A 72-year-old man with established systolic heart failure returns for follow-up. His LV dysfunction developed after a large anterolateral MI 2 years earlier. He is already receiving maximum tolerated doses of:
• an ACE-inhibitor
• a beta-blocker
• a mineralocorticoid receptor antagonist
• an SGLT2 inhibitor

Despite this, he still becomes severely breathless after walking a few metres. His BP is 116/72 mmHg, pulse 66 bpm in sinus rhythm.
Repeat echo shows LVEF 27%.

What is the next most appropriate medication change?

A. Start low-dose digoxin
B. Replace ACE-inhibitor with sacubitril/valsartan
C. Add hydralazine plus long-acting nitrate
D. Add ivabradine
E. Increase MRA dose further

Table of Contents

Correct Answer: B – Replace ACE-inhibitor with sacubitril/valsartan (ARNI)

Detailed Explanation

This man has heart failure with reduced ejection fraction (HFrEF) and is already on the “foundational 4 drugs” proven to prolong life:

ACE-inhibitor – reduces afterload and mortality
Beta-blocker – slows the heart, reduces arrhythmias, prolongs life
Mineralocorticoid receptor antagonist (MRA) – reduces fibrosis & mortality
SGLT2 inhibitor – reduces HF hospitalisations & mortality

Even though he is on these, he is still very symptomatic (NYHA III/IV equivalent).
According to NICE 2025 and major HF guidelines:

➡️ When symptoms persist despite optimal doses of all 4 foundational therapies, the ACE-inhibitor should be replaced with an ARNI (sacubitril/valsartan).

Why ARNI?

Sacubitril-valsartan:

Improves survival more than ACE-inhibitors
Reduces HF hospitalisations
Works by inhibiting neprilysin → ↑natriuretic peptides → vasodilation, natriuresis, less cardiac remodelling

Why NOT the other options?

Ivabradine

Only used if HR > 75 bpm in sinus rhythm
His HR = 66 → NOT eligible

Digoxin

Can help symptoms
Does NOT reduce mortality
Used mainly if AF present or after ARNI optimisation

Hydralazine + nitrate

Useful especially in Afro-Caribbean patients or ACEI/ARB intolerance
Not first choice before ARNI

Increasing MRA

He is already maximally titrated on the big 4

Therefore, the best evidence-based next step is switch ACE-I → ARNI.

Cheat Sheet (Exam-focused)

HFrEF first-line drug package (“Foundational 4”)

ACE-inhibitor (or ARB if intolerant)
Beta-blocker
MRA
SGLT2 inhibitor

If symptoms persist on all 4 → Next step

➡️ Switch ACE-I to ARNI (sacubitril–valsartan).
Requires washout of ACE-I for 36 hours.

When to use Ivabradine

Sinus rhythm
HR > 75 bpm
LVEF < 35%
On maximally tolerated beta-blocker

Digoxin – use when:

Symptomatic despite above
Coexistent AF requiring rate control
No mortality benefit

Hydralazine + nitrate

ACE-I/ARB/ARNI intolerance
Particularly beneficial for Afro-Caribbean patients

CRT consideration

QRS > 130 ms, especially LBBB pattern

Flashcards (20 total)

1. Q: What are the four foundational drugs for HFrEF?
A: ACE-I/ARB, beta-blocker, MRA, SGLT2 inhibitor.

2. Q: What replaces ACE-I when symptoms persist on all four foundational drugs?
A: Sacubitril-valsartan (ARNI).

3. Q: What is neprilysin inhibition?
A: Increases natriuretic peptides → vasodilation & reduced remodelling.

4. Q: Does ARNI reduce mortality?
A: Yes—more than ACE-I.

5. Q: HR requirement for ivabradine?
A: >75 bpm in sinus rhythm.

6. Q: LVEF requirement for ivabradine?
A: <35%.

7. Q: Digoxin’s main benefit in HF?
A: Symptom relief; especially if AF present.

8. Q: Does digoxin improve survival?
A: No.

9. Q: When is hydralazine-nitrate recommended?
A: ACE-I/ARB/ARNI intolerance or Afro-Caribbean ethnicity.

10. Q: Which HF drug needs a 36-hour washout after ACE-I?
A: Sacubitril-valsartan.

11. Q: What lab tests are essential when starting ACE-I/ARB/ARNI/MRA?
A: Urea, creatinine, potassium.

12. Q: When to check electrolytes after starting these drugs?
A: Before, 1–2 weeks after initiation, after dose changes, then every 3–6 months.

13. Q: Which drug class must NOT be used in angioedema?
A: ACE-inhibitors; ARBs/ARNIs may be alternatives depending on cause.

14. Q: Does spironolactone reduce mortality?
A: Yes.

15. Q: Do loop diuretics reduce mortality?
A: No—only symptom relief.

16. Q: When to give iron in HF?
A: Ferritin <100 ng/mL or TSAT <20%.

17. Q: First-line drugs in HFpEF?
A: MRA + SGLT2 inhibitor.

18. Q: What rhythm is required for ivabradine?
A: Sinus rhythm.

19. Q: Which therapy reduces HF hospitalisation the most early on?
A: SGLT2 inhibitors.

20. Q: What key ECG finding suggests CRT benefit?
A: LBBB with QRS ≥130 ms.

MCQs for Practice

1. A man on optimal doses of ACE-I, beta-blocker, MRA and SGLT2-I remains dyspnoeic. LVEF 25%. HR 62 bpm. Next step?

A. Add ivabradine
B. Start digoxin
C. Switch ACE-I → ARNI ✔️
D. Add hydralazine–nitrate
E. Start verapamil

**2. Which drug requires heart rate >75 bpm in sinus rhythm before use?**

A. Digoxin
B. Ivabradine ✔️
C. Hydralazine
D. Spironolactone
E. Dapagliflozin

3. Which HF medication does not provide mortality benefit?

A. MRA
B. SGLT2 inhibitor
C. ACE-inhibitor
D. Digoxin ✔️
E. ARNI

4. Which therapy is especially indicated in Afro-Caribbean patients when ACE-I cannot be used?

A. ARNI
B. Ivabradine
C. Hydralazine + nitrate ✔️
D. CRT
E. Digoxin

5. When starting sacubitril–valsartan, what is necessary?

A. Stop beta-blocker
B. 36-hour ACE-I washout ✔️
C. Reduce MRA dose
D. Add digoxin
E. Increase diuretics first

Summary for Quick Revision

Heart failure with reduced ejection fraction is treated first with a four-drug foundation: an ACE-inhibitor (or ARB), a beta-blocker, an MRA and an SGLT2 inhibitor. These are the only classes consistently proven to reduce mortality and rehospitalisation. If a patient remains symptomatic despite maximum tolerated doses of all four, the ACE-inhibitor should be switched to an ARNI such as sacubitril-valsartan, which further reduces cardiovascular death and HF hospitalisation. Ivabradine is only appropriate when the heart rate is above 75 bpm in sinus rhythm with LVEF <35%. Digoxin may help symptoms, especially in atrial fibrillation, but it does not improve survival. Hydralazine combined with nitrates is useful in patients intolerant of ACE-I/ARB/ARNI or in Afro-Caribbean patients. Renal function and potassium must be monitored regularly when using ACE-I, ARBs, ARNIs or MRAs. Loop diuretics relieve congestion but do not reduce long-term mortality. Patients with prolonged QRS duration, especially LBBB, may benefit from cardiac resynchronisation therapy. Iron deficiency should be routinely screened for and treated if present. Vaccination against influenza and pneumococcus is recommended. In summary, ARNI therapy is the key escalation step when symptoms persist despite all foundational medications.