Heart Failure
Clinical Snapshot
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]
Recognize the Condition
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.
Heart failure by ejection fraction
The primary classification driving pharmacotherapy selection throughout this chapter.
HFrEF — reduced ejection fraction
LVEF ≤40%. Decreased systolic (pump) function with left ventricular dilatation. Essentially all of the mortality-reducing pharmacotherapy in this chapter comes from HFrEF trial populations.
HFmrEF — mildly reduced ejection fraction
LVEF 41-49%. A less well-characterized, evolving category that may represent a transitional state toward HFrEF, or a recovering HFpEF. Managed together with HFpEF under the unified HFnrEF pharmacologic approach below.
HFpEF — preserved ejection fraction
LVEF ≥50%. Abnormal myocardial relaxation (diastolic dysfunction) with a non-dilated, often concentrically remodeled or hypertrophied left ventricle and left atrial enlargement. More common with older age, female sex, obesity, hypertension, atrial fibrillation, sleep apnea, and diabetes. Diagnosis is more challenging than HFrEF; potentially treatable etiologies (infiltrative, restrictive, inflammatory, or genetic cardiomyopathies) should be considered but are beyond the scope of this chapter.
HFimpEF — improved ejection fraction
Baseline LVEF ≤40% that has since increased by more than 10 points, with a second measurement above 40%. A heterogeneous group — some patients are in a treated "remission" that still requires indefinite therapy, others have genuinely recovered from a reversible cause with no remaining structural abnormality. Treatment strategy is individualized and this category is not specifically addressed by the 2025 HFnrEF guideline.
HFnrEF — nonreduced ejection fraction (2025 CCS/CHFS nomenclature)
LVEF >40% — the unified term the CCS/CHFS now use for pharmacologic-management purposes to cover both HFmrEF and HFpEF together, reflecting evidence of similar treatment responses across this range.[3]
Risk Factors
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).
Red Flags & Refer
Acute decompensation can progress quickly to cardiogenic shock. Any patient reporting the following needs urgent (same-day or emergency department) assessment, not a routine follow-up appointment:
- Rapid weight gain — 0.5 kg/day over several consecutive days, or 2 kg over 3 days.
- Significant new or worsening dyspnea, especially at rest or when lying flat.
- New or worsening orthopnea or paroxysmal nocturnal dyspnea.
- Symptomatic hypotension — dizziness, presyncope, or syncope.
- Signs of hypoperfusion or cardiogenic shock — cold extremities, altered mental status, reduced urine output.
- New resting tachycardia or a new arrhythmia (e.g., rapid atrial fibrillation).
- Chest pain suggesting concurrent myocardial ischemia — manage as suspected acute coronary syndrome.
- Hypoxia or signs of pulmonary edema.
- Severe volume overload that is not responding to an escalated home diuretic regimen.
- First (new) presentation of HF — this needs prompt diagnostic workup (echocardiography) and specialist involvement, not empiric chronic HF management alone.
- A new loud murmur, or any other finding suggesting a mechanical complication (e.g., papillary muscle rupture) or severe valvular disease.
- Potassium above 5.5-6.0 mmol/L or significant renal deterioration while on guideline-directed therapy — hold the likely offending agent(s) and seek urgent guidance rather than continuing to push toward target doses.
- Symptomatic bradycardia or advanced heart block that precludes beta-blocker therapy, or an otherwise-eligible device-therapy candidate (ICD/CRT) who has not yet been referred.
Assessment & Diagnosis
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.
New York Heart Association (NYHA) functional classification
Class I
No symptoms (dyspnea, fatigue, palpitations) with ordinary activity.
Class II
Symptoms occur with ordinary activity.
Class III
Symptoms occur with less than ordinary activity.
Class IV
Symptoms occur at rest or with minimal activity.
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]
| BNP (pg/mL) | NT-proBNP (pg/mL) | |||||
|---|---|---|---|---|---|---|
| Age <50 | Age 50-75 | Age >75 | Age <50 | Age 50-75 | Age >75 | |
| HF unlikely | <100 | <300 | ||||
| HF possible | 100-400 | 100-450 | 300-900 | 300-1800 | ||
| HF very likely | >400 | >450 | >900 | >1800 | ||
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.
Treatment Targets
- 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]
Choose Initial Treatment
Congestion — every HF phenotype
Assess volume status at every visit. In any patient with signs or symptoms of fluid overload, start a loop diuretic (usually furosemide) and titrate to the minimum dose that maintains euvolemia — diuretics relieve congestion and symptoms but do not modify the underlying disease course or reduce mortality, so they are titrated for symptom/volume control, not pushed as a mortality-reduction therapy.[1]
HFrEF (LVEF ≤40%) — the 4-pillar GDMT
Renin-angiotensin pillar, 1st line Start an ACE inhibitor in every HFrEF patient without contraindication (use an ARB instead if ACE-inhibitor cough or angioedema occurs). Titrate at 7-14 day intervals toward the target dose.
Preferred upgrade Switch to an ARNI (sacubitril/valsartan) in place of the ACE inhibitor or ARB in patients who remain symptomatic on standard therapy, including during an HF hospitalization; ARNI initiation should also be considered as the first RAAS agent in a newly diagnosed HFrEF patient admitted to hospital. A mandatory 36-hour washout is required after the last ACE inhibitor dose before starting an ARNI (no washout is needed when switching from an ARB).[5]
Beta-blocker pillar Start bisoprolol, carvedilol, or metoprolol (tartrate — the succinate CR/XL formulation with the strongest mortality evidence is not marketed in Canada; bisoprolol and carvedilol have more robust supporting data than metoprolol tartrate) in every hemodynamically stable, euvolemic HFrEF patient. Start at a very low dose and titrate slowly, at 2-4 week intervals — never initiate or up-titrate a beta-blocker during acute decompensation.
MRA pillar Start spironolactone or eplerenone in every HFrEF patient unless baseline potassium exceeds 5 mmol/L or creatinine clearance is under 30 mL/min.
SGLT2 inhibitor pillar Start dapagliflozin or empagliflozin in every HFrEF patient regardless of diabetes status, unless contraindicated (e.g., type 1 diabetes, allergy, history of euglycemic ketoacidosis).
There is no mandated order of initiation or up-titration across the 4 pillars — individualize based on patient preference, side-effect profile, comorbidities, and tolerability, with a goal of starting all 4 classes and reaching target or maximally tolerated doses within 3-6 months. It is not necessary to reach one pillar's target dose before starting the next.[5]
HFnrEF (HFmrEF + HFpEF, LVEF >40%) — 2025 CCS/CHFS approach
Strong recommendation Start an SGLT2 inhibitor (dapagliflozin or empagliflozin) in every symptomatic HFnrEF patient to reduce the risk of HF hospitalization.
Strong recommendation Start an MRA (spironolactone, eplerenone, or finerenone) in every symptomatic HFnrEF patient to reduce the risk of HF hospitalization.
Weak recommendation — if systolic BP ≥100 mmHg and not at risk of symptomatic hypotension Add an ARNI (sacubitril/valsartan), or candesartan if an ARNI is unavailable or not tolerated.
Weak recommendation — if LVEF ≥45% and BMI ≥30 kg/m² Add an evidence-based GLP-1 receptor agonist (semaglutide or tirzepatide) to reduce HF hospitalization risk and improve quality of life.
As with HFrEF, there is no mandated sequence for starting these agents within a given tier — individualize through shared decision-making based on patient characteristics.[3]
Non-Pharmacologic Treatment
- 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.
Special Populations
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.
Monitoring & Follow-Up
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.
Common Errors to Avoid
- 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.
Clinical Decision Algorithm
Drug Tables
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Furosemide | Oral: 20-500 mg/day PO in 1-2 (up to 3 for decompensated HF) divided doses IV, decompensated HF: 20-240 mg IV BID-QID | Hypokalemia, hypomagnesemia, hyponatremia, dehydration, azotemia, hyperuricemia, ototoxicity with rapid high-dose IV administration | Additive hypokalemia with thiazides/corticosteroids; digoxin toxicity risk if potassium depleted; reduced diuretic effect with NSAIDs; lithium toxicity | Give early in the day. Limit IV administration rate to 4 mg/min to reduce ototoxicity risk. |
| Bumetanide | Adults: 1-4 mg/day PO | Hypokalemia, hypomagnesemia, hypocalcemia, dehydration, azotemia, hyperuricemia | Same class effects as furosemide; lithium toxicity | 1 mg bumetanide is approximately equivalent to 40 mg furosemide. |
| Metolazone | Add-on to loop diuretic: 2.5-10 mg PO daily, or 2.5-5 mg daily-to-weekly when combined with a loop diuretic | Hypokalemia, hyponatremia, hypomagnesemia, dehydration, azotemia, hypercalcemia | Additive hypokalemia/dehydration with loop diuretics; lithium toxicity; reduced effect with NSAIDs | Add intermittently (e.g., a few times per week) to a loop diuretic for refractory congestion, under close monitoring of weight, renal function, and potassium given the risk of severe dehydration and electrolyte imbalance. Reserve for experienced clinicians. |
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Enalapril | Initial: 1.25-2.5 mg PO BID Target: 10 mg BID | Hypotension, hyperkalemia, dry cough, renal insufficiency, rare angioedema, taste disturbance | Hypotension with diuretics; hyperkalemia with potassium-sparing diuretics/ARBs/potassium supplements; reduced effect and renal risk with NSAIDs; lithium toxicity | Avoid in pregnancy. |
| Lisinopril | Initial: 2.5-5 mg PO daily Target: 20-35 mg daily | Hypotension, hyperkalemia, dry cough, renal insufficiency, rare angioedema | Same class interactions as enalapril | Avoid in pregnancy. |
| Perindopril erbumine | Initial: 2 mg PO daily Target: 8 mg daily | Hypotension, hyperkalemia, dry cough, renal insufficiency, rare angioedema | Same class interactions as enalapril | Avoid in pregnancy. |
| Ramipril | Initial: 1.25-2.5 mg PO BID Target: 5 mg BID | Hypotension, hyperkalemia, dry cough, renal insufficiency, rare angioedema | Same class interactions as enalapril | 1st-line RAAS agent for most HFrEF patients who have not yet moved to an ARNI. Avoid in pregnancy. |
| Trandolapril | Initial: 1 mg PO daily Target: 4 mg daily | Hypotension, hyperkalemia, dry cough, renal insufficiency, rare angioedema | Same class interactions as enalapril | Avoid in pregnancy. |
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Candesartan | Initial: 4-8 mg PO daily Target: 32 mg daily | Hypotension, hyperkalemia, renal insufficiency, rare angioedema (less frequent than ACE inhibitors) | Hyperkalemia with potassium-sparing diuretics/ACE inhibitors/potassium supplements; reduced effect and renal risk with NSAIDs; lithium toxicity | Avoid in pregnancy. |
| Losartan | Initial: 12.5 mg PO daily Target: 150 mg daily | Hypotension, hyperkalemia, renal insufficiency, rare angioedema | Same class interactions as candesartan | Avoid in pregnancy. |
| Valsartan | Initial: 40 mg PO BID Target: 160 mg BID | Hypotension, hyperkalemia, renal insufficiency, rare angioedema | Same class interactions as candesartan | Avoid in pregnancy. |
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Sacubitril/valsartan | Lower starting dose: 24/26 mg PO BID Standard starting dose: 49/51 mg PO BID Target: 97/103 mg PO BID | Hypotension (more common than with an ACE inhibitor alone), hyperkalemia, renal insufficiency, rare angioedema | Hyperkalemia with potassium-sparing diuretics/MRAs/potassium supplements; reduced effect and renal risk with NSAIDs; lithium toxicity | Assess fluid status and adjust diuretic dose when starting, given a diuretic-sparing/natriuretic effect. Avoid in pregnancy. |
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Bisoprolol | Initial: 1.25 mg PO daily Target: 10 mg daily | Orthostatic hypotension, worsening HF/fluid retention if titrated too quickly, bradycardia, fatigue, may mask hypoglycemia | Increased bradycardia with amiodarone, digoxin, diltiazem, ivabradine, verapamil | Selective beta-1 blocker. |
| Carvedilol | Initial: 3.125 mg PO BID Target: 25 mg PO BID | Orthostatic hypotension (more than bisoprolol), worsening HF/fluid retention if titrated too quickly, bradycardia, bronchospasm, may mask hypoglycemia | Increased bradycardia with amiodarone, digoxin, diltiazem, ivabradine, verapamil; CYP2D6 inhibitors increase levels | Nonselective, with added alpha-blocking (vasodilating) activity — consider preferentially with uncontrolled hypertension. |
| Metoprolol (tartrate) | Initial: 6.25 mg PO BID Target: 100 mg PO BID | Orthostatic hypotension, worsening HF/fluid retention if titrated too quickly, bradycardia, fatigue, may mask hypoglycemia | Increased bradycardia with amiodarone, digoxin, diltiazem, ivabradine, verapamil | Selective beta-1 blocker. The succinate CR/XL formulation with the strongest mortality data is not marketed in Canada; tartrate is generally considered second-line to bisoprolol/carvedilol given less robust supporting data. Preferred beta-blocker in pregnancy and breastfeeding. |
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Spironolactone | Initial: 12.5-25 mg PO daily Target: 25-50 mg daily | Hyperkalemia, gynecomastia (reversible), dehydration, nausea | Hyperkalemia with ACE inhibitor/ARB/ARNI/potassium supplements; reduced diuretic effect and renal risk with NSAIDs | Avoid in pregnancy. |
| Eplerenone | Initial: 25 mg PO daily Target: 50 mg daily | Hyperkalemia, dehydration, dizziness, diarrhea | Hyperkalemia with ACE inhibitor/ARB/ARNI/potassium supplements; reduced diuretic effect and renal risk with NSAIDs | No anti-androgen effect (unlike spironolactone) — preferred if a patient develops gynecomastia, impotence, or menstrual irregularity on spironolactone. Avoid in pregnancy. |
| Finerenone | Initial (eGFR ≥60): 20 mg PO daily Initial (eGFR 30-59, or hyperkalemia risk/frailty): 10 mg PO daily Target (eGFR ≥60): 40 mg daily Target (eGFR 30-59): 20 mg daily | Hyperkalemia | Hyperkalemia with ACE inhibitor/ARB/ARNI/potassium supplements | Nonsteroidal MRA specifically supported for HFnrEF by the 2025 CCS/CHFS guideline; not yet established for HFrEF. |
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Dapagliflozin | Adults: 10 mg PO daily | Volume depletion, urinary tract infection, genital mycotic infection; in diabetes — hypoglycemia, euglycemic diabetic ketoacidosis | Reassess diuretic, sulfonylurea, and insulin doses to reduce hypoglycemia/volume-depletion risk | Contraindicated in type 1 diabetes. |
| Empagliflozin | Adults: 10 mg PO daily, may increase to 25 mg | Volume depletion, urinary tract infection, genital mycotic infection; in diabetes — hypoglycemia, euglycemic diabetic ketoacidosis | Reassess diuretic, sulfonylurea, and insulin doses to reduce hypoglycemia/volume-depletion risk | Contraindicated in type 1 diabetes. |
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Semaglutide | Weeks 1-4: 0.25 mg SC once weekly Weeks 5-8: 0.5 mg once weekly Weeks 9-12: 1 mg once weekly Weeks 13-16: 1.7 mg once weekly Week 17 onward (target): 2.4 mg once weekly | Nausea, vomiting, diarrhea, constipation, reduced appetite; rare pancreatitis | Delayed gastric emptying may affect absorption of other oral drugs | Contraindicated with personal/family history of medullary thyroid cancer or MEN2, or in type 1 diabetes. |
| Tirzepatide | Initial: 2.5 mg SC once weekly for 4 weeks Titration: increase by 2.5 mg every 4 weeks as tolerated Target: up to 15 mg once weekly | Nausea, vomiting, diarrhea, constipation, reduced appetite; rare pancreatitis | Delayed gastric emptying may affect absorption of other oral drugs | Contraindicated with personal/family history of medullary thyroid cancer or MEN2, or in type 1 diabetes. |
If-channel inhibitor
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Ivabradine | Adults: 2.5-7.5 mg PO BID | Bradycardia, visual phosphenes/blurred vision, atrial fibrillation | Contraindicated with strong CYP3A4 inhibitors and verapamil/diltiazem (risk of excess bradycardia); avoid grapefruit juice; caution with other heart-rate-lowering drugs | LVEF ≤35%, NYHA II-III, sinus rhythm, resting HR ≥70-77 bpm despite a maximized (or maximally tolerated) beta-blocker, or beta-blocker intolerance. Not indicated in atrial fibrillation. Start at a lower dose in patients 75 years or older. |
Cardiac glycoside
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Digoxin | Adults: 0.0625-0.25 mg PO daily, individualized by age, weight, renal function, and interacting drugs | Nausea, anorexia, visual disturbance, confusion, arrhythmia (narrow therapeutic index) | Levels increased by amiodarone, clarithromycin, cyclosporine, erythromycin, itraconazole, propafenone, quinidine, ritonavir, tetracycline, verapamil; levels reduced by antacids, cholestyramine, colestipol, neomycin, rifampin, St. John's wort, sulfasalazine; increased bradycardia with amiodarone, beta-blockers, diltiazem, verapamil | Consider for persistent NYHA II-IV symptoms despite optimal GDMT, or for AF rate control when beta-blockers are insufficient/not tolerated. Target trough concentration 0.6-1.2 nmol/L, drawn at least 8 hours post-dose. |
Vasodilators
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Hydralazine + Isosorbide Dinitrate | Combo (initial): hydralazine 10-25 mg PO TID + isosorbide dinitrate 10-20 mg PO TID Combo (target): hydralazine 75 mg PO TID-QID + isosorbide dinitrate 40 mg PO TID-QID | Hypotension, headache, GI upset; drug-induced lupus-like syndrome with hydralazine | Severe hypotension with PDE5 inhibitors (isosorbide dinitrate component) | For HFrEF patients intolerant of an ACE inhibitor/ARB/ARNI due to renal dysfunction or hyperkalemia, or as add-on therapy in Black patients remaining symptomatic on standard GDMT. Isosorbide dinitrate alone relieves anginal/dyspneic symptoms but has no mortality benefit without hydralazine. |
Soluble guanylate cyclase stimulator
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Vericiguat | Initial: 2.5 mg PO daily Titration: double every 2 weeks as tolerated Target: 10 mg daily | Hypotension, anemia, dizziness | Severe hypotension with PDE5 inhibitors (e.g., sildenafil) | High-risk HFrEF (LVEF under 45%) with a recent HF hospitalization or need for outpatient IV diuretics, already on GDMT. Take with food. |
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Ferric carboxymaltose | Hb under 10 g/dL, weight under 35 kg: 500 mg total Hb under 10 g/dL, weight 35 to under 70 kg: 1500 mg total Hb under 10 g/dL, weight ≥70 kg: 2000 mg total Hb 10 to under 14 g/dL, weight under 35 kg: 500 mg total Hb 10 to under 14 g/dL, weight 35 to under 70 kg: 1000 mg total Hb 10 to under 14 g/dL, weight ≥70 kg: 1500 mg total Hb ≥14 g/dL, any weight: 500 mg total | Hypersensitivity/infusion reactions (including rare anaphylaxis), transient hypophosphatemia, headache, hypertension around the time of infusion | Do not co-administer with oral iron | Weight- and hemoglobin-based total cumulative dose; do not exceed 1000 mg (20 mL) in a single administration or per week. Observe for at least 30 minutes after each dose. |
| Iron sucrose | Adults: Per product-specific protocol for iron deficiency anemia | Hypotension, nausea, muscle cramps, altered taste, rare hypersensitivity | Do not co-administer with oral iron | Reasonable alternative when a heart-failure-specific IV iron formulation is not available; dose per its standard iron-deficiency-anemia protocol. |
Adjunct supplement
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Omega-3 polyunsaturated fatty acid (fish oil) | Adults: 1 g/day; avoid doses above 3 g/day | Mild GI upset; bleeding risk at higher doses | Additive bleeding risk with warfarin/DOACs at doses above 3 g/day | A food supplement, not a regulated drug product — help the patient select a reliable brand whose EPA/DHA content and ratio (roughly 850-882 mg combined, about 1:1.2 EPA:DHA as ethyl esters) matches what has been studied in HF. Consider the added polypharmacy/adherence burden given its modest effect. |
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).
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Atorvastatin | Adults: Dose per lipid-management/cardiovascular-risk indication | Myalgia, transaminase elevation | Increased levels with strong CYP3A4 inhibitors | |
| Rosuvastatin | Adults: Dose per lipid-management/cardiovascular-risk indication | Myalgia, transaminase elevation | Fewer CYP3A4 interactions than atorvastatin |
Calcium channel blocker — safe adjunct antihypertensive/antianginal in HFrEF
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Amlodipine | Adults: Per standard antihypertensive dosing | Dose-related peripheral edema (may worsen existing fluid retention) | None significant | Does not reduce HFrEF mortality or morbidity, but is considered safe. Useful for persistent angina despite beta-blocker/nitrate therapy, or uncontrolled hypertension despite an ACE inhibitor/ARB/ARNI, MRA, beta-blocker, and diuretic. |
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.
| Drug/class | Reason to avoid | Comments |
|---|---|---|
| Diltiazem | Non-dihydropyridine CCB — negative inotropic effect, worse outcomes in HFrEF | Oral diltiazem is specifically discouraged with significant LV dysfunction or pulmonary congestion. |
| Verapamil | Non-dihydropyridine CCB — negative inotropic effect, worse outcomes in HFrEF | Avoid in HFrEF for the same reason as diltiazem. |
| Felodipine | Lack of outcome data in HFrEF | Not shown to be harmful, but not established as safe/beneficial the way amlodipine is — prefer amlodipine if a dihydropyridine CCB is genuinely needed. |
| Nifedipine | Lack of outcome data in HFrEF | Same rationale as felodipine — prefer amlodipine if a dihydropyridine CCB is genuinely needed. |
| Dronedarone | Increased mortality in patients with severe/recently decompensated HF | Amiodarone remains the antiarrhythmic option of choice in HF when one is needed. |
| Class I antiarrhythmics (e.g., flecainide, propafenone) | Proarrhythmic and negative inotropic risk in structural heart disease | Avoid essentially all antiarrhythmics other than amiodarone and dofetilide in HF. |
| Thiazolidinediones (pioglitazone, rosiglitazone) | Sodium and fluid retention | Choose an alternative glucose-lowering agent — SGLT2 inhibitors and GLP-1 receptor agonists are often preferable in HF regardless. |
| NSAIDs (including COX-2-selective agents, high-dose salicylates) | Sodium/fluid retention and reduced diuretic/RAAS-blocker effect; renal risk | Recommend acetaminophen for routine analgesia when appropriate instead. |
References
- 2017 Comprehensive Update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure — Canadian Journal of Cardiology, Canadian Cardiovascular Society (Ezekowitz JA, O'Meara E, McDonald MA, et al.). Can J Cardiol 2017;33(11):1342-1433
- Universal Definition and Classification of Heart Failure — Journal of Cardiac Failure, Heart Failure Society of America/Heart Failure Association of the ESC/Japanese Heart Failure Society (Bozkurt B, Coats AJS, Tsutsui H, et al.). J Card Fail 2021;27(4):387-413
- Canadian Cardiovascular Society/Canadian Heart Failure Society 2025 Guideline Update for Pharmacologic Management of Heart Failure With Nonreduced Ejection Fraction (LVEF > 40%) — Canadian Journal of Cardiology, Canadian Cardiovascular Society/Canadian Heart Failure Society (Virani S, Zieroth S, Aleksova N, et al.). Can J Cardiol 2025;41(10):1857-1874
- Pharmacologic Pitfalls in Heart Failure: A Guide to Drugs That May Cause or Exacerbate Heart Failure — A European Journal of Heart Failure Expert Consensus Document — European Journal of Heart Failure, European Society of Cardiology Heart Failure Association (Abdin A, Bauersachs J, Abdelhamid M, et al.). Eur J Heart Fail 2025;27(12):2671-2690
- CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction — Canadian Journal of Cardiology, Canadian Cardiovascular Society/Canadian Heart Failure Society (McDonald M, Virani S, Chan M, et al.). Can J Cardiol 2021;37(4):531-546
- Intravenous Ferric Derisomaltose in Patients With Heart Failure and Iron Deficiency in the UK (IRONMAN): An Investigator-Initiated, Prospective, Randomised, Open-Label, Blinded-Endpoint Trial — The Lancet (Kalra PR, Cleland JGF, Petrie MC, et al.). Lancet 2022;400(10369):2199-2209
Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.