CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 4, July/August 2011
AFRICA
227
Safe use of ezetimibe plus simvastatin in high-risk vascular
patients (with chronic kidney disease and PAD)
The use of ezetimibe together with a
statin to reduce LDL cholesterol in high-
risk patients in whom raising the statin
dose is not desirable has been shown to be
safe in the SHARP trial and in a trial on a
small group of peripheral arterial disease
(PAD) patients.
1,2
The SHARP study (9 270 patients) has
shown that patients with chronic kidney
disease who take simvastatin (20 mg) plus
ezetimibe (10 mg) would typically reduce
their risk of non-fatal atherosclerotic
events by about a quarter (17%, CI: 0.74–
0.94). This study provides new evidence
for this group of patients as they are typi-
cally excluded from statin and cardiovas-
cular outcome trials. Importantly, there
was no increase in cancer rates or myopa-
thy in the ezetimibe-treated patients
followed for a mean period of 4.9 years.
This independent UK trial was under-
taken in patients with chronic kidney
disease (with one previous measure-
ment of serum/plasma creatine of at least
150 mmol/l in men and 130 mmol/l in
women), whether on dialysis or not, and
with no known history of myocardial
infarction or coronary revascularisation.
Initially, patients entered into the trial
were randomised in three ways: simvas-
tatin only (20 mg), simvastatin (20 mg)
and ezetimibe (10 mg) daily, or placebo,
so as to test for any safety concerns with
ezetimibe in the first year. No concerns
were evident, so then the simvastatin
group were further randomised to the
placebo or the simvastatin–ezetimibe
group. Patients were seen at two, six and
12 months, and every six months thereaf-
ter, for at least four years in total.
LDL cholesterol levels were lowered
by 0.80 mmol/l in patients not on dialysis
and 0.60 mmol/l in dialysis patients. A
third (33%) of the patients recruited were
on dialysis (maintenance, haemodialysis
and peritoneal) at randomisation, and a
further third went onto dialysis during the
trial, i.e. 60% of patients at the end of the
study were on dialysis.
Some 30% of patients discontinued
therapy with no excess of discontinua-
tion in the simvastatin–ezetimibe arm.
Because of non-study statin uptake in the
placebo arm during the study, the average
difference in proportion of those taking
simvastatin plus ezetimibe versus non-
study statin was 61%.
During the scheduled treatment peri-
od, there were 526 (11.3%) occurrences
of a first major atherosclerotic event
(non-fatal MI or coronary death, non-
haemorrhage stroke or any arterial revas-
cularisation) in the simvastatin–ezetimibe
arm compared to 619 (13.4%) in those
allocated to placebo.
Allocation to simvastatin–ezetimibe
was associated non-significantly with
fewer non-fatal MIs but no difference in
coronary mortality. There was however
a significant reduction in the risk of any
type of stroke and of the need for revas-
cularisation.
This trial’s outcome of beneficial
advantage to patients with chronic kidney
disease (without coronary heart disease)
should provide the basis for wider use of
cholesterol-lowering agents in patients
with chronic kidney disease, and also
those with coronary heart disease, who
are likely to benefit even more than the
SHARP cohort.
Comment to the
Cardiovascular
Journal of Africa
Prof Brian Rayner, University of Cape
Town
Chronic kidney disease (CKD) is now
recognised as an independent risk for
cardiovascular disease (CVD) and is the
most important cause of death in patients
with CKD. Statin therapy prevents adverse
cardiovascular outcomes in patients with-
out CKD, and
post hoc
analysis of cardio-
vascular studies suggests a benefit of
statin therapy in patients with reduced
glomerular filtration rate.
In patients receiving haemodialysis,
two trials (AURORA and 4D) showed no
benefit from statins on a composite cardi-
ovascular endpoint. However, CVD in
patients receiving chronic haemodialysis
is more complex, and whether the results
of AURORA and 4D can be generalised
to patients with CKD not receiving dialy-
sis, is questionable.
In the SHARP study, 4 650 patients
were assigned to receive simvastatin plus
ezetimibe and 4 620 to placebo.Allocation
to simvastatin plus ezetimibe yielded an
average LDL cholesterol difference of
0.85 mmol/l during a median follow up
of 4.9 years and produced a 17% propor-
tional reduction in major atherosclerotic
events with simvastatin plus ezetimibe
(526, 11.3%) vs placebo (619, 13.4%)
(RR
=
0.83,
p
=
0.0021).
Non-significantly fewer patients allo-
cated to simvastatin plus ezetimibe had
a non-fatal myocardial infarction or died
from coronary heart disease (RR
=
0.92,
p
=
0.37). There were significant reductions
in non-haemorrhagic stroke (RR
=
0.75,
p
=
0.01) and arterial revascularisation
procedures (RR
=
0.79,
p
=
0.0036). Risk
reduction was similar between dialysis
and non-dialysis patients. There was no
excess risk of myopathy, hepatitis, gall-
stones, cancer or non-vascular death.
This study definitively establishes the
safety and efficacy of LDL-C lower-
ing with simvastatin plus ezetimide in
patients with CKD, whether they are
receiving dialysis treatment or not.
The reasons for the difference between
AURORA and the 4D study is not estab-
lished, and may be due to differences
in power or definition of cardiovascular
events. However, until evidence is provid-
ed of the beneficial effects of statins in
randomised clinical trials in patients with
CKD, cardiologists and nephrologists
should prefer the combination therapy
with simvastatin and ezetimide, based on
the evidence. It is hoped that funders will
support this approach in this very high-
risk population, who require intensive
cardiovascular protection.
It's the
shell that
makes
safer.
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