JAMA: New cholesterol drug fails to prevent plaque development

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Daiichi Sankyo's ACAT inhibitor pactimibe had no effect on atherosclerosis in patients with familial hypercholesterolemia but did result in an increased incidence of cardiovascular events such as heart attack and stroke, according to CAPTIVATE trial results published in the March 18 issue of Journal of the American Medical Association.

One proposed method to help prevent cardiovascular disease is to block the action of acyl coenzyme A:cholesterol acyltransferase (ACAT), an enzyme involved in cholesterol accumulation. In theory, the authors wrote that the inhibition of ACAT-1 (an isoform of ACAT) could slow the progression of atherosclerosis, and prevent the development of vulnerable plaque. Previously, treatment with ACAT inhibitors, like pactimibe, has shown promising results for the prevention of atherosclerosis in animal tests.

Marijn C. Meuwese, MD, of the Academic Medical Center in Amsterdam, Netherlands, and colleagues assessed the efficacy and safety of pactimibe in reducing progression of atherosclerosis in 892 patients with a family history of high cholesterol, which is associated with a higher risk for atherosclerosis.

The randomized, placebo-controlled CAPTIVATE (Carotid Atherosclerosis Progression Trial Investigating Vascular ACAT Inhibition Treatment Effects) was conducted at 40 clinics in the U.S., Canada, Europe, South Africa and Israel between February 2004 and December 2005. The researchers administered either 100 mg/d of pactimibe (443 patients) or matching placebo (438 patients), in addition to standard lipid-lowering therapy.

The investigators assessed atherosclerosis by ultrasound measurements of carotid intima-media thickness (CIMT) at the beginning of the study and at 12, 18 and 24 months. The treatment and trial was discontinued on Oct. 26, 2005, when the parallel ACTIVATE study failed to demonstrate efficacy of pactimibe compared to placebo.

After six months of treatment with pactimibe, the average percentage change from baseline of low-density-lipoprotein cholesterol (LDL-C) significantly increased by 7.3 percent compared with 1.4 percent in the placebo group. The researchers said that they observed an increase in LDL-C throughout the study, which disappeared after discontinuation of pactimibe.

Meuwese and colleagues reported that the annual progression of maximum CIMT showed no difference between groups. However, the annual progression of the average CIMT showed a significant difference between groups as relative average CIMT increase was observed in patients receiving pactimibe (difference of -0.014 mm). They reported that the average CIMT progressed significantly in the pactimibe group within one year, whereas only minor progression of average CIMT was observed in the placebo group.

The researchers said that serious adverse events were reported more frequently by patients in the pactimibe group than in the placebo group (10 vs. 7.7 percent). Also, cardiovascular events (6.3 vs. 3.4 percent) as well as the composite of cardiovascular death, heart attack and stroke (2.3 vs. 0.2 percent) occurred more frequently in patients receiving pactimibe compared to placebo.

The authors wrote that "in patients with familial hypercholesterolemia, pactimibe had no effect on atherosclerosis as assessed by changes in maximum CIMT compared with placebo but was associated with an increase in mean CIMT as well as increased incidence of major cardiovascular events." They concluded that the findings from this study and findings from other studies lessen "the promise and further development of this class of drugs for cardiovascular prevention."