- Email: [email protected]
If Exercise Is the Best Medicine, Should Medicine Be More Focused on Exercise in HFpEF?∗
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 68, NO. 17, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2016.08.014
EDITORIAL COMMENT
If Exercise Is the Best Medicine, Should Medicine Be More Focused on Exercise in HFpEF?* Brent C. Lampert, DO, William T. Abraham, MD
H
eart failure with preserved ejection fraction
presenting to his or her physician with heart failure
(HFpEF) represents one-half of all clinical
syndrome, symptom improvement often trumps
heart failure cases (1). With an aging popu-
longer survival (5). The primary manifestation and
lation, the incidence and prevalence of HFpEF is
major determinant of impaired symptoms and qual-
increasing, and its prognosis is worsening (1). In
ity of life in HFpEF remains exercise intolerance (6).
contrast to tremendous benefits seen in numerous
Many patients with HFpEF are limited in their daily
clinical trials of neurohormonal antagonists for heart
activities and unable to walk 1 or 2 blocks at a
failure with reduced ejection fraction (HFrEF), major
normal pace. This can be objectively measured as
HFpEF trials have largely been neutral with regard
peak exercise oxygen consumption (VO 2 ) during
to improving traditional primary outcomes such as
metabolic exercise testing, with the reduction in
cardiovascular death and heart failure hospitaliza-
peak VO 2 in HFpEF being similar in severity to that
tions. These disappointing trial results mirror the
seen in HFrEF (6). Despite these functional capacity
frustration patients and physicians have with HFpEF
limitations and the importance of this clinical
care. Just making a diagnosis of HFpEF can be chal-
outcome to patients, it has received less attention as
lenging, with various criteria proposed to identify
a meaningful endpoint in the search for effective
the HFpEF syndrome (2). Treatment of HFpEF also re-
HFpEF therapies.
mains a conundrum, as the only strongly recommen-
SEE PAGE 1823
ded guideline-based therapies are blood pressure control and diuretic agents to relieve symptoms of volume overload (3).
In this issue of the Journal, Kosmala et al. (7) present the STRUCTURE (SpironolacTone in myocaRdial
The complex heterogeneity of the HFpEF syn-
dysfUnCTion with redUced exeRcisE capacity) trial,
drome likely governs why attempts at widespread
which evaluated the effects of spironolactone on
use of neurohumoral antagonists such as beta-
exercise capacity in patients with HFpEF with
blockers, angiotensin-converting enzyme inhibitors,
exercise-induced elevation of left ventricular filling
angiotensin receptor blockers, and aldosterone an-
pressures (LVFP). They hypothesized that an an-
tagonists in HFpEF trials have yet to demonstrate a
tifibrotic effect of spironolactone would reduce
mortality
in-
exercise-induced LVFP and improve exercise capacity
vestigators may consider mortality the paramount
in these patients. In this single-center trial, 131 sub-
endpoint for heart failure trials (4), for the patient
jects with HFpEF, New York Heart Association func-
benefit.
Although
expert
clinical
tional class II to III symptoms, and post-exercise ratio between early mitral inflow velocity and mitral *Editorials published in the Journal of the American College of Cardiology
annular early diastolic velocity (E/e0 ) >13 (reflecting
reflect the views of the authors and do not necessarily represent the
elevated
views of JACC or the American College of Cardiology. From the Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio. Both authors have reported
LVFP
during
exertion)
were
analyzed
after being randomized to 6 months of oral spironolactone 25 mg daily or placebo. At 6 months,
that they have no relationships relevant to the contents of this paper to
patients receiving spironolactone had a significant
disclose. P.K. Shah, MD, served as Guest Editor for this paper.
2.9 ml/min/kg improvement in their peak VO2.
1836
Lampert and Abraham
JACC VOL. 68, NO. 17, 2016 OCTOBER 25, 2016:1835–7
Medicine for Exercise in HFpEF
The spironolactone group also had significant im-
blood pressure, respectively, at follow-up. These
provements in exercise time, metabolic equivalents
changes were not statistically significant when
achieved, oxygen-uptake efficiency slope, anaerobic
compared with placebo, but the question remains
threshold, and respiratory exchange ratio. Follow-up
whether that would persist in a more robust sample.
echocardiographic imaging also showed significant
Only 15% of patients were on a loop diuretic agent at
improvements with spironolactone for exercise E/e 0 ,
baseline, and resting E/e0 was significantly improved
left ventricular mass index, and left atrial volume
in the spironolactone group, suggesting overall
index.
improved
volume
control.
Spironolactone
may
The STRUCTURE trial highlights some important
possess the unique benefits in HFpEF of decreasing
clinical and research considerations for the manage-
fibrosis, lowering blood pressure, and improving
ment of HFpEF. The heterogeneous pathophysiology
volume status. Still, determining which of these
of the HFpEF syndrome demands a more nuanced
mechanisms improves exercise capacity in HFpEF is
approach to clinical investigation and medical ther-
important to guide patient selection and future
apy than in HFrEF, where neurohormonal inhibition
research. It also determines whether modification of
has beneficial results regardless of the underlying
fibrosis with aldosterone antagonism represents a
etiology. By selecting patients with evidence of
new therapeutic mechanism to provide significant
exercise-induced elevations of LVFP, the personal-
benefit in HFpEF or whether we remain left with
ized treatment of HFpEF can be evaluated in a
blood pressure and volume control as our only
nontraditional way. Moreover, the use of exercise
meaningful guidelines.
capacity as the primary outcome is an important
Despite the promise seen in the results of the
concept that should carry more significance in future
STRUCTURE trial, excitement should be tempered. As
HFpEF trials, as exercise limitation is often severe
the authors note, the small sample size and single-
in patients with HFpEF. The use of such patient-
center recruitment affect the degree to which the
centered endpoints as exercise capacity and quality
findings can be generalized. Numerous medical
of life should be encouraged in HFpEF studies, where
therapies, including angiotensin receptor blockers
a generally elderly HFpEF population may be more
(8), aldosterone antagonists (9), and sildenafil (10),
concerned about improving functional status than
have previously shown promise in small preliminary
prolonging survival. In this context, a therapy that
trials in HFpEF only to have no favorable signals
makes patients with HFpEF feel better with a neutral
when tested more rigorously. Among other factors,
effect on survival should be viewed as beneficial and
patients were excluded from the STRUCTURE trial if
should achieve a high level of recommendation in
they had many of the other disease states commonly
clinical practice guidelines.
associated with HFpEF, such as atrial fibrillation or
Interestingly, 84% of the STRUCTURE trial patients
flutter, ischemic heart disease, moderate or greater
were women. Although patients with HFpEF are more
valvular disease, and a serum creatinine >1.5 mg/dl.
likely to be women (1), they are generally under-
Despite strict exclusion criteria, only about one-half
represented in clinical trials. The current work is an
of the patients screened who complained of exercise
important step to ensure that clinical research accu-
intolerance and satisfied the exclusion criteria were
rately represents the patient population that it aims
actually included in the final analysis. Spironolactone
to benefit.
may provide meaningful benefit to a select group of
How might spironolactone have been effective in
patients with HFpEF, but a tremendous need remains
improving the exercise capacity of patients with
for more generalized effective strategies to improve
HFpEF at 6 months? The authors postulate that
HFpEF management.
antifibrotic effects of spironolactone could improve
What then can we conclude about the role of spi-
myocardial compliance resulting in improved exer-
ronolactone in patients with HFpEF? Clearly, further
cise capacity. Could meaningful antifibrotic effects be
work remains. The TOPCAT (Treatment of Preserved
achieved in only 6 months? No significant differences
Cardiac Function Heart Failure with an Aldosterone
were noted in circulating galactin-3 at follow-up, and
Antagonist) trial demonstrated that spironolactone
patients with higher galactin-3 levels at baseline
can reduce heart failure hospitalizations (9), and in
(possibly reflecting more advanced fibrosis) had
post hoc analysis, it had a mortality benefit in pa-
less response. The benefit demonstrated with spi-
tients with HFpEF from the Americas (11). The
ronolactone could have otherwise been due to its ef-
STRUCTURE trial furthers the case for the use of
fect on blood pressure and volume control. Patients
spironolactone in HFpEF, but its improvements in
in the spironolactone group had mean 6.3- and
functional capacity should be tested in larger, multi-
3.2-mm Hg decreases in resting systolic and diastolic
center trials. Trials that test this hypothesis further
Lampert and Abraham
JACC VOL. 68, NO. 17, 2016 OCTOBER 25, 2016:1835–7
Medicine for Exercise in HFpEF
should work to differentiate how much antifibrotic
morbidity and mortality alone, in the ongoing search
effects contribute to overall benefit compared with
for more effective therapies.
what we already know about improved blood pressure and volume control. Regardless of the mecha-
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
nism, what patients want most from their doctors
William T. Abraham, Ohio State University, Division
is to feel better. Future HFpEF studies in general
of Cardiovascular Medicine, 473 West 12th Avenue,
should focus more on functional capacity (including
Room 110P DHLRI, Columbus, Ohio 43210-1252.
exercise endpoints) and quality of life, rather than on
E-mail: [email protected].
REFERENCES 1. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355:251–9.
5. Stanek EJ, Oates MB, McGhan WF, et al. Preferences for treatment outcomes in patients with heart failure: symptoms versus survival. J Card Fail 2000;6:225–32.
2. Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation 2000;101:2118–21.
6. Kitzman DW, Little WC, Brubaker PH, et al. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–50.
3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of
7. Kosmala W, Rojek A, Przewlocka-Kosmala M, Wright L, Mysiak A, Marwick TH. Effect of
9. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383–92. 10. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013;309:1268–77.
the American College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 2013;62:1495–539.
aldosterone antagonism on exercise tolerance in heart failure with preserved ejection fraction. J Am Coll Cardiol 2016;68:1823–34.
11. Pfeffer MA, Claggett B, Assmann SF, 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.
4. Zannad F, Garcia AA, Anker SD, et al. Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Associa-
8. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection
KEY WORDS aldosterone antagonism,
tion consensus document. Eur J Heart Fail 2013;15: 1082–94.
fraction: the CHARM-Preserved Trial. Lancet 2003;362:777–81.
echocardiography, heart failure with preserved ejection fraction, left ventricular filling pressure
1837
VOL. 68, NO. 17, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2016.08.014
EDITORIAL COMMENT
If Exercise Is the Best Medicine, Should Medicine Be More Focused on Exercise in HFpEF?* Brent C. Lampert, DO, William T. Abraham, MD
H
eart failure with preserved ejection fraction
presenting to his or her physician with heart failure
(HFpEF) represents one-half of all clinical
syndrome, symptom improvement often trumps
heart failure cases (1). With an aging popu-
longer survival (5). The primary manifestation and
lation, the incidence and prevalence of HFpEF is
major determinant of impaired symptoms and qual-
increasing, and its prognosis is worsening (1). In
ity of life in HFpEF remains exercise intolerance (6).
contrast to tremendous benefits seen in numerous
Many patients with HFpEF are limited in their daily
clinical trials of neurohormonal antagonists for heart
activities and unable to walk 1 or 2 blocks at a
failure with reduced ejection fraction (HFrEF), major
normal pace. This can be objectively measured as
HFpEF trials have largely been neutral with regard
peak exercise oxygen consumption (VO 2 ) during
to improving traditional primary outcomes such as
metabolic exercise testing, with the reduction in
cardiovascular death and heart failure hospitaliza-
peak VO 2 in HFpEF being similar in severity to that
tions. These disappointing trial results mirror the
seen in HFrEF (6). Despite these functional capacity
frustration patients and physicians have with HFpEF
limitations and the importance of this clinical
care. Just making a diagnosis of HFpEF can be chal-
outcome to patients, it has received less attention as
lenging, with various criteria proposed to identify
a meaningful endpoint in the search for effective
the HFpEF syndrome (2). Treatment of HFpEF also re-
HFpEF therapies.
mains a conundrum, as the only strongly recommen-
SEE PAGE 1823
ded guideline-based therapies are blood pressure control and diuretic agents to relieve symptoms of volume overload (3).
In this issue of the Journal, Kosmala et al. (7) present the STRUCTURE (SpironolacTone in myocaRdial
The complex heterogeneity of the HFpEF syn-
dysfUnCTion with redUced exeRcisE capacity) trial,
drome likely governs why attempts at widespread
which evaluated the effects of spironolactone on
use of neurohumoral antagonists such as beta-
exercise capacity in patients with HFpEF with
blockers, angiotensin-converting enzyme inhibitors,
exercise-induced elevation of left ventricular filling
angiotensin receptor blockers, and aldosterone an-
pressures (LVFP). They hypothesized that an an-
tagonists in HFpEF trials have yet to demonstrate a
tifibrotic effect of spironolactone would reduce
mortality
in-
exercise-induced LVFP and improve exercise capacity
vestigators may consider mortality the paramount
in these patients. In this single-center trial, 131 sub-
endpoint for heart failure trials (4), for the patient
jects with HFpEF, New York Heart Association func-
benefit.
Although
expert
clinical
tional class II to III symptoms, and post-exercise ratio between early mitral inflow velocity and mitral *Editorials published in the Journal of the American College of Cardiology
annular early diastolic velocity (E/e0 ) >13 (reflecting
reflect the views of the authors and do not necessarily represent the
elevated
views of JACC or the American College of Cardiology. From the Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio. Both authors have reported
LVFP
during
exertion)
were
analyzed
after being randomized to 6 months of oral spironolactone 25 mg daily or placebo. At 6 months,
that they have no relationships relevant to the contents of this paper to
patients receiving spironolactone had a significant
disclose. P.K. Shah, MD, served as Guest Editor for this paper.
2.9 ml/min/kg improvement in their peak VO2.
1836
Lampert and Abraham
JACC VOL. 68, NO. 17, 2016 OCTOBER 25, 2016:1835–7
Medicine for Exercise in HFpEF
The spironolactone group also had significant im-
blood pressure, respectively, at follow-up. These
provements in exercise time, metabolic equivalents
changes were not statistically significant when
achieved, oxygen-uptake efficiency slope, anaerobic
compared with placebo, but the question remains
threshold, and respiratory exchange ratio. Follow-up
whether that would persist in a more robust sample.
echocardiographic imaging also showed significant
Only 15% of patients were on a loop diuretic agent at
improvements with spironolactone for exercise E/e 0 ,
baseline, and resting E/e0 was significantly improved
left ventricular mass index, and left atrial volume
in the spironolactone group, suggesting overall
index.
improved
volume
control.
Spironolactone
may
The STRUCTURE trial highlights some important
possess the unique benefits in HFpEF of decreasing
clinical and research considerations for the manage-
fibrosis, lowering blood pressure, and improving
ment of HFpEF. The heterogeneous pathophysiology
volume status. Still, determining which of these
of the HFpEF syndrome demands a more nuanced
mechanisms improves exercise capacity in HFpEF is
approach to clinical investigation and medical ther-
important to guide patient selection and future
apy than in HFrEF, where neurohormonal inhibition
research. It also determines whether modification of
has beneficial results regardless of the underlying
fibrosis with aldosterone antagonism represents a
etiology. By selecting patients with evidence of
new therapeutic mechanism to provide significant
exercise-induced elevations of LVFP, the personal-
benefit in HFpEF or whether we remain left with
ized treatment of HFpEF can be evaluated in a
blood pressure and volume control as our only
nontraditional way. Moreover, the use of exercise
meaningful guidelines.
capacity as the primary outcome is an important
Despite the promise seen in the results of the
concept that should carry more significance in future
STRUCTURE trial, excitement should be tempered. As
HFpEF trials, as exercise limitation is often severe
the authors note, the small sample size and single-
in patients with HFpEF. The use of such patient-
center recruitment affect the degree to which the
centered endpoints as exercise capacity and quality
findings can be generalized. Numerous medical
of life should be encouraged in HFpEF studies, where
therapies, including angiotensin receptor blockers
a generally elderly HFpEF population may be more
(8), aldosterone antagonists (9), and sildenafil (10),
concerned about improving functional status than
have previously shown promise in small preliminary
prolonging survival. In this context, a therapy that
trials in HFpEF only to have no favorable signals
makes patients with HFpEF feel better with a neutral
when tested more rigorously. Among other factors,
effect on survival should be viewed as beneficial and
patients were excluded from the STRUCTURE trial if
should achieve a high level of recommendation in
they had many of the other disease states commonly
clinical practice guidelines.
associated with HFpEF, such as atrial fibrillation or
Interestingly, 84% of the STRUCTURE trial patients
flutter, ischemic heart disease, moderate or greater
were women. Although patients with HFpEF are more
valvular disease, and a serum creatinine >1.5 mg/dl.
likely to be women (1), they are generally under-
Despite strict exclusion criteria, only about one-half
represented in clinical trials. The current work is an
of the patients screened who complained of exercise
important step to ensure that clinical research accu-
intolerance and satisfied the exclusion criteria were
rately represents the patient population that it aims
actually included in the final analysis. Spironolactone
to benefit.
may provide meaningful benefit to a select group of
How might spironolactone have been effective in
patients with HFpEF, but a tremendous need remains
improving the exercise capacity of patients with
for more generalized effective strategies to improve
HFpEF at 6 months? The authors postulate that
HFpEF management.
antifibrotic effects of spironolactone could improve
What then can we conclude about the role of spi-
myocardial compliance resulting in improved exer-
ronolactone in patients with HFpEF? Clearly, further
cise capacity. Could meaningful antifibrotic effects be
work remains. The TOPCAT (Treatment of Preserved
achieved in only 6 months? No significant differences
Cardiac Function Heart Failure with an Aldosterone
were noted in circulating galactin-3 at follow-up, and
Antagonist) trial demonstrated that spironolactone
patients with higher galactin-3 levels at baseline
can reduce heart failure hospitalizations (9), and in
(possibly reflecting more advanced fibrosis) had
post hoc analysis, it had a mortality benefit in pa-
less response. The benefit demonstrated with spi-
tients with HFpEF from the Americas (11). The
ronolactone could have otherwise been due to its ef-
STRUCTURE trial furthers the case for the use of
fect on blood pressure and volume control. Patients
spironolactone in HFpEF, but its improvements in
in the spironolactone group had mean 6.3- and
functional capacity should be tested in larger, multi-
3.2-mm Hg decreases in resting systolic and diastolic
center trials. Trials that test this hypothesis further
Lampert and Abraham
JACC VOL. 68, NO. 17, 2016 OCTOBER 25, 2016:1835–7
Medicine for Exercise in HFpEF
should work to differentiate how much antifibrotic
morbidity and mortality alone, in the ongoing search
effects contribute to overall benefit compared with
for more effective therapies.
what we already know about improved blood pressure and volume control. Regardless of the mecha-
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
nism, what patients want most from their doctors
William T. Abraham, Ohio State University, Division
is to feel better. Future HFpEF studies in general
of Cardiovascular Medicine, 473 West 12th Avenue,
should focus more on functional capacity (including
Room 110P DHLRI, Columbus, Ohio 43210-1252.
exercise endpoints) and quality of life, rather than on
E-mail: [email protected].
REFERENCES 1. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355:251–9.
5. Stanek EJ, Oates MB, McGhan WF, et al. Preferences for treatment outcomes in patients with heart failure: symptoms versus survival. J Card Fail 2000;6:225–32.
2. Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation 2000;101:2118–21.
6. Kitzman DW, Little WC, Brubaker PH, et al. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 2002;288:2144–50.
3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of
7. Kosmala W, Rojek A, Przewlocka-Kosmala M, Wright L, Mysiak A, Marwick TH. Effect of
9. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383–92. 10. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013;309:1268–77.
the American College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 2013;62:1495–539.
aldosterone antagonism on exercise tolerance in heart failure with preserved ejection fraction. J Am Coll Cardiol 2016;68:1823–34.
11. Pfeffer MA, Claggett B, Assmann SF, 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.
4. Zannad F, Garcia AA, Anker SD, et al. Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Associa-
8. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection
KEY WORDS aldosterone antagonism,
tion consensus document. Eur J Heart Fail 2013;15: 1082–94.
fraction: the CHARM-Preserved Trial. Lancet 2003;362:777–81.
echocardiography, heart failure with preserved ejection fraction, left ventricular filling pressure
1837