Tuesday, April 17, 2007

ILLUSTRATE - Considerações

Title: Effect of Torcetrapib on the Progression of Coronary Atherosclerosis

Nissen SE, Tardif JC, Nicholls SJ, et al., on behalf of the ILLUSTRATE Investigators.

Citation: N Engl J Med. 2007;356:1304-1316.

Study Question: Does torcetrapib, a novel cholesteryl ester transfer protein (CETP) inhibitor that raises high-density lipoprotein cholesterol (HDL-C) by more than 50%, impact progression of coronary atherosclerosis?

Methods: A total of 1,188 patients with coronary disease underwent intravascular ultrasonography (IVUS). After treatment with atorvastatin to reduce levels of low-density lipoprotein cholesterol (LDL-C) to <100 mg/dl (2.59 mmol/L), patients were randomly assigned to receive either atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib daily. After 24 months, disease progression was measured by repeated IVUS in 910 patients (77%). Each target site for the primary analysis was required to have <50% obstruction throughout a segment of 40 mm or longer.
Results: Mean age was 57 years, 70% were men, and 91% were on a statin at baseline. Baseline mean LDL-C was 84 mg/dl and HDL-C was 45.5 mg/dl, and median LDL-C:HDL-C was 1.89. After 24 months, as compared with atorvastatin monotherapy, the effect of torcetrapib–atorvastatin therapy was an approximate 61% relative increase in HDL-C (43.9 mg/dl vs. 72.1 mg/dl) and a 20% relative decrease in LDL-C, reaching a ratio of LDL-C to HDL-C of <1.0. Torcetrapib was also associated with an increase in systolic blood pressure of 4.6 mm Hg. The percent atheroma volume (the primary efficacy measure) increased by 0.19% in the atorvastatin-only group and by 0.12% in the torcetrapib–atorvastatin group (p = 0.72). A secondary measure, the change in normalized atheroma volume, showed a small favorable effect for torcetrapib (p = 0.02), but there was no significant difference in the change in atheroma volume for the most diseased vessel segment.
Conclusions: The CETP inhibitor torcetrapib was associated with a substantial increase in HDL-C and decrease in LDL-C. It was also associated with an increase in blood pressure, and there was no significant decrease in the progression of coronary atherosclerosis. The lack of efficacy may be related to the mechanism of action of this drug class or to molecule-specific adverse effects.

Perspective: Previous similar IVUS studies have shown that intense lowering of LDL-C by statins decreases the total atheroma volume by as much as 14.7 mm3 at 24 months, and the infusion of A-1 Milano resulted in a 14.1 mm3 reduction in atheroma volume at 1 month. It would appear that increasing HDL particle cholesterol content with a CETP inhibitor does not result in better functioning HDL particles, and there are experimental data that these cholesterol-rich HDL particles may have proinflammatory effects. The clinical morbidity–mortality trial of torcetrapib–atorvastatin was prematurely terminated because of an increase in event rates that might be explained by both the increase in systolic blood pressure and dysfunctional HDL particles. In addition to niacin, several novel drugs/devices are currently being studied in randomized trials to determine their effect on atherosclerosis progression and events. Melvyn Rubenfire, M.D., F.A.C.C.

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