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DALLAS -- The TOPCAT trial evaluating spironolactone (Aldactone) in patients with heart failure and preserved ejection fraction did not meet its primary endpoint, but there was some evidence of benefit, a researcher reported here.

Through an average follow-up of 3.3 years, the rate of cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization was 18.6% in the spironolactone group and 20.4% in the placebo group (hazard ratio 0.89, 95% CI 0.77-1.04), according to , of Brigham and Women's Hospital in Boston.

The rate of heart failure hospitalization was, however, significantly reduced in the spironolactone group (12% versus 14.2%, HR 0.83, 95% CI 0.69-0.99), with no differences in the other components of the primary endpoint, he reported at the American Heart Association meeting.

"We did not achieve a reduction in our primary endpoint. For the purist, that's the message," Pfeffer said in an interview. "But we have to take care of these patients."

He said physicians will have to choose whether the reduction in heart failure hospitalization is enough to justify using spironolactone in these patients, in whom there are no proven treatments.

"I think they'll look carefully at our data and many will adopt that as an approach," Pfeffer said. "And others will say, 'Not enough for me,' and I would understand both sides."

If a physician did choose to use spironolactone, he said, "we also show how it can be safely done by monitoring potassium and creatinine and using a low dose."

, of the Mayo Clinic in Rochester, Minn., who was not involved in the study, said that "if a patient has another indication for a mineralocorticoid receptor antagonist -- hypertension, coronary disease -- definitely that specific [heart failure with preserved ejection fraction] patient should ... be treated with spironolactone."

"I would be tempted to take high-risk patients with very high [B-type natriuretic peptide and] lots of comorbidities that would suggest high oxidative stress and treat them, but the evidence is not really there," she added. "So I still think we need more studies."

, a cardiologist at Scott & White Hospital in Texas, commented that "based on these results, spironolactone should be used cautiously in the [heart failure with preserved ejection fraction] population. The reduction in heart failure hospitalizations is intriguing, but, by itself, may not be enough of a result to justify routine use in this population or to elevate aldosterone inhibition to 'Class I' in future guidelines."

Mineralocorticoid receptor antagonists like spironolactone have been shown to be beneficial in heart failure with reduced ejection fraction, but that hasn't been translated into patients with reduced ejection fraction, Pfeffer said.

Spironolactone was previously evaluated in the latter population in the 422-patient Aldo-DHF trial, which showed that the drug significantly improved left ventricular diastolic function but not exercise capacity, the two co-primary endpoints. There were no effects on heart failure symptoms, quality of life, or hospitalization rate.

The , which was conducted at 270 centers in six countries, evaluated the use of spironolactone in a larger population of patients with heart failure and preserved ejection fraction -- 3,445 enrolled from the U.S., Canada, Brazil, Argentina, Russia, and the Republic of Georgia.

All of the patients had symptomatic heart failure and a left ventricular ejection fraction of at least 45% (median 56%) and were enrolled on the basis of either a heart failure hospitalization in the past year (71.5%) or elevated natriuretic peptide levels (28.5%). They were randomized to placebo or spironolactone with a target dose of 30 mg daily.

The overall clinical outcome was no different between the two groups, although heart failure hospitalizations were lower in the spironolactone group.

The findings were consistent in 21 out of 22 prespecified subgroups, with a significant interaction between the reason for enrollment in the trial and spironolactone's effect on the primary endpoint (P=0.013). There was a significant benefit seen in the patients who were enrolled based on elevated natriuretic peptide levels, but not among those enrolled based on a recent heart failure hospitalization.

The percentage of patients who reported a serious adverse event was similar in the two groups -- 48.5% with spironolactone and 49.6% with placebo -- but patients treated with spironolactone were more likely to develop hyperkalemia (18.7% versus 9.1%, P<0.001) detected by a monitoring system the investigators had in place.

The spironolactone-treated patients also had an increased risk of having an elevation in creatinine of at least double the upper limit of normal (HR 1.49, 95% CI 1.18-1.87), but not an increased risk of needing dialysis (1.1% versus 1.9%).

The increases in potassium and creatinine are known risks associated with spironolactone, Redfield said.

"You've got to monitor the patients very carefully, and if you don't have the disease management system to do that, then you shouldn't use it or you can cause more harm than good," Redfield said. "But heart failure clinics use spironolactone all the time and they monitor their patients very carefully."

A post hoc analysis revealed a disparity in outcomes between the centers in North and South America and those in Eastern Europe. In the U.S., Canada, Brazil, and Argentina -- where the rate of the primary composite outcome was 31.8% in the placebo group -- spironolactone had a significant benefit (HR 0.82, 95% CI 0.69-0.98).

In Russia and the Republic of Georgia -- where the primary outcome occurred in only 8.4% of patients taking placebo -- spironolactone did not have any effect (HR 1.10, 95% CI 0.79-1.51).

"We feel that the event rate in the Americas is more reflective of the burden these patients feel," Pfeffer said.

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