Spironolactone for Heart Failure

(SPIRRIT Trial)

Recruiting at 36 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

Trial Summary

What is the purpose of this trial?

Heart failure with preserved ejection fraction (HFPEF) is common and deadly but without therapy. Inconclusive studies such as TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) suggest spironolactone may be effective in HFPEF, but it is generic and will not be studied by industry. SPIRRIT is a unique Registry-Randomized Clinical Trial (RRCT) that will test the hypothesis that spironolactone plus standard of care compared to standard of care alone reduces the composite of CV mortality and HF hospitalization as follows: Population: HFPEF patients in the Swedish Heart Failure Registry and HFPEF patients in US. HFPEF defined as symptoms/signs of HF, elevated NTproBNP (B-type Natriuretic Peptide; N-terminal pro b-type Natriuretic Peptide) and EF\>=40%. Intervention and control: Randomized 1:1 to intervention: spironolactone + usual care vs. control: usual care alone. Outcome: Primary outcome cardiovascular death or time to HF hospitalization. Secondary outcomes include hospitalization for various causes, adverse events and treatment adherence. In Sweden outcomes are obtained automatically by linking with the Population, Patient and Drug Dispensed Registries. In the US, outcomes will be reported by sites and supplemented by data from a call center. The trial is event-driven with enrollment 7 years and study duration 9 years. For the primary outcome (CV Death or first HF hospitalization) with an event target of 721 events the sample size requires 1985 patients conservatively rounded to approximately 2000 patients.

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.

What evidence supports the effectiveness of the drug Spironolactone for heart failure?

Research shows that Spironolactone helps reduce hospitalizations and improves outcomes in patients with heart failure by lowering inflammation and stress on the heart. ^{1 2 3 4 5}

Is spironolactone safe for heart failure patients?

Spironolactone is generally safe for heart failure patients, but it can cause high potassium levels (hyperkalemia), especially when used with other heart medications. Studies have shown it is well tolerated, but monitoring is important to avoid potential kidney issues and high potassium. ^{1 4 6 7 8}

What makes the drug spironolactone unique for treating heart failure?

Spironolactone is unique for treating heart failure because it not only acts as a diuretic but also reduces heart and blood vessel damage by blocking aldosterone, a hormone that can worsen heart failure. It has been shown to improve survival rates and reduce hospitalizations in heart failure patients. ^{1 2 4 6 9}

Research Team

Lars H Lund

Principal Investigator

Karolinska Institutet

Bertram Pitt

Principal Investigator

University of Michigan

Eligibility Criteria

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 am 50 years old or older.

I regularly take water pills for my condition.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 (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 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 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]

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, 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]

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 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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure? [2019]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Spironolactone inhibits production of proinflammatory cytokines by human mononuclear cells. [2013]

3. United States 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. [2020]

4. England pubmed.ncbi.nlm.nih.gov

The safety of spironolactone treatment in patients with heart failure. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Outcomes of spironolactone treatment in patients in Northeast China suffering from heart failure with mid-range ejection fraction. [2020]

6. England pubmed.ncbi.nlm.nih.gov

The spironolactone renaissance. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Spironolactone management of resistant hypertension. [2013]

8. United States pubmed.ncbi.nlm.nih.gov

Appropriateness of spironolactone prescribing in heart failure patients: a population-based study. [2015]

9. Canada pubmed.ncbi.nlm.nih.gov

EFFECT OF AN ALDOSTERONE ANTAGONIST (SPIRONOLACTONE) ON PATIENTS WITH SEVERE CONGESTIVE HEART FAILURE. [2018]