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Canadian Journal of Cardiology

A Novel Approach to Medical Management of Heart Failure With Reduced Ejection Fraction

  • Author Footnotes
    ∗ All authors contributed equally to this work.
    Robert J.H. Miller
    Footnotes
    ∗ All authors contributed equally to this work.
    Affiliations
    Division of Cardiology, Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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  • Author Footnotes
    ∗ All authors contributed equally to this work.
    Jonathan G. Howlett
    Correspondence
    Corresponding author: Dr Jonathan G. Howlett, Room C-838, 1403-29th Street NW, Calgary, Alberta, Canada T2N 2T9. Tel.: +1-403-944-3232; fax: +1-403-944-3262.
    Footnotes
    ∗ All authors contributed equally to this work.
    Affiliations
    Division of Cardiology, Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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  • Author Footnotes
    ∗ All authors contributed equally to this work.
    Nowell M. Fine
    Footnotes
    ∗ All authors contributed equally to this work.
    Affiliations
    Division of Cardiology, Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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  • Author Footnotes
    ∗ All authors contributed equally to this work.
Published:January 13, 2021DOI:https://doi.org/10.1016/j.cjca.2020.12.028

      Abstract

      The advent of newly available medical therapies for heart failure with reduced ejection fraction (HFrEF) has resulted in many potential therapeutic combinations, increasing treatment complexity. Publication of expert consensus guidelines and initiatives aimed to improve implementation of treatment has emphasized sequential stepwise initiation and titration of medical therapy, which is labour intensive. Data taken from heart failure registries show suboptimal use of medications, prolonged titration times, and consequently little change in dose intensity, all of which indicate therapeutic inertia. Recently published evidence indicates that 4 medication classes—renin-angiotensin-neprilysin inhibitors, β-blockers, mineralocorticoid antagonists, and sodium-glucose cotransporter inhibitors—which we refer to as Foundational Therapy, confer rapid and robust reduction in both morbidity and mortality in most patients with HFrEF and that they work in additive fashion. Additional morbidity and mortality may be observed following addition of several personalized therapies in specific subgroups of patients. In this review, we discuss mechanisms of action of these therapies and propose a framework for their implementation, based on several principles. These include the critical importance of rapid initiation of all 4 Foundational Therapies followed by their titration to target doses, emphasis on multiple simultaneous drug changes with each patient encounter, attention to patient-specific factors in choice of medication class, leveraging inpatient care, use of the entire health care team, and alternative (ie, virtual visits) modes of care. We have incorporated these principles into a Cluster Scheme designed to facilitate timely and optimal medical treatment for patients with HFrEF.

      Résumé

      L’avènement de nouveaux traitements médicaux de l’insuffisance cardiaque avec fraction d’éjection réduite (ICFER) a multiplié les associations thérapeutiques possibles, ce qui augmente la complexité du traitement. La publication de lignes directrices reposant sur le consensus de groupes d’experts et la mise en œuvre d’initiatives visant à améliorer les stratégies de traitement ont fait ressortir l’importance d’une amorce et d’un ajustement posologique progressifs et séquentiels des traitements médicaux, un processus exigeant beaucoup d’interventions. Les données tirées des registres des cas d’insuffisance cardiaque révèlent une utilisation sous-optimale des médicaments et un allongement des périodes d’ajustement posologique qui entraîne à son tour une faible intensification des doses, ce qui révèle une certaine inertie thérapeutique. Selon les données probantes publiées récemment, quatre classes de médicaments – à savoir les inhibiteurs de la néprilysine et du système rénine-angiotensine, les bêtabloquants, les antagonistes des récepteurs des minéralocorticoïdes et les inhibiteurs du cotransporteur sodium-glucose de type 2 – sont considérées comme étant les traitements fondamentaux de l’ICFER et procurent une réduction rapide et robuste de la morbidité et de la mortalité dans la plupart des cas, en plus d’avoir des effets additifs. Une hausse de la morbidité et de la mortalité peut être observée après l’ajout de plusieurs traitements personnalisés dans certains sous-groupes de patients. Nous présentons ici les modes d’action de ces traitements et proposons pour leur instauration un cadre fondé sur plusieurs principes : l’importance cruciale d’instaurer rapidement les quatre traitements fondamentaux et d’y apporter les ajustements posologiques nécessaires pour atteindre les doses cibles, la nécessité d’apporter simultanément plusieurs ajustements médicamenteux à chaque rencontre du patient, l’importance de prendre en compte les facteurs propres à chaque patient dans le choix d’une classe de médicaments, la mise à profit des soins en milieu hospitalier et le recours à tous les membres de l’équipe de soins de santé et à tous les modes de prestation de soins (p. ex. consultations virtuelles). Nous avons intégré ces principes en un modèle de regroupements conçu pour faciliter la mise en route d’un traitement médical optimal et en temps opportun chez les patients atteints d’ICFER.
      The last decade has seen substantial increase in the number of approved medical therapies for patients with heart failure (HF) caused by reduced ejection fraction (HFrEF). Increased treatment complexity, coupled with inadequate application of highly efficacious treatments, mandates a revamp of our approach to ensuring optimal and timely treatment. We will briefly review the pathophysiology of HFrEF and highlight mechanisms to target. We propose a novel framework for initiation and titration of combination medical therapy medication characterized by therapeutic class and placed in 2 therapeutic groups: Foundational Therapy and Personalized Therapy. Foundational Therapies are characterized by their rapid and additive benefits in both morbidity and mortality in most patients with HFrEF and include 4 medication classes: β-adrenergic receptor antagonists (β-blockers), renin-angiotensin-aldosterone system (RAAS) antagonists (including neprilysin inhibitors), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Personalized Therapies may provide further benefits in selected patients already receiving Foundational Therapy and include ivabradine, hydralazine-nitrate combinations, soluble guanylate cyclase (sGC) stimulators, diuretics, and oral inotropes. We advance new concepts, including the prioritization of initiating all Foundational Therapies before dose optimization, categorization of medication classes into 3 concurrently managed "Clusters," emphasis on in-hospital initiation and titration, and use of medication titration protocols using multidisciplinary teams and remotely assisted titration. Implantable cardiac devices, cardiac surgical interventions, and treatment of infiltrative or congenital cardiomyopathies or advanced heart failure are not included within the scope of this paper.
      • Huitema A.A.
      • Harkness K.
      • Malik S.
      • Suskin N.
      • McKelvie R.S.
      Therapies for advanced heart failure patients ineligible for heart transplantation: beyond pharmacotherapy.
      • Fine N.M.
      • Davis M.K.
      • Anderson K.
      • et al.
      Canadian cardiovascular society/canadian heart failure society joint position statement on the evaluation and management of patients with cardiac amyloidosis.
      • Kandolin R.M.
      • Wiefels C.C.
      • Mesquita C.T.
      • et al.
      The current role of viability imaging to guide revascularization and therapy decisions in patients with heart failure and reduced left ventricular function.
      • Crossland D.S.
      • Van De Bruaene A.
      • Silversides C.K.
      • Hickey E.J.
      • Roche S.L.
      Heart failure in adult congenital heart disease: from advanced therapies to end-of-life care.

      Pathophysiology of HFrEF

      HF is defined as a clinical syndrome caused by reduced cardiac output, resulting in insufficient end-organ tissue perfusion or maintenance of end-organ perfusion at the expense of elevated ventricular-filling pressure. HF is broadly categorized by left ventricular (LV) ejection fraction (LVEF) into HFrEF (EF < 40%), HF with mid-range ejection fraction (EF 40% to 50%), HF with preserved ejection fraction (EF > 50%), and HF with recovered LVEF (EF previously < 40% but improved to > 40% with medical therapy). Each of these patient groups deserves a specific approach to management; therefore, this paper will focus only on chronic HFrEF. The pathophysiology of HFrEF includes multiple complex mechanisms and pathways. These processes can be divided broadly into neurohormonal and hemodynamic alterations.
      • Benedict C.R.
      • Johnstone D.E.
      • Weiner D.H.
      • et al.
      Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction: a report from the registry of studies of left ventricular dysfunction.
      Although initially activated to preserve end-organ perfusion, these alterations eventually become maladaptive, propagating the adverse structural changes that characterize HF and cause the clinical syndrome.
      • Francis G.S.
      • Goldsmith S.R.
      • Levine T.B.
      • Olivari M.T.
      • Cohn J.N.
      The neurohumoral axis in congestive heart failure.
      This process is widely referred to as adverse remodelling, and its attenuation or reversal is the primary goal of most HFrEF therapies.
      The principal neurohormonal adaptations to HFrEF include activation of the sympathetic nervous system (SNS) and the RAAS. SNS activation can occur in the setting of low systemic pressure sensed by arterial baroreceptors. The result is increased release and reduced reuptake of catecholamines such as norepinephrine.
      • Anand I.S.
      • Fisher L.D.
      • Chiang Y.T.
      • et al.
      Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure trial.
      Early on, such changes preserve myocardial contractility and increase heart rate to maintain cardiac output. However, over time, the benefits of long-term SNS activation are blunted by downregulation and desensitization of cardiac β-adrenergic receptors (particularly β-1 receptors).
      • Vatner D.E.
      • Asai K.
      • Iwase M.
      • et al.
      Beta-adrenergic receptor-G protein-adenylyl cyclase signal transduction in the failing heart.
      ,
      • Bhargava V.
      • Shabetai R.
      • Mathiasen R.A.
      • Dalton N.
      • Hunter J.J.
      • Ross Jr., J.
      Loss of adrenergic control of the force-frequency relation in heart failure secondary to idiopathic or ischemic cardiomyopathy.
      Vasoconstriction caused by SNS activation increases ventricular afterload and can also cause renal vasoconstriction, which initially promotes filtration but ultimately stimulates proximal tubular sodium resorption, aggravating volume overload.
      Renal renin release stimulates the RAAS in response to reduced glomerular afferent arteriole stretch, reduced chloride delivery to the renal macula densa, and SNS activation
      (Fig. 1).
      • Zannad F.
      • Gattis Stough W.
      • Rossignol P.
      • et al.
      Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: Integrating evidence into clinical practice.
      This leads to increased conversion of angiotensin I to angiotensin II by angiotensin converting enzyme (ACE).
      • Zannad F.
      • Gattis Stough W.
      • Rossignol P.
      • et al.
      Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: Integrating evidence into clinical practice.
      Angiotensin II has similar effects as norepinephrine, including inducing systemic and renal vasoconstriction and increasing renal sodium resorption, in part mediated by increased aldosterone release.
      • Mizuno Y.
      • Yoshimura M.
      • Yasue H.
      • et al.
      Aldosterone production is activated in failing ventricle in humans.
      ,
      • Yogasundaram H.
      • Chappell M.C.
      • Braam B.
      • Oudit G.Y.
      Cardiorenal syndrome and heart failure-challenges and opportunities.
      Angiotensin II also promotes myocyte hypertrophy and apoptosis, leading to myocardial interstitial fibrosis.
      • Dostal D.E.
      • Baker K.M.
      The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function?.
      Figure thumbnail gr1
      Figure 1Pathologic mechanisms of the renin-angiotensin-aldosterone system involved in heart failure. ACE, angiotensin converting enzyme; Ang I, angiotensin I; ANG II, angiotensin II; AP-1, activator protein 1; AT1, angiotensin receptor type 1; AT2, angiotensin receptor type 2; CNS/ANS, central nervous system/autonomic nervous system; MRA, mineralocorticoid receptor antagonist; NAD(P)H, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide; PAI-1, plasminogen activator inhibitor; RAS, renin angiotensin system; ROS, reactive oxygen species. Adapted from Zannad et al.
      • Zannad F.
      • Gattis Stough W.
      • Rossignol P.
      • et al.
      Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: Integrating evidence into clinical practice.
      with permission from Oxford University Press.
      Natriuretic peptides are released from atrial (atrial natriuretic peptide [ANP]) and ventricular (B-type natriuretic peptide [BNP]) tissue in response to elevated intracardiac pressure. These peptides induce a variety of cardiovascular changes that, in general, counteract the effects of SNS and RAAS activation
      • Brunner-La Rocca H.P.
      • Kaye D.M.
      • Woods R.L.
      • Hastings J.
      • Esler M.D.
      Effects of intravenous brain natriuretic peptide on regional sympathetic activity in patients with chronic heart failure as compared with healthy control subjects.
      including the inhibition of vasoconstriction and myocardial collagen accumulation and fibroblast activity and promoting natriuresis. Another compound known to have vasodilatory effects is nitric oxide (NO), synthesized, in part, by endothelial cells. HFrEF is associated with endothelial dysfunction and resultant impairment of both release and sensitivity to NO, aggravating chronic vasoconstriction and ventricular loading.
      • Katz S.D.
      • Khan T.
      • Zeballos G.A.
      • et al.
      Decreased activity of the l-arginine-nitric oxide metabolic pathway in patients with congestive heart failure.
      Neurohormonal blockade achieved by simultaneous inhibition of the SNS and RAAS is central to the medical management of HFrEF

      Mechanisms of Action of Medical Therapies Used to Treat HFrEF

      β-Blockers

      β-blockers inhibit SNS activation and are 1 of the earliest classes to demonstrate improved outcomes for HFrEF. In addition to their role of reducing myocardial ischemia and antiarrhythmic effects, long-term SNS inhibition with β-blockers can augment energy available for myocyte repair and maintenance by promoting glucose rather than free fatty-acid myocyte substrate metabolism and even suppress renin secretion.
      • Cullington D.
      • Goode K.M.
      • Clark A.L.
      • Cleland J.G.
      Heart rate achieved or beta-blocker dose in patients with chronic heart failure: which is the better target?.
      Selective β-1 receptor antagonists, including bisoprolol, carvedilol and metoprolol succinate (latter not available in Canada), have demonstrated improved survival and favourable LV structural changes (ie, reverse remodelling) in HFrEF.
      • Packer M.
      • Bristow M.R.
      • Cohn J.N.
      • et al.
      The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.
      ,
      • Hjalmarson A.
      • Goldstein S.
      • Fagerberg B.
      • et al.
      Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure.
      Furthermore, reduction of heart rate has demonstrated survival and LV reverse remodelling benefits independent of SNS inhibition. These include improved LV diastolic function and end-diastolic pressure and increased endothelial cell function and proliferation, resulting in improved availability of NO.
      • Fang Y.
      • Debunne M.
      • Vercauteren M.
      • et al.
      Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia.

      RAAS inhibitors (ACE inibitors/angiotensin receptor blockers/angiotensin-neprilysin blockers)

      Multiple medication classes inhibit the RAAS at different steps of the pathway, including ACE inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) (Fig. 1).
      • Zannad F.
      • Gattis Stough W.
      • Rossignol P.
      • et al.
      Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: Integrating evidence into clinical practice.
      ACEIs have been considered the gold standard for RAAS inhibition in HFrEF for more than 3 decades. In clinical trials, both LV reverse remodelling and improved survival have been demonstrated.
      • Mancini G.B.
      • Howlett J.G.
      • Borer J.
      • et al.
      Pharmacologic options for the management of systolic heart failure: examining underlying mechanisms.
      ACEIs prevent the conversion of angiotensin I to angiotensin II, thus limiting the adverse effects of the latter. ACEIs also inhibit the breakdown of bradykinin, a potent vasodilatory inflammatory mediator, thereby promoting its beneficial effects and augmenting its potent afterload-reducing effects.
      • Su J.B.
      • Barbe F.
      • Houel R.
      • Guyene T.T.
      • Crozatier B.
      • Hittinger L.
      Preserved vasodilator effect of bradykinin in dogs with heart failure.
      ARBs are regarded as alternative therapy to ACEIs, often for patients who are intolerant of ACEIs. ARBs act by selectively blocking the angiotensin II type I receptor. Although inhibition of the adverse effects of angiotensin II is believed to be more complete with ARBs compared with ACEIs, owing to non-ACE pathway-related production of angiotensin II (Fig. 1), ARBs do not reduce bradykinin breakdown as do ACEIs.
      Angiotensin receptor-neprilysin inhibitor (ARNI) is a newer class of therapy for HFrEF treatment, represented by the addition of neprilysin inhibition to angiotensin receptor inhibition (valsartan) and valsartan (an ARB).
      • O’Meara E.
      • McDonald M.
      • Chan M.
      • et al.
      CCS/CHFS heart failure guidelines: clinical trial update on functional mitral regurgitation, SGLT2 inhibitors, ARNI in HFpEF, and tafamidis in amyloidosis.
      Neprilysin is an endopeptidase responsible for the breakdown of several endogenous vasoactive peptides, which are beneficial for patients with HFrEF, including natriuretic peptides, bradykinin, adrenomedullin, and others (Fig. 2).
      • Langenickel T.H.
      • Dole W.P.
      Angiotensin receptor-neprilysin inhibition with lcz696: a novel approach for the treatment of heart failure.
      These effects lead to greater hypotensive effect and additional efficacy compared with ACEIs or ARBs, but also to greater intolerance, necessitating ACEI or ARB therapy in a minority (10% to 20%) of patients. Sacubitril-valsartan (ARNI) has replaced ACEI or ARB therapy as the gold standard RAAS inhibitor because of its comparatively demonstrated clinical superiority for both acute and chronic HFrEF syndromes.
      • McMurray J.J.
      • Packer M.
      • Desai A.S.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      Figure thumbnail gr2
      Figure 2Mechanism of action of angiotensin-receptor neprilysin inhibition. ANG II, angiotensin II; AT1, angiotensin I, type 1 receptor; cGMP, cyclic guanosine monophosphate; GTP, guanylate triphosphate; NP, natriuretic peptide; NPR-A, atrial natriuretic peptide receptor; RAAS, renin-angiotensin-aldosterone system. Adapted from Langenickel et al.
      • Langenickel T.H.
      • Dole W.P.
      Angiotensin receptor-neprilysin inhibition with lcz696: a novel approach for the treatment of heart failure.
      under Creative Commons Attribution 3.0 Unported (CC BY 3.0).

      MRAs

      MRAs block binding of aldosterone to mineralocorticoid receptors, located predominantly in the myocardium and vascular smooth muscle cells, and have a number of other beneficial effects in HFrEF that are different from those of ACEIs or ARBs.
      • Jaffe I.Z.
      • Mendelsohn M.E.
      Angiotensin ii and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells.
      ,
      • Greene S.J.
      • Felker G.M.
      • Giczewska A.
      • et al.
      Spironolactone in acute heart failure patients with renal dysfunction and risk factors for diuretic resistance: from the ATHENA-HF trial.
      MRAs have demonstrated antifibrotic effects by inhibiting the production of matrix metalloproteinases and other enzymes responsible for interstitial myocardial remodeling.
      • Bunda S.
      • Wang Y.
      • Mitts T.F.
      • et al.
      Aldosterone stimulates elastogenesis in cardiac fibroblasts via mineralocorticoid receptor-independent action involving the consecutive activation of Gα13, c-Src, the insulin-like growth factor-1 receptor, and phosphatidylinositol 3-kinase/akt.
      MRAs also preserve potassium depletion while also improving endothelial function.

      SGLT2 inhibitors

      A category of agents that has more recently demonstrated efficacy for the treatment of HFrEF is the SGLT2 inhibitors. SGLT2 inhibitors increase urinary glucose excretion and were originally designed as oral hypoglycemic agents for the treatment of diabetes mellitus. However, they have since demonstrated beneficial effects for treatment of HFrEF in both diabetic and nondiabetic patients.
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      The mechanism for this is uncertain; however, their promotion of osmotic diuresis and natriuresis is speculated to contribute to the observed benefit. Many other hypotheses have been proposed, including modification of uric-acid metabolism, alteration of myocardial metabolism and hematopoiesis, alteration of pathways involved in programmed cell death,
      • Lopaschuk G.D.
      • Verma S.
      Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors.
      and reduction of cytokine production and attenuation of myocardial fibrosis.
      • Lytvyn Y.
      • Bjornstad P.
      • Udell J.A.
      • Lovshin J.A.
      • Cherney D.Z.I.
      Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials.

      Ivabradine

      Another agent that takes advantage of heart rate-lowering benefits for patients with HFrEF treatment is ivabradine, a selective sinus-node inhibitor that lowers heart rate by inhibiting the Ikf (inwardly rectifying potassium "funny") channel, slowing diastolic depolarization with no effect on blood pressure.
      • Ferrari R.
      Ivabradine: Heart rate and left ventricular function.
      Ivabradine is more effective at higher heart rates because a relatively higher proportion of Ikf channels are open.
      • Ferrari R.
      Ivabradine: Heart rate and left ventricular function.
      Ivabradine would be expected to exert no effect when administered during atrial fibrillation.

      Hydralazine and nitrates

      Many vasodilators have failed to improve outcomes in patients with HFrEF. However, hydralazine and nitrate combinations as a medication class are generally considered to improve control of symptoms for patients with HFrEF and have been demonstrated to improve outcomes in select HFrEF subpopulations such as those intolerant to RAAS inhibition.
      • Cohn J.N.
      • Archibald D.G.
      • Ziesche S.
      • et al.
      Effect of vasodilator therapy on mortality in chronic congestive heart failure.
      Nitrates reduce ventricular preload primarily by inducing venous vasodilation by increasing availability of NO; they also have anti-ischemic effects and can act as an arterial vasodilator, whereas hydralazine is more of a direct arterial vasodilator.

      Oral soluble guanylate cyclase stimulators

      The oral sGC stimulator vericiguat was recently found to improve outcomes among symptomatic higher-risk patients with HFrEF.
      • Armstrong P.W.
      • Pieske B.
      • Anstrom K.J.
      • et al.
      Vericiguat in patients with heart failure and reduced ejection fraction.
      Vericiguat sensitizes sGC to endogenous NO and enhances the pathway via direct binding to and stimulation of sGC, thereby promoting its vasodilatory effects.
      • Armstrong P.W.
      • Pieske B.
      • Anstrom K.J.
      • et al.
      Vericiguat in patients with heart failure and reduced ejection fraction.
      These agents, unlike nitrates, do not exhibit tachyphylaxis with sustained therapy and do not appear to be associated with excessive afterload reduction and hypotension.

      Diuretics

      For decades, diuretics have represented the mainstay of decongestive therapy for patients with decompensated HF. Loop diuretics are the most commonly used class and act by inhibiting the Na-K-2Cl cotransporter on the luminal membrane of the ascending limb of the loop of Henle to reduce renal reabsorption of sodium chloride. Furosemide is the most frequently used drug; however, torsemide, bumetanide, and ethacrynic acid are alternatives that may be used in select settings. Another class of agents used is thiazide-type diuretics such as hydrochlorothiazide and metolazone. These diuretics inhibit sodium reabsorption in the distal glomerular tubule and are often used to enhance the effect of loop diuretics, which increase the delivery of sodium to the distal tubule.

      Oral inotropes

      A final category of agents for HFrEF treatment is the category of positive oral inotropes such as digoxin and omecativ mecarbil. Digoxin is an older cardiac glycoside that increases contractility by promoting myocyte calcium influx. Digoxin improves symptoms and reduces hospitalizations for HF without mortality benefit
      • Digitalis Investigation G.
      The effect of digoxin on mortality and morbidity in patients with heart failure.
      and is now used primarily as an adjunctive therapy in symptomatic patients already receiving optimized therapy for HF. Omecamtiv mecarbil is a new agent that acts as a direct cardiac myosin activator, which increases the duration and number of actin-myosin links, effectively increasing the duration of systolic ejection time and LVEF. However, unlike other inotropic agents, there is no increase in intracellular calcium, ATP consumption, dP/dT, or ventricular arrhythmias. The recently completed phase 3 clinical trial demonstrated that this therapy reduced a composite endpoint of heart failure event of cardiovascular death in patients with HFrEF.
      • Teerlink J.R.
      • Diaz R.
      • Felker G.M.
      • et al.
      GALACTIC-HF Investigators. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure.
      This medication increases systolic ejection time and ejection fraction but, unlike other inotropic agents, does not increase maximal dP/dT, ventricular arrythmias, intracellular calcium concentration, or consumption of ATP.
      • Teerlink J.R.
      • Diaz R.
      • Felker G.M.
      • et al.
      GALACTIC-HF Investigators. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure.

      Proposed Classification of Medical Therapies

      Medical therapies for HFrEF may broadly be classified into Foundational Therapies and Personalized Therapies. The 3 common properties of these Foundational Therapies include rapid improvement in both cardiovascular morbidity and mortality, applicable to most patients with HFrEF, and synergistic and additive effects irrespective of background therapy. Foundational Therapies include β-blockers, RAAS inhibitors (ARNI, preferred; alternatively: ACEI/ARB), MRAs, and SGLT2 inhibitors and should be initiated routinely and titrated rapidly. Characteristics of Foundational Therapies and parameters for initiation and titration are outlined in Table 1.
      Table 1Foundational therapy characteristics and parameter surveillance
      ClassParameters for assessmentAllowable lab for initiation/titrationAllowable clinical findingLab parameter of intolerance
      ARNI (first) or ACEI/ARBLightheaded, postural symptoms sCr, K+, SBP

      Both classes
      eGFR > 30,

      K+ < 5.2

      Both classes
      ARNI, SBP > 100 mm Hg,

      ACEI/ARB, SBP

      > 90 mm Hg, no symptomatic hypotension
      Creatinine > 30% over baseline,

      K+ > 5.5

      Both classes
      BBLightheaded, postural symptoms

      HR
      Absence of high-grade AV block or pauses > 3 secSBP > 95 mm Hg

      HR > 60 bpm,

      No symptomatic hypotension or worsening HF
      Heart block
      MRALightheaded, postural symptoms sCr, K+, SBPeGFR > 30,

      K+ < 5.0
      SBP > 80 mm Hg,

      No symptomatic hypotension
      Creatinine > 30% over baseline,

      K+ > 5.5
      SGLT2iLightheaded, postural symptoms sCr, SBPeGFR > 25, stable blood glucose control if diabetes mellitusSBP > 90 mm Hg,

      No symptomatic hypotension or volume depletion
      Elevated lactate or ketones (if DM), creatinine > 30% from baseline
      This table shows the 4 Foundational Therapies that will be part of background treatment for most patients with HFrEF: ARNI/ACEI/ARB; BB; MRA; and SGLTI.
      ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; AV, atrioventricular; BB, β-blocker; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate in mL/min per 1.73 m2; HF, heart failure; HR, heart rate; K+, serum potassium in mmol/L; MRA, mineralocorticoid receptor antagonist; sCr, serum creatinine; SBP, systolic blood pressure; SGLT2I, sodium-glucose cotransport-2 inhibitor.
      Personalized Therapies differ from Foundational Therapies by virtue of their benefit in select patient populations or their lack of improvement of all-cause mortality. For example, the reduction of mortality from ivabradine has been shown only in patients with a resting sinus heart rate > 77 beats per minute.
      • Swedberg K.
      • Komajda M.
      • Böhm M.
      • et al.
      Ivabradine and outcomes in chronic heart failure (shift).
      Administration of these agents should generally follow titration of Foundational Therapy (Table 2).
      Table 2Characteristics of personalized therapies for patients with HFrEF
      MedicationPatient subtype for considerationTime course of benefitSide effectsAdvantages
      IvabradineSinus rhythm

      HR > 70, despite maximal tolerated β-blockade
      Ivabradine is approved and publicly reimbursed in Canada for use in addition to β-blockade to reduce cardiovascular mortality with sinus rate > 77 beats per minute but is recommended by the Canadian Cardiovascular Society for rates > 70 beats per minute.
      Within weeksFatigue, bradycardiaMortality benefit if HR > 77 bpm; very well tolerated, no impact on BP or renal function
      DigoxinOngoing symptoms despite maximal foundational therapy without heart block or symptomatic bradycardiaWithin weeksVentricular arrhythmias, heart block, toxicityNo impact on blood pressure, can be used in AF
      Hydralazine nitratesIntolerant of ACE/ARB/ARNI or self-identified African American with symptoms despite Foundational TherapyWithin weeksHypotension, up to 30%, rashMay be used with severe kidney disease
      Vericiguat
      Vericiguat is not yet available clinically.
      Recent hospitalization and elevated NPs despite optimal Foundational TherapyWithin weeksAnemia, mild early hypotension, 4 titrations neededLikely better tolerated than hydralazine nitrates; may be used with lower BP and eGFR.
      ACE, angiotensin converting enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BP, blood pressure; bpm, beats per minute; eGFR, estimated glomerular filtration rate; HR, heart rate; NP, natriuretic peptide.
      Ivabradine is approved and publicly reimbursed in Canada for use in addition to β-blockade to reduce cardiovascular mortality with sinus rate > 77 beats per minute but is recommended by the Canadian Cardiovascular Society for rates > 70 beats per minute.
      Vericiguat is not yet available clinically.

      Cumulative Benefits of Combination Therapy for HFrEF

      The expansion of therapeutic options for patients with HFrEF has substantially improved patient outcomes. Jhund et al. found that, between 1986 and 2003, the age-adjusted, 1-year, all-cause mortality rates following first HF hospitalization dropped from 32.9% to 27.6% in men and 30.6% to 25.6% in women.
      • Jhund P.S.
      • Macintyre K.
      • Simpson C.R.
      • et al.
      Long-term trends in first hospitalization for heart failure and subsequent survival between 1986 and 2003.
      Between 2002 and 2013, 1-year cardiovascular mortality rates decreased from 18% to 13% in a longitudinal analysis of patients in the United Kingdom.
      • Conrad N.
      • Judge A.
      • Canoy D.
      • et al.
      Temporal trends and patterns in mortality after incident heart failure: a longitudinal analysis of 86000 individuals.
      Although there are many potential combinations of medical therapy, Foundational Therapies are generally considered to have an additive benefit. In 2011, Fonarow et al. suggested that optimizing combination HFrEF therapy could prevent more than 65,000 deaths per year in the United States, assuming additive effects of therapies.
      • Fonarow G.C.
      • Yancy C.W.
      • Hernandez A.F.
      • Peterson E.D.
      • Spertus J.A.
      • Heidenreich P.A.
      Potential impact of optimal implementation of evidence-based heart failure therapies on mortality.
      The subsequent emergence of ARNI and SGLT2 inhibitors has further improved outcomes. For a typical patient with HFrEF, 1-year mortality could be reduced from 17% without therapy
      • Levy W.C.
      • Mozaffarian D.
      • Linker D.T.
      • et al.
      The seattle heart failure model: prediction of survival in heart failure.
      to as low as 4.2% with combination pharmacotherapy (Fig. 3). A recent study estimated that using the Foundational Therapies (ARNI, β-blocker, MRA, and SGLT2 inhibitor) could potentially prolong survival by 6.3 years in a 55-year-old patient compared with standard therapy with ACEIs/ARBs and β-blockers alone.
      • 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.
      • Docherty K.F.
      • Jhund P.S.
      • Inzucchi S.E.
      • et al.
      Effects of dapagliflozin in DAPA-HF according to background heart failure therapy.
      Figure thumbnail gr3
      Figure 3One-year outpatient mortality with combinations of medical therapy; estimated 1-year mortality rates with combinations of medical therapy for a typical patient with ischemic cardiomyopathy. Risk reduction with therapy extrapolated from previous estimations or landmark trials
      • McMurray J.J.
      • Packer M.
      • Desai A.S.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      ,
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ,
      • Swedberg K.
      • Komajda M.
      • Böhm M.
      • et al.
      Ivabradine and outcomes in chronic heart failure (shift).
      ,
      • Docherty K.F.
      • Jhund P.S.
      • Inzucchi S.E.
      • et al.
      Effects of dapagliflozin in DAPA-HF according to background heart failure therapy.
      and assuming additive benefits of therapy with assumption of additive benefits, with the understanding that relitigating efficacy of older therapies with additional outcome trials is unlikely to occur. Triple therapy includes β-blocker, mineralocorticoid receptor antagonist (MRA), and either angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), or angiotensin receptor neprilysin inhibitor (ARNI), as indicated. Foundational Therapy includes β-blocker, MRA, ARNI, and sodium-glucose cotransport-2 inhibitor. SNI, sinus node inhibitor.

      Initiation of Medical Therapy and Titration is Suboptimal in Clinical Practice

      Given the substantial potential benefits from medical therapy, it is critical to increase the proportion of patients receiving optimal therapy. In a contemporary cohort of patients in the United States with chronic HFrEF, most patients remained on less than 50% of the trial dose for β-blockers (56.7%), ACEIs/ARBs (75.5%), MRAs (65.3%), and ARNI (90.4%) during 12 months of follow-up, with many not even receiving those therapies.
      • Greene S.J.
      • Fonarow G.C.
      • DeVore A.D.
      • et al.
      Titration of medical therapy for heart failure with reduced ejection fraction.
      Ouwekerk et al. found a similarly high proportion of patients maintained on less than 50% of targeted doses but also found that patients maintained on < 50% of target doses had ∼70% increased risk of mortality.
      • Ouwerkerk W.
      • Voors A.A.
      • Anker S.D.
      • et al.
      Determinants and clinical outcome of uptitration of ACE inhibitors and beta-blockers in patients with heart failure: a prospective European study.
      Low rates of medical optimization of both established and newer therapies were noted.
      • Greene S.J.
      • Fonarow G.C.
      • DeVore A.D.
      • et al.
      Titration of medical therapy for heart failure with reduced ejection fraction.
      ,
      • Ouwerkerk W.
      • Voors A.A.
      • Anker S.D.
      • et al.
      Determinants and clinical outcome of uptitration of ACE inhibitors and beta-blockers in patients with heart failure: a prospective European study.
      Interestingly, ongoing titration was reported as a reason for nonoptimal medical therapy in nearly 30% of patients with > 6 months follow-up.
      Two recent studies provide further insights into the phenomenon of treatment inertia. The Guiding Evidence-Based Therapy Using Biomarker-Intensified Treatment in Heart Failure (GUIDE-IT) trial enrolled patients with HFrEF to a strategy of natriuretic peptide-based medication titration or usual care.
      • Felker G.M.
      • Anstrom K.J.
      • Adams K.F.
      • et al.
      Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction.
      ,
      • Fiuzat M.
      • Ezekowitz J.
      • Alemayehu W.
      • et al.
      Assessment of limitations to optimization of guideline-directed medical therapy in heart failure from the guide-it trial.
      In this trial, no benefit in either lowering of natriuretic peptides or in clinical outcomes was observed.
      • Felker G.M.
      • Anstrom K.J.
      • Adams K.F.
      • et al.
      Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction.
      Further analysis indicated that there was little overall (< 10%) increase in dosage of evidence-based therapies and nearly all changes occurred during the first 3 months.
      • Fiuzat M.
      • Ezekowitz J.
      • Alemayehu W.
      • et al.
      Assessment of limitations to optimization of guideline-directed medical therapy in heart failure from the guide-it trial.
      For each study visit, investigators were asked to provide reasons why no medication changes were made, and the most common answer was "patient stability."
      • Fiuzat M.
      • Ezekowitz J.
      • Alemayehu W.
      • et al.
      Assessment of limitations to optimization of guideline-directed medical therapy in heart failure from the guide-it trial.
      Jarjour et al. reported a somewhat higher dosage level after 6 months of follow-up.
      • Jarjour M.
      • Henri C.
      • de Denus S.
      • et al.
      Care gaps in adherence to heart failure guidelines: clinical inertia or physiological limitations?.
      A detailed chart review determined that many patients potentially eligible for dose titration had already demonstrated intolerance to higher doses, suggesting that physiological intolerance to high-dose therapy may be more common than expected.
      • Jarjour M.
      • Henri C.
      • de Denus S.
      • et al.
      Care gaps in adherence to heart failure guidelines: clinical inertia or physiological limitations?.
      The result was an approximate 10% to 15% rate of unexplained use of any Foundational Therapy, although this rate was much higher (46%) for prescription of ivabradine. Despite this, the authors noted "ongoing titration" of at least 1 Foundational Therapy in more than 30% in which dose was not optimized. This rate was highest (21%) for titration of β-blocker therapy, similar to previous reports. Ultimately, there are many potential barriers to optimization of medical therapy in patients with HFrEF, including patient, physician, and system factors such as intercurrent illness.
      • Fiuzat M.
      • Ezekowitz J.
      • Alemayehu W.
      • et al.
      Assessment of limitations to optimization of guideline-directed medical therapy in heart failure from the guide-it trial.
      ,
      • Marti C.N.
      • Fonarow G.C.
      • Anker S.D.
      • et al.
      Medication dosing for heart failure with reduced ejection fraction: opportunities and challenges.

      Time Is of the Essence

      Slow optimization of HF medications postpones initiation other life-prolonging medical therapies as well as device therapies, creating an unnecessary window of excess risk. Zaman et al. suggested that delayed initiation of optimal medical therapy may lead to excess absolute mortality of ~1% per month that therapy is delayed.
      • Zaman S.
      • Zaman S.S.
      • Scholtes T.
      • et al.
      The mortality risk of deferring optimal medical therapy in heart failure: a systematic comparison against norms for surgical consent and patient information leaflets.
      Another potential concern is the occurrence of sudden death. Of 1117 first primary endpoints in the Prospective Comparison od ARNi With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, these 459 (41%) were cardiovascular deaths, of which one-half were sudden cardiac deaths.
      • Desai A.S.
      • McMurray J.J.
      • Packer M.
      • et al.
      Effect of the angiotensin-receptor-neprilysin inhibitor lcz696 compared with enalapril on mode of death in heart failure patients.
      This supports early initiation of guideline-directed medical therapy (GDMT) in those patients considered to be clinically stable.
      However, it is reasonable to consider whether the guideline-endorsed iterative approach to initiating medications is contributory.
      • 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.
      This approach evolved with the HF evidence base and was designed to mirror clinical trial enrollment criteria. Indeed, titration protocols of landmark trials supporting Foundational Therapy have mandated completion of titration within 2 to 3 months.
      • Krum H.
      • Roecker E.B.
      • Mohacsi P.
      • et al.
      Effects of initiating carvedilol in patients with severe chronic heart failure.
      ,
      • Poole-Wilson P.A.
      • Cleland J.G.F.
      • Di Lenarda A.
      • et al.
      Rationale and design of the Carvedilol or Metoprolol European Trial in patients with chronic heart failure: COMET.
      Nevertheless, as mentioned here, reports from HF registries repeatedly simultaneously indicate ongoing titration and minimal net dosage change following 6 to 12 months.
      • Greene S.J.
      • Fonarow G.C.
      • DeVore A.D.
      • et al.
      Titration of medical therapy for heart failure with reduced ejection fraction.
      ,
      • Ouwerkerk W.
      • Voors A.A.
      • Anker S.D.
      • et al.
      Determinants and clinical outcome of uptitration of ACE inhibitors and beta-blockers in patients with heart failure: a prospective European study.
      Delaying the implantation of cardiac devices until after medical therapy is optimized potentially avoids the risks associated with implantation of devices in selected patients. However, the rationale for sequential initiation of medical therapy is related to avoiding potentially unnecessary costs associated with newer therapies, which is mitigated by an increased number of clinic visits and testing.
      • Wang N.
      • Salam A.
      • Webster R.
      • et al.
      Association of low-dose triple combination therapy with therapeutic inertia and prescribing patterns in patients with hypertension.
      For example, Grant et al. demonstrated that de novo initiation of ARNI is more cost effective compared with delayed initiation.
      • Grant A.D.M.
      • Chew D.S.
      • Howlett J.G.
      • Miller R.J.H.
      Cost-effectiveness of earlier transition to angiotensin receptor neprilysin inhibitor in patients with heart failure and reduced ejection fraction.
      In addition, only ∼25% of patients with HFrEF managed with current medical therapy will have an improvement in LVEF to ≥40%.
      • Savarese G.
      • Vedin O.
      • D'Amario D.
      • et al.
      Prevalence and prognostic implications of longitudinal ejection fraction change in heart failure.
      The effectiveness of HF therapies may not vary by symptom status.
      • Miller R.J.
      • Howlett J.G.
      • Exner D.V.
      • Campbell P.M.
      • Grant A.D.
      • Wilton S.B.
      Baseline functional class and therapeutic efficacy of common heart failure interventions.
      As a result, medication-initiation strategies that rely on patient response, either in terms of LVEF recovery or symptom status, may unnecessarily deprive patients of beneficial therapies and induce delays in medication titration. New strategies are clearly needed, but there is a paucity of evidence regarding the optimal initiation and titration of medications for patients with HFrEF.
      • Bhatt A.S.
      • Vaduganathan M.
      • Butler J.
      Growing mismatch between evidence generation and implementation in heart failure.

      In-Hospital Initiation and Optimization of Medical Therapy

      One clear path for more rapid medication initiation and titration is during hospitalizations, which most patients with HFrEF experience during the course of their diseases. Reports from several registries demonstrate the benefit of mulitple drug initiations registries demonstrate the benefit of multiple drug initiations over a short period of time during hospitalization. For example, of 158,922 patients enrolled during hospitalization in the Get With the Guidelines HF (GWTG-HF) registry, more than 20% of patients were eligible for 3 new medications during a median 4-day hospital stay, with more than 50% of them receiving them by hospital discharge.
      • Allen L.A.
      • Fonarow G.C.
      • Liang L.
      • et al.
      Medication initiation burden required to comply with heart failure guideline recommendations and hospital quality measures.
      Recent studies have significant clinical event reductions with in-hospital initiation of ARNI and SGLT2 inhibitors.
      • Velazquez E.J.
      • Morrow D.A.
      • DeVore A.D.
      • et al.
      Angiotensin-neprilysin inhibition in acute decompensated heart failure.
      ,
      • Bhatt D.L.
      • Szarek M.
      • Steg P.G.
      • et al.
      Sotagliflozin in patients with diabetes and recent worsening heart failure.
      Thus, hospitalizations may represent an attractive opportunity to initiate and titrate medications, including a transition to ARNI therapy.

      Relative Benefits of Dose Escalation vs New Drug Initiation

      Retrospective analyses of clinical trials and HF registries have reported variable morbidity and mortality advantage in patients taking higher doses of HF medications.
      • Fonarow G.C.
      • Yancy C.W.
      • Hernandez A.F.
      • Peterson E.D.
      • Spertus J.A.
      • Heidenreich P.A.
      Potential impact of optimal implementation of evidence-based heart failure therapies on mortality.
      ,
      • Ouwerkerk W.
      • Voors A.A.
      • Anker S.D.
      • et al.
      Determinants and clinical outcome of uptitration of ACE inhibitors and beta-blockers in patients with heart failure: a prospective European study.
      ,
      • Wikstrand J.
      • Hjalmarson A.
      • Waagstein F.
      • et al.
      Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure.
      ,
      • Vardeny O.
      • Claggett B.
      • Packer M.
      • et al.
      Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction.
      This has, in part, led to a strategy of single-drug initiation and titration before addition of other drug classes, which may contribute to less comprehensive treatment and slower times to medical optimization. Increasingly, calls for a change to early drug combination, drug initiation followed by dose escalation has been made. The advantages of this approach are summarized in Table 3.
      Table 3Probable relative benefits of foundational HFrEF therapy: initiation vs target dose
      For clarity, titration to target doses is associated with accrual of clinical benefits following drug initiation.
      Outcome affectedInitiation of therapeutic classTitration from initial to target dose
      SGLT2I trials have evaluated only 1 dose.
      Heart failure hospitalization endpointUp to two-thirds of overall benefit with ACE/ARB.

      Significant benefit with ARNI, MRA, SGLT2I observed within 4 to 6 weeks following randomization
      Further ~one-third benefit in ACE

      Uncertain for other Foundational Therapies
      Cardiovascular mortality endpointImprovement observed, event curves separate within 3 months following randomizationNo clear further benefit with ACE, ARB

      Further benefit possible with MRA, β-blockers
      Time course of benefits on combined cardiovascular death + heart failure hospitalization endpointInitial 2 to 4 weeks for all Foundational TherapiesEvent curves begin to separate 6 months following randomization
      Side effectsWithdrawal in < 10%Dose-related increase in side effects
      Combination with other Foundational TherapiesAdditive benefits in combinationAdditive benefits in combination
      ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT2I, sodium-glucose cotransport-2 inhibitor.
      For clarity, titration to target doses is associated with accrual of clinical benefits following drug initiation.
      SGLT2I trials have evaluated only 1 dose.
      The dose-related effects of ACEIs have been best studied. Packer et al. randomized 3793 patients with HFrEF to lisinopril, either 37.5 mg or 2.5 mg daily, and found no difference in mortality during a median of 47 months of follow-up and a 12% reduction in hospitalization that only became apparent after > 6 months of follow-up.
      • Packer M.
      • Poole-Wilson P.A.
      • Armstrong P.W.
      • et al.
      Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure.
      However, it is worth noting that the study may have been underpowered, owing to greater-than-expected benefit in the low-dose group. Similar findings were reported for the Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan (HEAAL) study, in which high-dose losartan reduced hospitalizations for HF by 12%, but no significant mortality benefit was demonstrated during 4.7 years' follow-up.
      • Konstam M.A.
      • Neaton J.D.
      • Dickstein K.
      • et al.
      Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure.
      In a meta-analysis, Turgeon et al. demonstrated that high-dose RAAS inhibition led to modest reduction of HF hospitalization and no significant reduction of mortality.
      • Turgeon R.D.
      • Kolber M.R.
      • Loewen P.
      • Ellis U.
      • McCormack J.P.
      Higher versus lower doses of ace inhibitors, angiotensin-2 receptor blockers and beta-blockers in heart failure with reduced ejection fraction.
      In relative terms, approximately two-thirds of the benefits in hospitalization occur at low doses.
      • Turgeon R.D.
      • Kolber M.R.
      • Loewen P.
      • Ellis U.
      • McCormack J.P.
      Higher versus lower doses of ace inhibitors, angiotensin-2 receptor blockers and beta-blockers in heart failure with reduced ejection fraction.
      However, dose titration is associated with significant increases in hypotension, worsening renal function, and hyperkalemia.
      Large randomized studies of high-dose vs low-dose β-blockade or MRA therapy do not exist. In the case of β-blockade, meta-analyses of small studies point to a dose-dependant benefit in recovery of LVEF and occurrence of side effects.
      • McAlister F.A.
      • Wiebe N.
      • Ezekowitz J.A.
      • Leung A.A.
      • Armstrong P.W.
      Meta-analysis: Beta-blocker dose, heart rate reduction, and death in patients with heart failure.
      Retrospective analyses of the large β-blocker trials suggest that the most important factors associated with mortality benefits are relative reduction of heart rate and lower on-treatment heart rate.
      • Metra M.
      • Torp-Pedersen C.
      • Swedberg K.
      • et al.
      Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure.
      Wikstrand et al., in Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), showed a mortality reduction from β-blockade of 38% (95% confidence interval [CI], 16-55) in patients taking > 100 mg per day (P = 0.0022) and also 38% (95% CI, 11-57) in those taking lower doses (P = 0.010).
      • Wikstrand J.
      • Hjalmarson A.
      • Waagstein F.
      • et al.
      Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure.
      In the Cardiac Insufficiency Bisopropol in the Elderly (CIBIS-ELD) study,
      • Dungen H.D.
      • Apostolovic S.
      • Inkrot S.
      • et al.
      Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure.
      despite the forced-titration study design, only 25% of elderly patients given β-blockers for HFrEF reached target dose within the 12-week time window. Short-term heart rate response to β-blockade, rather than β-blocker dose, was associated with improved rates of mortality.
      • Dungen H.D.
      • Apostolovic S.
      • Inkrot S.
      • et al.
      Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure.
      This finding was reinforced by conclusions made in a meta-regression by McAlister et al., in which reduction of heart rate was the primary mediator of β-blockade benefit.
      • McAlister F.A.
      • Wiebe N.
      • Ezekowitz J.A.
      • Leung A.A.
      • Armstrong P.W.
      Meta-analysis: Beta-blocker dose, heart rate reduction, and death in patients with heart failure.
      β-blockers improve outcomes irrespective of baseline ACEI dose, with subgroups from the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) and MERIT-HF studies showing equal improvement in outcomes when β-blockade was added to low- or high- dose ACEI therapy.
      • Krum H.
      • Haas S.J.
      • Eichhorn E.
      • et al.
      Prognostic benefit of beta-blockers in patients not receiving ACE inhibitors.
      Retrospective analysis of the Biology Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF) and Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registries, conducted by Ouwerkerk et al., sought to determine the relationship between ACEI and β-blocker doses and subsequent outcomes.
      • Ouwerkerk W.
      • Teng T.K.
      • Tromp J.
      • et al.
      Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction.
      In their analysis, increasing ACEI dose was associated with reduction in hospitalizations but not mortality, whereas increasing β-blocker dose was associated with greater reduction in mortality and increase in hospitalizations.
      • Ouwerkerk W.
      • Teng T.K.
      • Tromp J.
      • et al.
      Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction.
      Importantly, low doses of both drugs (< 50% target dose for both) was associated with improved outcomes compared with target dose of ACEI or β-blocker alone.
      In the case of sacubitril-valsartan, data show similar trends. In the PARADIGM-HF trial, 42% of study subjects in both treatment groups underwent temporary dose reduction of study medication.
      • McMurray J.J.
      • Packer M.
      • Desai A.S.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      The treatment benefit of sacubitril-valsartan over enalapril in this group was similar (hazard ratio [HR], 0.80; 95% CI, 0.70-0.93; P < 0.001) to that observed in patients who had not experienced any dose reduction (HR, 0.79; 95% CI, 0.71-0.88; P < 0.001).
      • Vardeny O.
      • Claggett B.
      • Packer M.
      • et al.
      Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction.
      Finally, data from the Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on Nt-Pro-Bnp in Patients Stabilized From an Acute Heart Failure Episode (PIONEER-HF) study showed an additional benefit of ARNI over ACEI when started during the inpatient setting.
      • Velazquez E.J.
      • Morrow D.A.
      • DeVore A.D.
      • et al.
      Angiotensin-neprilysin inhibition in acute decompensated heart failure.
      Notably, approximately 80% of the observed additional N-terminal proBNP (NTproBNP) reduction conferred by ARNI was apparent within the first 7 days of treatment.
      • Velazquez E.J.
      • Morrow D.A.
      • DeVore A.D.
      • et al.
      Angiotensin-neprilysin inhibition in acute decompensated heart failure.
      These effects were durable and associated with improved early (60-day) and 1-year outcomes, which were noted in patients with both de novo and chronic HF.
      • Velazquez E.J.
      • Morrow D.A.
      • DeVore A.D.
      • et al.
      Angiotensin-neprilysin inhibition in acute decompensated heart failure.
      In similar fashion, no definitive data regarding dosage-ranging effects of MRAs on clinical outcomes exist. One small dose-ranging trial of spironolactone addition to ACEI was not large enough to determine clinical benefit, but the occurrence of significant hyperkalemia rose in linear fashion up to 25%.
      • Pitt B.
      • Pierard L.A.
      • Bilge A.
      • et al.
      Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure.
      Investigators in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial were instructed to target 25 mg/day eplerenone for patients with estimated glomerular filtration rate (eGFR) <50 mL/min and otherwise 50 mg/day. In each group, the benefit of eplerenone over placebo was similar.
      • Ferreira J.P.
      • Abreu P.
      • McMurray J.J.V.
      • et al.
      Renal function stratified dose comparisons of eplerenone versus placebo in the EMPHASIS-HF trial.
      However, patients with lower eGFRs experienced a 4-fold higher adverse event rate, owing to renal and electrolyte abnormalities, despite receiving lower doses.
      • Ferreira J.P.
      • Abreu P.
      • McMurray J.J.V.
      • et al.
      Renal function stratified dose comparisons of eplerenone versus placebo in the EMPHASIS-HF trial.
      As only a single dose was evaluated for SGLT2 inhibition for HFrEF, it is not possible to determine the dose-ranging effects of these medications. However, data from both the
      Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial and Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction (EMPEROR-Reduced) show that the benefits of SGLT2 inhibitors are not dependent on baseline medical therapy or dose.
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ,
      • Docherty K.F.
      • Jhund P.S.
      • Inzucchi S.E.
      • et al.
      Effects of dapagliflozin in DAPA-HF according to background heart failure therapy.
      ,
      • Packer M.
      • Anker S.D.
      • Butler J.
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      It has been suggested that early introduction of newer therapies may impair the delivery of established medications. However, data from clinical registries and randomized trials show that neither dose intensity nor initiation of Foundational Therapies is adversely affected by introduction of new therapies.
      • Swedberg K.
      • Komajda M.
      • Böhm M.
      • et al.
      Ivabradine and outcomes in chronic heart failure (shift).
      ,
      • Greene S.J.
      • Fonarow G.C.
      • DeVore A.D.
      • et al.
      Titration of medical therapy for heart failure with reduced ejection fraction.
      • Ouwerkerk W.
      • Voors A.A.
      • Anker S.D.
      • et al.
      Determinants and clinical outcome of uptitration of ACE inhibitors and beta-blockers in patients with heart failure: a prospective European study.
      • Felker G.M.
      • Anstrom K.J.
      • Adams K.F.
      • et al.
      Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction.
      • Fiuzat M.
      • Ezekowitz J.
      • Alemayehu W.
      • et al.
      Assessment of limitations to optimization of guideline-directed medical therapy in heart failure from the guide-it trial.
      • Jarjour M.
      • Henri C.
      • de Denus S.
      • et al.
      Care gaps in adherence to heart failure guidelines: clinical inertia or physiological limitations?.
      ,
      • Mentz R.J.
      • DeVore A.D.
      • Tasissa G.
      • et al.
      Predischarge initiation of ivabradine in the management of heart failure.
      ,
      • Lopatin Y.M.
      • Cowie M.R.
      • Grebennikova A.A.
      • et al.
      Optimization of heart rate lowering therapy in hospitalized patients with heart failure: insights from the optimize heart failure care program.
      Rather, the major limitation has been unexplained poor uptake of the newer therapies themselves.

      Alternative Strategies to Improve Medication Titration

      Reliance on face-to-face clinic visits with a physician to initiate and titrate medications is not a viable strategy to rapidly achieve GDMT in most patients. Electronic patient-activation tools can be used to involve patients more directly in this process and have been shown to increase the intensification of GDMT significantly during clinic visits.
      • Allen L.A.
      • Venechuk G.
      • McIlvennan C.K.
      • et al.
      An electronically delivered, patient-activation tool for intensification of medications for chronic heart failure with reduced ejection fraction: the EPIC-HF trial.
      Involvement of allied health professionals, including nurse practitioners
      • Blood A.J.
      • Fischer C.M.
      • Fera L.E.
      • et al.
      Rationale and design of a navigator-driven remote optimization of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction.
      and pharmacists,
      • Schulz M.
      • Griese-Mammen N.
      • Anker S.D.
      • et al.
      Pharmacy-based interdisciplinary intervention for patients with chronic heart failure: results of the PHARM-CHF randomized controlled trial.
      or remote titration
      • 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.
      are additional strategies to improve patient adherence and optimize medical therapy more quickly.

      Proposed Medication Optimization Strategies

      We propose a new approach to medication implementation and titration: a cluster-based scheme (Fig. 4). For cluster-based titration, medications are grouped into 3 general clusters with similar hemodynamic or neurohormonal effects. Medications within each cluster should not be initiated or titrated on the same visit because of potential compounding side effects, but attempts should be made to optimize each cluster during each clinic visit (up to 3 changes per visit). Most nonfrail patients with HFrEF could likely be managed with the cluster scheme. Data taken from several studies indicate predictors of medication intolerance include advanced age, lower systolic blood pressure, and lower eGFR.
      • Massie B.M.
      • Armstrong P.W.
      • Cleland J.G.
      • et al.
      Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: results from the ATLAS trial.
      • Edelmann F.
      • Musial-Bright L.
      • Gelbrich G.
      • et al.
      Tolerability and feasibility of beta-blocker titration in HFpEF versus HFrEF.
      • Vardeny O.
      • Wu D.H.
      • Desai A.
      • et al.
      Influence of baseline and worsening renal function on efficacy of spironolactone in patients with severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study).
      In our experience, nonfrail patients with systolic blood pressure > 110 mm Hg, resting heart rate > 70 beats per minute, eGFR > 40, and serum K+ < 5.0 mmol/L can generally tolerate 3 medication changes with a low rate of side effects. An expedited version of the typical approach, with a single medication class change on a regular (biweekly or otherwise) basis, may be more appropriate for frail patients or those at risk for intolerance to medication. These titration schemes are constructed recognizing the need for personalized selection of medications, based on patient factors, including background tolerance, medical history, vital signs, and other factors. Table 4 outlines the guiding principles underpinning this novel approach. Further data relating to feasibility, tolerability, and efficiency of this approach in our 1200 active HF patient population will be forthcoming.
      Figure thumbnail gr4
      Figure 4Cluster titration scheme. For specific drug dosages, please refer to the 2021 CCS/CHFS HF Guidelines update.
      • 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.
      At each clinical interaction, efforts should be made to initiate or titrate a drug within each cluster. For most nonfrail patients, this will result in 3 medication adjustments per interaction. Our preferred drug for each cluster includes SGLT2I (excepting the need for diuretic manipulation symptoms of congestion or evidence of volume depletion) in Cluster A, ARNI (excepting hypotension) for Cluster B, and β-blocker for Cluster C.∗ For Cluster C, rapid and progressive β-blocker titration to target dose is preferred before use of ivabradine. Published trials indicate that titration may occur weekly, with maximum titration time of 2 to 3 months. Thus, prolonged or repeated attempts to titrate β-blockers unsuccessfully before initiation of a sinus node inhibitor (SNI) should be avoided if the sinus rate remains > 70 beats per minute. ARNI, angiotensin receptor neprilysin inhibitor; BB, β-blocker; MRA, mineralocorticoid receptor antagonist; SGLT2I, sodium-glucose cotransport-2 inhibitor.
      Table 4Principles for the cluster scheme approach to Foundational Therapy for HFrEF
      • 1.
        Combination therapy: All 4 Foundational Therapy classes should be trialed before routine addition of Personalized Therapies. Evidence-based medications as per CCS 2017 Guidelines should be used.
      • 2.
        Initiate first, then titrate: Initiation of all 4 Foundational Therapies should be attempted before dose titration. Ultimately, titration of Foundational Therapies to full target dose represents optimal GDMT.
      • 3.
        Clustering medications: The goal at every clinical encounter is to initiate or titrate 1 medication class within each cluster, to a maximum of 3.
        Preferred initial medication class. Cluster A: SGLT2 inhibitor is preferred over loop diuretic in the absence of significant volume overload. Cluster B: Because of superior efficacy, ARNI is preferred over ACEI or ARB in absence of special circumstances and over MRA. Cluster C: β- blocker is preferred over ivabradine, which is included in Cluster C, in deference to its complementary effect on reduction of heart rate.
      • 4.
        Individualization: Patient and laboratory characteristics should dictate which medication class within each cluster is chosen. In the absence of a preferred choice, alternating among classes within a cluster is suggested.
      • 5.
        Time is of the essence: Patient encounters during titration may occur every 1 to 2 weeks, if possible, with a goal of full Foundational Therapies titration within 12 weeks. Titration within each medication class should be no more frequent than every 1 to 2 weeks to limit side effects.
      • 6.
        Managing tolerance: Failure or intolerance of a medication initiation and titration that is not caused by volume depletion should halt further changes in that class until other Foundational Therapy titration has completed (ie, multiple attempts to titrate a particular medication class should not be attempted before adjusting other classes within the cluster).
      • 7.
        Diuretic therapy: Loop-diuretic adjustment should be limited to treatment of volume overload or depletion. In general, volume depletion should be avoided, as Foundational Therapy titration is well tolerated in euvolemic/mildly volume-overloaded settings.
      • 8.
        Opportunity: Hospitalization represents a key opportunity to initiate and titrate Foundational Therapy.
      • 9.
        Teams are critical: Titration may be most efficiently completed with collaborative involvement of nurses, nurse practitioners, and pharmacists and with the aid of telemedicine or other technologies.
      ACEI, angiotensin converting-enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNI, angiotensin neprilysin inhibitor; CCS, Canadian Cardiovascular Society; GDMT, guideline-directed medical treatment; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT2, sodium-glucose cotransport-2 inhibitor; SNI, sinus-node inhibitor.
      Preferred initial medication class. Cluster A: SGLT2 inhibitor is preferred over loop diuretic in the absence of significant volume overload. Cluster B: Because of superior efficacy, ARNI is preferred over ACEI or ARB in absence of special circumstances and over MRA. Cluster C: β- blocker is preferred over ivabradine, which is included in Cluster C, in deference to its complementary effect on reduction of heart rate.

      Conclusions

      Medical therapy for patients with HFrEF has become increasingly complicated, leading to confusion regarding initiation and titration of medication. There is a true sense of urgency to implementing medical therapy, given early and dramatic improvements in patient outcomes with appropriate treatment. The dramatic shift in landscape of medical therapy requires a compensatory paradigm shift in approach to managing these patients. We have proposed 2 medication-optimization strategies, which we believe can meet the clinical challenge of initiating and titrating medical therapies as quickly as possible while ensuring patient safety. Prospective trials are needed to determine the benefits of these pathways compared with the traditional incremental addition of treatments.

      Funding Sources

      The authors report no funding sources for this paper.

      Disclosures

      Dr Miller has received consulting support from Pfizer. Dr Howlett reports research and consulting support from Amgen, AstraZeneca, Bayer, Boerhinger Ingelheim, Janssen, Medtronic, Merck, Novartis, Pfizer, and Servierand and consulting support from Akcea, Alnylam, Cardiol, and Novo-Nordisk. Dr Fine reports research and consulting support from Pfizer, Akcea, Alnylam, and Eidos.

      References

        • Huitema A.A.
        • Harkness K.
        • Malik S.
        • Suskin N.
        • McKelvie R.S.
        Therapies for advanced heart failure patients ineligible for heart transplantation: beyond pharmacotherapy.
        Can J Cardiol. 2020; 36: 234-243
        • Fine N.M.
        • Davis M.K.
        • Anderson K.
        • et al.
        Canadian cardiovascular society/canadian heart failure society joint position statement on the evaluation and management of patients with cardiac amyloidosis.
        Can J Cardiol. 2020; 36: 322-334
        • Kandolin R.M.
        • Wiefels C.C.
        • Mesquita C.T.
        • et al.
        The current role of viability imaging to guide revascularization and therapy decisions in patients with heart failure and reduced left ventricular function.
        Can J Cardiol. 2019; 35: 1015-1029
        • Crossland D.S.
        • Van De Bruaene A.
        • Silversides C.K.
        • Hickey E.J.
        • Roche S.L.
        Heart failure in adult congenital heart disease: from advanced therapies to end-of-life care.
        Can J Cardiol. 2019; 35: 1723-1739
        • Benedict C.R.
        • Johnstone D.E.
        • Weiner D.H.
        • et al.
        Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction: a report from the registry of studies of left ventricular dysfunction.
        J Am Coll Cardiol. 1994; 23: 1410-1420
        • Francis G.S.
        • Goldsmith S.R.
        • Levine T.B.
        • Olivari M.T.
        • Cohn J.N.
        The neurohumoral axis in congestive heart failure.
        Ann Intern Med. 1984; 101: 370-377
        • Anand I.S.
        • Fisher L.D.
        • Chiang Y.T.
        • et al.
        Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure trial.
        Circulation. 2003; 107: 1278-1283
        • Vatner D.E.
        • Asai K.
        • Iwase M.
        • et al.
        Beta-adrenergic receptor-G protein-adenylyl cyclase signal transduction in the failing heart.
        Am J Cardiol. 1999; 83 (80-5H)
        • Bhargava V.
        • Shabetai R.
        • Mathiasen R.A.
        • Dalton N.
        • Hunter J.J.
        • Ross Jr., J.
        Loss of adrenergic control of the force-frequency relation in heart failure secondary to idiopathic or ischemic cardiomyopathy.
        Am J Cardiol. 1998; 81: 1130-1137
        • Zannad F.
        • Gattis Stough W.
        • Rossignol P.
        • et al.
        Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: Integrating evidence into clinical practice.
        Eur Heart J. 2012; 33: 2782-2795
        • Mizuno Y.
        • Yoshimura M.
        • Yasue H.
        • et al.
        Aldosterone production is activated in failing ventricle in humans.
        Circulation. 2001; 103: 72-77
        • Yogasundaram H.
        • Chappell M.C.
        • Braam B.
        • Oudit G.Y.
        Cardiorenal syndrome and heart failure-challenges and opportunities.
        Can J Cardiol. 2019; 35: 1208-1219
        • Dostal D.E.
        • Baker K.M.
        The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function?.
        Circ Res. 1999; 85: 643-650
        • Brunner-La Rocca H.P.
        • Kaye D.M.
        • Woods R.L.
        • Hastings J.
        • Esler M.D.
        Effects of intravenous brain natriuretic peptide on regional sympathetic activity in patients with chronic heart failure as compared with healthy control subjects.
        J Am Coll Cardiol. 2001; 37: 1221-1227
        • Katz S.D.
        • Khan T.
        • Zeballos G.A.
        • et al.
        Decreased activity of the l-arginine-nitric oxide metabolic pathway in patients with congestive heart failure.
        Circulation. 1999; 99: 2113-2117
        • Cullington D.
        • Goode K.M.
        • Clark A.L.
        • Cleland J.G.
        Heart rate achieved or beta-blocker dose in patients with chronic heart failure: which is the better target?.
        Eur J Heart Fail. 2012; 14: 737-747
        • Packer M.
        • Bristow M.R.
        • Cohn J.N.
        • et al.
        The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.
        N Engl J Med. 1996; 334: 1349-1355
        • Hjalmarson A.
        • Goldstein S.
        • Fagerberg B.
        • et al.
        Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure.
        JAMA. 2000; 283: 1295-1302
        • Fang Y.
        • Debunne M.
        • Vercauteren M.
        • et al.
        Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia.
        J Cardiovasc Pharmacol. 2012; 59: 260-267
        • Mancini G.B.
        • Howlett J.G.
        • Borer J.
        • et al.
        Pharmacologic options for the management of systolic heart failure: examining underlying mechanisms.
        Can J Cardiol. 2015; 31: 1282-1292
        • Su J.B.
        • Barbe F.
        • Houel R.
        • Guyene T.T.
        • Crozatier B.
        • Hittinger L.
        Preserved vasodilator effect of bradykinin in dogs with heart failure.
        Circulation. 1998; 98: 2911-2918
        • O’Meara E.
        • McDonald M.
        • Chan M.
        • et al.
        CCS/CHFS heart failure guidelines: clinical trial update on functional mitral regurgitation, SGLT2 inhibitors, ARNI in HFpEF, and tafamidis in amyloidosis.
        Can J Cardiol. 2020; 36: 159-169
        • Langenickel T.H.
        • Dole W.P.
        Angiotensin receptor-neprilysin inhibition with lcz696: a novel approach for the treatment of heart failure.
        Drug Discov. 2012; 9: e131-e139
        • McMurray J.J.
        • Packer M.
        • Desai A.S.
        • et al.
        Angiotensin-neprilysin inhibition versus enalapril in heart failure.
        N Engl J Med. 2014; 371: 993-1004
        • Jaffe I.Z.
        • Mendelsohn M.E.
        Angiotensin ii and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells.
        Circ Res. 2005; 96: 643-650
        • Greene S.J.
        • Felker G.M.
        • Giczewska A.
        • et al.
        Spironolactone in acute heart failure patients with renal dysfunction and risk factors for diuretic resistance: from the ATHENA-HF trial.
        Can J Cardiol. 2019; 35: 1097-1105
        • Bunda S.
        • Wang Y.
        • Mitts T.F.
        • et al.
        Aldosterone stimulates elastogenesis in cardiac fibroblasts via mineralocorticoid receptor-independent action involving the consecutive activation of Gα13, c-Src, the insulin-like growth factor-1 receptor, and phosphatidylinositol 3-kinase/akt.
        J Biol Chem. 2009; 284: 16633-16647
        • McMurray J.J.V.
        • Solomon S.D.
        • Inzucchi S.E.
        • et al.
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2019; 381: 1995-2008
        • Lopaschuk G.D.
        • Verma S.
        Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors.
        JACC Basic Transl Sci. 2020; 5: 632-644
        • Lytvyn Y.
        • Bjornstad P.
        • Udell J.A.
        • Lovshin J.A.
        • Cherney D.Z.I.
        Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials.
        Circulation. 2017; 136: 1643-1658
        • Ferrari R.
        Ivabradine: Heart rate and left ventricular function.
        Cardiology. 2014; 128: 226-230
        • Cohn J.N.
        • Archibald D.G.
        • Ziesche S.
        • et al.
        Effect of vasodilator therapy on mortality in chronic congestive heart failure.
        N Engl J Med. 1986; 314: 1547-1552
        • Armstrong P.W.
        • Pieske B.
        • Anstrom K.J.
        • et al.
        Vericiguat in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2020; 382: 1883-1893
        • Digitalis Investigation G.
        The effect of digoxin on mortality and morbidity in patients with heart failure.
        N Engl J Med. 1997; 336: 525-533
        • Teerlink J.R.
        • Diaz R.
        • Felker G.M.
        • et al.
        GALACTIC-HF Investigators. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure.
        N Engl J Med. 2021; 384: 105-116
        • Swedberg K.
        • Komajda M.
        • Böhm M.
        • et al.
        Ivabradine and outcomes in chronic heart failure (shift).
        Lancet. 2010; 376: 875-885
        • Jhund P.S.
        • Macintyre K.
        • Simpson C.R.
        • et al.
        Long-term trends in first hospitalization for heart failure and subsequent survival between 1986 and 2003.
        Circulation. 2009; 119: 515-523
        • Conrad N.
        • Judge A.
        • Canoy D.
        • et al.
        Temporal trends and patterns in mortality after incident heart failure: a longitudinal analysis of 86000 individuals.
        JAMA Cardiol. 2019; 4: 1102-1111
        • Fonarow G.C.
        • Yancy C.W.
        • Hernandez A.F.
        • Peterson E.D.
        • Spertus J.A.
        • Heidenreich P.A.
        Potential impact of optimal implementation of evidence-based heart failure therapies on mortality.
        Am Heart J. 2011; 161: 1024-1030.e1023
        • Levy W.C.
        • Mozaffarian D.
        • Linker D.T.
        • et al.
        The seattle heart failure model: prediction of survival in heart failure.
        Circulation. 2006; 113: 1424-1433
        • 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.
        Lancet. 2020; 396: 121-128
        • Docherty K.F.
        • Jhund P.S.
        • Inzucchi S.E.
        • et al.
        Effects of dapagliflozin in DAPA-HF according to background heart failure therapy.
        Eur Heart J. 2020; 41: 2379-2392
        • Greene S.J.
        • Fonarow G.C.
        • DeVore A.D.
        • et al.
        Titration of medical therapy for heart failure with reduced ejection fraction.
        J Am Coll Cardiol. 2019; 73: 2365-2383
        • Ouwerkerk W.
        • Voors A.A.
        • Anker S.D.
        • et al.
        Determinants and clinical outcome of uptitration of ACE inhibitors and beta-blockers in patients with heart failure: a prospective European study.
        Eur Heart J. 2017; 38: 1883-1890
        • Felker G.M.
        • Anstrom K.J.
        • Adams K.F.
        • et al.
        Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction.
        JAMA. 2017; 318: 713-720
        • Fiuzat M.
        • Ezekowitz J.
        • Alemayehu W.
        • et al.
        Assessment of limitations to optimization of guideline-directed medical therapy in heart failure from the guide-it trial.
        JAMA Cardiol. 2020; 5: 757-764
        • Jarjour M.
        • Henri C.
        • de Denus S.
        • et al.
        Care gaps in adherence to heart failure guidelines: clinical inertia or physiological limitations?.
        JACC Heart Fail. 2020; 8: 725-738
        • Marti C.N.
        • Fonarow G.C.
        • Anker S.D.
        • et al.
        Medication dosing for heart failure with reduced ejection fraction: opportunities and challenges.
        Eur J Heart Fail. 2019; 21: 286-296
        • Zaman S.
        • Zaman S.S.
        • Scholtes T.
        • et al.
        The mortality risk of deferring optimal medical therapy in heart failure: a systematic comparison against norms for surgical consent and patient information leaflets.
        Eur J Heart Fail. 2017; 19: 1401-1409
        • Desai A.S.
        • McMurray J.J.
        • Packer M.
        • et al.
        Effect of the angiotensin-receptor-neprilysin inhibitor lcz696 compared with enalapril on mode of death in heart failure patients.
        Eur Heart J. 2015; 36: 1990-1997
        • 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.
        Can J Cardiol. 2017; 33: 1342-1433
        • Krum H.
        • Roecker E.B.
        • Mohacsi P.
        • et al.
        Effects of initiating carvedilol in patients with severe chronic heart failure.
        JAMA. 2003; 289: 712-718
        • Poole-Wilson P.A.
        • Cleland J.G.F.
        • Di Lenarda A.
        • et al.
        Rationale and design of the Carvedilol or Metoprolol European Trial in patients with chronic heart failure: COMET.
        Eur J Heart Fail. 2002; 4: 321-329
        • Wang N.
        • Salam A.
        • Webster R.
        • et al.
        Association of low-dose triple combination therapy with therapeutic inertia and prescribing patterns in patients with hypertension.
        JAMA Cardiol. 2020; 5: 1219-1226
        • Grant A.D.M.
        • Chew D.S.
        • Howlett J.G.
        • Miller R.J.H.
        Cost-effectiveness of earlier transition to angiotensin receptor neprilysin inhibitor in patients with heart failure and reduced ejection fraction.
        CJC Open. 2020; 2: 447-453
        • Savarese G.
        • Vedin O.
        • D'Amario D.
        • et al.
        Prevalence and prognostic implications of longitudinal ejection fraction change in heart failure.
        JACC Heart Fail. 2019; 7: 306-317
        • Miller R.J.
        • Howlett J.G.
        • Exner D.V.
        • Campbell P.M.
        • Grant A.D.
        • Wilton S.B.
        Baseline functional class and therapeutic efficacy of common heart failure interventions.
        Can J Cardiol. 2015; 31: 792-799
        • Bhatt A.S.
        • Vaduganathan M.
        • Butler J.
        Growing mismatch between evidence generation and implementation in heart failure.
        Am J Med. 2020; 133: 525-527
        • Allen L.A.
        • Fonarow G.C.
        • Liang L.
        • et al.
        Medication initiation burden required to comply with heart failure guideline recommendations and hospital quality measures.
        Circulation. 2015; 132: 1347-1353
        • Velazquez E.J.
        • Morrow D.A.
        • DeVore A.D.
        • et al.
        Angiotensin-neprilysin inhibition in acute decompensated heart failure.
        N Engl J Med. 2019; 380: 539-548
        • Bhatt D.L.
        • Szarek M.
        • Steg P.G.
        • et al.
        Sotagliflozin in patients with diabetes and recent worsening heart failure.
        N Engl J Med. 2020; 384: 117-128
        • Wikstrand J.
        • Hjalmarson A.
        • Waagstein F.
        • et al.
        Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure.
        J Am Coll Cardiol. 2002; 40: 491-498
        • Vardeny O.
        • Claggett B.
        • Packer M.
        • et al.
        Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction.
        Eur J Heart Fail. 2016; 18: 1228-1234
        • Packer M.
        • Poole-Wilson P.A.
        • Armstrong P.W.
        • et al.
        Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure.
        Circulation. 1999; 100: 2312-2318
        • Konstam M.A.
        • Neaton J.D.
        • Dickstein K.
        • et al.
        Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure.
        Lancet. 2009; 374: 1840-1848
        • Turgeon R.D.
        • Kolber M.R.
        • Loewen P.
        • Ellis U.
        • McCormack J.P.
        Higher versus lower doses of ace inhibitors, angiotensin-2 receptor blockers and beta-blockers in heart failure with reduced ejection fraction.
        PLoS One. 2019; 14e0212907
        • McAlister F.A.
        • Wiebe N.
        • Ezekowitz J.A.
        • Leung A.A.
        • Armstrong P.W.
        Meta-analysis: Beta-blocker dose, heart rate reduction, and death in patients with heart failure.
        Ann Intern Med. 2009; 150: 784-794
        • Metra M.
        • Torp-Pedersen C.
        • Swedberg K.
        • et al.
        Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure.
        Eur Heart J. 2005; 26: 2259-2268
        • Dungen H.D.
        • Apostolovic S.
        • Inkrot S.
        • et al.
        Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure.
        Eur J Heart Fail. 2011; 13: 670-680
        • Krum H.
        • Haas S.J.
        • Eichhorn E.
        • et al.
        Prognostic benefit of beta-blockers in patients not receiving ACE inhibitors.
        Eur Heart J. 2005; 26: 2154-2158
        • Ouwerkerk W.
        • Teng T.K.
        • Tromp J.
        • et al.
        Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction.
        Eur J Heart Fail. 2020; 22: 1472-1482
        • Pitt B.
        • Pierard L.A.
        • Bilge A.
        • et al.
        Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure.
        Am J Cardiol. 1996; 78: 902-907
        • Ferreira J.P.
        • Abreu P.
        • McMurray J.J.V.
        • et al.
        Renal function stratified dose comparisons of eplerenone versus placebo in the EMPHASIS-HF trial.
        Eur J Heart Fail. 2019; 21: 345-351
        • Packer M.
        • Anker S.D.
        • Butler J.
        • et al.
        Cardiovascular and renal outcomes with empagliflozin in heart failure.
        N Engl J Med. 2020; 383: 1413-1424
        • Mentz R.J.
        • DeVore A.D.
        • Tasissa G.
        • et al.
        Predischarge initiation of ivabradine in the management of heart failure.
        Am Heart J. 2020; 223: 98-105
        • Lopatin Y.M.
        • Cowie M.R.
        • Grebennikova A.A.
        • et al.
        Optimization of heart rate lowering therapy in hospitalized patients with heart failure: insights from the optimize heart failure care program.
        Int J Cardiol. 2018; 260: 113-117
        • Allen L.A.
        • Venechuk G.
        • McIlvennan C.K.
        • et al.
        An electronically delivered, patient-activation tool for intensification of medications for chronic heart failure with reduced ejection fraction: the EPIC-HF trial.
        Circulation. 2021; 143: 427-437
        • Blood A.J.
        • Fischer C.M.
        • Fera L.E.
        • et al.
        Rationale and design of a navigator-driven remote optimization of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction.
        Clin Cardiol. 2020; 43: 4-13
        • Schulz M.
        • Griese-Mammen N.
        • Anker S.D.
        • et al.
        Pharmacy-based interdisciplinary intervention for patients with chronic heart failure: results of the PHARM-CHF randomized controlled trial.
        Eur J Heart Fail. 2019; 21: 1012-1021
        • 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.
        JAMA Cardiol. 2020; 5: 1-5
        • Massie B.M.
        • Armstrong P.W.
        • Cleland J.G.
        • et al.
        Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: results from the ATLAS trial.
        Arch Intern Med. 2001; 161: 165-171
        • Edelmann F.
        • Musial-Bright L.
        • Gelbrich G.
        • et al.
        Tolerability and feasibility of beta-blocker titration in HFpEF versus HFrEF.
        JACC Heart Fail. 2016; 4: 140-149
        • Vardeny O.
        • Wu D.H.
        • Desai A.
        • et al.
        Influence of baseline and worsening renal function on efficacy of spironolactone in patients with severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study).
        J Am Coll Cardiol. 2012; 60: 2082-2089
        • 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.
        Can J Cardiol. 2021; 37: 531-546