Chronic Kidney Disease, HFrEF - Heart Failure With Reduced Ejection Fraction
Conditions
Keywords
HFrEF - Heart Failure with Reduced Ejection Fraction, Chronic kidney disease, Heart failure, Chronic heart failure, HFrEF, CKD, Renal dysfunction, Kidney dysfunction, Renal impairment, Advanced, Severe, Mineralocorticoid receptor antagonists, MRA, Eplerenone, Sodium Zirconium Cyclosilicate, SZC
Brief summary
Previous studies have shown that patients with heart failure with reduced pumping function and preserved kidney function experience improved symptoms, longer survival, and fewer hospitalizations when treated with medications such as eplerenone. However, individuals with impaired kidney function have been excluded from these trials due to concerns about potential adverse effects on potassium levels, kidney function, and possibly also blood pressure. As a result, clear treatment recommendations for this high-risk group are lacking. In recent years, however, background therapies have been modernized and are now associated with a lower risk of potassium disturbances. Preliminary data also suggest that patients with impaired kidney function may benefit from eplerenone treatment. However, confirmation through dedicated studies is needed. The primary objective of this pilot trial is to assess the feasibility and safety of eplerenone in patients with heart failure with reduced pumping function and impaired kidney function. Treatment effectiveness will also be explored.
Detailed description
Virtually all major trials in heart failure with reduced ejection fraction (HFrEF), including those investigating mineralocorticoid receptor antagonists (MRAs) such as eplerenone, have excluded patients with severe chronic kidney disease (CKD). This exclusion has likely been driven by concerns over the risks of hyperkalemia and worsening renal function (WRF). However, post-hoc analyses of these major trials, along with data from registries and cohort studies, suggest that patients with more advanced renal impairment may still derive an overall benefit from MRA treatment. The objective of this pilot trial is to evaluate the feasibility and safety of eplerenone in patients with HFrEF and severe CKD. An exploratory analysis of efficacy will also be performed.
Interventions
DRUGEplerenone
Participants will receive eplerenone 25 mg once daily or every other day, based on baseline potassium levels, eGFR, systolic blood pressure, and concomitant use of weak or moderate CYP3A4 inhibitors. The study will implement a safety protocol with predefined procedures for managing significant hyperkalemia, worsening renal function, and hypotension. These will include temporary or permanent dose reduction or discontinuation of eplerenone, and, if necessary, administration of the potassium binder sodium zirconium cyclosilicate (SZC, Lokelma®).
Sponsors
Karolinska Institutet
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Transthoracic Echocardiography (TTE) analysis will take place retrospectively in a blinded manner
Intervention model description
ABA-design with a 12-week baseline, a 12-week intervention, and a 12-week withdrawal period. Two observational periods are chosen due to the high risk of natural clinical deterioration, even over a relatively short timeframe, and to enable within-participant comparison of outcome slopes across phases.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The participant has given their written consent to participate * A diagnosis of HFrEF according to current criteria, for at least three months before the screening visit * Echocardiography within 24 months of the screening visit with ejection fraction ≤ 40%. The responsible investigator is allowed to order a new TTE at their own discretion if clinically indicated - e.g. following the initiation of markedly intensified HFrEF-treatment or in the event of significant clinical deterioration. If the new TTE shows an EF \> 40%, the participant will not be eligible for inclusion. However, a potential echocardiographic worsening should not, by itself, preclude enrollment * New York Heart Association class II-III * Optimally treated and stable HFrEF (according to the investigator) since at least four weeks before the screening visit. Treatment should include beta-blockers, sodium/glucose co-transporter 2 inhibitors, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers if eGFR ≥ 20 ml/min/1.73m2 according to the revised Lund-Malmö method. Participants should also have cardiac resynchronization therapy or an implantable cardioverter-defibrillator if the indication exists according to current guidelines * eGFR \< 30 ml/min/1.73m2 according to the revised Lund-Malmö method at least once during the 12 months before the screening visit, and eGFR \< 45 ml/min/1.73m2 at the time of inclusion
Exclusion criteria
* P-K ≥ 5.6 * For the first ten study participants: eGFR \< 20 ml/min/1.73m2 according to the revised Lund-Malmö method, or projected decline in eGFR to \< 10 ml/min/1.73m2 during the 36-week study period. The projected decline will be estimated using the three most recent eGFR values from the previous 6-12 months \- For the remainder of the study participants: eGFR \< 10 ml/min/1.73m2 according to the revised Lund-Malmö method, or projected decline in eGFR to \< 10 ml/min/1.73m2 during the 36-week study period. The projected decline will be estimated using the three most recent eGFR values from the previous 6-12 months * Ongoing/planned dialysis * Systolic blood pressure \< 90 mmHg * Uncontrolled hypertension as judged by the investigator * Severe hepatic impairment (Child-Pugh C) * History of, or planned, heart transplantation or left ventricular assist device * Unwillingness to comply with highly effective contraceptive methods, or ongoing/planned pregnancy, or breastfeeding * Previous allergic reaction to an MRA or a potassium binder * Ongoing treatment with lithium, cyclosporine, tacrolimus, nonsteroidal anti-inflammatory drugs, trimethoprim, or strong CYP3A inhibitors (ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone) or inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's Wort) * QTc(f) ≥ 550 msec, history of QT prolongation associated with any medication requiring medication discontinuation, or congenital long QT syndrome * Uncontrolled arrhythmia as judged by the investigator * Acute cardiac hospitalization or procedure within four weeks before inclusion * Not suitable as judged by the investigator (presumed inability to participate, severe or terminal co-morbidity, and expected survival \< 12 months) * Previously enrolled in this trial or participation in another trial not approved for co-enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The primary endpoint is the proportion of participants who complete the treatment period with and without the need to use a potassium binder | Between the first and final day of the 12-week eplerenone treatment period | Without eplerenone interruption/discontinuation due to safety reasons, with and without SZC |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The occurrence of plasma potassium (P-K) ≥ 5.6 and ≥ 6.0 | Between the first and final day of each of the three 12-week study periods | Yes/no |
| Hospitalization for hyperkalemia | Between the first and final day of each of the three 12-week study periods | Primary or co-primary reason, yes/no |
| The occurrence of P-K < 3.0 | Between the first and final day of each of the three 12-week study periods | Yes/no |
| Hospitalization for hypokalemia | Between the first and final day of each of the three 12-week study periods | Primary or co-primary reason, yes/no |
| Decrease in eGFR of ≥ 30% and ≥ 50% | Between the first and final day of each of the three 12-week study periods | According to the revised Lund-Malmö method in ml/min/1.73 m2, compared to the start of each study period, yes/no |
| Hospitalization for renal failure | Between the first and final day of each of the three 12-week study periods | Primary or co-primary reason, yes/no |
| Initiation of dialysis | Between the first and final day of each of the three 12-week study periods | Yes/no |
| Participant-reported lightheadedness due to orthostatic hypotension as judged by the investigator | Between the first and final day of each of the three 12-week study periods | Yes/no |
| Participant-reported syncope | Between the first and final day of each of the three 12-week study periods | Yes/no |
| Any participant-reported side effect | Between the first and final day of each of the three 12-week study periods | Yes/No |
| Hospitalization for heart failure | Between the first and final day of each of the three 12-week study periods | Primary or co-primary reason, yes/no |
| All-cause hospitalization | Between the first and final day of each of the three 12-week study periods | Yes/no |
| Cardiovascular death | Between the first and final day of each of the three 12-week study periods | Primary reason, yes/no |
| All-cause death | Between the first and final day of each of the three 12-week study periods | Yes/no |
Countries
Sweden
Contacts
CONTACTCarl Haggård, MD, PhD
CONTACTKrister Lindmark, MD, PhD
STUDY_DIRECTORKrister Lindmark, MD, PhD
Karolinska Institutet
Outcome results
None listed