Trial: Routine Use of Spironolactone Not Beneficial After Acute Heart Attack

A 1999 clinical trial showed that the diuretic (water pill) spironolactone reduces the risk of death and cardiovascular complications in patients with severe heart failure with reduced ejection fraction (ineffective heart muscle contraction).[1]

Some researchers have speculated that spironolactone may improve outcomes after acute myocardial infarction (heart attack), a medical emergency in which the blood flow to the heart is blocked. However, a recent clinical trial demonstrates that spironolactone offers no benefit in reducing deaths or major cardiovascular complications in acute myocardial infarction subjects after they had a coronary intervention that mainly involved the use of a drug-eluting stent (mesh tube coated with a blood thinner) to reopen blocked coronary arteries and restore blood flow to the heart.[2]

The trial, called CLEAR, was funded in part by the Canadian Institutes of Health Research, and its findings were published in February 2025 in the NEJM.

About spironolactone

The Food and Drug Administration approved spironolactone in 1960. Public Citizen’s Health Research Group has designated single-active-ingredient spironolactone drugs (ALDACTONE, CAROSPIR and generics) as Limited Use. We have designated the combination formulation of spironolactone and the diuretic hydrochlorothiazide (ALDACTAZIDE and generics) as Do Not Use.

Spironolactone is a potassium-sparing diuretic because it causes less excretion of potassium into the urine than do other diuretics, such as hydrochlorothiazide (MICROZIDE and generics) and furosemide (LASIX and generics). It also blocks the effect of aldosterone, a hormone produced by the adrenal glands that controls blood pressure by regulating the levels of sodium and potassium in the body.

Spironolactone is approved for treating moderate-to-severe heart failure with reduced ejection fraction to reduce the rate of complications and improve survival.[3] It also is approved to treat hypertension (high blood pressure) and edema (swelling and water retention) associated with liver failure and a kidney disease known as nephrotic syndrome, as well as treating primary hyperaldosteronism (excessive production of aldosterone by the adrenal glands).

The CLEAR trial[4]

The trial recruited 7,062 subjects from 104 centers in several countries. These subjects had a recent myocardial infarction (95% had a serious type called ST-segment elevation myocardial infarction, which affects the heart’s lower chambers) and had undergone a coronary intervention to treat this condition. Approximately 91% of the subjects had no prior heart attacks, about 45% had hypertension, about 18% had diabetes, and only 1% had heart failure at the beginning of the trial. The mean age of the overall subjects was 61 years, and 80% of them were men.

Within a median of 29 hours from the onset of myocardial infarction symptoms, the investigators randomized 3,537 of the enrolled subjects to receive daily 25-milligram spironolactone tablets and the remaining 3,525 subjects to receive a matching placebo.

During the follow-up period (median of three years), there were no statistically significant differences between the two groups on two broad primary composites of cardiovascular outcomes. For the first primary outcome, there were 183 deaths due to cardiovascular causes or new or worsening heart failure events (1.7 per 100 patient-years) in the spironolactone-treated subjects and 220 events (2.1 per 100 patient-years) in the placebo subjects.

For the second primary outcome, cardiovascular death, stroke, heart attack, or new or worsening heart failure events occurred in 280 (7.9%) of the spironolactone-treated subjects and 294 (8.3%) of the placebo subjects.

The rate of serious adverse effects did not differ between subjects in the two groups. However, hyperkalemia (abnormally high potassium levels in the blood) leading to drug discontinuation occurred in 1.1% of spironolactone-treated subjects and 0.6% of the placebo subjects. Also, gynecomastia (benign breast enlargement in men) or breast tenderness (regardless of sex) occurred in approximately 2.9% of the spironolactone-treated subjects and 0.6% of the placebo subjects.

The implication of the CLEAR trial is that routine use of spironolactone should not be recommended for all patients who experience acute myocardial infarction who had undergone a coronary intervention. However, spironolactone should continue to be considered in patients with heart failure and others for whom the drug is indicated.

What You Can Do

Patients who have had heart attacks should discuss with their clinicians whether the use of spironolactone is appropriate for them. Do not take spironolactone if you have acute kidney failure or significant chronic kidney disease, hyperkalemia, or Addison’s disease (adrenal gland failure).[5]

If you take spironolactone, you should undergo close, regular monitoring of your blood potassium levels. Talk to your clinician before you take any medication or dietary supplement that contains potassium while taking spironolactone. See the November 2022 issue of Worst Pills, Best Pills News for examples of the drugs that can interact with spironolactone.[6]

If you take spironolactone, contact your clinician immediately if you experience symptoms that may suggest hyperkalemia, including fatigue, irregular heartbeat, muscle weakness, nausea or vomiting, shortness of breath, and numbness or tingling in the hands, feet or lips.[7],[8]
 

References

[1] Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341(10):709-717.

[2] Jolly SS, D’Entremont MA, Pitt B, et al. Routine spironolactone in acute myocardial infarction. N Engl J Med. 2025;392(7):643-652.

[3] Pfizer Inc. Label: spironolactone (ALDACTONE). December 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/012151s079lbl.pdf. Accessed February 4, 2025.

[4] Jolly SS, D’Entremont MA, Pitt B, et al. Routine spironolactone in acute myocardial infarction. N Engl J Med. 2025;392(7):643-652.

[5] Pfizer Inc. Label: spironolactone (ALDACTONE). December 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/012151s079lbl.pdf. Accessed February 4, 2025.

[6] Important drug interactions for the potassium-sparing diuretic spironolactone. Worst Pills, Best Pills News. November 2022. https://www.worstpills.org/newsletters/view/1502. Accessed February 4, 2025.

[7] U.K.’s National Health Service. Side effects of spironolactone. July 6, 2022. https://www.nhs.uk/medicines/spironolactone/side-effects-of-spironolactone. Accessed February 4, 2025.

[8] Update on drugs that can cause high blood potassium. Worst Pills, Best Pills News. December 2008. https://www.worstpills.org/newsletters/view/620. Accessed February 4, 2025.