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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 2, March/April 2019
106
AFRICA
mean ejection fraction compared to the larger clinic cohort
(LVEF: 20.9 vs 27.3%,
p
=
0.0001), as well as higher resting heart
rates (mean 94.2 vs mean 85.9 bpm,
p
=
0.006). In addition,
this subgroup had a shorter follow-up duration (43.3 vs 58.7
months,
p
=
0.006). Diabetes mellitus correlated with ivabadrine
suitability (
p
=
0.003), with these patients being twice as likely to
meet the criteria for ivabradine suitability. Not patient gender,
cause of heart failure, or associated treatments was statistically
associated with meeting the criteria for ivabradine therapy.
Discussion
Efficacy of beta-blockers in patients with HFrEF is well
established. However, actual use has been unsatisfactory,
largely due to perceptions about tolerability and consequent
reluctance among clinicians to up-titrate doses despite guideline
recommendations.
5
Unfortunately, the perceptions of danger and
intolerability of beta-blockers appear to be over-exaggerated by
many physicians, to the disadvantage of patients who would
benefit.
19,20
In this study, we have demonstrated that in a dedicated heart
failure clinic in a large urban public hospital in Johannesburg,
South Africa, the majority (97.8%) of HFrEF patients could
be prescribed a beta-blocker. In contrast to large international
surveys, we found that beta-blockers were generally well tolerated
by patients attending the heart failure clinic. Almost 88% of
these patients tolerated up-titration of their beta-blocker to
target or moderate target doses. In this real-world population,
we have shown that beta-blockers were used more often and at
much higher doses than those reported in multi-centre surveys
and registries in other parts of the world.
11,13
Furthermore, we have shown that in certain subgroups of
patients with co-morbid diseases, such as chronic obstructive
pulmonary disease, diabetes and peripheral arterial disease in
whom beta-blocker usage by clinicians is historically poor, the use
of beta-blockers is generally safe, with a small minority unable to
tolerate target doses. The only statistically significant predictors
for beta-blocker intolerance were concurrent asthma (but not
chronic obstructive pulmonary disease) and hypothyroidism.
Bradycardia was the commonest reason for patients not being at
target beta-blocker dosage, which is consistent with previously
reported data.
20
In the South African context, there are few published data
regarding beta-blocker use, tolerability and achievement of
target doses in chronic heart failure patients. In low- and middle-
income countries, it has been reported that only 34% of heart
failure patients receive beta-blocker therapy.
21
In the Heart of
Soweto Study cohort, 64% of patients received a beta-blocker
during the index admission for acute heart failure,
22
while in a
study in Cape Town the rate of beta-blocker use at the time of
discharge after an acute heart failure episode was only 42.7%.
23
However, data on out-patient beta-blocker use is lacking,
particularly in black patients, a group that has historically been
under-represented in major heart failure trials.
In the current study, black patients constituted 66% of
the cohort, whereas in the SHIFT study,
8
similar to most
international trials, the majority of patients were white (89%),
with black patients comprising less than 3% (grouped in category
of ‘other’). Although lacking specific data, it would appear that
the socio-economic status of our cohort of patients attending a
public hospital was substantially different from that of patients
enrolled in the large European and North American clinical
trials. Yet, despite the challenges of this relatively economically
poor group of patients, the majority of patients were able to be
compliant and were up-titrated successfully.
Our data also suggest that the role for additional rate-
control therapy beyond beta-blockers in systolic heart failure
patients is limited to only a small group of selected patients.
Although SHIFT
17
reported that heart rate reduction with
ivabradine reduced the composite end-point of mortality and
cardiovascular-associated hospitalisation was reduced by 18%,
background beta-blocker usage was substantially lower in the
trial population than would have been clinically expected by the
very clear guideline recommendation for patients with HFrEF.
In the SHIFT study, only 23% of the patients were at
target doses, and less than half (49%) were receiving 50% or
more of the target doses at enrolment. The authors of the
study explained that the low beta-blocker dose and frequency
of use was a result of standard clinical practice in their large
study population. However, criticism of applicability followed,
since under-treatment with beta-blockers could have inflated
the potential benefit and exaggerated the proposed role of
ivabradine as a treatment modality.
24,25
Despite the criticism, use
of ivabradine has been given a class IIa recommendation for the
reduction of hospitalisation or cardiovascular death in the latest
ESC heart failure guidelines.
7
The patient population studied in SHIFT was broadly similar
to our cohort but there are a number of notable differences. In
our study, patients were younger by five years (mean age 55.8 vs
60.1 years), included more females (47 vs 24%), and were more
ethnically diverse. Ischaemic heart disease was the predominant
cause of heart failure in SHIFT (68%), compared with 22% in
our study. LVEF at enrolment was slightly worse in our study
patients compared with the SHIFT population (27 vs 29%).
Mean estimated glomerular filtration rate (eGFR, ml/min per
1.73 m
2
) in our study patients was better (85.2 ml/min) compared
with the SHIFT cohort (74.6 ml/min).
These and possibly other unmeasured factors may have
played a role in the better response and tolerance of our patients
to beta-blockade. Despite these differences, our data suggest that
the findings of SHIFT (that beta-blocker intolerability is a major
indication for use of pure heart rate-reducing agents) are not
wholly applicable in our setting.
This study has some limitations. Selection and information
bias are known limitations in retrospective studies. Furthermore,
this was a single-centre study in a dedicated heart failure
clinic, which may mean that the findings may not be generally
applicable in less dedicated facilities and in other regions.
Conclusion
This study demonstrates that in a public hospital in South Africa,
a concerted strategy to initiate and progressively up-titrate
beta-blockers in patients with HFrEF was highly successful
in the majority of patients. Furthermore, beta-blockers were
found to be well-tolerated in this group of patients. Our results
suggest that the number of patients in South Africa who may
qualify for further heart rate-reduction therapy would be small
after deliberate efforts to initiate and up-titrate beta-blockers,
according to local and international standards.