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Cardiovascular Research 1998 40(2):265-271; doi:10.1016/S0008-6363(98)00222-3
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Copyright © 1998, European Society of Cardiology

Lipids and stroke: neglect of a useful preventive measure?

John A Papadakis, Dimitri P Mikhailidis and Anthony F Winder*

Department of Chemical Pathology and Human Metabolism, Royal Free Hospital and School of Medicine, University of London, Pond Street, London, NW3 2QG, UK

* Corresponding author. Tel.: +44-171-794-0500, ext. 3489; Fax: +44-171-794-9537.

Received 11 March 1998; accepted 3 June 1998


   Abstract
Top
 Abstract
1 Introduction
 2 Are lipids risk...
 3 Do lipid-lowering drugs...
 4 How could statins...
 5 Comments
 6 Conclusion
 References
 
The epidemiological studies linking lipid variables and stroke are reviewed. These studies indicate that serum total cholesterol (TC) levels are associated positively with thrombotic and negatively with haemorrhagic strokes. Relationships for other lipid fractions are not as clearly defined. The results of trials with lipid lowering drugs suggest that only statins effectively reduce the incidence of stroke. Differences between trial results may be due to variation in the extent of reduction of TC levels. Possible underlying mechanisms for benefit and the apparent superiority of statins are also discussed. The reduction in the risk of thrombotic stroke with statins is most evident through meta-analyses (p<0.001) and less impressive in individual trials (p<0.03). This difference is largely attributable to the small number of events in trials primarily aimed at evaluating ischaemic heart disease (IHD) reduction. This also means that benefit may be limited to those with established IHD. IHD and thrombotic stroke share common risk factors and patients with one condition are at high risk of developing the other. Therefore, one additional reason for using statins in these patients is that these drugs can effectively prevent IHD-related events including deaths.

KEYWORDS Statins; Stroke; Lipids; Stroke prevention; Lipid-lowering therapy; Ischaemic heart disease; Cerebrovascular events; Atherosclerosis


   1 Introduction
Top
 Abstract
 1 Introduction
2 Are lipids risk...
 3 Do lipid-lowering drugs...
 4 How could statins...
 5 Comments
 6 Conclusion
 References
 
Hyperlipidaemia is a powerful risk factor for ischaemic heart disease (IHD) and lipid-lowering drugs can significantly reduce the morbidity and/or mortality associated with IHD [1–3]. In contrast, there was, until recently, little evidence that lipids play a role in the pathogenesis and/or prevention of cerebrovascular accidents (CVA), one of the commonest causes of death and long-term severe disability [4].

In this review, we discuss the relationship between hyperlipidaemia and stroke.


   2 Are lipids risk factors for stroke?
Top
 Abstract
 1 Introduction
 2 Are lipids risk...
3 Do lipid-lowering drugs...
 4 How could statins...
 5 Comments
 6 Conclusion
 References
 
2.1 Total cholesterol levels and stroke:
Early studies did not suggest that raised serum total cholesterol (TC) levels consistently predict stroke-related death [5, 6]. Furthermore, in some studies, TC levels are strongly but inversely related to stroke death [7]. In a meta-analysis of 13,000 strokes in 450,000 people, there was no significant association between serum TC concentration and stroke [8]. Conflicting results were reported by the Framingham Heart Study [9](USA) in which TC was related positively to stroke mortality only in women aged less than 55 years, whereas for women aged 56–70 there was a significant U-shaped relationship between TC and stroke mortality. For women aged more than 70 years, there was an inverse relationship between TC and short-term mortality. In a study from Israel, patients with stroke had lower levels of serum TC and low-density lipoprotein (LDL) [10].

In Japan and China, the age-standardised annual death rate from CVA is greater than that from IHD, whereas in North European countries and the USA IHD-related deaths are 3–4 times more common [11]. In Mediterranean countries, deaths from both of these causes are about equal in frequency [11]. These observations indicate that there is a geographical variation in the relative risk of CVA. This could be related to low serum TC levels, alcohol intake and traditional diets [12]. The link with low serum TC levels is supported by reports from Japan suggesting that TC levels had no effect on stroke risk [13], or even had an inverse effect [14]. The Mediterranean diet is also beneficial in terms of the lipid profile [15–17].

In general, epidemiological surveys show an inverse association between TC levels and the risk of intracerebral haemorrhage [18–21]; this association is independent of age [22]and gender [23]. In the Akita study, from Japan, the incidence of cerebral haemorrhage was twice that in the FINMONICA study, in Finland [24]; the reverse was true for the incidence of cerebral infarction. In another Japanese study, the prevalence of transient ischaemic attacks (TIA), which are related to thrombotic events, was about one-third to one-half that in Western countries [25]. Other studies show that haemorrhagic strokes are more common in Japan and other Asian countries [26, 27]than in Europe or the USA.

One reason for the conflicting findings in earlier studies is that thrombotic and haemorrhagic strokes were not differentiated. In more recent studies, like the Multiple Risk Factor Intervention Trial (MRFIT), it became obvious that elevated TC levels were positively associated with non-haemorrhagic stroke, but negatively associated with intracranial haemorrhage [28, 29]. This conclusion is supported by the results of the autopsy-based Akita Pathology Study from Japan [30]. In addition, studies that focus on thrombotic stroke show that serum TC is an independent risk factor for stroke [31, 32]and TIA [33]. Nevertheless, the relationship between TC and thrombotic stroke does not appear to be as strong as it is with IHD [34, 35].

There is a strong association between stroke and clinically evident vascular disease. For example, intermittent claudication was found to be the third strongest predictor for stroke deaths, after increased systolic blood pressure and age [36].

2.2 Other ‘lipids’ and stroke
Elevated LDL and lipoprotein (a) [Lp(a)] levels are associated with an increased risk of non-haemorrhagic stroke [37–39]. Furthermore, recent studies suggest an association between elevated Lp(a) levels and carotid atherosclerosis [40]. However, it is not clear how much LDL contributed to this increased risk since Lp(a) levels were related to carotid intima media thickness but the serum TC level was also raised.

Reduced levels of high-density lipoprotein (HDL) [41–43], high levels of triglycerides (TG) [42–44]and a high TC:HDL ratio [45]are also associated with non- haemorrhagic stroke.

Conclusion: TC levels are associated positively with thrombotic and negatively with haemorrhagic strokes. The role of other lipid fractions is not as clearly defined.


   3 Do lipid-lowering drugs prevent stroke?
Top
 Abstract
 1 Introduction
 2 Are lipids risk...
 3 Do lipid-lowering drugs...
4 How could statins...
 5 Comments
 6 Conclusion
 References
 
3.1 Pre-statin trials:
Two meta-analyses reviewed the results from trials [46, 47]reported before 1995. They considered 46,538 and 36,422 participants with hyperlipidaemia, who experienced 430 and 435 strokes, respectively. The authors concluded that lowering the levels of TC is not associated with a reduction in stroke incidence. The results of another trial also suggested that treating hypercholesterolaemia might increase the risk of cerebral haemorrhage [48].

3.2 The three major statin trials (4S, CARE, WOSCOPS):
Three major statin trials have been published (4S [3], WOSCOPS [49]and CARE [50]) (Table 1). CARE and 4S are secondary prevention studies; WOSCOPS is a primary prevention trial. The statins used in these trials decreased IHD mortality by about 35% (range: 33–42%) and non-fatal ischaemic cardiac events by about 27% (range: 25–31%). TC and LDL levels were reduced by about 22% (range: 20–25%) and 30% (range: 26–35%), respectively.


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  		Table 1 Demographic features of the three major clinical trials using statins as lipid-lowering drugs

 
In 4S, there were similar numbers of CVA deaths in the placebo (n=12) and simvastatin (n=14) groups [3]. In contrast, there was a statistically significant decrease in the number of all strokes (98 vs 70) in the simvastatin group (Table 2). In 4S, ischaemic non-embolic strokes (categorised by CT scans) and TIAs were reduced in the simvastatin group by 51 and 35%, respectively [3]. There were only two clearly defined haemorrhagic strokes in 4S; both occurred in the placebo group. With these small numbers it is difficult to decide if there was a significant effect on haemorrhagic stroke incidence.


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  		Table 2 Fatal and non-fatal strokes in the three major statin trials listed in Table 1

 
In CARE [50], the pravastatin group had a 31% lower incidence of all strokes (54 vs. 78; p=0.03), while the fatal strokes were about the same (10 and 6) in both groups (Table 2). In WOSCOPS [49]there were 46 strokes (6 fatal) in the pravastatin group and 51 (4 fatal) in the placebo group (p=0.67).

3.3 Meta-analyses considering all the statin trials:
In 1997, three new meta-analyses were published [51–53]. The authors calculated the number of strokes in all trials using statins to prevent IHD. The reduction in risk of stroke was significant in all three meta-analyses but mortality from all strokes was not significantly altered [51–53]. One of these meta-analyses [53]considers primary and secondary prevention separately and the results are summarised in Table 3.


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  		Table 3 Stroke morbidity and mortality in 14 cholesterol lowering trials (which include those listed in table 2) using statins for primary or secondary prevention. Adapted from Hebert et al. [53]

 
These beneficial effects could be limited to thrombotic stroke since there is an inverse association between serum TC levels and the risk of intracerebral haemorrhage [19–21], as discussed above. This explanation may also account for the fact that, in the overall analysis of 14 statin-based trials [53], the numbers of fatal strokes, which are more likely to be haemorrhagic, were similar in the placebo and treatment groups (26 and 31, respectively). In contrast, non-fatal strokes were significantly less frequent in the treated group (193 vs. 261; odds ratio: 0.71; 95% CI: 0.59–0.86; p<0.0001).

There was a large and highly significant reduction in risk of stroke (38%; p<0.0001) in secondary prevention trials and a smaller nonsignificant reduction (20%) in primary prevention trials (Table 3). Consequently, it is not possible to be sure if the benefits from statins, in terms of stroke reduction, are limited to those with IHD.

There was no indication of an increase in non-cardiovascular disease (e.g. cancer) incidence or mortality in these meta-analyses [53].

In support of our conclusions, the preliminary results of another secondary prevention trial (LIPID: more than 9,000 men and women aged 31–75 years; fasting TC 4.0–7.0 mmol/l; mean follow-up=6 years) [54]show a significant reduction in stroke incidence (20%; p=0.022).

Only 37% of the 4S participants were taking aspirin; in CARE and LIPID, the use of this antiplatelet drug was above 80%. The use of angiotensin II converting enzyme inhibitors and β-blockers [3, 50, 54]followed a similar pattern. Therefore, patients in CARE and LIPID had additional preventive measures for stroke. This could account for the apparently lower incidence of ‘all strokes’ in the placebo group in CARE compared to 4S (Table 2).

In 1998, a meta-analysis of all published lipid-lowering trials [55], showed that only those using statins significantly reduced the incidence of all strokes (relative risk, RR=0.76; 95% CI: 0.62–0.92; p=0.01), whereas trials using fibrates, resins or dietary interventions had RR values of 1.12, 1.07 and 0.98, respectively.

Conclusion: Statins significantly reduce the incidence of thrombotic stroke. However, this conclusion is largely based on the results of meta-analyses and may be limited to patients with established IHD.


   4 How could statins prevent stroke?
Top
 Abstract
 1 Introduction
 2 Are lipids risk...
 3 Do lipid-lowering drugs...
 4 How could statins...
5 Comments
 6 Conclusion
 References
 
Several mechanisms are potentially involved. For example, statins reduce the incidence of MI [3, 49, 50]and the risk of stroke following MI is increased [56]; we would therefore expect a beneficial effect on both conditions. This MI-stroke link may reflect the extent of atherosclerosis or the formation of mural thrombi that produce embolic stroke [53]. In addition, treatment would probably result in less ventricular dysfunction and arrhythmias and thus less potential for cardiogenic emboli [57].

There is an association between elevated TC and extracranial carotid atherosclerosis [52, 58]. Furthermore, three lipid lowering intervention studies, using lovastatin (ACAPS) [59]and pravastatin (PLAC-II, KAPS) [60, 61], demonstrated a slowing down of the progression of carotid stenosis. These findings may reflect increased atherosclerotic plaque stability [62, 63]. In 4S, simvastatin substantially reduced the risk of a new or worsening carotid bruit (RR=0.52; 95% CI: 0.32–0.85; p=0.009) [64]. These benefits may not be evident if the correction of the dyslipidaemia (e.g. by dietary measures or non-statin drugs) is not extensive.

Statins may beneficially influence thrombogenic (e.g. platelet function) and fibrinolytic factors [63, 65–67].

Simvastatin rapidly (within one month) improved forearm blood flow in hypercholesterolaemic patients [68]. These changes probably reflect the restoration of normal endothelial function [63, 65, 68]. It is well known that the endothelium plays an important role in regulating vascular tone, platelet aggregation and smooth muscle cell proliferation [65]. Do similar changes occur in the cerebral circulation?

Some statins have antioxidant capacity [69]. This property may reduce LDL oxidation, an important factor in atherogenesis.

It remains unclear as to whether these effects are specific to statins or relate to the extensive reduction in serum LDL concentration achieved by these drugs.


   5 Comments
Top
 Abstract
 1 Introduction
 2 Are lipids risk...
 3 Do lipid-lowering drugs...
 4 How could statins...
 5 Comments
6 Conclusion
 References
 
The present overview of published statin studies provides evidence of benefit in terms of stroke incidence. However, this conclusion is largely based on the results of meta-analyses and may be limited to patients with established IHD [51–53]. The most obvious reason why previous studies failed to express the same view is that LDL levels were reduced by 25–35% by statins compared with reductions of 10–12% in studies using diet or non-statin medication [46, 47, 55]. In addition, several non-lipid actions of statins [55, 70, 71]may exert favourable effects on CVA-related events. Statins also have fewer side-effects than other lipid lowering drugs (e.g. fibric acid derivatives) which were evaluated in the earlier studies; this factor suggests better compliance with statins [46, 52]. It is therefore unclear whether the above mentioned favourable effect of statins can be generalised to other drugs or interventions which reduce circulating TC levels.

Because there is evidence that reduced levels of HDL and hypertriglyceridaemia increase the risk of stroke (see above) we need to establish if raising HDL or decreasing TG levels translates into clinical benefit. Fibric acid derivatives exert favourable effects on both HDL and TG. However, as mentioned above, these drugs have less effect on TC and LDL levels when compared with statins. Fibric acid derivatives also reduce the circulating levels of fibrinogen and possibly of Lp(a) [72]. Both these variables are predictors of stroke [37, 38, 73]. Therefore, it would be interesting to evaluate a statin + fibrate combination in stroke prevention.

Another potential use of lipid lowering drugs is as an alternative to surgery for carotid atherosclerosis, especially if patients have a high operative risk of stroke and death. This risk is greater in women, as well as in patients aged 75 or over [74]. Statins may also be worth considering if there is some controversy regarding the best treatment option (e.g. asymptomatic carotid artery stenosis).

The absolute risk of death from stroke is not uniform across the world. For example, in Eastern Asia this risk is greater than that of death from IHD [11, 24–27]. Furthermore, in these countries if we consider all CVAs, haemorrhagic strokes may be twice as common when compared to ‘North European’ populations [11, 24–27]. Therefore, it is not certain if lowering TC levels will reduce the risk of stroke in all countries, because haemorrhagic CVAs may increase with lowering TC, as mentioned above. In addition, in countries like Japan, the risk of IHD is low and the benefit from lipid-lowering drugs could be limited.

The results of trials of lowering TC levels should be placed in context of other measures aimed at stroke prevention. A meta-analysis (37,000 hypertensive patients) of the effect of treating hypertension suggests a potential to reduce stroke incidence by approximately 40% [75]. Similarly, another meta-analysis shows that in patients with previous coronary events, antiplatelet agents reduce the incidence of stroke by approximately 35% [76]. These reductions are comparable with those reported in the statin trials.

Cholesterol lowering in those at risk of stroke should be evaluated within the context of the significant reduction in IHD-related events. IHD is a major public health problem in most countries and it shares risk factors with stroke [77]. Furthermore, IHD is common and is a major cause of death in patients with TIA or stroke [77]. Therefore, it makes sense to treat hyperlipidaemia in those at risk of, or with established, stroke or IHD [77].

It may be relevant to establish if a stroke is haemorrhagic or thrombotic before evaluating any benefit from lipid lowering treatment.


   6 Conclusion
Top
 Abstract
 1 Introduction
 2 Are lipids risk...
 3 Do lipid-lowering drugs...
 4 How could statins...
 5 Comments
 6 Conclusion
References
 
Statins significantly reduce the risk of thrombotic stroke. However, this conclusion is largely based on highly significant (p<0.001) meta-analyses. The statistical significance in individual trials is not as impressive (p<0.03). This is largely attributable to the small number of events in trials primarily aimed at evaluating IHD reduction. This also means that benefit may be limited to those with established IHD. The benefit from statins, in terms of stroke reduction, may not be the same in all countries.

IHD and thrombotic stroke share common risk factors and patients with one condition are at high risk of developing the other. Therefore, one additional reason for using statins following a thrombotic stroke or TIA is that these drugs effectively prevent IHD-related events and/or deaths.

Time for primary review 20 days.


   References
Top
 Abstract
 1 Introduction
 2 Are lipids risk...
 3 Do lipid-lowering drugs...
 4 How could statins...
 5 Comments
 6 Conclusion
 References
 

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