When to initiate and avoid certain medications, such as Angiotensin-Converting Enzyme (ACE) inhibitors, Angiotensin II Receptor Blockers (ARBs), beta-blockers, and aldosterone antagonists, in patients with heart failure?

Heart Failure Medication Management: When to Initiate and Avoid

All patients with heart failure and reduced ejection fraction (HFrEF) should receive simultaneous treatment with four foundational medication classes—ACE inhibitors/ARBs/ARNI, beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors—with diuretics added as needed for fluid management, unless specific contraindications exist. 1

ACE Inhibitors: First-Line Therapy

When to Initiate

• Start ACE inhibitors as first-line therapy in all patients with HFrEF (LVEF ≤40-45%), regardless of symptom status (NYHA class I-IV). 2, 1
• Initiate in asymptomatic patients with documented left ventricular systolic dysfunction to delay or prevent development of symptomatic heart failure. 2
• Begin in post-myocardial infarction patients with signs or symptoms of heart failure, even if transient, to improve survival and reduce reinfarctions. 2
• Start in patients with hypertension, diabetes, or chronic kidney disease with LVEF <40%. 2

Specific Dosing Protocol

Start low and titrate aggressively to target doses proven in clinical trials: 2

• Enalapril: Start 2.5 mg twice daily → Target 10-20 mg twice daily
• Lisinopril: Start 2.5-5.0 mg once daily → Target 30-35 mg once daily
• Ramipril: Start 2.5 mg once daily → Target 5 mg twice daily or 10 mg once daily
• Captopril: Start 6.25 mg three times daily → Target 50-100 mg three times daily

Double the dose at minimum 2-week intervals until target dose is achieved. 2 High doses (not low doses) reduce hospitalizations by 24% and death/hospitalization by 12%. 3

When to Avoid or Seek Specialist Advice

Absolute contraindications: 2

• Bilateral renal artery stenosis
• History of angioedema with previous ACE inhibitor therapy

Seek specialist advice before initiating when: 2

• Creatinine >2.5 mg/dL (>221 μmol/L)
• Potassium >5.0 mmol/L
• Systolic blood pressure <90 mmHg with symptoms

Monitoring and Problem-Solving

Monitor blood chemistry (urea, creatinine, potassium) and blood pressure: 2

• Before initiation
• 1-2 weeks after each dose increase
• At 3-6 month intervals once stable

Acceptable changes after initiation: 2

• Creatinine increase up to 50% above baseline OR up to 3 mg/dL (266 μmol/L), whichever is greater
• Potassium up to 6.0 mmol/L is acceptable

When creatinine or potassium rise excessively: 2

1. Stop nephrotoxic drugs (NSAIDs, calcium channel blockers, nitrates)
2. Stop potassium supplements and potassium-retaining diuretics (triamterene, amiloride)
3. Reduce diuretic dose if no signs of congestion
4. If potassium rises to 6.0 mmol/L or creatinine increases by 100% or above 4 mg/dL (354 μmol), seek specialist advice

Asymptomatic hypotension does not require treatment changes. 2 For symptomatic hypotension, reduce non-essential vasodilators and consider reducing diuretics if no congestion present. 2

ACE inhibitor-induced cough rarely requires discontinuation. 2 Only switch to ARB when cough is severe enough to prevent sleep and proven due to ACE inhibitor (recurs after withdrawal and rechallenge). 2

Angiotensin Receptor Blockers (ARBs): Second-Line Alternative

When to Use ARBs

ARBs are indicated ONLY in specific circumstances—they are NOT first-line therapy: 1, 4, 5

• Primary indication: ACE inhibitor intolerance due to intractable cough or angioedema. 2, 1
• In patients with heart failure or post-MI with LVEF ≤40% who cannot tolerate ACE inhibitors. 2
• As additive therapy in patients already on maximal ACE inhibitor and beta-blocker therapy who remain symptomatic, especially if unable to tolerate beta-blockade. 4

When to Avoid ARBs

Do not use ARBs as first-line therapy when ACE inhibitors are tolerated. 1, 5 ACE inhibitors remain superior due to bradykinin-mediated vascular benefits not provided by ARBs. 5

Avoid triple combination of ACE inhibitor + ARB + aldosterone antagonist due to substantial risk of hyperkalemia. 6

Do not co-administer with aliskiren in patients with diabetes or renal impairment (GFR <60 mL/min). 7

Beta-Blockers: Essential Mortality-Reducing Therapy

When to Initiate

Start beta-blockers in all patients with stable symptomatic HFrEF (NYHA class II-IV). 2, 1

Patients must be relatively stable without IV inotropes or marked fluid retention before initiating. 1

Continue indefinitely in all patients who have had myocardial infarction, acute coronary syndrome, or left ventricular dysfunction with or without heart failure symptoms. 2

Which Beta-Blockers to Use

Only three beta-blockers have proven mortality reduction—benefits cannot be assumed as a class effect: 1

• Bisoprolol
• Carvedilol
• Metoprolol succinate extended-release

Selective β₁ receptor blockers may be preferred in patients with low blood pressure due to lesser BP-lowering effect. 2

When to Avoid

Do not initiate during acute decompensated heart failure or when patient requires IV inotropes. 1

The most common error is underutilization of beta-blockers, especially in older adults and those with comorbidities. 1 This represents a critical missed opportunity for mortality reduction.

Mineralocorticoid Receptor Antagonists (MRAs): Third Pillar

When to Initiate

Add MRAs (spironolactone or eplerenone) in patients with NYHA class II-IV who remain symptomatic despite ACE inhibitor and beta-blocker therapy. 2, 1

In post-MI patients already on therapeutic doses of ACE inhibitor and beta-blocker with LVEF ≤40% and either diabetes or heart failure. 2

When to Avoid

Do not initiate when: 2

• Significant renal dysfunction (creatinine >2.5 mg/dL in men, >2.0 mg/dL in women)
• Potassium >5.0 mEq/L at baseline

Avoid triple combination with ACE inhibitor + ARB due to hyperkalemia risk. 6

Monitor potassium closely when combined with ACE inhibitors, as MRAs attenuate potassium loss from thiazide diuretics but increase hyperkalemia risk. 7

SGLT2 Inhibitors: Fourth Pillar

SGLT2 inhibitors should be initiated as first drug class in treatment-naïve patients with persistent low blood pressure, as they have the least effect on blood pressure but rapid beneficial effects. 2 This represents the most recent advancement in HFrEF therapy as part of the four-pillar approach. 1

Diuretics: Essential Adjunctive Therapy

When to Use

Add diuretics for fluid overload to reduce heart failure hospitalizations. 1 Loop diuretics or thiazides should always be administered in addition to ACE inhibitors, not as monotherapy. 1

Diuretics are NOT considered one of the foundational "pillars" because they do not reduce mortality. 1

Monitoring

Adjust diuretics according to volume status—overdiuresis may result in lower blood pressure and necessitate reduction. 2

Special Populations and Situations

Low Blood Pressure in Treatment-Naïve Patients

In patients with persistent low BP (SBP <90 mmHg) who are asymptomatic or mildly symptomatic with adequate perfusion: 2

1. Start SGLT2 inhibitors and MRAs first (least BP effect)
2. Add low-dose beta-blocker if HR >70 bpm OR very low-dose sacubitril/valsartan (25 mg twice daily)
3. If sacubitril/valsartan not tolerated, use low-dose ACE inhibitor
4. Consider ivabradine if beta-blockers not tolerated hemodynamically
5. Up-titrate one drug at a time using small increments

Medications to Discontinue

Stop or reduce non-heart failure cardiovascular medications that worsen outcomes: 2

• Calcium channel blockers (unless absolutely essential for angina or hypertension)
• Centrally acting antihypertensive drugs
• Alpha-blockers
• Non-essential vasodilators (nitrates unless for angina)

Implementation Strategy

Recent evidence supports predischarge initiation of all four pillars simultaneously with rapid up-titration within 1 month, 1 rather than the older sequential approach. 1 This aggressive strategy maximizes mortality benefit.

Remember: Some ACE inhibitor is better than no ACE inhibitor. 2 Aim for target doses, but if not achievable, use the highest tolerated dose rather than discontinuing therapy.