RELieving Increasing oEdema Due to Heart Failure

A Phase IV, Registry-based, Randomised, Controlled, Open-label Trial Investigating the Potential for Patiromer-facilitated Use of Higher Doses of MRAs in Addition to Standard Care to Improve Congestion, Well-being, Morbidity and Mortality

Status

Terminated

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04142788

Acronym

RELIEHF

Enrollment

Registered

2019-10-29

Start date

2020-08-26

Completion date

2022-12-20

Last updated

2025-03-04

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heart Failure，Congestive

Brief summary

This trial will investigate the potential for patiromer-facilitated use of higher doses of mineralocorticoid antagonists in addition to standard care (compared to standard care alone) to improve congestion, well-being and mortality in people who have worsening congestion due to heart failure and hyperkalaemia.

Detailed description

People with worsening congestive heart failure may benefit from treatment with higher doses of MRA if they are administered patiromer to treat or prevent hyperkalaemia. Potential participants with worsening heart failure will be identified by their care teams and asked to participate in a research registry. If eligible, registry participants will be asked to take part in the RELIEHF randomised trial. The randomised trial will investigate whether patiromer allows patients with worsening heart failure to be titrated to higher doses of MRA (predominantly spironolactone). Participants assigned to patiromer may be titrated to 200mg/day spironolactone or the highest licensed dose of eplerenone (50mg/day). Participants who are not assigned to patiromer should have titration to guideline-recommended doses of MRA attempted. The registry and trial will take place in about 100 secondary care sites across the UK. At the end of the trial, participants will be followed through their electronic medical records via record linkage for up to 10 years

Interventions

DRUGPatiromer

Patiromer (8.4g/day to 25.2g/day) and spironolactone (up to 200mg/day) or eplerenone (up to 50mg/day if spironolactone not acceptable). Treatments should be titrated to maintain serum potassium close to the target of 4.5mmol/L.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

SINGLE (Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

A. For the Screening Log (no follow-up envisaged nor linkage to electronic medical records) 1. ≥18 years 2. Heart failure in the investigators opinion (new onset or decompensated chronic heart failure) 3. Planned to receive\>80mg/day of furosemide or equivalent (IV, SC or oral) in the next 24 hours. 4. Worsening symptoms & signs of congestion in the prior 10 days requiring at least one of the following: 1. hospitalisation 2. administration of intravenous diuretics 3. an increase in the dose of loop diuretic by at least 40mg/day of furosemide (or equivalent) to a total of at least 80mg/day of furosemide (or equivalent) 4. addition of a thiazide diuretic to treatment with a loop diuretic B. For the Consented Registry (with linkage to electronic medical records) 1. Fulfils the criteria for the screening log 2. Able and willing to provide written informed consent for registry participation C. For Randomised Trial Run-in 1. Fulfils criteria for the consented registry 2. Clinical diagnosis of heart failure for at least 4 weeks 3. Congestion as shown by at least one of the following: 1. Peripheral oedema 2. Raised venous pressure 3. Inferior vena cava diameter \>20mm 4. Cardiac dysfunction documented by at least one of the following in the previous three years: 1. A LVEF\<50%or a report of moderate or severe left ventricular dysfunction 2. Left atrial diameter \>3.0cm/m2 (body surface area) 3. Elevated BNP or NT-proBNP (BNP \>150ng/L if in sinus rhythm or \>450ng/L if not in sinus rhythm; NT-proBNP \>500ng/L if in sinus rhythm and \>1500ng/L if not in sinus rhythm) 5. Able and willing to provide written informed consent for the randomised trial D. For Randomisation 1. Serum potassium \>5.0mmol/L * Patients with a serum potassium \>5.0mmol/L may be randomised immediately unless they have severe hyperkalaemia requiring, in the investigators opinion, intravenous treatment or a potassium binding agent. * Severe hyperkalaemia should be managed according to the UK Renal Association guidelines of 2014 (https://renal.org/wp-content/uploads/2017/06/hyperkalaemia-guideline-1.pdf). Participants may be reconsidered for the trial once such interventions are no longer considered necessary. * Patients with a serum potassium ≤5.0mmol/L should be initiated on spironolactone or have the dose increased up to 100mg/day and randomised only if serum potassium exceeds 5.0mmol/L. Those intolerant of or unwilling to take spironolactone should be offered eplerenone titrated to a maximum dose of 50mg/day. * A run-in period of up to 35 days is permitted (the run-in period will usually occur during hospitalisation or a course of day-care or intense management). 2. After ingestion of a test-dose of patiromer, 1. the patient is willing to continue in the trial 2. the investigator considers the patient can follow instructions on preparing patiromer

Exclusion criteria

A, For the Screening Log & Registry \- None B. For the Randomised Trial 1. eGFR \<30ml/minute/1.73m2 (if clinically appropriate, the dose of other agents such as loop diuretics, ACE inhibitors, angiotensin receptor blockers, beta-blockers and sacubitril-valsartan may be adjusted to allow eGFR to increase) 2. Systolic BP \<90mmHg 3. Uncorrected valve disease as the main cause of heart failure in the investigators opinion 4. Hepatic encephalopathy or known severe liver disease 5. Infection currently requiring intravenous antibiotics or temperature \>38°C 6. Myocardial ischaemia currently requiring intravenous therapy or coronary intervention in the previous 7 days 7. Arrhythmia requiring urgent cardioversion or intravenous therapy 8. Severe hyperkalaemia requiring, in the investigator's opinion, intravenous treatment or a potassium-binding agent 9. The patient is already receiving a potassium-binding agent (this includes patiromer) or the treating physician has already decided to use one 10. Known hypersensitivity to patiromer or any of the excipients 11. Known intolerance to both spironolactone and eplerenone (not including hyperkalaemia) 12. Known hypersensitivity to the active substance or excipients of spironolactone and eplerenone as per the current Summary of Product Characteristics (Note: actual medicine supplied to participants will vary depending on local arrangements) 13. Women of childbearing potential. For the purposes of this trial this means any woman aged \<60 years unless they have had a hysterectomy or bilateral tubal ligation or are aged \>50 years and have undergone the menopause and had amenorrhea for at least 3 years 14. Patients taking the following systemic medicines: * strong inhibitors of CYP 3A4 (e.g. itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone) * Lithium * Tacrolimus or Cyclosporin 15. The combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) 16. Rare hereditary problems of galactose or fructose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption 17. Known amyloid heart disease 18. Cancer likely to cause death or major disability within the next three years 19. Patients requiring mechanical circulatory support and 20. Patients who do not develop a serum potassium \>5.0mmol/L despite receiving up to 100mg/day of spironolactone or 50mg/day of eplerenone during the run in phase.

Design outcomes

Primary

Measure	Time frame	Description
Congestion Index on Day 60	After 400 patients have been evaluated at Day 60	To find out whether administering patiromer and higher-dose MRA improves evidence of congestion on Day 60 compared to standard care.
Morbidity/Mortality	Through study completion	Composite of time to need for parenteral diuretic therapy (subsequent to initial discharge) for worsening or recalcitrant heart failure, (re-)hospitalisation for worsening heart failure or non-cancer deaths.
Morbidity and Mortality	Periodically up to 10 years	Composite of time to (re-)hospitalisation or death

Secondary

Measure	Time frame	Description
Quality of Life (EQ-5D)	Days 7 and 60	Quality of Life using validated EQ-5D questionnaire for all trial participants (visual analogue score - min 0, max 100, higher means better outcome; calculated score min 0, max 1, higher means better outcome)
Quality of Life Kansas City Cardiomyopathy Questionnaire (KCCQ-12)	Days 7 and 60	Quality of Life using validated KCCQ-12 questionnaire for all trial participants (score - min 0, max 100; higher means better outcome)
NYHA Class	Days 7 and 60	NYHA class (I-IV) for all trial participants
Patient Global Assessment	Days 7 and 60	Patient Global Assessment to measure quality of life for all trial participants (ranges from markedly improved to markedly worsened; markedly improved means a better outcome)
Reduced All-cause Mortality	Through study completion, up to 5 years	All-cause mortality for all trial participants
Reduced Non-cancer Mortality	Through study completion, up to 5 years	Non-cancer mortality for all trial participants
Reduced Cardiovascular Mortality	Through study completion, up to 5 years	Cardiovascular mortality for all trial participants
Reduced Mortality/Morbidity - HF/Non-cancer	During first year	Days lost to hospitalisation for heart failure or non-cancer deaths over 12 months for all trial participants
Dose of MRA	Days 7 and 60	Dose of MRA achieved for all trial participants
QALY	Through study completion, up to 5 years	Quality adjusted life-years for duration of the trial for all trial participants
Proportion Alive and Well at 12 Months	At 12 months	Proportion alive and well at 12 months (well-being defined by KCCQ-12 score) for all trial participants
Dose of Oral Diuretics Other Than MRA	At 6 months and 12 months	Dose of oral diuretics other than MRA for all trial participants
Participant Characteristics and Assessment of Morbidity and Mortality	Periodically up to 10 years	Time to cardiovascular (re-)hospitalisation or non-cancer death for registry/trial participants
Participant Characteristics/Assessment of Morbidity/Mortality	Periodically up to 10 years	Time to heart failure (re-)hospitalisation or non-cancer death for registry/trial participants
Characteristics and Assessment of Morbidity/Mortality	Periodically up to 10 years	Incidence rate for hospitalisation for registry/trial participants
Characteristics/Assessment of Morbidity/Mortality	Periodically up to 10 years	Time to death (all-causes, cardiovascular causes, heart failure causes, cancer causes, and other) for registry and trial participants
Reduced Mortality/Morbidity - Any	During first year	Days lost to any hospitalisation or any death over 12 months for all trial participants
Congestion Index	Days 7 and 60	Congestion Index score for all trial participants
Days Dead or Hospitalised During the First 60 Days	Through 60 days	Days dead or hospitalised during the first 60 days for all trial participants

Countries

United Kingdom

Participant flow

Recruitment details

Participants were screened across 12 sites between 13/03/2020 and 16/03/2022. The first participant to the registry was consented on 26/08/2020 and the last participant was consented to the registry on 17/03/2022. Participants to the trial that successfully completed run-in were randomised between 14/10/2021 and 16/03/2022.

Pre-assignment details

139 participants entered the registry but the trial was stopped because of low recruitment into the run-in phase (due, in part at least, the COVID pandemic), and because of the 19 patients who did enter the run-in phase, despite receiving up to spironolactone 100mg/day or eplerenone 50mg/day, only 4 patients developed a serum potassium \>5.0 mmol/L, which was a requirement to enter the randomised phase of the trial.

Participants by arm

Arm	Count
Standard Dose MRA Participants in this arm will have titration to guideline-recommended doses of MRA attempted.	2
Patiromer and High Dose MRA Participants assigned to patiromer may be titrated to 200mg/day spironolactone or the highest licensed dose of eplerenone (50mg/day). Patiromer: Patiromer (8.4g/day to 25.2g/day) and spironolactone (up to 200mg/day) or eplerenone (up to 50mg/day if spironolactone not acceptable). Treatments should be titrated to maintain serum potassium close to the target of 4.5mmol/L.	2
Total	4

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Trial terminated prematurely	2	2

Baseline characteristics

Characteristic	Patiromer and High Dose MRA	Standard Dose MRA	Total
Age, Customized Age group (years) <50	0 Participants	0 Participants	0 Participants
Age, Customized Age group (years) 50-60	1 Participants	2 Participants	3 Participants
Age, Customized Age group (years) >60	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Ethnicity Asian/Asian British	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Ethnicity Black/African/Caribbean/Black British	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Ethnicity Mixed/Multiple ethnic groups	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Ethnicity Other ethnic group	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Ethnicity White	2 Participants	2 Participants	4 Participants
Region of Enrollment United Kingdom England	2 Participants	0 Participants	2 Participants
Region of Enrollment United Kingdom Scotland	0 Participants	0 Participants	0 Participants
Region of Enrollment United Kingdom Wales	0 Participants	2 Participants	2 Participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	2 Participants	2 Participants	4 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 15	0 / 2	0 / 2
other Total, other adverse events	0 / 0	0 / 2	1 / 2
serious Total, serious adverse events	2 / 15	1 / 2	1 / 2

Outcome results

Primary

Congestion Index on Day 60

To find out whether administering patiromer and higher-dose MRA improves evidence of congestion on Day 60 compared to standard care.

Time frame: After 400 patients have been evaluated at Day 60