CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 4, July/August 2011
214
AFRICA
Drug Trends in Cardiology
The evolution of heart rate: past, present and future
Prof Prakash Deedwania, Chief of Cardiology Division, UCSF, Fresno, CA
‘Heart rate is simple – and simple is
not “sexy”. This has led to the mistaken
impression that heart rate is not impor-
tant. But, in fact, nothing is more impor-
tant than heart rate.’ This is the viewpoint
of Prof Prakash Deedwania, who was
in South Africa recently as a guest of
Servier.
Prof Deedwania cited a study that
evaluated variables in heart failure.
‘Heart rate was shown to be the most
powerful predictor of outcome’, he said.
‘Increments in heart rate are essential in
causing ischaemia.’ He pointed out that
animals with the slowest heart rates have
the longest life spans. Tortoises, at six
beats per minute (bpm), live an average
177 years, while mice, at 600 bpm, live a
mere two years.
The first evidence of the prognostic
importance of heart rate was published
in the
Journal of the American Medical
Association
as long ago as 1945. The
study in question showed that even tran-
sient tachycardia was associated with
negative effects and, in the years since,
many other studies have produced similar
results, notably that a heart rate above 80
bpm is associated with higher cardiovas-
cular and absolute mortality risk.
Prof Deedwania highlighted the
following. The Paris Prospective study,
published in 2005, showed that risk of
sudden death increased progressively
with resting heart rate in the general
population. In the National FINRISK
study published last year, elevated resting
heart rate was found to be an independent
risk factor for total mortality in healthy
men and women.
The 1999 French Cohort study
showed that resting heart rate indepen-
dently predicted both cardiovascular and
total mortality in both genders, while the
Framingham study found that all-cause
mortality increased progressively with
resting heart rate in men with hyperten-
sion. ONTARGET and TRANSCEND
found that increased heart rate was asso-
ciated with an increased risk of major
cardiovascular events in stable coronary
artery disease (CAD) patients.
‘When we look at myocardial infarc-
tion (MI), left ventricular ejection frac-
tion (LVEF) is a powerful predictor, but
no more so than heart rate’, he contin-
ued. ‘This was shown in GISSI-3, which
looked at in-hospital mortality and six-
month mortality in MI survivors.’
‘The more heart rate increases, the
more the ischaemia. Heart rate is there-
fore a very powerful predictor of ischae-
mia. Without increased heart rate, it is
difficult to produce ischaemia.’
The place of ivabradine in CAD
management
Prof Deedwania feels that ivabradine
is a useful addition to the beta-blocker
category of drugs as it offers pure heart
rate reduction without negative effects
on other aspects of cardiac function-
ing. ‘It improves coronary perfusion and
maintains cardiac performance better than
alternative drug therapy, with no effect
on blood pressure, ventricular relaxa-
tion and contractile force’, he said. ‘The
Primary Efficacy study, published in
2003, showed that it reduced heart rate at
rest and also proportionally, during exer-
cise. However, it is important to ensure
a therapeutic dose to achieve an optimal
response.’
While dose for dose relative to ateno-
lol, ivabradine offers similar heart rate
reduction and comparable anti-anginal
efficacy in respect of resting heart rate,
it also improves exercise tolerance,
something beta-blockers do not do. In
the ASSOCIATE study, which evalu-
ated ivabradine versus atenolol in well-
controlled patients, ivabradine further
reduced heart rate in patients already on
beta-blockers, with an associated benefit
in most exercise parameters. ‘Adding
ivabradine to beta-blockers is therefore
beneficial’, said Prof Deedwania. ‘It’s
also a very good choice in the approxi-
mately 30% of patients who are intolerant
of beta-blockers.’
Relative to amlodipine, ivabradine
has also been shown to be non-inferi-
or in respect of anti-anginal and anti-
ischaemic efficacy. ‘It has been shown
to work as monotherapy and to further
enhance the benefits of beta-blockers and
calcium channel blockers’, observed Prof
Deedwania.
The BEAUTIFUL study evaluated
high-risk patients with chronic stable
CAD and a LVEF below 40%. ‘The lesson
learned from the trial’s placebo arm was
that a heart rate
≥
70 bpm was associated
with a significant increase in mortality.
Ivabradine reduced coronary risk in these
patients, and the benefits were particular-
ly apparent in those who had both stable
CAD and angina. Ivabradine is the only
anti-anginal agent that actually reduces
cardiovascular events in angina patients.’
Heart rate as a risk factor in
chronic heart failure
Worldwide, heart failure is increasing
rapidly and is a major factor in healthcare
expenditure. The EPHESUS trial showed
that heart rate is a powerful predictor
of outcome in heart failure, responsible
for a significant increase in all-cause
and cardiovascular mortality as well as
combined cardiovascular mortality and
hospitalisation – and this despite patients
receiving optimal therapy.
The SHI
f
T trial’s primary objective
was to ascertain whether ivabradine
improves cardiovascular outcomes in
moderate to severe chronic heart failure.
Participants had heart rates
≥
70 bpm and
LVEFs
≤
35% and were receiving recom-
mended therapy.
‘We learned that heart rate is a risk
factor in these patients, and that on aver-
age ivabradine reduced heart rate from 80
to 64 bpm, something that was sustained
through two-and-a-half years of follow
up. Cardiovascular death/hospitalisation
declined by a significant 18%, heart fail-
ure hospitalisation was reduced by an
