Heart Failure Agents

High-yield Verified · Oct 2026

Prototype: sacubitril/valsartan

Heart Failure Agents are a class of medications added to standard therapy in chronic heart failure to reduce cardiovascular death and heart-failure hospitalization.

Medical view → mechanisms, drug comparisons and Step 1 pharmacology

Added to standard heart-failure therapy to cut cardiovascular death and hospitalization — each with a signature safety catch: angioedema and the ACE-inhibitor washout, bradycardia, or pregnancy.

How it works in the body

The system involved, what goes wrong, and how the drug and body interact.

01 Three newer drugs, three new targets

Heart failure sets off a maladaptive renin–angiotensin–aldosterone (RAAS) response — vasoconstriction, aldosterone, sympathetic tone and, eventually, cardiac remodeling. At the same time the body releases natriuretic peptides, which cause vasodilation, natriuresis and diuresis and work against the RAAS.

Each drug here acts on a different part of that picture: sacubitril/valsartan keeps natriuretic peptides around longer while blocking angiotensin II; ivabradine slows the heart rate at the sinus node; and vericiguat restores the nitric oxide–cGMP signal that is impaired in heart failure. Their names carry WHO stems: -sartan (angiotensin II receptor antagonists), -tril (endopeptidase inhibitors, sacubitril), -bradine (bradycardic agents) and -ciguat (guanylate cyclase activators and stimulators).

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Three heart-failure drugs, three different targets.

02 Sacubitril/valsartan — boosting natriuretic peptides while blocking angiotensin II

Sacubitril is a prodrug; esterases convert it to LBQ657, which inhibits neprilysin, the enzyme that degrades natriuretic peptides. Valsartan blocks the angiotensin II type-1 (AT1) receptor. The benefit in heart failure is attributed to the extra natriuretic peptides plus the simultaneous block of angiotensin II.

Neprilysin also breaks down angiotensin II — so a neprilysin inhibitor cannot be given alone; it is paired with an ARB. It breaks down bradykinin too, which is why the combination must never be given with an ACE inhibitor: angioedema risk. Do not give it within 36 hours of switching from or to an ACE inhibitor.

Because BNP is a neprilysin substrate, it rises on sacubitril/valsartan and is not a reliable marker of worsening heart failure; NT-proBNP is not a neprilysin substrate and is used instead.

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Neprilysin breaks down three peptides — which explains both the benefit and the ACE-inhibitor rule.

03 Ivabradine — slowing the sinus node without weakening the heart

Ivabradine blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel that carries the cardiac pacemaker If ("funny") current in the sinoatrial node. Heart rate falls and diastole lengthens, with no negative inotropic effect and no effect on ventricular repolarization.

It only works when the sinus node sets the rhythm, so it is used in sinus rhythm with a resting heart rate of at least 70 beats per minute, on top of a maximally tolerated beta-blocker (or when a beta-blocker cannot be used). It also inhibits the similar retinal Ih current, which explains its unique luminous phenomena (phosphenes). It is cleared by CYP3A4, the source of its key interactions.

04 Vericiguat — restoring cGMP when nitric oxide signaling fails

When nitric oxide binds soluble guanylate cyclase (sGC), the enzyme makes cGMP, which helps regulate vascular tone, cardiac contractility and remodeling. Heart failure impairs NO synthesis and lowers sGC activity.

Vericiguat stimulates sGC directly — independently of and synergistically with NO — raising cGMP and relaxing smooth muscle. It is used after a recent worsening of heart failure (a hospitalization or outpatient IV diuretics). Its signature catch is a boxed embryo-fetal toxicity warning: pregnancy is excluded before starting and prevented during treatment.

Drug names

Generic Brand

sacubitril/valsartan Entresto, Entresto Sprinkle

ivabradine —

vericiguat Verquvo

Indications

Sacubitril/valsartan to reduce cardiovascular death and heart-failure hospitalization in adults with chronic heart failure (benefit clearest when LVEF is below normal)
Sacubitril/valsartan for symptomatic heart failure with systemic left ventricular systolic dysfunction in children aged 1 year and older
Ivabradine to reduce hospitalization for worsening heart failure in stable symptomatic chronic heart failure with LVEF ≤ 35% (sinus rhythm, resting heart rate ≥ 70 bpm, on a maximally tolerated beta-blocker or unable to take one)
Vericiguat to reduce cardiovascular death and heart-failure hospitalization after a heart-failure hospitalization or outpatient IV diuretics, in adults with symptomatic chronic heart failure and ejection fraction below 45%

Mechanism of action

Sacubitril/valsartan: sacubitril’s active metabolite LBQ657 inhibits neprilysin (neutral endopeptidase), raising natriuretic peptides, while valsartan blocks the angiotensin II AT1 receptor and angiotensin II-dependent aldosterone release. Ivabradine blocks the HCN channel carrying the sinoatrial pacemaker If current, lowering heart rate without negative inotropy. Vericiguat stimulates soluble guanylate cyclase independently of and synergistically with nitric oxide, raising cGMP and causing smooth-muscle relaxation and vasodilation.

In plain terms

One drug helps the body’s own pressure-relieving hormones last longer while blocking a constricting one; one gently slows the heartbeat; and one boosts a relaxing signal inside blood-vessel and heart cells.

Therapeutic effects — what you'll see working

These drugs are added to standard heart-failure therapy. Success is fewer hospitalizations and longer survival, followed in practice by symptoms, weight, volume status, blood pressure, heart rate and labs.

Fewer deaths and hospitalizations (sacubitril/valsartan) Slower heart rate, fewer admissions (ivabradine) Fewer deaths and hospitalizations after worsening HF (vericiguat)

Fewer deaths and hospitalizations (sacubitril/valsartan): Reduces cardiovascular death and heart-failure hospitalization in adults with chronic heart failure; it lowers NT-proBNP.
Slower heart rate, fewer admissions (ivabradine): Heart rate falls by about 10 beats per minute at rest and during exercise, and hospitalization for worsening heart failure is reduced.
Fewer deaths and hospitalizations after worsening HF (vericiguat): Reduces cardiovascular death and heart-failure hospitalization after a recent worsening event; NT-proBNP falls in a dose-dependent way.

Adverse effects

Learn each drug by its catch: angioedema, hypotension, hyperkalemia and renal change with the ARNI; bradycardia, atrial fibrillation and phosphenes with ivabradine; hypotension, anemia and fetal harm with vericiguat.

Common

Hypotension, hyperkalemia, cough, dizziness and renal impairment (sacubitril/valsartan); bradycardia, hypertension, atrial fibrillation and phosphenes (ivabradine); hypotension and anemia (vericiguat).

Sacubitril/valsartan’s most common reactions (≥ 5%) are hypotension, hyperkalemia, cough, dizziness and renal failure. Ivabradine’s phosphenes — transiently enhanced brightness in part of the visual field, halos or multiple images — are usually triggered by sudden changes in light, start within the first 2 months, are mild to moderate and mostly resolve. Vericiguat’s most common reactions (≥ 5%) are hypotension and anemia.

Angioedema (sacubitril/valsartan) Report immediately

Angioedema with sacubitril/valsartan — laryngeal involvement can be fatal.

If angioedema occurs, stop the drug immediately, treat, and monitor the airway; it must not be given again. Angioedema is more frequent in Black patients and in those with a prior history of angioedema, and the drug should not be used in hereditary angioedema.

Hypotension, renal impairment and hyperkalemia (sacubitril/valsartan) Hold & notify

Symptomatic hypotension, a fall in renal function and hyperkalemia with sacubitril/valsartan.

Hypotension is more likely in volume- or salt-depleted patients (for example on high-dose diuretics). Renal function can fall in patients whose kidneys depend on the RAAS (severe heart failure, renal artery stenosis). Hyperkalemia risk rises with severe renal impairment, diabetes, hypoaldosteronism or a high-potassium diet.

Bradycardia, conduction disturbances and atrial fibrillation (ivabradine) Hold & notify

Bradycardia, sinus arrest, heart block and atrial fibrillation with ivabradine.

Bradycardia risk rises with sinus-node dysfunction, conduction defects, ventricular dyssynchrony and other negative chronotropes (digoxin, diltiazem, verapamil, amiodarone); bradycardia may increase the risk of QT prolongation and torsade de pointes. Regularly monitor the rhythm and stop ivabradine if atrial fibrillation develops.

Fetal toxicity (ivabradine)

Ivabradine may cause fetal harm based on animal studies (cardiac malformations).

Females of reproductive potential should use effective contraception, and breastfeeding is not recommended.

■ Boxed warning · fetal toxicity (sacubitril/valsartan)

Drugs acting directly on the renin–angiotensin system can injure or kill the developing fetus — stop sacubitril/valsartan as soon as pregnancy is detected.

In the second and third trimesters, drugs acting on the RAS reduce fetal renal function and increase fetal and neonatal morbidity and death.

■ Boxed warning · embryo-fetal toxicity (vericiguat)

Do not give vericiguat in pregnancy. Exclude pregnancy before starting; females of reproductive potential must use effective contraception during treatment and for one month after stopping.

In rabbits, vericiguat caused malformations of the heart and major vessels; vericiguat is contraindicated in pregnancy.

Interactions

ACE inhibitors (sacubitril/valsartan) drug

Contraindicated — angioedema risk; allow 36 hours when switching from or to an ACE inhibitor.

ARBs (sacubitril/valsartan) drug

Avoid — sacubitril/valsartan already contains the ARB valsartan.

Aliskiren (sacubitril/valsartan) drug

Contraindicated in diabetes; avoid when eGFR is below 60 mL/min/1.73 m².

Potassium-sparing diuretics, potassium supplements or potassium salt substitutes (sacubitril/valsartan) drug

Can raise serum potassium.

NSAIDs, including COX-2 inhibitors (sacubitril/valsartan) drug

Can worsen renal function, even to acute renal failure, in older, volume-depleted or renally impaired patients — monitor renal function.

Lithium (sacubitril/valsartan) drug

Higher lithium levels and lithium toxicity — monitor lithium levels.

CYP3A4 inhibitors and inducers (ivabradine) drug

Strong inhibitors (azole antifungals such as itraconazole, clarithromycin, HIV protease inhibitors, nefazodone) are contraindicated; avoid moderate inhibitors (diltiazem, verapamil) and inducers (St. John’s wort, rifampin, barbiturates, phenytoin).

Grapefruit juice (ivabradine) food

A moderate CYP3A4 inhibitor that raises ivabradine levels — avoid.

Other negative chronotropes — beta-blockers, digoxin, amiodarone (ivabradine) drug

Add to the bradycardia risk — monitor heart rate.

Other soluble guanylate cyclase stimulators (vericiguat) drug

Contraindicated together.

PDE-5 inhibitors (vericiguat) drug

Not recommended — additive hypotension.

Contraindications

The contraindications follow each mechanism: bradykinin and angioedema for the ARNI, a slow or unstable heart for ivabradine, and pregnancy or a second sGC stimulator for vericiguat.

Sacubitril/valsartan with an ACE inhibitor, or within 36 hours of switching from or to one

Neprilysin inhibition plus ACE inhibition raises bradykinin and the risk of angioedema (labeled contraindication).

Sacubitril/valsartan with a history of angioedema from a previous ACE inhibitor or ARB

Labeled contraindication — prior angioedema raises the risk of angioedema with sacubitril/valsartan.

Sacubitril/valsartan with aliskiren in a patient with diabetes

Labeled contraindication — the same dual-RAS rule as on the ACE-inhibitor and ARB pages (hypotension, hyperkalemia, renal impairment).

Ivabradine with acute decompensated heart failure, clinically significant hypotension or bradycardia, or sick sinus syndrome, sinoatrial block or third-degree AV block without a functioning demand pacemaker

Labeled contraindications — ivabradine slows the sinus node and can cause bradycardia, sinus arrest and heart block.

Ivabradine with severe hepatic impairment, pacemaker dependence, or a strong CYP3A4 inhibitor

Labeled contraindications — strong CYP3A4 inhibitors raise ivabradine levels and worsen bradycardia; a pacemaker-dependent rhythm cannot be slowed.

Ivabradine with second-degree AV block, or a demand pacemaker set at 60 beats per minute or more use caution

Not recommended (avoid second-degree block unless a functioning demand pacemaker is present); a pacemaker set at 60 or more prevents the heart-rate target.

Vericiguat in pregnancy, or with another soluble guanylate cyclase stimulator

Labeled contraindications — vericiguat may cause fetal harm (boxed warning).

When to hold

Assess before giving — these findings mean hold the dose and act.

Ivabradine — resting heart rate below 50 bpm or symptoms of bradycardia

Hold and notify — the label calls for a dose decrease, or stopping if bradycardia persists.

Ivabradine — new atrial fibrillation

Notify the prescriber — the label says to discontinue ivabradine if atrial fibrillation develops.

Sacubitril/valsartan — swelling of the face, lips, tongue or throat

Stop it and treat as an emergency — protect the airway; it must never be given again.

Sacubitril/valsartan — symptomatic hypotension

Notify the prescriber — diuretics or other antihypertensives may be adjusted first; the dose may be reduced or briefly stopped.

Pregnancy detected (sacubitril/valsartan, vericiguat)

Stop and notify — both carry boxed fetal-toxicity warnings.

Labs & levels

Test Therapeutic / normal Toxic / critical

Serum potassium (sacubitril/valsartan) Periodically, especially with severe renal impairment, diabetes, hypoaldosteronism or a high-potassium diet — —

Serum creatinine / renal function (sacubitril/valsartan) Closely, especially in patients whose renal function depends on the RAAS or with renal artery stenosis — Clinically significant fall in renal function → down-titrate or interrupt

NT-proBNP rather than BNP (sacubitril/valsartan) When worsening heart failure is suspected — BNP is a neprilysin substrate and rises on the drug; NT-proBNP is not — —

Pregnancy test (vericiguat) Before starting, in females of reproductive potential — Positive → do not start (contraindicated in pregnancy)

Nursing considerations

The RN-specific layer — each action paired with the reason it matters.

Sacubitril/valsartan

Confirm the ACE inhibitor has been stopped for at least 36 hours before the first dose, and that the patient has no history of ACE-inhibitor or ARB angioedema.

Why: Combined neprilysin and ACE inhibition raises bradykinin and the risk of angioedema.

Check blood pressure, potassium and creatinine at the start and with dose changes; report symptomatic hypotension, potassium rises or a fall in renal function.

Why: Hypotension, hyperkalemia and renal impairment are labeled warnings, most likely in volume-depleted patients or those with renal disease.

Teach the patient to seek emergency care for swelling of the face, lips, tongue or throat.

Why: Angioedema involving the larynx can be fatal; it is more frequent in Black patients.

When worsening heart failure is suspected, interpret NT-proBNP, not BNP.

Why: BNP is degraded by neprilysin, so it rises on the drug; NT-proBNP is not a neprilysin substrate.

Ivabradine

Check the apical pulse and rhythm before each dose; hold and report a resting rate below 50 bpm, bradycardia symptoms (dizziness, fatigue, hypotension) or an irregular rhythm.

Why: Ivabradine causes bradycardia and conduction disturbances and increases the risk of atrial fibrillation.

Give it with food, and review the medication list for strong or moderate CYP3A4 inhibitors (including diltiazem and verapamil), inducers and grapefruit juice.

Why: Food increases exposure as labeled; CYP3A4 drugs change ivabradine levels and diltiazem and verapamil also lower heart rate.

Warn about phosphenes (brief brightness, halos or multiple images, often with sudden changes in light) and advise care when driving in changing light.

Why: Phosphenes come from inhibition of the retinal Ih current; they usually begin in the first 2 months and mostly resolve.

Advise effective contraception for females of reproductive potential and no breastfeeding.

Why: Ivabradine may cause fetal harm based on animal studies.

Vericiguat

Obtain a pregnancy test before the first dose in females of reproductive potential and confirm effective contraception during treatment and for one month after stopping.

Why: Boxed embryo-fetal toxicity warning; vericiguat is contraindicated in pregnancy.

Give it with food; tablets may be crushed and mixed with water for patients who cannot swallow them.

Why: Bioavailability is 93% when taken with food, and crushed tablets give comparable results.

Monitor blood pressure and hemoglobin; ask about PDE-5 inhibitor use.

Why: Hypotension and anemia are its most common adverse reactions, and PDE-5 inhibitors add to the hypotension.

Common questions

What are Heart Failure Agents used for?

Sacubitril/valsartan to reduce cardiovascular death and heart-failure hospitalization in adults with chronic heart failure. Sacubitril/valsartan for symptomatic heart failure with systemic left ventricular systolic dysfunction in children aged 1 year and older. Ivabradine to reduce hospitalization for worsening heart failure in stable symptomatic chronic heart failure with LVEF ≤ 35%. Vericiguat to reduce cardiovascular death and heart-failure hospitalization after a heart-failure hospitalization or outpatient IV diuretics.

How do Heart Failure Agents work?

What are the serious side effects of Heart Failure Agents?

Watch for angioedema with sacubitril/valsartan — laryngeal involvement can be fatal; symptomatic hypotension, a fall in renal function and hyperkalemia with sacubitril/valsartan; bradycardia, sinus arrest, heart block and atrial fibrillation with ivabradine.

When should a nurse hold Heart Failure Agents, and what safety checks apply?

Ivabradine — resting heart rate below 50 bpm or symptoms of bradycardia: hold and notify — the label calls for a dose decrease, or stopping if bradycardia persists. Ivabradine — new atrial fibrillation: notify the prescriber — the label says to discontinue ivabradine if atrial fibrillation develops. Sacubitril/valsartan — swelling of the face, lips, tongue or throat: stop it and treat as an emergency — protect the airway; it must never be given again. Sacubitril/valsartan — symptomatic hypotension: notify the prescriber — diuretics or other antihypertensives may be adjusted first; the dose may be reduced or briefly stopped. Pregnancy detected (sacubitril/valsartan, vericiguat): stop and notify — both carry boxed fetal-toxicity warnings.

What labs should be monitored with Heart Failure Agents?

Monitor serum potassium (sacubitril/valsartan), serum creatinine / renal function (sacubitril/valsartan), NT-proBNP rather than BNP (sacubitril/valsartan), and pregnancy test (vericiguat).

Sources

Reviewed by Hae Suk Lee, RN

Educational summary for nursing students. Always verify against current prescribing information and your institution's protocols before administering. Not medical advice.