CLEAR SYNERGY: Can routine spironolactone improve post-MI outcomes?

Routine spironolactone after myocardial infarction (MI) did not reduce cardiovascular adverse events in the CLEAR SYNERGY (OASIS 9) trial.

Prof. Sanjit Jolly (McMaster University, Canada) and colleagues evaluated whether routine spironolactone could reduce cardiovascular adverse events among patients with ST-elevation MI (STEMI) or large non-STEMI [1,2]. The international CLEAR SYNERGY trial (NCT03048825) with a 2-by-2 factorial design randomised 7,602 participants who underwent percutaneous coronary intervention (PCI) 1:1 to spironolactone, 25 mg daily, or placebo within 72 hours of the procedure. Both groups were then further randomised to receive either colchicine or placebo.

The primary endpoints were a composite of cardiovascular death or new or worsening heart failure (HF), evaluated as the total number of events, and a composite of the first occurrence of cardiovascular death, MI, stroke, or new or worsening HF. Prof. Jolly presented the results of the spironolactone and matching placebo groups [2].

After a total of 403 events, no significant differences were seen between the study arms in the first primary endpoint (HR 0.89; 95% CI 0.73–1.08; P=0.23). The authors did see a trend towards a reduction in new or worsening HF in the spironolactone arm compared with the placebo arm (1.6% vs 2.4%; HR 0.69; 95% CI 0.49–0.96). “Since the primary endpoint was not met, this is only explorative information,” clarified Prof. Jolly.

The on-treatment analysis displayed a treatment effect in the first (1.5% vs 2.0%; HR 0.79; 95% CI 0.63–1.00; P=0.047) and second primary endpoint (5.8% vs 7.2%; HR 0.83; 95% CI 0.69–1.00; P=0.046). Prof. Jolly mentioned that although the serious adverse event rates were comparable (7.2% vs 6.8%), they observed higher rates of hyperkalaemia leading to study drug continuation (1.1% vs 0.05%; P=0.01) and gynecomastia (2.3% vs 0.5%; P<0.001) in the experimental arm.

“Post-MI outcomes have improved remarkably over the last 20 years, which may explain why it is so difficult to show an effect of an additional drug in this population,” argued Prof. Jolly.

“The event rates were very low in the CLEAR SYNERGY study,” said discussant Prof. Marc Bonaca (University of Colorado, CO, USA). “This is probably due to the fact that all patients were treated with primary PCI, less than 1% had a Killip class of 2 or greater or a history of HF, and the provided medical therapy was excellent. These low event rates make it difficult to show an incremental benefit of a novel therapy.” Moreover, Prof. Bonaca mentioned that the trial may have been underpowered to observe a benefit of the magnitude that was seen in prior studies of MRAs, such as the EPHESUS trial, which showed a benefit for eplerenone in higher risk patient but with a similar relative risk reductions [3].

1. 
   
   1. Jolly SS, et al. N Engl J Med 2024; Nov 17. DOI:10.1056/NEJMoa2405923.
   2. Jolly SS, et al. Routine spironolactone in acute myocardial infarction, results from the CLEAR SYNERGY (OASIS 9) trial. LBS.04, AHA Scientific Sessions 2024, 16–18 November, Chicago, USA.
   3. Pitt B, et al. N Engl J Med 2003;348:1309-1321.

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Posted on 3 February 2025