Solomon SD, Claggett B, Lewis EF, et al, for the TOPCAT Investigators
Eur Heart J 2016 37: 455-462

Background

Trials in patients with heart failure with preserved ejection fraction (HFpEF) have used different definitions of the condition, ranging from >40% to >55% [1,2]. Thus, these studies have included patients with left ventricular ejection fraction (LVEF) below the normal range.
In HF with reduced EF (HFrEF), EF is an important predictor of outcomes, but it is less prognostic when higher than 40-45% [3,4]. To date, no benefit with any therapy has been demonstrated in clinical outcome trials for HFpEF [5]. It is unclear if the effectiveness of therapies for HFpEF is affected by LVEF.
The TOPCAT trial evaluating the mineralocorticoid receptor antagonist (MRA) spironolactone included HFpEF patients with LVEF>45% [6]. Treatment with spironolactone was associated with reduced hospitalisation for HF (HFH), but did not reduce the primary outcome of HFH, CV death or aborted cardiac arrest [7].
This analysis aimed to establish whether the efficacy of spironolactone was different in the prespecified subgroups of LVEF above or below 50%. LVEF at baseline was available in 3444 patients. Median LVEF was 56% (IQR: 51, 61%) and the range was 44 to 85%. Four EF categories were defined: <50 (n=520), 50–54.9 (n=712), 55–59.9 (n=879), and >60% (n=1333).

Main results

• Differences in baseline characteristics were seen between LVEF categories. For instance, patients in higher EF categories were older, more often female, less likely to have a history of myocardial infarction and they more often had a history of hypertension and diabetes. NYHA functional class did not differ by EF.
• After adjustment for baseline covariates, CV death showed a pattern where the incidence declined rapidly until an LVEF of ~55%. HFH did not vary by EF after correction for baseline covariates.
• A significant interaction between LVEF as continuous variable and treatment (P=0.046) was seen for the primary endpoint. HR for treatment effects ranged from 0.72 (95%CI: 0.50-1.05) in the lowest EF category to 0.97 (95%CI: 0.76-1.23) in the highest EF group.
• HFH also showed a significant interaction between continuous LVEF and treatment (P=0.039), with HRs for treatment effect ranging from 0.76 (95%CI: 0.46-1.27) to 0.98 (95%CI: 0.74-1.30), with the lowest 3 categories largely overlapping.
• No significant continuous LVEF*treatment interactions were seen for CV death (P=0.61) and death (P=0.99).

Conclusion

These analyses in LVEF-based HFpEF subgroups from TOPCAT show large differences in baseline characteristics between HFpEF patients with different LVEFs in the preserved range.
The data suggest that patients with LVEF at the lower end of the spectrum may benefit from treatment with spironolactone in reducing the primary endpoint and in HF hospitalisation. Patients with LVEF >65% derive minimal benefit from the MRA. Although overall in TOPCAT, no benefit was seen, these findings suggest that the potential benefit of spironolactone in HFpEF, if any, may be greatest in those in whom the pathophysiology resembles HFrEF.

Editorial comment [8]

Previously, studies have defined HFpEF using various EF values, ranging from 40% to 55%. This likely resulted in significant mechanistic heterogeneity. It would be helpful to determine the “optimal EF partition value that allows us to categorize HF patients into more homogenous groups that display similar pathophysiologies, natural histories, and responses to treatment”.
The current analysis contributes to “understanding of how even minor differences in EF may reflect more fundamental differences in underlying pathophysiology”. The different characteristics in participants with higher vs. lower EF mirror those observed previously in comparisons of HFpEF and HFrEF. “These results strongly support what has long been suspected—that people with mildly depressed EF are probably best categorized and treated as if they had HFrEF”. (…) “these data certainly support 50% as the better choice than 40% or even 45%. That finding alone has impact and value.” (…)
“Benefits from RAAS antagonists in HFrEF seem to relate to how effectively they elicit reverse remodelling, and perhaps the lack of chamber dilatation in HFpEF makes this group less responsive to agents that reduce ventricular size.” Trial data to date suggest that RAAS activation is not as central in HFpEF. There may be other primary unifying abnormalities that can be targeted. We need to make an effort to find those.

Find this article online at Eur Heart J

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