In this presentation Dr. Nissen presents new data from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, showing the effects of intensive versus moderate statin treatment on the rate of progression of atherosclerosis in patients with coronary artery disease.

By comparing the amount of atheroma in the wall of the coronary artery at different time points it is possible to gauge the progression or regression of atherosclerosis, and this can be done using the intravascular ultrasound (IVUS) technique. As atherosclerotic plaque develops, the lumen size of the vessel can stay the same for a long time, so by using IVUS it is possible to track the disease irrespective of the change in lumen size.

Serum cholesterol levels even in the low range have been found to be related to the risk of coronary heart disease mortality (1) and it has been shown angiographically that LDL cholesterol (LDL-C) lowering reduces the rate of progression of coronary disease (2). The hypothesis that “lower is better” with regards to LDL-C lowering was tested in the REVERSAL trial. 654 patients with symptomatic coronary artery disease were randomized to a moderate statin regimen of pravastatin 40mg or an intensive regimen of atorvastatin 80mg, for 18 months, and 502 patients completed the study. IVUS computation of atheroma volume was used to gauge atherosclerosis progression or regression.

A significantly greater reduction in LDL-C was seen in the atorvastatin 80mg arm. Did this additional cholesterol reduction reduce disease progression? In terms of atheroma volume following treatment, moderate statin therapy was associated with an actual progression of disease, whereas the intensively treated patients had halted disease progression. Both treatments were well tolerated. Interestingly some patients on intensive therapy showed a reduction in plaque area, indicating a reversal of disease (3).

Soon after, another study called the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy- Thrombolysis in Myocardial Infarction 22) trial was published, in which patients who were hospitalized for an acute coronary syndrome were randomized also to moderate (standard) or intensive statin therapy with pravastatin 40mg or atorvastatin 80mg respectively, with a mean follow-up of 2 years. Intensive LDL-C lowering with atorvastatin 80mg significantly reduced morbidity and mortality compared to the moderate statin regimen (4). Risk reductions were seen as early as 30 days in this study.

In recently published findings from the REVERSAL study, there was a linear and continuous relationship between the rate of progression of atherosclerosis and the change in LDL-C concentration. When the intensive and moderate statin treatments were compared it was found that for the same amount of LDL-C lowering, there was a lower rate of progression of atherosclerosis in the intensively treated group. After multivariate analysis this difference in benefit could be mostly explained by C-reactive protein (CRP). The relationship between change in CRP concentration and the rate of atherosclerosis progression was similar to that seen with change in LDL-C concentration, and LDL-C and CRP reduction were found to be independent effects of statin treatment (5). These data indicate that both LDL-C and CRP reduction are important effects of statin therapy.

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After viewing this presentation the participant will be able to discuss:

- Data from the REVERSAL trial on the rate of atherosclerosis progression with intensive vs moderate statin therapy in patients with CAD
- Data from the PROVE IT-TIMI 22 trial on the risk of morbidity and mortality with intensive vs moderate statin therapy in patients with ACS

1. Chen Z, Peto R, Collins R, MacMahon S, Lu J, Li W.Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrationsBMJ. 1991 Aug 3;303(6797):276-82.

2. Ballantyne CM, Herd JA, Dunn JK, Jones PH, Farmer JA, Gotto AM Jr.
Effects of lipid lowering therapy on progression of coronary and carotid artery diseaseCurr Opin Lipidol. 1997 Dec;8(6):354-61.

3. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN; REVERSAL Investigators.Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.JAMA. 2004 Mar 3;291(9):1071-80.

4. Christopher P. Cannon, M.D., Eugene Braunwald, M.D., Carolyn H. McCabe, B.S., Daniel J. Rader, M.D., Jean L. Rouleau, M.D., Rene Belder, M.D., Steven V. Joyal, M.D., Karen A. Hill, B.A., Marc A. Pfeffer, M.D., Ph.D., Allan M. Skene, Ph.D., for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary SyndromesNEJM.2004;350:1495-1504.

5. Steven E. Nissen, M.D., 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., Raymond D. Magorien, M.D., Charles O'Shaughnessy, M.D., Peter Ganz, M.D., for the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators Statin Therapy, LDL Cholesterol, C-Reactive Protein, and Coronary Artery Disease NEJM.2005;Volume 352:29-38.