An Intensive Lipid-lowering Statin Drug Regimen Provides Greater Protection Against Death or Major Cardiovascular Events Than a Standard Regimen

By Ronald Baker, PhD

Many HIV patients using HAART develop high levels of cholesterol and triglycerides that may put them at increased risk for cardiovascular disease. For these patients, physicians commonly prescribe lipid-lowering agents such as atorvastatin (Lipitor) or pravastatin (Pravachol) to reduce abnormally high levels of these lipid indicators.

Recent results of a large trial of HIV negative patients who have recently had an acute coronary syndrome show that high-dose atorvastatin (80 mg/daily) provides significantly more protection than standard therapy (40 mg pravastatin) against death or major cardiovascular events.

Clearly, these results are most relevant for patients with a prior history of a serious cardiovascular event (such as heart attack). Still, they also have relevance for HIV patients at risk for cardiovascular disease due to high lipid levels, especially for those who have other risk factors for cardiovascular events (e.g smoking or history of smoking).

Following is a brief description of the trial, published in this week’s issue of The New England Journal of Medicine.

Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear.

Researchers enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared use of 40 mg  pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy).

The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring re-hospitalization, re-vascularization (performed at least 30 days after randomization), and stroke.

The study was designed to establish the non inferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24).

Results

The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001).

Kaplan-Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent).

National guidelines call for levels of LDL cholesterol, the kind associated with heart disease, to be below 100 milligrams per deciliter in high-risk patients. But this 2-year study asked whether reducing cholesterol levels far below 100 milligrams would be beneficial. It found that the answer was yes.

When the study began, the patients' cholesterol was no higher than the level specified by the national guidelines. But those who began taking Lipitor were later found to have a median LDL level far below that — 62, compared with 95 among those who took Pravachol.

Among patients using the high-dose Lipitor, cholesterol levels dropped to 130 (on average). More importantly, levels of LDL (“bad” cholesterol) fell to 62. Current guidelines call for LDL levels to be no higher than 100.

The study did not meet the pre-specified criterion for equivalence but did identify the superiority of the more intensive atorvastatin regimen.

Conclusions

Among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen.

These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels.

Commentary

This work is being hailed by medical experts as a landmark study. The results, they say, are likely to influence physicians to give higher doses of lipid-lowering drugs to their patients with severe heart problems. In addition, many providers will likely start giving these medications to patients who are not yet taking them at all and to increase the dosage of the drugs in order to push the cholesterol levels even lower.

“It’s a breakthrough study, said Dr. Frank Sacks, professor of cardiovascular disease prevention at the Harvard School of Public Health. It shows for the first time that lowering  [cholesterol levels] to very low levels is better.” Other heart disease specialists called the study a “turning point” in the treatment of cardiovascular disease.

“What the study results tell us is “treating cholesterol is very important, not just for high risk patients, but for everyone,” said Dr. Christopher Cannon, a cardiologist at Brigham and Women’s Hospital in Boston who led the study.

Impact on HIV Patients with Elevated Lipids

How these study findings will impact the use of cholesterol-lowering drugs in HIV positive individuals on HAART with abnormally high cholesterol levels remains to be seen. Discussions of some sort of recommendation will likely take place at the 6^th Annual Lipodystrophy Workshop to be held this year in Washington DC, October 25-28, 2004.

Until a consensus is reached about use of higher dose statin therapy in HIV patients at risk for cardiovascular disease, HIV patients already on lower doses of the drugs may want to discuss with their doctors the pros and cons of increasing their daily dosage.

Full text of the NEJM article in PDF

03/10/04

Source
C P Cannon and others. Comparison of Intensive and Moderate Lipid Lowering with Statins after Acute Coronary Syndromes. The New England Journal of Medicine 350(15). April 8, 2004 [early publication on March 8, 2004].