Lovastatin Prevents Coronary Artery Disease in "Low Risk" Patients
ABSTRACTS & COMMENTARY
Sources: Downs JR, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TEXCAPS. JAMA 1998;279:1615-1622; Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins. Implications for cardiovascular event reduction. JAMA 1998;279:1643-1650.
Several clinical trials of 3-hydroxy-3-methlglutaryl coenzyme A reductase inhibitors or statins have demonstrated the effectiveness of these agents in reducing mortality and morbidity in patients either with established coronary artery disease1,2 or at high risk for myocardial infarction because of elevated cholesterol levels.3
The report of Downs and colleagues differs from previous randomized, placebo-controlled, clinical trials of statins in the prevention of atherosclerotic coronary artery disease, because the study population had no evidence of vascular disease and had average, not elevated, low-density lipoprotein (LDL) cholesterol levels. The study subjects, however, did have increased risk for coronary artery disease, mainly because of low levels of high-density lipoprotein (HDL) cholesterol.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AF/TEXCAPS) compared lovastatin 20-40 mg daily with placebo in addition to a low saturated fat, low-cholesterol diet for prevention of a first, acute, major coronary event defined as fatal or nonfatal myocardial infarction (MI), unstable angina, or sudden cardiac death. The study enrolled 5608 men and 997 women with average total cholesterol and LDL cholesterol and below average HDL cholesterol. (See Table 1.) The average follow-up was 5.2 years.
Overall mortality and the incidence of fatal and nonfatal cancer did not differ between treated and control groups. Treatment with lovastatin resulted in a 37% reduction (P < 0.001) in the risk of first acute, major coronary events. (See Table 2.) The difference between treated and placebo groups appeared as early as one year. Lovastatin reduced the risk of fatal or nonfatal MI by 40% and unstable angina by 32%. In addition, lovastatin reduced the risk for the need for revascularization by one-third and the risk for both cardiovascular and coronary events by one-fourth. (See Table 2.)Ta
Table 1
Characteristics of Study Subjects
| Characteristics |
|
|
| Men number (%) |
|
|
| Women number (%) |
|
|
| Age mean (SD) years |
|
|
| Men |
|
|
| Women |
|
|
| Race number (%) |
|
|
| White |
|
|
| Black |
|
|
| Hispanic |
|
|
Table 2
End Points, Placebo vs. Lovastatin
| End Points |
|
|
|
|
| Acute major coronary events* |
183
|
116
|
|
< 0.001 |
| Revascularizations |
157
|
106
|
|
0.001 |
| Unstable angina |
87
|
60
|
|
0.02 |
| Myocardial infarction** |
95
|
57
|
|
0.002 |
| Cardiovascular events** |
255
|
194
|
|
0.003 |
| Coronary events** |
215
|
163
|
|
0.006 |
* Fatal or nonfatal MI, unstable angina, sudden death.
** Fatal or nonfatal.
The AF/TEXCAPS has demonstrated the efficacy of statin therapy in the lowest risk group studied to date, namely patients with LDL cholesterol levels below those recommended for treatment by the National Cholesterol Education Program.4 This study suggests that an estimated six million Americans currently not recommended for drug treatment could benefit from LDL-cholesterol reduction with lovastatin or other statins.
In the same issue of JAMA, Rosenson and Tangney point out that the beneficial effects of statins may be independent of their lipid lowering actions. In clinical trials of statins, baseline or treated LDL cholesterol levels often did not correlate with coronary angiographic changes or cardiovascular events. Experiments in animal models demonstrate that statins modify endothelial function, inflammatory responses, atherosclerotic plaque stability, and thrombus formation. Following disruption of a plaque, statins influence thrombosis by variable inhibitory actions on platelet adhesion and aggregation, coagulation, rheology, and fibrinolysis. Since their non lipid lowering properties differ, qualitative differences among statins may influence their effectiveness in preventing progression of atherosclerosis and cardiovascular events. Therefore, the comparative clinical efficacy of these agents needs to be determined by randomized clinical trials.
COMMENTARY
AF/TEXCAPS has established that statin therapy is effective primary prevention for relatively low-risk groups but carries a high monetary cost for preventing each new case of coronary artery disease. As pointed out by Pearson in an editorial commentary,5 five years of lovastatin treatment in 1000 asymptomatic individuals would prevent only 12 MIs and 17 revascularization procedures and would not affect overall mortality. The annual cost per thousand for lovastatin, apart from other costs, such as for physician visits and blood tests, would be approximately $1.5 million. Therefore, Pearson suggests that, until the cost of statin drugs decreases, it is reasonable for physicians to limit their use in primary prevention to those subgroups of patients with low HDL cholesterol and additional risk factors such as smoking, diabetes, hypertension, or a family history of coronary artery disease. In AF/TEXCAPS these individuals had high event rates in the placebo group that were reduced substantially by lovastatin. Nevertheless, a physician is justified in treating any patient with low HDL cholesterol levels regardless of the presence or absence of other risk factors.
The review by Rosenson and Tangney suggests that all statins may not be of equal efficacy in their anti-atherothrombotic properties. Further data from randomized clinical trials are necessary on this point. -jjc
References
1. Scandinavian simvastatin survival study group. Lancet 1994;344:11383-1389.
2. Sacks FM, et al. N Engl J Med 1996;335:1001-1009.
3. Shepherd J, et al. N Engl J Med 1995;333:1301-1307.
4. National Cholesterol Education Program Expert Panel. JAMA 1993;269:3015-3023.
5. Pearson TA. JAMA 1998;279:1659-1660.
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