8.1 Heart Failure with Reduced & Preserved Ejection Fraction (GDMT & Monitoring)

8.1 Heart Failure with Reduced & Preserved Ejection Fraction (GDMT & Monitoring)

Heart failure (HF) is a complex, progressive clinical syndrome resulting from structural or functional cardiac abnormalities that impair ventricular filling or blood ejection to systemic tissues. In response to diminished cardiac output, chronic neurohormonal activation—principally involving the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS)—initially compensates but ultimately drives pathological myocardial remodeling, progressive left ventricular dilatation, pump failure, and premature death.

Contemporary management guided by the Canadian Cardiovascular Society (CCS) heart failure guidelines emphasizes rapid foundational neurohormonal blockade. Canadian pharmacists must master guideline-directed medical therapy (GDMT), drug titration protocols, safety thresholds, and adverse event mitigation across outpatient and inpatient practice settings.

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Classification of Heart Failure

Clinical classification of heart failure relies on two primary frameworks: left ventricular ejection fraction (LVEF) measured via echocardiography, and functional symptom severity assessed using the New York Heart Association (NYHA) classification.

1. Classification by Left Ventricular Ejection Fraction (LVEF)

2. New York Heart Association (NYHA) Functional Classification

• NYHA Class I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea.
• NYHA Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitations, or shortness of breath.
• NYHA Class III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity (e.g., walking across a room, dressing) causes fatigue, palpitation, or dyspnea.
• NYHA Class IV: Inability to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency are present even at rest; severe discomfort with any physical exertion.

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The Four Pillars of GDMT for HFrEF

In patients with symptomatic HFrEF (NYHA Class II to IV, LVEF <= 40%), contemporary CCS guidelines strongly recommend rapid implementation of the Four Foundational Pillars of medical therapy. Rather than titrating one agent to maximum dose before starting the next, clinicians should initiate all four drug classes concurrently or in rapid sequence within 2 to 4 weeks at low doses, subsequently titrating to target doses.

                     THE FOUR FOUNDATIONAL PILLARS OF GDMT
 ┌─────────────────────────────────────────────────────────────────────────────┐
 │ 1. ARNI (Sacubitril/Valsartan) [Preferred] or ACEi / ARB                    │
 │    - Blocks RAAS & inhibits neprilysin (prevents natriuretic peptide breakdown) │
 │    - MANDATORY: 36-hour washout period when switching from ACEi             │
 ├─────────────────────────────────────────────────────────────────────────────┤
 │ 2. Evidence-Based Beta-Blocker (Bisoprolol, Carvedilol, Metoprolol CR/XL)  │
 │    - Attenuates sympathetic toxicity, decreases sudden cardiac death        │
 │    - Start low, go slow; initiate ONLY in stable, euvolemic patients        │
 ├─────────────────────────────────────────────────────────────────────────────┤
 │ 3. Mineralocorticoid Receptor Antagonist (MRA: Spironolactone, Eplerenone)  │
 │    - Blocks aldosterone; prevents myocardial fibrosis & potassium wasting   │
 │    - Safety gate: Baseline K+ <= 5.0 mmol/L and eGFR >= 30 mL/min/1.73 m^2  │
 ├─────────────────────────────────────────────────────────────────────────────┤
 │ 4. SGLT2 Inhibitor (Dapagliflozin 10 mg daily or Empagliflozin 10 mg daily)│
 │    - Reduces CV death and HF hospitalizations independent of diabetes       │
 │    - Fixed once-daily dosing; no dose titration required                    │
 └─────────────────────────────────────────────────────────────────────────────┘

Pillar 1: Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

Sacubitril/Valsartan (Entresto) is a first-in-class supramolecular sodium salt complex combining a neprilysin inhibitor prodrug (sacubitril) with an angiotensin II receptor blocker (valsartan):

• Mechanism: Sacubitril inhibits the neutral endopeptidase neprilysin, preventing the degradation of beneficial vasoactive peptides including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), adrenomedullin, and bradykinin. This promotes natriuresis, vasodilation, and antifibrotic signaling. Valsartan selectively blocks the AT1 receptor, counteracting the compensatory increase in angiotensin II that results from neprilysin inhibition.
• Clinical Evidence: In the landmark PARADIGM-HF trial, sacubitril/valsartan demonstrated a 20% relative risk reduction in the primary composite endpoint of cardiovascular death or heart failure hospitalization compared to enalapril 10 mg twice daily.
• First-Line Recommendation: CCS guidelines recommend sacubitril/valsartan as the preferred first-line agent over ACE inhibitors or ARBs in all patients with HFrEF, including de novo initiation in treatment-naive outpatients or stabilized inpatients.

• Dosing & Titration:
  • Standard starting dose: 49/51 mg PO BID (delivering 48.6 mg sacubitril / 51.4 mg valsartan).
  • Reduced starting dose: 24/26 mg PO BID if patient was on low-dose ACEi/ARB (e.g., enalapril <= 10 mg/day, ramipril <= 5 mg/day), ACEi/ARB-naive, or has severe renal impairment (eGFR < 30 mL/min/1.73 m^2) or moderate hepatic impairment (Child-Pugh Class B).
  • Target maintenance dose: 97/103 mg PO BID, doubling the dose every 2 to 4 weeks as tolerated by blood pressure, renal function, and serum potassium.
• Monitoring: Blood pressure (symptomatic hypotension occurs more frequently with ARNI than ACEi), serum potassium, and serum creatinine. Note: Sacubitril inhibits BNP degradation, causing measured circulating BNP levels to rise; N-terminal proBNP (NT-proBNP) is not a neprilysin substrate and must be used to assess biochemical response in patients taking an ARNI.

Pillar 2: Evidence-Based Beta-Blockers

Chronic sympathetic stimulation induces beta-1 receptor downregulation, cardiomyocyte apoptosis, myocardial hypertrophy, and fatal ventricular arrhythmias. Beta-blockers reverse these processes, restoring cardiac function and reducing all-cause mortality by approximately 35%.

• Evidence-Based Agents Only: In Canadian practice, only three specific beta-blockers possess conclusive, randomized trial evidence for mortality reduction in HFrEF:
  1. Bisoprolol (CIBIS-II trial): Beta-1-selective antagonist. Initial dose 1.25 mg PO once daily; target dose 10 mg PO once daily.
  2. Carvedilol (COPERNICUS and US Carvedilol trials): Non-selective beta-1/beta-2 antagonist with alpha-1-blocking peripheral vasodilatory properties. Initial dose 3.125 mg PO BID; target dose 25 mg PO BID (50 mg PO BID for patients weighing > 85 kg).
  3. Metoprolol Succinate CR/XL (MERIT-HF trial): Beta-1-selective antagonist in extended-release formulation. Initial dose 12.5 to 25 mg PO once daily; target dose 200 mg PO once daily.
• Formulation Pitfall: Standard short-acting metoprolol tartrate twice daily has no proven mortality benefit in heart failure trials and must not be substituted for metoprolol succinate CR/XL.
• Initiation Rules:
  • Patient must be clinically stable and euvolemic ('dry') without overt signs of peripheral edema, elevated jugular venous pressure, or pulmonary crackles.
  • Contraindicated during acute decompensation: Never initiate or acutely uptitrate a beta-blocker in an acutely decompensated or hospitalized patient with congestion or hypoperfusion ('wet and cold'). In patients already maintained on chronic beta-blocker therapy who experience a mild-to-moderate decompensation, therapy should generally be continued unless cardiogenic shock, marked bradycardia, or severe hypoperfusion occurs.
  • Titration: 'Start low, go slow.' Double the dose every 2 to 4 weeks while monitoring resting heart rate (target 55 to 65 bpm), blood pressure, and volume status.

Pillar 3: Mineralocorticoid Receptor Antagonists (MRAs)

Aldosterone promotes myocardial and vascular fibrosis, endothelial dysfunction, sodium retention, and renal potassium and magnesium wasting. In the RALES and EMPHASIS-HF trials, MRAs demonstrated a 30% reduction in mortality and heart failure hospitalizations in HFrEF.

• Agents:
  • Spironolactone: Non-selective MRA. Initial dose 12.5 to 25 mg PO once daily; target dose 25 to 50 mg PO once daily. Inhibits androgen and progesterone receptors, frequently causing endocrine side effects (gynecomastia, mastodynia, and erectile dysfunction in up to 10% of males).
  • Eplerenone: Highly selective MRA lacking androgen receptor affinity. Preferred when spironolactone causes painful gynecomastia or breast tenderness. Initial dose 25 mg PO once daily; target dose 50 mg PO once daily.
• Mandatory Safety Preconditions:
  • Baseline serum potassium <= 5.0 mmol/L.
  • Baseline renal function eGFR >= 30 mL/min/1.73 m^2 (or serum creatinine <= 220 umol/L in men, <= 180 umol/L in women).
• Monitoring Protocol: Check serum electrolytes and creatinine at 1 week and 4 weeks after initiation or dose titration, then at 3, 6, 9, and 12 months, and every 6 months thereafter. Discontinue or halve the dose if potassium exceeds 5.5 mmol/L; stop immediately if potassium exceeds 6.0 mmol/L or eGFR drops below 20 mL/min/1.73 m^2.

Pillar 4: SGLT2 (Sodium-Glucose Cotransporter-2) Inhibitors

Originally developed for type 2 diabetes, SGLT2 inhibitors represent a foundational breakthrough in heart failure pharmacotherapy. In landmark trials (DAPA-HF with dapagliflozin and EMPEROR-Reduced with empagliflozin), SGLT2 inhibitors reduced cardiovascular mortality and HF hospitalizations by 25% in HFrEF patients regardless of whether they had diabetes.

• Approved Agents and Dosing:
  • Dapagliflozin (Forxiga): 10 mg PO once daily.
  • Empagliflozin (Jardiance): 10 mg PO once daily.
• Key Clinical Advantage: Unlike other pillars, SGLT2 inhibitors require no dose titration. The starting dose is the definitive target therapeutic dose.
• Renal Cut-offs: Initiated down to eGFR >= 20 to 25 mL/min/1.73 m^2. SGLT2 inhibitors produce an expected, reversible initial drop in eGFR of 2 to 4 mL/min due to restored tubuloglomerular feedback and reduced intraglomerular hyperfiltration, which should not prompt drug discontinuation.
• Patient Counselling & Safety:
  • Maintain good perineal hygiene to prevent mycotic genital infections.
  • Mild osmotic diuresis may necessitate a modest reduction in the patient's baseline loop diuretic dose to avoid volume depletion.
  • Educate patients on sick-day rules: temporarily hold SGLT2 inhibitors during acute dehydrating illness, vomiting, prolonged fasting, or prior to major surgery to mitigate the risk of rare euglycemic diabetic ketoacidosis (euDKA) in diabetic patients.

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Symptomatic Volume Management: Loop Diuretics

While the four pillars target disease progression and mortality, loop diuretics are essential for symptomatic relief and maintaining euvolemia:

• Agent: Furosemide (Lasix) is the most widely utilized loop diuretic in Canadian practice. Bioavailability is variable (approximately 50%, range 10% to 90%).
• Primary Purpose: Eliminates fluid overload, alleviates pulmonary congestion (dyspnea, orthopnea, paroxysmal nocturnal dyspnea), and resolves peripheral edema.
• Mortality Impact: Loop diuretics do not reduce mortality in heart failure. The goal is to titrate to the lowest effective maintenance dose that keeps the patient at their optimal 'dry weight.'
• Overdiuresis Risks: Excessive diuretic dosing causes prerenal azotemia (elevated BUN/creatinine ratio), hypovolemia, hypotension, hypokalemia, and hypomagnesemia, which in turn triggers compensatory neurohormonal activation.
• Diuretic Resistance: In severe gut wall edema or advanced renal impairment, oral bioavailability declines and tubular delivery is impaired. Strategies include: combining furosemide with a thiazide diuretic (e.g., metolazone 2.5 to 5 mg PO given 30 to 60 minutes before furosemide for sequential nephron blockade), switching to continuous IV furosemide infusion, or utilizing subcutaneous furosemide formulations.

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Second-Line and Add-On Therapies for HFrEF

When patients remain symptomatic or exhibit specific physiological phenotypes despite optimal foundational GDMT, second-line therapies are indicated:

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Management of Heart Failure with Preserved Ejection Fraction (HFpEF)

HFpEF accounts for approximately half of all heart failure admissions in Canada, primarily affecting elderly patients with hypertension, obesity, metabolic syndrome, and chronic kidney disease:

• First-Line Proven Pharmacotherapy: SGLT2 inhibitors (Empagliflozin based on the EMPEROR-Preserved trial, and Dapagliflozin based on the DELIVER trial) were the first drug class shown to improve cardiovascular outcomes in HFpEF, with about a 20% reduction in the composite of cardiovascular death or worsening heart failure.
• Congestion Management: Judicious use of loop diuretics (furosemide) to relieve pulmonary congestion and peripheral edema. Because HFpEF patients operate on a steep ventricular pressure-volume curve, excessive diuresis rapidly precipitates severe hypovolemia, hypotension, and prerenal azotemia.
• Comorbidity & Blood Pressure Control: Stringent blood pressure management (target SBP < 130 mmHg), heart rate and rhythm control in atrial fibrillation, and weight reduction.
• Mineralocorticoid Receptor Antagonists: The non-steroidal MRA finerenone reduced the composite of cardiovascular death and worsening heart failure events in patients with LVEF ≥ 40% (FINEARTS-HF, 2024). Check its current Canadian indication and coverage before recommending it. Spironolactone may be considered in selected patients with elevated natriuretic peptides and LVEF at the lower end of the preserved range, based on the regional and post-hoc TOPCAT analyses. Monitor potassium and renal function with either drug.

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Hazardous Medications Strictly Contraindicated in Heart Failure

Prescription and non-prescription drug reconciliation is a vital Canadian pharmacist responsibility to prevent drug-induced decompensation. The following agents must be avoided or deprescribed:

1. Non-Dihydropyridine Calcium Channel Blockers (Diltiazem, Verapamil):
   • Exert potent negative inotropic actions that directly depress left ventricular systolic function.
   • Strictly contraindicated in HFrEF (LVEF <= 40%); can precipitate acute pulmonary edema and cardiogenic shock.
2. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs & COX-2 Inhibitors):
   • Inhibit renal cyclooxygenase, suppressing vasodilatory renal prostaglandins (PGE2, PGI2).
   • Cause profound sodium and water retention, blunt the response to loop diuretics, worsen systemic hypertension, and induce acute kidney injury.
3. Thiazolidinediones (Rosiglitazone, Pioglitazone):
   • Stimulate renal peroxisome proliferator-activated receptor-gamma (PPAR-gamma), causing fluid retention and plasma volume expansion.
   • Cause a documented two-fold increase in heart failure hospitalizations; contraindicated in NYHA Class I to IV heart failure.
4. Class I Antiarrhythmics (Flecainide, Propafenone):
   • Exert negative inotropic effects and potent proarrhythmic actions. In the classic CAST trial, sodium channel blockers significantly increased cardiac mortality in patients with structural heart disease.
5. High-Sodium OTC Formulations & Effervescent Tablets:
   • Effervescent analgesic and antacid tablets contain large quantities of sodium bicarbonate (up to 400 to 500 mg sodium per tablet), triggering acute volume overload.

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Clinical Case Scenario: Outpatient GDMT Optimization

A 68-year-old male with ischemic cardiomyopathy (post-anterior STEMI 6 months ago) presents for medication review. An echocardiogram confirms HFrEF with LVEF 32%. His current medications are ramipril 5 mg PO daily, bisoprolol 2.5 mg PO daily, furosemide 20 mg PO daily, and atorvastatin 80 mg PO daily. Blood pressure is 126/78 mmHg, resting heart rate is 64 bpm, serum potassium is 4.4 mmol/L, eGFR is 58 mL/min/1.73 m^2, and he has trace ankle edema (NYHA Class II).

Clinical Action Plan:

1. Upgrade RAAS Inhibition to ARNI: Transition from ramipril to sacubitril/valsartan to maximize mortality reduction. The pharmacist must explicitly counsel the patient and prescriber to withhold ramipril for a full 36 hours before taking the first dose of sacubitril/valsartan 24/26 mg or 49/51 mg BID.
2. Initiate SGLT2 Inhibitor: Start empagliflozin 10 mg PO once daily or dapagliflozin 10 mg PO once daily. Educate on perineal hygiene and sick-day rules.
3. Initiate MRA: Because baseline K+ <= 5.0 mmol/L (4.4 mmol/L) and eGFR >= 30 mL/min (58 mL/min), add spironolactone 12.5 mg PO once daily. Schedule repeat electrolytes and creatinine in 1 and 4 weeks.
4. Beta-Blocker Optimization: Maintain bisoprolol at 2.5 mg daily for now; once volume status and blood pressure are re-evaluated in 2 to 4 weeks, titrate toward the target dose of 10 mg daily.