Routine Spironolactone in Acute Myocardial Infarction - CLEAR SYNERGY (OASIS 9)

Nov 17, 2024
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Dharam J. Kumbhani, MD, SM, FACC
Trial Sponsor:
Population Health Research Institute, Boston Scientific
Date Presented:
11/17/2024
Date Published:
11/17/2024
Original Posted Date:
11/17/2024
References

Contribution To Literature:

The CLEAR SYNERGY (OASIS 9) trial showed that in patients with STEMI or high-risk NSTEMI undergoing PCI, spironolactone did not reduce MACE at a median follow-up of 3 years compared with placebo.

Description:

The goal of the trial was to determine the potential cardiovascular (CV) benefit of spironolactone following percutaneous coronary intervention (PCI) for ST-segment or large non–ST-segment elevation myocardial infarction (STEMI or NSTEMI, respectively) regardless of post-MI left ventricular ejection fraction (LVEF).

Study Design

  • International
  • 2x2 factorial randomization
  • Double-blind

Patients with acute MI were randomized in 1:1 fashion to receive spironolactone 25 mg daily (n = 3,537) or placebo (n = 3,525) following PCI, preferably with the Boston Scientific SYNERGY everolimus-eluting platinum chromium stent system. Each arm was further randomized to receive colchicine or placebo. The current data compare the spironolactone and matching placebo arms irrespective of colchicine use.

  • Total number of enrollees: 7,062
  • Median duration of follow-up: 3 years
  • Mean patient age: 61 years
  • Percentage female: 20%

Inclusion criteria:

  • Age ≥18 years
  • STEMI with PCI ≤12 hours since symptom onset and enrollment in SYNERGY registry
  • STEMI with PCI ≤48 hours since symptom onset and not enrolled in registry
  • NSTEMI with PCI, high-sensitivity (hs) or non-hs troponin ≥200 or ≥100 times upper limit of normal, respectively, and ≥1 of: LVEF ≤45%, diabetes, multivessel disease, prior MI, or age >60 years

Exclusion criteria:

  • Current or planned use of cyclosporine, everolimus, antiretroviral protease inhibitors, azoles, or macrolides
  • Cirrhosis or other severe liver disease
  • Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2
  • Serum potassium >5.0 mEq/L
  • Active diarrhea

Other salient features/characteristics:

  • Diabetes: 18%
  • STEMI: 95%
  • Median number of stents: 1.0
  • Multivessel coronary artery disease: 49%
  • Ticagrelor or prasugrel at discharge: 55%

Principal Findings:

Co-primary outcome 1, composite of CV death or new or worsening HF, for spironolactone vs. placebo, was: 1.7 vs. 2.1 per 100 patient-years, adjusted hazard ratio (aHR) 0.91 (95% confidence interval [CI] 0.69-1.21), p = 0.51 (α = 4%).

  • Interaction with colchicine assignment: p = 0.23

Co-primary outcome 2, composite of first MI, stroke, new or worsening HF, or CV death, was: 7.9% vs. 8.3%, aHR 0.96 (95% CI 0.81-1.13), p = 0.60 (α = 1.85%).

  • Interaction with colchicine assignment: p = 0.80

Secondary outcomes for spironolactone vs. placebo:

  • CV death: 3.2% vs. 3.3%, HR 0.98 (95% CI 0.76-1.27)
  • Recurrent MI: 3.0% vs. 3.0%, HR 1.02 (95% CI 0.77-1.35)
  • Stroke: 1.4% vs. 1.2%, HR 1.15 (95% CI 0.72-1.84)
  • New or worsening HF: 1.6% vs. 2.4%, aHR 0.77 (95% CI 0.51-1.16)

Safety outcomes for spironolactone vs. placebo:

  • Serum potassium >5.5 mmol/L: 1.1% vs. 0.6%, p = 0.01
  • Sustained eGFR drop ≥40%: 0.9% vs. 1.1%, odds ratio 0.84 (95% CI 0.52-1.34)
  • Gynecomastia: 2.3% vs. 0.5%, p < 0.001
  • Drug discontinuation: 28.0% vs. 24.4%

Interpretation:

The RALES and EPHESUS trials previously demonstrated the significant mortality and HF hospitalization benefit of mineralocorticoid receptor antagonists in acute MI complicated by depressed LVEF. A subgroup analysis of the subsequent ALBATROSS trial, which studied spironolactone post-MI regardless of LVEF, suggested a potential benefit in STEMI patients despite an overall negative primary outcome.

The current data, in which STEMI patients were overwhelmingly represented, failed to demonstrate a reduction in major adverse cardiovascular events (MACE) and CV death. Although HF events were numerically lower in the spironolactone arm, this was not seen in the ALBATROSS trial, and adjustment for competing risks attenuated the potential significance of the point estimates. It is possible, as the authors posit, that contemporary advances in MI treatment and intervention may lessen the potential benefit of routine mineralocorticoid receptor antagonism in all-comers. This study therefore does not support an expanded indication for these agents beyond post-MI LV systolic dysfunction.

References:

Jolly SS, d’Entremont MA, Pitt B, et al., for the CLEAR Investigators. Routine Spironolactone in Acute Myocardial Infarction. N Engl J Med 2024;Nov 17:[Epub ahead of print].

Presented by Dr. Sanjit S. Jolly at the American Heart Association Scientific Sessions, Chicago, IL, November 17, 2024. 

Clinical Topics: Cardiovascular Care Team, Stable Ischemic Heart Disease, Vascular Medicine, Chronic Angina

Keywords: Mineralocorticoid Receptor Antagonists, Non-ST Elevated Myocardial Infarction, Spironolactone, ST Elevation Myocardial Infarction, AHA Annual Scientific Sessions, AHA24


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