CardioExchange Archive

CardioExchange welcomes Philip Barter and Christopher P. Cannon, two of the investigators for the DEFINE trial, which was recently published in the New England Journal of Medicine. Here, they answer questions posed by CardioExchange’s editors. First, some background about the trial:

In DEFINE, 1623 patients with or at high risk for coronary disease were randomized to receive either 100 mg of anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, or placebo daily for 18 months. By week 24, the mean LDL level had dropped significantly more with anacetrapib (from 81 to 45 mg/dL) than with placebo (from 82 to 77 mg/dL), and the mean HDL level had increased significantly more with anacetrapib (from 41 to 101 mg/dL) than with placebo (from 40 to 46 mg/dL). The incidence of prespecified cardiovascular events was similar in the two groups (2.0% with the drug, 2.6% with placebo; P=0.40). Anacetrapib’s manufacturer funded the study.

Q: You performed a prespecified Bayesian analysis with respect to the incidence of cardiovascular events. What does that analysis indicate regarding a reduction in those events with anacetrapib? 

A: The prespecified Bayesian analysis indicated with 94% confidence that anacetrapib would not be associated with a 25% increase in cardiovascular events — an increase previously documented with torcetrapib. The analysis does not tell us anything with respect to a decrease in cardiovascular events. In fact, the trial was not designed (or powered) to assess efficacy. The observed possible reduction in events should be interpreted with this in mind. The results should instead simply offer comfort about going ahead with a very large clinical-outcomes trial that is designed (and powered) to test the hypothesis that inhibiting CETP will limit the incidence of cardiovascular events.

Q: In terms of anacetrapib’s potential benefit, how important is the change in HDL relative to the change in LDL?

A: It’s not possible to say from this trial, but the results of a large clinical-outcomes trial might provide an answer.

Q: Given the same change in LDL from using a statin, what would the adjudicated cardiovascular events have looked like? In other words, why didn’t we see a greater reduction in events with the drug, just from the LDL lowering alone? Would a statin-related reduction in LDL like this have a stronger effect?

A: The DEFINE trial was too small and too short (and thus seriously underpowered) to provide a sensible answer to this question.

Q: Anacetrapib yielded a roughly 40% reduction in LDL but only a roughly 20% reduction in apolipoprotein B (apoB). Did the treated group have more small, dense LDL particles? If so, is that a good or a bad thing? And could it account for the lack of significant improvement in cardiovascular events?

A: The LDL reduction resulted from at least two mechanisms. First, inhibiting CETP reduces the amount of cholesterol transferred from HDL to LDL and, thus, reduces the cholesterol content of the LDL particle. Second, there is evidence that inhibiting CETP up-regulates the LDL receptor (by an unknown mechanism) and, therefore, increases the removal of LDL particles (and thus apoB) from plasma. The enhanced LDL removal reduces the concentration of both apoB and LDL; the inhibition of CETP reduces LDL but not apoB. Hence, the reduction in LDL was greater than that in apoB. The implication that the LDL particle size may have been smaller is probably of little consequence when you consider that the number of LDL particles was clearly reduced. But, again, we will not know the clinical significance of these details until we have data from a large clinical-outcomes trial.

Q: A few CETP inhibitors are being developed. Are there important differences among them that we should know about?

A: Ongoing research should provide answers. For now, we just don’t know.

Pose your own questions to Drs. Barter and Cannon, and share your thoughts about the DEFINE trial here on CardioExchange.