The routine administration of spironolactone to patients after a myocardial infarction (MI) did not reduce either of the coprimary outcomes in the CLEAR SYNERGY (OASIS 9) trial.
However, there was a suggestion that the mineralocorticoid receptor antagonist may reduce new or worsening heart failure. And although the trial had a high rate of study-drug discontinuation, an on-treatment analysis suggested a benefit of spironolactone on both coprimary outcomes.
“This on-treatment analysis has to be considered as exploratory and hypothesis generating, but the drug discontinuations in this trial were higher than we expected,” said Sanjit Jolly, MD, professor of medicine at McMaster University in Hamilton, Ontario, Canada, and lead investigator of the CLEAR SYNERGY trial.
“That’s when the on-treatment analysis becomes more important,” he reported during his presentation of the spironolactone results at the American Heart Association (AHA) Scientific Sessions in Chicago, which were simultaneously published online in the New England Journal of Medicine.
“I think a more tolerable drug, perhaps finerenone, might have a better chance of showing an effect,” he added.
Another important issue is that this was a modern acute MI trial, so there was very good background medical therapy, Jolly pointed out. “Over the last 20 years, outcomes after MI have improved remarkably, and the event rate was lower than expected in this trial, which makes it more challenging to show a difference with a new drug,” he said.
CLEAR SYNERGY, OASIS 9 Trial
The trial had a 2 × 2 factorial design and also investigated the effect of colchicine, an anti-inflammatory agent, in the same population. The results of this arm of the trial, presented at the recent Transcatheter Cardiovascular Therapeutics meeting, showed no benefit with colchicine.
For patients with acute MI with heart failure, eplerenone, a related mineralocorticoid receptor antagonist, was shown to be beneficial in the EPHESUS trial, with a 15% reduction in mortality.
“What is unclear is whether these agents will also be beneficial in acute MI patients who do not have heart failure. That is the question the CLEAR SYNERGY trial was trying to answer,” Jolly said.
The 7062 study participants, who had acute MI and had undergone primary percutaneous coronary intervention, were randomized to receive either spironolactone or placebo and either colchicine or placebo, in accordance with the 2 × 2 factorial design.
For the spironolactone group, there were two primary outcomes: a composite of cardiovascular death and new or worsening heart failure, evaluated as the total number of events; and a composite of the first occurrence of MI, stroke, new or worsening heart failure, and cardiovascular death.
For the first primary outcome, there were 183 events (1.7 per 100 patient-years) in the spironolactone group and 220 events (2.1 per 100 patient-years) in the placebo group over a median follow-up period of 3 years (hazard ratio [HR], 0.91; 95% CI, 0.69-1.21; P=.51).
For the second primary outcome, an event occurred in 280 of 3537 patients (7.9%) in the spironolactone group and 294 of 3525 patients (8.3%) in the placebo group (HR, 0.96; 95% CI, 0.81-1.13; P=.60).
New or worsening heart failure was reduced by about a third in the spironolactone group, which was statistically significant (1.6% vs 2.4%; HR, 0.69; 95% CI, 0.49-0.96).
Serious adverse events were reported in 255 patients (7.2%) in the spironolactone group and 241 (6.8%) in the placebo group. Hyperkalemia (serum potassium> 5.5 mmol/L) leading to discontinuation of the study drug was more common in the spironolactone group than in the placebo group (1.1% vs 0.6%), as was gynecomastia (2.3% vs 0.5%).
The on-treatment analysis for the first primary outcome assessed 131 events (1.5 per 100 patient-years) in the spironolactone group and 179 events (2.0 per 100 patient-years) in the placebo group (HR, 0.79; 95% CI, 0.63-1.00).
The second primary outcome occurred in 204 patients (5.8%) in the spironolactone group and 250 (7.2%) in the placebo group (HR, 0.83; 95% CI, 0.69-1.00).
The on-treatment analysis showed a reduction in new or worsening heart failure similar to that in the intention-to-treat analysis.
Benefit in Preventing Heart Failure?
It is important to note that most of the patients in this trial had an ST elevation myocardial infarction (STEMI) with very little left ventricular dysfunction or heart failure at presentation, said Roxana Mehran, MD, from the Mount Sinai School of Medicine, New York City, during an AHA press conference. And although the intention-to-treat analyses were completely negative, there was “an incredibly low number of events in the trial, which will have impacted the ability to show any difference.”
Referring to the benefit suggested in the on-treatment analysis, Mehran pointed out that “when you have a negative study, it’s hard to look into that, but it makes sense when you also consider the reduced new or worsening heart failure. I think that’s something to be taken away from this trial.”
An interesting finding here is that spironolactone may be beneficial in reducing new or worsening heart failure in patients presenting with a STEMI, she added. “But more granular data are needed to identify which patients might benefit the most.”
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