TOPCAT: Spironolactone effectiveness differed by region

CHICAGO — A post-hoc analysis of the TOPCAT trial indicated regional differences in outcomes and responses associated with the use of spironolactone in patients with HF and preserved ejection fraction.

Among those studied, patients from the United States, Argentina, Brazil and Canada showed a better response to spironolactone compared with patients from the Republic of Georgia and Russia, Marc A. Pfeffer, MD, PhD, FACEP, FAHA, the Dzau professor of medicine at Harvard University Medical School and the cardiovascular division of Brigham & Women’s Hospital, said at the American Heart Association Scientific Sessions.

Marc A. Pfeffer

Pfeffer reported a fourfold difference between patients in the Americas and patients in Eastern Europe in the event rate for the primary composite outcome of time to CV death, aborted cardiac arrest or hospitalization for HF. Among those assigned placebo, 31% in the Americas experienced the primary outcome (12.6 events per 100 patient-years) vs. 8.4% in Russia and Georgia (2.3 events per 100 patient-years).

“The magnitude of this is what led us to do some additional analyses,” Pfeffer said.

Further analysis

A demographic analysis revealed that patients in the Americas and patients in Georgia and Russia had significant differences in 34 of 38 baseline characteristics. However, the analysis yielded “no particular pattern of higher or lower risk,” Pfeffer said. Within those regions, the baseline characteristics were balanced between the groups assigned spironolactone or placebo, Pfeffer said.

Compared with patients from the Americas, those from Georgia and Russia were younger; had less atrial fibrillation; had less diabetes; were more likely to have had a prior MI; were more likely to have been hospitalized for HF; had lower left ventricular ejection fraction; had lower creatinine; and had higher diastolic BP (P<.001 for all).

Patients in the Americas assigned spironolactone were more likely to have hyperkalemia (OR=3.46; 95% CI, 2.62-4.56) and doubling of creatinine (HR=1.6; 95% CI, 1.25-2.05) and less likely to have hypokalemia (OR=0.51; 95% CI, 0.4-0.64) compared with those in the Americans assigned placebo. The researchers observed no significant treatment effects in patients in Georgia and Russia.

At 1 year, assignment to spironolactone was associated with a decline in systolic BP of –4.2 mm Hg in the Americas, but a decline of only –0.6 mm Hg in Georgia and Russia, (P<.001), Pfeffer said.

Irrespective of treatment, patients in the Americas were more likely than those in Georgia and Russia to experience the primary outcome, CV mortality, hospitalization for HF or all-cause mortality (P<.001 for all), he said.

Spironolactone was associated with a lower rate of the primary outcome in patients from the Americas (HR=0.82; 95% CI, 0.69-0.98), but not in those from Russia and Georgia (HR=1.1; 95% CI, 0.79-1.51). Pfeffer noted that the results for the Americas were driven by CV mortality and hospitalization for HF.

Use in the Americas

“We had differences in the patient populations, differences in their prognosis, and major differences in their response to spironolactone, whether it be potassium changes, creatinine or BP,” Pfeffer said. “I probably would not cross this line if we had things to do for these patients, but this is a growing and frustrating part of the HF syndrome. If we have something that will help [the estimated] 40% to 50% of people with symptomatic HF and an impaired prognosis, if we could improve their prognosis, especially if we take care about these safety measures, then I do [state] that in our observations in the Americas, spironolactone was associated with reduced CV death as well as hospitalizations for HF, and that should be taken into account.” – by Erik Swain

For more information:

Pfeffer MA. CS.01: Update on Randomized Trials. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.

Pfeffer MA. Circulation. 2014;doi:10.1161/CIRCULATIONAHA.114.013255.

Disclosure: The study was funded by the NHLBI. Pfeffer reports consulting for Aastrom, Abbott Vascular, Amgen, Cerenis, Concert, Daiichi Sankyo, Fibrogen, Genzyme, GlaxoSmithKline, Hamilton Health Sciences, Medtronic, Merck, Novo Nordisk, Roche, Salix, Sanderling, Sanofi Aventis, Serono, Servier and Teva; research grants from New England Research Institute via subcontract from the NIH, Amgen, Celladon, Novartis, and Sanofi-Aventis; and being a co-inventor on a patent held by Brigham and Women’s Hospital and licensed to Novartis, for which his share is transferred to charity.