Spironolactone Misses the Mark in Acute MI Without HF

CHICAGO — A mineralocorticoid receptor antagonist (MRA) was unable to further improve 3-year outcomes of acute myocardial infarction (MI) in the modern era, based on the CLEAR OASIS 9 trial.

Among heart attack survivors without heart failure who were on “very good” background medical therapy, routine spironolactone was no better than placebo regarding the trial’s two coprimary endpoints on intention-to-treat analysis:

• Cardiovascular (CV) death or new/worsening heart failure (HF): 1.7% vs 2.1%, HR 0.89 (95% CI 0.73-1.08)
• CV death, MI, stroke, or new/worsening HF: 7.9% vs 8.3%, HR 0.95 (95% CI 0.80-1.12)

In contrast, as many patients had discontinued their assigned study drug (28.0% of spironolactone group vs 24.4% of placebo), an on-treatment analysis did suggest statistically significant benefits to spironolactone:

• CV death or new/worsening HF: 1.5% vs 2.0%, HR 0.79 (95% CI 0.63-1.00)
• CV death, MI, stroke, or new/worsening HF: 5.8% vs 7.2%, HR 0.83 (95% CI 0.69-1.00)

“However, this is exploratory and hypothesis-generating,” said Sanjit Jolly, MD, of Hamilton Health Sciences and McMaster University in Hamilton, Ontario, Canada. “The most important thing is, in fact, over the last 20 years, the outcomes post-MI have improved remarkably, so that it’s actually more challenging to show a difference. We’re looking at heart failure event rates of 2% or 3% whereas 20 years ago, it was probably 10% or 15%.”

Jolly presented the spironolactone arm of the 2×2 factorial trial CLEAR OASIS 9 at the American Heart Association (AHA) annual meeting. The data were simultaneously published in the New England Journal of Medicine.

Over 2 decades ago, the aldosterone antagonist eplerenone proved beneficial after MI complicated by left ventricular dysfunction and HF. Testing whether a MRA’s benefits can be extended to MI patients without HF, the later REMINDER and ALBATROSS studies were ultimately underpowered to detect any morbidity and mortality benefits.

CLEAR thus represents the attempt by Jolly’s group to test MRA therapy in this setting with a larger trial of over 7,000 patients. With the same large cohort, investigators did a separate analysis on colchicine and found it to be no help for reducing combined CV death, MI, stroke, or ischemia-driven revascularization at 5 years.

Any benefit of spironolactone in CLEAR appeared to be driven by reduced new/worsening HF.

As for safety, some of the higher-than-expected spironolactone discontinuations were attributed to hyperkalemia (1.1% vs 0.05%, P=0.01). Also observed was more gynecomastia with this therapy (2.3% vs 0.5%, P

Roxana Mehran, MD, of Icahn School of Medicine at Mount Sinai in New York City, commented that “more granular data are needed to identify which patients might benefit the most [from spironolactone].”

“These results of the CLEAR SYNERGY [OASIS-9] trial may have been impacted by a lower than expected event rate and the concomitant administration of colchicine,” Mehran cautioned during an AHA press conference. “There was more diarrhea, for example, in the colchicine arm, and one doesn’t know if there was higher discontinuation of the drugs due to this.”

Jolly suggested that a more tolerable drug, perhaps finerenone (Kerendia), may offer a better chance of MRAs showing an effect in the MI setting.

The FDA has approved finerenone for renal and CV protection in adults with chronic kidney disease associated with type 2 diabetes. The nonsteroidal MRA is expected to gain an HF indication after FINEARTS-HF met the primary endpoint in patients with ejection fractions above 40%.

“I believe that further investigation should clarify the role of MRAs in patients with preserved ejection fraction and/or no history of heart failure, especially after a STEMI [ST-segment elevation MI]. And of course, it’s very, very important to think about that in heart failure patients as well,” Mehran said.

CLEAR OASIS 9 enrolled patients from 104 sites spanning several continents from 2018 to 2022. Eligible participants were acute MI patients who were referred for percutaneous coronary intervention (PCI). Patients with LV dysfunction were allowed, but not those with HF.

The spironolactone report counted the 7,062 patients randomized to spironolactone 25 mg once daily versus placebo within 72 hours following PCI. Patients logged a median 3 years of follow-up.

The overall cohort had a mean age just over 60, with approximately 20% women and 95% having STEMI. Prevalence of diabetes was around 18%, and prior MI around 9%.

Patients by and large took standard medications such as aspirin and statins. The P2Y12 inhibitor of choice was often ticagrelor (Brilinta; 45%); less so clopidogrel (Plavix; 42%) or prasugrel (Effient; 11%).

The trial’s prespecified on-treatment analysis excluded patients who discontinued the trial regimen on the day of randomization and censored patients 7 days after permanent discontinuation of the trial regimen.

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