By Van Selby, MD
Assistant Professor of Medicine, University of California - San Francisco, Cardiology Division, Advanced Heart Failure Section
Dr. Selby reports no financial relationships relevant to this field of study.
SOURCE: Pfeffer M, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation 2015;131:34-42.
To date, no treatment has been shown to improve outcomes in heart failure with preserved ejection fraction (HFPEF). The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial randomized patients with symptomatic heart failure, LV ejection fraction ≥ 45%, and either a heart failure-related hospitalization in the previous 12 months or an elevated serum brain natriuretic peptide to spironolactone or placebo. Spironolactone failed to demonstrate a significant impact on the primary outcome of cardiovascular death, aborted cardiac arrest, or hospitalization for heart failure. Post-hoc analyses found substantial differences between the groups enrolled from Russia/Georgia and those enrolled from the Americas (United States, Argentina, Brazil, and Canada). To better understand these differences, Pfeffer and colleagues compared the baseline characteristics, prognosis, and response to spironolactone between the two regions.
The authors found significant regional differences in nearly every important baseline variable. Patients from the Americas represented a higher-risk cohort, with a primary event rate of 12.6 events per 100 patient years in the Americas compared to an event rate of 2.3 per 100 patient years in Russia/Georgia (P < 0.01). The primary event rate among patients from the Americas was similar to what has been previously reported in trials of patients with HFPEF, while the event rate in patients from Russia/Georgia was multifold lower. Patients from the Americas who were randomized to spironolactone also had significantly greater risk of hyperkalemia, rise in serum creatinine, and decrease in blood pressure compared to those from Russia/Georgia.
Along with baseline differences, there was marked regional variation in the effect of spironolactone. In the Americas, spironolactone was associated with a significant reduction in the primary endpoint (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.69-0.98), whereas subjects from Russia/Georgia saw no difference (HR, 1.10; 95% CI, 0.79-1.51). In the Americas, spironolactone was also associated with significant reductions in both cardiovascular death and hospitalization for heart failure. The authors acknowledge the general limitations of post-hoc analyses, but conclude that in the absence of stronger data, these findings may be informative to clinicians treating HFPEF in North America.
COMMENTARY
Large clinical trials have identified multiple therapies with clear, meaningful benefit for patients with heart failure and reduced ejection fraction, with an associated improvement in prognosis. For the half of heart failure patients with preserved ejection fraction, finding effective therapies has proven much more elusive, and current guidelines for the treatment of HFPEF are sparse. The reasons for this are multifactorial. Diagnostic uncertainty is one reason, and probably explains much of the observed variation in baseline characteristics identified in this analysis. Other reasons include substantial heterogeneity in both the phenotype and pathophysiology of HFPEF.
Renin angiotensin aldosterone system (RAAS) inhibition, a fundamental component of therapy for heart failure with reduced ejection fraction, has now been evaluated in three trials of patients with HFPEF (CHARM-Preserved, I-PRESERVE, and TOPCAT). None demonstrated clear benefit. The findings of Pfeffer and colleagues challenge these negative findings, and renew hope for RAAS inhibition in the treatment of HFPEF. Furthermore, this study provides crucial guidance for the design of future trials in patients with HFPEF, and emphasizes the challenge and importance of identifying patients with true HFPEF as opposed to those with dyspnea due to other causes.
Secondary analyses must be interpreted with caution. TOPCAT was a negative trial, and the regional comparison was one of 15 prespecified subgroups. Subgroup testing increases the risk of chance findings, and results are generally considered hypothesis-generating rather than conclusive. That said, this analysis deserves further consideration for several reasons, and may influence the clinical management of patients with HFPEF in the Americas. First, the authors found a clear mechanism to explain the observed difference in benefit from spironolactone. The observed characteristics and event rates in Russia/Georgia suggest that many of the enrolled patients may not have had HFPEF as it is generally defined in the Americas. Subjects in the Americas also had a markedly different physiologic response to spironolactone, with greater effect on blood pressure, serum potassium, and creatinine. Taken together, it is easy to argue the observed differences were due to more than just chance.
The second reason Pfeffer’s findings may influence management is the complete absence of alternative therapies to treat HFPEF. Despite the caveats of secondary analyses, physicians may see spironolactone as preferable to doing nothing for these high-risk patients. At the American Heart Association annual scientific sessions in November, many heart failure experts commented that they plan to use spironolactone in the management of HFPEF, and it will be interesting to see how these findings are addressed in future guidelines. In deciding to treat HFPEF with spironolactone, it is important to make sure the patient has an anticipated risk profile similar to those enrolled from the Americas.
No treatment has been shown to improve outcomes in heart failure with preserved ejection fraction.
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