JACC: HEART FAILURE
VOL. 3, NO. 3, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 2213-1779/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jchf.2014.12.007
EDITORIAL COMMENT
How Many Patients Will Benefit From a New Therapy for Chronic Systolic Heart Failure, and What Difference Does it Make?* Jeffrey S. Borer, MD
T
he importance of heart rate lowering in opti-
evaluation specifically of the benefit of heart rate
mizing natural history among patients with
reduction, separate from other pharmacological ef-
chronic systolic heart failure (HF) has been
fects. Ivabradine seems to have only 1 action on the
increasingly clear for 15 years, certainly at least since
cardiovascular system, that of blocking f-channels in
Kjekshus and Gullestad reported a cross-sectional
sinoatrial nodal cells, thereby reducing or eliminating
analysis of the HF mortality trials then completed (1).
the small f-current (I f) generated across these chan-
This assessment revealed that placebo-subtracted
nels. Physiologically, this current increases heart rate
mortality changes among the trials were directly pro-
by increasing the slope of spontaneous sinoatrial dia-
portional to placebo-subtracted heart rate changes.
stolic depolarization (itself a function of ion movement
This relationship was most strongly influenced by
through calcium and potassium channels). Adminis-
the trials of beta-blocking drugs by then available,
tration of ivabradine enables rigorous testing of the
but extended to non–beta-blockers as well. Subse-
hypothesis that heart rate lowering, alone, provides
quent meta-regression analyses confirmed these find-
important benefit to patients with systolic HF. This
ings (2,3) and further indicated that the mortality
hypothesis is highly plausible: the “mechanism” of
benefit was highly significantly related to heart rate
such benefit is not fully understood, but it is known
reduction, but not at all to beta-blocker dose (2).
that in the failing myocardium, high-energy substrates
However, the beta-blocker trials were based on hy-
are relatively deficient; increasing heart rate increases
potheses about the net effect of all beta-blocker phar-
demand for this resource while decreasing the
macological actions, in addition to heart rate slowing,
myocardial perfusion that could help to replenish it.
which might, in theory, improve myocardial function;
Consistent with this putative mechanism, increasing
no target heart rates were developed for use of the
the frequency of electrical stimulation of isolated
drugs. The relatively recent availability of ivabradine,
papillary muscle strips from the hearts of humans with
a “pure” heart rate–slowing drug, has allowed
New York Heart Association functional class IV HF results in progressively diminishing contractile force, whereas similarly stimulating normal human papillary
*Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology. From the Division of Cardiovascular Medicine, The Howard Gilman Institute for Heart Valve Disease, and the Schiavone Institute for Car-
muscle strips increases contractile force (4). With this background, SHIFT (Systolic Heart failure treatment with the I f inhibitor ivabradine Trial) was designed to test the hypothesis that heart rate lowering in
diovascular Translational Research, State University of New York
addition to that achievable with beta-blockade, and on
Downstate Medical Center, Brooklyn and New York, New York. Dr. Borer
a
is a consultant to Servier Laboratoires, the manufacturer of ivabradine,
other drugs now routinely applied in chronic systolic
and Amgen, Inc., the American licensee of the drug; and has received honoraria/fees not related to ivabradine from Novartis, Celladon, Armgo,
background
of
evidence-based
doses
of
the
HF, would diminish the frequency of either cardio-
Pfizer, Cardiorentis, Salix, Takeda USA, Celgene, Boehringer Ingelheim,
vascular death or hospitalizations for worsening
Somahlution, Sanofi, and JenaValve.
HF (the primary pre-specified composite endpoint)
232
Borer
JACC: HEART FAILURE VOL. 3, NO. 3, 2015 MARCH 2015:231–3
Ivabradine: How Many Will Benefit?
among patients with moderate-to-severe symptoms,
and so on), thus suggesting that the drug will be pre-
left ventricular ejection fraction #35% and heart rate at
scribed in many patients whose heart rate could
rest $70 beats/min (5). The trial was highly positive,
be lowered with higher beta-blocker doses alone but
demonstrating an 18% reduction of the primary com-
who cannot tolerate such dose increases.
posite endpoint compared with placebo, 26% reduc-
The Dierckx et al. (8) data differ from those of recent
tion in HF hospitalizations, and 26% reduction in
large multicenter registries noted in the preceding text
death attributable specifically to HF. Importantly, by
that indicate a larger proportion of patients with sys-
virtue of the study design, benefit only could be
tolic HF whose heart rates are not optimally controlled
inferred in patients whose heart rate, for whatever
despite current therapy. (Moreover, the SHIFT data
reason (drug intolerance, adverse drug effects,
suggest that optimal outcomes require achievement of
insensitivity to drugs, and so on) could not be low-
heart rates #60 beats/min [12], though this is not yet
ered to 70 beats/min (or, according to the European
altering therapy now exists), that many already had
labeling instructions, >75 beats/min), ivabradine
achieved heart rates 75 beats/min, for whom there is high likelihood
Jeffrey S. Borer, State University of New York Down-
of reduction in mortality alone). Conversely, ivabra-
state Medical Center and College of Medicine, Divi-
dine is devoid of several of the adversities associated
sion of Cardiovascular Medicine, 47 East 88th Street,
with beta-blockers (exacerbation of pulmonary dis-
New York, New York 10128-1152. E-mail: jsborer1@
ease [9], conduction abnormalities [10], diabetes [11],
gmail.com.
REFERENCES 1. Kjekshus J, Gullestad L. Heart rate as a therapeutic target in heart failure. Eur Heart J 1999;1 Suppl H:H64–9. 2. McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med 2009;150: 784–94.
3. Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol 2008;101:865–9. 4. Böhm M, La Rosee K, Schmidt U, et al. Force-frequency relationship and inotropic
stimulation in the nonfailing and failing human myocardium: implications for the medical treatment of heart failure. Clin Invest 1992;70: 421–5. 5. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–85.
Borer
JACC: HEART FAILURE VOL. 3, NO. 3, 2015 MARCH 2015:231–3
Ivabradine: How Many Will Benefit?
6. Fonarow GC, Albert NM, Curtis AB, et al. Improving evidence-based care for heart failure in outpatient cardiology practices: primary results of the registry to Improve the Use of Evidence-
9. Tavazzi L, Swedberg K, Komajda M, et al. Clinical profiles and outcomes of patients with chronic heart failure and chronic obstructive pulmonary disease: an efficacy and safety of SHIFT study.
13. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 2011;123:
Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF). Circulation 2010;122: 585–96.
Int J Cardiol 2013;170:182–8.
933–44.
10. Reil J-C, Robertson M, Ford I, et al. Interaction of left bundle branch block on heart rate and ivabradine in patients with chronic heart failure. Eur J Heart Fail 2013;15:1044–52.
14. Dickstein K, Cohen-Solal A, Filippatos G, et al.
7. Peterson PN, Chan PS, Spertus JA, et al. Practice-level variation in use of recommended medications among outpatients with heart failure: insights from the NCDR PINNACLE program. Circ Heart Fail 2013;6:1132–8. 8. Dierckx R, Cleland JGF, Parsons S, et al. Prescribing patterns to optimize heart rate: analysis of 1,000 consecutive outpatient appointments to a single heart failure clinic over a 6-month period. J Am Coll Cardiol HF 2015; 3:224–30.
11. Borer JS, Tardif J-C. Efficacy of ivabradine, a selective If inhibitor, in diabetic patients with chronic stable angina. Am J Cardiol 2010;105:29–35. 12. Böhm M, Swedberg K, Komajda M, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised, placebo-controlled trial. Lancet 2010;376:886–94.
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. Eur J Heart Fail 2008;10:933–89. 15. Ekman I, Chassany O, Komajda M, et al. Relationship between heart rate reduction with ivabradine and health-related quality of life in chronic heart failure patients: results from the SHIFT study. Eur Heart J 2011;32:2395–404.
KEY WORDS f-channels, heart rate reduction, myocardial function
233
VOL. 3, NO. 3, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 2213-1779/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jchf.2014.12.007
EDITORIAL COMMENT
How Many Patients Will Benefit From a New Therapy for Chronic Systolic Heart Failure, and What Difference Does it Make?* Jeffrey S. Borer, MD
T
he importance of heart rate lowering in opti-
evaluation specifically of the benefit of heart rate
mizing natural history among patients with
reduction, separate from other pharmacological ef-
chronic systolic heart failure (HF) has been
fects. Ivabradine seems to have only 1 action on the
increasingly clear for 15 years, certainly at least since
cardiovascular system, that of blocking f-channels in
Kjekshus and Gullestad reported a cross-sectional
sinoatrial nodal cells, thereby reducing or eliminating
analysis of the HF mortality trials then completed (1).
the small f-current (I f) generated across these chan-
This assessment revealed that placebo-subtracted
nels. Physiologically, this current increases heart rate
mortality changes among the trials were directly pro-
by increasing the slope of spontaneous sinoatrial dia-
portional to placebo-subtracted heart rate changes.
stolic depolarization (itself a function of ion movement
This relationship was most strongly influenced by
through calcium and potassium channels). Adminis-
the trials of beta-blocking drugs by then available,
tration of ivabradine enables rigorous testing of the
but extended to non–beta-blockers as well. Subse-
hypothesis that heart rate lowering, alone, provides
quent meta-regression analyses confirmed these find-
important benefit to patients with systolic HF. This
ings (2,3) and further indicated that the mortality
hypothesis is highly plausible: the “mechanism” of
benefit was highly significantly related to heart rate
such benefit is not fully understood, but it is known
reduction, but not at all to beta-blocker dose (2).
that in the failing myocardium, high-energy substrates
However, the beta-blocker trials were based on hy-
are relatively deficient; increasing heart rate increases
potheses about the net effect of all beta-blocker phar-
demand for this resource while decreasing the
macological actions, in addition to heart rate slowing,
myocardial perfusion that could help to replenish it.
which might, in theory, improve myocardial function;
Consistent with this putative mechanism, increasing
no target heart rates were developed for use of the
the frequency of electrical stimulation of isolated
drugs. The relatively recent availability of ivabradine,
papillary muscle strips from the hearts of humans with
a “pure” heart rate–slowing drug, has allowed
New York Heart Association functional class IV HF results in progressively diminishing contractile force, whereas similarly stimulating normal human papillary
*Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology. From the Division of Cardiovascular Medicine, The Howard Gilman Institute for Heart Valve Disease, and the Schiavone Institute for Car-
muscle strips increases contractile force (4). With this background, SHIFT (Systolic Heart failure treatment with the I f inhibitor ivabradine Trial) was designed to test the hypothesis that heart rate lowering in
diovascular Translational Research, State University of New York
addition to that achievable with beta-blockade, and on
Downstate Medical Center, Brooklyn and New York, New York. Dr. Borer
a
is a consultant to Servier Laboratoires, the manufacturer of ivabradine,
other drugs now routinely applied in chronic systolic
and Amgen, Inc., the American licensee of the drug; and has received honoraria/fees not related to ivabradine from Novartis, Celladon, Armgo,
background
of
evidence-based
doses
of
the
HF, would diminish the frequency of either cardio-
Pfizer, Cardiorentis, Salix, Takeda USA, Celgene, Boehringer Ingelheim,
vascular death or hospitalizations for worsening
Somahlution, Sanofi, and JenaValve.
HF (the primary pre-specified composite endpoint)
232
Borer
JACC: HEART FAILURE VOL. 3, NO. 3, 2015 MARCH 2015:231–3
Ivabradine: How Many Will Benefit?
among patients with moderate-to-severe symptoms,
and so on), thus suggesting that the drug will be pre-
left ventricular ejection fraction #35% and heart rate at
scribed in many patients whose heart rate could
rest $70 beats/min (5). The trial was highly positive,
be lowered with higher beta-blocker doses alone but
demonstrating an 18% reduction of the primary com-
who cannot tolerate such dose increases.
posite endpoint compared with placebo, 26% reduc-
The Dierckx et al. (8) data differ from those of recent
tion in HF hospitalizations, and 26% reduction in
large multicenter registries noted in the preceding text
death attributable specifically to HF. Importantly, by
that indicate a larger proportion of patients with sys-
virtue of the study design, benefit only could be
tolic HF whose heart rates are not optimally controlled
inferred in patients whose heart rate, for whatever
despite current therapy. (Moreover, the SHIFT data
reason (drug intolerance, adverse drug effects,
suggest that optimal outcomes require achievement of
insensitivity to drugs, and so on) could not be low-
heart rates #60 beats/min [12], though this is not yet
ered to 70 beats/min (or, according to the European
altering therapy now exists), that many already had
labeling instructions, >75 beats/min), ivabradine
achieved heart rates 75 beats/min, for whom there is high likelihood
Jeffrey S. Borer, State University of New York Down-
of reduction in mortality alone). Conversely, ivabra-
state Medical Center and College of Medicine, Divi-
dine is devoid of several of the adversities associated
sion of Cardiovascular Medicine, 47 East 88th Street,
with beta-blockers (exacerbation of pulmonary dis-
New York, New York 10128-1152. E-mail: jsborer1@
ease [9], conduction abnormalities [10], diabetes [11],
gmail.com.
REFERENCES 1. Kjekshus J, Gullestad L. Heart rate as a therapeutic target in heart failure. Eur Heart J 1999;1 Suppl H:H64–9. 2. McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med 2009;150: 784–94.
3. Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol 2008;101:865–9. 4. Böhm M, La Rosee K, Schmidt U, et al. Force-frequency relationship and inotropic
stimulation in the nonfailing and failing human myocardium: implications for the medical treatment of heart failure. Clin Invest 1992;70: 421–5. 5. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–85.
Borer
JACC: HEART FAILURE VOL. 3, NO. 3, 2015 MARCH 2015:231–3
Ivabradine: How Many Will Benefit?
6. Fonarow GC, Albert NM, Curtis AB, et al. Improving evidence-based care for heart failure in outpatient cardiology practices: primary results of the registry to Improve the Use of Evidence-
9. Tavazzi L, Swedberg K, Komajda M, et al. Clinical profiles and outcomes of patients with chronic heart failure and chronic obstructive pulmonary disease: an efficacy and safety of SHIFT study.
13. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 2011;123:
Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF). Circulation 2010;122: 585–96.
Int J Cardiol 2013;170:182–8.
933–44.
10. Reil J-C, Robertson M, Ford I, et al. Interaction of left bundle branch block on heart rate and ivabradine in patients with chronic heart failure. Eur J Heart Fail 2013;15:1044–52.
14. Dickstein K, Cohen-Solal A, Filippatos G, et al.
7. Peterson PN, Chan PS, Spertus JA, et al. Practice-level variation in use of recommended medications among outpatients with heart failure: insights from the NCDR PINNACLE program. Circ Heart Fail 2013;6:1132–8. 8. Dierckx R, Cleland JGF, Parsons S, et al. Prescribing patterns to optimize heart rate: analysis of 1,000 consecutive outpatient appointments to a single heart failure clinic over a 6-month period. J Am Coll Cardiol HF 2015; 3:224–30.
11. Borer JS, Tardif J-C. Efficacy of ivabradine, a selective If inhibitor, in diabetic patients with chronic stable angina. Am J Cardiol 2010;105:29–35. 12. Böhm M, Swedberg K, Komajda M, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised, placebo-controlled trial. Lancet 2010;376:886–94.
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. Eur J Heart Fail 2008;10:933–89. 15. Ekman I, Chassany O, Komajda M, et al. Relationship between heart rate reduction with ivabradine and health-related quality of life in chronic heart failure patients: results from the SHIFT study. Eur Heart J 2011;32:2395–404.
KEY WORDS f-channels, heart rate reduction, myocardial function
233
