Circulation: Cardiovascular Quality and Outcomes

CARDIOVASCULAR PERSPECTIVE

Does a Target Dose or a Target Heart Rate

Matter to Outcomes When Prescribing
β-Blockers to Patients With Chronic Heart
Failure?

F
or better or worse, many cardiovascular disorders are treated based on Milton Packer, MD
changes in a biomarker. Antihypertensive drugs are titrated to achieve spe-
cific decreases in blood pressure, and the doses of lipid-lowering drugs are
often adjusted based on serum cholesterol. Investigators have proposed measur-
ing natriuretic peptides and C-reactive protein to titrate drugs for heart failure and
for high-risk coronary artery disease, respectively. Use of a biomarker often rep-
resents an effort to practice personalized medicine; theoretically, a drug is given
only to people who need it and only in a dose that achieves what is perceived to
be a worthwhile change. Yet, biomarkers present us with challenges. When ob-
served in populations, even small differences in a biomarker—for example, 1- to
2-mm Hg difference in blood pressure—are clinically important; yet, when treat-
ing individuals, few physicians are inclined to increase the dose of an antihyper-
tensive drug with the primary intent of achieving such a small additional decrease
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in blood pressure.
The oldest biomarker in cardiovascular medicine is resting heart rate. Physicians
have been monitoring the rapidity and quality of the pulse for several thousand
years, and great emphasis has been placed on changes in heart rate as an indica-
tor of impending improvement or deterioration. Many patients suffer when their
heart rates are too fast or too slow. Yet, even in the absence of a tachyarrhythmia
or bradyarrhythmia, physicians dutifully record the resting heart rate during normal
sinus rhythm at nearly every patient encounter.
The resting heart rate has recently gained attention as a biomarker in the man-
agement of patients with chronic heart failure. Heart rate (measured at rest and
during sinus rhythm) has prognostic importance in patients with left ventricular
systolic dysfunction, and changes in heart rate are predictive of outcomes.1 The If
current antagonist ivabradine was specifically developed to modulate heart rate
during sinus rhythm. When prescribed to patients with heart failure, the resting
heart rate is not only used to identify those who might benefit from the drug but
it is also typically used to titrate the appropriate dose of the agent.2 When adminis-
tered to patients who are already receiving a β-blocker and who continue to dem-
onstrate elevated heart rates, the decreases in sinus rate achieved by ivabradine
are accompanied by a reduction in the combined risk of cardiovascular death and
hospitalization for heart failure.2
In addition, a recent meta-analysis found that—in patients with chronic heart
failure in sinus rhythm—achievement of a low-target heart rate with a β-blocker
was an important determinant of survival, regardless of the dose that was pre-
scribed.3 This analysis has provided unintended support for the existing widespread Key Words:  heart rate ◼ heart failure
practice of titrating the dose of a β-blocker to achieve a target heart rate at rest,
© 2018 American Heart Association, Inc.
even though such a dosing strategy was not utilized in the large-scale clinical trials
that established the benefits of these drugs on survival. Indeed, many might argue http://circoutcomes.ahajournals.org

Circ Cardiovasc Qual Outcomes. 2018;11:e004605. DOI: 10.1161/CIRCOUTCOMES.118.004605 April 2018 1

 Packer; Titration of β-Blockers in Heart Failure
that titrating the dose of a β-blocker based on rest-
ing heart rate is physiologically irrational because the
degree of β1-blockade is most validly assessed by the
heart rate response during exercise rather than at rest.
Nevertheless, it is the resting heart rate that is mea-
sured by most physicians. So is it a reasonable biomark-
er for patients with chronic heart failure? And if it is,
what magnitude of change in heart rate is important?
Physicians can readily believe that a major decline—
for example, from 90 to 70 bpm—seems meaningful.
However, is a decrease of only 10 bpm important? How
about 5 bpm? Or even 1 bpm? At first glance, such
small changes in resting heart rate may seem trivial. Yet,
in the large-scale trial with ivabradine, changes in rest-
ing heart rate of 5 bpm (mainly in patients suboptimally
treated with β-blockers) were accompanied by mean-
ingful differences in the risk of the primary outcome.1 Is
that the threshold for a clinically meaningful difference?
Studies of the heart rate changes with ivabradine can-
not inform physicians about the importance of heart
rate changes with β-blockers. Yet, many physicians
might ask: If the dose of a β-blocker was uptitrated to
lower heart rate by an additional 5 bpm, would that
be worthwhile, if it was well tolerated? Some might
respond by suggesting that this question warrants the
conduct of a new large-scale clinical trial to settle the
matter once and for all.
Yet, interestingly, it seems likely that the proposed
clinical trial may have already been performed—15
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years ago. COMET (Carvedilol or Metoprolol Europe-
an Trial)4 was a randomized double-blind trial, which
compared the effects of carvedilol and metoprolol on
all-cause mortality in 3029 patients with classes II to IV
heart failure and an ejection fraction ≤35%. Metoprolol
tartrate was used at a target dose of 100 mg daily (50
mg BID), and carvedilol was used at a target dose of
50 mg daily (25 mg BID). These doses provided some-
what different degrees of β1-blockade but were select-
ed based on the best available evidence at the time.
The primary end point of the trial was all-cause mortal-
ity, with a target of 1020 fatal events to detect a 20%
reduction in risk. Patients were followed for an average
of 58 months; only 5 patients were lost to follow-up. In
the trial, treatment with carvedilol led to a 17% lower
risk of death and a 20% lower risk of cardiovascular
death, when compared with metoprolol (P=0.0017 and
0.0004, respectively).
Was the superiority of carvedilol in COMET related
to greater β1-blockade or to additional properties of
the drug? Metoprolol selectively blocks β1-adrenergic
receptors, whereas carvedilol antagonizes α1, β1, and
β2 receptors and has additional effects whose clini-
cal significance is unknown. Guidelines do not place
much emphasis on the actions of carvedilol beyond
β1-blockade, largely because the point estimates of the
mortality reduction in the large-scale placebo-controlled
Circ Cardiovasc Qual Outcomes. 2018;11:e004605. DOI: 10.1161/CIRCOUTCOMES.118.004605
clinical trials with metoprolol succinate, carvedilol, and
bisoprolol were similar.5–7 Consequently, the findings of
COMET have largely been interpreted as being reflec-
tive of a greater degree of β1-blockade achieved by
carvedilol when compared with the short-acting formu-
lation of metoprolol that was utilized in the study.
In COMET, the resting heart rate was lower in the
carvedilol group than in the metoprolol group. Yet, the
difference was only 1.6 bpm and was seen only dur-
ing the first several months after randomization. After
16 months, the between-group difference in heart rate
was even smaller and was no longer statistically signifi-
cant. Therefore, if resting heart rate is used to assess
the magnitude of β1-blockade (as is usually the case in
clinical practice), then a treatment that yielded only an
additional 1- to 2-bpm decrease in resting heart rate
(on a population basis) was accompanied by an addi-
tional 20% reduction in cardiovascular mortality! This
impressive finding suggests the intriguing possibility
that the final steps in the uptitration of a β-blocker to
target doses may have unexpectedly large and impor-
tant benefits.
Does this mean that titrating β-blockers to achieve
even small incremental decreases in heart rate is worth-
while? The answer is no—for 2 good reasons. First, the
measurement of heart rate is so variable that it would
be impossible for a physician to know that dose increas-
es had actually been responsible for any observed
change in heart rate. The between-group differences
in heart rate in COMET were seen in populations, not
in individuals. Second and importantly, analyses of the
large-scale outcomes trial with ivabradine have shown
that incremental decreases in heart rate as much as 10
bpm produced by the drug in patients receiving target
doses of a β-blocker exerted no benefits on morbidity
and mortality.8
Therefore, it is not the additional 1- to 2-bpm slow-
ing of heart rate that matters. It is the recognition of
the importance of prescribing drugs in a manner that
closely mimics the way they were used in clinical trials
that demonstrated their value rather than in the way
we might think they should be prescribed based on
assumptions about their mechanism of action.9 In all
the large-scale trials that showed a substantial reduc-
tion in mortality in chronic heart failure,5–7 the dose of
β-blocker was increased to the target level designated
in the study protocol (if tolerated), even if the use of
subtarget doses led to a decrease in their heart rates
into a range that could be imagined to be desirable.
Are physicians heeding these results? Currently,
there is little emphasis on achieving target doses of a
β-blocker in clinical practice. The approach described
in the guidelines inadvertently allows physicians to
believe they are in compliance even if they are prescrib-
ing subtarget doses to patients, including those who
are able to receive higher doses successfully. Less than
April 2018 2
 Packer; Titration of β-Blockers in Heart Failure
20% of patients with chronic heart failure are receiving
β-blockers at a target dose.10 The findings of COMET
should make us worry about this a great deal.
Several large-scale outcome trials have established
the proper dosing for β-blockers in heart failure, and
it is based on dose and not on heart rate. The goal of
β-blockers is not to achieve a slow heart rate; the goal
is to save lives.
ARTICLE INFORMATION
Correspondence
Milton Packer, MD, Baylor Heart and Vascular Institute, Baylor University
Medical Center, 621 N Hall St, Dallas, TX 75226. E-mail milton.packer@
baylorhealth.edu
Affiliation
Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX.
Disclosures
Dr Packer has recently consulted for Amgen, AstraZeneca, Bayer, Boehringer
Ingelheim, Cardiorentis, Celyad, Daiichi Sankyo, Gilead, Novartis, NovoNordisk,
Relypsa, Sanofi, Takeda, and ZS Pharma. None of these relationships have any
bearing on the topic of this article.
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