Lowering of low-density lipoprotein cholesterol (LDL-C) with statins has in the last decade become part of the standard treatment regimen in patients with established coronary heart disease (CHD), according to background information in the article. The most common treatment regimen for such patients in northern Europe has been simvastatin, 20 to 40 mg/d. In a recent trial among patients with acute coronary syndromes, incremental benefit was demonstrated with more intensive lowering of LDL-C to well below 100 mg/dL. Another study comparing high and low doses of atorvastatin in stable nonacute CHD found significant improvement in prognosis with respect to cardiovascular disease. In that study, however, the benefit of reduced cardiovascular death appeared to have been offset by a higher number of deaths due to noncardiovascular causes. Although this difference did not reach statistical significance and could well be due to chance, it led to a call for further safety information on the use of atorvastatin at a dose of 80 mg/d.
Terje R. Pedersen, M.D., Ph.D., of Ulleval University Hospital, Oslo, Norway and colleagues with the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study examined whether intensive lowering of LDL-C with atorvastatin at the highest recommended dose would be more beneficial compared with the moderate, most widely used dose of simvastatin. The randomized trial was conducted at 190 cardiology care and specialist practice centers in northern Europe between March 1999 and March 2005, with a median (mid-point) follow-up of 4.8 years.
The study included 8,888 patients aged 80 years or younger with a history of acute myocardial infarction (MI; heart attack). Patients were randomly assigned to receive a high dose of atorvastatin (80 mg/d (n=4,439), or usual-dose simvastatin (20 mg/d; n=4,449).
During treatment, mean LDL-C levels were 104 mg/dL in the simvastatin group and 81 mg/dL in the atorvastatin group. The primary end point of coronary death, acute myocardial infarction, or cardiac arrest with resuscitation occurred in 463 patients (10.4 percent) in the simvastatin group and in 411 (9.3 percent) in the atorvastatin group and was not statistically significantly different between the two groups. There were 178 coronary deaths (4.0 percent) in the simvastatin group vs. 175 (3.9 percent) in the atorvastatin group. Nonfatal myocardial infarction occurred in 321 patients (7.2 percent) in the simvastatin group and in 267 (6.0 percent) in the atorvastatin group.
The composite secondary end point of a major cardiovascular event including stroke was reduced in the atorvastatin group. Similarly, there were reductions in the risk of nonfatal MI, any CHD event, and any cardiovascular event. The risk of death from any cause was similar in both study groups. There were no significant differences in noncardiovascular deaths between the treatment groups. There were no significant differences in the frequency of serious adverse clinical events between the 2 groups. Patients in the atorvastatin group had higher rates of drug discontinuation due to nonserious adverse events.
"In summary, when comparing standard and intensive LDL-C-lowering therapies in patients with previous myocardial infarction, there was no statistically significant reduction in the primary end point of major coronary events, but there was reduced risk of other composite secondary end points and nonfatal acute MI. There were no differences in cardiovascular and all-cause mortality. The results indicate that patients with myocardial infarction may benefit from intensive lowering of LDL-C without increase in noncardiovascular mortality or other serious adverse reactions," the authors conclude. (JAMA.2005; 294:2437-2445. Available pre-embargo to the media at www.jamamedia.org)
This study was sponsored by Pfizer Inc. For the financial disclosures of the authors, please see the JAMA article.
Editorial: The IDEAL Cholesterol - Lower is Better
In an accompanying editorial, Christopher P. Cannon, M.D., of Brigham and Women's Hospital and Harvard Medical School, Boston, discusses the results of the study by Pedersen et al.
"What are the messages for patients from the IDEAL and other statin trials? First, for the 'bad' cholesterol, LDL-C, lower is better for preventing MI stroke, need for cardiac procedures, and death. Second, statins are safe overall, even for patients with extremely low treatment LDL-C levels. However, patients and physicians have to work as partners to monitor for adverse effects, which can occur in up to 5 percent of patients but that only rarely can be life-threatening. Fortunately, these are almost always reversible and do not lead to any permanent damage. Third, patients should know their cholesterol numbers, for both LDL-C and HDL-C, to enable them to see how much lowering is needed to reach targets of an LDL-C level of less than 100 mg/dL for patients with risk factors or less than 70 mg/dL for patients with heart disease."
"And fourth, any drug treatment should be taken together with an appropriate diet and exercise program to lower cholesterol and overall vascular risk. The amount of LDL-C lowering with diet is only in the range of 7 percent to 12 percent. Clearly, diet is a central part of the treatment, but to get the benefits of very low cholesterol levels, drug treatment is often necessary. Optimal use of diet and appropriate use of medications will dramatically reduce the risk of MI, stroke, and death from heart disease. These new data should help motivate any patients who have been hesitating about treating their cholesterol to talk with their physician to get the benefits of intensive cholesterol lowering."
"Finally, the scientific community needs to continue to pursue new avenues of treatment, with approaches that may well be 'beyond statins.' Even with intensive statin therapy, the current best evidence-based treatment available, many patients still will have recurrent cardiovascular events. New strategies may include development of new agents to achieve even lower target LDL-C levels, substantially increase HDL-C levels, reduce triglycerides, reduce C-reactive protein and other components of inflammation, and modify many other identified components of vascular disease," Dr. Cannon writes.
(JAMA.2005; 294:2492-2494. Available pre-embargo to the media at www.jamamedia.org)
Editor's Note: For the financial disclosures of Dr. Cannon, please see the JAMA article.