ILLUSTRATE, RADIANCE, and ERASE: What Do the Imaging Trials With Torcetrapib Tell Us?

Linda Brookes, MSc

Disclosures

June 12, 2007

In This Article

Investigation of Lipid Level Management Using Coronary Ultrasound To Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE)

The ILLUSTRATE trial, supported by Pfizer, was designed to assess whether torcetrapib plus atorvastatin would slow progression of coronary artery disease (CAD), measured by intravascular ultrasound (IVUS), compared with atorvastatin alone. The results, presented by Steven E. Nissen, MD (Cleveland Clinic, Cleveland, Ohio),[3] and published simultaneously in The New England Journal of Medicine,[4] showed that despite the substantial increase in HDL cholesterol and decrease in low-density lipoprotein (LDL) cholesterol produced by torcetrapib administered in combination with atorvastatin, there was no significant slowing of progression of coronary atherosclerosis. The torcetrapib-atorvastatin combination was also accompanied by an increase in blood pressure.

The patients in ILLUSTRATE were enrolled at 137 centers in North America and Europe with evidence of CAD and ≥ 1 stenosis with ≥ 20% narrowing on angiography. All patients entered a run-in period of 4-10 weeks on atorvastatin 10-80 mg daily targeted to achieve an LDL cholesterol level within ± 15 mg/dL of 100 mg/dL. A total of 1188 patients achieved this goal and were then randomized to treatment with either atorvastatin monotherapy (at the dose established during the run-in period) or atorvastatin plus torcetrapib 60 mg daily for 24 months.

All patients underwent IVUS at baseline (prior to the run-in period) and at 24 months; 910 underwent repeat IVUS of the same target vessel originally imaged to measure disease progression. The average age of the patients in the study was 57 years, 70% were men, 75% had hypertension, and 21% had diabetes mellitus; 91% were on statin therapy and 94% were taking aspirin. After the run-in, the average LDL/HDL cholesterol levels were 84 mg/dL and 46 mg/dL, respectively.

After 24 months, torcetrapib-atorvastatin therapy had increased HDL cholesterol by 58.6% and reduced LDL cholesterol by 13.3%, compared with baseline levels. Compared with atorvastatin monotherapy, this represented a relative increase of 60.8% and a relative decrease of 19.9%, respectively ( Table 1 ).

Torcetrapib-atorvastatin failed to reduce the progression of coronary atherosclerosis for the primary efficacy measure, change in percent atheroma volume, which instead was increased by 0.12% in the torcetrapib-atorvastatin group and by 0.19% in the atorvastatin monotherapy group (P = .72) ( Table 2 ). One secondary efficacy measure, change in normalized atheroma volume, showed a small favorable effect for torcetrapib-atorvastatin (P = .02 vs atorvastatin monotherapy), but there was no significant difference in the change in atheroma volume in 10 mm of the most diseased vessel segment between the 2 treatment groups.

All of the effects on atheroma were unaffected by sex, age, smoking/no smoking, baseline LDL or HDL cholesterol level, high-sensitivity C-reactive protein (hsCRP), or the presence or absence of diabetes or metabolic syndrome. An almost significant effect of torcetrapib-atorvastatin was seen in patients whose percent atheroma volume was equal to or greater than the median at baseline (≥ 36.8%) ( Table 3 ). In the patients with percent atheroma volume less than median (< 36.5%), there was an almost significant effect with atorvastatin monotherapy. However, these were marginal findings and they may not be clinically significant, Dr. Nissen stressed.

During the trial, systolic/diastolic blood pressure in the torcetrapib-atorvastatin group rose by an average of 6.5/2.8 mm Hg compared with 2.0/0.8 mm Hg in the atorvastatin monotherapy group. Patients on torcetrapib-atorvastatin had more investigator-reported hypertensive adverse events (AEs), more blood pressure values > 140/90 mm Hg, and a higher rate of patients with an increase of > 15 mm Hg in systolic blood pressure (SBP) ( Table 4 ).

Rates of other, major AEs did not differ significantly between the 2 treatment groups ( Table 5 ).

Dr. Nissen commented that "the absence of a beneficial effect for torcetrapib was particularly striking for the achieved level of 70 mg/dL, 20% lower than atorvastatin monotherapy." He suggested 3 possible mechanisms of action that may explain these results:

  1. CETP inhibition may not generate HDL particles that function normally in facilitating reverse cholesterol transport. In vivo modification may result in abnormal particles with proinflammatory, proatherogenic particles.

  2. The increase in blood pressure associated with torcetrapib-atorvastatin may have counterbalanced the favorable effects on lipid levels. Evaluation of the effects of blood pressure on coronary atherosclerosis in the Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study, also carried out by Dr. Nissen's group, showed a relation between blood pressure and progression of coronary atherosclerosis.[5,6]

  3. The increase in blood pressure may reflect a more generalized vascular toxicity, simultaneously preventing beneficial effects on progression and increasing adverse clinical outcomes, which were numerically greater in the torcetrapib-atorvastatin group in ILLUSTRATE.

Although the results of ILLUSTRATE were discouraging, Dr. Nissen and his colleagues do not believe that they preclude the possibility of favorable effects with another CETP inhibitor (such as JTT-705 [Roche, Basel, Switzerland] or MK-0859 [Merck, Whitehouse Station, New Jersey]). However, these findings "raise the bar," he cautioned. He later drew an analogy with the statins in support of the continued development of CETP inhibitors: "If Baycol [cerivastatin] had been the first statin on the market and after it was taken off the market we stopped development of all other statins, we would have made a terrible mistake," he said. "With the next CETP inhibitor it will be necessary to do small imaging studies before doing a morbidity and mortality trial, and we should look for slow progression or regression, and if we see that, then we can proceed to the morbidity and mortality trial," he concluded.

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