Drugs for Chronic Heart Failure
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Drugs for Chronic Heart Failure
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Med Lett Drugs Ther. 2021 Jun 14;63(1626):89-96
 Select a term to see related articles  Accupril   ACE inhibitors   Aldactone   Altace   ARBs   Atacand   Beta blockers   BiDil   Bisoprolol   Bumetanide   Burinex   Candesartan   Captopril   Carvedilol   cilazapril   Coreg   Corlanor   Coversyl   Cozaar   dapagliflozin   Digoxin   Diovan   Diuretics   empagliflozin   Enalapril   Entresto   Eplerenone   Farxiga   Forxiga   Fosinopril   Furosemide   Heart Failure   Hydralazine   Inhibace   Inspra   Isosorbide dinitrate   ivabradine   Jardiance   Lancora   Lasix   Lisinopril   Losartan   Mavik   Metoprolol   Perindopril   Prinivil   Quinapril   Ramipril   sacubitril   Spironolactone   Toprol   torsemide   Trandolapril   Valsartan   Vasotec   vericiguat   Verquvo   Zestril 
Summary: Drugs for Treatment of HFrEF1-3
  • An angiotensin receptor-neprilysin inhibitor (ARNI) is now preferred over an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) for patients with NYHA class II-IV heart failure, especially those with a reduced ejection fraction (HFrEF; LVEF ≤40%).
  • In addition to an ARNI, ACE inhibitor, or ARB, all patients with ACC/AHA Stage C HFrEF should take, unless contraindicated, an evidence-based beta blocker, a mineralocorticoid receptor antagonist (MRA), and a sodium-glucose cotransporter 2 (SGLT2) inhibitor.
  • In patients who are volume overloaded, a diuretic should be added. Loop diuretics are more effective than thiazide diuretics.
  • Black patients with HFrEF, especially those with persistent NYHA class III-IV symptoms despite use of target or maximally tolerated doses of an ARNI, ACE inhibitor, or ARB, a beta blocker, and an MRA, can benefit from addition of isosorbide dinitrate and hydralazine.
  • In patients with NYHA class II-III heart failure and a LVEF ≤35% who are in sinus rhythm with a resting heart rate of ≥70 bpm despite use of target or maximally tolerated doses of a beta blocker, addition of the If channel inhibitor ivabradine should be considered.
  • In patients with symptomatic heart failure and a LVEF ≤45% who were recently hospitalized or required treatment with an IV diuretic, addition of the soluble guanylate cyclase stimulator vericiguat modestly reduced the composite risk of first hospitalization for heart failure or cardiovascular death, but not the risk of cardiovascular death alone.
  • Digoxin can decrease symptoms and the rate of hospitalization for heart failure in patients with HFrEF, but it does not reduce mortality. Data on the benefits of digoxin in the setting of contemporary heart failure treatments are lacking.

Among patients with chronic heart failure, those with a left ventricular ejection fraction (LVEF) ≤40% are considered to have heart failure with reduced ejection fraction (HFrEF). Patients with a LVEF ≥50% are considered to have heart failure with preserved ejection fraction (HFpEF). Those with a LVEF of 41-49% are an intermediate group more similar to patients with HFpEF.1

STANDARD TREATMENT — An angiotensin receptor-neprilysin inhibitor (ARNI) is now preferred over an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) for patients with NYHA class II-IV heart failure. The benefits are most evident in those with HFrEF. In patients who are unable to tolerate an ARNI or cannot access an ARNI due to cost, an ACE inhibitor or ARB should be used instead.

All patients with ACC/AHA Stage C (structural heart disease with prior or current heart failure symptoms) HFrEF should take, unless contraindicated, an ARNI (preferred), ACE inhibitor, or ARB, an evidence-based beta blocker, a mineralocorticoid receptor antagonist (MRA), and a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and if volume overloaded, a diuretic. Black patients, especially those with persistent NYHA class III-IV symptoms despite standard therapy, can benefit from addition of isosorbide dinitrate and hydralazine.

Addition of the If channel inhibitor ivabradine should be considered for patients with NYHA class II-III heart failure who have a LVEF ≤35% and a resting heart rate of ≥70 bpm in sinus rhythm despite use of target or maximally tolerated doses of a beta blocker.2,3

In patients with symptomatic chronic heart failure and a LVEF ≤45%, the oral soluble guanylate cyclase (sGC) inhibitor vericiguat has modestly reduced the risk of a composite endpoint of first hospitalization for heart failure or cardiovascular death.4

Digoxin can decrease heart failure symptoms and the rate of hospitalization for heart failure in patients with HFrEF, but it does not reduce mortality.1,3

ARNI — The fixed-dose combination of the neprilysin inhibitor sacubitril and the ARB valsartan (Entresto) is FDA-approved to reduce the risk of hospitalization for heart failure and cardiovascular death in all patients with chronic heart failure, but the benefits are most evident in patients with HFrEF.5

In a randomized, double-blind trial in patients with NYHA class II-IV HFrEF (PARADIGM-HF), the composite rate of cardiovascular death or hospitalization for heart failure was significantly lower with sacubitril/valsartan than with the ACE inhibitor enalapril (21.8% vs 26.5%).6 A similar study comparing sacubitril/valsartan with valsartan alone in patients with HFpEF (PARAGON-HF) narrowly missed statistical significance for the same primary endpoint, but subgroup analyses suggested that sacubitril/valsartan may be more effective than valsartan alone in patients with a LVEF of 45-57% and in women.7,8

Preliminary results of a randomized, double-blind trial (LIFE) in 335 patients with advanced heart failure (NYHA class IV heart failure in the previous 3 months, LVEF ≤35%, elevated natriuretic peptides, systolic blood pressure ≥90 mm Hg, and ≥1 additional objective finding of advanced heart failure) did not show an advantage for sacubitril/valsartan over valsartan alone for reduction of natriuretic peptides or improvement in clinical outcomes at 24 weeks.9

Dosage – Patients previously taking a moderate- to high-dose ACE inhibitor or ARB can be started on sacubitril/valsartan 49/51 mg twice daily. ACE inhibitor treatment should be stopped for 36 hours before starting the combination. The dose of sacubitril/valsartan should be doubled every 2 weeks as tolerated to a target of 97/103 mg twice daily. The recommended dosage is 24/26 mg twice daily for de novo therapy, for patients currently taking a low-dose ACE inhibitor or ARB, and for those with an eGFR <30 mL/min/1.73 m2, moderate hepatic impairment (Child-Pugh B), or hypotension. Sacubitril/valsartan is not recommended for use in patients with severe hepatic impairment (Child-Pugh C).

Adverse Effects – Hypotension, renal impairment, and hyperkalemia can occur with the combination, although less often than with ACE inhibitors and ARBs. Sacubitril/valsartan may cause angioedema, especially in Black patients and in those with a history of angioedema. It is contraindicated for use in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy and in those with hereditary angioedema.

Drug Interactions – Sacubitril/valsartan is contraindicated for use with or within 36 hours after the last dose of an ACE inhibitor because of the increased risk of angioedema. It should not be used with an ARB. Concurrent use of sacubitril/valsartan and potassium-sparing diuretics, renin inhibitors, trimethoprim/sulfamethoxazole, or other drugs that increase potassium levels increases the risk of hyperkalemia. Worsening of renal function and acute renal failure could occur in patients taking sacubitril/valsartan and an NSAID concurrently. Concurrent use of lithium and an ARB can increase lithium serum concentrations; frequent monitoring is recommended. Valsartan is a substrate of organic anion transporting polypeptide (OATP) 1B1; concomitant use of drugs that inhibit OATP1B1, such as atorvastatin (Lipitor, and others), could increase valsartan serum concentrations.10,11

For a more detailed table, click here.

ACE INHIBITORS — Treatment with an ACE inhibitor improves symptoms (generally over 4-12 weeks), decreases hospitalizations for heart failure, and prolongs survival in patients with HFrEF. No data are available showing that one ACE inhibitor is more effective than any other for treatment of HFrEF.

Dosage – ACE inhibitors should be started at low doses and titrated to the highest tolerated dose, targeting the usual maximum daily dosages listed in Table 2.

Adverse Effects – The most common adverse effects of ACE inhibitors are related to increased levels of bradykinin (cough and, less commonly, angioedema), suppression of angiotensin II (hypotension and renal insufficiency), and reduction of aldosterone production (hyperkalemia); blood pressure, renal function, and serum potassium concentrations should be monitored. ACE inhibitors should be used cautiously in patients who are at risk for excessive hypotension or have a serum creatinine level >3 mg/dL, a serum potassium level >5.0 mEq/L, or bilateral renal artery stenosis. They should not be used in patients with a history of angioedema. ACE inhibitor-induced angioedema is more likely to occur in Black patients.

Drug Interactions – ACE inhibitors should not be used with an ARB or ARNI. Use of ACE inhibitors with potassium-sparing diuretics, renin inhibitors, trimethoprim/sulfamethoxazole, or other drugs that increase serum potassium levels increases the risk of hyperkalemia. NSAIDs may decrease the effectiveness of ACE inhibitors and increase the risk of renal impairment. Concurrent use of lithium and an ACE inhibitor can increase lithium serum concentrations; frequent monitoring is recommended. Concurrent use of a thiopurine and an ACE inhibitor can cause leukopenia and anemia. Captopril is a substrate of CYP2D6; use with a CYP2D6 inhibitor may increase its serum concentrations.10 Quinapril (Accupril, and generics) contains magnesium, which can decrease absorption of oral tetracyclines.12

ARBs — Long-term ARB therapy reduces hospitalizations for heart failure and may reduce mortality in patients with HFrEF. ARBs can be used in patients who cannot tolerate an ACE inhibitor because of cough or angioedema and in those who were already taking an ARB prior to the diagnosis of heart failure. Candesartan (Atacand, and generics) and valsartan (Diovan, and generics) are the only ARBs that are FDA-approved for treatment of heart failure; losartan (Cozaar, and generics) has also been widely used.13

Dosage – ARBs should be started at low doses and titrated to the highest tolerated dose, which is generally achieved by doubling the dose until the usual maximum daily dose is reached (see Table 2).

Adverse Effects – ARBs, like ACE inhibitors, block the effects of angiotensin II and may cause hypotension, renal impairment, and hyperkalemia, but they do not typically cause cough. As with ACE inhibitors, blood pressure, renal function, and serum potassium concentrations should be monitored. ARBs probably do not cause angioedema.

Drug Interactions – ARBs should not be used with an ACE inhibitor or ARNI. Use of ARBs with potassium-sparing diuretics, renin inhibitors, trimethoprim/sulfamethoxazole, or other drugs that increase potassium levels increases the risk of hyperkalemia. NSAIDs may decrease the effectiveness of ARBs and increase the risk of renal impairment. Concurrent use of lithium and an ARB can increase lithium serum concentrations; frequent monitoring is recommended. Losartan is a substrate of CYP3A4 and CYP2C9; inducers of these isozymes could decrease its efficacy and inhibitors could increase its serum concentrations and toxicity.10 Valsartan is a substrate of OATP1B1; concomitant use of drugs that inhibit OATP1B1, such as atorvastatin, could increase valsartan serum concentrations.11

BETA BLOCKERS — Long-term therapy with a beta blocker improves symptoms and clinical outcomes in patients with HFrEF. Carvedilol (Coreg, and others), metoprolol succinate (Toprol XL, and generics), and bisoprolol have been shown to reduce the rates of hospitalization for heart failure and death in patients with HFrEF. Bisoprolol is not FDA-approved for treatment of heart failure.

Dosage – Beta blockers should be started at low doses and increased gradually, usually at 2-week intervals, to the highest tolerated dose (see Table 2). Transient worsening of symptoms can occur following initiation of therapy, and full clinical benefits may not occur for 3-6 months or longer.

Adverse Effects – Fatigue, hypotension, bradycardia, asymptomatic fluid retention, and worsening heart failure may occur during the first few weeks of treatment. Increasing the dose of a concurrent diuretic may be helpful. Carvedilol, which has vasodilatory activity, may cause more hypotension than metoprolol or bisoprolol. Beta blockers should be used cautiously, if at all, in patients with severe bradycardia or significant asthma; the risk of bronchospasm may be lower with metoprolol and bisoprolol because of their beta-1 selectivity.

Drug Interactions – Carvedilol and metoprolol are substrates of CYP2D6; concurrent use of a CYP2D6 inhibitor may increase their serum concentrations and toxicity. Carvedilol is also an inhibitor of the drug transporter P-glycoprotein (P-gp) and can increase serum concentrations of P-gp substrates such as digoxin. Bisoprolol is a substrate of CYP3A4; use with CYP3A4 inducers may decrease its efficacy.10,12

MRAs — When added to standard therapy in patients with HFrEF, MRAs have been shown to reduce the risk of hospitalization for heart failure and death.14,15 Addition of eplerenone (Inspra, and generics) or spironolactone (Aldactone, and generics) is recommended for patients with NYHA class II-IV heart failure who have a LVEF ≤35%, a serum potassium level <5.0 mEq/L, and either an eGFR ≥30 mL/min/1.73 m2 or a serum creatinine level ≤2.5 mg/dL in men or ≤2.0 mg/dL in women. Eplerenone is similar in efficacy to spironolactone, but it costs more.

Dosage – Initial dosage recommendations and dose adjustments for MRAs are based on serum potassium levels (see Table 2).

Adverse Effects – Hyperkalemia occurs frequently with MRAs; the risk is higher in patients also taking an ACE inhibitor or an ARB, and in those with renal impairment. MRAs should not be started in patients with a serum potassium level >5.0 mEq/L and should be used cautiously in those with renal impairment. Potassium and serum creatinine concentrations and renal function should be monitored during treatment.

Spironolactone has anti-androgenic activity; it can cause erectile dysfunction and painful gynecomastia in men, menstrual irregularities in women, and hair loss in both men and women. Eplerenone has less anti-androgenic activity and has been associated with a lower incidence of these effects.

Drug Interactions – Use of an MRA with other drugs that increase serum potassium concentrations increases the risk of hyperkalemia. Eplerenone is a substrate of CYP3A4. Use of eplerenone with CYP3A4 inducers could decrease its serum concentrations and efficacy, and use with CYP3A4 inhibitors could increase its toxicity; concurrent use of eplerenone and CYP3A4 strong inhibitors is contraindicated.10,12

SGLT2 INHIBITORS — Addition of an SGLT2 inhibitor is recommended for patients with NYHA class II-IV HFrEF and adequate renal function (eGFR ≥30 mL/min/1.73 m2 for dapagliflozin and ≥20 mL/min/1.73 m2 for empagliflozin). Initially FDA-approved to improve glycemic control in patients with type 2 diabetes, all currently available SGLT2 inhibitors have been shown to reduce the risk of hospitalization for heart failure by ~30% in such patients.16 In patients with HFrEF, with or without type 2 diabetes, the SGLT2 inhibitors dapagliflozin (Farxiga) and empagliflozin (Jardiance) have reduced a composite risk of hospitalization for heart failure or cardiovascular death (see Table 3).17,18

Dosage – Renal function should be assessed before starting treatment with an SGLT2 inhibitor. Doses should be taken in the morning to avoid nocturia.

Adverse Effects – Urinary tract infections and genital mycotic infections are the most common adverse effects of SGLT2 inhibitors. Fournier's gangrene can also occur.

Drug Interactions – Hypoglycemia can occur when an SGLT2 inhibitor is used in combination with insulin or a sulfonylurea.

DIURETICS — Most patients with heart failure have fluid retention. Diuretics can relieve symptoms in these patients, but their effect on survival is unclear. Diuretics provide symptomatic relief of pulmonary and peripheral edema more rapidly than other drugs used for treatment of heart failure. Loop diuretics such as furosemide (Lasix, and generics), bumetanide, and torsemide are more effective in patients with heart failure than thiazide-type diuretics such as hydrochlorothiazide and chlorthalidone. Torsemide and bumetanide have longer half-lives and are better absorbed than furosemide, but there is no clinical evidence that either is more effective.

Dosage – Diuretics should be started at a low dose, which can be titrated upward until urine output increases and weight decreases (see Table 2). Higher starting doses can be used in patients with renal impairment or prior refractoriness to loop diuretics. Intravenous administration, concurrent use of two diuretics (a loop and a thiazide-like diuretic), or addition of an MRA can sometimes overcome diuretic resistance.

Adverse Effects – The most common adverse effect of loop diuretics is hypokalemia. Diuretics can also cause worsening of renal function.

Drug Interactions – NSAIDs can decrease the effectiveness of diuretics. Concurrent use of lithium and a diuretic could increase lithium serum concentrations; frequent monitoring is recommended. Torsemide is a substrate of CYP2C9; use with CYP2C9 inducers could decrease its efficacy and use with CYP2C9 inhibitors could increase its serum concentrations and toxicity.10,12

VASODILATORS — Black patients with HFrEF who remain symptomatic on standard therapy, especially those with NYHA class III-IV heart failure, can benefit from addition of a combination of isosorbide dinitrate and hydralazine (available separately and in a fixed-dose combination as BiDil). The combination has been shown to reduce the rate of first hospitalization for heart failure and improve survival.19

The benefit in non-Black patients is less well established, but use of the combination can be considered in those who cannot tolerate an ARNI, an ACE inhibitor, or an ARB.

Dosage – Isosorbide dinitrate/hydralazine should be started at a low dose, which can be titrated upward every 2-4 weeks (see Table 2). Patients should be monitored for hypotension.

Adverse Effects – Isosorbide dinitrate/hydralazine can cause hypotension, headache, and dizziness. Hydralazine alone can cause tachycardia, peripheral neuritis, and a lupus-like syndrome.

Drug Interactions – Phosphodiesterase 5 (PDE5) inhibitors such as sildenafil (Viagra, Revatio, and generics) should not be taken concurrently with isosorbide dinitrate/hydralazine because of the risk of additive hypotensive effects.

IVABRADINE — The If channel inhibitor ivabradine (Corlanor) slows the heart rate of patients in sinus rhythm by inhibiting the cardiac pacemaker If current. It has no effect on contractility.

In a randomized trial (SHIFT) in patients with symptomatic heart failure, a LVEF ≤35%, and a resting heart rate of ≥70 bpm despite maximally tolerated beta blocker therapy, addition of ivabradine significantly reduced the rates of hospitalization for worsening heart failure and death due to heart failure, but not cardiovascular death, compared to placebo. The patients in the trial were not receiving maximally tolerated beta blocker therapy.20,21

Dosage – The initial dosage of ivabradine is 5 mg taken twice daily with meals. A lower starting dosage of 2.5 mg twice daily can be used in patients who have underlying conduction defects or are at higher risk of hemodynamic compromise. The dosage should be adjusted every two weeks to achieve a target heart rate of 50-60 bpm (maximum of 7.5 mg twice daily; see Table 2). Ivabradine is contraindicated for use in patients with severe hepatic impairment (Child-Pugh C).

Adverse Effects – Symptomatic bradycardia, hypertension, atrial fibrillation, and visual effects (transient increases in brightness due to inhibition of electric currents in the retina) have been reported with ivabradine. It should not be used in patients with atrial fibrillation.

Drug Interactions – Ivabradine is a substrate of CYP3A4; use with strong CYP3A4 inhibitors is contraindicated and use with CYP3A4 inducers or moderate CYP3A4 inhibitors should be avoided.10,12

VERICIGUAT — Vericiguat (Verquvo), an oral soluble guanylate cyclase (sGC) stimulator, is FDA-approved to reduce the risk of hospitalization for heart failure and cardiovascular death following a worsening heart failure event (hospitalization for heart failure or treatment with IV diuretics as an outpatient) in patients with symptomatic heart failure and a LVEF <45%.

In one clinical trial (VICTORIA), addition of vericiguat to standard therapy that generally did not include an ARNI or SGLT2 inhibitor modestly reduced the risk of a composite endpoint of cardiovascular death or first hospitalization for heart failure. The effect was primarily on hospitalization; cardiovascular death as a lone endpoint was not reduced.4

Dosage – The initial dosage of vericiguat is 2.5 mg taken once daily with food; the dose should be doubled every two weeks as tolerated to reach a target dose of 10 mg (see Table 2).

Adverse Effects – Anemia occurred in 10% of patients who received vericiguat compared to 7% of those who received placebo. There were no significant differences between the two groups in the rates of symptomatic hypotension or syncope.

Drug Interactions – Phosphodiesterase 5 (PDE5) inhibitors such as sildenafil (Viagra, Revatio, and generics) should not be taken concurrently with vericiguat because of the risk of additive hypotensive effects.

DIGOXIN — In patients with HFrEF, digoxin can improve symptoms and decrease hospitalization rates, but in a long-term trial conducted primarily in patients with NYHA class II-III HFrEF, 2-5 years of digoxin treatment had no effect on mortality.1,22 Data on the benefits of digoxin in the setting of contemporary heart failure treatments are lacking. A low dose (0.125 mg daily) is sometimes used in patients with HFrEF who remain symptomatic on standard therapy; digoxin levels of 0.5-0.9 ng/mL are recommended. Dose adjustments based on renal function, age, and concomitant medications may be required.

Adverse Effects – The most common adverse effects of digoxin are conduction disturbances, cardiac arrhythmias, nausea, vomiting, confusion, and visual disturbances.

Drug Interactions – Digoxin is a substrate of P-gp; use with P-gp inducers could decrease its serum concentrations and efficacy, and use with inhibitors (such as carvedilol) could increase its toxicity.10 Potassium-sparing diuretics (mainly spironolactone) may decrease the efficacy of digoxin and loop diuretics may increase its toxicity. Concurrent use of digoxin and ivabradine can increase the risk of bradycardia.12

PREGNANCY — ARNIs, ACE inhibitors, and ARBs are contraindicated for use during pregnancy because they increase the risk of fetal renal failure and death.

Beta blockers have been associated with fetal growth restriction, but beta-1-selective drugs (e.g., metoprolol, bisoprolol) are less likely to cause this effect. A review of 13 population-based studies found that use of beta blockers during the first trimester was not associated with an overall increase in congenital malformations, but in some studies, their use early in pregnancy has been associated with increased rates of cleft lip/palate and cardiovascular and neural tube defects.23

MRAs are teratogenic and should not be used during pregnancy. SGLT2 inhibitors are not recommended during the second and third trimesters of pregnancy based on adverse renal effects in animals.

Diuretic therapy should be initiated with caution during pregnancy because these drugs cause volume depletion during their first weeks of use that may reduce uteroplacental perfusion; women already taking a diuretic who become pregnant can generally continue taking it.

No data are available on the safety of isosorbide dinitrate/hydralazine use during pregnancy.

Fetal toxicity and cardiac teratogenic effects have occurred in animal studies with ivabradine; women of childbearing age should use effective contraception while taking the drug. Pregnant women taking ivabradine should be monitored for bradycardia, destabilization of heart failure, and preterm birth (in the third trimester).

Administration of vericiguat to pregnant animals resulted in cardiac malformations, increased abortions and resorptions, decreased pup weight, and increased mortality; it is contraindicated for use during pregnancy. An effective form of contraception should be used during treatment with vericiguat and for 1 month after stopping it. Digoxin is generally considered safe for use during pregnancy.

LACTATION — There are no data on the presence of ARNIs or ARBs in breast milk. Low levels of some ACE inhibitors have been found in human breast milk, but no adverse effects are expected in breastfed infants. Metoprolol is the beta blocker of choice for treatment of heart failure in breastfeeding women; beta blockers with low protein binding (e.g., bisoprolol) are more likely to be excreted into breast milk and should be avoided. MRAs and SGLT2 inhibitors are not recommended for breastfeeding women. Diuretics decrease fluid volume, which may impact lactation; they have been used to intentionally suppress lactation. There are no data on the presence of loop diuretics in breast milk. Thiazide diuretics are present in breast milk in low concentrations; no adverse effects are expected in breastfed infants. There are no data on the presence of isosorbide dinitrate/hydralazine in breast milk. Women taking ivabradine or vericiguat should avoid breastfeeding. Digoxin levels in breast milk are low; avoidance of breastfeeding for two hours post-dose is recommended.

Additional Content Available: Comparison Chart: Some Drugs for HFrEF

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