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ACCELERATE: Evacetrapib does not reduce major CV events
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CHICAGO — The ACCELERATE trial of the cholesteryl ester transfer protein inhibitor evacetrapib was stopped early because the drug did not reduce major CV events, researchers reported at the American College of Cardiology Scientific Session.
Evacetrapib (Eli Lilly) is the third CETP inhibitor to fail to demonstrate CV benefits in a clinical trial, joining torcetrapib (Pfizer) and dalcetrapib (Hoffman-La Roche).
The researchers randomly assigned 12,092 patients at high vascular risk — defined a ACS between 30 and 365 days, peripheral artery disease, diabetes with CAD or cerebrovascular disease — to receive evacetrapib 130 mg or placebo. The mean age of patients was 65 years, 77% were men and 83% were white.
The primary endpoint was a composite of CV death, MI, stroke, coronary revascularization or hospitalization for angina. The trial was scheduled to last until 1,670 patients experienced the primary endpoint and 700 experienced CV death, MI or stroke, with a minimum follow-up of 1.5 years.
The trial was stopped after a preliminary analysis showed that the drug had no impact on the primary endpoint despite raising HDL and lowering LDL, Stephen J. Nicholls, MBBS, PhD, deputy director at the South Australian Health and Medical Research Institute, professor at the University of Adelaide, Australia, and cardiologist at Royal Adelaide Hospital, said during a press conference.
Stephen J. Nicholls
At the time of the preliminary analysis, the evacetrapib group had mean HDL of 104 mg/dL vs. 46 mg/dL for the placebo group (mean difference, 130%), according to Nicholls.
Mean LDL levels were 55 mg/dL in the evacetrapib group and 84 mg/dL in the placebo group (mean difference, 37%), he said.
“We had animal and genetic data that suggested that having less CETP is a good thing,” Nicholls said. “We brought evacetrapib to phase 3 having done phase 2 studies with robust HDL raising and LDL lowering on top of a statin, reducing [lipoprotein (a)] and improving cholesterol efflux in cell studies, all of which we thought were good. … We saw the lipid changes that we would have expected from phase 2.”
The primary endpoint occurred in an almost identical proportion of both groups at the time of the preliminary analysis (evacetrapib, 12.8%; placebo, 12.7%; HR = 1.01; 95% CI, 0.91-1.12).
The lipid changes “translat[ed] to no benefits whatsoever,” Nicholls said. “There is no event curve separation, not even the slightest suggestion of it.”
The researchers found no significant differences in any of the components of the primary endpoint, although there was a trend toward reduced all-cause mortality in the evacetrapib group (3.8% vs. 4.1%; HR = 0.84; 95% CI, 0.71-1.01). “We think that that’s a chance finding,” Nicholls said.
“Importantly, the atherosclerotic events are all completely null,” Nicholls said. “This reflects why we do these kinds of trials. At the end of the day, it’s the clinical event that counts, and we see no benefit here.”
Nicholls announced that Eli Lilly and the investigators have agreed to make the ACCELERATE database available to independent investigators. – by Erik Swain
Reference:
Nicholls SJ, et al. Joint ACC/JAMA Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; April 2-4, 2016; Chicago.
Disclosure: The study was funded by Eli Lilly. Nicholls reports receiving research support from Amgen, Anthera, AstraZeneca, Cerenis, Eli Lilly, InfraRedX, Novartis, Resverlogix, Roche and The Medicines Company, and receiving consultant fees and honoraria from Anthera, AstraZeneca, Boehringer Ingelheim, CSL Behring, Esperion, Eli Lilly, Merck, Resverlogix, Sanofi Aventis and Takeda.
Perspective
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B. Hadley Wilson , MD, FACC
The main takeaway from the ACCELERATE study is that, despite the optimism about a new agent to increase HDL and lower LDL, it was not proven to be beneficial. This class has not proven to be effective, so it will be difficult for future CETP inhibitors to be tried, though I don’t think that should exclude us from looking for one that is effective in improving outcomes.
On a positive note, the agent was very effective in improving HDL and LDL. We just haven’t found the right formula for translating that into improved outcomes.
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