Effect of Lipid-Lowering Therapies on Stroke Prevention

Abstract & Commentary

Synopsis: Lipid-lowering therapy reduces stroke incidence in coronary patients, especially when total cholesterol level is lowered to less than 232 mg/dL (6.0 mmol/L), which explains the best results being obtained with statins.

Source: Corvol JC, et al. Arch Intern Med. 2003;163:669-676.

Stroke is the third leading cause of mortality in the United States after coronary heart disease and cancer and is the leading cause of disability.1 Primary end points in clinical trials using lipid-lowering therapies have usually been coronary events and/or mortality and, in fact, as of this date no randomized trials with stroke as the primary end point have been completed. However, data from many randomized trials have clearly suggested that cholesterol lowering produced primarily by hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) effectively reduces stroke incidence.2-6

Corvol and associates carefully evaluated the effects of lipid-lowering therapy on stroke prevention in coronary patients by conducting a meta-analysis of the literature from 1966 through 2001 including randomized trials of primary and secondary coronary artery disease prevention using satins and nonstatin drugs, diet, and other interventions that provided data on stroke incidence. They analyzed 38 trials that studied 83,161 patients for an average follow-up of 4.7 years. The results of this literature search revealed that lipid-lowering therapy significantly reduced all (fatal plus nonfatal) stroke incidence by 17 percent. However, the best efficacy was obtained with statin therapy (ie, relative risk reduction of 24%) and secondary prevention (ie, relative risk reduction of 26%). Stroke incidence reduction was significantly

correlated with cholesterol reduction, with the final cholesterol level proving to be the best value, which allowed a clear separation between absence or presence of stroke reduction with the best results noted to occur when the cholesterol level was less than 232 mg/dL.

Comment by Harold L Karpman, MD, FACC, FACP

The results of the meta-analysis conducted by Corvol et al provide strong evidence in favor of the potential of lipid-lowering therapy to prevent stroke. The most convincing results were obtained using statin drugs—probably a reflection of the efficacy of these agents in their ability to lower blood lipid levels. However, since none of the published trials have had stroke as the primary end point, the incidence of stroke was very low, especially is the case of primary cardiovascular disease prevention, thereby reducing the power of the comparison. In fact, stroke reduction proved to be significant only in cardiovascular secondary prevention (19%) and not in primary prevention (5%) presumably because the ages included in the primary prevention studies were much lower. Controlled lipid-lowering trials that have stroke prevention as a primary end point are ongoing and will include a much more aged population who obviously are at a higher risk of stroke.

In cardiovascular secondary prevention trials, statins reduced stroke incidence by 26%, which is close to the benefit obtained with antithrombotic drugs in secondary prevention of stroke.7,8 The best effects were attained with statins because either stroke prevention with lipid-lowering therapy is related to cholesterol lowering (nonstatin therapies are less effective than statins are in this biochemical action) or because statins have other properties in addition to cholesterol lowering that may explain their ability to reduce stroke incidence. It appears to be critical to reduce the final cholesterol levels to less than 232 mg/dL with whatever drug is being used to reduce the cholesterol level.

In summary, lipid-lowering therapy appears to reduce stroke incidence in coronary artery disease patients, and the benefit appears to relate to the ability of drugs to lower the blood cholesterol level adequately. Therefore, it would appear that statin drug therapy may be extended to the higher-risk stroke population both for primary and secondary prevention, especially if ongoing randomized clinical trials confirm the findings of the meta- analysis performed by Corvol et al.

References

1. Williams GR, et al. Stroke. 1999;30:2523-2528.

2. Blauw GJ, et al. Stroke. 1997;28:946-950.

3. Hebert PR, et al. JAMA. 1997;278:313-321.

4. Hebert PR, et al. Arch Intern Med. 1995;155:50-55.

5. Di Mascio R, et al. Cerebrovasc Dis. 2000;10:85-92.

6. Atkins D, et al. Ann Intern Med. 1993;119:136-145.

7. The ESPS Group. Lancet. 1987;2:1351-1354.

8. Bousser MG, et al. Stroke. 1983;14:5-14.

Dr. Karpman, Clinical Professor of Medicine, UCLA School of Medicine, is Associate Editor of Internal Medicine Alert.