In addition to today’s resource, please review The Curbsiders‘ #458 Heart Failure with Reduced Ejection Fraction.*
*Gorth DJ, Kittleson MM, Williams PN, Watto MF. “#458 Heart Failure with Reduced Ejection Fraction”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast October 21, 2024.
This blog has a number of posts on diuretic resistance. To access, type Diuretic Resistance in the search box.
Today, I review, link to, and excerpt from the 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 [No Abstract Available] [Full-Text HTML] [Full-Text PDF]. 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.
Overview
The 2021 Update to the 2017 American College of Cardiology (ACC) Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction1 provided a practical, streamlined resource for clinicians managing patients with heart failure with reduced ejection fraction (HFrEF). The expert consensus decision pathway (ECDP) provided guidance on introducing the numerous evidence-based therapies, improving adherence, overcoming treatment barriers, acknowledging contraindications and situations for which little data exist, affording expensive therapies, treating special cohorts, and making the transition to palliative care. Rather than focusing on extensive text, the document provided practical tips, tables, and figures to make clear the steps, tools, and provisos needed to treat the patient with HFrEF successfully and expeditiously. Many of the pivotal issues addressed in the ECDP were not the substance of clinical trials; rather, they represent the challenge of clinical practice.
Since publication of the 2021 ECDP, new data have developed that necessitate an update to the ECDP, including publication of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.2 This update thus serves as updated guidance to clinicians based on contemporary knowledge. The treatment of HFrEF can feel overwhelming, and many opportunities to improve patient outcomes are being missed; hopefully, this ECDP will streamline care to realize the best possible patient outcomes in HF (heart failure).
1 Introduction
The prevalence of HF is escalating rapidly, with a projected increase of 34% in upcoming decades.3,4 Compounding this, HF is a syndrome that consumes substantial health care resources, inflicts considerable morbidity and mortality, and adversely affects quality of life. Important breakthroughs have redefined opportunities to change the natural history of HF with a broad range of medical therapies, devices, and care strategies.
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.
2 Assumptions and Definitions
To limit inconsistencies in interpretation, specific assumptions (eg, treatment effects in varied populations) were considered by the writing group in development of the ECDP. References are supplied when applicable or appropriate.
2.1 General Clinical Assumptions
1. Although many topics are generalizable to all patients with HF, the focus of this effort is on patients with HFrEF. The reader is directed to the 2023 ACC ECDP on Management of HFpEF for more focused details on care for this population.5
2. Although some of the recommendations may be relevant to patients hospitalized with acute HF or in those with left ventricular ejection fractions (LVEFs) higher than 40%, this document focuses primarily on the management of patients with chronic HFrEF with LVEF ≤40% in the ambulatory setting and without symptoms or signs of clinical instability. For a patient presenting with symptoms of orthopnea or uncomfortable peripheral edema, the initial therapy would include diuretic agent therapy with early follow-up to ensure progress toward decongestion; following that, the steps outlined in this document would apply. For more information on care of worsening HF/congestion, the reader is directed to the ACC ECDP on Risk Assessment, Management, and Clinical Trajectory of Patients Hospitalized with HF.6
3. The expert consensus Writing Committee endorses the evidence-based approaches to HF therapy and management enumerated in the 2022 AHA/ACC/HFSA HF guideline.2
4. These algorithms assume the clinician will seek input as needed from a pharmacist, a cardiologist, an HF specialist, and/or a disease management program, and/or other relevant specialists (eg, endocrinologists or nephrologists) to guide clinical management.
5. In all cases, patient preferences and values, in addition to evidence-based clinical judgment, should guide clinical decision-making.
6. At any point in time, these suggestions and algorithms may be superseded by new data.
2. “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”. J Am Coll Cardiol . 2022;79:e263-e421.
5. “2023 ACC expert consensus decision pathway on management of heart failure with preserved ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee”. J Am Coll Cardiol . 2023;81:1835-1878.
6. “2019 ACC expert consensus decision pathway on risk assessment, management, and clinical trajectory of patients hospitalized with heart failure: a report of the American College of Cardiology Solution Set Oversight Committee”. J Am Coll Cardiol . 2019;74:1966-2011.
2.2 Definitions
AHA/ACC/HFSA Stages of HF:
▪ Stage A: At risk for HF but without symptoms, structural heart disease, or cardiac biomarkers of stretch or injury (eg, patients with hypertension, atherosclerotic cardiovascular disease, diabetes, metabolic syndrome and obesity, exposure to cardiotoxic agents, genetic variant for cardiomyopathy, or positive family history of cardiomyopathy).
▪ Stage B: Structural heart disease but no prior or current signs or symptoms of HF. Structural heart disease may include reduced left or right ventricular function, left ventricular (LV) hypertrophy, chamber enlargement, wall motion abnormalities, or valvular heart disease. Additionally, evidence for increased filling pressures by invasive hemodynamic measurements or imaging as well as elevated concentrations of B-type natriuretic peptide (BNP)/N-terminal pro–B-type natriuretic peptide (NT-proBNP) or high-sensitivity cardiac troponins.
▪ Stage C: Structural heart disease with prior or current symptoms of HF.
▪ Stage D: Marked HF symptoms that interfere with daily life, with recurrent hospitalizations despite attempts to optimize GDMT.
GDMT: Guideline-directed medical therapy, representing treatment options supported for use by clinical practice guidelines.
HFrEF: Clinical HF and LVEF ≤40%.
New York Heart Association (NYHA) functional classification:
▪ Class I: No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.
▪ Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF.
▪ Class III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF.
▪ Class IV: Unable to perform any physical activity without symptoms of HF, or symptoms of HF at rest.
Optimal therapy: GDMT provided at either the target or the highest-tolerated dose for a given patient.
Target doses: Doses targeted in clinical trials.
3 Pathway Summary Graphic
Figure 1 is an update of the 2017 ACC ECDP Summary Graphic outlining the 10 pivotal issues about HFrEF
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.8-14 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.15-18
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.
Figure 1
Ten Pivotal Issues About HFrEF
CV = cardiovascular; GDMT, guideline-directed medical treatment; HF = heart failure; HFrEF = heart failure with reduced ejection fraction.
Table 1Starting and Target Doses of GDMT for HF (Choice and timing of each therapy and who should have them added are discussed in the text)∗
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.
∗ Digoxin remains indicated for HFrEF, but there are no contemporary data to warrant additional comment in this document. The reader is referred to already available guideline statements.2
† Isosorbide mononitrate is not recommended by the 2022 ACC/AHA/HFSA HF guideline.2
‡ The 2022 ACC/AHA/HFSA HF guideline2 considers either the fixed-dose combination or the separate combination of isosorbide dinitrate and hydralazine as appropriate guideline-directed therapy for HF.
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 2Indications 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
