Heart failure: Long-term management

1

How are heart failure symptoms classified?

• Symptoms are most commonly classified using the New York Heart Association (NYHA) classification system. This symptom-based scale is often how patients are enrolled in clinical trials.

• Class I: No limitation; ordinary physical activity does not cause excess fatigue, shortness of breath, or palpitations.

• Class II: Slight limitation of physical activity; ordinary physical activity results in fatigue, shortness of breath, palpitations, or angina.

• Class III: Marked limitation of physical activity; ordinary activity will lead to symptoms.

• Class IV: Inability to carry on any physical activity without discomfort; symptoms of congestive heart failure are present even at rest; increased discomfort is experienced with any physical activity.

2

What is the stage system for classifying heart failure?

• In 2001 the American College of Cardiology/American Heart Association (ACC/AHA) introduced a system to categorize the stages of heart failure highlighting the structural development and progression of heart failure rather than focusing solely on clinical symptoms. In addition, the 2013 Heart Failure Guidelines suggested appropriate therapy for each stage emphasizing the differences in HFrEF and HFpEF at Stage C ( Fig. 27.1 ). There is ongoing discussion about the management of patients with ejection fraction (EF) between 40% and 50%.

  

• Stage A: Asymptomatic patients at high risk for developing heart failure but without structural heart disease. Includes patients with hypertension, coronary artery disease (CAD), obesity, diabetes, history of drug or alcohol abuse, history of rheumatic fever, family history of cardiomyopathy, and treatment with cardiotoxins.

• Stage B: Asymptomatic patients with structural heart disease. Includes patients with previous myocardial infarction (MI), left ventricular (LV) remodeling including LV hypertrophy (LVH) and decreased EF, and asymptomatic valvular disease.

• Stage C: Patient with structural heart disease with prior or current symptoms of heart failure.

• Stage D: Patient with refractory heart failure requiring specialized interventions.

  • The key point with the stage system is that once symptoms of heart failure develop, the patient is Stage C and that there are therapies for HF that are indicated in the asymptomatic Stage A and B to try to delay or prevent clinical heart failure.

3

Which medical treatments have been shown to decrease mortality in patients with heart failure?

• Pharmacotherapies that have been shown to decrease mortality in patients with HFrEF include the following and are summarized in Table 27.1 .

  Table 27.1

  Magnitude of Benefit of Specific Medical Therapy as Demonstrated by Clinical Trials

  Adapted from Yancy, C. W., Jessup, M., Bozkurt, B., Butler, J., Casey, D. E., Jr., Drazner, M. H., et al. (2013). 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. Journal of the American College of Cardiology , 62(16), e179.

  MEDICAL THERAPY	RR REDUCTION IN MORTALITY (%)	NNT FOR MORTALITY REDUCTION	RR HEART FAILURE HOSPITALIZATIONS (%)
  ACE inhibitors or ARBs	17	26	31
  ARNI	16	27	21
  Beta-blocker	39	4	41
  Aldosterone antagonist	30	6	35
  Hydralazine/nitrate	43	7	33
  SGLT2 inhibition	17	22	30
  CRT	36	8	52
  ICD	23	23	—

  ACE, Angiotensin-converting enzyme; ARBs, angiotensin II receptor blockers; ARNI, angiotensin receptor neprilysin inhibitor; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; NNT, number needed to treat; SGLT2, sodium-glucose co-transporter 2; RR, relative risk.

• Renin-angiotensin-aldosterone system (RAAS) blockade:

• Angiotensin-converting enzyme (ACE) inhibitors are first-line agents in those with depressed EF because they have been convincingly shown to improve symptoms, decrease hospitalizations, and reduce mortality. Angiotensin II receptor blockers (ARBs) are used in those who are ACE inhibitor intolerant because of persistent cough or in some cases after an episode of angioedema.

• The mineralocorticoid receptor antagonist (MRA) or selective aldosterone antagonist (SARA), spironolactone or eplerenone, is recommended as an additional therapy in carefully selected patients with preserved renal function already on standard heart failure therapies. These agents have an additive decrease in mortality in patients with NYHA Class II-IV heart failure symptoms.

• The combination of a neprilysin inhibition with ARB forms a class of medications (angiotensin receptor neprilysin inhibitors [ARNIs]). There is one currently available: sacubitril and valsartan (Entresto©). It can be used in patients with HFrEF who are either not already on an ACE inhibitor/ARB or in substitution for current ACE inhibitor/ARB therapy.

• Hydralazine and isosorbide dinitrate are used in patients who are unable to tolerate ACE inhibitors, ARBs, or ARNIs because of renal failure, angioedema, or as a consideration for add-on therapy. Hydralazine and isosorbide dinitrate should be considered in addition to an ACE inhibitor, ARB, or ARNI in Blacks in particular because it appears to have an added mortality benefit and can be considered as an add-on therapy in others if the patient’s blood pressure allows.

Sympathetic nervous system blockade:

• The beta-blockers metoprolol succinate (Toprol XL©), carvedilol (Coreg©), and bisoprolol (Zybeta©) have been shown to decrease mortality in appropriately selected patients. These agents should be initiated in euvolemic patients on stable background heart failure therapy including ACE inhibitors or ARBs. Carvedilol may be preferable in those with higher blood pressures, while metoprolol succinate may be more potent as an antiarrhythmic agent.

Implantable electronic devices:

• Implantable cardioverter defibrillators (ICDs) are considered for primary prevention of sudden cardiac death in patients whose EF remains less than 30% to 35% despite optimal medical therapy and who have a good-quality life expectancy of at least 1 year.

• Biventricular pacing for resynchronization therapy. Biventricular pacing (BiV) or cardiac resynchronization therapy (CRT) should be considered for patients in sinus rhythm with NYHA class II-IV symptoms, LVEF less than 35%, and QRS greater than 150 milliseconds with a left bundle branch. CRT can be implanted with or without a defibrillator. Consultation with an electrophysiologist is recommended.

4

What is the suggested dosing regimen of sacubitril and valsartan?

• For patients being switched from an ACE inhibitor to sacubitril/valsartan, the product package insert recommended starting dose is 49/51 mg (sacubitril/valsartan) twice daily. A washout period of 36 hours between discontinuation of the ACE inhibitor and initiation of sacubitril/valsartan is recommended. It is recommended to double the dose of the drug combination after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated.

• It is recommended that the starting dose be reduced to 24/26 mg twice daily for:

• Patients not currently taking an ACE inhibitor or ARB or previously taking a low dose of these agents.

• Patients with severe chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m ² ).

• Patients with moderate hepatic information.

  • Sacubitril/valsartan should not be used in patients with severe liver disease, pregnancy, concomitant use of ACE inhibitors (allow a washout period of 36 hours), and those with a history of angioedema related to previous ACE inhibitor or ARB therapy. Important side effects of the drug combination include hyperkalemia, renal impairment, hypotension, and angioedema.

5

What additional class of medications has recently shown to have mortality benefit in heart failure?

• Recently the SGLT2 class of medications, initially intended to be used for the management of diabetic patients, were shown to have significant benefit for heart failure–related hospitalization and death irrespective of the presence of type 2 diabetes. Dapagliflozin and empagliflozin both have shown to decrease mortality and heart failure hospitalizations.

6

Which therapies in heart failure have been shown to reduce hospitalization?

• All the aforementioned medical therapies reduce heart failure symptoms and to a degree heart failure hospitalizations. However, the therapies for heart failure are also aimed at symptom management. In addition to diuretic therapy, the following medications impact only heart failure hospitalization and symptoms.

• Digoxin has been shown to decrease heart failure symptoms and long-term risk of rehospitalization in patients already on medical therapy. The Digitalis Investigation Group (DIG) trial was a multicenter, randomized, double-blinded, placebo-controlled study of 6801 symptomatic patients with heart failure and EF less than 45%. Digoxin did not improve total mortality or deaths from cardiovascular causes. However, hospitalizations as a result of worsening heart failure (a secondary endpoint) were significantly reduced by digoxin.

• Ivabradine, a funny-channel blocker, was introduced in 2015 as a therapy for those with chronic HFpEF already on maximally tolerated beta-blocker doses, but with persistent resting heart rates (HRs) over 70 beats/min. In the randomized SHIFT study, it was found to decrease hospitalization from heart failure. It might also reasonable to use in patients with tachycardia who are unable to tolerate beta-blocker therapy.

7

What is the suggested dosing regimen of ivabradine?

• Per the package insert, ivabradine is indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with LVEF ≤35% who are in sinus rhythm with a resting HR ≥70 beats/min and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.

• Contraindications to ivabradine include acute decompensated heart failure, hypotension, sick sinus syndrome, third-degree heart block (unless a pacemaker is present), resting HR <60 beats/min, severe liver disease, and pacemaker dependence (HR maintained exclusively by a pacemaker).

• The recommended starting dose of ivabradine is 5 mg twice daily. After 2 weeks of treatment, the dose can be adjusted based on HR. The maximum drug dose is 7.5 mg twice daily.

• In patients with conduction defects or in whom bradycardia could lead to hemodynamic compromise, the initial recommended dose is 2.5 mg twice daily.

• Suggested dose adjustments are as follows:

• HR >60 beats/min: increase dose by 2.5 mg (given twice daily) up to a maximum dose of 7.5 mg twice daily.

• HR 50 to 60 beats/min: maintain current dose.

• HR <50 beats/min or signs/symptoms of bradycardia: decrease dose by 2.5 mg (given twice daily); if current dose is 2.5 mg twice daily, discontinue therapy.

8

How do ACE inhibitors and ARBs work?

• ACE inhibitors inhibit ACE, thus blocking the conversion of angiotensin I to angiotensin II. ACE is predominantly found in the pulmonary and to a lesser extent in the renal endothelium. By decreasing the production of angiotensin II, ACE inhibitors attenuate sympathetic tone, decrease arterial vasoconstriction, and attenuate myocardial hypertrophy. Because angiotensin II stimulates aldosterone production, circulating levels of aldosterone are reduced. This results in decreased in sodium chloride absorption, decreased potassium excretion in the distal tubules, and decreased water retention. Through a decrease in antidiuretic hormone (ADH) production, ACE inhibitors also decrease water absorption in the collecting ducts.

• ARBs selectively block the binding of angiotensin II to the AT ₁ receptor, thereby blocking the effect of angiotensin II on end organs.

• The net effect of decreased angiotensin II on end organs of both classes of medications results in attenuation of sympathetic tone, decrease in arterial vasoconstriction, and attenuation of myocardial hypertrophy. Because angiotensin II stimulates aldosterone production, circulating levels of aldosterone are reduced. This results in a decrease in sodium chloride absorption, potassium excretion in the distal tubules, and water retention.

9

What approach should be taken if a patient treated with an ACE inhibitor develops a cough?

• Nonproductive cough related to ACE inhibitors occurs in 5% to 10% of White patients of European descent and in up to 50% of Chinese patients. The cough is believed to be related to kinin potentiation. The cough usually develops within the first month of therapy and disappears within 1 to 2 weeks of discontinuation of therapy. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines suggest one should first make sure the cough is related to treatment and not another condition. The guidelines state that the demonstration that the cough disappears after drug withdrawal and recurs after rechallenge with another ACE inhibitor strongly suggests that ACE inhibition is the cause of the cough. They emphasize that patients should be re-challenged, because many will not redevelop a cough, suggesting the initial development of cough was coincidental and may have been related to heart failure. Patients who do have ACE inhibitor–related cough and cannot tolerate symptoms should be treated with an ARB or ARNI.

10

How do aldosterone antagonists work?

• ARBs block the mineralocorticoid receptor in the distal renal tubules, thereby decreasing sodium chloride absorption, potassium excretion, and water retention. In addition, they block the direct deleterious effects of aldosterone on the myocardium and may thus decrease myocardial fibrosis and its consequences.

11

List the two primary indications of aldosterone antagonists in heart failure.

• Current primary indications of aldosterone antagonists in heart failure include the following:

  • Chronic NYHA class II-IV heart failure and LVEF 35% or less who are already receiving standard therapy for heart failure, including ACE inhibitors, beta-blockers, and diuretics (based on the evaluation of spironolactone in the RALES trial and eplerenone in the EMPHASIS trial).

  • Post-MI patients with LV dysfunction (EF less than 40%) and heart failure symptoms who are already receiving standard therapy, including ACE inhibitors and beta-blockers (EPHESUS study of eplerenone).

12

What is the recommended dosing of aldosterone antagonists in heart failure?

• Dosing of aldosterone antagonists in heart failure is as follows:

• Spironolactone: 12.5 to 25 mg daily, increased to up to 25 mg twice daily.

• Eplerenone: 25 mg daily, increased to 50 mg daily.

  • The dosing regimen for aldosterone antagonists in heart failure, as well as for other medications, are summarized in Table 27.2 .

    Table 27.2

    Initial and Target Doses for Commonly Utilized Drugs for Patients with Depressed Systolic Ejection Fraction and/or Congestive Heart Failure

    Adapted from Yancy, C. W., Jessup, M., Bozkurt, B., Butler, J., Casey, D. E., Jr., Drazner, M. H., et al. (2013). 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. Journal of the American College of Cardiology , 62(16), e175.

    DRUG	INITIAL DAILY DOSES	TARGET/MAXIMUM DOSES
    Angiotensin-Converting Enzyme Inhibitors
    Captopril	6.25 mg TID	50 mg TID
    Enalapril	2.5 mg BID	10–20 mg BID
    Lisinopril	2.5–5 mg daily	20–40 mg daily
    Perindopril	2 mg daily	8–16 mg daily
    Ramipril	1.25–2.5 mg daily	10 mg daily
    Trandolapril	1 mg daily	4 mg daily
    Angiotensin Receptor Blockers
    Losartan	25–50 mg daily	50–150 mg daily
    Candesartan	4–8 mg daily	32 mg daily
    Valsartan	20–40 mg BID	160 mg BID
    Angiotensin Receptor Neprilysin Inhibitor
    Sacubitril/valsartan	24/26–49/51 mg BID	97/103 mg BID
    Aldosterone Antagonists
    Spironolactone	12.5–25 mg daily	25 mg daily or BID
    Eplerenone	25 mg daily	50 mg daily
    Additional Potassium-Sparing Diuretics
    Amiloride	5–10 mg daily	10–20 mg (with caution)
    Triamterene	50–100 mg daily (or divided BID)	Max daily dose 300 mg
    Additional Potassium-Sparing Diuretics
    Bisoprolol	1.25 mg daily	10 mg daily
    Carvedilol	3.125 mg BID	25 mg BID (50 mg BID if >85 kg)
    Metoprolol succinate	12.5–25 mg daily	200 mg daily
    Cyclic Nucleotide-Gated Channel Blocker
    Ivabradine	2.5–5 mg BID	2.5–7.5 mg BID (based on HR)
    Loop Diuretics
    Bumetanide	0.5–1.0 mg daily-BID	Max daily dose 10 mg
    Furosemide	20–40 mg daily-BID	Max daily dose 600 mg
    Torsemide	10–20 mg daily	Max daily dose 200 mg
    Thiazide Diuretics
    Chlorothiazide	250–500 mg daily-BID	Max daily dose 1000 mg
    Chlorthalidone	12.5–25 mg daily	Max daily dose 100 mg
    Hydrochlorothiazide	25 mg daily-BID	Max daily dose 200 mg
    Metolazone	2.5 mg daily	Max daily dose 20 mg
    SGLT2 Inhibitors
    Empagliflozin	10–12.5 mg daily	Max daily dose 25 mg
    Dapagliflozin	10 mg daily	Max daily dose 10 mg

    HR, Heart rate.