Frimley GuidelinesFrimley Health Guidelines

Eplerenone, Initiation and Titration

Initiation and Titration of Eplerenone in Adults with Heart Failure with Reduced Ejection Fraction (HFrEF) previously known as Left Ventricular Systolic Dysfunction (LVSD)

Key Points

This advice applies to monitoring of pharmacotherapy in clinically stable patients; it does NOT apply to patients with intercurrent acute illness
Please ensure patient has a genuine AKI (rapidly deteriorating renal function) before prognostic medication is discontinued
If prognostic medication is stopped due to AKI/acutely unwell patient, please consider restarting if renal function recovers

Licensed for use within 3-14 days post MI if patient has an ejection fraction (EF) ≤ 40% and HFrEF with an EF ≤30% with NYHA II symptoms

Version:	6
Date Issued:	27/06/2025
Review Date:	01/07/2028
Key words:	Angiotensin receptor blocker, eplerenone, initiation, titration.

This is a controlled document. If you are using a printed copy, check it against the guidelines site to ensure you are using the latest edition. Print copies must be destroyed after use.

Abbreviations

ARB	Angiotensin II receptor blockers
ACEI	Angiotensin converting enzyme inhibitor
AKI	Acute kidney injury
ARNI	Angiotensin receptor neprilysn Inhibitor
BP	Blood pressure
CHF	Congestive heart failure
CKD	Chronic Kidney disease
CYP3A4	Cytochrome P450 3A4
eGFR	Estimated glomerular filtration rate
HFrEF	Heart failure reduced ejection fraction
HFmrEF	Heart failure with mildly reduced ejection fraction
K	Potassium
MI	Myocardial infarction
MRA	Mineralocorticoid receptor antagonists
NSAIDs	Nonsteroidal anti-inflammatory drugs
NYHA	New York heart association
OTC	Over the counter
PVD	Peripheral vascular disease
SBP	Systolic blood pressure

Contra-indications

Cautions

Anuria
Acute renal insufficiency or rapidly deteriorating renal function. (AKI 1 or above)
Renal impairment (eGFR< 30ml/minute).
Hypersensitivity to eplerenone or any of the excipients.
Hyperkalaemia defined as K+>5.0mmol/L at initiation.
Combination of ACEI and ARB.
Severe hepatic insufficiency (Child Pugh Class C)
Co-prescription of potassium sparing diuretics. Potassium supplements (short courses of 2-3 days may be permitted).
Co-prescription of strong inhibitors of CYP 3A4 (e.g., ketoconazole, clarithromycin).

Renal impairment (eGFR<60ml/minute).
Lower starting dose recommended if
eGFR 30-60 ml/minute (25mg alternate days).
There is no experience in post MI patients with eGFR< 50ml/minute.
Monitor electrolytes (particularly potassium)
carefully if renal dysfunction.
Hepatic impairment (Child Pugh Class A&B,
monitor electrolytes closely).
Pregnancy & Lactation.
Elderly.
Drug interactions (see below).

Aim to increase the dose at 4 weeks to a maximum of 50mg daily following the guide below.

Serum potassium (mmol/L)	Action	Dose Adjustment
<5	Increase dose	25mg every other day to 25mg daily 25mg daily to 50mg daily
5.0 - 5.4	Maintain dose	No dose adjustment
5.5 – 5.9	Decrease dose	50mg daily to 25mg daily 25mg daily to 25mg every other day 25mg every other day to withhold drug
≥ 6	Withhold drug	n/a

If withdrawal due to hyperkalaemia, re-start at a dose of 25mg every other day if K+<5.0mmol/L

Worsening renal function

Eplerenone is a disease modifying drugs in patients with HFrEF so it improves patient outcomes. The risk of stopping or reducing dose is, in general, likely to be of greater detriment to a patient’s prognosis than a modest increase in serum creatinine, or mild hyperkalaemia.

These guidelines are generally for management of CKD

An increase in urea, creatinine and K+ is to be expected after initiation/titration of eplerenone. If the increase is small and asymptomatic, no action is necessary. Please see the table below for recommended actions.

Please ensure patient has a genuine AKI (rapidly deteriorating renal function) before prognostic medication is discontinued.

If prognostic medication is stopped due to AKI/acutely unwell patient, please consider restarting if renal function recovers. Please liaise with the heart failure team for further advice.

Potassium	Action
Mild hyperkalaemia (5.5 – 5.9mol/L) Management depends on clinical context	If the patient is acutely unwell, or has AKI, stop the eplerenone and consider referral to hospital If the patient is clinically stable (i.e., the test was done as a routine check, and there is no AKI warning stage test result), undertake medication review. If hyperkalaemia is unexpected, consider arranging a repeat test within 3 days, taking steps to minimise any of the factors that can cause artifactual hyperkalaemia Look for and remove other contributors to hyperkalaemia, including trimethoprim/co-trimoxazole, potassium supplements, potassium-sparing diuretics, salt substitutes e.g., ‘LoSalt’, NSAIDs, non-selective beta-blockers, digoxin toxicity Review the patient clinically: reduce/stop diuretics if evidence of over-diuresis. Consider reducing the dose by following the dose adjustment advice shown above in ‘dose titration’ Consider providing patients with a diet advice sheet on reduction of potassium intake. If problems with hyperkalaemia persist, refer to renal medicine for dietetic advice Consider seeking advice from local heart failure specialist team if the indication for treatment was HFrEF
Moderate hyperkalaemia (6.0-6.4mmol/L) Management depends on clinical context	Stop eplerenone If the patient is acutely unwell, or has AKI refer to hospital for immediate assessment Re-start at lower dose once serum K≤5.5 mmol/L and continue to monitor. If patient on combination of ACEI and/or Angiotensin Receptor Blocker, or Angiotensin Receptor Neprilysn Inhibitor (ARNI) with Mineralocorticoid Receptor Antagonist (MRA) restart one of these drugs at a time. If the patient is clinically stable (i.e., the test was done as a routine check rather than for acute illness, and there is no AKI warning stage test result), undertake medication review within 1 working day of the result. If hyperkalaemia is unexpected, consider arranging a repeat test the following day taking steps to minimise any of the factors that can cause artefactual hyperkalaemia Look for and remove other contributors to hyperkalaemia as indicated in ‘mild hyperkalaemia’
Severe hyperkalaemia (≥ 6.5 mmol/L)	Refer to hospital (via A&E) for immediate assessment and treatment

Increases in serum creatinine and urea are an expected consequence of haemoconcentration caused by diuretic treatment, and do not necessarily mean that the drugs have caused kidney damage. Treat the patient not the blood test: repeated clinical examination is key, paying attention to avoidance of hypovolaemia and hypotension. Disproportionate rises in blood urea may reflect effective hypovolaemia and should prompt clinical reassessment.

Creatinine	Action
Creatinine ↑ > 15% but <30% from initial baseline	Continue, but repeat U&Es in a further 1 to 2 weeks Arrange clinical review including assessment of fluid status and blood pressure Try to continue eplerenone treatment, consider reducing the dose by reversing the information in “dose titration” Reduce or stop other BP lowering drugs (e.g., calcium channel blockers, alpha blockers) if SBP <120 mmHg Reduce concurrent diuretics if there is clinical evidence of hypovolaemia/overdiuresis If the patient is acutely unwell, or has AKI, consider stopping the eplerenone
Creatinine increases at any point by ≥ 30% from initial baseline	Arrange clinical review including assessment of fluid status and blood pressure Consider: Try to continue eplerenone, consider dose reduction by reversing information in “dose titration” Reduce or stop other BP lowering drugs (e.g., calcium channel blockers, alpha blockers) if SBP <120 mmHg Reduce concurrent diuretics if there is clinical evidence of hypovolaemia/overdiuresis Re-check renal function within 5-7 days If the patient is acutely unwell, or has AKI, consider stopping the eplerenone and referral to hospital
If serum creatinine remains >30% from initial baseline with above measures.	Stop the eplerenone or reduce the dose to a previously tolerated dose and re-check renal function in 5-7 days Obtain advice from local heart failure specialist team if the indication for treatment was heart failure with reduced ejection fraction: continuing eplerenone in HFrEF may be beneficial even if serum creatinine rises by >30% Consider obtaining advice from nephrology, even if serum creatinine returns to baseline If the patient is acutely unwell, or has AKI, stop the eplerenone and consider referral to hospital

(See BNF for full list of interactions)

Interacting Drug	Action to be taken
ACE inhibitors/Angiotensin receptor blockers	Monitor serum K+ levels closely if combination therapy used especially with any changes in treatment or in the patient’s clinical condition Avoid combination of ACEI + ARB +eplerenone
Amiodarone	The dose of eplerenone should not exceed 25mg daily. N.B. hypokalaemia can exacerbate the Q-T prolonging effects of amiodarone
Antihypertensives	Monitor for hypotension/postural hypotension.
Calcium channel blockers (diltiazem, verapamil)	The dose of eplerenone should not exceed 25mg daily
Anti-epileptics - carbamazepine, phenobarbital, phenytoin	Concurrent use not recommended by manufacturers
Ciclosporin	Concurrent use to be avoided wherever possible. If this is not possible, monitor ciclosporin levels, K+ and renal function frequently until stable
Digoxin	Caution if digoxin levels near the upper end of the therapeutic range
St John’s Wort (hypericum perforatum)	Concurrent use not recommended by manufacturers
Itraconazole, ketoconazole	Contra-indicated
Fluconazole	The dose of eplerenone should not exceed 25mg daily
Lithium	UK manufacturers recommend avoidance or closely monitor lithium levels. Ensure patients are aware to report symptoms of lithium toxicity immediately.
Macrolides	The dose of eplerenone should not exceed 25mg daily when concurrently taking erythromycin. Concurrent use of telithromycin or clarithromycin with eplerenone is contra-indicated
NSAIDS (preferably avoided in patients with heart failure)	Caution with combination use. Patients should be well hydrated and have their renal function checked before starting this combination.
Potassium	Concurrent use contra-indicated (short course of 2-3 days are permitted)
Protease inhibitors	The dose of eplerenone should not exceed 25mg daily when concurrently taking saquinavir. Concurrent use of nelfinavir or ritonavir with eplerenone is contraindicated
Rifampicin	Concurrent use not recommended by manufacturers
Tacrolimus	Concurrent use to be avoided. If concurrent use essential, monitor potassium levels closely.
Trimethoprim	Monitor serum potassium and renal function particularly in patients with renal impairment and the elderly.
Warfarin	Caution if warfarin is dosed near the upper limit of therapeutic range.

Version:	6
Guidelines Lead:	Dr Lydia Sturridge, Consultant Cardiologist
Contributor:
Lead Director / Chief of Service:	Dr Peter Clarkson, CoS for Cardiology
Library check completed:	7 March 2022
Ratified at:	Cardiologist Clinical Governance 18/06/2025
Date Issued:	27/06/2025
Review Date:	01/07/2028
Pharmaceutical dosing advice and formulary compliance checked by:	Alexandra Kirke, Lead Cardiology Pharmacist, 16 April 2025
Key words:	Angiotensin receptor blocker, eplerenone, initiation, titration

This guideline has been registered with the Trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt, contact a senior colleague or expert. Caution is advised when using guidelines after the review date.
This guideline is for use in Frimley Health NHS Foundation Trust hospitals only. Any use outside this location will not be supported by the Trust and will be at the risk of the individual using it.

Version Control Sheet

Version	Date	Guideline Lead(s)	Status	Comment
4	September 2018	Dr Lydia Sturridge, Ann Parker	Final	Ratified at APC
5	February 2022	Dr Lydia Sturridge, Ann Parker	Final	Changed to new format and references checked by Library team.
6	June 2025	Dr Lydia Sturridge	Final	Scheduled review

Key Points

Guideline rationale

Indications

Contra-indications and Cautions

Initiation and Monitoring

Dose Titration

Problem Solving

Worsening renal function

Patient information

Drug Interactions

References

Full version control record