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. However, the on-treatment analysis suggested that the study drug may have a benefit for the population.

Prof. Sanjit Jolly (McMaster University, Canada) and colleagues evaluated whether routine spironolactone was able to reduce cardiovascular adverse events among patients with ST-elevation MI (STEMI) or large non-STEMI. The international CLEAR SYNERGY trial (NCT03048825) with a 2x2 factorial design randomised 7,602 patients who underwent percutaneous coronary intervention (PCI) 1:1 to 25 mg daily spironolactone or placebo within 72 hours of the procedure [1,2]. Both groups were then further randomised to receive colchicine or placebo.

The primary endpoints were a composite of cardiovascular death or new or worsening heart failure, evaluated as the total number of events, and a composite of the first occurrence of cardiovascular death, MI, stroke, or new or worsening heart failure. 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 heart failure 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 on 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 at the end of his presentation.

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.

Medical writing support was provided by Robert van den Heuvel.
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Posted on 19 November 2024