January 12, 2005
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
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.