Stein_revised.qxp 26/2/09 02:29 Page 22
Cholesterol Management and Risk Reduction
significant differences in cardiovascular outcomes between the two Recruitment into ASAP took place in 1997, when general statin use,
groups. The additional significant LDL-C reduction seen in the ezetimibe mostly at low doses, had only recently been introduced, the highest
plus simvastatin group of 16.5% (p<0.01) was as anticipated: mean dosage of simvastatin was 40mg and atorvastatin had just been approved
LDL-C levels fell from 317.8±66.1 to 192.7±60.3mg/dl in patients treated for general use. Thus, in ASAP few patients had received prior statin
with simvastatin, and from 319.0±65.0 to 141.3±52.6 mg/dl in patients therapy, and none of them would have received the long-term aggressive
receiving ezetimibe/simvastatin. Furthermore, patients receiving the statin therapy that had become more conventional by the time the
combination therapy experienced significantly greater reductions in ENHANCE trial began enrolment. Since 80% of the patients enrolled in
triglyceride and hsCRP levels compared with the simvastatin group ENHANCE had previous treatment with statins and other lipid-lowering
(p<0.01 for both). The results of ENHANCE were also different from agents, and given the thin baseline cIMT indicating minimal
those of ASAP in the simvastatin monotherapy group in that cIMT was atherosclerosis, the aggressive LDL-C reduction with the addition of
not significantly different from baseline and failed to show the ezetimibe to high-dose simvastatin may not have had any ability to further
progression seen in ASAP. In light of the lack of regression in cIMT in the alter cIMT. Indeed, a follow-up study of the initial treatment period in
ezetimibe-treated group, the only possible way left to show ‘benefit’ ASAP found that there was minimal subsequent progression and no
resulted in questions about whether there exist any additional regression (0.005mm/year) with atorvastatin 80mg/day, suggesting that
cardiovascular benefits with combination therapy. continued LDL-C lowering may have had only a minimal impact on cIMT
progression after a period of statin treatment.
27
This is further supported
The Design of the ENHANCE Trial by two other FH cIMT trials where patients who continued on aggressive
There has been much speculation, albeit by a vocal few, on the neutral statin therapy showed no change and no regression in cIMT over two
outcome of the study, with the results being interpreted as the LDL-C years: Rating Atherosclerotic Disease Change by Imaging with a new CETP
reduction with ezetimibe having no additional benefit, possibly even Inhibitor Trial (RADIANCE 1) and Efficacy and Safety of the ACAT Inhibitor
raising the risk of cardiovascular disease, or as evidence against the CS-505 (CAPTIVATE).
30,31
The minimal atherosclerosis seen at baseline by
LDL-C hypothesis. However, as this discussion will outline, the study itself cIMT in ENHANCE is thus very likely due to the high incidence of previous
contained a number of critical flaws in its design. statin treatment and may therefore have led to a lack of difference in cIMT
progression over 24 months of treatment with ezetimibe, in spite of the
As outlined earlier, ENHANCE was based on ASAP, a smaller study that 16.5% greater reduction in LDL-C levels.
found that atorvastatin could significantly reduce the progression of cIMT
in patients with FH compared with low doses of simvastatin.
26,27
The The Arguments
rationale for selecting a similar population of patients with FH for Critics of the ENHANCE study have been quick to accuse ezetimibe of
ENHANCE was that these patients would have significantly lipid-enriched having no impact on atherosclerosis or to suggest that the LDL-C
and thickened carotid arteries, reflected by a baseline cIMT that would be hypothesis is flawed, questioning the role of LDL-C as a proven
higher than average, as well as an accelerated progression rate even on surrogate for atherosclerosis.
32–34
Some critics have proposed that the
high-dose therapy.
24
This hypothesis turned out to be significantly inability of ezetimibe to inhibit atherosclerosis may be due to an off-
flawed: baseline thickness was not only not thickened but also consistent target effect that negates the benefits of LDL-C lowering, comparing
with the thinnest cIMT seen in epidemiological studies in low-risk the function of ezetimibe with that of oral oestrogen and torcetrapib.
women,
25
and this was further compounded by the negligible While oral oestrogen and torcetrapib can lower LDL-C, randomised,
progression rate observed in both treatment groups. Where other trials controlled, prospective outcome trials have shown that these drugs
studying cIMT progression had set a minimum cIMT entry criterion, increase the risk of cardiovascular events.
35,36
The increase in
ENHANCE did not. The baseline cIMT was expected to be similar to the cardiovascular events observed with these two agents is large and
0.93mm observed in ASAP, but the resulting baseline measurement of robust, and can be explained by well-documented mechanisms: oral
0.69mm was significantly lower than that observed in other trials, many oestrogen and progesterone are prothrombotic,
37
and torcetrapib
of which list a thickness of >0.7mm as a minimum enrolment criterion. substantially raises blood pressure through increased aldosterone
The one-year Carotid Atorvastatin Study in Hyperlipidemic Post- production.
38
In comparison, the pathway by which ezetimibe lowers
menopausal Women: a Randomized Evaluation (CASHMERE), which plasma LDL-C is similar to that of statins and BAS, where the LDL
enrolled patients with similarly thin cIMT, found no statistical difference receptor is upregulated secondary to hepatic intracellular cholesterol
in cIMT results when comparing placebo with atorvastatin 80mg in 399 depletion. Statins function by inhibiting cholesterol synthesis, lowering
post-menopausal women; in fact, atorvastatin resulted in more hepatic intracellular cholesterol, upregulating LDL receptors and
progression than placebo.
28
Baseline cIMT was reported as 0.69mm, and promoting LDL-C clearance. BAS interfere with the reabsorption of bile
the most likely reason for the observed ‘failure’ of CASHMERE was the acid in the ileum, decreasing intracellular hepatic cholesterol and
lack of carotid atherosclerosis at entry or the development of the disease upregulating LDL receptors. Ezetimibe works in a similar fashion,
during the trial. Just as in ENHANCE, the data from CASHMERE point decreasing cholesterol return to the liver to lower hepatic intracellular
towards a flawed design, even with a valid surrogate marker, rather than levels and upregulate LDL receptors.
39
Animal studies have shown that
flaws in the efficacy of the therapy. In comparison, a recent cIMT trial ezetimibe can reduce atherosclerosis
40
and enhance macrophage efflux
studying patients with relatively mild hypercholesterolaemia, Rosuvastatin of cholesterol, potentially increasing reverse cholesterol transport.
41
on Progression of cIMT of Low-Risk Individuals with Subclinical Thus, ezetimibe is unlikely to have an off-target effect.
Atherosclerosis (METEOR), enrolled only statin-naïve patients with a
minimum mean cIMT of >0.7mm.
29
Thus, the majority of patients The LDL-C hypothesis has also been called into question, where
enrolled in ENHANCE and CASHMERE, with only minimal carotid opponents believe that the pleiotropic effects of statins in reducing
atherosclerosis, would not have qualified for a trial such as METEOR. inflammation ultimately have a favourabe impact on atherosclerosis, and
22 ASIA-PACIFIC CARDIOLOGY
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