CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 5, September/October 2011
AFRICA
291
Heart rate now a risk factor for cardiovascular disease
SHI
f
T echocardiographic
study supports ivabradine’s
heart rate-lowering benefits
The need to accept heart rate as a causa-
tive risk factor that provokes adverse
events in patients at risk, including those
with heart failure, was evident from
the results presented by the SHI
f
T and
CLARIFY trialists at the recent 2011
ESC congress in Paris.
While some clinicians had felt that
the results of the SHI
f
T trial published
last year,
1
and earlier beta-blocker trials
had made a strong case for heart rate
being a risk factor rather than a marker
of poorer prognosis, the vital element of
demonstrating reversal of disease when
the risk factor is knocked out of the ring,
was missing.
The results of the prospective echocar-
diographic study on a sub-group of the
heart failure patients in the SHI
f
T trial
2
now suggest that left ventricular remodel-
ling in heart failure can be modified by
ivabradine, the novel, pure heart rate-
lowering agent.
The echocardiographic study was
undertaken in 411 patients participating
in SHI
f
T and it evaluated left ventricu-
lar function at both baseline and after
eight months of ivabradine therapy. The
primary endpoint was the change in left
ventricular end-systolic volume index
between baseline and eight months.
The population in the echocardiogra-
phy study mirrored the overall population
of SHI
f
T, mainly older Caucasian men
with non-valvular heart failure in sinus
rhythm. The study showed that ivabradine
therapy lowered the left ventricular end-
systolic volume index (LVESVI) by –7.0
ml/m
2
compared to no change in patients
on standard background therapy for heart
failure. Similarly, the left ventricular end-
diastolic volume index (LVEDVI) was
also decreased by ivabradine by –7.9 ml/
m
2
, whereas with placebo, the volumes
were little changed.
The decrease in left ventricular
volumes were associated with a signifi-
cant increase in the ivabradine-treated
group (+2.4 versus –0.1;
p
<
0.001)
compared to the standard-care group. ‘It
is worth noting that the standard care in
SHI
f
T was good, with 90% of patients
on RAAS inhibitors and beta-blockers.
One-third of the patients were treated to
the target beta-blocker dose while 54%
received 50% of targeted doses’, Dr Karl
Swedberg, Gothenburg, Sweden said.
‘These changes show some reversal of
the adverse cardiac remodelling in heart
failure. In addition, the improvements in
left ventricular systolic function occurred
independently of beta-blocker use, aetiol-
ogy of heart failure, whether ischaemic or
non-ischaemic, and the baseline ejection
fractions’, study presenter Professor Jean-
Claude Tardif from the Montreal Heart
Institute Canada commented. He also
indicated that ‘when these cardiac chang-
es were related to heart rate, we found that
greater decreases in heart rate were asso-
ciated with greater increases in LVEF.’
These results provide a mechanistic
and pathophysiological explanation for
the results of SHI
f
T, which enrolled 6 500
patients in sinus rhythm, with moder-
ate to severe chronic heart failure and a
LVEF
<
35%. Treatment with ivabradine
superimposed on standard background
therapy for heart failure was associated
with an 18% reduction in risk for the
primary composite endpoint of cardiovas-
cular death or hospitalisation for worsen-
ing heart failure (
p
<
0.0001) and a 26%
reduction in heart failure deaths (
p
=
0.014).
A further interesting animal model
study in diabetic mice, presented at the
ESC, showed that ivabradine reduced
vascular and left ventricle stiffness, there-
by improving left ventricular contractility
and diastolic functioning.
3
Improving quality of life: a
new evaluation within the
SHI
f
T study
A second SHI
f
T analysis set out to
assess whether quality of life in heart-fail-
ure patients was related to prognosis and
changes in heart rate.
4
It involved 1 944
patients with chronic heart failure from
24 participating countries, with no bias-
ing reason for exclusion, except where the
relevant questionnaire was not available
and standardised in the local languages.
Health-related quality of life
was assessed using the Kansas City
Cardiomyopathy Questionnaire (KCCQ),
a validated, disease-specific measure
of functional status and quality of life.
The 23 items of the questionnaire are
divided into two sets of scores, the clin-
ical summary score assesses physical
limitation and symptoms and the overall
summary score assessing social limita-
tions in chronic heart-failure patients. The
higher the score, the better the quality of
life.
By one year, the study showed that the
risk of a cardiovascular event increased in
patients with lower KCCQ scores (equat-
ing to a lower health-related quality of
life). The reduction in heart rate achieved
through treatment with ivabradine
was associated with almost double the
improvement in quality of life compared
to the control group. This improvement
was observed in both the disease-related
component and the social component
of the scores. Practically speaking, this
means that patients treated with ivabra-
dine were able to participate in a greater
number of everyday activities, consider-
ably changing their day-to-day life.
Comments from South
African experts
Prof Karen Sliwa, University of Cape
Town
It is reassuring to have an explanation of
ivabradine’s action in terms of improved
left ventricular function, reduction in left
ventricular size and improvement in the
contractility of the left ventricle. The data
come from a thorough echocardiographic
study of a sub-set of patients that was well
matched to the profile of the heart-failure
patients within the overall SHI
f
T study.
The importance for the clinician is
to underscore the opportunity to further
improve outcomes in heart-failure patients
who are receiving maximum ACE inhibi-
tion and beta-blocker therapy and yet have
a heart rate above 70 beats per minute.
While ivabradine is not yet widely used in
the South African public sector, this new
finding of reversal of disease progression
could help to make a powerful case for
its wider use; for example, in younger
patients where longer-term benefits can
accrue with significant cost savings in
both hospitalisation and chronic care.
We should not be too concerned by
the slow uptake around the world of this
novel modality, including of course in
South Africa. I was struck by the results
of the PURE study, also released at this
meeting by Dr Salim Yusuf, which has
shown a huge under-use of cheap and
