recognizes that the glucosuric effects of SGLT inhibitors may be less pronounced in those with markedly reduced eGFR; however, this does not attenuate the CV benefits of SGLT inhibitors for HFrEF.⁵¹ Pivotal trials examining SGLT inhibitors in HFrEF typically had lower eGFR cutoffs of 20 to 30 mL/min/1.73 m²; however, recent label updates now have lower limits of 25 mL/min/1.73 m² for dapagliflozin and sotagliflozin, and no lower bound cutoff for empagliflozin. Following initiation of an SGLT inhibitor, a drop in eGFR is expected in many individuals (because of an increase in afferent glomerular arteriolar tone). Clinicians should not necessarily adjust or discontinue medications solely based on this expected change. In the clinical trials of dapagliflozin and empagliflozin, study participants with an eGFR below 20 mL/min/1.73 m² nonetheless continued treatment, with considerable benefits.⁵² Closer monitoring of such individuals is advised; however, in most cases, SGLT inhibitors should be continued. In contrast, in studies of sotagliflozin, the drug was discontinued if the eGFR dropped below 15 mL/min/1.73 m², so data with this agent in individuals with end-stage kidney disease are lacking.

Despite previous concerns about risk for limb amputation among those with diabetes treated with SGLT-2 inhibitors, this therapy has been repeatedly shown to be safe, even in those with peripheral arterial disease.^2,7,53 Similar to ARNI, the Writing Committee recognizes the potential financial burden related to drug costs of SGLT inhibitors; the reader is directed to the discussion on costs of care in Section 4.7.

4.1.5. Ivabradine

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