Spironolactone for Heart Failure

(SPIRRIT Trial)

Recruiting at 39 trial locations

Overseen By Will Simmons (US)

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Uppsala University

Must be taking: Loop diuretics

Must not be taking: Lithium

Disqualifiers: Chronic liver disease, Cardiomyopathy, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 5 years

2000 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether adding spironolactone to usual care can reduce the risk of death or hospital visits in people with heart failure and a specific type of heart function. It targets those with stable heart failure symptoms and an ejection fraction of 40% or higher. Participants should have regularly used diuretics (medicines that help remove extra fluid) and meet certain heart health criteria. The trial will compare spironolactone plus standard care to standard care alone to determine if it improves outcomes. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking advancements in heart failure treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must not be using lithium or participating in another trial with similar drugs. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that spironolactone is likely to be safe for humans?

Research has shown mixed results regarding the safety of spironolactone for heart failure. One study found that spironolactone reduced certain heart-related problems and deaths, indicating some positive effects. However, another study found that high doses did not improve outcomes in sudden heart failure.

Spironolactone can cause side effects. In one study, about 25% of patients stopped taking it due to issues like high potassium levels and kidney problems. Another study highlighted increased safety concerns, especially for older adults.

The FDA has already approved spironolactone for other uses, suggesting it is generally safe when used correctly. However, those considering joining a trial should discuss potential risks with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for heart failure?

Researchers are excited about spironolactone for heart failure because it offers a unique approach by targeting the mineralocorticoid receptor, which is not the primary focus of many standard treatments like ACE inhibitors or beta-blockers. This mechanism helps reduce fluid retention and lower blood pressure, which can significantly alleviate symptoms of heart failure. Additionally, spironolactone can be a valuable option for patients who do not tolerate other medications well, providing more personalized care and potentially improving quality of life.

What evidence suggests that spironolactone might be an effective treatment for heart failure?

Research has shown that spironolactone can benefit individuals with heart failure with preserved ejection fraction (HFPEF). One study found that spironolactone reduced the risk of serious heart problems in patients with elevated levels of certain heart-related proteins. Another study demonstrated that spironolactone led to better treatment outcomes compared to not using it. In this trial, participants will receive either spironolactone treatment or standard care alone. Spironolactone has already improved outcomes for heart failure patients with reduced ejection fraction, suggesting it might also aid those with HFPEF. These findings support the potential of spironolactone to lower the risk of heart-related issues and hospital visits for heart failure patients. ^{1 6 7 8 9}

Who Is on the Research Team?

Lars H Lund

Principal Investigator

Karolinska Institutet

Bertram Pitt

Principal Investigator

University of Michigan

Are You a Good Fit for This Trial?

This trial is for people over 50 with heart failure where the heart still pumps well (LVEF ≥40%), experiencing symptoms most days, and on diuretics. They must have high levels of a specific heart stress marker in their blood. It's not for those with severe kidney issues, on dialysis, pregnant or might become so, using lithium, or if they've had a very weak heart pump (<40%) before.

Inclusion Criteria

Written informed consent

I regularly take water pills for my condition.

I have moderate to severe heart condition symptoms.

Exclusion Criteria

Your heart's ejection fraction has been measured and it is less than 40%.

My doctor says I cannot take certain mineral-related medications.

Previously enrolled in this study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive spironolactone plus standard care or standard care alone

5 years

Follow-up

Participants are monitored for cardiovascular death or heart failure hospitalization

4 years

Data Collection

Data on outcomes such as hospitalization and mortality are collected and analyzed

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Spironolactone

Trial Overview The SPIRRIT study is checking if adding spironolactone to usual care helps patients with HFPEF better than usual care alone by reducing death from cardiovascular causes or hospital stays due to heart failure. Participants are randomly chosen to receive either spironolactone plus standard treatment or just standard treatment.

How Is the Trial Designed?

Group I: Spironolactone treatment Active Control 1 Intervention

Spironolactone will be prescribed by the Investigator and filled by patient at conventional pharmacies as 25 mg tablets. The treatment will be on top of standard care. Initial dose is 25 mg/day, which will be increased to target dose 50 mg/day if tolerated. Eplerenone can be prescribed if spironolactone is not tolerated.

Group II: Standard care alone Placebo Group 1 Intervention

Patients in the control arm will get the standard care alone

Spironolactone is already approved in United States, European Union for the following indications:

Approved in United States as Aldactone for:

• High blood pressure
• Heart failure
• Liver scarring
• Kidney disease
• Low blood potassium
• Early puberty in boys
• Acne
• Excessive hair growth in women

Approved in European Union as Aldactone for:

• Fluid retention due to heart failure
• Liver scarring
• Kidney disease
• High blood pressure
• Low blood potassium

Who Is Running the Clinical Trial?

Uppsala University

Lead Sponsor

Trials

529

Recruited

3,333,000+

Karolinska University

Collaborator

Trials

3

Recruited

7,000+

Duke Clinical Research Institute

Collaborator

Trials

69

Recruited

242,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

In a study of 125 elderly patients with severe congestive heart failure (CHF) treated with spironolactone (SPL), adverse effects such as hyperkalemia and impaired renal function were found to be more common than previously reported, with 36% experiencing elevated potassium levels and 55% showing significant increases in serum creatinine.

The study highlights the need for careful monitoring and management of SPL treatment, especially in patients with an LVEF <20%, and suggests discontinuing potassium supplements and adjusting diuretic doses to mitigate risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure? Svensson, M., Gustafsson, F., Galatius, S., et al.[2019]

Spironolactone, traditionally used for hyperaldosteronism and as a diuretic, has been found to significantly reduce the risk of death in heart failure patients by 30%, as shown in the RALES clinical trial involving heart failure patients.

Beyond its effects on aldosterone receptors, spironolactone also improves heart function and vascular health by reducing fibrosis, improving endothelial function, and potentially treating conditions like left ventricular hypertrophy and acne, indicating its versatile therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The spironolactone renaissance. Doggrell, SA., Brown, L.[2019]

In a study of six patients with chronic severe congestive heart failure, spironolactone demonstrated a moderate diuretic effect in two patients, while others showed minimal or no response, indicating its limited efficacy.

The treatment did not significantly affect potassium excretion, but four patients experienced a decrease in serum sodium levels alongside an increase in serum potassium, suggesting a complex interaction in electrolyte balance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EFFECT OF AN ALDOSTERONE ANTAGONIST (SPIRONOLACTONE) ON PATIENTS WITH SEVERE CONGESTIVE HEART FAILURE. CARRUTHERS, BM., LEDRAY, RD., SERAGLIA, M., et al.[2018]

In a study of 247 patients with heart failure and preserved ejection fraction, 12 months of spironolactone treatment significantly reduced levels of NT-proBNP and BNP, which are biomarkers indicating cardiac stress, compared to placebo.

No significant changes were observed in other biomarkers like cardiac troponin I or inflammatory markers, suggesting that spironolactone specifically targets cardiac wall stress rather than broader systemic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanistic Effects of Spironolactone on Cardiovascular and Renal Biomarkers in Heart Failure With Preserved Ejection Fraction: A TOPCAT Biorepository Study. Myhre, PL., Vaduganathan, M., O'Meara, E., et al.[2020]

In a study of 279 patients with mid-range ejection fraction heart failure (HFmrEF), treatment with spironolactone significantly reduced the rates of death and heart failure-related rehospitalization compared to an untreated group, with a follow-up duration of 1 year.

Both high (50 mg) and low (25 mg) doses of spironolactone showed similar efficacy in reducing major adverse cardiovascular events, indicating that higher doses do not provide additional benefits over lower doses in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of spironolactone treatment in patients in Northeast China suffering from heart failure with mid-range ejection fraction. Xin, YG., Chen, X., Zhao, YN., et al.[2020]

Spironolactone, a potassium-sparing diuretic, effectively lowers blood pressure in patients with resistant hypertension, showing an average reduction of 22/10 mm Hg in several studies involving both prospective and retrospective designs.

While spironolactone is beneficial for managing resistant hypertension, it can cause significant side effects such as hyperkalemia, gynecomastia, and renal insufficiency, which require careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone management of resistant hypertension. Marrs, JC.[2013]

In a retrospective analysis, patients taking spironolactone alongside ACE inhibitors or AT2 antagonists had a higher rate of stopping spironolactone and developed hyperkalaemia more frequently than expected, indicating a significant risk associated with this combination.

Patients with diabetes or lower haematocrit levels were particularly at risk for developing hyperkalaemia, highlighting the need for careful monitoring in these populations when prescribing spironolactone with other heart failure medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of spironolactone treatment in patients with heart failure. Anton, C., Cox, AR., Watson, RD., et al.[2019]

Spironolactone (SPIR) effectively reduces the production of proinflammatory cytokines like TNF-alpha, IL-6, and IFN-gamma in human immune cells, which may help improve outcomes in patients with congestive heart failure (CHF).

The inhibition of these cytokines occurs at the transcriptional level and does not rely on SPIR's known mineralocorticoid or antiandrogen effects, suggesting a novel mechanism contributing to its therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone inhibits production of proinflammatory cytokines by human mononuclear cells. Hansen, PR., Rieneck, K., Bendtzen, K.[2013]

In a study of 9165 heart failure patients, 18% of those prescribed spironolactone experienced elevated potassium levels during hospitalization, indicating a significant risk of hyperkalemia associated with its use.

Many patients receiving spironolactone had chronic renal insufficiency, suggesting that it was often prescribed to individuals with contraindications, emphasizing the need for careful patient selection to prevent serious complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Appropriateness of spironolactone prescribing in heart failure patients: a population-based study. Ko, DT., Juurlink, DN., Mamdani, MM., et al.[2015]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7083406/

Spironolactone use is associated with improved outcomes ... Spironolactone has been shown to improve outcomes in patients with heart failure (HF) with reduced ejection fraction (EF).

2. ahajournals.org ahajournals.org/doi/10.1161/JAHA.120.018827

Spironolactone Use and Improved Outcomes in Patients ... The present study demonstrated that spironolactone use led to a decreased risk of composite cardiovascular events, all‐cause mortality, and ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1313731

Spironolactone for Heart Failure with Preserved Ejection ... Spironolactone significantly reduced the rate of the primary outcome among patients enrolled on the basis of an elevated natriuretic peptide ...

4. cfrjournal.com cfrjournal.com/articles/cardiovascular-benefits-spironolactone-heart-failure-mildly-reduced-or-preserved-ejection?language_content_entity=en

Spironolactone's Cardiovascular Benefits in Heart Failure Hierarchical analysis of the primary composite outcome revealed a significant higher probability of win (28.3%) compared to loss (23.1%) in the ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02429388?term=Spironolactone&viewType=Table&rank=1

High-Dose Aldactone for Treatment of Diuretic Resistant ... Prospective, open-label, randomized cohort study comparing adding high-dose spironolactone to usual heart failure care versus usual care in patients with ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5675712/

Efficacy and Safety of Spironolactone in Acute Heart Failure High-dose spironolactone in AHF was not associated with improvement in either the primary or the secondary outcomes in the ATHENA-HF trial. This ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0735109702026943

Clinical study: heart failure Complications of inappropriate ... Our study reveals that complications with spironolactone use in patients with HF are greater in clinical practice than reported in a rigorous trial.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/19006114/

Safety of spironolactone use in ambulatory heart failure ... The rate of spironolactone withdrawal was 25% (19 out of 76). Reasons for suspension were hyperkalemia (17.1%), renal function deterioration (14.5%), ...

9. jacc.org jacc.org/doi/10.1016/j.jchf.2019.08.019

Influence of Age on Efficacy and Safety of Spironolactone ... However, spironolactone was associated with an increased risk of the safety endpoint (hazard ratio: 2.54; 95% confidence interval: 1.91 to 3.37; ...