Download Heart failure highlights in 20122013

REVIEW
European Journal of Heart Failure (2014) 16, 122–132
doi:10.1002/ejhf.43
Heart failure highlights in 2012–2013
Licette C. Y. Liu, Kevin Damman, Eric Lipsic, Alexander H. Maass,
Michiel Rienstra, and B. Daan Westenbrink*
The Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Received 21 October 2013; revised 4 November 2013; accepted 8 November 2013 ; online publish-ahead-of-print 26 December 2013
Heart failure has become the cardiovascular epidemic of the century. The European Journal of Heart Failure is dedicated to the advancement
of knowledge in the field of heart failure management. In 2012 and 2013, several pioneering scientific discoveries and paradigm-shifting
clinical trials have been published. In the current paper, we will discuss the most significant novel insights into the pathophysiology, diagnosis,
and treatment of heart failure that were published during this period. All relevant research areas are discussed, including pathophysiology,
co-morbidities, arrhythmias, biomarkers, clinical trials, and device therapy, including left ventricular assist devices.
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Heart failure • Highlights 2012/13 • Pathophysiology • Co-morbidities • Atrial fibrillation •
Biomarkers • Pharmacological therapy • Interventional treatment • CRT • Assist devices
Introduction
As in previous years,1 several pioneering scientific discoveries and
paradigm-shifting clinical trials were published this year. In the
current paper, we will discuss the most significant novel insights
into the pathophysiology, diagnosis, and treatment of heart failure
(HF) that were published in 2012 or 2013. The most important
clinical trials are summarized in Table 1.
Pathophysiology
Loss of functional myocardium is the major cause for cardiac dysfunction and HF. The ability to regenerate functional myocardium
has therefore been considered the holy grail of cardiovascular science for decades. While initial approaches were focused on injection of undifferentiated stem cells or their progeny into diseased
myocardium,13,14 the paradigm appears to have shifted towards
manipulation of resident cardiac tissue instead. In 2012, remarkable progress was made in this field. First, Senyo et al. showed that
pre-existing cardiomyocytes rather than resident cardiac progenitor cells are the dominant source of endogenous cardiomyocyte
renewal. These findings indicate that stimulation of endogenous
cardiomyocyte proliferation could result in regeneration of diseased myocardium.15 Secondly, a high-throughput screen of human
microRNAs (miRNAs) identified miR-590-3p and miR-199a-3p to
be potent inducers of cardiomyocyte proliferation in vitro and
in vivo.16 Remarkably, forced expression of these miRNAs in
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Keywords
cardiomyocytes after myocardial infarction was associated with
almost complete recovery of cardiac viability and function. Thirdly,
two independent groups convincingly demonstrated that cardiac
fibroblasts can be reprogrammed into fully functional cardiomyocytes in their native environment, thereby reducing myocardial infarct size and improving cardiac function.17,18 Whether
these experimental observations will translate into clinical practice
remains to be established.
Another (re) emerging field of HF research is metabolic and
mitochondrial dysfunction.19 Mitochondria account for ∼30% of
cardiac mass and serve crucial roles in energy production, calcium handling, and cell viability.20 However, mitochondria are also
an important source of cardiac pathology. For instance, Oka
et al. revealed that ‘rogue’ mitochondrial DNA that escapes from
mitophagy is a major source of cardiac inflammation and may
cause cardiac dysfunction.21 Furthermore, several signal transduction pathways that have been implicated in cardiac pathophysiology appear to do so in part through modulation of mitochondrial
function and integrity.22,23 While it is generally accepted that the
failing heart is energy starved, direct evidence for this assumption
is sparse. Gupta et al. tested this hypothesis by generating mice
in which myocardial energy availability is increased through conditional cardiomyocyte-specific overexpression of creatine kinase
(CK).24 Overexpression of CK in mice with HF resulted in marked
improvement of cardiac function, but the functional improvement
was rapidly lost when CK expression was normalized to control values. While these observations strongly suggest that the
*Corresponding author. Tel.: +31 50 361 6161, Fax: +31 50 361 1347, Email: [email protected]
© 2013 The Authors
European Journal of Heart Failure © 2013 European Society of Cardiology
© 2013 The Authors
European Journal of Heart Failure © 2013 European Society of Cardiology
ASTRONAUT
Gheorghiade et al.
March, 2013
RED-HF
SHOCK2
Thiele et al.
August, 2012
Chronic heart failure
Swedberg et al.
March, 2013
RELAX-AHF
CARRESS-HF
Teerlink et al.
January, 2013
Acute heart failure
Bart et al.
December, 2012
Multicentre,
double-blind,
placebo-controlled,
phase III
Multicentre,
double-blind,
placebo-controlled
phase III
Multicentre,
prospective open
label, phase III
Multicentre,
prospective,
double-blind,
placebo-controlled,
phase II/III
Prospective,
randomized,
controlled phase III
Systolic heart failure
patients with
anaemia
Hospitalized patients,
stabilized after an
acute heart failure
episode
1615
2278
Cardiogenic shock
complicating an
acute myocardial
infarction
Acute
decompensated
heart failure
patients
1161
600
Acute
decompensated
heart failure
patients
188
To evaluate whether
treatment with
darbepoetin alfa
improves clinical
outcomes
To investigate the
effect of in-hospital
initiation of
aliskiren, on top of
current background
heart failure
therapy
Determine the
efficacy of
intra-aortic balloon
counterpulsation
To assess the effect of
serelaxin on
dyspnoea relief and
clinical outcomes
Compare safety and
efficacy of
ultrafiltration with
diuretic-based
congestion relief
Primary endpoints
Composite of all-cause
mortality or
hospitalizations for
worsening heart failure
Primary endpoints Efficacy:
30-day all-cause
mortality
Safety: bleeding,
peripheral
complications, sepsis,
and stroke
Primary endpoints
Cardiovascular death
or rehospitalization for
heart failure
Primary endpoint
Dyspnoea
improvement
Primary endpoints
Δ Serum Creatinine
Δ Weight
No between-group
differences in the primary
outcomes.
Thrombo-embolic events
were more frequent in the
darbepoetin alfa group.
Aliskiren did not improve
clinical outcomes.
Ultrafiltration resulted in
higher increases in serum
creatinine, despite similar
reductions in weight. The
incidence of serious
adverse events was also
higher in the ultrafiltration
group.
Serelaxin slightly improved
dyspnoea over placebo.
Mortality at 180 days was
lower in the serelaxin
group (RELAX-AHF was
not designed to evaluate
this endpoint).
No between-group
differences in efficacy or
safety endpoints.
6
5
4
3
2
Author and
Acronym
Study design
n
Study population
Aims
Endpoints
Main results
References
publication date
.........................................................................................................................................................................................
Table 1 Major clinical trials published in 2012–2013
Heart failure highlights in 2012–2013
123
PARAMOUNT
ALDO-DHF
Solomon et al.
October, 2012
Edelmann et al.
February, 2013
WARCEF
Homma et al.
May, 2012
ARTS
EchoCRT
Ruschitzka et al.
September, 2013
Pitt et al.
May, 2013
BLOCK-HF
Curtis et al.
April, 2013
Multicentre,
placebocontrolled,
double-blind,
parallel-group,
phase II
Parallel-group,
double-blind
phase II
Multicentre,
parallel-group,
double-blind
phase II
Prospective,
multicentre,
double-blind,
double dummy,
phase III
Prospective,
multicentre,
double-blind
phase III
Prospective,
multicentre,
double-blind
phase III
422
301
457
2305
809
691
Patients with heart
failure with
preserved ejection
fraction
Patients with heart
failure with
preserved ejection
fraction
Chronic systolic heart
failure patients
Systolic heart failure
patients in sinus
rhythm
Systolic heart failure
patients with
indication for
ventricular pacing
due to
atrioventricular block
Stable NYHA class III
or IV heart failure,
LVEF < 35%, QRS
<130 ms,
dyssynchrony
To evaluate effects of
spironolactone on
diastolic function
and exercise
capacity
To assess safety and
efficacy of LCZ696
compared with
valsartan
To compare safety
and efficacy of BAY
94-8862 with
placebo and
spironolactone
To evaluate the
efficacy of CRT in
patients with al
dyssynchrony and a
narrow QRS
complex
To compare the safety
and efficacy of
warfarin and aspirin
To compare
biventricular pacing
with right
ventricular pacing
Δ E/e’
Δ peak VO
Δ serum NT-proBNP
Blood pressure
Echocardiography
Primary endpoint
Composite of
ischaemic stroke,
intracerebral
haemorrhage, or
all-cause mortality.
Δ serum potassium
serum NTproBNP
Primary End Point
Composite of all-cause
mortality, heart failure
hospitalizations or15%
increase in LV
end-systolic volume
Primary endpoint
Composite of death
from any cause or first
hospitalization for
worsening heart failure
No difference in the primary
composite outcome.
Warfarin reduced
incidence of ischaemic
stroke, but increased the
risk of major haemorrhage.
Comparable BNP and
NT-proBNP reductions in
both treatment groups.
Treatment with BAY 94-8862
resulted in lower incidence
of hyperkalaemia or
worsening renal function.
Treatment with LCZ696
significantly reduced
NT-proBNP levels, NYHA
functional class and left
atrial size at 36 weeks.
Spironolactone improved
diastolic function.
No differences were seen in
exercise capacity,
symptoms, or quality of
life.
No between-group
differences in the primary
composite endpoint. CRT
was associated with
increased mortality.
Biventricular pacing reduced
the incidence of the
primary endpoint.
12
11
10
9
8
7
Author and
Acronym
Study design
n
Study population
Aims
Endpoints
Main results
References
publication date
.........................................................................................................................................................................................
Table 1 Continued
124
L.C.Y. Liu et al.
© 2013 The Authors
European Journal of Heart Failure © 2013 European Society of Cardiology
125
failing heart is energetically starved, clinical evaluation of cardiac
substrate availability will be challenging. For instance, circulating
levels of metabolic substrates are not correlated with exercise
capacity or survival in patients with HF.25 Recent advancements
in magnetic resonance spectroscopy suggest that detailed noninvasive analysis of cardiac mitochondrial respiration may become
available soon.26
Co-morbidities in heart failure
In the past decade, the importance of concomitant organ dysfunction in the syndrome of HF has increasingly been recognized. Not
only are co-morbidities frequently present in patients with HF, but
their presence is also associated with an increased risk for death
and rehospitalizations for HF. Among known co-morbidities, renal
dysfunction is now a well-established and important co-morbidity.
However, the prediction of deterioration of renal function in HF is
still difficult. In a study of 399 acute HF patients, Collins et al. found
that urinary neutrophil gelatinase-associated lipocalin (NGAL) may
identify patients at risk for worsening renal function and impaired
clinical outcome.27 Interestingly, data from REVERSE, a trial on
cardiac resynchronization in mild HF, suggested that the presence
of renal impairment is not an innocent bystander, but also hampers the ability of cardiac reverse remodelling to occur by cardiac
resynchronization therapy (CRT).28 Most important data on renal
function in HF in 2012 come from the CARRESS-HF trial where
ultrafiltration was compared with a stepped diuretic regimen in
patients who had deterioration in renal function and persistent
signs of congestion.2 In CARRESS-HF, ultrafiltration showed higher
increases in serum creatinine, despite similar reduction in weight.
Overall, there were several potential problems in the design and
execution of CARRESS-HF; there were crossovers among treatment groups, patients were not truly resistant to diuretics considering strong diuresis in the medical therapy group, and patients
were allowed inotropes in the medical group, but not in the ultrafiltration group. Therefore, the interpretation of the study is difficult
from a clinical perspective. For now, standard ultrafiltration therapy
in these patients does not appear to be justifiable.
Anaemia is also common in HF patients, and the presence of
anaemia has consistently been associated with increased morbidity
and mortality in HF. However, several mechanisms may contribute
to the high prevalence of anaemia in HF. Blunted erythropoietin
production and reduced sensitivity of bone marrow to endogenous
erythropoietin have consistently been implicated.29,30 Treatment
with recombinant human erythropoietin would thus appear to be
feasible. Based on two semi-large phase II clinical trials,31,32 which
showed potentially promising effects on quality of life and clinical
outcome, the RED-HF trial was initiated in 2006. In this doubleblind, placebo-controlled trial, 2278 patients with systolic HF and
mild-to-moderate anaemia were randomized to receive darbepoetin alpha or placebo for a median follow-up of 28 months.33 At
baseline, the groups were well balanced,34 and the pre-specified
haemoglobin target was achieved in the active treatment group.
However, the incidence of the primary composite endpoint of allcause mortality or hospitalization for worsening HF did not differ
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Heart failure highlights in 2012–2013
© 2013 The Authors
European Journal of Heart Failure © 2013 European Society of Cardiology
between the groups.6 There were also no significant betweengroup differences in any of the secondary outcomes. Instead, a
slight but significant increase in the incidence of thrombo-embolic
events was observed on darbepoetin alfa treatment. While these
results will probably lead to the end of therapeutic exploration of
erythropoietin in HF,35 this does not mean that anaemia should
be dismissed as a therapeutic target altogether. For instance, correction of iron deficiency, a well-established cause of anaemia, has
recently been shown to improve exercise capacity and quality of
life in HF patients with or without anaemia.36,37
The incidence of diabetes is increasing, and diabetes is a common precursor of HF.38 Indeed, HF that occurs in diabetic patients
is considered to result from a unique diabetes-related mechanism, which is often referred to as ‘diabetic cardiomyopathy’. Several mechanisms have been attributed as underlying diabetic heart
disease,39 and specific therapeutics for this emerging cardiomyopathy are under investigation.40 The concept that diabetes inevitably
propagates into diabetic cardiomyopathy was, however, challenged
in 2012. In a post-hoc analysis of the ASPIRE trial, patients with
diabetes were not more prone to develop left ventricular (LV)
dilatation or LV systolic dysfunction.41 Moreover, long-term and
detailed follow-up of Zucker diabetic rats showed that, despite
severe diabetes with renal complications, these rats did not develop
systolic LV dysfunction.42 Finally, antidiabetic drugs may have beneficial cardiac effects. For instance, sitagliptin, a dipeptidyl peptidase
IV (DPP4), improved cardiorenal function in HF by interfering with
brain natriuretic peptide (BNP) degradation.43
Cognitive impairment is a lesser known co-morbidity in HF
patients. Compared with matched controls, patients with decompensated HF displayed significantly impaired cognitive function.
Although cognitive performance was restored to some extent after
recompensation, it did not normalize to control values.44 A history
of stroke has been observed in up to 10% of patients with HF, and
∼10% of patients with acute stroke have HF.45 The latter was found
to be mainly attributable to cardio-embolism secondary to atrial
fibrillation (AF). The presence of HF in acute stroke was found to
be predictive of clinical outcome, independent of the presence of
AF. Finally, patients with chronic HF have a reduction in bone mass
loss, even increased compared with age-matched controls, and this
was associated with secondary hyperparathyroidism.45 Since it was
also associated with clinical outcome, this highlights the need to
look more closely at less frequent co-morbidities in HF, and may
call for a multidisciplinary approach.
Atrial fibrillation
Atrial fibrillation and HF remain one of the most important
cardiovascular problems in the 21st century. From the Framingham
Heart Study it is known that individuals with both AF and HF have
a worse prognosis than individuals with either condition alone.46
Since AF can beget HF and vice versa, via diverse mechanisms
and potential genetic susceptibility, whether AF or HF develops
first may affect prognosis. Smit et al. studied 182 consecutive
AF patients hospitalized for chronic heart failure with reduced
ejection fraction (HFREF).47 The majority of patients hospitalized
126
Biomarkers in heart failure
Last year was no exception to the ongoing trend on biomarker
papers in cardiovascular disease. An increasing number of
biomarker studies also focused on HF patients with preserved
ejection fraction (HFPEF).54,55 In a small study, Santhanakrishnan
et al. studied the diagnostic capability of growth differentiating
factor 15 (GDF-15), N-terminal pro brain natriuretic peptide
(NT-proBNP), ST2, and high sensitive troponin T.56 Their results
indicated that NT-proBNP and GDF-15 were extremely accurate
in distinguishing HF patients with HFREF from controls, while
the ratio between NT-proBNP and GDF-15 may give some information on the difference between HFREF and HFPEF. However,
discrimination between HFREF and HFPEF using any biomarker
or combination was moderate at best. In another study, however,
........................................................................................................................................................................
for AF and HF consisted of patients who had developed AF first.
Prognosis was worse in hospitalized patients with HF first and
who subsequently developed AF. In addition, a substudy of the
EVEREST trial in acute HFREF demonstrated that AF patients
received less evidence-based therapies and had increased mortality
and rehospitalization compared with patients in sinus rhythm.48
Thus, left ventricular ejection fraction (LVEF) does not appear
to improve risk prediction for adverse prognosis in this patient
population. Although interesting and novel, it is still uncertain
whether AF is a marker of the progression and severity of HFREF,
or whether AF is causally related to mortality in these patients.49
Beta-blockers have been shown to reduce morbidity and mortality in HF patients and are recommended as first-line therapy in
all patients with HF.50 In the 2012 European Society of Cardiology
(ESC) guidelines for HF, the recommendation for beta-blockers is
not restricted to patients with sinus rhythm and includes all HF
patients (i.e. also for those with AF), but it is unknown whether
beta-blockers reduce mortality in HF patients with AF. The
SENIORS investigators compared nebivolol with placebo in elderly
patients with HF.51 In contrast to the overall study, nebivolol did
not affect outcomes in patients with AF at baseline (738 out of
the 2128 patients). Next, the BEST investigators compared the
effect of bucindolol in patients with HFREF between patients in AF
or in sinus rhythm.52 They observed that in both AF (303 of the
2708 patients) and sinus rhythm patients who achieved a resting
heart rate ≤80 b.p.m., there were beneficial effects of bucindolol
on cardiovascular mortality and hospitalizations. In patients that
did not achieve a resting heart rate ≤80 b.p.m., bucindolol was
not associated with improvements in outcome. A meta-analysis
included four placebo-controlled, randomized beta-blocker therapy studies, which enrolled 8680 patients with HF, and 1677
of them had AF (842 treated with beta-blocker and 835 with
placebo).53 In AF patients, beta-blockers did not reduce mortality
and HF hospitalizations, while in sinus rhythm patients there was a
significant reduction. This suggests that the effect of beta-blockers
on outcome in AF patients with HF and reduced LVEF is less than
that in those who have sinus rhythm. Prospective randomized controlled trials specifically aiming at HF patients with AF are eagerly
awaited.
L.C.Y. Liu et al.
GDF-15 was able to improve reclassification of patients with
possible HFREF, and was shown to outperform NT-proBNP.57
In an elegant study, GDF-15, a marker of fibrosis, was found in
high concentrations in severely decompensated HF patients.58
However, this was not associated with higher myocardial messenger RNA (mRNA) levels of GDF-15. Even more strikingly,
GDF-15 levels decreased strongly in a majority of patients that
received a left ventricular assist device (LVAD), suggesting that
activation of the profibrotic pathways may be reversible by cardiac
unloading. The activity of these pathways seems to be different in
men vs. women, since women experience lower levels of markers
of fibrosis, inflammation, and extracellular matrix remodelling,
which may be a reason for the difference in mortality rates across
genders.59 A new spectrum of biomarkers is emerging in which
miRNAs play a central role. Vogel et al. recently showed that
either as a single biomarker, or as a combination, several miRNAs
are not only dysregulated in non-ischaemic HFREF patients, but
also carry important diagnostic capabilities.60
Biomarkers may also be used to differentiate between diseases
that present with similar signs and symptoms but have different
pathophysiology. An important example was presented by data
coming from the BACH trial.61 In this substudy analysis, the
authors evaluated the diagnostic capabilities of procalcitonin (PCT)
in patients presenting with dyspnoea. In 1641 patients, the authors
found that elevated PCT levels were strongly associated with the
diagnosis of pneumonia, even in the presence of the diagnosis of
obstructive lung disease or HF. PCT levels also predicted outcome,
and patients had worse outcomes when they were not treated with
antibiotics. Overall these findings have improved our knowledge on
the pathophysiology, therapy, diagnosis, and prognosis of patients
with HFREF and HFPEF.
Pharmacological therapy
Several randomized clinical trials were the subject of significant
interest recently. Arguably the most important breakthrough for
drug discovery came from the RELAX-AHF. In RELAX-AHF, 1161
acute HF patients were randomized to serelaxin, a recombinant
form of the human vasodilatator relaxin-2, or placebo.3 Treatment
with serelaxin resulted in mild improvements in dyspnoea compared with placebo. At 60 days, no differences were observed in the
secondary endpoints of the study; days alive out of hospital, and cardiovascular death or readmission. Interestingly, while only administrated for 2 days, serelaxin was associated with a significant reduction of mortality up to 180 days, with curves separating from day
5 for cardiovascular death [hazard ratio (HR) 0.63, P = 0.028] and
all-cause mortality (HR 0.63, P = 0.02).3 Post-hoc analyses demonstrated that serelaxin was associated with significant reductions in
markers of end-organ damage,62 suggesting that serelaxin might
possess organ-protective properties that may explain the postdischarge mortality benefit. It must be stressed, however, that 180day mortality was not among the primary endpoints of the study
and that the trial was not designed to address these endpoints.
Thus, although the results are exciting and potentially paradigm
shifting, they need to be confirmed by the replicate phase III study
© 2013 The Authors
European Journal of Heart Failure © 2013 European Society of Cardiology
127
investigating the effect of serelaxin on cardiovascular death and
other clinical outcomes that is currently ongoing (RELAX-AHF-2,
NCT01870778).
Other clinical trials in acute HF that did not yield such exciting results were presented as the COMPOSE programme.63
The COMPOSE programme consisted of three randomized
clinical trials that tested the efficacy of cinaciguat, a nitric oxideindependent soluble guanylate cyclase activator that produces
vasodilatation. All three studies of the COMPOSE programme
were terminated early due to a high incidence of adverse events.
The majority of patients treated with cinaciguat developed
hypotension, with no improvements in dyspnoea and cardiac
index, even with low doses. Therefore, it seems unlikely that
further trials including cinaciguat will be conducted in acute HF.
Another exciting new drug in clinical development is the firstin-class cardiac myosin activator omecamtiv mecarbil, which has
been shown to enhance cardiac contractility without modulating adrenergic receptors or calcium transients.64,65 Previous
studies reported that omecamtiv was well tolerated and had dosedependent inotropic effects.66,67 It should be noted, however, that
myocardial ischaemia occurred at higher concentrations, probably
due to shortening of the diastolic period. Although the first presentation of data from the ATOMIC-AHF at the 2013 ESC congress
revealed that omecamtiv did not improve dyspnoea in patients
with acute HF, trends toward reduction of worsening HF were
observed. Currently, omecamtiv is being investigated in chronic
HF in the COSMIC-HF trial (NCT01786512). Aliskiren, a direct
renin inhibitor, has been shown to have favourable neurohormonal
effects in chronic HF.68,69,70 In the ASTRONAUT study, aliskiren had
no effect on mortality and HF rehospitalizations in stable acute HF
patients, despite a significant reduction in NT-proBNP levels.5 The
ongoing ATMOSPHERE study may provide further insights regarding the incremental value of aliskiren in the treatment of chronic
HF (NCT00853658).71,72
During the late breaking clinical trial sessions of the HF meeting in Lisbon in 2013, results of the ARTS trial were presented.10
Treatment with the novel non-steroidal mineralocorticoid receptor antagonist (MRA) BAY 94-8862 in patients with systolic HF
and mild to moderate chronic kidney disease was associated with
a reduced incidence of hyperkalaemia or worsening renal function than spironolactone, while the reduction in NT-proBNP levels
was comparable.10 These results suggest that BAY 94-8862 may be
applicable in HF patients with poor renal function, in whom the prescription of current MRAs is limited. Currently, a larger phase IIb
trial with BAY 94-8862, recently named as finerenone, is ongoing
in patients with worsening chronic systolic HF and type 2 diabetes
and/or chronic kidney disease (ARTS-HF; NCT01807221).
As previous pharmacological interventions have failed to show
improvements of morbidity and mortality in HFPEF, novel and
effective drugs for these patients are urgently needed. A large
community-based study is underway to evaluate the prevalence,
clinical characteristics, and diagnostic accuracy of current tests
for HFPEF.73 Hopefully the insights obtained from this study will
result in new therapeutic approaches for this devastating disease.
LCZ696, a novel dual-acting angiotensin receptor and neprilysin
inhibitor, is currently under investigation as a treatment for HFPEF.
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Heart failure highlights in 2012–2013
© 2013 The Authors
European Journal of Heart Failure © 2013 European Society of Cardiology
In PARAMOUNT, a phase II double-blind randomized controlled
trial, LCZ696 was well tolerated and significantly reduced NTproBNP levels at 12 weeks compared with valsartan. At 36 weeks,
the observed difference in NT-proBNP levels was no longer
significant, but improvements in New York Heart Association
(NYHA) functional class and reduction in left atrial size were
observed.11 However, as endpoints of PARAMOUNT were surrogate, further research is needed to evaluate the impact of LCZ696
on clinical outcomes in HFPEF. LCZ696 is currently being investigated in patients with heart failure with reduced ejection fraction
(PARADIGM-HF, NCT0103522) and soon a large phase II trial will
take off investigating the impact of LCZ696 on clinical outcomes in
HFPEF (PARAGON-HF trial, NCT01920711).
The effect of spironolactone was investigated for the first time
in HFPEF during the ALDO-DHF trial.12 Although treatment with
spironolactone improved diastolic function, LVEF, LV remodelling,
and NTproBNP levels, these beneficial effects were not associated
with improvements in exercise capacity and symptoms. Additionally, the late breaking clinical trial, TOPCAT, recently presented
at the 2013 American Heart Association Congress demonstrated
that spironolactone did not resulted in a benefit for the primary
composite endpoint compared with placebo. However, patients
receiving spironolacton did experience fewer hospitalizations for
heart failure.
Finally, the efficacy of anticoagulation in patients with systolic HF
in sinus rhythm was finally disproven in the WARCEF study.9 Using
an elegant double-blind, double-dummy design, >2300 patients
were randomized to warfarin or placebo and followed up for
a median of 3.5 years. While warfarin reduced the incidence of
ischaemic stroke, the incidence of the primary composite endpoint of ischaemic stroke, intracerebral haemorrhage, or all-cause
mortality was comparable between groups. The reduced risk of
ischaemic stroke with warfarin was offset by an increased risk of
major haemorrhage. Whether the novel oral anticoagulants will be
associated with a more favourable risk–benefit ratio remains to be
determined.74
Interventional treatment
Despite the absence of adequately powered randomized controlled
trials, intra-aortic balloon counterpulsation (IABP) has been routinely used for haemodynamic support in patients with cardiogenic
shock due to acute myocardial infarction (MI). The IABP-SHOCK
2 trial was a landmark study which investigated the effect of IABP
in the setting of acute MI complicated by cardiogenic shock.4 In
this trial, 600 patients expected to undergo early revascularization
were randomized to IABP or no IABP (control group). The primary
endpoint was 30-day all-cause mortality. Primary percutaneous
coronary intervention was performed in 95.8% of all patients. The
median duration of IABP support was 3 days. At 30 days, mortality was similar among patients in the IABP group and those in the
control group (39.7% and 41.3%, respectively, P = 0.69). This result
was consistent across all pre-defined subgroups, including different
age categories, stratification according to various cardiovascular
risk factors, and types and location of MI. There were also no significant differences in a number of secondary and safety endpoints,
128
Defibrillators
and resynchronization therapy
The field of cardiac devices evolves further with a shift of focus
to new areas, such as treatment of HFPEF and the prevention
of HF. Implantable cardioverter defibrillators (ICDs) are currently
mainly utilized for primary prevention of sudden cardiac death in
HF patients. After its introduction, the use of total subcutaneous
ICD (S-ICD) has increased.79 A first report of real-life utilization
of this device outside of clinical studies demonstrates a learning
curve, with lower rates of complications in recent patients.80 How
S-ICD compares with transvenous ICDs in terms of efficacy and
complication rates remains to be determined.
Research on CRT is also still ongoing. This therapy seems to be
as effective in a real-life population as in randomized controlled
trials, although CRT-ICD seems to be superior to CRT pacemakers in terms of mortality reduction.81 Even though CRT is a relatively new treatment option, reduction of mortality persists in
the long term and it is also effective in patients older than those
that were usually include in randomized controlled trials.82 The
exact mechanisms of reverse remodelling remain speculative, as
there is no reduction of serum markers of extracellular matrix
proteins.83 Non-response to CRT without reverse remodelling
remains the most important problem. An important issue to target
........................................................................................................................................................................
such as time to haemodynamic stabilization, length of intensive care
unit stay, and rate of ischaemic or bleeding complications. In conclusion, use of IABP does not improve the prognosis of patients
with cardiogenic shock during acute MI and its standard use in this
clinical setting should be discouraged.
The implantation of a MitraClip is a new treatment modality for
severe mitral regurgitation (MR) in patients who are inoperable
or who are at high risk for conventional mitral valve surgery.
The majority of patients who undergo this procedure have a
functional MR (67%), a reduced systolic LV function (71%), with
functional NYHA class III or IV (93%). MitraClip therapy not only
reduces MR severity acutely in the majority (94%) of patients, but
also leads to improvement in functional capacity in about twothirds of patients.75 Future randomized studies in pre-specified HF
populations are ongoing and will give us a more definitive answer on
the additional value of MitraClip implantation in patients suffering
from both HF and severe MR.76 Another percutaneous modality
for MR treatment is mitral annuloplasty using a Carillon Mitral
Contour System.77 This is a double anchor device positioned in
the coronary sinus/great cardiac vein which plicates the periannular
tissue after deployment. First results in patients treated with this
procedure showed a significant reduction of MR and also reverse
LV remodelling.
Recently, renal denervation emerged as a treatment option for
patients with therapy-resistant hypertension. The goal of this intervention is to inhibit sympathetic activity, which beyond any doubt
also plays a crucial role in the pathogenesis of HF.78 Several ongoing trials are already investigating the effects of renal denervation
in both systolic and diastolic HF, and their results are expected to
be published soon.
L.C.Y. Liu et al.
non-response might be adequate lead positioning.84 There is accumulating evidence that the region of latest mechanical activation
can govern lead position. To place three ventricular leads, either
two LV or two right ventricular (RV) leads, seems to be better
than conventional CRT,68 whereas the position of the RV lead per
se (apical or outflow tract) seems to be insignificant.85 At least in
patients with preserved atrioventricular (AV) conduction, an RV
lead might not be necessary at all and LV pacing only may be as
effective.86
Two major trials published in 2012–2013 attempted to expand
the boundaries of the current indications for CRT. The BLOCK-HF
trial compared biventricular with univentricular pacing in patients
with symptomatic HF (LVEF <50%) and an AV block that required
pacing.7 A CRT device (with or without ICD) was implanted
and patients were subsequently randomized to receive either
biventricular or RV pacing. Biventricular pacing was associated with
a significant reduction in the primary endpoint of time to death
from any cause, an urgent care visit for HF, or a ≥15% increase in
the LV end-systolic volume index. This study therefore advocates
a more lenient approach towards CRT implantation in HF patients
with an AV block. In the EchoCRT trial, patients with symptomatic
systolic HF, a narrow QRS, but with echocardiographic evidence
of LV dyssynchrony received a CRT device and were randomized
to have the CRT capability turned on or off.8 In these patients,
resynchronization therapy did not modulate the incidence of the
primary composite outcome of death from any cause or first
hospitalization for worsening HF. Remarkably, the incidence of
all-cause mortality was significantly increased in the CRT group.
Therefore, this study shows that CRT should not be used to treat
dyssynchrony in patients with a narrow QRS.
Device therapy for HFPEF seems a potentially attractive novel
target.8 Patients with HFPEF have a high incidence of sudden cardiac
death, and ICD therapy for this patient group is an interesting
hypothesis that still needs to be tested. In a subgroup of patients,
biatrial pacing can improve diastolic filling and exercise capacity.87,88
The term atrial resynchronization therapy can be coined for
this therapy and might be new in the arsenal of treatments for
HFPEF and to prevent AF.89 In addition to atrial resynchronization,
ventricular resynchronization can also be effective in patients with
HFPEF.90 Biventricular pacing might be the preferred strategy in
any patient that needs continuous ventricular pacing.7 Whether
this is true for all patients remains unknown. Future studies will
have to investigate predictors for worse outcome with RV pacing,
such as genetic factors or functional criteria. In patients that have
been made pacemaker dependent with AV junction ablation, the
advantage of biventricular over RV pacing might be limited.91
Ventricular assist devices
Heart transplantation represents the standard of care for eligible
NYHA class IV HF patients, and outcomes of heart transplant
recipients keep improving.92 However, the limited availability of
suitable donor hearts has restricted its application to <1500
patients per year in Europe. As a result, the proportion of patients
with long-term ventricular assist devices (VADs) continues to
© 2013 The Authors
European Journal of Heart Failure © 2013 European Society of Cardiology
129
increase rapidly.93,94 Starling et al. demonstrated in the post-US
Food and Drug Administration-approval study that survival was
85% for the HeartMate II continuous-flow LVAD vs. 70% for
other types of LVADs [79% HeartMate XVE, 21% implantable
VAD (Thoratec Corporation)].95,96 Also, haemodynamic recovery,
exercise tolerance, and quality of life improved at 3 months, and
the improvement in quality of life was sustained up to 12 months of
LVAD treatment.95 VAD therapy is now recommended in the 2012
ESC HF guidelines as bridge to transplant (class I recommendation,
level of evidence B) and as destination therapy for patients not
eligible for heart transplantation (class IIa recommendation, level
of evidence B).50 VAD therapy has thus transformed into an
established HF treatment, and studies aimed at improving VADassociated therapy are warranted.
While ICDs are indicated for patients with advanced HF, a small
number of patients will not have an ICD at the time of VAD implantation. The question that arises is whether they should receive
both devices. Garan et al. published a paper on ventricular arrhythmias and ICD therapy in 94 patients with continuous-flow LVADs
(77 with ICD, 17 without ICD).97 They found that patients with
pre-LVAD ventricular arrhythmias were at risk of recurrent ventricular arrhythmias while receiving continuous-flow LVAD therapy and
may need an ICD to minimize sustained ventricular arrhythmias.
Patients without pre-LVAD ventricular arrhythmias are at low risk
and may not need active ICD therapy. New developments in LVAD
technology may also improve survival and quality of life. Totally
implantable LVADs may reduce infection rates,97 and perhaps modulations of LVAD pump speed during exercise may improve exercise
tolerance.98 Finally, end of life decisions will become inevitable
in some patients, which will require cessation of LVAD therapy.
Appropriate protocols for cessation of LVAD therapy need to be
developed.99 Increased experience with LVAD therapy will probably contribute to improvements in the care for patients with
advanced HF.
Funding
None.
Conflict of interest: All authors have nothing to disclose.
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© 2013 The Authors
European Journal of Heart Failure © 2013 European Society of Cardiology