HFrEF management
Contents
LVEF ≤40%. Four drug classes reduce mortality/HF hospitalisation: RAS inhibition (ACEi, ARB, or ARNI) + BB + MRA + SGLT2i. Afterload reduction (RAS inhibition) is the cornerstone — prioritise and optimise this first. No RCT supports simultaneous over sequential initiation; a stepwise approach is better tolerated in practice. Target doses of all agents by 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.
RAS inhibition (ACEi, ARB, or ARNI) is the most important drug class in HFrEF — it directly addresses the elevated SVR that drives the disease. Prioritise establishing adequate afterload reduction before layering additional agents. Patients with marginal blood pressure often improve haemodynamically with RAS inhibition as cardiac output rises. Do not withhold ACEi/ARB/ARNI because of low SBP — low SBP is often the reason to start it.
No RCT has compared starting all four classes simultaneously versus sequential addition and uptitration. Observational data associating rapid GDMT initiation with better outcomes are confounded by indication — patients who tolerate rapid uptitration are inherently more robust. A sequential approach (RAS inhibition → BB → MRA → SGLT2i) allows identification of the rate-limiting agent and is better tolerated by most patients in practice.
| Class | Agents | Key initiation points | Target dose |
|---|---|---|---|
| ACEi/ARB or ARNI | enalapril, ramipril, valsartan, candesartan, sacubitril/valsartan | establish RAS inhibition first — this is the cornerstone; ACEi/ARB and ARNI all achieve afterload reduction; see callout below for choosing between them | ACEi: enalapril 10–20 mg BID, ramipril 5 mg BID; ARB: valsartan 160 mg BID; ARNI: 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 |
- ACEi — strongest evidence base, including post-MI with LV dysfunction; first-line if cost or access is a factor
- ARB — equivalent afterload reduction; use if ACEi-intolerant (cough)
- ARNI — option over ACEi/ARB based on PARADIGM-HF (see caveats below); requires 36h ACEi washout before switching
- Never combine ACEi + ARB. Never combine ACEi + ARNI (angioedema risk).
Titration strategy:
- titrate every 2–4 weeks
- prioritise RAS inhibitor dose optimisation — afterload reduction drives the largest haemodynamic benefit
- 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)
- cost: generic ACEi + BB + spironolactone ≈ $12/month — cost should not be a barrier to the foundational triple therapy
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 |
- Double run-in phase — patients intolerant of either enalapril or sacubitril/valsartan were excluded before randomisation, enriching for ARNI tolerability
- Dose asymmetry — enalapril 10 mg BID (moderate dose) vs sacubitril/valsartan 200 mg BID (maximum dose); no trial compares ARNI to maximum-dose ACEi or ARB
- ACEi/ARB remain the backbone of RAS inhibition in HFrEF. ARNI is an option, not a mandate — an adequately dosed ACEi or ARB achieves the critical afterload reduction
| 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 — but require vigilant monitoring.
After publication of RALES, Ontario spironolactone prescriptions increased substantially, but hospitalisations for hyperkalaemia also increased (from 2.4 to 11.0 per 1,000 HF patients) with an associated increase in hyperkalaemia-related mortality — and HF hospitalisations did not decrease. Trial-level monitoring (K⁺ within 1 week, then regularly) is mandatory. — Juurlink et al. NEJM. 2004
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.