The totality of the evidence suggests that HMG-CoA reductase inhibitors, unlike previously studied cholesterol-lowering drugs, 6,7
lower total stroke risk. However, we found that the majority of the reduction lies in reducing nonfatal stroke events. We observed a small increase in risk for fatal stroke events; this was about 25% overall and 34% in trials of secondary prevention. This observation was nonsignificant with wide confidence intervals, which cannot exclude either a protective or deleterious effect from this class of drugs. In support of a deleterious effect is the hypothesis suggested from observational trials 2,3
and prior meta-analyses 6,7
that lowering cholesterol below 200 mg/dL may increase fatal strokes by weakening small cerebral vessels and cause hemorrhagic strokes. In support for either a null or beneficial effect, we did not find a strong or significant association between initial cholesterol level or the degree of cholesterol lowering and risk of fatal stroke.
This meta-analysis, like prior ones, suffers several limitations. With the exception of the 4S trial, which subclassified stroke among nonfatal events only, all other trials did not have any data on the pathology of stroke types for fatal and nonfatal events. Hemorrhagic strokes have a 30-day fatality rate of 40% to 50% as compared with 10% to 20% for ischemic strokes.102
The much greater proportion of hemorrhagic strokes that are fatal as compared with ischemic strokes leads us to infer that it is possible that the majority of fatal stroke events were hemorrhagic in nature, while most of the nonfatal stroke events were ischemic.6,7
This assumption may be erroneous because most strokes are ischemic in absolute number (approximately 85% of total strokes); therefore, the majority of fatal strokes still may represent large ischemic events.103
Although our meta-analysis failed to demonstrate a beneficial effect of statins on fatal stroke risk, we observed a modest and significant decrease in the relative risk of nonfatal stroke (OR = 0.64). For a null effect, that is, an equal risk of fatal stroke on statin and placebo, we postulate that statins' benefit on ischemic events is offset by an increase in fatality due to hemorrhage. Although there is a greater chance of having a nonfatal stroke event from small vessel disease as compared with large vessel disease, the majority of nonfatal events are from large vessel ischemia (emboli or thrombotic).104
We suspect that statins are beneficial in preventing ischemic processes in all types of cerebrovascular disease. However, their effect may be more beneficial for small vessel disease than for large vessel disease as their tiny caliber would make hemostatic and vascular wall changes more pronounced. Therefore, our data could suggest that statins prevent nonfatal stroke events by lowering the incidence of small vessel thrombotic stroke (lacunes) more than the potentially lethal cardioembolic or large vessel infarcts. Cholesterol lowering may have a greater effect on small vessels to prevent lacunar infarcts, just as the effect of cholesterol lowering can more profoundly cause arterial rupture in these small vessels by weakening the intimal lining.105
Our overall case-fatality rate for stroke was 13%, whereas that seen in general stroke populations is about 30%.106,107
The lower fatality rate in our study is expected, as the study population was younger, healthier, and predominantly white. As 40% of our patients were in primary prevention studies (which excluded coronary artery disease, myocardial infarction, and stroke), they were generally a healthy group. Stroke mortality rises exponentially with age and doubles every 10 years.108
Our average age was young (57.2 years), whereas the majority of strokes occur in people over age 65. Race is also important in stroke mortality. African Americans have a twofold higher mortality than their white counterparts.109,110
Although we did not study the data on race, over 11,000 patients in this meta-analysis were Scandinavian or Scottish and presumably unrepresentative of the African-American population.
Some of the observed effects of statins in reducing stroke events may reflect their non-lipid-lowering properties. Statins have antithrombotic effects on endothelial function, plaque stability, and thrombus formation.111
Statins also cause platelet inhibition and facilitate fibrinolysis. These effects could also explain the lowered incidence of nonfatal stroke by preventing ischemia, however, causing fatal strokes by facilitating bleeding.
Our results are concordant with the four meta-analyses published after our search was concluded.112–115
All four studies showed statistically significant reductions in total stroke risk. The two that were able to discriminate fatal from nonfatal strokes, 113,114
as we did, found a significant reduction in nonfatal stroke risk and a nonsignificant increase in fatal stroke events on statins. Two of these four overviews also conducted separate meta-analyses for trials of primary and secondary coronary disease prevention.112,113
They found, as we did, a significant reduction in total and nonfatal stroke risk only for trials of secondary coronary disease prevention. Although the studies included in our meta-analysis were similar to the others, 112–115
two randomized controlled trials using statins 21,58
were excluded from analysis on the basis that they did not report stroke data. Two of the four recent meta-analyses 113,114
included data on the Multicenter Anti-Atheroma Study (MAAS), 21
while no data were available for the other excluded trial.58
The MAAS study was an angiographic trial of 381 patients assigned to simvastatin or placebo for 4 years.21
The trial demonstrated no fatal stroke events on either arm of therapy, two nonfatal strokes on placebo, and one nonfatal stroke on simvastatin. Recalculating the meta-analysis by including the MAAS data, we found exactly the same summary point estimates and confidence limits for both fatal and nonfatal stroke outcomes (fatal stroke, OR 1.25; 95% CI 0.71, 2.24; nonfatal stroke, OR 0.64; 95% CI 0.51, 0.79). The Sahni et al. trial was an angiography study that evaluated the effect of lovastatin on restenosis rates after coronary angioplasty.58
This trial included 157 patients followed for an average duration of 4 months. Although no stroke data were reported in their publication, it is doubtful that their results would appreciably alter our overall summary estimates.
In this meta-analysis, the aggregation of summary statistics from a wide diversity of patients to arrive at a point estimate of relative risk may obscure the ability to determine whom this type of therapy is most or least likely to benefit. Although we did find that the relative risk reduction in nonfatal stroke from secondary prevention trials may be more than twice that of primary prevention trials, this difference was not significant and had overlapping confidence intervals. While the relative risk of stroke did not show a significant relation to baseline cardiac risk, our weighted linear regression model did support a significant trend between the absolute risk reduction and baseline risk for cardiac events. This relation implies that while the relative benefit may be similar between primary and secondary prevention, patients with a greater background risk of cardiovascular events, such as those with established coronary artery disease or with multiple risk factors, will benefit the most in stroke reduction from statin therapy.
Our meta-analysis did not find that the initial and net percentage of change in cholesterol levels obtained on statin therapy were significantly correlated with the relative risk reduction for fatal or nonfatal stroke. Our findings therefore imply that the relative benefit is fairly uniform for a magnitude of total cholesterol change within a 15% to 30% range, as well as a starting total cholesterol level of 200 to 300 mg/dL as observed in the included trials. Also, any potential deleterious effects of cholesterol reduction cannot be attributed to the observed magnitude of cholesterol change or range of baseline cholesterol values. Regardless of the reduction in serum cholesterol, our observations could support a therapeutic effect on ischemia and a deleterious effect to promote hemorrhage due to the non-lipid-related properties of the statins. Alternatively, it is possible that the initial mean cholesterol levels were too high or that the cholesterol reductions were too small to detect an increase in fatal stroke risk. Perhaps, consistent with some observational studies, hemorrhagic stroke risk may become pronounced at cholesterol levels less than or equal to 160 mg/dL.2,3
Obtaining individual patient data may then be useful in assessing the relative risk of fatal stroke at very low cholesterol levels and at very high cholesterol reductions. However, it is probable that with only 54 fatal events in nearly 20,000 patients, this question could not be answered due to the rarity of these events. In fact, to detect an absolute risk difference in fatal stroke of 0.06% between treatment and placebo groups, as found in our meta-analysis, would require 121,402 patients in each group to be 80% certain of showing a significant difference between the groups at the p
= .05 level.116
It is doubtful that such a trial would be considered in the future.
With such a small difference in absolute risk, if a 25% increase in relative risk of fatal stroke does exist, what would the risk-benefit ratio be, assuming a 36% decrease in nonfatal stroke risk observed in these trials, and how will these results be placed in view of the much larger protective effect of statins on cardiac risk? Our data suggest that for every 10,000 patients treated per year with statins, we can expect to prevent 91 myocardial infarctions and 18 nonfatal strokes and to cause one fatal stroke.
In summary, we believe the best available evidence supports the use of statins to prevent the morbidity associated with stroke. However, its ability to affect mortality rates, either beneficially or deleteriously, is uncertain owing to the low event rates found in these clinical trials of cardiovascular disease prevention. Further research will need to focus on defining the etiology of strokes observed in patients on statin medications to better understand the impact of lipid-lowering therapy on cerebrovascular diseases. For the present, we conclude that the benefits of statins on coronary morbidity and mortality far outweigh their impact on stroke events. We estimate that, on average, one cardiac event is prevented for every 26 patients treated, and one stroke is prevented for every 143 patients treated with statins over a 4-year period.