RELIEHF: RELieving Increasing oEdema Due to Heart Failure
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 4 |
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
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| No Intervention: Standard dose MRA Participants in this arm will have titration to guideline-recommended doses of MRA attempted. |
|
| Experimental: 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). |
Drug: 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.
Other Names:
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Outcome Measures
Primary Outcome Measures
- "Congestion index" on Day 60 (trial participants) [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 (trial participants) [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/mortality (registry/trial participants) [Periodically up to 10 years]
Composite of time to (re-)hospitalisation or death
Secondary Outcome Measures
- Dose of MRA [Days 7 and 60]
Dose of MRA achieved 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
- 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 mortality [Through study completion, up to 5 years]
All-cause mortality for all trial participants
- Reduced mortality [Through study completion, up to 5 years]
Non-cancer mortality for all trial participants
- Reduced mortality [Through study completion, up to 5 years]
Cardiovascular mortality for all trial participants
- Reduced mortality/morbidity [During first year]
Days lost to hospitalisation for heart failure or non-cancer deaths over 12 months for all trial participants
- Reduced mortality/morbidity [During first year]
Days lost to any hospitalisation or any death over 12 months 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 MRA [At 6 months and 12 months]
Dose of MRA 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
- NYHA class [At 6 months and 12 months]
NYHA class (I-IV) for all trial participants
- Patient Global Assessment [At 6 months and 12 months]
Patient Global Assessment to measure quality of life for all trial participants
- Participant characteristics and assessment of morbidity/mortality [Periodically up to 10 years]
Time to cardiovascular (re-)hospitalisation or non-cancer death for registry/trial participants
- Participant characteristics and assessment of morbidity/mortality [Periodically up to 10 years]
Time to heart failure (re-)hospitalisation or non-cancer death for registry/trial participants
- Participant characteristics and assessment of morbidity/mortality [Periodically up to 10 years]
Incidence rate for hospitalisation for registry/trial participants
- Participant characteristics and assessment of morbidity/mortality [Periodically up to 10 years]
Time to death for registry/trial participants
Eligibility Criteria
Criteria
Inclusion Criteria
- 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)
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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
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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
- For the Consented Registry (with linkage to electronic medical records)
-
Fulfils the criteria for the screening log
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Able and willing to provide written informed consent for registry participation
- For Randomised Trial Run-in
-
Fulfils criteria for the consented registry
-
Clinical diagnosis of heart failure for at least 4 weeks
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Congestion as shown by at least one of the following:
-
Peripheral oedema
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Raised venous pressure
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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
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Left atrial diameter >3.0cm/m2 (body surface area)
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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
- 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.
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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).
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After ingestion of a test-dose of patiromer,
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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
- 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
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Hepatic encephalopathy or known severe liver disease
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Infection currently requiring intravenous antibiotics or temperature >38°C
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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
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The patient is already receiving a potassium-binding agent (this includes patiromer) or the treating physician has already decided to use one
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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)
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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
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Patients taking the following systemic medicines:
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strong inhibitors of CYP 3A4 (e.g. itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone)
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Lithium
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Tacrolimus or Cyclosporin
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The combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB)
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Rare hereditary problems of galactose or fructose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
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Known amyloid heart disease
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Cancer likely to cause death or major disability within the next three years
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Patients requiring mechanical circulatory support and
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Glasgow Royal Infirmary | Glasgow | Strathclyde | United Kingdom | G4 0SF |
| 2 | Basildon University Hospital | Basildon | United Kingdom | ||
| 3 | Blackpool Victoria Hospital | Blackpool | United Kingdom | ||
| 4 | Princess of Wales Hospital | Bridgend | United Kingdom | ||
| 5 | Royal Devon and Exeter Hospital | Exeter | United Kingdom | ||
| 6 | Queen Elizabeth University Hospital | Glasgow | United Kingdom | ||
| 7 | Castle Hill Hospital | Hull | United Kingdom | ||
| 8 | Victoria Hospital | Kirkcaldy | United Kingdom | ||
| 9 | Guy's and St Thomas's Hospital | London | United Kingdom | ||
| 10 | King's College Hospital | London | United Kingdom | ||
| 11 | St George's Hospital | London | United Kingdom |
Sponsors and Collaborators
- NHS Greater Glasgow and Clyde
- University of Glasgow
Investigators
- Principal Investigator: John Cleland, University of Glasgow
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- GN17CA082
- 2018-003662-14