Statin research calls current guidelines into question

LDL-C levels may need to be lower than 100 mg/dL

New research is challenging the current guidelines of how to treat atherosclerotic coronary disease with statin drugs. Current guidelines by the National Cholesterol Education Program have set a therapy target of 100 mg/dL.

Two recent head-to-head trials, however, suggest that intensive statin therapy may be of greater benefit.

"The implications of this turning point — that is, of the new era of intensive statin therapy — are profound," says Eric J. Topol, MD, chairman and professor at the Department of Cardiology of The Cleveland Clinic Foundation. Topol’s comments appeared in an editorial in the April 8 issue of the New England Journal of Medicine.

One of the trials, Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL), compared the effects of patients randomly assigned a moderate lipid-lowering regimen consisting of 40 mg pravastatin or an intensive lipid-lowering regimen consisting of 80 mg atorvastatin.

Between June 1999 and September 2001, 654 patients were randomized and received the study drug; 502 had intravascular ultrasound examinations to evaluate build-up in coronary arteries at baseline and after 18 months of treatment.

Baseline LDL-C level was reduced to 110 mg/dL in the pravastatin group and to 79 mg/dL in the atorvastatin group. In addition, progression of coronary atherosclerosis occurred in the pravastatin group (2.7%) compared with baseline. Progression did not occur in the atorvastatin group (-0.4%) compared with baseline. Both drugs showed a similar incidence of side effects.

"For patients with coronary heart disease, intensive lipid-lowering treatment with atorvastatin reduced progression of coronary atherosclerosis compared with pravastatin," the researchers concluded. The study was funded by Pfizer, which makes atorvastatin, but was conducted independently by The Cleveland Clinic Cardiovascular Coordinating Center. The results of the study were published in the March 3 issue of the Journal of the American Medical Association.

Bristol-Myers Squibb, the maker of pravastatin, criticized the research. The company argued that a halt in the growth of plaque was not necessarily the same as a reduction in heart attacks and deaths. It then funded Harvard Medical School researchers to prove that its drug treatment was as good as atorvastatin. And PROVE-IT they did, although not in the way Bristol-Myers Squibb would have liked.

The TIMI 22 study (Pravastatin or Atorvastatin Evaluation and Infection Therapy; PROVE-IT) enrolled 4,162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days. The researchers compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy).

The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an endpoint event. The primary endpoint was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. Follow-up lasted 18-36 months, with a mean of 24 months.

The median LDL-cholesterol level achieved during treatment was 95 mg/dL in the standard-dose pravastatin group and 62 mg/dL in the high-dose atorvastatin group. Atorvastatin showed superiority to pravastatin, resulting in a 16% lower risk of the primary endpoint.

Intensive therapy with high-dose atorvastatin had a consistent beneficial effect on cardiac events, including a significant 29% reduction in the risk of recurrent unstable angina and a 14% reduction in the need for revascularization. The reduction in clinical events with the more intensive lipid-lowering therapy was apparent as early as 30 days after the start of therapy. Patients treated with high-dose atorvastatin, however, had significantly more liver-related side effects than patients treated with standard-dose pravastatin.

The researchers conclude that "given the substantially lower LDL-cholesterol levels achieved in the group given 80 mg of atorvastatin daily [median, 62 mg/dL], our results suggest that after an acute coronary syndrome, the target LDL-cholesterol level may be lower than that recommended in the current guidelines."

Taken together, the REVERSAL and PROVE-IT trials herald a shake-up in the field, Topol says. "We know that atherosclerotic progression and clinical outcomes will be ameliorated by much more aggressive use of statins. Indeed, the 80 mg dose of atorvastatin is the most intensive LDL-lowering regimen for which data on clinical outcomes are available. Unfortunately, we do not know the precise mechanism of action responsible for atorvastatin’s superiority." He suggests more investigation is needed to untangle the independent and interdependent effects of statins on LDL-cholesterol levels and the process of arterial inflammation.

One obstacle to a change to more intensive statin therapy would be cost. The recommended starting dose of atorvastatin is 10 mg per day. The cost at this dosage in Cleveland pharmacies is $900 per year, Topol says. The 80 mg dose costs $1,400 per year. "The statin drugs already account for the largest prescription drug expenditure in the United States, at $12.5 billion per year. Treatment based on the new data could cause the costs associated with statin therapy to skyrocket even further."

Still, Topol predicts there will soon be a sea change in the prevention and management of atherosclerotic vascular disease. "The proportional reduction in major clinical outcomes that results from aggressive statin therapy is of the same order of magnitude as that seen when statins were compared with placebo in controlled trials. Intensive therapy with statins, monitored by means of measurements of LDL-cholesterol or biologic markers of inflammation, is likely to result in even greater steps toward actualizing the full benefit of this remarkable class of medicines."