RELIEHF (RELieving Increasing oEdema due to Heart Failure), v1.0
Research type
Research Study
Full title
Patiromer-facilitated, dose-escalation of mineralocorticoid antagonists for the management of worsening congestion in people with heart failure and hyperkalaemia. A Phase IV, registry-based, randomised, controlled, open-label trial investigating 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, morbidity and mortality.
IRAS ID
253294
Contact name
John Cleland
Contact email
Sponsor organisation
NHS Greater Glasgow & Clyde
Eudract number
2018-003662-14
Clinicaltrials.gov Identifier
NA, NA
Duration of Study in the UK
25 years, 0 months, 1 days
Research summary
Research Summary
Many forms of heart disease may lead to heart failure, one of the most common causes of hospitalisation (>3 million bed-days per year in the UK) and death.Hospitalisation is often necessary because of increasing fluid retention leading to swelling of the legs and breathlessness even on slight exertion or when lying down. Fluid retention is, in part, due to an excess of a hormone called aldosterone.
Mineralocorticoid antagonists (MRA), such as spironolactone, block aldosterone's effects and have become a cornerstone of treatment heart failure. Their use is associated with striking reductions in morbidity and mortality, particularly for patients with fluid overload. However, MRA cause blood potassium concentrations to rise, kidney function to decline(although may protect long-term function)and blood pressure to fall. These effects may limit the dose of MRA and often lead them to being stopped.
Patiromer is an agent that binds potassium in the gut and may be used to lower blood potassium. We propose to do a randomised trial comparing standard care (including standard-dose MRA if tolerated) compared to high-dose MRA plus patiromer to control potassium for patients with worsening heart failure requiring treatment intensification.
We will compare how effective each strategy is at correcting fluid overload and improving symptoms and whether there is a difference in long-term morbidity and mortality. Patients and investigators will know what they are receiving, which increases the flexibility and safety of management.
Higher doses of MRA may not be tolerated because of (reversible) worsening of kidney function and low blood pressure. Investigators may be able to adjust other treatments to allow higher doses of MRA to be used. There is a risk that patients will stop either their MRA or patiromer, which might lead to large changes in blood potassium.
Clearly there are both potential risks and benefits to each strategy, creating equipoise.
Summary of results
Heart damage can lead to heart failure, which can cause the body to retain water, leading to swelling of the ankles, legs and tummy. This swelling is called ‘congestion’ and when it causes the legs to swell it is called ’peripheral oedema’.Several medicines are used to treat congestion, the most powerful of these are called “loop diuretics” (e.g. furosemide and bumetanide), which usually cause people to pass a lot more urine. However, the kidney may eventually become resistant to their effects. Another group of medicines are the mineralocorticoid antagonists (MRAs), which block the effects of aldosterone (a hormone that causes salt and water retention). Examples of these are spironolactone and eplerenone.
Several previous trials have shown that MRAs in ‘standard’ doses reduce congestion and prolong life, however, the amount of MRAs that can be taken is often limited because they cause the level of potassium in the blood to become too high (this is called ‘hyperkalaemia’), which can be dangerous.
If the blood potassium becomes too high, current medical practice is to reduce the dose of MRAs, or stop them altogether. A medicine called patiromer has recently been approved for the treatment of high levels of potassium in the blood. Giving patients patiromer may allow higher doses of MRA to be taken, which might improve the control of congestion.
The RELIEHF trial was set up to find out if giving patiromer allows higher doses of MRAs to be used and, if so, whether this improves the control of congestion in both the short- and long-term.
The RELIEHF trial opened for recruitment in March 2020 but before the first patient could be enrolled, the COVID pandemic struck, effectively preventing recruitment. Despite gallant efforts by clinical trials unit staff and investigators in the aftermath of the pandemic, recruitment never gained momentum. Moreover, despite administration of substantial doses of MRA, few patients developed a high blood potassium concentration (an important finding). Accordingly, the trial was stopped for futility after only 19 patients had entered the run-in phase of the trial and only 4 patients had been randomised.
Despite early termination, a substantial amount of data has been collected in the screening-logs and consented registries and from the open-label run-in on MRA that might be useful for the design of future clinical trials and for clinical practice.
Of the 492 patients recorded in the screening log, 249 were not asked to participate, mainly because the care team felt it inappropriate because the patient was to frail or lacked capacity to consent due to dementia.
Of 245 screened patients who were asked to participate, 102 declined, of whom 61 said they were not interested and 28 said they felt too unwell. Only seven indicated concerns over data privacy.
Of the 141 patients who agreed to participate in the registry, 102 also agreed to participate in the randomised trial but (mostly due to the effects of the COVID pandemic we think) only 19 patients (median age 71 years; 7 women) entered the run-in phase.
Of the 19 patients who entered the run-in phase, 15 received spironolactone (median dose at end of run-in 75mg/day compared to guideline-recommended dose of 50mg/day) and two received eplerenone (both 50mg/day; the guideline-recommended and maximum licensed dose). In clinical practice, many patients are not given any dose of MRA and the average dose of spironolactone is less than 75 mg/day.
Despite using substantially higher doses of MRA, only four patients developed hyperkalaemia and in no case was this severe (maximum value 5.5 mmol/L).
Two patients were randomised to usual care and two to patiromer. All patients survived until termination of the trial. Two patients experienced serious adverse events related to worsening kidney function, both of which were considered mild.
In summary, the trial shows that many patients who might be considered eligible for trials of worsening heart failure based on administrative records are considered unsuitable for inclusion in clinical registries and trials by clinical investigators. Almost 60% of patients who are asked are willing to participate in a 'low-burden' research registry and about 40% to participate in the much more onerous undertaking of a randomised trial.
The trial also shows that most patients considered eligible for the randomised trial could tolerate higher doses of MRA than is common in clinical practice without developing hyperkalaemia. Whether there is a substantial requirement for patiromer in this population remains to be established.
REC name
London - City & East Research Ethics Committee
REC reference
19/LO/0093
Date of REC Opinion
21 Feb 2019
REC opinion
Favourable Opinion