Cholesterol Tied to Death Risk from Ischemic Heart Disease but Not Stroke

OXFORD, England, Nov. 30 -- Cholesterol levels are closely linked to cardiovascular mortality, especially among middle-age patients, but not to stroke-related deaths, researchers here found.
Action Points
Explain to interested patients that the study did not find much of a link between stroke mortality and cholesterol levels in observational studies although previous randomized trials have linked cholesterol to stroke risk.
Inform patients that randomized trials constitute stronger evidence for a benefit of statins in stroke than observational studies.
For every 1 mmol/L decrease in cholesterol, ischemic heart disease mortality dropped by half among patients ages 40 to 49, by a third among those 50 to 69, and by a sixth among those 70 to 89, according to a review of observational studies in the Dec. 1 issue of The Lancet.
The association appeared independent of blood pressure, reported Sarah Lewington, D.Phil., of the University of Oxford, and colleagues.
A weak association was found between higher cholesterol and stroke mortality, but only in middle age and it was mostly accounted for by blood pressure, the researchers said.
"The absence of an independent positive association of cholesterol with stroke mortality, especially at older ages or higher blood pressures, is unexplained," they said.
Nevertheless, a link between cholesterol and the risk of stroke probably exists, commented Pierre Amarenco, M.D., and P. Gabriel Steg, M.D., of Bichat-Claude Bernard University Hospital in Paris, in an accompanying editorial.
"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 said.
Whatever the explanation for the disconnect between cholesterol and stroke mortality, the researchers said, "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."
To see how blood pressure and cholesterol levels jointly impact vascular mortality, the researchers conducted a meta-analysis of almost 900,000 patients initially free of heart disease in 61 prospective observational studies.
Altogether, there were 55,000 vascular deaths during 11.6 million person-years of follow-up for patients ages 40 to 89 without baseline disease.
Mean total cholesterol measurement at baseline was 5.8 mmol/L. Mean HDL cholesterol was 1.4 mmol/L and the mean total-to-HDL cholesterol ratio was 4.6.
Regardless of cholesterol level after adjustment for age, sex, and study, systolic blood pressure increased about 2.4 mm Hg per 1 mmol/L increase in total cholesterol.
For ischemic heart disease mortality, every 1 mmol/L decrease in total cholesterol cut mortality 56% for participants ages 40 to 49 (hazard ratio: 0.44, 95% confidence interval: 0.42 to 0.48), 34% for those 50 to 69 (HR: 0.66, 95% CI: 0.65 to 0.68), and 17% in those 70 to 89 (HR: 0.83, 95% CI: 0.81 to 0.85).
Although the proportionate risk decreased with age, mortality increased with age such that the absolute difference increased with age per 1 mmol/L increase in cholesterol level.
Adjustment for systolic blood pressure had little effect on this association.
Ischemic heart disease was more common with higher systolic blood pressure, so the absolute mortality difference for a given difference in total cholesterol was similar at every systolic blood pressure level, the researchers said.
The strongest predictor of ischemic heart disease mortality was the ratio of total cholesterol to HDL cholesterol. The ratio was more than twice as informative as total cholesterol and 40% more predictive than non-HDL cholesterol level alone.
For every 1.33 lower total-to-HDL cholesterol ratio, ischemic heart disease mortality dropped by a third.
"These findings argue for applying the benefits of statins to high-risk patients, regardless of age and blood pressure," the editorialists concluded, "and suggest that clinicians might need to consider the ratio of total-to-HDL cholesterol rather than the LDL cholesterol level to which they have become accustomed."
Total stroke mortality and ischemic stroke mortality were weakly associated with increasing total cholesterol only among middle-age patients (mortality ratio: 0.93 at ages 60 to 69), the researchers noted.
Each 1 mmol/L of total cholesterol was associated with about 2 mm Hg systolic blood pressure, which was associated with a similar stroke hazard ratio of about 0.92 for the same age group.
"The positive association in middle age can be largely or wholly accounted for by the association of total cholesterol with systolic blood pressure," they added.
The lack of association between cholesterol and stroke mortality is unexplained and will require further research, Dr. Lewington and colleagues said.
Drs. Amarenco and Steg pointed out, however, that "although analyses were standardized by age to avoid survival bias, patients who die from coronary heart disease at earlier ages cannot contribute to a later risk of atherothrombotic stroke. Hence, the proportion of patients with atherothrombotic disease at risk of stroke decreases over time relative to other causes that increase with age."
Furthermore, the editorialists added, "whether raising HDL cholesterol, lowering triglyceride, or reducing inflammation and high-sensitivity C-reactive protein will further decrease stroke risk remains to be evaluated in randomized trials."