The Effect of Cholesterol Lowering with Statin Drugs on Stroke and Total Mortality

ABSTRACT & COMMENTARY

Synopsis: The authors conclude that their overview of all published randomized trials of statin drugs demonstrated large reductions in cholesterol and LDL cholesterol and clear evidence of benefit on stroke and total mortality rates.

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

Lowering of the total serum cholesterol and LDL cholesterol have clearly been demonstrated to decrease the risk of coronary artery disease.1-3 However, whether it decreases the risk of strokes and total mortality had not been clearly defined. The recent publication of three large trials has finally given well-controlled, double-blind evidence of the ability of the statin drugs to lower total and LDL cholesterol levels and also of the efficacy of these agents in preventing the onset of symptomatic coronary artery disease.4-8

Hebert and associates from the Division of Preventative Medicine of the Brigham and Women’s Hospital and the Harvard Medical School conducted a computerized literature survey to identify all statin drug trials published between 1985 and 1995. They identified a total of 16 individual trials that used only statin drugs (i.e., rather than other lipid-lowering agents) involving approximately 29,000 patients who were treated and followed for an average of 3.3 years. The average reductions in total and low density lipoprotein (LDL) cholesterol achieved were 22% and 30%, respectively. Of the total of 454 strokes, those patients who were administered statin drugs experienced a significant reduction in the risk of stroke by 29% and in the risk of total mortality by 22%; these reduced risks were attributed primarily to the significant reduction of cardiovascular disease death by 28%. There was no evidence of increased risk in non-cardiovascular mortality (i.e., from cancer and/or violent deaths), and, in addition, there was no significant increase in the risk of cancer. The authors conclude that their overview of all published randomized trials of statin drugs demonstrated large reductions in cholesterol and LDL cholesterol and clear evidence of benefit on stroke and total mortality rates. There was, as expected, a large and significant decrease in cardiovascular disease and mortality, but there was no significant evidence of any increases in either non-cardiovascular disease deaths or cancer.

COMMENT BY HAROLD L. KARPMAN, MD

The beneficial effects of statin drugs observed in the current overview of all published trials of statin drugs should lay to rest a number of controversies that have been scattered throughout the medical literature, especially over the last 10 years. Data from observational studies in the past had suggested that cholesterol is not as strong a risk factor for stroke as it had been determined to be for coronary artery disease. In fact, a recently published overview of 45 prospective observational cohorts reporting on 13,000 strokes occurring in a population of 450,000 individuals demonstrated no independent association between baseline blood cholesterol and stroke risk.9 On the other hand, the more current literature search by Hebert et al demonstrated a significant reduction in strokes in patients who were receiving statin drugs. Most likely, the statins help to diminish the incidence of stroke by virtue of their ability to reduce the risk of new or recurrent myocardial infarctions. However, of course, one cannot exclude the possibility that cholesterol-lowering by statin agents may decrease risk of stroke by primarily preventing or reversing atherosclerosis in extracranial arteries or by improving their endothelial function.

With respect to mortality, a number of previous reviews have suggested that the benefits of cholesterol lowering on coronary disease are proportional to the size of reduction. With this in mind, it should be noted that in older trials, the average reduction in cholesterol was only approximately 10%, whereas, with statin drugs, the reduction tends to be 20% or greater. The much larger reduction in fatal coronary heart disease (31%) reported in the current study translates into a larger reduction (22%) in total mortality, thus showing a clear-cut beneficial relationship between the cholesterol-lowering effects of the statin drugs on total mortality.

Treatment with statin drugs has been demonstrated to significantly reduce total mortality in primary as well as secondary prevention trials both in low-risk as well as in higher risk individuals.4-8 Of interest is that one of the more recently published trials demonstrated that patients with higher pre-treatment cholesterol levels demonstrated significant reductions in the primary end points of fatal and/or non-fatal coronary artery events as well as a significant reduction in the risk of stroke.8

In conclusion, the reported overview of 16 individual trials studying 29,000 patients clearly demonstrates the significant effectiveness of the statin drugs in preventing stroke and total mortality. In addition, the data also reveal that there is no evidence of any increase in non-CVD deaths or in overall cancer rates associated with cholesterol-lowering by these agents.

References

1. Rossouw JE, et al. The value of lowering cholesterol after myocardial infarction. N Engl J Med 1990; 323:1112-1119.

2. Law MR, et al. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischemic heart disease. BMJ 1994;308:367-372.

3. Gould LA, et al. Cholesterol reduction yields clinical benefit: A new look at old data. Circulation 1995; 92:2274-2282.

4. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Group (4S). Lancet 1994; 344:1383-1389.

5. Scandinavian Simvastatin Survival Study Group. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study Group (4S). Lancet 1995;1274-1275.

6. Sheperd J, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-1307.

7. The West of Scotland Coronary Prevention Study Group. A coronary primary prevention study of Scottish men aged 45-64 years; trial design. J Clin Epidemiol 1992;45:849-860.

8. Sacks FM, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-1009.

9. Prospective Studies Collaboration. Cholesterol diastolic blood pressure, and stroke: 13,000 strokes in 450,000 prospective cohorts. Lancet 1995;346: 1647-1653.