Angiotensin Receptor Blockers in HFrEF
ARBs are recommended as second-line therapy for HFrEF patients who cannot tolerate ACE inhibitors due to cough or angioedema, with proven mortality and morbidity reduction (Class I, Level of Evidence A). 1
Primary Role: Alternative to ACE Inhibitors
ARBs should be used specifically when ACE inhibitors are not tolerated, not as routine first-line therapy. 1 The evidence hierarchy for renin-angiotensin system inhibition in HFrEF is:
- ARNI (sacubitril/valsartan) - Superior to ACE inhibitors for reducing cardiovascular death and HF hospitalization in NYHA class II-III patients who tolerate ACE inhibitors or ARBs 1
- ACE inhibitors - First-line therapy with proven mortality reduction across all HFrEF severity levels 1, 2
- ARBs - For ACE inhibitor-intolerant patients 1
Evidence for Efficacy
ARBs have demonstrated in large randomized controlled trials:
- Reduction in mortality in patients with HFrEF 1
- Reduction in heart failure hospitalizations 1
- Hemodynamic and neurohormonal effects consistent with renin-angiotensin system blockade 1
When compared head-to-head with ACE inhibitors in real-world data, ARBs showed similar mortality (HR 0.97,95% CI 0.91-1.03) but slightly higher HF hospitalization risk (HR 1.08,95% CI 1.02-1.15). 3
Specific Indications for ARB Use
Use ARBs in these clinical scenarios:
- ACE inhibitor-induced cough (occurs in up to 20% of patients) 1
- ACE inhibitor-induced angioedema (occurs in <1% but more frequently in Black patients and women) 1
- Patients already on ARBs for other indications who subsequently develop HFrEF 1
Critical caveat: Although ARBs are alternatives for ACE inhibitor-induced angioedema, some patients develop angioedema with ARBs as well—use with caution and monitor closely. 1
Dosing Strategy
Start low and titrate to target doses used in clinical trials: 1
- Candesartan: Start 4-8 mg once daily, target 32 mg once daily
- Valsartan: Start 40 mg twice daily, target 160 mg twice daily
- Losartan: Start 25-50 mg once daily, target 150 mg once daily
Titrate doses every 2-4 weeks as tolerated, doubling the dose at each step. 1
Monitoring Requirements
Check within 1-2 weeks after initiation or dose changes: 1
- Blood pressure (including orthostatic measurements)
- Serum creatinine and estimated GFR
- Serum potassium
Exercise caution and monitor closely in patients with: 1
- Systolic blood pressure <80-90 mmHg
- Serum creatinine >2.5 mg/dL (men) or >2.0 mg/dL (women)
- Serum potassium >5.0 mEq/L
- Low serum sodium
- Diabetes mellitus
What NOT to Do
Do not combine ARB + ACE inhibitor + aldosterone antagonist - this triple combination is potentially harmful and increases risk of hypotension, renal dysfunction, and life-threatening hyperkalemia (Class III: Harm). 1
Do not routinely use ARB + ACE inhibitor combination - this combination showed increased HF hospitalizations (HR 1.49) and composite outcomes (HR 1.35) without mortality benefit in real-world data. 3 The combination may be considered only in persistently symptomatic patients already on ACE inhibitor and beta-blocker when aldosterone antagonist is not tolerated (Class IIb). 1
Do not use ARBs as first-line when ACE inhibitors are tolerated - ACE inhibitors remain the preferred first-line agent, and if the patient tolerates an ACE inhibitor, switching to ARNI (sacubitril/valsartan) provides superior outcomes. 1
Transition to ARNI
For patients on ARBs who are stable and symptomatic (NYHA class II-III), consider switching to sacubitril/valsartan for further mortality and morbidity reduction (Class I, Level of Evidence B-R). 1 No head-to-head comparisons exist between ARB and ARNI, but ARNI has shown 20% reduction in cardiovascular death or HF hospitalization compared to enalapril. 4, 5
When switching from ARB to ARNI: Can transition immediately without washout period (unlike ACE inhibitors which require 36-hour washout). 6
Cost-Effectiveness
ARBs provide high value therapy for HFrEF given their similar efficacy to ACE inhibitors and low-cost generic availability. 1