Effects of High and Low Dose Atorvastatin on Major Cardiovascular Events in Patients with Stable Coronary Heart Disease

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.

Synopsis: Compared to patients over the age of 65 years who were receiving 10 mg of atorvastatin daily, the elderly patients who received 80 mg daily experienced significantly reduced major cardiovascular and coronary events and hospitalizations for congestive heart failure; however, it could not be determined whether the clinical benefit was related to the higher statin dose, the lower resultant LDL-cholesterol levels, or to both factors.

Source: Wenger NK, et al. Ann Int Med. 2007;147:1-9.

Cardiovascular risk increases steadily with age and is associated with an increase in the burden of chronic cardiovascular disease (CVD) including coronary heart disease (CHD) and stroke.1 Large, randomized, placebo-controlled clinical trials have produced statistically significant results which have clearly demonstrated that decreasing low-density lipoprotein (LDL) cholesterol levels with statin therapy will reduce the risk for CHD in older persons.2-4 The recommendation of the National Cholesterol Education Program Adult Treatment Panel5 in 2001 that persons older than 65 years of age should not be denied lipid lowering has been further strengthened by later publications6-7 leading the National Cholesterol Education Program to conclude in 2004 that intensive LDL cholesterol-lowering therapy was justified in high-risk older persons with established CVD.8 The American Heart Association and the American College of Cardiology guidelines quite recently supported the position that it was reasonable to reduce LDL cholesterol levels to 70 mg/dL or less in any patient with established CHD, including elderly patients even though they were under-represented in many of the clinical trials that were evaluated.9-10

Wenger and her colleagues performed a secondary analysis of the results of the Treating to New Targets (TNT) study11 evaluating data from that study regarding the efficacy and safety of high-dose atorvastatin treatment in patients 65 years of age or older.12 In the double-blind TNT clinical trial, 3089 patients 65 years of age and older were randomly assigned to receive atorvastatin in either 10 or 80 mg/d dosage at 256 sites in 14 countries. The primary endpoint was the occurrence of a first major cardiovascular event (ie, death from CHD, nonfatal non procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke). The high-dose atorvastatin group was found to have a 2.3% absolute risk reduction for major cardiovascular events and a 19% reduction in relative risk compared to the low dose atorvastatin group. Mortality rates from CHD, nonfatal non-procedure-related myocardial infarction, and fatal or nonfatal stroke were all lower although the difference was not statistically significant for each individual component. The authors concluded that the analysis of the published TNT data suggested that additional clinical benefit could be achieved by treating older patients with CHD more aggressively by reducing LDL cholesterol levels to less than 100 mg/dL.

Commentary

Secondary analyses and meta analyses of large randomized, placebo-controlled trials have clearly demonstrated that the cardiovascular benefits of statin therapy observed in older patients with CHD are similar to those benefits occurring in younger patients.2-4,6,7,13 One major trial7 which was conducted exclusively in older individuals (age 70-82 years) revealed a significant reduction in major cardiovascular events among patients who received statin therapy compared to those who received placebo, but it showed no reduction in risk for stroke although this finding may have been due to the relatively short duration of follow-up in that trial. Other studies have demonstrated the benefits of statin therapy compared with placebo in reducing the risk of stroke in older patients3,6 and, interestingly enough, the Wenger analysis revealed that the rate of fatal and nonfatal stroke was lower in the 80 mg high-dose group than it was in the 10 mg low-dose atorvastatin group although the difference was not statistically significant.12 The rate of liver function abnormalities was similar for both dosage groups as it was for both the younger and older groups of patients. The small increase in treatment-related adverse events and trial withdrawals in the 80 mg atorvastatin group was similar to what was observed to occur in the younger patient group and was consistent with what had previously been reported in statin trials.2 Finally, it is important to note that it could not be determined whether the observed clinical benefit was related to the higher statin dose, to the lower resultant LDL-cholesterol levels, or to both factors and therefore, any benefits observed in patients receiving the higher dose conceivably may also have occurred in those patients who achieve low LDL cholesterol levels even with relatively low dose statin therapy.

In summary, intensive lipid lowering therapy using 80 mg of atorvastatin (compared to 10 mg) in patients over the age of 65 years significantly reduced major cardiovascular and coronary events and hospitalizations for congestive heart failure. Older patients who received the 80 mg dose reduced their risk for major cardiovascular events to about that of patients younger than 65 years treated with 10 mg of atorvastatin. As noted above, it could not be determined whether the clinical benefit was related to the higher statin dose, to the lower resultant LDL-cholesterol levels, or to both factors. However, these findings support the most recent ACC, AHA and National Cholesterol Education Program guideline recommendations8 for high-risk older patients with established CHD; that is, LDL cholesterol levels should be reduced to 70 mg/dL or lower in all patients with established CHD.9

References

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10. Deedwania P, et al. Effects of intensive versus moderate lipid lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE). Circulation. 2007;115:700-707.

11. Waters DD, et al. Treating to New Targets (TNT) study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol. 2004; 93:154-158.

12. Wenger NK, et al. Outcomes of using high or low dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007;147: 1-9.

13. Baigent C, et al. Lancet. 2005; 366:1267-1278. Erratum in: Lancet. 2005;366(9494):1358.