http://www.annals.org/cgi/content/full/145/7/520

REVIEW
Narrative Review: Lack of Evidence for Recommended Low-Density
Lipoprotein Treatment Targets: A Solvable Problem
Rodney A. Hayward, MD; Timothy P. Hofer, MD, MSc; and Sandeep Vijan,
MD, MSc

3 October 2006 | Volume 145 Issue 7 | Pages 520-530

Recent national recommendations have proposed that physicians should
titrate lipid therapy to achieve low-density lipoprotein (LDL)
cholesterol levels less than 1.81 mmol/L (<70 mg/dL) for patients at
very high cardiovascular risk and less than 2.59 mmol/L (<100 mg/dL)
for patients at high cardiovascular risk. To examine the clinical
evidence for these recommendations, the authors sought to review all
controlled trials, cohort studies, and case-control studies that
examined the independent relationship between LDL cholesterol and major
cardiovascular outcomes in patients with LDL cholesterol levels less
than 3.36 mmol/L (<130 mg/dL).

For those with LDL cholesterol levels less than 3.36 mmol/L (<130
mg/dL), the authors found no clinical trial subgroup analyses or valid
cohort or case-control analyses suggesting that the degree to which
LDL cholesterol responds to a statin independently predicts the degree
of cardiovascular risk reduction. Published studies had avoidable
limitations, such as a reliance on ecological (aggregate) analyses, use
of analyses that ignore statins' other proposed mechanisms of action,
and failure to account for known confounders (especially healthy
volunteer effects). Clear, compelling evidence supports near-universal
empirical statin therapy in patients at high cardiovascular risk
(regardless of their natural LDL cholesterol values), but current
clinical evidence does not demonstrate that titrating lipid therapy to
achieve proposed low LDL cholesterol levels is beneficial or safe.

Key Summary Points
No high-quality evidence could be found that suggests that titrating
lipid therapy to recommended low-density lipoprotein (LDL) cholesterol
targets is superior to empirically prescribing doses of statins used in
clinical trials for all patients at high cardiovascular risk.

Studies addressing benefits of achieving LDL cholesterol goals have had
avoidable problems, such as reliance on ecological (aggregate)
analyses, ignoring statins' other proposed mechanisms of action, and
not accounting for known confounders (especially healthy volunteer
effects).

Much more reliable evidence on currently proposed LDL cholesterol goals
could be expeditiously produced by conducting cohort analyses of past
statin trials that control for statin dose and pill adherence.

Dichotomous comparisons (such as comparing those who reach goal vs.
those who do not) can mistakenly suggest that not achieving the
treatment goal results in moderate risk when in fact almost all of the
risk is caused by large deviations from the ideal goal.

Proposals for treatment goals should also consider the risks, patient
burden, and societal costs of the treatments that may be needed to
reach those goals.

In 2004, a National Cholesterol Education Program (NCEP) expert panel
recommended that physicians titrate lipid therapy to reach a
low-density lipoprotein (LDL) cholesterol level less than 1.81 mmol/L
(<70 mg/dL) in patients at very high risk for cardiovascular events (1,
2). The panel stated that consistent and compelling evidence showed a
strong relationship between LDL cholesterol level and cardiovascular
outcomes down to this level (1, 2). However, others have reviewed the
same literature and have concluded that there is no valid evidence from
clinical trials (see Glossary) supporting this conclusion (3, 4). Since
the early 1900s, we have known that familial hyperlipidemia syndromes
result in premature cardiovascular disease, and in the United States
and northern Europe, cohort studies have usually found that LDL
cholesterol is a major independent cardiovascular risk factor at levels
above 3.75 mmol/L (>145 mg/dL) (5, 6). However, these studies had
limited ability to assess whether this relationship continued at lower
LDL cholesterol levels, and some suggested that this association was
less marked as LDL cholesterol level approached 3.36 mmol/L (130
mg/dL), especially when high-density lipoprotein cholesterol levels
were normal (7, 8). Furthermore, studies in southern Europe, where LDL
cholesterol levels tend to be lower in general, have often found a less
strong association than those conducted in northern Europe, even in the
moderate LDL cholesterol range (3.36 to 4.14 mmol/L [130 to 160 mg/dL])
(7, 8). In addition, studies in Asia and in elderly persons have often
found no decrease or even an increase in cardiovascular risk when LDL
cholesterol level drops below 3.36 mmol/L (130 mg/dL) (9). These
results raised questions about whether the strong association found at
higher levels of LDL cholesterol could be extended to lower LDL
cholesterol levels; they also raised concerns that total LDL
cholesterol is an unreliable marker of benefit and may be confounded by
dietary factors or LDL subparticles that are the true causal factors
(7-11).

These concerns seemed to be allayed when multiple clinical trials
showed that statin therapy dramatically decreased cardiovascular events
in almost all groups at high risk and that this benefit extended to
those with pretreatment LDL cholesterol levels of 2.33 to 2.59 mmol/L
(90 to 100 mg/dL) (1, 2, 12-17). Several recent trials have also
shown greater benefits for high-dose statin therapy compared with low
to moderate doses for those with acute coronary syndromes (14, 17) and
known coronary artery disease (15, 16) (although the results in the
IDEAL [Incremental Decrease in Endpoints Through Aggressive Lipid
Lowering] study [16], in which participants had stable coronary artery
disease, did not reach statistical significance). However, these
studies generally used fixed doses of statins (placebo vs. statin or
low-dose vs. high-dose statin) and therefore cannot directly shed light
on whether clinicians should prescribe the doses used in the studies or
titrate lipid therapy to achieve recommended LDL cholesterol goals.

This is particularly relevant because statins do much more than
decrease LDL cholesterol levels. Although strong mechanistic evidence
supports the LDL hypothesis, strong basic science evidence (18) also
suggests that the effects of statins on inflammation, thrombosis, and
oxidation are plausible mechanisms for mediating the benefits of statin
therapy (often referred to as "pleiotropic effects") (Appendix Table
1). Indeed, some statin trials seem to run counter to the LDL
hypothesis. For example, trials have found that statins substantially
reduce the risk for stroke, which is more consistent with their
hypothesized antithrombotic effects than with their LDL-lowering
effects (high LDL levels are not a major independent risk factor for
stroke) (19). In addition, a recent large statin trial conducted in
patients receiving dialysis found no substantial benefit despite
reductions of 42% in LDL cholesterol levels (20), suggesting that even
dramatic reductions are not always associated with clinically
significant lowering of cardiovascular risk.