- Email: [email protected]
Does Lowering Heart Rate Improve Outcomes in Children With Dilated Cardiomyopathy and Chronic Heart Failure?∗
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 70, NO. 10, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2017.07.749
EDITORIAL COMMENT
Does Lowering Heart Rate Improve Outcomes in Children With Dilated Cardiomyopathy and Chronic Heart Failure?* Steven E. Lipshultz, MD,a,b Paul R. Barach, MD, MPH,a James D. Wilkinson, MD, MPHa,b
T
he paper by Bonnet et al. (1) in this issue of
secondary endpoint, quality-of-life scores, improved
the Journal describes the results of a clinical
slightly in the treatment group, but the improvement
trial of ivabradine, a drug that lowers heart
was not statistically significant. The quality-of-life
rate by inhibiting the funny channel, a mechanism
metric is useful because patient-reported outcomes
different from that of calcium-channel blockers or
are increasingly considered to be as important as clin-
beta-blockers.
age-
ical responses (2). The trial design and analysis were
stratified, double-blind, placebo-controlled trial stud-
robust, and the investigators appropriately inter-
This
multisite,
randomized,
ied 116 children with dilated cardiomyopathy and
preted the results. This study is a significant addition
chronic heart failure and followed them for 12 months
to the few clinical trials of drugs for treating heart failure in this population.
SEE PAGE 1262
One of the only similar studies is a randomized,
(1). Most children were concomitantly receiving 1 or
multicenter, multidose trial of carvedilol in 161 chil-
more heart failure drugs, including angiotensin-
dren with symptomatic heart failure and LV ejection
converting
beta-
fractions <40% (3). The primary efficacy endpoint
receptor
was a composite of the following: death; hospitali-
antagonists. The proportion of children taking any
zation for heart failure; change in heart failure class;
of these drugs did not differ by treatment group.
treatment failure; or administrative reasons, such as
Briefly, the ivabradine group was substantially more
withdrawal
likely to reach the primary endpoint of a 20% reduc-
included LV echocardiographic measurements and
tion in heart rate than was the placebo group at
serum B-type natriuretic peptide plasma concentra-
12 months. The secondary, echocardiographic end-
tions. The groups did not differ in the primary clinical
points of left ventricular (LV) fractional shortening
composite endpoint, although LV fractional short-
and LV end-systolic volume at 12 months also
ening improved somewhat in the treatment groups.
blockers,
enzyme digitalis,
inhibitors, and
diuretics,
angiotensin
II
improved markedly in the ivabradine group. Another
of
consent.
Secondary
endpoints
Similarly, the adverse event profiles did not differ between groups. Both the ivabradine study and the carvedilol study have improved our knowledge of
*Editorials published in the Journal of the American College of Cardiology
treating heart failure in children, but the fact that
reflect the views of the author and do not necessarily represent the views
perhaps only 2 such trials have been completed in the
of JACC or the American College of Cardiology.
past 11 years highlights the challenges of conducting
From the Department of Pediatrics, Wayne State University School of
such
Medicine, Detroit, Michigan; and the bChildren’s Hospital of Michigan,
funding.
a
Detroit, Michigan. Drs. Lipshultz and Wilkinson have received funding from Amgen for a descriptive pediatric heart failure study not involving ivabradine or any other pharmaceutical agent. Dr. Barach has reported
trials,
including
research
complexity
and
One of the major challenges to conducting trials in children with dilated cardiomyopathy and heart fail-
that he has no relationships relevant to the contents of this paper to
ure is the number of eligible patients. The estimated
disclose.
incidence of dilated cardiomyopathy in children is
1274
Lipshultz et al.
JACC VOL. 70, NO. 10, 2017 SEPTEMBER 5, 2017:1273–5
Improving Outcomes in Children With Heart Failure
0.50 cases per 100,000 children per year, with
dilated cardiomyopathy and heart failure. However,
approximately 70% of these children presenting with
extended sustained follow-up periods are needed to
heart failure (4). Several reports estimate that,
validate these endpoints and should be part of future
annually in the United States, between 12,000 and
trials.
35,000 children <19 years of age with congenital
In 2013, the National Heart, Blood, and Lung
cardiomyopathy
Institute (NHLBI) published a report titled, “New
have heart failure. (5) In the current study, 116 chil-
Targets for Pediatric Heart Failure” (14) that included
dren were enrolled at 47 pediatric heart centers in 16
6 recommendations for research in this area: 1) create
countries. The enrollment data from the multisite
new paradigms for pediatric heart failure, including
carvedilol trial were similar. These sample sizes are
“avoiding
about one-tenth of the size of those in trials of ivab-
research”; 2) focus research on molecular mecha-
cardiovascular
malformations
or
hand-me-down
dogma
from
adult
radine or similar agents in adults (6,7), thus empha-
nisms of specific relevance to pediatric heart failure;
sizing the challenges of conducting robust trials and
3) encourage collaboration among those studying and
considering their external generalizability in a small
treating heart failure to augment existing resources,
population of children with a common phenotype but
including developing a national pediatric heart fail-
of multiple causes.
ure registry; 4) expand existing phenotype registries
Another challenge to conducting trials in children
and databases; 5) develop surrogate endpoints rele-
with heart failure is selecting appropriate endpoints.
vant to pediatric heart failure; and 6) create industry
Methods for selecting and interpreting study end-
partnerships, including leveraging regulatory oppor-
points in the evaluation of policy and service in-
tunities, such as the U.S. Food and Drug Administra-
terventions remain contested (8). In children with
tion’s Orphan Disease program and their pediatric
idiopathic or familial dilated cardiomyopathy, most
exclusivity patent extension program. When imple-
of the important clinical events, death or heart
mented fully, these recommendations could address
transplantation, occur within 24 months after diag-
many of the challenges of conducting clinical trials of
nosis (9). The time-to-event curves for events beyond
pediatric heart failure, as exemplified by the current
24 months are nearly flat. Therefore, in contrast to
ivabradine study.
studies in adults, using such “hard” endpoints in
A better framework for and a better approach to
trials of children with chronic heart failure will not
treating children with heart failure are needed,
likely detect improved efficacy, and so these end-
including a consensus on common diagnostic defini-
points
tions and ensuring their widespread and consistent
are
probably
not
appropriate
for
this
population.
use by providers, regulators, insurers, and policy
The third challenge to investigators conducting
makers. The first step in implementing the “new
trials in these children is to identify validated surro-
paradigm” recommended in the NHLBI report noted
gate endpoints. Many studies of these children have
earlier is for stakeholders to distinguish children with
tested the utility of serum biomarkers, imaging
dilated cardiomyopathy and heart failure from adults
studies, and disease severity as surrogate endpoints.
with these conditions, given that the disease in each
Although such endpoints have been proven useful for
age group has distinct causes, clinical courses, out-
risk stratification, none has been validated as a pre-
comes, and research needs. Such a distinction would
dictive proxy surrogate for “hard” clinical endpoints
ensure that pediatric cardiomyopathy and heart fail-
in this population (9,10). The 2 exceptions are
ure meet the National Institutes of Health’s definition
elevated concentrations of N-terminal pro-brain
of rare “orphan” diseases (affecting <200,000 per-
natriuretic peptide (a marker of cardiomyopathy and
sons in the United States), which would open funding
heart failure) and cardiac troponin T (a marker of
opportunities for industry sponsors, as well as pro-
myocardial injury) in children with cancer who are
moting clinical trials of children with these condi-
receiving chemotherapy including anthracyclines.
tions to test efficacy and safety of treatments (15).
Both are validated surrogate endpoints for patholog-
These conditions also affect families and commu-
ical cardiac changes for $5 years after the end of
nities, factors that should be included in developing
chemotherapy (11). We have also validated echocar-
trial-specific aims, methods, outcomes, and may
diographic measurements of LV structure and func-
enable a better understanding of their clinical impli-
tion as predictive of subsequent clinical outcome in
cations (2).
children with dilated cardiomyopathy who are infec-
In summary, this report highlights both the
ted with human immunodeficiency virus (12,13).
importance of clinical trials for studying heart failure
These studies emphasize the need to validate surro-
in children and the challenges in doing so. In this
gate endpoints in other populations of children with
randomized trial of children with heart failure by
Lipshultz et al.
JACC VOL. 70, NO. 10, 2017 SEPTEMBER 5, 2017:1273–5
Improving Outcomes in Children With Heart Failure
Bonnet et al. (1), ivabradine lowered heart rate to the desired level. Of course, the larger question remains
ADDRESS FOR CORRESPONDENCE: Dr. Steven E.
unanswered: whether ivabradine, beyond heart rate
Lipshultz, Department of Pediatrics, Wayne State
reduction, is associated with sustained improved
University School of Medicine, 3901 Beaubien Boule-
outcomes for children with dilated cardiomyopathy
vard, Pediatric Administration, T121A, Detroit, Mich-
and heart failure.
igan 48201. E-mail: [email protected].
REFERENCES 1. Bonnet D, Berger F, Jokinen E, Kantor PF, Daubeney PEF. Ivabradine in children with dilated cardiomyopathy and symptomatic chronic heart
7. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
12. Lipshultz SE, Easley KA, Orav EJ, et al., for the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV
failure. J Am Coll Cardiol 2017;70:1262–72.
Lancet 2010;376:875–85.
2. Sleeper LA, Towbin JA, Colan SD, et al. Healthrelated quality of life and functional status are associated with cardiac status and clinical
8. Lilford R, Chilton PJ, Hemming K, Brown C,
Infection Study Group. Cardiac dysfunction and mortality in HIV-infected children: the prospective P2C2 HIV Multicenter Study. Circulation 2000;102:1542–8.
outcome in children with J Pediatr 2016;170:173–80.
cardiomyopathy.
3. Shaddy RE, Boucek MM, Hsu DT, et al. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA 2007; 298:1171–9.
Girling A, Barach P. Evaluating policy and service interventions: framework to guide selection and interpretation of study end points. BMJ 2010;341: c4413. 9. Alvarez JA, Orav EJ, Wilkinson JD, et al. Competing risks for death and cardiac transplantation in children with dilated cardiomyopathy: results from the Pediatric Cardiomyopathy
4. Lipshultz SE, Sleeper LA, Towbin JA, et al. The incidence of pediatric cardiomyopathy in two regions of the United States. N Engl J Med 2003;
Registry. Circulation 2011;124:814–23.
348:1647–55.
opathy in children. JAMA 2006;296:1867–76.
5. Hsu D, Pearson G. Heart failure in children part I: history, etiology, and pathophysiology. Circ Heart Fail 2009;2:63–70. 6. Gidding SS. The importance of randomized controlled trial in pediatric cardiology. JAMA 2007;298:1214–6.
10. Towbin JA, Lowe AM, Colan SD, et al. Incidence, causes and outcomes of dilated cardiomy-
11. Lipshultz SE, Miller TL, Scully RE, et al. Changes in cardiac biomarkers during doxorubicin treatment of patients with high-risk acute lymphoblastic leukemia: associations with longterm echocardiographic outcomes. J Clin Oncol 2012;30:1042–9.
13. Fisher SD, Easley KA, Orav EJ, et al. Mild dilated cardiomyopathy and increased left ventricular mass predict mortality: the prospective P2C2 HIV Multicenter Study. Am Heart J 2005;150: 439–47. 14. Redington AN, Towbin JA, for the NHLBI Working Group. New Targets for Pediatric Heart Failure. Available at: https://www.nhlbi.nih. gov/research/reports/2013-pediatric-heart-failure. Accessed July 12, 2017. 15. Rare Diseases Clinical Research Network. Available at: https://report.nih.gov/NIHfactsheets/View FactSheet.aspx?csid¼126. Accessed July 12, 2017.
KEY WORDS children, heart failure, heart rate, ivabradine
1275
VOL. 70, NO. 10, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2017.07.749
EDITORIAL COMMENT
Does Lowering Heart Rate Improve Outcomes in Children With Dilated Cardiomyopathy and Chronic Heart Failure?* Steven E. Lipshultz, MD,a,b Paul R. Barach, MD, MPH,a James D. Wilkinson, MD, MPHa,b
T
he paper by Bonnet et al. (1) in this issue of
secondary endpoint, quality-of-life scores, improved
the Journal describes the results of a clinical
slightly in the treatment group, but the improvement
trial of ivabradine, a drug that lowers heart
was not statistically significant. The quality-of-life
rate by inhibiting the funny channel, a mechanism
metric is useful because patient-reported outcomes
different from that of calcium-channel blockers or
are increasingly considered to be as important as clin-
beta-blockers.
age-
ical responses (2). The trial design and analysis were
stratified, double-blind, placebo-controlled trial stud-
robust, and the investigators appropriately inter-
This
multisite,
randomized,
ied 116 children with dilated cardiomyopathy and
preted the results. This study is a significant addition
chronic heart failure and followed them for 12 months
to the few clinical trials of drugs for treating heart failure in this population.
SEE PAGE 1262
One of the only similar studies is a randomized,
(1). Most children were concomitantly receiving 1 or
multicenter, multidose trial of carvedilol in 161 chil-
more heart failure drugs, including angiotensin-
dren with symptomatic heart failure and LV ejection
converting
beta-
fractions <40% (3). The primary efficacy endpoint
receptor
was a composite of the following: death; hospitali-
antagonists. The proportion of children taking any
zation for heart failure; change in heart failure class;
of these drugs did not differ by treatment group.
treatment failure; or administrative reasons, such as
Briefly, the ivabradine group was substantially more
withdrawal
likely to reach the primary endpoint of a 20% reduc-
included LV echocardiographic measurements and
tion in heart rate than was the placebo group at
serum B-type natriuretic peptide plasma concentra-
12 months. The secondary, echocardiographic end-
tions. The groups did not differ in the primary clinical
points of left ventricular (LV) fractional shortening
composite endpoint, although LV fractional short-
and LV end-systolic volume at 12 months also
ening improved somewhat in the treatment groups.
blockers,
enzyme digitalis,
inhibitors, and
diuretics,
angiotensin
II
improved markedly in the ivabradine group. Another
of
consent.
Secondary
endpoints
Similarly, the adverse event profiles did not differ between groups. Both the ivabradine study and the carvedilol study have improved our knowledge of
*Editorials published in the Journal of the American College of Cardiology
treating heart failure in children, but the fact that
reflect the views of the author and do not necessarily represent the views
perhaps only 2 such trials have been completed in the
of JACC or the American College of Cardiology.
past 11 years highlights the challenges of conducting
From the Department of Pediatrics, Wayne State University School of
such
Medicine, Detroit, Michigan; and the bChildren’s Hospital of Michigan,
funding.
a
Detroit, Michigan. Drs. Lipshultz and Wilkinson have received funding from Amgen for a descriptive pediatric heart failure study not involving ivabradine or any other pharmaceutical agent. Dr. Barach has reported
trials,
including
research
complexity
and
One of the major challenges to conducting trials in children with dilated cardiomyopathy and heart fail-
that he has no relationships relevant to the contents of this paper to
ure is the number of eligible patients. The estimated
disclose.
incidence of dilated cardiomyopathy in children is
1274
Lipshultz et al.
JACC VOL. 70, NO. 10, 2017 SEPTEMBER 5, 2017:1273–5
Improving Outcomes in Children With Heart Failure
0.50 cases per 100,000 children per year, with
dilated cardiomyopathy and heart failure. However,
approximately 70% of these children presenting with
extended sustained follow-up periods are needed to
heart failure (4). Several reports estimate that,
validate these endpoints and should be part of future
annually in the United States, between 12,000 and
trials.
35,000 children <19 years of age with congenital
In 2013, the National Heart, Blood, and Lung
cardiomyopathy
Institute (NHLBI) published a report titled, “New
have heart failure. (5) In the current study, 116 chil-
Targets for Pediatric Heart Failure” (14) that included
dren were enrolled at 47 pediatric heart centers in 16
6 recommendations for research in this area: 1) create
countries. The enrollment data from the multisite
new paradigms for pediatric heart failure, including
carvedilol trial were similar. These sample sizes are
“avoiding
about one-tenth of the size of those in trials of ivab-
research”; 2) focus research on molecular mecha-
cardiovascular
malformations
or
hand-me-down
dogma
from
adult
radine or similar agents in adults (6,7), thus empha-
nisms of specific relevance to pediatric heart failure;
sizing the challenges of conducting robust trials and
3) encourage collaboration among those studying and
considering their external generalizability in a small
treating heart failure to augment existing resources,
population of children with a common phenotype but
including developing a national pediatric heart fail-
of multiple causes.
ure registry; 4) expand existing phenotype registries
Another challenge to conducting trials in children
and databases; 5) develop surrogate endpoints rele-
with heart failure is selecting appropriate endpoints.
vant to pediatric heart failure; and 6) create industry
Methods for selecting and interpreting study end-
partnerships, including leveraging regulatory oppor-
points in the evaluation of policy and service in-
tunities, such as the U.S. Food and Drug Administra-
terventions remain contested (8). In children with
tion’s Orphan Disease program and their pediatric
idiopathic or familial dilated cardiomyopathy, most
exclusivity patent extension program. When imple-
of the important clinical events, death or heart
mented fully, these recommendations could address
transplantation, occur within 24 months after diag-
many of the challenges of conducting clinical trials of
nosis (9). The time-to-event curves for events beyond
pediatric heart failure, as exemplified by the current
24 months are nearly flat. Therefore, in contrast to
ivabradine study.
studies in adults, using such “hard” endpoints in
A better framework for and a better approach to
trials of children with chronic heart failure will not
treating children with heart failure are needed,
likely detect improved efficacy, and so these end-
including a consensus on common diagnostic defini-
points
tions and ensuring their widespread and consistent
are
probably
not
appropriate
for
this
population.
use by providers, regulators, insurers, and policy
The third challenge to investigators conducting
makers. The first step in implementing the “new
trials in these children is to identify validated surro-
paradigm” recommended in the NHLBI report noted
gate endpoints. Many studies of these children have
earlier is for stakeholders to distinguish children with
tested the utility of serum biomarkers, imaging
dilated cardiomyopathy and heart failure from adults
studies, and disease severity as surrogate endpoints.
with these conditions, given that the disease in each
Although such endpoints have been proven useful for
age group has distinct causes, clinical courses, out-
risk stratification, none has been validated as a pre-
comes, and research needs. Such a distinction would
dictive proxy surrogate for “hard” clinical endpoints
ensure that pediatric cardiomyopathy and heart fail-
in this population (9,10). The 2 exceptions are
ure meet the National Institutes of Health’s definition
elevated concentrations of N-terminal pro-brain
of rare “orphan” diseases (affecting <200,000 per-
natriuretic peptide (a marker of cardiomyopathy and
sons in the United States), which would open funding
heart failure) and cardiac troponin T (a marker of
opportunities for industry sponsors, as well as pro-
myocardial injury) in children with cancer who are
moting clinical trials of children with these condi-
receiving chemotherapy including anthracyclines.
tions to test efficacy and safety of treatments (15).
Both are validated surrogate endpoints for patholog-
These conditions also affect families and commu-
ical cardiac changes for $5 years after the end of
nities, factors that should be included in developing
chemotherapy (11). We have also validated echocar-
trial-specific aims, methods, outcomes, and may
diographic measurements of LV structure and func-
enable a better understanding of their clinical impli-
tion as predictive of subsequent clinical outcome in
cations (2).
children with dilated cardiomyopathy who are infec-
In summary, this report highlights both the
ted with human immunodeficiency virus (12,13).
importance of clinical trials for studying heart failure
These studies emphasize the need to validate surro-
in children and the challenges in doing so. In this
gate endpoints in other populations of children with
randomized trial of children with heart failure by
Lipshultz et al.
JACC VOL. 70, NO. 10, 2017 SEPTEMBER 5, 2017:1273–5
Improving Outcomes in Children With Heart Failure
Bonnet et al. (1), ivabradine lowered heart rate to the desired level. Of course, the larger question remains
ADDRESS FOR CORRESPONDENCE: Dr. Steven E.
unanswered: whether ivabradine, beyond heart rate
Lipshultz, Department of Pediatrics, Wayne State
reduction, is associated with sustained improved
University School of Medicine, 3901 Beaubien Boule-
outcomes for children with dilated cardiomyopathy
vard, Pediatric Administration, T121A, Detroit, Mich-
and heart failure.
igan 48201. E-mail: [email protected].
REFERENCES 1. Bonnet D, Berger F, Jokinen E, Kantor PF, Daubeney PEF. Ivabradine in children with dilated cardiomyopathy and symptomatic chronic heart
7. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
12. Lipshultz SE, Easley KA, Orav EJ, et al., for the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV
failure. J Am Coll Cardiol 2017;70:1262–72.
Lancet 2010;376:875–85.
2. Sleeper LA, Towbin JA, Colan SD, et al. Healthrelated quality of life and functional status are associated with cardiac status and clinical
8. Lilford R, Chilton PJ, Hemming K, Brown C,
Infection Study Group. Cardiac dysfunction and mortality in HIV-infected children: the prospective P2C2 HIV Multicenter Study. Circulation 2000;102:1542–8.
outcome in children with J Pediatr 2016;170:173–80.
cardiomyopathy.
3. Shaddy RE, Boucek MM, Hsu DT, et al. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA 2007; 298:1171–9.
Girling A, Barach P. Evaluating policy and service interventions: framework to guide selection and interpretation of study end points. BMJ 2010;341: c4413. 9. Alvarez JA, Orav EJ, Wilkinson JD, et al. Competing risks for death and cardiac transplantation in children with dilated cardiomyopathy: results from the Pediatric Cardiomyopathy
4. Lipshultz SE, Sleeper LA, Towbin JA, et al. The incidence of pediatric cardiomyopathy in two regions of the United States. N Engl J Med 2003;
Registry. Circulation 2011;124:814–23.
348:1647–55.
opathy in children. JAMA 2006;296:1867–76.
5. Hsu D, Pearson G. Heart failure in children part I: history, etiology, and pathophysiology. Circ Heart Fail 2009;2:63–70. 6. Gidding SS. The importance of randomized controlled trial in pediatric cardiology. JAMA 2007;298:1214–6.
10. Towbin JA, Lowe AM, Colan SD, et al. Incidence, causes and outcomes of dilated cardiomy-
11. Lipshultz SE, Miller TL, Scully RE, et al. Changes in cardiac biomarkers during doxorubicin treatment of patients with high-risk acute lymphoblastic leukemia: associations with longterm echocardiographic outcomes. J Clin Oncol 2012;30:1042–9.
13. Fisher SD, Easley KA, Orav EJ, et al. Mild dilated cardiomyopathy and increased left ventricular mass predict mortality: the prospective P2C2 HIV Multicenter Study. Am Heart J 2005;150: 439–47. 14. Redington AN, Towbin JA, for the NHLBI Working Group. New Targets for Pediatric Heart Failure. Available at: https://www.nhlbi.nih. gov/research/reports/2013-pediatric-heart-failure. Accessed July 12, 2017. 15. Rare Diseases Clinical Research Network. Available at: https://report.nih.gov/NIHfactsheets/View FactSheet.aspx?csid¼126. Accessed July 12, 2017.
KEY WORDS children, heart failure, heart rate, ivabradine
1275