Heart Failure

Heart failure (HF) is a clinical syndrome caused by a range of underlying etiologies and pathophysiologic mechanisms, recognized by a cluster of signs and symptoms — dyspnea, fluid retention, fatigue — together with structural or functional heart disease, corroborated by either elevated natriuretic peptide levels or objective evidence of cardiogenic pulmonary or systemic congestion.^[1] HF is dynamic: symptoms and disease trajectory change over time and can have real periods of remission. The most common underlying causes are hypertension, ischemic heart disease, and valvular heart disease.

HF is classified according to left ventricular ejection fraction (LVEF) into HFrEF (reduced, ≤40%), HFmrEF (mildly reduced, 41-49%), and HFpEF (preserved, ≥50%).^[2] Because HFmrEF and HFpEF show similar treatment responses across the LVEF >40% range, the CCS/CHFS have consolidated both into a single unified pharmacologic category — HFnrEF (heart failure with nonreduced ejection fraction) — in their 2025 guideline update; this chapter uses "HFnrEF" for pharmacologic decisions and the older individual terms when discussing pathophysiology or diagnosis, since both remain in everyday clinical use.^[3]

Symptoms

• Dyspnea (on exertion, at rest, or with lying flat).
• Orthopnea and paroxysmal nocturnal dyspnea (PND).
• Fatigue and reduced exercise tolerance.
• Cough.
• Bendopnea (breathlessness when bending forward).

Signs

• Elevated jugular venous pressure (JVP) and a positive hepatojugular reflux.
• Laterally displaced apical impulse and a third heart sound (S3) — the more specific findings.
• Peripheral edema, pulmonary rales, tachycardia, and cold extremities — less specific findings.
• Unintentional weight gain, particularly more than 2 kg in a week.

Risk factors for developing heart failure

• Age.
• Hypertension.
• Ischemic heart disease.
• Valvular heart disease.
• Dyslipidemia.
• Obesity.
• Smoking.
• Atrial fibrillation.
• Diabetes.
• Chemotherapy and chest radiation exposure.
• Family history of cardiomyopathy.
• Substance use — alcohol, cocaine, amphetamines.

Factors that can precipitate or exacerbate heart failure

• Nonadherence to drug therapy or dietary (sodium/fluid) restrictions.
• Anemia.
• New or worsening arrhythmias.
• Infections.
• Myocardial ischemia.
• Pulmonary embolism.
• Renal dysfunction.
• Thyroid dysfunction.
• Uncontrolled hypertension.
• Worsening valvular heart disease.

Drugs that can cause or exacerbate heart failure

A pharmacist-relevant list — reviewed at every medication reconciliation in a patient with (or at risk of) HF.^[4]

Drugs causing sodium/fluid retention: androgens, corticosteroids, drugs with a high sodium content, licorice-containing products, minoxidil, NSAIDs (including selective COX-2 inhibitors and high-dose salicylates), pregabalin, and thiazolidinediones (pioglitazone, rosiglitazone).

Negative inotropes: most antiarrhythmic agents (amiodarone and dofetilide are the exceptions), beta-blockers when initiated or up-titrated during acute decompensation, itraconazole, non-dihydropyridine calcium channel blockers (diltiazem, verapamil), and some anesthetic agents (e.g., propofol).

Cardiotoxic drugs: alcohol, amphetamines, cocaine, clozapine, and cancer therapies — 5-fluorouracil, alkylating agents (cyclophosphamide, ifosfamide), anthracyclines (doxorubicin, epirubicin, mitoxantrone), bevacizumab, trastuzumab, and tyrosine kinase inhibitors (imatinib, sunitinib).

History

• Symptoms and functional limitation (see Recognize the Condition and the NYHA classification below).
• History of cardiac disease, risk factors, and exacerbating factors (see Risk Factors).
• Comorbidities and a full medication review, including over-the-counter and natural health products.

Physical examination

• Vital signs and weight.
• Volume status.
• Heart, lung, abdominal, and peripheral vascular examination.

NYHA class feeds directly into device-therapy eligibility (see Non-Pharmacologic Treatment) and several drug-specific indications later in this chapter (e.g., ivabradine requires NYHA II-III).

Initial investigations

• Chest radiograph.
• Electrocardiogram.
• Laboratory tests: natriuretic peptides (see below), troponin, CBC, electrolytes, serum creatinine/eGFR, urinalysis, glucose, thyroid function tests, and iron studies.

Natriuretic peptide interpretation

BNP or NT-proBNP testing is most useful when the diagnosis of HF is clinically unclear, providing a "rule in" or "rule out" result; it adds little when the clinical signs and symptoms already clearly indicate HF. Note that an ARNI (sacubitril/valsartan) raises BNP levels through its mechanism of action, making BNP unreliable in patients already on an ARNI — use NT-proBNP instead in that situation, since it is not affected the same way.^[1]

Echocardiography and further testing

Perform echocardiography in every patient with a clinical diagnosis of HF to assess ventricular size and function (including LVEF) and cardiac structures such as valves. Cardiac MRI or cardiac catheterization may follow to determine a specific etiology and guide targeted treatment.

Diagnosing HFnrEF specifically

The 2025 CCS/CHFS guideline defines HFnrEF (LVEF >40%) as requiring all three of the following: (1) symptoms/signs of HF, (2) LVEF >40% on dedicated cardiac imaging, and (3) evidence of elevated cardiac filling pressures — at least one of elevated BNP/NT-proBNP, structural heart disease or diastolic dysfunction on imaging, or hemodynamic confirmation (e.g., elevated pulmonary capillary wedge pressure). A preserved LVEF on a routine echocardiogram does not by itself rule out the clinical syndrome of HF if other indicators point toward the diagnosis.^[3]

Differential diagnosis

When investigations are unrevealing, consider alternative explanations for the presenting symptoms rather than defaulting to a HF diagnosis: COPD or asthma, pneumonia, pulmonary embolism, cirrhosis or nephrotic syndrome (for edema), chronic venous insufficiency, anemia, deconditioning, and anxiety/hyperventilation.

• Reduce mortality.
• Reduce morbidity — fewer HF hospitalizations and exacerbations, improved symptoms, exercise tolerance, and quality of life, and slowed disease progression.
• Achieve and maintain euvolemia.
• Treat modifiable risk factors and manage concomitant conditions.
• For HFrEF: initiate all 4 pillars of guideline-directed medical therapy (GDMT) and up-titrate each to target or maximally tolerated dose within 3-6 months.^[5]
• For HFnrEF: initiate SGLT2 inhibitor and MRA therapy as foundational treatment, adding ARNI/candesartan and a GLP-1 receptor agonist based on patient-specific criteria.^[3]

• Manage concomitant conditions — coronary artery disease and other vascular disease, diabetes, dyslipidemia, hypertension, obesity, sleep apnea, and supraventricular/ventricular arrhythmias.
• Avoid the exacerbating risk factors and drugs listed under Risk Factors.
• Recommend moderate regular physical activity in stable patients; refer to cardiac rehabilitation when appropriate.
• Limit alcohol to no more than 1 drink per day; avoid completely in alcoholic cardiomyopathy.
• Restrict sodium intake to under 2-3 g/day in all patients.
• Restrict fluid intake to under 1.5-2 L/day in patients whose fluid retention is not easily controlled with diuretics, or who have hyponatremia.
• Recommend routine influenza, pneumococcal, and SARS-CoV-2 vaccination.
• Have patients weigh themselves daily and alert their care team for a gain of 0.5 kg/day over several consecutive days, or 2 kg over 3 days.

Device and procedural therapy

Generally reserved for patients without significant comorbidities expected to substantially limit survival.^[1]

• Implantable cardioverter defibrillator (ICD) — secondary prevention after sudden cardiac arrest, ventricular fibrillation, or hemodynamically unstable sustained ventricular tachycardia without a reversible cause. Primary prevention should be considered in ischemic cardiomyopathy with NYHA II-III and LVEF ≤35%, or NYHA I with LVEF ≤30% (measured at least 1 month post-MI and/or at least 3 months after revascularization); in nonischemic cardiomyopathy, consider primary ICD for NYHA II-III with LVEF ≤35% after at least 3 months of optimal medical therapy.
• Cardiac resynchronization therapy (CRT) — consider in NYHA II-III (or ambulatory IV) despite optimal medical therapy, in sinus rhythm, with QRS ≥130 msec, left bundle branch block morphology, and LVEF ≤35%. For NYHA II specifically, CRT is recommended with QRS ≥130 msec, LBBB morphology, and LVEF ≤30%. Patients with QRS >150 msec derive the most benefit.
• Revascularization (percutaneous coronary intervention or CABG) — for select patients to relieve symptomatic ischemia or dysfunctional but viable myocardium.
• Cardiac transplantation — for severe, refractory HF despite optimal therapy in a patient who would otherwise have a reasonable life expectancy.
• Left ventricular assist device (LVAD) — used as a bridge to transplantation, and occasionally as destination therapy in ineligible patients; use as a bridge to recovery is not well established.

Pregnancy

Pregnancy causes major hemodynamic change (increased blood volume, heart rate, and cardiac output; reduced peripheral vascular resistance and BP), which can meaningfully worsen existing HF depending on its severity. Refer patients with known pre-existing HF for pre-conception counselling with an HF-and-pregnancy specialist whenever possible, and monitor closely through pregnancy, delivery, and the postpartum period; obtain an echocardiogram if worsening HF is suspected.^[1]

Peripartum cardiomyopathy (PPCM) is defined as HF with LVEF <45% presenting in the last month of pregnancy or within 5 months of delivery, without pre-existing cardiac disease. Advise patients whose LVEF does not recover against a future pregnancy given the high risk of cardiac morbidity/mortality; patients who do recover should be counselled about a real risk of recurrent LV dysfunction in a subsequent pregnancy.

Avoid ACE inhibitors, ARBs, ARNI, and MRAs in pregnancy — all are known teratogens. Avoid ivabradine and SGLT2 inhibitors given limited safety data. Beta-blockers can be used; beta-1-selective agents (e.g., metoprolol) are generally preferred to minimize increased uterine tone and reduced uterine perfusion, and the newborn should be monitored for 48 hours after delivery for bradycardia, hypoglycemia, and respiratory depression. Furosemide can be used with care to avoid dehydration and reduced placental perfusion. Digoxin can be used safely, though higher doses may be needed given the increased volume of distribution in pregnancy — reduce the dose after delivery. Hydralazine with nitrates can be used to manage symptoms, and hydralazine specifically is a treatment option for elevated BP in pregnancy. In patients with pre-existing HF, resume (or restart) chronic therapy after delivery and continue indefinitely.

Breastfeeding

Beta-blockers are considered safe; metoprolol has the most supporting data and may be preferred. Furosemide and spironolactone can be used, with only minimal transfer into breast milk described for spironolactone. Enalapril, fosinopril, quinapril, and ramipril transfer into breast milk only in limited quantities and can be used safely; data for ARBs and ARNI are more limited, so an ACE inhibitor is preferred when one is needed during lactation. Avoid ivabradine and SGLT2 inhibitors — it is not known whether they transfer into breast milk.

Older adults

Use a lower ARNI starting dose (24/26 mg BID) in patients over 75 years, and start ivabradine at a lower dose in this group as well. Older patients are more susceptible to hypotension and falls during GDMT titration — titrate more gradually and monitor more closely, without withholding GDMT on the basis of age alone.

Renal impairment

Avoid MRA therapy at CrCl <30 mL/min. Use the lower ARNI starting dose (24/26 mg BID) at eGFR <30 mL/min/1.73m². Expect an early SGLT2-inhibitor-associated eGFR dip (up to 15%, resolving by about 12 weeks) — this is acceptable and not itself a reason to stop therapy. Loop diuretics often require higher doses in renal impairment to achieve adequate glomerular drug delivery.

Hepatic impairment

Use the lower ARNI starting dose (24/26 mg BID) in moderate hepatic impairment (Child-Pugh Class B).

Pediatrics

This chapter addresses adult HF only. Pediatric and congenital heart failure have distinct etiologies and management and should be referred to pediatric cardiology.

Assess fluid/volume status at every visit, and have patients weigh themselves daily at home. Check serum creatinine, electrolytes, and BP before starting — and 7-14 days after starting or increasing the dose of — an ACE inhibitor, ARB, ARNI, MRA, or diuretic. For MRA therapy specifically, check renal function and potassium 1 week after initiation or any dose change, then approximately every 3 months once the patient is stable on a steady dose; hold or reduce the MRA if creatinine rises more than 30%, potassium exceeds 5.4 mmol/L, or symptomatic hypotension develops, and discontinue outright if potassium reaches 6.0 mmol/L or higher on a non-hemolyzed sample.^[3] Keep serum potassium at or above 4 mmol/L, since hypokalemia increases the risk of fatal ventricular arrhythmia and digoxin toxicity.

Reassess NYHA functional class and overall symptom burden at each visit. Check digoxin levels when renal function changes significantly, when an interacting drug is started or stopped, during a significant dehydrating illness, or when toxicity is suspected — trough concentration at least 8 hours post-dose, target range 0.6-1.2 nmol/L. Monitor heart rate (and ECG where relevant) with ivabradine. With an SGLT2 inhibitor, watch for volume depletion, genital mycotic infections, and urinary tract infections, and expect the early eGFR dip described above.

Hold the ACE inhibitor/ARB/ARNI, MRA, and SGLT2 inhibitor as part of standard sick-day management during an acute dehydrating illness.^[1] Periodically reassess iron status (ferritin, transferrin saturation) even in the absence of anemia, and reassess LVEF and device-therapy eligibility (ICD/CRT) at the appropriate post-MI, post-revascularization, or post-optimization interval. Expect closer monitoring during the initiation/titration phase, tapering to less frequent visits once the patient is stable on target or maximally tolerated GDMT.

1. Confirm adherence to prescribed GDMT and to non-pharmacologic measures (sodium/fluid restriction, daily weighing) before escalating or changing therapy.
2. Look for and treat a reversible precipitant (see Risk Factors) — infection, new arrhythmia, myocardial ischemia, pulmonary embolism, anemia, thyroid dysfunction, uncontrolled hypertension, nonadherence, or a newly added offending drug.
3. Reassess volume status. Undertreated congestion is the most common cause of a HFrEF patient appearing to "fail" therapy — escalate the loop diuretic dose, frequency, or route (consider IV, or add a low-dose intermittent thiazide such as metolazone under close monitoring for diuretic-resistant congestion) before assuming the GDMT itself has failed.
4. Confirm all 4 GDMT pillars have actually been started and are being actively titrated toward target or maximally tolerated doses within the 3-6 month window — undertreatment, not true drug failure, is the most common cause of persistent HFrEF symptoms.
5. If hypotension or renal dysfunction is limiting further GDMT titration, reduce the diuretic dose first — it is often the actual limiting factor — rather than backing off GDMT.
6. Once GDMT has been optimized for the appropriate duration, reassess LVEF and device-therapy eligibility (ICD/CRT).
7. For persistent NYHA II-IV symptoms despite optimized GDMT: consider digoxin, ivabradine (if HR ≥70 bpm in sinus rhythm on a maximized beta-blocker), or vericiguat (recent HF hospitalization/high-risk features).
8. For a Black patient who remains symptomatic on standard therapy: add hydralazine plus isosorbide dinitrate.
9. Refer for advanced HF, transplantation, or mechanical circulatory support evaluation if HF remains refractory despite all of the above.

• Initiating or up-titrating a beta-blocker during acute decompensation — start only once the patient is euvolemic and hemodynamically stable.
• Stopping GDMT permanently after a single episode of hypotension or renal dysfunction instead of first checking and reducing the diuretic dose.
• Attributing new peripheral edema to isolated venous insufficiency without reassessing HF volume status.
• Using NSAIDs (including OTC and COX-2-selective agents) in a patient with HF — sodium and fluid retention risk.
• Using a non-dihydropyridine calcium channel blocker (diltiazem, verapamil) or an antiarrhythmic other than amiodarone/dofetilide in HFrEF.
• Assuming a stable low blood pressure or asymptomatic bradycardia automatically means GDMT should be reduced — reassess the clinical context before reflexively cutting doses.
• Missing iron-deficiency screening in HFrEF simply because hemoglobin is normal — HF-relevant iron deficiency is defined by ferritin/transferrin saturation, not hemoglobin.
• Using oral iron for HF-related iron deficiency — it has not been shown to be effective; IV iron is required.
• Treating HFpEF as "nothing to treat" — the 2025 CCS/CHFS update establishes real, evidence-based pharmacotherapy for HFnrEF.
• Forgetting to hold the ACE inhibitor/ARB/ARNI, MRA, and SGLT2 inhibitor during an acute dehydrating illness (sick-day rules).
• Substituting an ARB for an ACE inhibitor specifically to avoid hyperkalemia or renal dysfunction — both classes carry the same risk, so this does not solve the underlying problem.
• Starting an ARNI without the mandatory 36-hour washout after the last ACE inhibitor dose.
• Missing digoxin toxicity risk when potassium is low, or failing to recheck levels after a significant interacting-drug or renal-function change.

How to use this table: Doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Select any drug name to open its complete Pharmasist Drug Database page.

Diuretics — congestion management (all HF phenotypes)

Diuretics relieve symptoms and signs of volume overload but do not modify the underlying disease course or reduce mortality. Reassess regularly and use the minimum effective dose.

ACE inhibitors — HFrEF pillar 1 (or alternative RAAS agent when ARNI is not appropriate)

Titrate at 7-14 day intervals; check creatinine, potassium, and BP before starting and 7-14 days after any dose increase. A creatinine rise of up to 30% is expected and acceptable.

Angiotensin II receptor blockers — ACE-inhibitor-intolerant HFrEF, or HFnrEF add-on when ARNI unavailable

Same monitoring approach as ACE inhibitors; do not use specifically to avoid hyperkalemia/renal dysfunction seen with an ACE inhibitor, since the risk is shared across both classes.

Angiotensin receptor-neprilysin inhibitor (ARNI)

The preferred RAAS agent for symptomatic HFrEF, and a weak-recommendation add-on for HFnrEF when systolic BP is at least 100 mmHg without hypotension risk. Requires a 36-hour washout after the last ACE inhibitor dose (no washout needed from an ARB). Use the lower 24/26 mg BID starting dose for patients on a low/medium-dose ACE inhibitor or ARB (or ACEi/ARB-naive), severe renal impairment (eGFR <30), moderate hepatic impairment (Child-Pugh B), age over 75, or systolic BP 100-120 mmHg; use 49/51 mg BID as the starting dose for patients already on a high-dose ACE inhibitor or ARB, or with systolic BP ≥120 mmHg. Check creatinine, potassium, and BP 1 week after initiation, and titrate every 2-4 weeks toward target if stable.

Beta-blockers — HFrEF pillar 2

Start at a very low dose and titrate slowly, at 2-4 week intervals. Never initiate or increase the dose during acute decompensation; do not stop abruptly except in an emergency, given rebound tachycardia risk. Check BP and heart rate before starting and before each dose increase.

Mineralocorticoid receptor antagonists — HFrEF pillar 3, and a strong recommendation for HFnrEF

Avoid if baseline potassium exceeds 5 mmol/L or CrCl is under 30 mL/min. Check creatinine and potassium 3 and 7 days after initiation or a dose change, then monthly for 3 months, then every 3 months once stable.

SGLT2 inhibitors — HFrEF pillar 4, and a strong recommendation for HFnrEF

Regardless of diabetes status. Assess fluid status and reduce the diuretic dose if euvolemic before starting, given a mild osmotic diuretic effect. An eGFR dip of up to 15% in the first 4 weeks, resolving by about 12 weeks, is expected and acceptable.

Evidence-based GLP-1 receptor agonists — HFnrEF add-on with LVEF ≥45% and BMI ≥30 kg/m²

Weak recommendation to reduce HF hospitalization risk and improve quality of life; not indicated for HFnrEF outside this specific obesity/EF-defined group. Titrate slowly; if GI side effects occur, consider staying at the current dose longer before the next increase.

If-channel inhibitor

Cardiac glycoside

Vasodilators

Soluble guanylate cyclase stimulator

Parenteral iron replacement — iron deficiency in HFrEF

Confirm iron deficiency by laboratory testing (ferritin <100 ng/mL, or 100-299 ng/mL with transferrin saturation <20%) before treating, regardless of whether anemia is present. Oral iron has not been shown to be effective for HF-related iron deficiency and should not be used. The specific IV iron formulations with the strongest heart-failure outcome evidence are ferric carboxymaltose and ferric derisomaltose^[6]; other IV iron formulations (e.g., iron sucrose) are reasonable alternatives, dosed per their standard iron-deficiency-anemia protocol, when a heart-failure-specific formulation is not available.

Adjunct supplement

HMG-CoA reductase inhibitors (statins)

Evidence for a mortality benefit specifically from starting a statin in HF is limited, but it remains reasonable to continue statin therapy in patients already taking one, and to start a statin in younger patients or those at high cardiovascular risk (recent MI, diabetes, known vascular disease).

Calcium channel blocker — safe adjunct antihypertensive/antianginal in HFrEF

Drugs to avoid or use with caution in HFrEF

See Risk Factors above for the fuller list of drugs that can cause or exacerbate HF in general; the following are specifically discouraged as chronic HFrEF therapy.