HFrEF management
Contents
LVEF ≤40%. Quadruple therapy (ARNI + BB + MRA + SGLT2i) is the standard of care — each class independently reduces mortality and HF hospitalisation. Start all four early, titrate to target doses over 3–6 months. Layer additional therapies (ivabradine, vericiguat, hydralazine/ISDN, IV iron) based on phenotype. Devices (ICD, CRT) after ≥3 months on optimal medical therapy.
quadruple therapy — the backbone
All four classes should be initiated in every HFrEF patient unless contraindicated. Start low, go slow — but get all four on board before maximising any single agent.
| Class | Agents | Key initiation points | Target dose |
|---|---|---|---|
| ARNI | sacubitril/valsartan | first-line over ACEi/ARB if new dx or symptomatic on ACEi/ARB; 36h ACEi washout required; can start de novo in hospital | 97/103 mg BID |
| beta-blocker | bisoprolol, carvedilol, metoprolol XL | start when euvolaemic and haemodynamically stable; do NOT start in NYHA IV; use only evidence-based agents | bisoprolol 10 mg, carvedilol 25 mg BID, metoprolol XL 200 mg |
| MRA | spironolactone, eplerenone | monitor K⁺ and Cr within 1 week, then regularly; hold if K⁺ >5.5 or eGFR <30 | spironolactone 50 mg, eplerenone 50 mg |
| SGLT2i | dapagliflozin, empagliflozin | regardless of diabetes status; no dose titration; do not start if eGFR <20 | dapa 10 mg, empa 10 mg |
If ARNI not tolerated (hypotension, angioedema): ACEi or ARB. Never combine ACEi + ARB. Never combine ACEi + ARNI (angioedema risk).
Titration strategy:
- titrate every 2–4 weeks
- goal: target doses of all agents by 3–6 months
- tolerability-limiting factors: hypotension (reduce non-HF antihypertensives first), hyperkalaemia (dietary counselling, adjust MRA), bradycardia (reduce BB if HR <50 and symptomatic)
SBP 85–100 mmHg should prompt caution, not cessation. Subgroup analyses consistently show benefit across BP strata:
- carvedilol beneficial even at SBP 85–95 mmHg — COPERNICUS (2001)
- sacubitril/valsartan consistent benefit across all BP strata — PARADIGM-HF (2014)
- MRA and SGLT2i similarly effective in low BP groups — RALES (1999), DAPA-HF (2019)
Reduce non-HF antihypertensives (amlodipine, nitrates, alpha-blockers) before withholding GDMT. Low SBP is a reason to be careful — not a reason to stop.
evidence by drug class
Meta-analysis of quadruple therapy vs placebo (95,444 patients): all-cause mortality HR 0.39 — 61% RRR. Compared to ACEi + BB alone: HR 0.38 (62% RRR). — Vaduganathan et al. Lancet. 2020
Estimated additional years of life with optimised GDMT vs ACEi + BB alone:
- age 55: +6.3 years survival / +8.3 years free of CV death or HF admission
- age 65: +4–5 years
- age 70: +3–4 years
| Class | Key trial(s) | Mortality outcome | ARR | RRR | NNT |
|---|---|---|---|---|---|
| ACEi | SOLVD (1991) | 39.7% → 35.2% | 4.5% | 16% | ~22 |
| beta-blocker | MERIT-HF (1999) | annual 11.0% → 7.2% | 3.8%/yr | 34% | 26 |
| COPERNICUS (2001) | annual 19.7% → 12.8% | 6.9%/yr | 35% | 14 | |
| MRA | RALES (1999) | 46% → 35% | 11% | 30% | 9 |
| EMPHASIS-HF (2011) | all-cause mortality | — | 24% | 51 | |
| ARNI (vs ACEi) | PARADIGM-HF (2014) | 19.8% → 17.0% | 2.8% | 16% | 36 |
| SGLT2i | DAPA-HF (2019) + EMPEROR-Reduced (2020) meta | CV death/HF hosp composite | — | 25–26% | 17 |
| all-cause mortality alone | — | 13–17% | 58 |
MRAs have the lowest NNT for mortality of any HFrEF drug class and remain underused.
steroidal vs non-steroidal MRAs
Steroidal MRAs (spironolactone, eplerenone) and non-steroidal MRAs (finerenone) are not interchangeable across HF phenotypes — Harrington et al. JACC Heart Fail. 2025:
| Steroidal (spironolactone, eplerenone) | Non-steroidal (finerenone) | |
|---|---|---|
| tissue distribution | higher renal binding | more even heart/kidney distribution |
| MR antagonism potency | lower | higher |
| off-target effects | gynecomastia, hyperkalaemia | fewer off-target effects |
| HFrEF | proven mortality benefit (RALES, EMPHASIS-HF) | role unclear |
| HFpEF/HFnrEF | role unclear (TOPCAT equivocal) | proven benefit (FINEARTS-HF) |
For HFrEF: use spironolactone or eplerenone. Finerenone is not a substitute.
additional therapies — phenotype-driven
| Indication | Therapy | Evidence |
|---|---|---|
| sinus rhythm + resting HR >70 despite maximised BB | ivabradine | SHIFT (2010) |
| recent HF hospitalisation (within 6 months) on GDMT | vericiguat | VICTORIA (2020) |
| Black patients on optimal GDMT | hydralazine + ISDN (add to, not replace, ARNI/ACEi/ARB) | A-HeFT (2004) |
| iron deficiency: ferritin <100 or ferritin 100–299 + TSAT <20% | IV iron (ferric carboxymaltose) | AFFIRM-AHF (2020) |
| congestion | loop diuretics — symptom relief, no mortality benefit | see diuretic therapy in acute heart failure |
drugs to avoid in HFrEF
| Drug / Class | Why |
|---|---|
| non-DHP CCBs (verapamil, diltiazem) | negative inotropy → worsens HF |
| DHP CCBs other than amlodipine | less safety data; amlodipine OK for HTN/angina |
| thiazolidinediones (pioglitazone, rosiglitazone) | fluid retention, increased HF hospitalisation |
| saxagliptin | increased HF hospitalisation — SAVOR-TIMI 53 |
| NSAIDs | Na⁺/water retention, blunt diuretic response, worsen renal function |
| dronedarone if NYHA III–IV | increased mortality — ANDROMEDA |
device therapy
ICD — primary prevention
ICD assessment only after: ≥3 months OMT, ≥3 months post-revascularisation, ≥40 days post-MI. LVEF may recover with GDMT — re-image before implant.
| Aetiology | LVEF | NYHA | Recommendation |
|---|---|---|---|
| ischaemic | ≤35% | II–IV | class I |
| ischaemic | ≤30% | I | class I |
| non-ischaemic | ≤35% | II–III | class I |
CRT — strong recommendation
| Criteria | All required |
|---|---|
| rhythm | sinus |
| symptoms | NYHA II–III (or ambulatory IV) |
| GDMT | optimised |
| LVEF | ≤35% |
| ECG | typical LBBB + QRS ≥130 ms |
Weaker indications (class IIa/IIb):
- non-LBBB + QRS ≥150 ms
- permanent AF (ensure biventricular pacing >99% — may need AV node ablation)
- patients requiring chronic RV pacing (upgrade to CRT)
when to refer — “I NEED HELP”
| Letter | Criterion |
|---|---|
| I | IV inotropes needed |
| N | NYHA IIIB / IV |
| E | end-organ dysfunction |
| E | EF ≤35% |
| D | defibrillator shocks |
| H | hospitalisations >1 for HF |
| E | edema despite escalating diuretics |
| L | low SBP ≤90 mmHg |
| P | progressive GDMT intolerance |
Advanced therapies assessment: LVAD, transplant listing, palliative care pathway, mechanical circulatory support, inotrope infusions, clinical trial enrolment.