This page shows what was measured, who it was measured in, and what that does not settle.
What Spironolactone does in the body
Spironolactone occupies the receptor that hormone uses, so the kidney lets salt and water go and keeps potassium.
A hormone called aldosterone tells your kidneys to hold on to salt and water and to throw away potassium, and it also promotes scarring in heart muscle. Keeping potassium is both the benefit and the danger: it is why the drug does not deplete you like other diuretics, and why it can raise potassium to a level that stops the heart.
Why people take it. Used for heart failure, fluid retention and hard-to-control high blood pressure.
What happened in people
In severe heart failure, adding low-dose spironolactone reduced deaths by about 30%.
✓ Reviewed first-read answer
Where this came from
A person wrote this and a reviewer approved it against this exact record. It carries no effect size.
A reviewer approved this against this record. The reviewed-claim record carrying the exact population and effect size does not exist yet.
No source is stored against this line.
The limit that matters most
A later heart-failure study produced sharply different results across regions, making its overall result hard to interpret.
Where it acts
Distal convoluted tubule and cortical collecting duct of the nephron
Kind of result
The kind of result is not recorded
Supervision
RNAWiki has not recorded a supervision or regulatory status for this substance.
What the registries record it as
The substance registry classes this as chemical.
FDA substance registry · 27O7W4T232 · read 2026-08-29
Where each sentence above came from
A person wrote this explanation into the record, with the studies named in the path below.
A reviewer approved this sentence against this exact record and its sources.
The limit a reviewer approved as the one that matters most here.
The four opening statements run to 102 words.
Words this page uses
Four words worth knowing first
Chosen from what this page shows, with each one explained before the word it depends on.
Comparator
A comparator is whatever the treatment was measured against.
A picture of it, and where the picture fails
It is like the other runner in a race.
Where that stops being true. A race has one winner. A study can show both arms improved.
What people get wrong. Results are read without asking what the other group got. Beating nothing is not beating a treatment.
The control condition against which the experimental intervention is assessed.
Randomisation
Randomisation means chance decides who gets which treatment.
A picture of it, and where the picture fails
It is like a coin toss deciding the groups.
Where that stops being true. A coin toss is fair once. Fairness here comes from doing it for everyone.
What people get wrong. It is thought to make groups identical. It makes them similar on average, including on things nobody measured.
Allocation of participants to arms by a chance process, so that unmeasured factors are balanced in expectation.
Absolute difference
An absolute difference is how many more people in a hundred were affected.
A picture of it, and where the picture fails
It is like counting heads in two rooms of a hundred.
Where that stops being true. Heads are easy to count. Study results carry a margin of error too.
What people get wrong. It is confused with a percentage change, which can look far larger.
The arithmetic difference in event rates between arms.
Confidence interval
A confidence interval is the range the true answer is likely to sit in.
A picture of it, and where the picture fails
It is like a weather forecast giving a range rather than one number.
Where that stops being true. A forecast range covers tomorrow. This one covers what the study could resolve.
What people get wrong. The middle number is read as the answer. A range crossing zero means no change is still possible.
An interval estimate that would contain the true parameter in a stated proportion of repeated studies.
What happened in people◇Read from sources, not yet reviewed
What happened in people
Each card is one study: the exact question it asked, who was in it, and whether it showed what it set out to show.
Death from all causes in severe heart failure with ejection fraction ≤35%
✓ The study showed what it set out to show
Who was studied
RALES
How many people
1663
Study design
Randomised double-blind placebo-controlled trial, stopped early, mean 24 months
Compared against
A dummy treatment
Kind of result
Living longer, or avoiding a major event
What was found
Relative risk 0.70 (95% CI 0.60-0.82), P < 0.001
Repeated elsewhere
Partially Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. Serious hyperkalaemia was described as minimal — in a trial that excluded creatinine above 2.5 mg/dL and monitored potassium closely. The population-level experience afterwards was very different.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet in several strengths, and an oral suspension
Interval reported. 95% CI 0
Written into the record, not signed off as a reviewed claim.
Composite of cardiovascular death, aborted cardiac arrest or hospitalisation for heart failure, ejection fraction ≥45%
✗ The study did not show it
Who was studied
TOPCAT (NCT00094302)
How many people
3445
Study design
Randomised double-blind placebo-controlled trial, mean 3.3 years
Compared against
A dummy treatment
Kind of result
Living longer, or avoiding a major event
What was found
HR 0.89 (95% CI 0.77-1.04), P = 0.14
Repeated elsewhere
Failed to Replicate
What this does not prove. A study that did not show an effect does not show that no effect exists anywhere.
The limits of this study, and where it came from
Main limit. Hyperkalaemia doubled, 18.7% against 9.1%. A post-hoc analysis found a fourfold regional difference in event rates, with no detectable drug effect on potassium or creatinine in the Russia and Georgia cohort.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet in several strengths, and an oral suspension
Interval reported. 95% CI 0
Written into the record, not signed off as a reviewed claim.
Co-primary: total events of cardiovascular death or new or worsening heart failure; and first occurrence of infarction, stroke, new or worsening heart failure or cardiovascular death
Difference in home systolic blood pressure between spironolactone and placebo in resistant hypertension
✓ The study showed what it set out to show
Who was studied
PATHWAY-2 (NCT02369081)
How many people
335
Study design
Randomised double-blind crossover trial with rotating treatment cycles
Compared against
Not recorded for this study
Kind of result
A number that stands in for health
What was found
-8.70 mm Hg (95% CI -9.72 to -7.69), P < 0.0001
Repeated elsewhere
Unreplicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. Serum potassium exceeded 6.0 mmol/L on one occasion in 6 of 285 patients receiving spironolactone. The endpoint is blood pressure, not events.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet in several strengths, and an oral suspension
Interval reported. 95% CI -9
Written into the record, not signed off as a reviewed claim.
RNAWiki holds 4 written-up human studies for this substance, each with the question it asked.
How we know it
Each card names the study, the number of people and what the study set out to measure.
What this does not prove
These summaries were written by a person and have not been signed off as reviewed claims.
Why it matters
A study that failed is as informative as one that worked, and both are here.
What we still do not know
No reviewed claim exists, so no exact population, effect size or interval is published yet.
What it changes in the body◇Read from sources, not yet reviewed
The path through the body
From what a person takes to what changes. A solid line is a step measured in people. A dashed line is a step nobody has measured that way.
Where a source records it acting
Kidneys: Antagonist of aldosterone through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule
US prescribing information · 08738ad4-1607-4d55-af71-6790477353bd · read 2026-08-27
Start
Spironolactone
What a person takes: Oral tablet in several strengths, and an oral suspension.
The measurement behind this step
Once daily, taken with food because absorption is improved by it. Effect builds over days because most of the activity resides in metabolites with long half-lives, and for the same reason it does not disappear immediately on stopping.
Getting in
Absorbed with food, and converted into longer-lasting active metabolites
The tablet is better absorbed with food. The liver then converts most of it into other molecules that are themselves active and last far longer than the original.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Absorption is enhanced by food. Spironolactone undergoes extensive and rapid first-pass metabolism to canrenone, 7-alpha-thiomethylspironolactone and 6-beta-hydroxy-7-alpha-thiomethylspironolactone, all pharmacologically active with half-lives considerably longer than the parent. Consequently the duration of effect is set by metabolite kinetics, and steady-state effect takes several days to establish.
It enters the kidney tubule cell and reaches a receptor in the cytoplasm
Unlike most kidney drugs, this one has to get inside the cell, because its target is not on the surface — it is a receptor that travels to the nucleus and switches genes on.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
The mineralocorticoid receptor is a cytoplasmic nuclear-receptor-family transcription factor, expressed in principal cells of the distal convoluted tubule and cortical collecting duct, and also in cardiac myocytes, fibroblasts and vascular smooth muscle. Being a lipophilic steroid, spironolactone crosses the membrane passively, which is why it acts from the blood side rather than requiring luminal delivery like the loop and thiazide diuretics.
It occupies the aldosterone pocket and blocks the receptor from activating genes
The drug binds where the hormone would and prevents the receptor moving into the nucleus in an activating shape. It also blocks the male hormone receptor, which is where the breast effects come from.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
Competitive antagonism at the mineralocorticoid receptor ligand-binding domain prevents the conformational change required for coactivator recruitment. Because spironolactone is a steroid, it also antagonises the androgen receptor and inhibits testosterone biosynthesis, producing gynaecomastia in 10% of men in RALES, and has weak progestogenic activity — the off-target profile eplerenone was designed to remove.
Sodium channels and pumps are not made, so sodium leaves and potassium stays
Without the hormone signal, the cell stops making the sodium doorways and pumps it would otherwise build. Sodium and water are excreted, and potassium is retained instead of being thrown away.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Reduced transcription of the epithelial sodium channel subunits SCNN1A, SCNN1B and SCNN1G, of serum and glucocorticoid-regulated kinase 1 and of the basolateral sodium-potassium ATPase lowers apical sodium entry. The reduced electrochemical driving force cuts potassium secretion through ROMK — the mechanism of the natriuresis, of the potassium sparing, and of the hyperkalaemia. Separately, mineralocorticoid receptor blockade in cardiac fibroblasts reduces collagen deposition, the proposed basis of the RALES mortality benefit beyond diuresis.
Deaths fall in reduced ejection fraction; potassium rises in everyone
In severe heart failure it reduced deaths by 30%. In preserved ejection fraction it did not reach significance. Everywhere it is used, it doubles the rate of high potassium.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
RALES: death 35% against 46%, relative risk 0.70, p<0.001. TOPCAT: primary composite hazard ratio 0.89, p=0.14, with hyperkalaemia 18.7% against 9.1%. CLEAR SYNERGY: adjusted hazard ratios 0.91 and 0.96 for the two primary outcomes. PATHWAY-2: home systolic pressure 8.70 mm Hg below placebo.
No suggested links are held for this record, so nothing is hidden from this path.
What we know
The record describes 5 steps from taking it to an effect in a person.
How we know it
Each step names the study behind it in the technical detail beside it.
What this does not prove
A change inside the body is a reason to look. It is not a result in a person.
Why it matters
A reader can see exactly where the chain stops being measured in people.
What we still do not know
No reviewed claim binds any of these steps to a named population.
What is missing or unclear◇Read from sources, not yet reviewed
Were people like you studied?
RNAWiki cannot tell whether a study fits you. It can show who was in it, and where the result stops carrying.
Who was studied
People similar to this profile were included.
People with heart failure and reduced ejection fraction, people with resistant hypertension, people with cirrhotic ascites, and people with primary hyperaldosteronism. It is on the WHO Model List of Essential Medicines and is also used off-label for acne and hirsutism because of its anti-androgen activity.
Who is missing from the studies
Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
Who a named study recorded including and excluding
label:clinical-studies recorded its participants as: 87% of patients were white, 7% black, 2% Asian. 73% were male and median age was 67..
US prescribing information · 08738ad4-1607-4d55-af71-6790477353bd · read 2026-08-27
It included: an ejection fraction of ≤ 35%; NYHA class III-IV symptoms; a history of NYHA class IV symptoms within the last 6 months before enrollment.
US prescribing information · 08738ad4-1607-4d55-af71-6790477353bd · read 2026-08-27
It excluded: a baseline serum creatinine of >2.5 mg/dL or a recent increase of 25%; a baseline serum potassium of >5.0 mEq/L.
US prescribing information · 08738ad4-1607-4d55-af71-6790477353bd · read 2026-08-27
What the label states about particular groups
On pediatric, the label states: “Safety and effectiveness in pediatric patients have not been established.”
US prescribing information · eb27a2d2-1d28-4780-8e69-5fe613a0335e · read 2026-08-30
On older people, the label states: “Spironolactone is substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.”
US prescribing information · eb27a2d2-1d28-4780-8e69-5fe613a0335e · read 2026-08-30
On people who are pregnant, the label states: “Risk Summary Based on mechanism of action and findings in animal studies, spironolactone may affect sex differentiation of the male during embryogenesis (see Data) .”
US prescribing information · eb27a2d2-1d28-4780-8e69-5fe613a0335e · read 2026-08-30
On people who are breastfeeding, the label states: “Risk Summary Spironolactone is not present in breastmilk; however, limited data from a lactating woman at 17 days postpartum reports the presence of the active metabolite, canrenone, in human breast milk in low amounts that are expected to be clinically inconsequential.”
US prescribing information · eb27a2d2-1d28-4780-8e69-5fe613a0335e · read 2026-08-30
Where the result stopped carrying
TOPCAT missed its primary endpoint at p=0.14, with only heart failure hospitalisation reaching significance among the components
CLEAR SYNERGY found adjusted hazard ratios of 0.91 and 0.96 on its two primary outcomes in 7,062 patients after myocardial infarction
The population rollout of RALES produced an estimated 560 extra hyperkalaemia hospitalisations and 73 extra hospital deaths in one Canadian province in 2001 alone
This is a scope explorer, not a diagnosis engine.
It shows who was studied so you can see whether people similar to you were included.
RNAWiki cannot tell whether a study fits you. It can show who was in it.
What it would be like to take◇Read from sources, not yet reviewed
Why it might seem to do nothing
A real effect and a noticed effect are different things. These are the recorded reasons the two come apart.
It was studied in different people
The people in the studies were not much like the reader.
On this record: Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
The evidence may simply be wrong
Small early studies often do not hold up.
On this record: RNAWiki has not yet published a reviewed conclusion for this use.
Other reasons RNAWiki checked and found nothing for (11)
It was studied for a different goal
The studies measured something else entirely. Nothing in this record points to this reason.
A different form was studied
The studied form is not the form on the shelf. Nothing in this record points to this reason.
There was nothing to correct
Where a level is already normal, topping it up may change nothing. Nothing in this record points to this reason.
Something else had to happen too
In the studies it was paired with training, a diet or another treatment. Nothing in this record points to this reason.
The change is too small to feel
A real change can still sit below what a person notices. Nothing in this record points to this reason.
Day-to-day swing hides it
Sleep, food, stress and time of day move most numbers more than this would. Nothing in this record points to this reason.
Not enough time yet
The studies ran longer than the person has waited. Nothing in this record points to this reason.
It was not taken as studied
Missed days change the result, and studies count them. Nothing in this record points to this reason.
Something else changed at the same time
Two changes at once cannot be told apart afterwards. Nothing in this record points to this reason.
The product may not be what it says
Contents of a sold product are not always what the label states. Nothing in this record points to this reason.
No recorded reason
RNAWiki has nothing stored that would explain it. Nothing in this record points to this reason.
None of these is a reason to take more. Taking more is not a step this page ever suggests.
What it would be like to take◇Read from sources, not yet reviewed
What taking it involves
The recorded facts about getting hold of it and using it. Nothing here is a suggestion about what you should do.
How it is supplied
Prescription only
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Read from the recorded approval status.
No source is stored against this line.
Form and route
Oral tablet in several strengths, and an oral suspension
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form and route recorded on this substance.
No source is stored against this line.
Who oversees it
RNAWiki has not recorded a supervision or regulatory status for this substance.
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
No register row and no identity class settled the question.
No source is stored against this line.
What is in the pack
Once daily, taken with food because absorption is improved by it. Effect builds over days because most of the activity resides in metabolites with long half-lives, and for the same reason it does not disappear immediately on stopping.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on how this is sold and what that means for what is in the pack.
No source is stored against this line.
Where it is registered
Regulatory records are listed in the technical disclosure at the foot of this page.
# Counted from records
Where this came from
A count of rows RNAWiki holds. It describes our records, not your body.
Register entries are stored per jurisdiction and shown with their dates.
No source is stored against this line.
Why people stop
Not recorded.
∅ Nothing recorded
Where this came from
RNAWiki holds nothing here and says so rather than guessing.
No record of why people stopped taking it is stored for this substance.
No source is stored against this line.
What it would be like to take◇Read from sources, not yet reviewed
What can go wrong
Sorted by where each line came from. A regulator's label and a report somebody sent in are not the same kind of fact.
·Worth asking a clinician aboutWritten into the record from the studies named on this page
Hyperkalaemia is the defining risk: 18.7% against 9.1% on placebo in TOPCAT, and the Ontario time-series measured the population consequence of prescribing without the trial's monitoring. Risk rises with renal impairment, with ACE inhibitors or angiotensin receptor blockers, with potassium supplements and with potassium-based salt substitutes. Gynaecomastia or breast pain occurred in 10% of men in RALES against 1% on placebo. Menstrual irregularity occurs in women. Serum creatinine rises. It is contraindicated in pregnancy because of anti-androgen activity.
Nobody counted how many people took this and were fine, so this cannot be turned into a rate.
Over a long time. No completed tested study window is recorded, so long-term effects are not established by the registry record.
Groups the studies covered thinly. Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What is missing or unclear◇Read from sources, not yet reviewed
Does the exact form matter?
Evidence belongs to the exact thing that was tested. A different salt, a different mixture or a different preparation is a different question.
The form that was studied
Oral tablet in several strengths, and an oral suspension
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form used in the studies cited on this page.
No source is stored against this line.
What is sold
Effect builds over days because most of the activity resides in metabolites with long half-lives, and for the same reason it does not disappear immediately on stopping.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on which forms are sold and how they compare.
No source is stored against this line.
What is recorded as being sold
207 products list this as an active ingredient in the United States drug directory. 195 of them contain it and nothing else.
FDA National Drug Code directory · 72162-1626 · read 2026-08-29
They are sold as powder, solution/ drops, suspension, tablet, tablet, coated and tablet, film coated, taken oral.
FDA National Drug Code directory · 72162-1626 · read 2026-08-29
The regulator's established pharmacologic class for it is aldosterone antagonist [epc] and aldosterone antagonists [moa].
FDA National Drug Code directory · 72162-1626 · read 2026-08-29
143 published labels name it as an active ingredient. 131 of them describe this substance alone, which is where its own label text on this page comes from.
US prescribing information · eb27a2d2-1d28-4780-8e69-5fe613a0335e · read 2026-08-29
Those labels are classed as human prescription drug.
US prescribing information · eb27a2d2-1d28-4780-8e69-5fe613a0335e · read 2026-08-29
Spironolactone is tablets at Tablets: 25 mg, 50 mg, and 100 mg, recorded as prescription product; fda label in effect 2025-11-19 in the United States.
US prescribing information · 08738ad4-1607-4d55-af71-6790477353bd · read 2026-08-27
Recorded price in US: 0.04303–0.1699 USD per one unit as the pricing file counts it — a tablet, capsule, patch or single item, across 82 priced products whose strengths and pack forms differ, as of 2026-08-26, paid by retail pharmacies buying the product, as surveyed by the Centers for Medicare & Medicaid Services. It is not a list price, an insurance price, or what anyone pays at a counter..
Recorded source · 2026-08-26 · read 2026-08-28
Recorded price in US: 1.5664–1.8338 USD per one millilitre, across 6 priced products whose strengths and pack forms differ, as of 2026-08-26, paid by retail pharmacies buying the product, as surveyed by the Centers for Medicare & Medicaid Services. It is not a list price, an insurance price, or what anyone pays at a counter..
Recorded source · 2026-08-26 · read 2026-08-28
Evidence carries across two names for one substance. It does not carry across a salt, a mirror form or a mixture.
What it would be like to take◇Read from sources, not yet reviewed
What you could measure
This one is decided with a clinician, so this section holds questions to ask rather than a plan to run.
RNAWiki could not confidently classify this substance, so no self-experiment plan is offered.
Questions worth asking
Which of the trials of Spironolactone studied people like me?
What was measured, and for how long?
Was the result a laboratory value or a health outcome?
What would we watch for, and when would we stop?
Tracking can show whether something changed for you. It cannot show what caused it.
RNAWiki records evidence. It does not say whether this substance is right for you.
What is missing or unclear◇Read from sources, not yet reviewed
Claims that go past the evidence
Things said about this substance that sound reasonable, and the exact step that is missing between the evidence and the claim.
✗Goes past the evidence
That the RALES benefit transfers to routine prescribing without the trial's exclusions and monitoring — the Ontario data measured what happened when it did not
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That spironolactone benefits heart failure with preserved ejection fraction in the Americas — a post-hoc geographic subgroup of a trial that missed
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That the RALES mortality result extends to the post-infarction setting — CLEAR SYNERGY tested that in 7,062 patients and both primary outcomes were null
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That "serious hyperkalaemia was minimal" in RALES describes the risk in practice — the trial excluded creatinine above 2.5 mg/dL and monitored potassium closely
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
What is missing or unclear◇Read from sources, not yet reviewed
What nobody knows yet
Open questions, each with why it is open and what would close it.
Missing populations
Which groups were under-represented in the studies has not been recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing long-term data
No completed tested study window is recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
No reviewed conclusion
RNAWiki has not yet published a reviewed conclusion for this use.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing interaction studies
No interaction was found in the registers checked. Not finding one is not the same as showing there is none.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Formulation uncertainty
Several salts, forms or products of Spironolactone are recorded. Results from one form may not transfer to another.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Mechanism not reviewed
No reviewed mechanism story exists for this substance.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
What happened in people◇Read from sources, not yet reviewed
Check any of this yourself
Every line above traced back to the study it came from. This is the technical layer, and the vocabulary changes here.
Every line above can be traced to the study named beside it. Follow the link and read it.
RALES: all-cause death from 46% to 35%, and the trial was stopped early
In plain words
In more than sixteen hundred patients with severe heart failure already on standard treatment, adding a low dose of spironolactone reduced deaths by 30%. The trial was halted early because the benefit was so clear.
What was measured
Death from all causes over a mean 24 months in severe heart failure
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
RALES enrolled 1,663 patients with severe heart failure and left ventricular ejection fraction of 35% or less, already treated with an ACE inhibitor, a loop diuretic and in most cases digoxin, randomising 822 to spironolactone 25 mg daily and 841 to placebo. The trial was discontinued early after a mean 24 months on an interim efficacy analysis. There were 386 deaths in the placebo group (46%) against 284 in the spironolactone group (35%): relative risk of death 0.70 (95% CI 0.60 to 0.82), p<0.001, attributed to fewer deaths from both progressive heart failure and sudden cardiac causes. Hospitalisation for worsening heart failure fell 35% (relative risk 0.65, 0.54 to 0.77, p<0.001) and NYHA functional class improved significantly (p<0.001). Gynaecomastia or breast pain occurred in 10% of men on spironolactone against 1% on placebo (p<0.001). Serious hyperkalaemia was described as minimal in both groups.
Written into the record, not signed off as a reviewed claim
Publishing RALES caused a measurable increase in deaths from high potassium
In plain words
After the trial was published, prescribing rose more than fourfold and hospital admissions for dangerously high potassium rose from 2.4 to 11.0 per thousand patients, with associated deaths rising sevenfold.
What was measured
Population rates of spironolactone prescribing, hyperkalaemia hospitalisation and associated mortality before and after RALES
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Juurlink and colleagues linked prescription claims and hospital admission records for more than 1.3 million adults aged 66 or older in Ontario from 1994 to 2001. Among patients on ACE inhibitors recently hospitalised for heart failure, spironolactone prescribing rose from 34 per 1,000 patients in 1994 to 149 per 1,000 by late 2001 (p<0.001), rising immediately after RALES was published. Hospitalisation for hyperkalaemia rose from 2.4 to 11.0 per 1,000 patients (p<0.001) and associated mortality from 0.3 to 2.0 per 1,000 (p<0.001). Against expected numbers, 2001 saw 560 additional hyperkalaemia hospitalisations (95% CI 285 to 754) and 73 additional hospital deaths (27 to 120) in that population. Publication was not associated with significant decreases in readmission for heart failure or in all-cause death. RALES had excluded patients with a creatinine above 2.5 mg/dL and monitored potassium closely; routine practice did neither.
Written into the record, not signed off as a reviewed claim
TOPCAT: missed its primary endpoint in preserved ejection fraction
In plain words
In nearly three and a half thousand patients with heart failure and a normal pumping fraction, the combined endpoint did not fall significantly. Only heart failure hospitalisation did, and hyperkalaemia doubled.
What was measured
Composite of cardiovascular death, aborted cardiac arrest or heart failure hospitalisation over a mean 3.3 years
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
TOPCAT randomised 3,445 patients with symptomatic heart failure and ejection fraction of 45% or more to spironolactone 15 to 45 mg daily or placebo, mean follow-up 3.3 years. The primary composite of cardiovascular death, aborted cardiac arrest or hospitalisation for heart failure occurred in 320 of 1,722 (18.6%) against 351 of 1,723 (20.4%): hazard ratio 0.89 (95% CI 0.77 to 1.04), p=0.14. Of the components, only heart failure hospitalisation was significantly lower: 206 (12.0%) against 245 (14.2%), hazard ratio 0.83 (0.69 to 0.99), p=0.04. Neither total deaths nor all-cause hospitalisations were significantly reduced. Spironolactone raised serum creatinine and doubled the rate of hyperkalaemia, 18.7% against 9.1%, while reducing hypokalaemia. With frequent monitoring there were no significant differences in serious adverse events, creatinine of 3.0 mg/dL or above, or dialysis.
Written into the record, not signed off as a reviewed claim
The TOPCAT regional analysis is post hoc, and it changes the reading of the trial
In plain words
Patients enrolled in Russia and Georgia had roughly a quarter the event rate of those in the Americas and showed no drug effect on anything, including potassium. Restricting to the Americas, the drug looks like it worked. That comparison was made after the fact.
What was measured
That spironolactone benefits heart failure with preserved ejection fraction in the Americas — a post-hoc geographic subgroup of a trial that missed its primary endpoint
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
A post-hoc analysis identified an approximately fourfold difference in the primary composite event rate between the 1,678 patients randomised in Russia and Georgia and the 1,767 enrolled in the United States, Canada, Brazil and Argentina. The Russia and Georgia patients were younger, had less atrial fibrillation and diabetes, more prior infarction or heart failure hospitalisation, lower ejection fraction and creatinine and higher diastolic pressure, all p<0.001. In the Americas, spironolactone significantly reduced the primary outcome, cardiovascular death and heart failure hospitalisation, and produced the expected rises in potassium and creatinine. In Russia and Georgia there was no detectable effect on any outcome — and, critically, no detectable effect on potassium or creatinine either, which is a pharmacological signal rather than a clinical one and is difficult to explain if the drug was being taken. The analysis is post hoc and hypothesis-generating; it is also the reason many clinicians treat TOPCAT as a positive trial in the Americas, which is an interpretation and not a result.
Written into the record, not signed off as a reviewed claim
CLEAR SYNERGY: no benefit after myocardial infarction in 7,062 patients
In plain words
A large modern trial gave spironolactone routinely after a heart attack and followed patients for three years. Neither of its two primary endpoints moved.
What was measured
Total cardiovascular death or new or worsening heart failure events, and a first-event composite, over a median 3 years
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
CLEAR SYNERGY (OASIS 9) randomised 7,062 patients with myocardial infarction who had undergone percutaneous coronary intervention, at 104 centres in 14 countries, in a 2-by-2 factorial design of spironolactone or placebo and colchicine or placebo; 3,537 received spironolactone and 3,525 placebo. Over a median 3 years, the first primary outcome, total events of cardiovascular death or new or worsening heart failure, was 183 events (1.7 per 100 patient-years) against 220 (2.1 per 100 patient-years): hazard ratio adjusted for the competing risk of non-cardiovascular death 0.91 (95% CI 0.69 to 1.21), p=0.51. The second primary outcome, first occurrence of infarction, stroke, new or worsening heart failure or cardiovascular death, occurred in 280 of 3,537 (7.9%) against 294 of 3,525 (8.3%): adjusted hazard ratio 0.96 (0.81 to 1.13), p=0.60. Serious adverse events were 7.2% against 6.8%. Vital status was unknown for 45 patients (0.6%).
Written into the record, not signed off as a reviewed claim
PATHWAY-2: the best fourth-line drug for resistant hypertension, by a clear margin
In plain words
In a rotating comparison against a beta blocker, an alpha blocker and placebo, spironolactone lowered home blood pressure more than any of them, and by most in patients whose renin was low.
What was measured
Average reduction in home systolic blood pressure against placebo and against two active comparators
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
PATHWAY-2 screened 436 patients with resistant hypertension and randomised 335 through rotating cycles; 285 received spironolactone, 282 doxazosin, 285 bisoprolol and 274 placebo, with 230 completing all cycles. Average reduction in home systolic pressure with spironolactone was superior to placebo by 8.70 mm Hg (95% CI -9.72 to -7.69, p<0.0001), superior to the mean of the two other active treatments by 4.26 mm Hg (-5.13 to -3.38, p<0.0001), superior to doxazosin by 4.03 (-5.04 to -3.02, p<0.0001) and superior to bisoprolol by 4.48 (-5.50 to -3.46, p<0.0001). Spironolactone was the most effective across the whole distribution of baseline plasma renin, with its margin of superiority many-fold greater at the lower end — consistent with sodium retention being the dominant mechanism in resistant hypertension. All treatments were well tolerated; in 6 of 285 patients on spironolactone, serum potassium exceeded 6.0 mmol/L on one occasion.
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The record as stored
The full record, for auditing
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The older medicine-wide conclusion held in this record
Written for a clinical reader, and about the medicine as a whole rather than about one indication, population and set of trials. RNAWiki does not treat it as a programme conclusion and no reviewer has signed it off in that form. It is here word for word because it is what the record holds.
A 1950s aldosterone antagonist that cut all-cause death from 46% to 35% in 1,663 patients with severe heart failure, missed its primary endpoint in 3,445 patients with preserved ejection fraction where a post-hoc analysis found a fourfold regional difference in event rates, and failed again in 7,062 patients after myocardial infarction in 2025.
Recorded evidence blocks (11)
Q1
On the Spironolactone label: indicated for what?
"Spironolactone oral suspension is an antagonist of aldosterone indicated for: the treatment of NYHA Class III-IV heart failure and reduced ejection fraction to increase survival, manage edema, and to reduce the need for hospitalization for heart failure ( 1.1 ) use as an add-on therapy for the treatment of…": indications and usage on Spironolactone's label. DailyMed label · 122558a0-57bb-4195-9adf-d37b049cbfb5 · 2026-08-26
Q2
199 registered trials of Spironolactone — at which phases?
Registered studies posting no result
159 of 199
199 registered studies of Spironolactone: 65 phase4, 52 phase2, 33 phase3, 27 na, 20 phase1, 12 na or unstated, 4 early phase1. CLINICALTRIALS_SNAPSHOT · 2026-09-01
877 with a PubMed record
Show the evidence
phase4
65
phase2
52
phase3
33
na
27
phase1
20
na or unstated
12
10 more recorded rows
early phase1
4
completed
103
unknown
44
recruiting
17
withdrawn
13
terminated
8
not yet recruiting
7
active not recruiting
3
enrolling by invitation
2
suspended
2
recorded 2026-09-01 · last checked 2026-09-04
Q3
22 of Spironolactone's trials stopped: safety, accrual/recruitment, funding/business, other?
safety (1), accrual/recruitment (7), funding/business (6) and other (8): Spironolactone's stop wording, clustered. CLINICALTRIALS_SNAPSHOT · 2026-09-01
"Poor compliance with the therapy and lot of patients were lost to follow up."; 22 of 199 registered studies
Show the evidence
Trial
NCT00125437
terminated; "Poor compliance with the therapy and lot of patients were lost to follow up."
NCT00226109
suspended; "Problems recruting patients"
NCT00328809
withdrawn; "personnel shortage"
NCT00430794
terminated; "Difficulties with recruitment."
NCT00548912
withdrawn; "study ended"
NCT00709137
withdrawn; "lack of enrollment"
14 further recorded trials
NCT00773084
withdrawn; "Difficulty in recruiting patients and then the PI left the institution"
NCT01488877
terminated; "See termination reason in detailed description."
NCT01843309
terminated; "Not possible to complete the sample within the estimated time by the use of new antifungals"
NCT01855334
withdrawn; "change of funding leading to major redesign"
NCT02299726
withdrawn; "Study was not funded"
NCT02429388
withdrawn; "Principal Investigator left institution prior to subjects being enrolled"
NCT02483195
withdrawn; "PI indicating she was withdrawing her study submission due to lack of funding as of 6/20/2016"
NCT02501213
terminated; "Lack of enrollment"
NCT03597035
terminated; "The study could not enroll patients owing to the inclusion exclusion criteria"
NCT03682497
terminated; "Attendance at study sites carries risk of COVID-19 infection. Non-attendance at planned study site visits has unacceptable study related patient safety risk."
NCT03777319
terminated; "Inability to recruit participants."
NCT03953209
withdrawn; "Conflict with funding"
NCT04100083
withdrawn; "Lack of funding"
NCT04190433
withdrawn; "Administratively closed due to low/no accrual"
recorded 2026-09-01 · last checked 2026-09-04
Q4
Human studies of Spironolactone used Spironolactone (Spironol) 25 mg — over how long?
Human studies of Spironolactone used "Spironolactone (Spironol) 25 mg". ClinicalTrials.gov · 2026-09-01
20 recorded entries; human; orally; also "Spironolactone 25mg", "Aldactone 25 mg daily", "Spironolactone 50 mg (SPL 50)"
Show the evidence
human
NCT00528385
Spironolactone (Spironol) 25 mg
NCT01069510
Spironolactone 25mg
NCT01069510
Aldactone 25 mg daily
NCT01103245
Spironolactone 50 mg (SPL 50)
NCT01294319
Spironolactone 200 MG
NCT01294319
Mifepristone 400 MG and Spironolactone 200 MG
14 more recorded rows
humanNCT01843309
Spironolactone 100mg
humanNCT01843309
Spironolactone 200mg
humanNCT02053974
orally; 25 mg spironolactone orally
humanNCT02483195
200mg Spironolactone
humanNCT03020303
Spironolactone 25Mg Tablet
humanNCT03206658
Spironolactone 25 mg
humanNCT03206658
aldactone 25 mg
humanNCT03744767
Spironolactone 50 MG
humanNCT03953209
Spironolactone 50Mg Tablet
humanNCT03953209
Spironolactone 100Mg Tablet
humanNCT03953209
Spironolactone 200Mg
humanNCT04100083
Spironolactone 200 mg
humanNCT04853355
Spironolactone 50 mg
humanNCT05092984
Spironolactone Mylan 25mg
recorded 2026-09-01 · last checked 2026-09-04
Q5
Spironolactone's half-life is 1- 2 hour — which schedules were studied?
1- 2 hour, the half-life Spironolactone's label states: "Elimination The half-life of spironolactone is approximately 1- 2 hour, and the half-life of canrenone, 7-α-(thiomethyl) spirolactone (TMS), and 6-ß-hydroxy-7-α-(thiomethyl) spirolactone (HTMS) ranged from 10 to 35 hours." DailyMed label · 122558a0-57bb-4195-9adf-d37b049cbfb5 · 2026-08-26
tmax 0.5 to 1.5 hours; bioavailability 57 %.
Show the evidence
half lifepharmacokinetics
1- 2 hour; Elimination The half-life of spironolactone is approximately 1- 2 hour, and the half-life of canrenone, 7-α-(thiomethyl) spirolactone (TMS), and 6-ß-hydroxy-7-α-(thiomethyl) spirolactone (HTMS) ranged from 10 to 35 hours.
tmaxpharmacokinetics
0.5 to 1.5 hours; Absorption The peak plasma concentration (C max ) of spironolactone is reached 0.5 to 1.5 hours after dosing in healthy volunteers; for the active metabolite canrenone, the C max is reached around 2.5 to 5 hours after dosing.
bioavailabilitypharmacokinetics
57 %; Effect of food: A high fat and high calorie meal (57% of the ~1000 kcal of the meal were from fat) increased the bioavailability of spironolactone (as measured by AUC) by approximately 90%.
metabolismpharmacokinetics
Metabolism Spironolactone is rapidly and extensively metabolized primarily by CYP 3A4/5, and to a lesser extent by CYP2C8.
recorded 2026-08-26 · last checked 2026-09-04
Q6
Which running trial of Spironolactone could settle inflammatory markers?
NCT05092984 measures Proportion of patients achieving DAS28-CRP < 3.2, comparison between spironolactone and placebo arms., reading out 2026-03.
3 open trials; n 154; "Evaluation of Spironolactone Efficacy in Patient with Rheumatoid Arthritis (RA)"
Show the evidence
Trial
NCT05092984
"Evaluation of Spironolactone Efficacy in Patient with Rheumatoid Arthritis (RA)"; n 154; "Proportion of patients achieving DAS28-CRP < 3.2, comparison between spironolactone and placebo arms."; 2026-03
NCT01712620
"Spironolactone for Pulmonary Arterial Hypertension"; n 70; "Change in placebo corrected 6-minute walk distance"; 2026-12-31
NCT03984591
"A Registry-based Cluster Randomized Trial to Compare the Effect of Spironolactone vs. Eplerenone on Clinical Outcomes in Patients With Symptomatic Systolic Heart Failure"; n 7200; "Mortality"; 2028-12-31
Q7
Which 57 trials of Spironolactone posted no result?
Posted no result
57 of 57 completed trials
Registrations
NCT00004311, NCT00001202, NCT00306696, NCT00106561, NCT00317954 and NCT00276289, and 51 more
Completion dates
oldest 1996-01; newest 2024-08-09
Show the evidence
Trial
NCT00004311
1996-01
NCT00001202
2004-01
NCT00306696
2004-01
NCT00106561
2004-09
NCT00317954
2005-07
NCT00276289
2006-06
14 further recorded trials
NCT00498537
2006-06
NCT00860340
2006-10
NCT00335413
2007-04
NCT00224809
2007-05
NCT01089309
2007-06
NCT00291720
2007-12
NCT00295347
2008-06
NCT00842140
2009-01
NCT00175617
2009-03-09
NCT00865501
2009-12
NCT01083290
2010-04
NCT00523757
2010-04-30
NCT00206232
2010-07
NCT00857909
2010-07
Q8
At the median, Spironolactone's trials enrolled 60 people — anything larger?
Median enrolment
60
Largest enrolment
22213
Registered trials counted
196
Q9
What do 9097 spontaneous reports say about Spironolactone — and not say?
These are reports people sent to a regulator. They do not show the medicine caused the reaction. Nobody counted how many people took the medicine and reported nothing. The same event can be reported more than once, and many reports are incomplete. News coverage, lawsuits and new warnings change how often people report. A count is not a rate and not a risk.
Spironolactone appears in spontaneous reports to regulators. Across the 10 most-reported reaction terms, 9097 reaction mentions were counted: hyperkalaemia 2140; acute kidney injury 1671; hyponatraemia 938; hypotension 802. FAERS via Open Targets · CHEMBL1393 · 2026-06-24
Show the evidence
hyperkalaemia
2140
acute kidney injury
1671
hyponatraemia
938
hypotension
802
drug interaction
702
renal failure acute
702
4 more recorded rows
dehydration
698
fall
550
bradycardia
471
renal failure
423
recorded 2026-06-24 · last checked 2026-09-04
Q10
Which 10 reactions does Spironolactone's label not list?
7.7 CYP2C8 and CYP3A Substrates Spironolactone is an irreversible inhibitor for CYP2C8 and CYP3A4/5 in vitro [see Clinical Pharmacology ( 12.3 )] .
drug_interactions
Therefore, spironolactone may increase the exposure of other coadministered drugs that are metabolized by CYP2C8 and CYP3A4/5.
drug_interactions
Dosage adjustments of the drugs metabolized by CYP2C8 (e.g., repaglinide) and CYP3A4/5 (e.g., midazolam, sirolimus and tacrolimus) may be necessary if they are given concurrently with spironolactone.
pharmacokinetics
Metabolism Spironolactone is rapidly and extensively metabolized primarily by CYP 3A4/5, and to a lesser extent by CYP2C8.
pharmacokinetics
In Vitro Studies: Spironolactone is an irreversible inhibitor for CYP2C8 and CYP3A4/5.
clinical_pharmacology
Metabolism Spironolactone is rapidly and extensively metabolized primarily by CYP 3A4/5, and to a lesser extent by CYP2C8.
1 more recorded row
Interaction statementclinical_pharmacology
In Vitro Studies: Spironolactone is an irreversible inhibitor for CYP2C8 and CYP3A4/5.
ChEMBL 37 — CC BY-SA 3.0 Unported · ChEMBL ATC CC BY-SA · ClinicalTrials.gov — US Government work · Open Targets 26.06 — CC0 · mixed register set; per-register licences in docs/specs/corpus-20k-sources.md · openFDA / DailyMed — US Government work
✗ required summary fields resolved: 4 required field(s) not terminal: Why people use it, Best-supported result, Biggest unanswered question, Human evidence
✓ public claims reviewed: 0 reviewed claim(s); drafts are never rendered
✓ source coverage passed: 6 source rows
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✓ no raw internal fields: enforced by the copy-contract test over the rendered page
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