Cholesterol and strokes

Strong correlations between plasma lipoprotein concentrations and the risk of stroke have never been clearly established. Unlike coronary heart disease, there is no significant direct relation between an increased risk of stroke and increased plasma total cholesterol or low density lipoprotein (LDL) cholesterol; nor is there an inverse relation with high density lipoprotein (HDL) cholesterol.¹ Indeed, an inverse relation exists between total cholesterol concentrations and cerebral haemorrhage.²

The reasons for this weak or absent relation are several. The most compelling is that virtually all coronary heart disease can be ascribed to coronary atheroma, whereas less than half the incidence of stroke is due to large vessel atheroma. Non-atheromatous causes such as cardiac arrhythmias, small cerebral artery disease, and cortical degeneration are responsible for most of the rest. Another is that, in general, coronary deaths occur at a younger age than strokes, so the population with raised plasma lipids and large vessel atheroma, such as carotid artery disease, is diminished by the age when strokes occur. A third is that plasma total and LDL cholesterol decrease with advanced age, as does their relation to coronary heart disease.³

Since no large randomised controlled trial designed specifically to assess the effect of cholesterol lowering in patients with stroke has yet been completed, we need to consider surrogate data from coronary prevention trials and atheroma regression trials (coronary and carotid) in assessing the value of cholesterol lowering.

The evidence of benefit of cholesterol lowering on coronary morbidity and mortality is now incontrovertible. These data come from five large randomised controlled trials of five or more years' duration using a statin to reduce LDL cholesterol in patients with coronary heart disease^4–6 and in asymptomatic middle aged individuals.⁷,⁸ The three largest secondary prevention trials showed that lowering LDL cholesterol concentrations reduced the incidence of coronary heart disease and stroke to a similar degree—but the benefit was for non-fatal strokes. ^4–6,⁹ Even with the large numbers (17 617) of patients with coronary disease included in these trials, it was not possible to conclude that cholesterol lowering reduced stroke mortality. For example, the 4S trial showed that the relative risk of cerebrovascular events was reduced by 37% (P=0.024), similar to the reduction in subsequent coronary events, but the benefit was confined to non-embolic strokes and transient ischaemic attacks. Embolic strokes, haemorrhagic strokes, and those that could not be classified were not reduced.⁴ This emphasises that strokes with a basis of large vessel atheroma are most likely to be reduced.

In essence the many coronary atheroma regression trials show that when LDL cholesterol is lowered by at least 20% by a statin or by ileal bypass surgery there is less progression of coronary atheroma and fewer new atheromatous lesions develop. But this improvement is not immediate and may take up to four years of treatment.¹⁰ Statins may, however, have earlier effects on vascular endothelial reactivity and on vasomotor tone—possibly independently of LDL cholesterol lowering—which might be particularly beneficial in stroke patients. Meta-analyses of the coronary prevention trials, including the smaller atheroma regression trials and covering nearly 29 000 patients, indicate that reduction in LDL cholesterol concentrations reduced the overall risk of stroke by about 30%, but without reducing mortality from stroke.¹¹,¹²

More relevant are the findings of carotid regression trials. High resolution ultrasonography conducted in nearly 6000 subjects aged over 65 years has clearly established that thickening of the carotid artery intima and media are predictors for strokes.¹³ Trials in asymptomatic people and in patients with known coronary disease, using B mode ultrasound assessment of common carotid lesions,¹⁴ have shown that reduction of plasma LDL cholesterol by 25% or more, usually with a small increase in HDL cholesterol, prevented over a four year period any detectable progress in carotid wall thickening and reduced the development of new lesions.

All patients under 75 recovering from a stroke with evidence of carotid atheroma as the cause, or with a history of coronary heart disease, should be considered for treatment with a statin to reduce the risk of recurrences. Patients with carotid atheroma identified angiographically should also be considered for statin treatment. But, as yet, there is no clear evidence that cholesterol lowering is beneficial against either further coronary events or strokes in patients over about 75. At present, it is better to choose a natural statin since only these have been submitted to rigorous long term trials.¹⁵ Cholesterol lowering does not, however, reduce stroke mortality. Prevention should be directed to patients with raised plasma cholesterol and LDL concentrations, particularly when diabetes mellitus or hypertension coexist. Patients with a stroke resulting from a cardiac arrhythmia (unless due to coronary heart disease) or non-atheromatous small cerebral artery disease should not expect to benefit from cholesterol lowering.