TOPCAT Analysis: Spironolactone Benefits HFPEF in Americas

November 26, 2014

CHICAGO, IL — A new post hoc analysis of the TOPCAT trial of spironolactone in patients with heart failure with preserved ejection fraction (HFPEF) has shown that the aldosterone antagonist did appear to produce benefit in patients enrolled in the Americas but not in those from Russia/Georgia, which could be explained by large differences in baseline characteristics between the different populations[1].

The main results of the TOPCAT trial, as reported last year by heartwire , did not show a significant reduction in the primary outcome, a composite of cardiovascular death, aborted cardiac arrest, or hospitalization for heart failure, with spironolactone in the overall population. But an unusually large difference was identified in the placebo group primary event rate in different geographical areas, with this being much lower in patients from Russia and Georgia compared with those from the United States, Argentina, Brazil, and Canada (the Americas).

The current presentation, at last week's American Heart Association (AHA) 2014 Scientific Sessions, focused on exploring reasons for this difference and the differing effects of spironolactone in the two populations.

Did Patients Actually Have Heart Failure?

Lead investigator Dr Mark Pfeffer (Brigham and Women's Hospital, Boston, MA) reported that baseline characteristics were distinctly different between patients from the Americas and those from Russia/Georgia for almost every important variable, with patients from the Americas having a much higher-risk spectrum of characteristics. "The regional differences in almost every important baseline variable suggest that clinical diagnostic criteria were not uniformly interpreted or applied," he noted.

Although patients from Russia/Georgia had a higher rate of previous hospitalization for heart failure—one of the eligibility criteria for the trial, Pfeffer suggested that their much lower clinical event rate during the trial raises questions about whether these hospitalizations were actually for heart failure. He said the current observations showed that "making the assessment that the dyspnea and fatigue of a patient with a preserved ejection fraction are attributed to heart failure rather than to the commonly associated comorbidities is notoriously difficult."

He reported that in the population from the Americas, spironolactone was associated with an 18% reduction in the primary outcome; a 26% reduction in cardiovascular mortality, an 18% reduction in hospitalization for heart failure, and a 25% reduction in total HF-hospitalization events. "For none of these outcomes does the upper confidence interval exceed 1," he stated. In contrast, none of these outcomes were reduced in the population from Russia/Georgia.

In addition, spironolactone was also associated with much greater effects on blood pressure, potassium, and creatinine in the population from the Americas than those from Russia/Georgia.

Pfeffer concluded: "Yes, this is a post hoc analysis, but there are obviously differences in the populations from the Americas and those from Russia/Georgia. These include differences in their prognosis and in their response to spironolactone with regard to blood pressure, potassium, and creatinine, and the effect on clinical outcomes."

A Place for Spironolactone?

Referring to the fact that these observations came from a post hoc analysis, Pfeffer said: "I normally draw a line here, and I wouldn't cross this line if we had things to do for these patients."

But he added: "This is a growing part of the heart-failure syndrome. And if we have something that can help these 40% to 50% of people with symptomatic heart failure and an impaired prognosis—if we can improve their prognosis and take care of the safety measures—then I will go below this line by stating that our observations in the Americas—that spironolactone was associated with reduced CV deaths and hospitalizations for CHF—should be taken into account."

Discussant of the AHA presentation, Dr Judith Hochman (New York University School of Medicine, NY), was in agreement. She noted that the marked difference in numerous important patient characteristics, including age, diabetes, creatinine levels, and AF, all pointed to a higher-risk profile of patients from the Americas. "So we are dealing with different populations with more pathophysiology of HFPEF in the population from the Americas." She added: "Clearly the different response to spironolactone is likely due to patient differences."

Hochman noted that interpreting subgroups was always challenging and firm conclusions can never be drawn from post hoc analysis. "This was a negative trial overall. . . . This was a prespecified subgroup, but there were 15 subgroups, which increase the risks of chance findings."

But she argued: "On the flip side, there is mechanism to explain the differential—there was a physiologic response to spironolactone that paralleled the apparent outcome response."

More Data From CHARM-Preserved and I-PRESERVE

The TOPCAT paper was published online in Circulation to coincide with its presentation at the AHA.

To provide more information on this issue, another analysis by Dr John JV McMurray (University of Glasgow, Scotland) et al, also published online in Circulation[2], examines the data from two other HFPEF trials—the CHARM-Preserved trial with candesartan (Atacand, AstraZeneca) and the I-PRESERVE trial with irbesartan—and found a similar geographical disparity in outcomes (particularly HF hospitalization) between Eastern Europe and America. This persisted after adjustment for key baseline prognostic variables, which also differed by geographical region.

Hochman suggested that the data from these other trials reinforced the idea that HFPEF may be regarded as different entities in Eastern Europe and America and raises the question: "What proportion of patients in these studies did not truly have HFPEF?"

Hochman concludes that the entry criteria for future studies of this condition obviously need refinement, but that in the meantime "it is reasonable to try a mineralocorticoid-receptor antagonist for symptomatic HFPEF patients with anticipated risks similar to those enrolled in the Americas, which require careful monitoring of potassium and creatinine."

HF Hospitalization Misleading for Defining HFPEF

In an editorial accompanying the two reports in Circulation[3], Drs Patrick Rossignol and Faiez Zannad (INSERM, Nancy, France) emphasize that a history of heart-failure hospitalization, although frequently used to enrich event rates, is "obviously a very weak and possibly confounding criterion" when used to define HFPEF.

"The threshold for admitting patients for HF varies so much in different geographical areas that history of HF admission, especially when not adjudicated (which is the most common practical option), is misleading and should no longer be used in HFPEF trials with no other strong criteria such as natriuretic peptides," they conclude.

The TOPCAT trial was funded by the US National Heart, Lung, and Blood Institute. Pfeffer has received consulting fees from Aastrom, Abbott Vascular, Amgen, Cerenis, Concert, Daiichi Sankyo, Fibrogen, Genzyme, GlaxoSmithKline, Hamilton Health Sciences, Medtronic, Merck, Novo Nordisk, Roche, Salix, Sanderling, Sanofi, Serono, Servier, and Teva, as well as research grants from New England Research Institute via subcontract from the National Institutes of Health, Amgen, Celladon, Novartis, and Sanofi. The Brigham and Women's Hospital has patents for the use of inhibitors of the renin-angiotensin system in selected survivors of MI with Novartis Pharmaceuticals on which Pfeffer is a coinventor. His share of the licensing agreement is irrevocably transferred to charity. Disclosures for the coauthors are listed in the article. McMurray and coauthors report they have no relevant financial relationships. Rossignol is a consultant to Relypsa. Zannad is a consultant to Pfizer, Bayer, and Relypsa. Rossignol and Zannad are cofounders of CardioRenal Diagnostics .

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