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Am J Cardiovasc Drugs 2012; 12 (6): 357-359
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COMMENTARY
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Ivabradine in Heart Failure
Hope or Hype?
Prakash C. Deedwania
University of California, San Francisco School of Medicine, Fresno, CA, USA
During the past two decades considerable progress has been
made in understanding the pathophysiology of heart failure
(HF) and subsequent development of several therapeutic agents
primarily based on the neurohormonal blockade with reninangiotensin-aldosterone system (RAAS) blocking agents (e.g.,
angiotension-converting enzyme inhibitors [ACEIs], angiotensin
II receptor blockers [ARBs], and aldosterone receptor blockers)
and b-blockers.[1] Although these drugs are highly effective in
reducing the morbidity and mortality in HF, there is considerable residual risk that remains despite appropriate use of these
agents. Ivabradine, which is a specific heart rate (HR)-lowering
agent that acts by inhibiting funny channels (If), a key ‘pacemaker’ current in the sino-atrial node, has recently been shown
to be effective in the treatment of patients already receiving
guideline-based therapy with RAAS blocking agents and bblockers bringing new hope of further reducing the residual risk
of recurrent hospitalization and death due to HF. In this issue of
the American Journal of Cardiovascular Drugs, the Drug Profile
on ivabradine[2] provides an excellent overview regarding the
pharmacology of this drug and its role in the treatment of HF
based on the results of SHIFT (Systolic Heart failure treatment
with If inhibitor ivabradine Trial).[3] Despite the obvious and
highly significant benefit observed during treatment with ivabradine in the SHIFT study, there has been some discussion and
debate in the academic community regarding the precise role of
ivabradine in patients with HF in the clinic.[4,5]
A careful examination of the SHIFT study shows that
treatment with ivabradine was indeed associated with significant reduction in the primary composite endpoint consisting of
cardiovascular death and hospitalization for worsening HF.[3]
There was a 26% reduction in hospitalizations due to worsening
HF and also a 26% reduction in deaths related to HF. These
effects were seen primarily in the patients who had baseline HR
‡75 beats/min.[6] The fact that ivabradine was primarily effective in those with higher HR should not be surprising given the
fact that it works primarily by slowing the HR by blocking the If
channels. Although there are some data in experimental settings demonstrating various other actions, these require further
confirmation and evaluation in humans.
1. Heart Rate (HR) in Heart Failure (HF) and
Effects of Ivabradine
The role of HR in various cardiovascular disorders and
specifically in HF has been extensively evaluated and most
studies show a strong association of higher HR with worse
outcome.[7,8] The evidence is now overwhelming that elevated
HR is a powerful predictor of mortality and morbidity in a
range of chronic cardiovascular disorders including HF, independent of other risk factors and clinical variables.[7,8] In the
placebo arm of the SHIFT study, patients with the highest HR
(‡87 beats/min) had more than twice the risk of primary endpoint
compared with those with a lower HR (70 to <72 beats/min). It
was also shown that with every 1 beat/min increase from
baseline during the follow-up the risk of primary endpoint increased by 3%. These data clearly establish the adverse effects of
increased HR in HF.
Although the precise mechanism responsible for adverse
outcome associated with higher rate in HF is not established, it
might be related to increased energy expenditure as well as
perpetuating myocardial ischemia in those with ischemic cardiomyopathy. Whatever the underlying mechanism for the
adverse consequences of increased HR might be, the beneficial
effects of ivabradine, a pure HR-slowing agent devoid of effect
on other hemodynamic parameters, or on myocardial function,
as seen in SHIFT, clearly establishes the importance of slowing
the HR in the setting of HF. The beneficial effects of b-blockers
are also thought to be related, at least in part, to their HRlowering effect. However, b-blockers do have other hemodynamic actions as well as effects on cellular transcription factors
that might also contribute to their effects on cardiac remodeling, a critical process in HF.
Deedwania
358
2. Is Reduction in Hospitalization for Worsening
HF a Valid and Important Endpoint?
The significant reduction in hospitalization for worsening
HF in SHIFT was one of the main components responsible for
the positive results of the study as there was no reduction in
cardiovascular deaths, the other component of the composite
primary endpoint. Although this has been a topic of some
discussion, it is important to emphasize that hospitalization for
HF is not only a major contributor to the high morbidity but
also relates to the escalating cost of health-care expenditure in
HF. Admission for HF is the main reason for hospitalization in
people >65 years of age in the USA, and accounts for more than
1 million admissions per year. It is also known that once hospitalized the rate of recurrent hospitalizations over the subsequent year is quite high (25–40%) in patients with HF. The
recent sub-analysis from SHIFT showing a significant decrease
in the rate of recurrent hospitalizations for worsening HF in
patients treated with ivabradine is a further testament of its
efficacy in reducing this important sequela of HF.[9]
3. b-Blocker Therapy versus Ivabradine in HF
Based on the results of several large randomized controlled
trials (RCTs), b-blocker use has been well established as an
integral part of standard guideline-based therapy for all
patients with HF. One of the criticisms of the SHIFT results has
been focused on the fact that some of the patients in the study
were not receiving a b-blocker at all and others were not getting
recommended and adequate doses of b-blockers.[4] However, it
is important to note that 89% of patients in SHIFT were receiving b-blockers and the majority were receiving an adequately tolerated dose of a b-blocker. It was prespecified in the
investigator brochure that unless contraindicated or not tolerated all patients were to receive the recommended dose of
b-blockers. A recent sub-analysis of SHIFT evaluated the effects of ivabradine in combination with b-blocker therapy and
demonstrated that it was the magnitude of HR reduction with
ivabridine rather than the dose of b-blocker patients were receiving that determined the subsequent effects on clinical outcome.[10] These findings clearly emphasize two main points:
first, whenever possible an adequate dose of b-blocker must be
given to obtain optimal control of HR, and second, ivabradine
provides additional benefit in patients with HF who have a
faster HR (>75 beats/min) despite the use of a b-blocker as well
as in those who cannot tolerate b-blocker therapy.
It is well recognized that despite the compelling evidence of
the benefit of b-blockers in HF they are under-prescribed, both
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in terms of the proportion of patients who receive them and the
doses achieved. Much of this under-prescription is linked to
their range of actions additional to HR lowering, which may
result in an absolute or relative contraindication and a reluctance among physicians to prescribe. The prescribing of bblockers in HF has increased in recent years. However, the
doses received remain low and evidence from registry studies
indicates that HR control remains poor. In the IMPROVE HF
(Registry to Improve the Use of Evidence-Based Heart Failure
Therapies in the Outpatient Setting) study, although 84.1% of
HF patients without devices received b-blockers, only 15.3%
took them at recommended target doses and the median resting
HR was 72.2 beats/min.[11] In the OPTIMIZE-HF (Organized
Program To Initiate life-saving treatMent In hospitaliZEd
patients with Heart Failure) registry, only 17.5% and 7.9% of
hospitalized patients with chronic systolic HF treated in cardiology practices were receiving recommended target doses of
carvedilol and metoprolol succinate, respectively, at the 60- to
90-day post-discharge follow-up.[12] Similarly, in the ESC-HF
(European Society of Cardiology Heart Failure) pilot study,
86.7% of patients received b-blockers, but target doses of carvedilol, bisoprolol, and metoprolol were reached in only 37.3,
20.7, and 21.4% of patients, respectively, and the mean HR was
72 beats/min.[13]
Older patients and those with more severe HF symptoms are
more likely not to receive b-blocker therapy or to receive only
low doses,[14] a phenomenon that has been termed the ‘risktreatment mismatch’ in the pharmacotherapy of HF.[15] It
seems clear that the way b-blockers are used in current clinical
practice does not produce HR control in the optimal
50–60 beats/min range in most patients.
Because ivabradine is devoid of some of the major side effects
associated with b-blockers (e.g., fatigue, erectile dysfunction,
glycemic perturbations, etc.) it is likely to be better tolerated by
patients with HF. Furthermore, many patients with bronchospastic lung disease, peripheral vascular disease, diabetes mellitus, and atrioventricular blocks who have contraindications to
the use of b-blockers can now be given ivabradine to provide
them with additional therapeutic benefit.
4. Summary
Based on careful examination of the available evidence it is
clear that ivabradine does provide hope for many patients with
HF, especially those who continue to be symptomatic and are at
risk of recurrent hospitalization for worsening HF. Specifically,
this should include patients with HF who continue to have a
faster HR despite currently recommended therapy as well as
Am J Cardiovasc Drugs 2012; 12 (6)
Ivabradine in Heart Failure
those who cannot tolerate treatment with an adequate dosage of
b-blockers and those in whom b-blocker use is contraindicated.
Acknowledgments
Dr Deedwania serves as a consultant and advisor for Forrest Pharmaceuticals, Servier laboratories and Takeda Pharmaceuticals.
References
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Correspondence: Dr Prakash Deedwania MD, FACC, FAHA, Chief Cardiology
Division, VACCHCS/UCSF, Fresno, CA, Professor of Medicine, UCSF School
of Medicine, San Francisco, 2615 E. Clinton Ave, Fresno, CA 93703, USA.
E-mail: [email protected]
Am J Cardiovasc Drugs 2012; 12 (6)