CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 2, March/April 2011
AFRICA
83
inhibitor ramipril in black Africans.
Although there is evidence to suggest that ACE inhibi-
tors lower BP to a lesser extent when used as monotherapy in
African-Americans,
15,16
the ASTRAL study has demonstrated
that the combination of ACE inhibitor and thiazide diuretic was
effective in controlling BP in black Africans. This is given that
a high number of the patients reached target goals of BP control
despite a substantial number of them either initially not receiv-
ing pharmacological treatment (8.9%) or being on a single agent
for BP control (61.9%). The lower attainment of BP goals in the
diabetic group, as was also indicated by the logistic regression
analysis, may be an indication of the lower target and the degree
of diabetic end-organ damage, including nephropathy.
Similar results were reported from South Africa where enal-
april was ineffective as monotherapy but the addition of either a
diuretic or reserpine dramatically increased BP control rates.
17
Underscoring the efficacy of fixed-dose ramipril/HCTZ in this
study was the sustained and significant change in SBP and
DBP from week zero to week eight and the fact that most of the
patients remained on standard or half-standard dose of ramipril/
HCTZ throughout the study duration.
In addition to its effects on BP, ramipril offers additional
benefits on target-organ protection in patients of African descent.
In the African-American Study of Kidney Disease (AASK),
18
ramipril was superior to amlodipine on renal outcomes in
patients with hypertensive nephrosclerosis for comparable BP
control. Other studies like HOPE
19
and AIRE
20
(although not
directly linked to African patients because of small numbers of
black patients enrolled), showed important benefits of ramipril
in patients at high CV risk or with cardiac failure, respectively.
The present study was however not designed to assess other
additional benefits of ramipril.
During the ASTRAL study period, there were eight episodes
of reported adverse events by six patients who were on either
half-standard or standard therapy, suggesting that the adverse
events may not have been dose related. It is nonetheless not
surprising that facial oedema and dry cough were the two most
common, given that these two, together with hyperkalaemia,
hypotension and renal dysfunction, are known and commonly
reported adverse effects of ACE inhibitor use.
In the HOPE study,
19
reasons for discontinuation of the study
were cough (7.3%), hypotension (1.9%) and angio-oedema
(0.4%). However, given the short duration of the present study,
it may be difficult to conclude that the study drug is safe with
a small adverse-events profile, even though there has been a
relatively low frequency of reported adverse events. A particular
concern for clinicians in Africa may be the increased risk of
angio-oedema
21
and deaths
22
reported with enalapril in African-
Americans compared to whites, suggesting that there may be
racial differences in the predilection to angio-oedema with the
use of ACE inhibitors. In the ASTRAL study, the incidence of
ACE inhibitor-related angio-oedema was 0.45%, which closely
approximates the incidence reported in the HOPE study.
19
One limitation of the ASTRAL study has been the inability to
measure or document changes in serum electrolytes and certain
metabolic parameters, such as sodium, potassium, uric acid and
glucose, which are known to be affected by thiazide diuretics.
The modern tendency is for low-dose HCTZ (12.5 mg) to be
recommended to avoid these metabolic complications and this
has been incorporated into recent guidelines.
23
However HCTZ
12.5 mg as monotherapy has never been shown to improve
outcomes and has a very weak anti-hypertensive activity in
African patients.
16
The higher dose of HCTZ (25 mg) offers more
effective antihypertensive activity, particularly in combination
with inhibitors of the renin–angiotensin system.
There are also concerns, particularly regarding the increased
incidence of new-onset diabetes with the higher dose. This is
a controversial topic but it has never been shown in a large
outcome study that new-onset diabetes worsens outcomes.
24
Although there was no measurement of blood glucose in this
study there were no reported cases of new-onset diabetes.
A few patients were titrated upwards to ramipril 10 mg/
HCTZ 50 mg for better BP control and although no significant
adverse effects were reported, this raises some concerns about
evaluating drug efficacy against its potential adverse effects,
particularly electrolyte imbalances. Although this high dose of
HCTZ has been used in major outcome studies, we would rather
recommend the addition of alternative anti-hypertensive agents
to achieve BP control until further safety information is avail-
able. In this study, the majority of patients did not require more
than 25 mg HCTZ in the fixed-dose combination to achieve BP
control.
Conclusion
Fixed-dose combination of ramipril/HCTZ is an effective, toler-
able anti-hypertensive agent with a good safety profile, which
can be used to control BP in black Africans. This combination
may be more effective in non-diabetics than patients with diabe-
tes mellitus. Extended study with this combination is still needed
to assess its long-term efficacy and safety.
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