Cluster Scheme Approach to Foundational Heart Failure With Reduced Ejection Fraction Therapy

      Highlights

      • 1.
        Foundational 4 therapies are started before personalized therapies.
      • 2.
        Each visit, NPs initiate or titrate 1 medication from each cluster to a maximum of 3.
      • 3.
        Patient and laboratory characteristics guide selection of medication class within each cluster.
      • 4.
        Titration occurs every 1-2 weeks with a goal of full titration of foundational 4 within 12 weeks.

      Abstract

      This review presents an evidence-based approach to heart failure with reduced ejection fraction (HFrEF), focusing on the foundational 4 drugs: renin-angiotensin-aldosterone system inhibitors/angiotensin receptor-neprilysin inhibitor, β-blockers, mineralocorticoid receptor antagonist, and sodium–glucose cotransporter-2 inhibitor. Given the benefits of the foundational 4 drugs, combined initiation of these therapies is preferable to the conventional paradigm of targeting maximally tolerated β-blockers and renin-angiotensin-aldosterone system inhibitors before adding other therapies. The conventional approach is linked to treatment gaps and delayed introduction of life-saving therapies in patients with HFrEF. The conventional approach was replaced with the cluster approach, based on large-scale randomized control trials. The cluster approach demonstrated a reduction in morbidity and mortality in patients with HFrEF.

      Keywords

      American Association of Nurse Practitioners (AANP) members may receive 1.0 continuing education contact hour, approved by AANP, by reading this article and completing the online posttest and evaluation at aanp.inreachce.com.

      Introduction

      Heart failure (HF) is inadequate cardiac output caused by structural or functional cardiac deformity,
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      contributing to increased mortality and morbidity of affected patients.
      • Jonsson A.
      • Norberg H.
      • Bergdahl E.
      • Lindmark K.
      Obstacles to mineralocorticoid receptor antagonists in a community-based heart failure population.
      The heart’s inability to pump enough blood and oxygen can result in end-organ damage.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      HF with reduced ejection fraction (HFrEF) is the diagnosis given to patients when their left ventricular ejection fraction (LVEF) is ≤40%.
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.
      Given the low ejection fraction, the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS) mediate a compensatory neurohormonal reaction to boost cardiac output.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Initially, these systems act by increasing the myocardial contractility and heart rate; however, prolonged activation of the compensatory mechanisms becomes maladaptive, leading to myocardial hypertrophy and downregulation of the β-1 adrenergic receptor.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The compensatory activation of SNS and stimulation of the RAAS result in the release of angiotensin II and aldosterone, which trigger vasoconstriction and sodium and water reabsorption, respectively.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      In turn, the blood volume increases, resulting in distention of the cardiac chamber and subsequent release of atrial natriuretic peptides (ANP) and B-type natriuretic peptides (BNP) from the atria and ventricles.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The ANP and BNP counterbalance the maladaptive neurohormonal mechanisms by producing vasodilation, natriuresis, and diuresis.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Similarly, endothelial cells release nitric oxide, which favors vasodilation.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Current pharmacologic treatments for HFrEF aim to block these maladaptive neurohormonal compensatory mechanisms to attenuate or reverse their adverse remodeling effect on the myocardial muscle.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      ,
      • El Hussein M.T.
      • Blayney S.
      • Clark N.
      ABCs of heart failure management: a guide for nurse practitioners.
      The latest Canadian Cardiovascular Society (CCS) guideline (2021) emphasizes the importance of using the pharmacologic titration steps based on the New York Heart Association (NYHA) functional classes (Table 1)
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.
      and the patients’ tolerability of drug therapy.
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      The aim of this review is to provide an updated and comprehensive overview of the current titration approach of pharmacotherapy in patients with HFrEF.
      Table 1Definition of New York Heart Association Classification
      ClassDefinitionDescriptor
      INo symptoms. No limitation of physical activityAsymptomatic
      IISymptoms with ordinary activity. Comfortable at restMild symptoms
      IIISymptoms with less than ordinary activityModerate symptoms
      IVSymptoms at rest or with any minimal activitySevere symptoms
      Adapted from Ezekowitz et al.
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.

      Conventional Approach vs Cluster Approach Strategies

      Compared with conventional therapy, the cluster approach can add nearly 6 years to the life expectancy of patients with HFrEF.
      • Vaduganathan M.
      • Claggett B.L.
      • Jhund P.S.
      • et al.
      Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials.
      Inadequate optimizations of the foundational 4 therapy results in clinical inertia where patients fall short of receiving evidence-based therapy.
      • Greene S.J.
      • Butler J.
      • Fonarow G.C.
      Simultaneous or rapid sequence initiation of quadruple medical therapy for heart failure—optimizing therapy with the need for speed.
      In following the conventional approach, it may take 6 months to prescribe all of the recommended therapies to achieve the target doses of each drug class.
      • Vaduganathan M.
      • Claggett B.L.
      • Jhund P.S.
      • et al.
      Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials.
      A delay of 6 months of therapeutic outcomes can lead to hospitalization
      • Vaduganathan M.
      • Claggett B.L.
      • Jhund P.S.
      • et al.
      Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials.
      and a higher risk for mortality and morbidity.
      • Greene S.J.
      • Butler J.
      • Fonarow G.C.
      Simultaneous or rapid sequence initiation of quadruple medical therapy for heart failure—optimizing therapy with the need for speed.
      Hence, it is best for practitioners to promptly implement the foundational 4 therapies when not contraindicated.
      • Greene S.J.
      • Butler J.
      • Metra M.
      Another reason to embrace quadruple medical therapy for heart failure: medications enabling tolerance of each other.
      On the other hand, the cluster approach ensures a concise, timely, and practical guide for treating patients with HFrEF.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      The cluster approach emphasizes in-hospital initiation and titration because it allows close monitoring of the patients and early recognition of adverse effects.
      • Dixit N.M.
      • Shah S.
      • Ziaeian B.
      • Fonarow G.C.
      • Hsu J.J.
      Optimizing guideline-directed medical therapies for heart failure with reduced ejection fraction during hospitalization.
      After discharge from the hospital, the nurse practitioner (NP) or general practitioner in the clinic can use the cluster approach algorithms to expedite the process of further titration and initiation of drug therapy.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The cluster-based strategy consists of 3 clusters, where each cluster represents a category of drugs with similar hemodynamic or neurohormonal effects.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Cluster A includes sodium–glucose cotransporter-2 inhibitor (SGLT2I) and loop diuretics. Cluster B includes angiotensin receptor-neprilysin inhibitor (ARNI) as the preferred medication instead of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) and mineralocorticoid receptor antagonists (MRAs). Cluster C includes β-blockers and ivabradine.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      To implement the cluster approach, NPs should be cognizant of the risks of starting additional HFrEF therapies before all of the foundational 4 drug classes are initiated.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The NP should wait at least 1 to 2 weeks before starting uptitration within each drug class to avoid adverse effects.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Moreover, Miller et al
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      indicated that patients with systolic blood pressure >110 mm Hg, heart rate >70 beats/min, estimated glomerular filtration rate (eGFR) >40 mL/min/1.73 m2, and potassium ˂5.0 mmol/L can typically withstand 3 drug class changes per visit with a low risk of adverse effects. Whereas for weaker patients possibly intolerant to medication, changing a single drug class every 2 weeks is recommended.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Although McDonald et al
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      recommend a fast and rapid titration interval of 2 to 4 weeks to target dose or a maximally tolerated dose over 3 to 6 months, Miller et al
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      recommend a faster titration interval of 1 to 2 weeks within 3 months, suggesting rapid changes can optimize HFrEF treatment outcomes.

      The Foundational Four

      The developers of guideline-directed medical therapy for HFrEF evidence-based recommendations include the simultaneous use of 4 foundational medications to improve clinical outcomes and achieve maximal benefits in terms of mortality, morbidity, and quality of life.
      • Dixit N.M.
      • Shah S.
      • Ziaeian B.
      • Fonarow G.C.
      • Hsu J.J.
      Optimizing guideline-directed medical therapies for heart failure with reduced ejection fraction during hospitalization.
      These include (1) β-blockers, (2) ACEIs or ARBs, or ARNI, (3) SGLT2Is, and (4) aldosterone antagonists.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      While the guidelines encourage clinicians to gradually uptitrate the doses of these classes to reach the maximally tolerated dose within 3 to 6 months, reaching medication optimization can take an average of 12 months.
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      Data from the United States registries suggest that only 25% of patients with HFrEF are on optimized guideline-directed medical therapy,
      • Komajda M.
      • Anker S.D.
      • Cowie M.R.
      • et al.
      Physicians’ adherence to guideline-recommended medications in heart failure with reduced ejection fraction: data from the QUALIFY global survey.
      while a large percentage of these patients do not receive the foundational 4 or receive suboptimal dosing, resulting in frequent hospitalization, poor quality of life, and sometimes death.
      • Greene S.J.
      • Butler J.
      • Albert N.M.
      • et al.
      Medical therapy for heart failure with reduced ejection fraction: the CHAMP-HF Registry.
      Given the high risk for mortality associated with this population, it is imperative to start the foundational 4 at the time of diagnosis.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      ,
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      The cluster is an evidence-based approach developed to overcome the conundrum of slow or delayed initiation of the foundational 4.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      ,
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      It includes the simultaneous and rapid sequence initiation and titration of the foundational 4 therapy and is linked to improved survival by achieving timely targeted or maximally tolerated doses.
      • Greene S.J.
      • Butler J.
      • Fonarow G.C.
      Simultaneous or rapid sequence initiation of quadruple medical therapy for heart failure—optimizing therapy with the need for speed.

      RAAS Inhibitors

      The first drug therapy in the foundational 4 are medicines that inhibit the RAAS system, including the ACEIs, the ARBs, and the ARNI.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The NP may select from these 3 drug classes depending on the patient’s allergies and tolerances.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      ACEIs were the gold standard medication for HFrEF patients for the past 3 decades because of their ability to inhibit ACEs that convert angiotensin I to angiotensin II.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Inhibiting the release of angiotensin II reverses myocardial remodeling and fibrosis and improves survival rates.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      Furthermore, ACEI decreases the cardiac afterload by inhibiting the degradation of bradykinin, a peptide that promotes vasodilation.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.

      Angiotensin Receptor Blockers

      ARBs, on the other hand, do not cause an increase in bradykinin because they do not block ACE.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Instead, they are receptor antagonists that block angiotensin II type receptors.
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ,
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Tia et al
      • Tai C.
      • Gan T.
      • Zou L.
      • et al.
      Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular events in patients with heart failure: a meta-analysis of randomized controlled trials.
      conducted a meta-analysis of 38 randomized controlled trials. They established that the use of ACEI is associated with a reduction in all-cause mortality and cardiovascular mortality compared with ARBs, where ACEI administration reduced all-cause mortality by 11% (P < .001) and cardiovascular mortality by 14% (P < .001).
      • Tai C.
      • Gan T.
      • Zou L.
      • et al.
      Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular events in patients with heart failure: a meta-analysis of randomized controlled trials.
      However, ARBs are recognized as an alternative to ACEI if the latter induces adverse effects of dry cough or angioedema.
      • Tai C.
      • Gan T.
      • Zou L.
      • et al.
      Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular events in patients with heart failure: a meta-analysis of randomized controlled trials.

      Angiotensin Receptor-Neprilysin Inhibitor

      The ARNIs are combination products of neprilysin inhibitors, sacubitril, and valsartan (an ARB).
      • Dargad R.R.
      • Prajapati M.R.
      • Dargad R.R.
      • Parekh J.D.
      Sacubitril/valsartan: a novel angiotensin receptor-neprilysin inhibitor.
      ARNI works by blocking the action of neprilysin, thus preventing the breakdown of the natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide [BNP]) and bradykinin.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      In the 2021 CCS guideline, McDonald et al
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      recommend that it is best practice for NPs to prescribe and/or titrate ARNI during HFrEF patient hospitalizations. The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial (n = 8,399) investigated patients with NYHA functional class II to IV classification and with LVEF of ≤40% already taking HF medications to determine the efficacy of ARNI over ACEI.
      • Okumura N.
      • Jhund P.S.
      • Gong J.
      • et al.
      Effects of sacubitril/valsartan in the PARADIGM-HF Trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) according to background therapy.
      The PARADIGM-HF trial has proven that using ARNI vs ACEI reduced recurring hospitalization and, most significantly, the risk of cardiovascular deaths in patients with chronic HF (P < .001).
      • Okumura N.
      • Jhund P.S.
      • Gong J.
      • et al.
      Effects of sacubitril/valsartan in the PARADIGM-HF Trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) according to background therapy.
      The initiation of ARNI vs ACEI also showed benefits in reducing cardiovascular (CV) deaths or HF hospitalization when started before discharge.
      • Wachter R.
      • Senni M.
      • Belohlavek J.
      • et al.
      Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study.
      ,
      • DeVore A.D.
      • Braunwald E.
      • Morrow D.A.
      • et al.
      Initiation of angiotensin-neprilysin inhibition after acute decompensated heart failure: secondary analysis of the open-label extension of the PIONEER-HF Trial.
      Therefore, it is best practice for the NPs to initiate ARNI and titrate it accordingly during hospitalization (Table 2).
      • Greene S.J.
      • Butler J.
      • Fonarow G.C.
      Simultaneous or rapid sequence initiation of quadruple medical therapy for heart failure—optimizing therapy with the need for speed.
      ,
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      ,
      • Maddox T.M.
      • Januzzi Jr., J.L.
      • et al.
      Writing Committee
      2021 Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee.
      ,
      • McDonagh T.A.
      • Metra M.
      • Adamo M.
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [published correction appears in Eur Heart J. Oct 14, 2021].
      ARNIs should be avoided in patients with a history of angioedema.
      • Maddox T.M.
      • Januzzi Jr., J.L.
      • et al.
      Writing Committee
      2021 Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee.
      Table 2Canadian Cardiovascular Society Initial and Target Dosing for Foundational Therapies and Additional Therapies
      Adapted from McDonald et al.7
      Drug ClassSpecific AgentStart DoseTarget Dose
      ARNI
      Adaptad from Maddox et al19 and McDonagh et al.20
      Sacubitril-valsartan24/26-49/51 mg bid97/103 mg bid
      ACEIEnalapril1.25-2.5 mg bid10 mg bid/20 mg bid (NYHA IV)
      Lisinopril2.5-5 mg daily20-35 mg daily
      Perindopril2-4 mg daily4-8 mg daily
      Ramipril1.25-2.5 mg bid5 mg bid
      Trandolapril1-2 mg daily4 mg daily
      ARBCandesartan4-8 mg daily32 mg daily
      Valsartan40 mg bid160 mg bid
      β-BlockerCarvedilol3.125 mg bid25 mg bid/50 mg bid (>85 kg)
      Bisoprolol1.25 mg daily10 mg daily
      Metoprolol (CR/XL)12.2-25 mg daily200 mg daily
      MRASpironolactone12.5 mg daily25-50 mg daily
      Eplerenone25 mg daily50 mg daily
      SGLT2 inhibitorDapagliflozin10 mg daily10 mg daily
      Empagliflozin10 mg daily10-25 mg daily
      Canagliflozin100 mg daily100-300 mg daily
      Sinus node inhibitorIvabradine2.5-5 mg bid7.5 mg bid
      sGC stimulatorVericiguat2.5 mg daily10 mg daily
      VasodilatorHydralazine and isosorbide dinitrate10-37.5 mg tid/10-20 mg tid75-100 mg tid or qid/40 mg tid
      Cardiac glycosidesDigoxin0.0625-0.125 mg dailyNot applicable: monitor for toxicity
      ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; bid = twice daily; CR/XR = controlled release/extended release; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; sGC = soluble guanylate cyclase; SGLT2 = sodium-glucose transporter 2; tid = thrice daily; qid = 4 times daily.
      a Adapted from McDonald et al.
      • Greene S.J.
      • Butler J.
      • Fonarow G.C.
      Simultaneous or rapid sequence initiation of quadruple medical therapy for heart failure—optimizing therapy with the need for speed.
      b Adaptad from Maddox et al
      • Maddox T.M.
      • Januzzi Jr., J.L.
      • et al.
      Writing Committee
      2021 Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee.
      and McDonagh et al.
      • McDonagh T.A.
      • Metra M.
      • Adamo M.
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [published correction appears in Eur Heart J. Oct 14, 2021].

      β-Blocker

      The second class of medication of the foundational 4 is β-blockers, a group of drugs that inhibit the SNS activation and halt renin activities.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Selective β-1, such as bisoprolol and metoprolol succinate, can reverse remodeling in the left ventricle, decrease heart rate (independent of SNS inhibition), and promote nitric oxide production.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      β-Blockers are the most beneficial agent in reducing the morbidity and mortality associated with HFrEF.
      • Narayanan M.A.
      • Reddy Y.N.
      • Baskaran J.
      • Deshmukh A.
      • Benditt D.G.
      • Raveendran G.
      Ivabradine in the treatment of systolic heart failure-a systematic review and meta-analysis.
      They reduce myocardial workload due to their effective rate-lowering action and their interference with catecholamine-related ventricular tachyarrhythmias.
      • Packer M.
      • McMurray J.J.V.
      Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction.
      Packer et al
      • Packer M.
      • McMurray J.J.V.
      Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction.
      from the European Society of Cardiology (ESC) showed that β-blockers reduced all-cause mortality among patients with severe HF or recent decompensation by 34% to 35% demonstrated in 3 large-scale trials. On the other hand, the American College of Cardiology 2021 recommended avoiding β-blockers in patients with decompensated HF and monitoring heart rate, blood pressure, and signs of congestion during and after their administration.
      • Maddox T.M.
      • Januzzi Jr., J.L.
      • et al.
      Writing Committee
      2021 Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee.
      It is recommended that the β-blockers dose be adjusted every 2 weeks
      • Maddox T.M.
      • Januzzi Jr., J.L.
      • et al.
      Writing Committee
      2021 Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee.
      (the incremental initiation and target dose are detailed in Table 2). To ensure that β-blockers are initiated safely, practitioners should ensure that patients are clinically euvolemic before starting therapy.
      • Packer M.
      • McMurray J.J.V.
      Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction.
      The practitioner should monitor the patient for possible fluid retention and congestion development and be prepared to start diuretics.
      • Packer M.
      • McMurray J.J.V.
      Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction.
      Failure to do so may result in worsening HF.
      • Packer M.
      • McMurray J.J.V.
      Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction.
      Following the cluster approach, it is best practice to combine β-blockers with SGLT2Is or add diuretics when needed.
      • Packer M.
      • McMurray J.J.V.
      Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction.
      The NPs should be cognizant that β-blockers may take between 6 and 12 months to reach their full potential in improving LVEF.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      Moreover, it is recommended that cardiologists initiate and monitor the effects of β-blockers in patients with NYHA class III or IV.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      Noncardiologists can initiate and adjust β-blockers in patients with NYHA classes I or II.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      According to a meta-analysis, 18 trials included 3,023 patients, with 1,305 treated with placebo and the remaining 1,718 with β-blockers.
      • Zhang X.
      • Shen C.
      • Zhai S.
      • Liu Y.
      • Yue W.W.
      • Han L.
      A meta-analysis of the effects of β-adrenergic blockers in chronic heart failure.
      Of these patients, 116 (9.6%) experienced hospitalizations, which was statistically significant (P < .001).
      • Zhang X.
      • Shen C.
      • Zhai S.
      • Liu Y.
      • Yue W.W.
      • Han L.
      A meta-analysis of the effects of β-adrenergic blockers in chronic heart failure.
      Ezekowitz et al
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.
      and McDonald et al
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      CCS guidelines recommend initiating β-blockers as a first-line treatment in the foundational 4 therapies immediately after a HF diagnosis using NYHA class I to III without disruption unless contraindicated. For NYHA class IV, initiate a β-blocker once patients’ symptoms have stabilized.
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.
      ,
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      It is highly recommended that NPs start β-blockers in all patients with a history of myocardial infarction and an LVEF ≤40%.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      β-Blockers should be initiated to an optimal or maximal tolerated dose (Table 2) as long as excessive bradycardia and hypotension are not a deterring factor.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.

      Mineralocorticoid Receptor Antagonist

      MRA is the third drug class of the foundational 4.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      MRA antagonizes the action of mineralocorticoid aldosterone at its receptor in the myocardium and vascular smooth muscle cells.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Moreover, MRAs exert antifibrotic properties by decreasing the synthesis of matrix metalloproteinases and other enzymes involved in interstitial myocardium remodeling.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      In 2016, Berbenetz and Mrkobrada
      • Berbenetz N.M.
      • Mrkobrada M.
      Mineralocorticoid receptor antagonists for heart failure: Systematic review and meta-analysis.
      conducted a systematic review and meta-analysis to examine the effectiveness of MRAs in HFrEF, focusing on cardiovascular death, all-cause mortality, and cardiac hospitalization as the main composite end points. They established that MRAs are linked to a reduction in cardiovascular death (relative risk, 0.81; 95% CI, 0.75-0.87), all-cause mortality (relative risk, 0.83; 95% CI, 0.77-0.88), and cardiac hospitalization (relative risk, 0.80; 95% CI, 0.70-0.92) in patients with HFrEF.
      • Berbenetz N.M.
      • Mrkobrada M.
      Mineralocorticoid receptor antagonists for heart failure: Systematic review and meta-analysis.

      Sodium–Glucose Cotransporter-2 Inhibitors

      The last drug class of the foundational 4 is SGLT2Is.
      • El Hussein M.T.
      • Bell N.
      Sodium-glucose cotransporter-2 inhibitors: heart failure and renal protection indications.
      Although SGLT2Is were initially studied and indicated for treating diabetes mellitus (DM) by increasing the urinary excretion rate of glucose, they have shown favorable outcomes in HFrEF patients.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Evidence was strong enough for a class SGLT2I recommendation in the 2021 CCS guidelines.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      The diuretic and natriuretic action of SGLT2I are thought to be responsible for the observed cardiovascular benefits.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      ,
      • El Hussein M.T.
      • Bell N.
      Sodium-glucose cotransporter-2 inhibitors: heart failure and renal protection indications.
      The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial results showed that individuals with HFrEF who received SGLT2I had a reduced risk of worsening HF or CV death (P = .00001) compared with placebo.
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      Additionally, SGLT2Is reduced the risk of having the first incidence of worsening HF, hospitalization for HF/urgent HF visits, and the risk of CV mortality.
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      Similarly, the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and Reduced Ejection Fraction (EMPEROR-Reduced) established low CV mortality and HF hospitalization rates, regardless of DM status, in patients who were given SGLT2I (P ˂ .0001).
      • Packer M.
      • Anker S.D.
      • Butler J.
      • et al.
      Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: The EMPEROR-Reduced Trial [published correction appears in Circulation. 2021;143(4):e30].
      All-cause deaths and CV deaths were also lower in both landmark trials.
      • Zannad F.
      • Ferreira J.P.
      • Pocock S.J.
      • et al.
      SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.
      Of note, empagliflozin resulted in a 20% to 40% improvement in NYHA functional class,
      • Packer M.
      • Anker S.D.
      • Butler J.
      • et al.
      Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: The EMPEROR-Reduced Trial [published correction appears in Circulation. 2021;143(4):e30].
      whereas canagliflozin and dapagliflozin reduced the decline in eGFR and renal outcomes.
      • Packer M.
      • Anker S.D.
      • Butler J.
      • et al.
      Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: The EMPEROR-Reduced Trial [published correction appears in Circulation. 2021;143(4):e30].
      ,
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      SGLT2Is were highly beneficial with optimized HF background therapies.
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ,
      • Packer M.
      • Anker S.D.
      • Butler J.
      • et al.
      Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: The EMPEROR-Reduced Trial [published correction appears in Circulation. 2021;143(4):e30].
      SGLT2I seldom causes hypoglycemia unless administered concurrently with insulin secretagogue treatment.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      Dapagliflozin 10 mg is administered for HF management in patients with or without DM with no need for further titration.
      • Packer M.
      • Anker S.D.
      • Butler J.
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      Empagliflozin is also given 10 mg daily for HF management and may increase to 25 mg if being used for glycemic control.
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      Canagliflozin does not yet have an HF dosing schedule.
      • El Hussein M.T.
      • Blayney S.
      • Clark N.
      ABCs of heart failure management: a guide for nurse practitioners.
      NPs should incorporate SGLT2Is as part of the standard foundational 4 therapy in HFrEF patients with or without DM (Table 2).
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      Owing to the progression of HF and renal events, particularly patients presenting with albuminuria, NPs should use SGLT2Is, such as canagliflozin or dapagliflozin, regardless of DM status.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.

      Assess for Additional Therapies

      In additional to the foundational 4, the NP should consider adding additional therapies to better control HFrEF symptoms and improve clinical outcomes.

      Ivabradine

      Ivabradine should be added to patients with HF in sinus rhythm with heart rate ≥70 beats/min in combination with foundational therapies to prevent CV death and reduce the incidence of HF hospitalization.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      ,
      • McDonagh T.A.
      • Metra M.
      • Adamo M.
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [published correction appears in Eur Heart J. Oct 14, 2021].
      Ivabradine reduces the heart rate through its selective inhibition of f-channels (If) in the sinus node.
      • Ferrari R.
      Ivabradine: heart rate and left ventricular function.
      While ivabradine is not indicated in patients with atrial fibrillation
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      , it is beneficial in patients in normal sinus rhythm with contraindication to β-blockers.
      • Maddox T.M.
      • Januzzi Jr., J.L.
      • et al.
      Writing Committee
      2021 Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee.
      A systematic review and meta-analysis of 6 studies that included patients with HFrEF (LVEF ˂40%) and mean heart rate ≥70 beats/min, who were on ivabradine and β-blockers or β-blocker alone, showed a significant reduction in heart rates in the combination group compared with the β-blocker group (P ˂ .001).
      • Hartmann C.
      • Bosch N.L.
      • de Aragão Miguita L.
      • Tierie E.
      • Zytinski L.
      • Baena C.P.
      The effect of ivabradine therapy on heart failure patients with reduced ejection fraction: a systematic review and meta-analysis.
      Unlike β-blocker, ivabradine does not impact blood pressure or myocardial contractility
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.
      ,
      • Narayanan M.A.
      • Reddy Y.N.
      • Baskaran J.
      • Deshmukh A.
      • Benditt D.G.
      • Raveendran G.
      Ivabradine in the treatment of systolic heart failure-a systematic review and meta-analysis.
      and should not be given to patients with advanced liver disease.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      Ivabradine is not a substitute for a β-blocker.
      • Maddox T.M.
      • Januzzi Jr., J.L.
      • et al.
      Writing Committee
      2021 Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee.
      The 2017 CCS and the 2021 American College of Cardiology guidelines recommend that NPs should make every attempt to reach the target or maximum tolerable β-blocker dosages before initiating ivabradine.
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.
      ,
      • Maddox T.M.
      • Januzzi Jr., J.L.
      • et al.
      Writing Committee
      2021 Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee.

      Oral Soluble Guanylate Cyclase Stimulators

      The addition of oral soluble guanylate cyclase (sGC) stimulator, such as vericiguat, increases cyclic guanylate monophosphate, thus increasing the sensitivity of endogenous sGC to nitric oxide.
      • Armstrong P.W.
      • Roessig L.
      • Patel M.J.
      • et al.
      A multicenter, randomized, double-blind, placebo-controlled trial of the efficacy and safety of the oral soluble guanylate cyclase stimulator.
      Nitric oxide, in turn, causes relaxation of myocardial muscle and vasodilation of blood vessels,
      • Hartmann C.
      • Bosch N.L.
      • de Aragão Miguita L.
      • Tierie E.
      • Zytinski L.
      • Baena C.P.
      The effect of ivabradine therapy on heart failure patients with reduced ejection fraction: a systematic review and meta-analysis.
      thus promoting physiologic adaptation processes to limit myocardial remodeling and deterioration of HF.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      ,
      • Hartmann C.
      • Bosch N.L.
      • de Aragão Miguita L.
      • Tierie E.
      • Zytinski L.
      • Baena C.P.
      The effect of ivabradine therapy on heart failure patients with reduced ejection fraction: a systematic review and meta-analysis.
      In the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial, the researchers enrolled 5,050 patients with chronic HF NYHA class II, III, or IV, LVEF ˂45%, and high levels of BNP or pro-BNP to determine the impact of vericiguat in reducing CV death or first HF hospitalization.
      • Armstrong P.W.
      • Pieske B.
      • Anstrom K.J.
      • et al.
      Vericiguat in patients with heart failure and reduced ejection fraction.
      The results were favorable among the 2526 vericiguat group (P = .02).
      • Armstrong P.W.
      • Roessig L.
      • Patel M.J.
      • et al.
      A multicenter, randomized, double-blind, placebo-controlled trial of the efficacy and safety of the oral soluble guanylate cyclase stimulator.
      CV death and primarily hospitalization for HF were lower in the vericiguat group than the placebo group.
      • Armstrong P.W.
      • Pieske B.
      • Anstrom K.J.
      • et al.
      Vericiguat in patients with heart failure and reduced ejection fraction.
      The new current Canadian guidelines recommend against using vericiguat in patients with systolic blood pressure ˂100 mm Hg or patients on nitrate therapy.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      ,
      • Armstrong P.W.
      • Pieske B.
      • Anstrom K.J.
      • et al.
      Vericiguat in patients with heart failure and reduced ejection fraction.
      Patients with natriuretic peptide levels >8,000 pg/mL did not benefit from the therapy compared with patients in the lower quartile range of natriuretic peptide.
      • Ezekowitz J.A.
      • O’Connor C.M.
      • Troughton R.W.
      • et al.
      N-terminal pro-B-type natriuretic peptide and clinical outcomes.
      Regarding safety and tolerability, vericguat appeared to be safe without severe adverse effects on renal function or electrolytes compared with the placebo.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      Based on the VICTORIA outcomes and when vericiguat is approved by Health Canada, NPs can prescribe sGC stimulator for HFrEF patients with worsening symptoms that leads to hospitalization.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.

      Hydralazine and Nitrates

      Hydralazine is a direct arterial vasodilator, and nitrates exhibit vasodilatory effects by promoting nitric oxide production.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Several studies reported outcomes of patients with class III or IV HF who were randomly assigned to isosorbide dinitrate plus hydralazine or placebo in addition to foundational 4 therapy for HF.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      Hydralazine and isosorbide dinitrate (H-ISDN) compared with placebo reduced all-cause mortality, initial hospitalization for HF, and optimized the quality of life in Black patients.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      In self-identified Black patients with HFrEF and NYHA class III to IV, the 2016 ESC, CCS 2017, and 2021 American College of Cardiology guidelines recommend H-ISDN be initiated in Black patients to reduce hospitalization for HF and CV death.
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ,
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.
      ,
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      H-ISDN is particularly useful for those who do not respond or have adverse reactions to ACEI, ARB, or ARNI.
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.
      ,
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      H-ISDN can be used in patients with a serum creatinine >220 mmol/L (2.49 mg/dL) due to renal insufficiency or experienced hyperkalemia from RAASI therapies.
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.
      ,
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      Similarly, Ziaeian et al
      • Ziaeian B.
      • Fonarow G.C.
      • Heidenreich P.A.
      Clinical effectiveness of hydralazine–isosorbide dinitrate in African-American patients with heart failure.
      found that most patients on H-ISDN had a history of renal insufficiency, hyperkalemia, or ACEI/ARB intolerance. Although H-ISDN therapy is the preferred treatment in the Black patients’ subgroup, ARNI (or alternatively ACEI/ARB) must be considered and carefully introduced before adding H-ISDN.
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.
      ,
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      Based on previous research and the current findings, NPs should consider the H-ISDN combination (not separately) for Black patients with HFrEF after thorough clinical assessment and consideration of foundational therapies.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.

      Oral Inotropes

      Digoxin increases contractility and raises the intracellular levels of calcium by decreasing its efflux.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Omecamtiv mecarbil (OM) is a relatively novel drug that acts as a cardiac-specific myosin activator.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      OM has an inotropic effect, which improves the heart’s systolic function without raising its energy demand or the risks associated with increased calcium in cardiac myocytes or increasing the risk of ventricular arrhythmias.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Studies have shown that in individuals with HFrEF, OM treatment decreased the composite outcome of HF episodes and CV mortality.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      No recommendations have been given at this time due to the drug’s relatively small impact compared with placebo in a high-risk HF patient and the uncertainty surrounding whether OM will obtain regulatory approval in Canada.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      The 2016 ESC and the 2017 and 2021 CCS guidelines recommend using digoxin for patients in sinus rhythm with persistent symptoms of HF despite optimal therapy.
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ,
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.
      ,
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      The ESC and CCS recommend using digoxin in patients who require additional rate control for atrial fibrillation despite β-blocker therapy.
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ,
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      Low potassium levels and renal insufficiency can increase the risk of cardiac arrhythmias with a high digoxin dose.
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure.
      ,
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      NPs should monitor digoxin toxicity because there is no defined maximum dose (Table 2).
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.

      Sequencing Strategy

      Ideally, NPs should aim to optimize each cluster during a clinic visit and initiate 1 drug class within each cluster to a maximum of 3 changes per visit.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Drugs within each cluster should not be initiated or titrated on the same visit to prevent exacerbated adverse effects.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Using the cluster approach is safer than starting all the foundational classes of 4 drugs at once.
      • Packer M.
      • McMurray J.J.V.
      Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction.
      Starting all 4 classes at once may increase the risk of orthostatic hypotension, hyperkalemia, and worsening eGFR.
      • Komajda M.
      • Anker S.D.
      • Cowie M.R.
      • et al.
      Physicians’ adherence to guideline-recommended medications in heart failure with reduced ejection fraction: data from the QUALIFY global survey.
      Frail patients specifically may not tolerate starting all 4 classes at once, and features such as advanced age, lower systolic blood pressure, and lower eGFR should guide which medication class within each cluster is chosen to avoid medication intolerance.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      During the first face-to-face encounter, NPs should prescribe the preferred medications in each cluster; as such, SGLT2I, ARNI, and β-blocker should be initiated simultaneously.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      On the second encounter within 1 to 2 weeks, NPs can see the patients face-to-face or virtually to continue SGLT2I in cluster A, start MRA in cluster B, and adjust cluster C.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The third visit can be a virtual visit, and NPs can add a loop diuretic as needed to achieve euvolemia and treat volume overload, titrate cluster B medication (ARNI, MRAs), and titrate cluster C (β-blockers) medication.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      For cluster C, β-blocker can be titrated weekly for up to 2 to 3 months, and if the sinus rate remains >70 beats/min, ivabradine, a selective sinus node inhibitor, is recommended.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      ESC noted that MRA could be initiated before ARNI if the patient cannot tolerate the hypotensive episodes of angiotensin receptor–neprilysin inhibition (eg, patients with a systolic blood pressure <100 mm Hg).
      • Packer M.
      • McMurray J.J.V.
      Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction.
      Furthermore, if the patient only has exposure to renin-angiotensin system inhibitors, switching to ARNI and MRA at the same time is feasible.
      • Packer M.
      • McMurray J.J.V.
      Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction.
      NPs should continue to manage foundational therapies, monitor patient’s characteristics, and add additional therapies as needed.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.

      Adherence to the Cluster Approach

      Shah et al
      • Shah S.P.
      • Dixit N.M.
      • Mendoza K.
      • et al.
      Integration of clinical pharmacists into a heart failure clinic within a safety-net hospital. J Am Pharm Assoc (2003).
      noted that patients’ adherence to drug therapy, clinical improvements between clinic visits, and low hospital readmissions could be maintained by involving clinical pharmacists. Similarly, providing safe and rapid titration for HFrEF patients can be maintained while transitioning from the inpatient to outpatient environment.
      • Dixit N.M.
      • Shah S.
      • Ziaeian B.
      • Fonarow G.C.
      • Hsu J.J.
      Optimizing guideline-directed medical therapies for heart failure with reduced ejection fraction during hospitalization.
      Dixit et al
      • Dixit N.M.
      • Shah S.
      • Ziaeian B.
      • Fonarow G.C.
      • Hsu J.J.
      Optimizing guideline-directed medical therapies for heart failure with reduced ejection fraction during hospitalization.
      indicated that strategies such as telephone follow-up, education, self-management, weight monitoring, sodium restriction or dietary advice, exercise recommendations, medication review, and social and psychological support can be used to help with the implementation of the cluster approach.
      Further, within 1 to 2 weeks after discharge, laboratory results, such as renal function indicators, potassium, and glucose, should be examined to assess for adverse responses to foundational therapies.
      • Dixit N.M.
      • Shah S.
      • Ziaeian B.
      • Fonarow G.C.
      • Hsu J.J.
      Optimizing guideline-directed medical therapies for heart failure with reduced ejection fraction during hospitalization.
      Similarly, BNP and N-terminal pro-BNP can be evaluated for possible rehospitalization and response to therapy.
      • Dixit N.M.
      • Shah S.
      • Ziaeian B.
      • Fonarow G.C.
      • Hsu J.J.
      Optimizing guideline-directed medical therapies for heart failure with reduced ejection fraction during hospitalization.
      Specialized nurses and pharmacists can continue escalating foundational therapy through telehealth in liaison with the cardiologist.
      • Dixit N.M.
      • Shah S.
      • Ziaeian B.
      • Fonarow G.C.
      • Hsu J.J.
      Optimizing guideline-directed medical therapies for heart failure with reduced ejection fraction during hospitalization.
      Desai et al
      • Desai A.S.
      • Maclean T.
      • Blood A.J.
      • et al.
      Remote optimization of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction [published correction appears in JAMA Cardiol. 2021;6(4):485].
      stated that using a remote medication optimization approach enhanced initiation and titration of foundational 4 therapy to target dosage and bridged the gap between guideline-directed medical therapy guidelines and clinical application. At 3 months, 197 of 1,131 patients who were enrolled in the remote medication approach demonstrated favorable increase in baseline use of renin-angiotensin system antagonists (138 [70.1%] to 170 [86.3%]; P < .001) and β-blockers (152 [77.2%] to 181 [91.9%]; P < .001) but not MRA (51 [25.9%] to 60 [30.5%]; P = .14) due to its assessment difficulties.
      • Desai A.S.
      • Maclean T.
      • Blood A.J.
      • et al.
      Remote optimization of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction [published correction appears in JAMA Cardiol. 2021;6(4):485].
      Rossignol et al
      • Rossignol P.
      • Coats A.J.
      • Chioncel O.
      • Spoletini I.
      • Rosano G.
      Renal function, electrolytes, and congestion monitoring in heart failure [published correction appears in Eur Heart J Suppl. 2019;21(Suppl M):M72].
      indicated that measuring renal function and electrolytes is based on the patient’s characteristics and the clinical incidence of complications. In stable patients, serum electrolytes, creatinine, and serum urea nitrogen are regularly tested every 1 to 3 months.
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      In patients with worsening symptoms, the NPs should measure serum creatinine at each visit (or virtual).
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      Creatinine should be tested every 5 to 10 days after adding or increasing the dose of diuretic
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      and after initiation or change in ACEI, ARB, MRA, or nonsteroidal anti-inflammatory drug treatment.
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      If the patient’s serum potassium is close to or >5.0 mEq/L, serum potassium should be tested every 3 to 5 days.
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      After that, within 1 to 2 days of sodium (calcium or sodium polystyrene) or calcium resonium use or initiation/change in potassium supplement therapy.
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      Howlett et al
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      recommended early serum creatinine measurements when the renal status is impacted by illness such as gastroenteritis or influenza, or after surgery.
      Aside from controlling systemic hypertension, there is no agreement on which blood pressure is optimal.
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      For patients with reduced LVEF, some clinicians would seek to maintain systolic blood pressure between <110 and 120 mm Hg.
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      Certain clinical barriers to foundational therapies that can hinder optimal HF management are presented in (Table 3).
      • Dixit N.M.
      • Shah S.
      • Ziaeian B.
      • Fonarow G.C.
      • Hsu J.J.
      Optimizing guideline-directed medical therapies for heart failure with reduced ejection fraction during hospitalization.
      Medications provided at discharge are adhered to and continued in the outpatient setting.
      • Dixit N.M.
      • Shah S.
      • Ziaeian B.
      • Fonarow G.C.
      • Hsu J.J.
      Optimizing guideline-directed medical therapies for heart failure with reduced ejection fraction during hospitalization.
      Further adherence strategies for medical optimization include pillboxes, smartphone apps, medications logs, and referral to HF-specific medication titration clinics.
      • Dixit N.M.
      • Shah S.
      • Ziaeian B.
      • Fonarow G.C.
      • Hsu J.J.
      Optimizing guideline-directed medical therapies for heart failure with reduced ejection fraction during hospitalization.
      A simplified HFrEF medication sequencing algorithm is illustrated in the Figure.
      Table 3Overcoming Common Clinical Barriers to Guideline-Directed Medical Therapies Optimization
      Adapted from Dixit et al.10
      Barrier to OptimizationFirst-Line StrategySecond-Line Strategy
      Acute kidney injury
      • Reduce dose or hold RAAS-I/ARNI. Retrial once renal function improves
      • Reduce diuretic dose to the lowest dose required to maintain euvolemia
      • Switch RAAS-I/ARNI to combination of hydralazine/nitrate only after multiple failed trial
      Hyperkalemia
      • Remove potassium supplementation
      • Consider addition of potassium-binders and low potassium diet
      • Add SGLT2I
      • Retrial with ARNI (instead of ACEI or ARB)
      • Reduce or hold doses of RAAS-I/ARNI or MRA. Retrial one at a time
      • Switch RAAS-I/ARNI to combination of hydralazine/nitrate only after multiple failed trial
      Symptomatic hypotension
      • Reduce or remove medications that lower BP and are not guideline recommended
      • Stagger doses of foundational therapy that lower BP (eg, morning and evening doses)
      • Reduce foundational therapy dose based on symptoms of hypotension, not BP parameters alone
      • Reduce diuretic dose to the lowest dose to required maintain euvolemia
      • Prioritize β-blocker dosage
      • Switch carvedilol to metoprolol succinate
      • Reduce dosage of RAAS-I/ARNI
      • Switch ARNI to ACEI/ARB and retrial with ARNI in future
      • Reduce SGLT2I dose and retrial at regular dose in future
      Adherence
      • Medication reminders (eg, pillboxes, smartphone apps, medication logs). Use once daily medications
      • Postdischarge telehealth.
      • Refer to HF-specific medication titration clinics
      Cost/insurance
      • Submit prior authorization requests early in hospitalization
      • Assess patient willingness and ability to pay and prescribe more affordable medications, if necessary
      • Periodically reassess availability of new/higher cost medications
      • Perform institution-specific cost-effectiveness analysis
      ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; BP = blood pressure; HF = heart failure; MRA = mineralocorticoid receptor antagonist; RAAS-I = renin-angiotensin-aldosterone system inhibitor; SBP = systolic blood pressure; SGLT2I = sodium–glucose cotransporter-2 inhibitor.
      a Adapted from Dixit et al.
      • Dixit N.M.
      • Shah S.
      • Ziaeian B.
      • Fonarow G.C.
      • Hsu J.J.
      Optimizing guideline-directed medical therapies for heart failure with reduced ejection fraction during hospitalization.
      Figure thumbnail gr1
      FigureSimplified medication sequencing algorithm for heart failure with reduced ejection fraction. aVericiguat is not yet approved by Health Canada. Adapted from Miller et al
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      and McDonald et al.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      AF = atrial fibrillation; ARNI = angiotensin receptor neprilysin inhibitor; BB = β-blocker; HF = heart failure; HR = heart rate; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; SGLT2i = sodium–-glucose cotransport-2 inhibitor; SR = sinus rhythm.
      Lengthy or repeated attempts to titrate β-blockers without result should be avoided before starting sinus node inhibitor.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      All foundational 4 classes must be initiated before adding personalized medications and before dose titration.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Personalized therapies are given to benefit certain subgroups of patients with HFrEF.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Furthermore, the mentioned cluster scheme was designed with the understanding that patients require personalized therapies based on parameters such as tolerability, medical history, vital signs, and so on.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Therefore, personalized therapies alone cannot improve all-cause mortality.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      For instance, ivabradine can only improve mortality if the patient’s heart rate is >77 beats/min despite the maximal tolerated β-blockade.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Similarly, digoxin can be used for atrial fibrillation or ongoing symptoms despite optimal therapy.
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      Hydralazine nitrates are proven to be beneficial in self-identified Black ethnicity on foundational therapy or intolerant of ACE/ARB/ARNI.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Vericiguat has shown benefit in recent HF hospitalization and elevated natriuretic peptide.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The NP should attempt to initiate or titrate 1 medication class within each cluster at every clinical encounter, to a maximum of 3.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The purpose of each clinical visit is to start or titrate 1 drug class within each cluster. For instance, practitioners cannot titrate ARNI and MRA simultaneously because they are in a similar cluster.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The NP prescription practices of choosing medication from a particular cluster should be guided by the patient and laboratory characteristics.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The NP can alternate between medication classes within a cluster in the absence of a preferred choice.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The NP should attempt to schedule a meeting with the patient every 1 to 2 weeks, if possible, with a goal of full foundational therapy titration within 12 weeks.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The NP should wait at least 2 weeks before attempting titration within each medication to improve tolerance and mitigate adverse effects.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Intolerance of a medication initiation/titration not related to volume depletion should stop further changes in that class until other foundational therapy titration is achieved.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      The NP should avoid multiple attempts to titrate a particular medication class before adjusting the other cluster classes.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.
      Although there is some preferability in sequencing order of HFrEF drugs; for example, starting only with ARNI or combined with SGLT2I as a first step, followed by simultaneous treatment of β-blocker and MRA as a second step, ESC noted it is unwise to debate the subtle differences.
      • Packer M.
      • McMurray J.J.V.
      Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction.
      Instead, practitioners should aim to initiate the 4 foundational drugs within a few weeks.
      • Packer M.
      • McMurray J.J.V.
      Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction.
      The in-hospital environment showed significant benefits and an opportunity to initiate and titrate HFrEF therapy.
      • Miller R.J.H.
      • Howlett J.G.
      • Fine N.M.
      A novel approach to medical management of heart failure with reduced ejection fraction.

      Conclusion

      The NP should focus on initiating the foundational 4 drug classes as soon as HFrEF is diagnosed. Mortality and morbidity are reduced when 4 foundational drug classes therapy are initiated within 4 weeks; thus, the rate of medication titration should not exceed 3 months (12 weeks) when possible. It is critical to initiate 1 medication from each cluster at each visit and uptitrate simultaneously. Initiating medications from the same cluster is not recommended within the same visit. In the absence of a preferred choice within a cluster, uptitrate each at alternating visits. The NP can make up to 3 changes per visit based on their assessment of the patient’s symptoms, vital signs, and renal function. The cluster approach to HFrEF therapy titration can guide NPs to improve morbidity and mortality in this high-risk patient population.

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      Biography

      Mohamed Toufic El Hussein, PhD, NP, is professor at the school of Nursing and Midwifery, Faculty of Health, Community & Education, Mount Royal University and adjunct associate professor, Faculty of Nursing, University of Calgary, and Acute Care Nurse Practitioner Medical Cardiology, Coronary Care Unit, Rockyview General Hospital, Calgary, Alberta, Canada, and can be contacted at [email protected] and on twitter @drmohamednp.
      Samir Negash is a BN student at Mount Royal University, Calgary, Alberta, Canada.