By Ashley Starkweather, B.S. and Asher Kimchi M.D.

Cleveland, OH – A randomized trial of moderate versus intensive statin treatment in patients with atherosclerotic disease showed that intensive therapy lowers both LDL cholesterol and C-reactive protein levels more effectively than moderate therapy, and furthermore slows disease progression. The results of this study were published by Steven E. Nissen, M.D., from the Cleveland Clinic Foundation in the January 6, 2005 issue of the New England Journal of Medicine. 

Statins have been proven in recent studies to have a wide range of biologic effects, the most exploited being the reduction of LDL cholesterol. However, it also has a lowering effect on circulating levels of C-reactive protein, a marker of inflammation. Considering that inflammation plays a critical role in atherosclerosis, the question remains if statins effectively decrease inflammation as well as lowering LDL cholesterol, and if so, would this result in a slowed progression of atherosclerotic disease. 

In this study 502 patients at 34 U.S. centers were enrolled between June 1999 and September 2001. Eligible patients had to have an LDL cholesterol level of 125 to 210mg/dL after a statin-free washout period of 4 to 10 weeks. Patients were randomly assigned to receive either 40mg of pravastatin or 80mg of atorvastatin orally daily, and all patients as well as study personnel were blind to these assignments and lab results. 

Patients underwent intravascular sonography at the outset of the trial, with a follow-up study performed 18 months later to assess the severity and progression of their atherosclerosis. In order to be eligible, patients had to have single vessel stenosis of at least 20 percent on angiography prior to the study.  

The baseline measurements of the study population were a mean LDL cholesterol of 150.2mg/dL and mean C-reactive protein of 2.9mg/L. At the 18 month follow-up, the mean LDL cholesterol was 94.5mg/dL and mean CRP was 2.3mg/L. There were significantly (P<0.001) greater reductions in both LDL and CRP in the 80mg/day atorvastatin group than the 40mg/day pravastatin group. 

The progression measurements showed a close correlation with both the LDL and CRP levels. CRP levels had a correlation coefficient of 0.11 on univariate analysis for both percent and total atheroma volume (P=0.01 and P=0.02, respectively). LDL levels showed a stronger correlation, with a coefficient of 0.12 for total atheroma volume (P=0.005) and 0.14 for percent atheroma volume (P=0.002). 

These findings confirm that not only is intensive statin therapy more effective in slowly atherosclerotic disease progression than moderate therapy, but also suggest that the level of CRP may ultimately represent an important therapeutic target in managing coronary artery disease. More research into this question is warranted, and an ongoing clinical trial is currently assessing the use of CRP levels to guide therapy in patients who do not have elevated LDL cholesterol. 

Coauthors: E. Murat Tuzcu, M.D., Paul Schoenhagen, M.D., Tim Crowe, B.S., William J. Sasiela, Ph.D., John Tsai, M.D., John Orazem, Ph.D., and Peter Ganz, M.D.