Cholesterol and stroke: A paradox

November 29, 2007   Lisa Nainggolan

Oxford, UK - A new analysis of 61 prospective observational studies
has failed to find any association of total cholesterol (TC) with
stroke mortality [1]. The research, from the Prospective Studies
Collaboration (PSC; Clinical Trial Service Unit, University of Oxford,
UK), appears in the December 1, 2007 issue of the Lancet.

Trial coordinator Dr Sarah Lewington (Clinical Trial Service Unit)
told heartwire that while the stroke finding "was surprising, it is
actually in line with previous observational studies. There has always
been this discrepancy between the observational data and the
randomized trials." However, she stressed that, despite their
findings, "there is conclusive evidence from randomized trials that
statins reduce stroke rate to the same degree that they reduce
coronary event rates."

She adds that the most important result from the PSC study, to her
mind, is that "cholesterol is a risk factor for heart disease not just
in middle age, but also in old age. Because the risk in old age is so
much greater, the absolute relevance of cholesterol is even greater
for older people," she notes. Another key finding was that "high-
density lipoprotein cholesterol adds to the prediction. We found the
ratio of TC to HDL is more informative than HDL-C alone and much more
informative than TC. So doctors should be measuring HDL-C as well as
total cholesterol, if they can. You're much more likely to be able to
determine someone's risk if you measure their HDL-C."

No lower threshold for cholesterol

The PSC researchers obtained information from 61 prospective
observational studies, mostly in Western Europe or North America,
although there were a few studies from China. The total trial
population was almost 900 000 adults without previous disease and with
baseline measurements of TC and blood pressure. The research was
mostly conduced during the 1980s, when TC was routinely measured
rather than LDL cholesterol, Lewington explained.

During nearly 12 million person-years at risk between the ages of 40
and 89, there were 55 000 vascular deaths (34 000 ischemic heart
disease [IHD], 12 000 stroke, 10 000 other). Information about HDL-C
was available for 150 000 participants, among whom there were 5000
vascular deaths (3000 IHD, 1000 stroke, 1000 other).

TC was positively associated with IHD mortality in both middle and old
age and at all blood-pressure levels. A 1-mmol/L-lower TC was
associated with about a half (hazard ratio 0.44), a third (HR 0.66),
and a sixth (HR 0.83) lower IHD mortality in both sexes at ages 40 to
49, 50 to 69, and 70 to 89 years, respectively, throughout the main
range of cholesterol in most developed countries, with no apparent
threshold.

This latter point is important, says Lewington. "We found no threshold
level below which lower cholesterol is not associated with lower risk,
so there is no worry about lowering cholesterol as far as heart
disease is concerned. Because we had a lot of data we could divide the
bottom group up, and even below 3.5 mmol/L there was still an
indication that lower cholesterol gave lower risk of heart disease.
This shows conclusively there is no risk [to lowering cholesterol]."

The researchers also performed a parallel analyses of the Multiple
Risk Factor Intervention Trial (MRFIT) that involved a further 34 242
vascular deaths--the combined results showed similar findings to the
PSC study overall.

Despite lack of association of TC and stroke, treatment should be
guided by RCTs

The PSC researchers found a positive relation between cholesterol and
stroke only in middle age and only in those with below-average BP; at
older ages (70-89), and particularly for those with systolic BP
greater than 145 mm Hg, total cholesterol was negatively related to
hemorrhagic and total stroke mortality.

"The absence of any independently positive association between TC and
stroke mortality in middle age (after allowing for systolic blood
pressure [SBP]) or in those with SBP below 145 mm Hg and the negative
association of cholesterol with stroke mortality at older ages or at
higher blood pressures are unexplained and invite research," they
observe. "Further investigation of exactly how lipoprotein particles
affect stroke risks might help to explain this striking discrepancy."

In an accompanying comment [2], Drs Pierre Amarenco (Bichat-Claude
Bernard University Hospital, Paris, France) and P Gabriel Steg
(Université Paris 7-Denis Diderot, France) note the lack of a clear
association between cholesterol and stroke in the PSC study.

But they point out, "The various causes of ischemic stroke might have
different associations with cholesterol. While myocardial infarction
almost always follows atherothrombotic disease, brain infarction stems
from conditions ranging from rheumatic heart disease to
atherosclerotic carotid stenosis. Blood cholesterol is associated with
carotid stenosis, and carotid stenosis causes stroke, so observational
studies including stroke associated with carotid stenosis might mimic
the findings with IHD."

And they note that stroke risk reduction with statins was recently
confirmed in SPARCL in the secondary prevention of stroke or transient
ischemic attack: "The lower the achieved LDL cholesterol over the
course of the trial, the greater the reduction in the risk of
recurrent stroke," they say. Amarenco was in fact the principal
investigator of SPARCL, which was published in the New England Journal
of Medicine in 2006.

However, they also observe that, as in another trial, baseline LDL
cholesterol was not predictive of stroke in SPARCL, and the treatment
effect was observed regardless of baseline LDL-C, findings they say
are "puzzling."

Nevertheless, "a link between cholesterol and stroke risk probably
exists (at least with atherothrombotic stroke), and there is good
evidence that lowering blood cholesterol with statins reduces stroke
risk and carotid atherosclerosis, independently of blood cholesterol,
blood pressure, and age," they state.

Lewington and the PSC group agree: "Treatment should be guided
principally by the definitive evidence from randomized trials, that
statins substantially reduce not only coronary-event rates but also
total stroke rates in patients with a wide range of ages and blood
pressures."

Move over LDL: TC/HDL ratio is more informative

With regard to the HDL analyses, the PSC found that the ratio of TC/
HDL-C was the strongest predictor of IHD mortality--40% more
informative than non-HDL cholesterol and more than twice as
informative as TC.

Amarenco and Steg also comment on this finding: "Interestingly, TC/HDL
cholesterol is more informative in this meta-analysis than HDL, non-
HDL, or TC. This result parallels the observation in the INTERHEART
study that the apoB/apoA-1 ratio was the most informative variable.

"These findings argue for applying the benefits of statins to high-
risk patients, regardless of age and blood pressure, and suggest that
clinicians might need to consider the ratio of TC/HDL cholesterol,
rather than the LDL-cholesterol level to which they have become
accustomed," the French doctors conclude.

The Clinical Trial Service Unit is involved in clinical trials of
cholesterol modification therapy with funding from various companies
(Merck, Schering, Solvay) as research grants to (and administered by)
Oxford University. Amarenco and Steg report receiving honoraria,
speaker's fees, and research funding from a variety of companies,
listed in their paper.