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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 3  |  Issue : 2  |  Page : 31-35

Pharmacologic management of chronic heart failure


1 Division of Cardiology, Morehouse School of Medicine, Atlanta, GA, USA
2 Division of Cardiology, Morehouse School of Medicine; Heart Failure Program, Grady Health System, Atlanta, GA, USA

Date of Web Publication15-Apr-2019

Correspondence Address:
Anekwe Onwuanyi
Division of Cardiology, Morehouse School of Medicine, Atlanta, GA
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njct.njct_1_19

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  Abstract 


Heart failure (HF) is a complex progressive clinical syndrome that is associated with high morbidity and mortality. Although several pharmacologic therapy have become available for treatment of certain HF phenotypes, HF still is characterized by recurrent hospitalizations and need for advanced therapy resulting in huge economic burden. The optimal management of HF includes modifying risk factors, identifying and treating reversible causes, address socioeconomic barriers to care and instituting appropriate pharmacologic and device treatments. In this brief review, we summarize the pharmacologic treatment of chronic heart failure and highlight a few major landmark trials that provide the basis for specific therapy in clinical practice.

Keywords: GDMT, heart failure, HFrEF, pharmacologic management


How to cite this article:
Egbuche O, Cross JA, Onwuanyi A. Pharmacologic management of chronic heart failure. Niger J Cardiovasc Thorac Surg 2018;3:31-5

How to cite this URL:
Egbuche O, Cross JA, Onwuanyi A. Pharmacologic management of chronic heart failure. Niger J Cardiovasc Thorac Surg [serial online] 2018 [cited 2019 Sep 18];3:31-5. Available from: http://www.nigjourcvtsurg.org/text.asp?2018/3/2/31/256250




  Introduction Top


Chronic heart failure (HF) is a progressive medical condition characterized by recurrent hospitalizations and high mortality. It presents a major health challenge, especially as its prevalence continues to rise owing to an aging population and an epidemic of hypertension, obesity, and coronary artery disease.[1] The lifetime risk of developing HF is 20% for Americans ≥40 years of age and approximately 5.1 million persons in the United States have clinically manifest HF. Although survival has improved, the absolute mortality rates for HF remain approximately 50% within 5 years of diagnosis.[2] Depending on the left ventricular ejection fraction (LVEF), individuals with HF may be categorized into different phenotypes. Recent guidelines from the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) have defined HF with reduced ejection fraction (HFrEF) as having symptoms and signs of HF with an LVEF ≤40%, whereas HF with preserved ejection fraction (HFpEF) as HF with an LVEF ≥50%. Patients with HF and LVEF in the range of 41%–49% were categorized as borderline HFpEF. The pharmacologic management of HF is guided by assessment of the LVEF, which has been shown to be predictive of adverse outcomes even in the absence of symptomatic HF.[3] Although pharmacologic therapy is not a consistent determinant of health-related quality of life (HRQOL), therapies such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers modestly improve HRQOL or delay the progressive worsening of HRQOL in HF.[2] The current review is focused on pharmacologic management of chronic HF and emphasizes individualized therapy.

While the management of HFpEF is focused on control of blood pressure, volume status, comorbidities, and risk factor modification; the management of HFrEF is focused on appropriate and optimal use of guideline-directed medical therapy (GDMT) to reduce HF hospitalizations and improve survival. GDMT for the management of HFrEF encompasses clinical evaluation, diagnostic testing, and pharmacological and interventional treatments that provide tailored yet optimal care for patients with HFrEF.[4] Till date, no pharmacologic therapy has demonstrated mortality benefit in patients with HFpEF.


  Blood Pressure Control Top


Optimal blood pressure control in patients with HFpEF may be achieved using calcium channel blockers, ACEIs, thiazides, and loop diuretics. Therapy may be escalated with addition of other blood pressure lowering agents, including beta blockers, hydralazine, and nitrates. As there is no pharmacologic therapy that has demonstrated mortality benefit in patients with HFpEF, therapy is directed at achieving optimal blood pressure control by escalating antihypertensive medications. Use of ACEI, loop diuretics, beta blockers, and hydralazine/nitrate combination is described in the management of HFrEF.


  Pharmacologic Management of Heart Failure With Preserved Ejection Fraction Top


Low effective arterial volume in patients with HFrEF leads to over-activation of the sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAAS), and production of anti-diuretic hormone (ADH). Over-activation of the SNS leads to chronic adrenergic states that characterize HFrEF. Chronic adrenergic activation has been directly linked to cardiac myocyte necrosis, fibrosis, and hypertrophy in animal models.[5],[6] Activation of the RAAS system leads to increased production of angiotensin II, aldosterone, and ADH. This ultimately leads to vasoconstriction, salt and water retention, thus propagating ventricular hypertrophy and remodeling. Pharmacologic therapy is, therefore, focused on inhibiting these systems.


  Angiotensin-Converting Enzyme Inhibitors Top


This therapy targets and inhibits the conversion of angiotensin I to angiotensin II, and therefore, prevents the downstream effects of angiotensin II. The Cooperative North Scandinavian Enalapril Survival Study trial demonstrated reduction in mortality in HFrEF patients. In their study, the intervention (enalapril) group had a 40% of reduction in mortality at 6 months compared to the control (placebo) group.[7] Similar results were reproduced by the studies of left ventricular dysfunction trial which showed 16% of reduction in mortality as well as reduction in hospitalization when enalapril is added to conventional therapy in patients with HFrEF.[8] The ACCF/AHA strongly recommends (class of recommendation-1; level of evidence-A) the use of ACEI in all patients with HFrEF unless contraindicated.[4] Therapy is typically initiated at low doses and should be used cautiously in patients with renal dysfunction and elevated serum potassium. Some of the adverse reactions of ACEIs include cough, hypotension, worsening renal function, and hyperkalemia.


  Angiotensin-Receptor Blockers Top


Angiotensin-receptor blockers inhibit the effect of angiotensin II on type 1 angiotensin (AT-1) receptors. The mortality benefit of this therapy was demonstrated in the Candesartan in HF Assessment of Reduction in Mortality and Morbidity-Alternative trial which showed a reduction in composite outcome of cardiovascular mortality or HF hospitalizations in HFrEF patients treated with candesartan compared to the placebo.[9] Angiotensin Receptor Blockers (ARBs) are class 1A recommendation for use in HFrEF patients with current or prior symptoms who are ACEI intolerant. Routine use of an ARB in HFrEF patients already on ACEI and an aldosterone antagonist (AA) is discouraged.[2] Therapy is initiated at a low dose and titrated to tolerable doses to reach the maximum effective dose. Renal function and serum potassium should be closely monitored at least within 2 weeks of initiation of therapy.


  Beta-Adrenoceptor Antagonists (Beta-Blockers) Top


Beta-blocker therapy targets the adrenergic receptors to inhibit the systemic effects of chronic SNS activation. However, the benefit of beta blockers is not a class effect and was only demonstrated with specific beta-blockers. In the Cardiac Insufficiency Bisoprolol Study (CIBIS), bisoprolol was compared to placebo in HFrEF patients. Bisoprolol reduced hospitalizations, improved the functional status with improvement in the reported New York Heart Association functional (NYHA) class by at least one.[10] The CIBIS-II randomized trial demonstrated survival benefits in stable HFrEF patients with NYHA functional Class III or IV. Beyond the reduction in sudden death, the study also demonstrated a reduction in all-cause mortality.[11] The Metoprolol CR/XL randomized intervention trial in congestive HF, a 34% reduction in all-cause mortality was noted in HFrEF patients treated with Metoprolol XL when compared to the placebo. A composite outcome of all-cause mortality and all-cause hospitalizations was also reduced with the use of Metoprolol XL.[12] The Carvedilol prospective randomized cumulative survival study group demonstrated that carvedilol reduced annual mortality rates, hospitalizations, and cardiogenic shock when compared to the placebo.[13]

The ACCF/AHA recommends (class 1A) the use of any one of these specified beta-blockers in patients with HFrEF except when contraindicated. Therapy should be used with caution in patients with low heart rate or symptomatic reactive airway disease. In the absence of cardiogenic shock, in-hospital therapy may be continued during acute decompensation in patients who have been compliant with their beta blockers as long as the patient is being adequately diuresed. Initiation of beta blocker before hospital discharge is also safe provided intravenous inotropic therapy for management of decompensated HF was not required in that index admission.[2] Therapy is also safe in patients with urine toxicology tests positive for cocaine except for patients with symptoms and signs of acute cocaine intoxication.[14] Goal dose for each beta-blocker should be similar to those used in the individual trials except when limited by adverse effects.


  Aldosterone Antagonists Top


These pharmacologic agents inhibit the effect of aldosterone on the mineralocorticoid receptors thereby preventing the downstream effects of sodium and water retention. The evidence for their use was shown in the randomized aldactone evaluation study trial. In their study, spironolactone resulted in a 30% mortality reduction, 35% reduction in HF hospitalizations, and improved NYHA functional class when compared to placebo in patients with NYHA III-IV symptoms and LVEF <35% already on a loop diuretic.[15] The Eplerenone in Mild Patients Hospitalization and Survival Study in HF (EMPHASIS-HF) trial demonstrated a reduction in death and hospitalizations in patients with LVEF ≤35% and NYHA class II symptoms by eplerenone when compared to placebo.[16]

AA therapy is a class 1 LOE-A recommendation for patients with NYHA class II-IV who have LVEF of 35% or less and are already receiving beta blocker and ACEI therapy. Careful risk assessment and close monitoring are necessary during initiation and maintenance of AA therapy. Renal function and potassium levels should be checked within the 1st week after initiation of therapy and subsequently depending on the stability of the renal function.


  Hydralazine-Isosorbide Dinitrate Therapy Top


This therapy has vasodilator properties which help reduce both preload and afterload in patients with HFrEF. The A-HeFT trial demonstrated improved survival and reduction in hospitalization among black HFrEF patients with the addition of this therapy to standard therapy of ACEI, beta-blocker, and diuretics.[17] The trial was terminated early when addition of this therapy showed nearly 40% reduction in all-cause mortality and 33% reduction in first hospitalizations due to HF. The ACCF/AHA recommends this therapy for self-described African Americans with NYHA class III-IV HFrEF who are already receiving optimal therapy with ACEI and beta blocker. It is also suggested for use in a similar cohort of patients who are intolerant to ACEI or ARB.[2]


  Angiotensin Receptor-Neprilysin Inhibitor Therapy Top


The angiotensin receptor-neprilysin inhibitor (ARNI) therapy prevents the breakdown of natriuretic peptide and blocks the effect of angiotensin on AT 1 receptor resulting in multiple pharmacologic effects that counterbalance those of chronic RAAS stimulation. The prospective comparison of ARNI with ACEI to determine the impact on global mortality and morbidity in HF trial demonstrated a 20% of reduction in composite outcome of cardiovascular mortality or HF hospitalizations when ARNI was compared to enalapril in NYHA class II-IV HFrEF patients. Caution should be taken in patients who are already on ACEI before switching to ARNI. Concomitant administration of these medication or use within 36 h results to the high incidence of angioedema and is contraindicated.


  Ivabradine Therapy Top


This therapy selectively inhibits the pacemaker current (If) in the sinoatrial node to slow the heart rate. The Systolic HF treatment with the If inhibitor ivabradine (SHIFT) trial demonstrated that addition of ivabradine to contemporary medical therapy (ACEI/ARB, beta blocker, and MRA) resulted in 18% of reduction in the composite outcome of HF mortality or hospitalization. The benefit of ivabradine was mostly driven by a 26% reduction in HF hospitalization and a 2% absolute reduction in HF mortality.[18] Importantly, there was no demonstrable all-cause mortality benefit. Since patients enrolled in this trial were on GDMT that has demonstrated mortality benefit in different trials, it is pertinent to initiate and titrate these agents to target doses or as tolerated before considering ivabradine initiation. This therapy is a class IIa LOE-B recommendation to reduce HF hospitalization for symptomatic NYHA class II-III HFrEF patients who are receiving maximal tolerated doses of GDMT and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest.[4]


  Diuretics Top


This include medications that block the Na+/K+/Cl-transporter in the loop of Henle and the Na+/Cl-co-transporter in the distal convoluted tubule of the kidney resulting to salt and water loss. Diuretic therapy is the mainstay for decongestion and optimizing volume status in acutely decompensated HFrEF patients. Furosemide, bumetanide, and torsemide are the loop diuretics that are most frequently used. Thiazide diuretics in addition to a loop diuretic strategy may be used in patients with diuretic resistance. Therapy should generally be given intravenously to optimize bioavailability in patients with acute decompensated HF. Intravenous furosemide is effective for diuresis regardless of the administration strategy. The Diuretic Optimization Strategy Evaluation (DOSE) trial demonstrated no substantial difference between bolus injection and continuous infusion of equal doses of furosemide for treatment of hospitalized patients with HF.[19]


  Digoxin Top


Digoxin is a cardiac glycoside targeted at inhibiting the Na+/K+ ATPase thereby increasing the intracellular Na + concentration. Increased intracellular Na + reduces the Na + concentration gradient required for efflux of Ca2+ via the Ca2+/Na+ exchanger resulting in increased intracellular Ca2+ that produce the mild inotropic effects of digoxin. The Digitalis Investigation Group trial demonstrated that digoxin reduced HF hospitalizations by 28% but does not impact mortality when compared to placebo in HFrEF patients.[20] The ACCF/AHA recommend consideration of digoxin for adjunctive use in HFrEF patients with persistent symptoms despite use of GDMT.[2] Doses of digoxin that achieve a plasma concentration of drug in the range of 0.5–0.9 ng/mL are suggested by the ACCF/AHA to minimize side effects which include cardiac arrhythmias, nausea, vomiting, visual disturbances, disorientation, and confusion. Although toxicity may occur at any supratherapeutic dose of digoxin, overt toxicity is commonly associated with levels >2 ng/ml.[2]


  Inotropic Therapy Top


This therapy specifically improves cardiac contractility in addition to their drug-specific pharmacologic effects. The most frequently used inotropes in HFrEF patients are dobutamine and milrinone. Dobutamine stimulates B1, B2, and A1 receptors leading to conversion of adenosine triphosphate to cyclic adenosine monophosphate (cAMP) by adenylyl cyclase. This results in increased intracellular calcium leading to improved force of contraction. Milrinone inhibits phosphodiesterase-3 preventing the conversion of cAMP to its inactive form. Increased cAMP leads to increased intracellular calcium with resultant positive inotropic effect. Although they have not demonstrated improved outcomes, these therapies have found their use in improving the hemodynamic compromise that occurs in cardiogenic shock complicating acute decompensated HF. To minimize side effects from this therapy, it is preferable to use low medication doses and for the shortest period of time necessary to improve hemodynamic compromise and end-organ perfusion.[2] Although it has more arrhythmogenic effects, hypotensive effects, and more likely to result in adverse events in patients with renal impairment; better survival have been reported with milrinone when compared to dobutamine among all patients placed on inotropes.[21],[22] The ACCF/AHA recommend therapy only for specific category of HFrEF patients and in specific clinical contexts, including temporary use for inotropic support in cardiogenic shock patients pending definitive therapy, and continuous inotropic support as a palliative therapy or bridge to transplant in stage D HFrEF patients refractory to GDMT. Use is discouraged in hospitalized patients without documented severe systolic dysfunction and cardiogenic shock.[2]


  Conclusion Top


The pharmacologic management of chronic HF continues to improve as advances and newer therapies evolve. There are robust data to support use of the identified GDMT for management of HFrEF. Appropriate individualized medication combination and medication titration to maximal tolerable doses are essential to improve HRQOL and achieve any morbidity or mortality benefits associated with therapy. Pharmacologic therapy to improve survival in our HFpEF population is lacking. Further clinical trials that address new therapeutic options and strategies, especially in the HFpEF population are vital to future advances in pharmacologic management of chronic HF.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Biglane JB, Becnel MF, Ventura HO, Krim SR. Pharmacologic therapy for heart failure with reduced ejection fraction: Closing the gap between clinical guidelines and practice. Prog Cardiovasc Dis 2017;60:187-97.  Back to cited text no. 1
    
2.
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr., Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American heart association task force on practice guidelines. J Am Coll Cardiol 2013;62:e147-239.  Back to cited text no. 2
    
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Hsu JJ, Ziaeian B, Fonarow GC. Heart failure with mid-range (Borderline) ejection fraction: Clinical implications and future directions. JACC Heart Fail 2017;5:763-71.  Back to cited text no. 3
    
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Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr. Colvin MM, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the heart failure society of America. J Card Fail 2017;23:628-51.  Back to cited text no. 4
    
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Michel FS, Magubane M, Mokotedi L, Norton GR, Woodiwiss AJ. Sex-specific effects of adrenergic-induced left ventricular remodeling in spontaneously hypertensive rats. J Card Fail 2017;23:161-8.  Back to cited text no. 5
    
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Gibbs M, Veliotes DG, Anamourlis C, Badenhorst D, Osadchii O, Norton GR, et al. Chronic beta-adrenoreceptor activation increases cardiac cavity size through chamber remodeling and not via modifications in myocardial material properties. Am J Physiol Heart Circ Physiol 2004;287:H2762-7.  Back to cited text no. 6
    
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SOLVD Investigators, Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN, et al. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.  Back to cited text no. 8
    
9.
Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-alternative trial. Lancet 2003;362:772-6.  Back to cited text no. 9
    
10.
A randomized trial of beta-blockade in heart failure. The cardiac insufficiency bisoprolol study (CIBIS). CIBIS investigators and committees. Circulation 1994;90:1765-73.  Back to cited text no. 10
    
11.
The cardiac insufficiency bisoprolol study II (CIBIS-II): A randomised trial. Lancet 1999;353:9-13.  Back to cited text no. 11
    
12.
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF) Lancet 1999;353:2001-7.  Back to cited text no. 12
    
13.
Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-8.  Back to cited text no. 13
    
14.
Egbuche O, Ekechukwu I, Effoe V, Maduabum N, Millard HR, Maihemuti A, et al. Effect of β-blocker therapy on hospital readmission and mortality in heart failure patients with concurrent cocaine use. J Cardiovasc Pharmacol Ther 2018;23:518-23.  Back to cited text no. 14
    
15.
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators. N Engl J Med 1999;341:709-17.  Back to cited text no. 15
    
16.
Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21.  Back to cited text no. 16
    
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Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R Jr., Ferdinand K, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-57.  Back to cited text no. 17
    
18.
Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010;376:875-85.  Back to cited text no. 18
    
19.
Allen LA, Turer AT, Dewald T, Stough WG, Cotter G, O'Connor CM, et al. Continuous versus bolus dosing of furosemide for patients hospitalized for heart failure. Am J Cardiol 2010;105:1794-7.  Back to cited text no. 19
    
20.
Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525-33.  Back to cited text no. 20
    
21.
Hashim T, Sanam K, Revilla-Martinez M, Morgan CJ, Tallaj JA, Pamboukian SV, et al. Clinical characteristics and outcomes of intravenous inotropic therapy in advanced heart failure. Circ Heart Fail 2015;8:880-6.  Back to cited text no. 21
    
22.
King JB, Shah RU, Sainski-Nguyen A, Biskupiak J, Munger MA, Bress AP, et al. Effect of inpatient dobutamine versus milrinone on out-of-hospital mortality in patients with acute decompensated heart failure. Pharmacotherapy 2017;37:662-72.  Back to cited text no. 22
    




 

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  In this article
Abstract
Introduction
Blood Pressure C...
Pharmacologic Ma...
Angiotensin-Conv...
Angiotensin-Rece...
Beta-Adrenocepto...
Aldosterone Anta...
Hydralazine-Isos...
Angiotensin Rece...
Ivabradine Therapy
Diuretics
Digoxin
Inotropic Therapy
Conclusion
References

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