RELieving Increasing oEdema Due to Heart Failure

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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Heart Failure，Congestive

Intervention / Treatment
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* Drug: Patiromer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria A. For the Screening Log (no follow-up envisaged nor linkage to electronic medical records) ≥18 years Heart failure in the investigators opinion (new onset or decompensated chronic heart failure) Planned to receive>80mg/day of furosemide or equivalent (IV, SC or oral) in the next 24 hours. Worsening symptoms & signs of congestion in the prior 10 days requiring at least one of the following: hospitalisation administration of intravenous diuretics 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) addition of a thiazide diuretic to treatment with a loop diuretic B. For the Consented Registry (with linkage to electronic medical records) Fulfils the criteria for the screening log Able and willing to provide written informed consent for registry participation C. For Randomised Trial Run-in Fulfils criteria for the consented registry Clinical diagnosis of heart failure for at least 4 weeks Congestion as shown by at least one of the following: Peripheral oedema Raised venous pressure Inferior vena cava diameter >20mm Cardiac dysfunction documented by at least one of the following in the previous three years: A LVEF<50%or a report of moderate or severe left ventricular dysfunction Left atrial diameter >3.0cm/m2 (body surface area) 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) Able and willing to provide written informed consent for the randomised trial D. For Randomisation 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). After ingestion of a test-dose of patiromer, the patient is willing to continue in the trial 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 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) Systolic BP <90mmHg Uncorrected valve disease as the main cause of heart failure in the investigators opinion Hepatic encephalopathy or known severe liver disease Infection currently requiring intravenous antibiotics or temperature >38°C Myocardial ischaemia currently requiring intravenous therapy or coronary intervention in the previous 7 days Arrhythmia requiring urgent cardioversion or intravenous therapy Severe hyperkalaemia requiring, in the investigator's opinion, intravenous treatment or a potassium-binding agent The patient is already receiving a potassium-binding agent (this includes patiromer) or the treating physician has already decided to use one Known hypersensitivity to patiromer or any of the excipients Known intolerance to both spironolactone and eplerenone (not including hyperkalaemia) 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) 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 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 The combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) Rare hereditary problems of galactose or fructose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption Known amyloid heart disease Cancer likely to cause death or major disability within the next three years Patients requiring mechanical circulatory support and 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard dose MRA<br>Participants in this arm will have titration to guideline-recommended doses of MRA attempted. | |
| Experimental: Patiromer and high dose MRA<br>Participants assigned to patiromer may be titrated to 200mg/day spironolactone or the highest licensed dose of eplerenone (50mg/day). | Drug: Patiromer<br>* 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.<br>* Other names: Veltassa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Congestion index on Day 60 (trial participants) | To find out whether administering patiromer and higher-dose MRA improves evidence of congestion on Day 60 compared to standard care. | After 400 patients have been evaluated at Day 60 | 
| Morbidity/mortality (trial participants) | 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. | Through study completion | 
| Morbidity/mortality (registry/trial participants) | Composite of time to (re-)hospitalisation or death | Periodically up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose of MRA | Dose of MRA achieved for all trial participants | Days 7 and 60 | 
| Congestion Index | Congestion Index score for all trial participants | Days 7 and 60 | 
| Days dead or hospitalised during the first 60 days | Days dead or hospitalised during the first 60 days for all trial participants | Through 60 days | 
| Quality of Life (EQ-5D) | 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) | Days 7 and 60 | 
| Quality of Life Kansas City Cardiomyopathy Questionnaire (KCCQ-12) | Quality of Life using validated KCCQ-12 questionnaire for all trial participants (score - min 0, max 100; higher means better outcome) | Days 7 and 60 | 
| NYHA class | NYHA class (I-IV) for all trial participants | Days 7 and 60 | 
| Patient Global Assessment | 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) | Days 7 and 60 | 
| Reduced mortality | All-cause mortality for all trial participants | Through study completion, up to 5 years | 
| Reduced mortality | Non-cancer mortality for all trial participants | Through study completion, up to 5 years | 
| Reduced mortality | Cardiovascular mortality for all trial participants | Through study completion, up to 5 years | 
| Reduced mortality/morbidity | Days lost to hospitalisation for heart failure or non-cancer deaths over 12 months for all trial participants | During first year | 
| Reduced mortality/morbidity | Days lost to any hospitalisation or any death over 12 months for all trial participants | During first year | 
| QALY | Quality adjusted life-years for duration of the trial for all trial participants | Through study completion, up to 5 years | 
| Proportion alive and well at 12 months | Proportion alive and well at 12 months (well-being defined by KCCQ-12 score) for all trial participants | At 12 months | 
| Dose of MRA | Dose of MRA for all trial participants | At 6 months and 12 months | 
| Dose of oral diuretics other than MRA | Dose of oral diuretics other than MRA for all trial participants | At 6 months and 12 months | 
| NYHA class | NYHA class (I-IV) for all trial participants | At 6 months and 12 months | 
| Patient Global Assessment | Patient Global Assessment to measure quality of life for all trial participants | At 6 months and 12 months | 
| Participant characteristics and assessment of morbidity/mortality | Time to cardiovascular (re-)hospitalisation or non-cancer death for registry/trial participants | Periodically up to 10 years | 
| Participant characteristics and assessment of morbidity/mortality | Time to heart failure (re-)hospitalisation or non-cancer death for registry/trial participants | Periodically up to 10 years | 
| Participant characteristics and assessment of morbidity/mortality | Incidence rate for hospitalisation for registry/trial participants | Periodically up to 10 years | 
| Participant characteristics and assessment of morbidity/mortality | Time to death for registry/trial participants | Periodically up to 10 years |