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ENHANCE – After the Dust Has Settled, Is LDL Cholesterol Lowering What It Once Was?
that changes in hsCRP may better predict risk reduction than decreases LDL-C and triglyceride levels compared with placebo, it failed to show
in LDL-C levels. While ezetimibe monotherapy induces very little any significant difference in cIMT progress from placebo. Additionally,
reduction in hsCRP, which has led critics to question the there is no evidence at this time that the addition of fenofibrate to statin
antiatherosclerotic effects of ezetimibe relative to statins, the addition of therapy will have any cardiovascular benefit. Results from the Action to
ezetimibe to simvastatin, as in ENHANCE, results in a significantly robust Control Cardiovascular Risk (ACCORD) study are needed to provide a
incremental decrease in hsCRP, nearly doubling the effect of simvastatin more definitive answer regarding the effect of fenofibrate with statin
alone (decrease of 23.5% versus 49.2%; p<0.01).
23
The greater versus statin alone on cardiovascular disease.
reduction in hsCRP is consistent with previous data that ezetimibe can
accentuate this effect of statins, even in the absence of a high statin Indeed, current guidelines by the National Cholesterol Education
dose.
22
If anything, the results from ENHANCE could raise questions Program’s Adult Treatment Panel III (ATP III) specify targets for
about the role of hsCRP and inflammation on atherosclerosis, rather than lipoprotein target goals in light of the available clinical evidence,
the reliability of the LDL-C hypothesis. Data have shown a correlation rather than the use of specific drugs.
7,47
This approach is confirmed by
between cardiovascular benefits and hsCRP reduction in lipid-lowering the recent FDA statement.
46
These guidelines are based on decades of
trials,
42
although additional studies are clearly needed to determine randomised end-point trials of statins and other lipid-lowering
whether this association is independent of the LDL-C reduction. therapies assessing clinical events that have shown that the
cardiovascular risk reduction associated with a reduction in cholesterol
Lowering of Low-density Lipoprotein Cholesterol – is similar regardless of how the cholesterol lowering came about.
22,48–52
Where Do We Currently Stand? The FDA and the American College of Cardiology (ACC) recommend
Two additional cIMT lipid-lowering trials, one with fenofibrate and that conclusions regarding ezetimibe not be made until larger, well-
another with statin alone or in combination with ezetimibe, have designed clinical outcome trials with ezetimibe are completed, and
recently been reported. Both trials measured changes in cIMT in middle- that ezetimibe remain an option for patients who are unable to reach
aged patients with diabetes who were naïve to lipid-lowering therapy their LDL-C goal on high-dose statins, who cannot tolerate statins or
and lacking existing clinical evidence of cardiovascular disease: the who can tolerate only a low-dose statin.
53
The Improved Reduction of
double-blind, placebo-controlled Fenofibrate Intervention and Event Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), treating
Lowering in Diabetes (FIELD) substudy and the open-label, post hoc 18,000 patients with acute coronary syndrome with simvastatin with
analysed Stop Atherosclerosis in Native Diabetics (SANDS) substudy.
43,44
or without ezetimibe, is currently under way, with completion planned
for 2012. The study is designed to determine whether the combination
Baseline measures of cIMT in both studies ranged between 0.8 and of ezetimibe and simvastatin can reduce the rates of heart attacks,
1.0mm, successfully enrolling patients with significant carotid strokes and death.
atherosclerosis. While no difference was observed in cIMT between
fenofibrate and placebo after five years in the FIELD substudy Thus, the controversy following publication of ENHANCE data, and for
(p=0.987),
43
in SANDS, patients aggressively treated to a low LDL-C that matter CASHMERE, can be largely attributed to the inadequate
target of ≤70mg/dl with either high-dose statin or low-dose statin plus design of the study and the underlying lack of scientifically sound
ezetimibe exhibited a highly significant difference (p<0.0001) in cIMT criteria for patient enrolment, rather than the study treatments
than those treated with low-dose statins to moderate LDL-C levels of themselves. It seems obvious now from ENHANCE, CASHMERE and
≤100mg/l.
44
Rather than focusing on the actual statistical results of other cIMT studies that any use of cIMT in future trials will require the
ENHANCE, which show no difference between treatment arms, critics use of a baseline cIMT that is consistent with the presence of
have opted to deem the small numerical differences of 0.0058mm on detectable disease, and that patients with prior lipid-lowering therapy
simvastatin monotherapy versus 0.0111mm on simvastatin plus should be excluded from participation. Although it appears easier to
ezetimibe as potential harm.
32,45
By the same illogical argument, the use cIMT to detect whether a drug is harmful and accelerates cIMT
results from SANDS – in which the same LDL-C reduction with the regardless of the baseline cIMT, it is much more difficult to show
ezetimibe/statin combination achieved a cIMT regression of -0.025mm beneficial effects in the absence of a population that has met strict
compared with a regression of -0.012mm with high-dose statin enrolment criteria including a proven lipid-rich atherosclerotic burden.
monotherapy – could be interpreted as enhanced benefits for ezetimibe
over statin monotherapy. Evidence from the two cIMT studies involving The ENHANCE study serves as a reminder to the preventative
ezetimibe – ENHANCE and SANDS – despite the former being littered cardiologist or lipidologist that in spite of overwhelming evidence, the
with design flaws and the latter being only a small post hoc substudy, LDL-C hypothesis and ‘lower is better’ are still not accepted universally.
certainly show no harm, and suggest a benefit associated with Although statins undoubtedly have antiatherosclerotic benefits, the
continued use of the drug, consistent with the well-proven LDL-C idea of conferring pleiotropic effects to statins over LDL-C reduction
hypothesis. In response to any concerns that may have arisen regarding distracts many clinicians from the requisite aggressive LDL-C lowering.
how to proceed in clinical practice, the US Food and Drug Thus far, LDL-C – or closely associated components of LDL, such as
Administration (FDA) recently issued a statement following extensive apolipoprotein B – remains the most specific and modifiable biomarker
review of ENHANCE, stating in part: “Based on current available data, for reducing coronary heart disease,
54
and can arguably be considered
patients should not stop taking Vytorin or other cholesterol-lowering the gold standard of cardiovascular risk factors. Statin therapy
medications.”
46
After ENHANCE, critics
32,45
suggested that clinicians should therefore remain the cornerstone for preventing cardiovascular
adopt the strategy of adding to statins other drugs that have shown disease, with the option of titration up to higher and more aggressive
clinical benefits when added to statins, such as fibrates. However, in the doses as needed in order to achieve the necessarily low LDL-C
FIELD cIMT substudy, while fenofibrate induced significant differences in goals.
55,56
However, considering that each doubling of a statin dose
ASIA-PACIFIC CARDIOLOGY 23
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