Author + information
- Brent C. Lampert, DO and
- William T. Abraham, MD∗ ()
- Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio
- ↵∗Reprint requests and correspondence:
Dr. William T. Abraham, Ohio State University, Division of Cardiovascular Medicine, 473 West 12th Avenue, Room 110P DHLRI, Columbus, Ohio 43210-1252.
- aldosterone antagonism
- heart failure with preserved ejection fraction
- left ventricular filling pressure
Heart failure with preserved ejection fraction (HFpEF) represents one-half of all clinical heart failure cases (1). With an aging population, the incidence and prevalence of HFpEF is increasing, and its prognosis is worsening (1). In contrast to tremendous benefits seen in numerous clinical trials of neurohormonal antagonists for heart failure with reduced ejection fraction (HFrEF), major HFpEF trials have largely been neutral with regard to improving traditional primary outcomes such as cardiovascular death and heart failure hospitalizations. These disappointing trial results mirror the frustration patients and physicians have with HFpEF care. Just making a diagnosis of HFpEF can be challenging, with various criteria proposed to identify the HFpEF syndrome (2). Treatment of HFpEF also remains a conundrum, as the only strongly recommended guideline-based therapies are blood pressure control and diuretic agents to relieve symptoms of volume overload (3).
The complex heterogeneity of the HFpEF syndrome likely governs why attempts at widespread use of neurohumoral antagonists such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists in HFpEF trials have yet to demonstrate a mortality benefit. Although expert clinical investigators may consider mortality the paramount endpoint for heart failure trials (4), for the patient presenting to his or her physician with heart failure syndrome, symptom improvement often trumps longer survival (5). The primary manifestation and major determinant of impaired symptoms and quality of life in HFpEF remains exercise intolerance (6). Many patients with HFpEF are limited in their daily activities and unable to walk 1 or 2 blocks at a normal pace. This can be objectively measured as peak exercise oxygen consumption (VO2) during metabolic exercise testing, with the reduction in peak VO2 in HFpEF being similar in severity to that seen in HFrEF (6). Despite these functional capacity limitations and the importance of this clinical outcome to patients, it has received less attention as a meaningful endpoint in the search for effective HFpEF therapies.
In this issue of the Journal, Kosmala et al. (7) present the STRUCTURE (SpironolacTone in myocaRdial dysfUnCTion with redUced exeRcisE capacity) trial, which evaluated the effects of spironolactone on exercise capacity in patients with HFpEF with exercise-induced elevation of left ventricular filling pressures (LVFP). They hypothesized that an antifibrotic effect of spironolactone would reduce exercise-induced LVFP and improve exercise capacity in these patients. In this single-center trial, 131 subjects with HFpEF, New York Heart Association functional class II to III symptoms, and post-exercise ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e′) >13 (reflecting elevated LVFP during exertion) were analyzed after being randomized to 6 months of oral spironolactone 25 mg daily or placebo. At 6 months, patients receiving spironolactone had a significant 2.9 ml/min/kg improvement in their peak VO2. The spironolactone group also had significant improvements in exercise time, metabolic equivalents achieved, oxygen-uptake efficiency slope, anaerobic threshold, and respiratory exchange ratio. Follow-up echocardiographic imaging also showed significant improvements with spironolactone for exercise E/e′, left ventricular mass index, and left atrial volume index.
The STRUCTURE trial highlights some important clinical and research considerations for the management of HFpEF. The heterogeneous pathophysiology of the HFpEF syndrome demands a more nuanced approach to clinical investigation and medical therapy than in HFrEF, where neurohormonal inhibition has beneficial results regardless of the underlying etiology. By selecting patients with evidence of exercise-induced elevations of LVFP, the personalized treatment of HFpEF can be evaluated in a nontraditional way. Moreover, the use of exercise capacity as the primary outcome is an important concept that should carry more significance in future HFpEF trials, as exercise limitation is often severe in patients with HFpEF. The use of such patient-centered endpoints as exercise capacity and quality of life should be encouraged in HFpEF studies, where a generally elderly HFpEF population may be more concerned about improving functional status than prolonging survival. In this context, a therapy that makes patients with HFpEF feel better with a neutral effect on survival should be viewed as beneficial and should achieve a high level of recommendation in clinical practice guidelines.
Interestingly, 84% of the STRUCTURE trial patients were women. Although patients with HFpEF are more likely to be women (1), they are generally under-represented in clinical trials. The current work is an important step to ensure that clinical research accurately represents the patient population that it aims to benefit.
How might spironolactone have been effective in improving the exercise capacity of patients with HFpEF at 6 months? The authors postulate that antifibrotic effects of spironolactone could improve myocardial compliance resulting in improved exercise capacity. Could meaningful antifibrotic effects be achieved in only 6 months? No significant differences were noted in circulating galactin-3 at follow-up, and patients with higher galactin-3 levels at baseline (possibly reflecting more advanced fibrosis) had less response. The benefit demonstrated with spironolactone could have otherwise been due to its effect on blood pressure and volume control. Patients in the spironolactone group had mean 6.3- and 3.2-mm Hg decreases in resting systolic and diastolic blood pressure, respectively, at follow-up. These changes were not statistically significant when compared with placebo, but the question remains whether that would persist in a more robust sample. Only 15% of patients were on a loop diuretic agent at baseline, and resting E/e′ was significantly improved in the spironolactone group, suggesting overall improved volume control. Spironolactone may possess the unique benefits in HFpEF of decreasing fibrosis, lowering blood pressure, and improving volume status. Still, determining which of these mechanisms improves exercise capacity in HFpEF is important to guide patient selection and future research. It also determines whether modification of fibrosis with aldosterone antagonism represents a new therapeutic mechanism to provide significant benefit in HFpEF or whether we remain left with blood pressure and volume control as our only meaningful guidelines.
Despite the promise seen in the results of the STRUCTURE trial, excitement should be tempered. As the authors note, the small sample size and single-center recruitment affect the degree to which the findings can be generalized. Numerous medical therapies, including angiotensin receptor blockers (8), aldosterone antagonists (9), and sildenafil (10), have previously shown promise in small preliminary trials in HFpEF only to have no favorable signals when tested more rigorously. Among other factors, patients were excluded from the STRUCTURE trial if they had many of the other disease states commonly associated with HFpEF, such as atrial fibrillation or flutter, ischemic heart disease, moderate or greater valvular disease, and a serum creatinine >1.5 mg/dl. Despite strict exclusion criteria, only about one-half of the patients screened who complained of exercise intolerance and satisfied the exclusion criteria were actually included in the final analysis. Spironolactone may provide meaningful benefit to a select group of patients with HFpEF, but a tremendous need remains for more generalized effective strategies to improve HFpEF management.
What then can we conclude about the role of spironolactone in patients with HFpEF? Clearly, further work remains. The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial demonstrated that spironolactone can reduce heart failure hospitalizations (9), and in post hoc analysis, it had a mortality benefit in patients with HFpEF from the Americas (11). The STRUCTURE trial furthers the case for the use of spironolactone in HFpEF, but its improvements in functional capacity should be tested in larger, multicenter trials. Trials that test this hypothesis further should work to differentiate how much antifibrotic effects contribute to overall benefit compared with what we already know about improved blood pressure and volume control. Regardless of the mechanism, what patients want most from their doctors is to feel better. Future HFpEF studies in general should focus more on functional capacity (including exercise endpoints) and quality of life, rather than on morbidity and mortality alone, in the ongoing search for more effective therapies.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose. P.K. Shah, MD, served as Guest Editor for this paper.
- American College of Cardiology Foundation
- Vasan R.S.,
- Levy D.
- Yancy C.W.,
- Jessup M.,
- Bozkurt B.,
- et al.
- Kosmala W.,
- Rojek A.,
- Przewlocka-Kosmala M.,
- Wright L.,
- Mysiak A.,
- Marwick T.H.
- Pfeffer M.A.,
- Claggett B.,
- Assmann S.F.,
- et al.