ACC.15: PCSK9 inhibitor appears to improve outcomes

SAN DIEGO—The human monoclonal antibody evolocumab plus standard therapy not only lowered low-density lipoprotein (LDL) cholesterol but it also cut the rate of cardiovascular events by about half compared with standard therapy alone, according to results presented March 15 at the American College of Cardiology scientific session.

Evolocumab (Amgen) is a new class of drugs that inhibits proprotein convertase subtilisin-kexin 9 (PCSK9). The phase 2 OSLER-1 (Open-Label Study of Long-term Evaluation against LDL Cholesatrol-1) and phase 3 OSLER-2 trials evaluated the drug’s safety and effectiveness at lowering LDL cholesterol. At the late-breaking clinical trials, Marc Sabatine, MD, of Brigham and Women’s Hospital in Boston, shared findings on cardiovascular outcomes.

Patients who completed the trials had the option to enroll in extension studies. About three-quarters of them chose to participate, with 2,976 randomized to receive evolocumab plus standard therapy and 1,489 to standard therapy alone. They were followed for a median 11.1 months.

At week 12, LDL cholesterol was lowered by 61 percent in the evolocumab group compared with standard therapy alone. That translated to a mean absolute decrease of 73 mg per deciliter to a median of 48 mg per deciliter. “That exceeds what has been seen in virtually every statin trial,” Sabatine said.

Cardiovascular events were lower in the evolocumab group compared with the control group at one year, at 0.95 percent vs. 2.18 percent. “Evolocumab decreased cardiovascular outcomes by 51 percent at one year,” he said. “We need to acknowledge that there were few events. However, the event curves diverged early over time.”

The treatment appeared to be safe and well tolerated, but the rate of neurocognitive adverse events—while rare—was higher in the evolocumab group, which should be further studied, Sabatine said.

Panelist Judith Hochman, MD, of the NYU Langone Medical Center in New York City, asked for more details about the type of neurocognitive testing used in the trial. Sabatine replied that these were recorded as adverse events and not based on formal neurocognitive tests. He called it "a grab bag of events: forgetfulness, transient confusion and delirium all fall in there.”

The FOURIER trial, which is under way, will include a dedicated neurocognitive study. Sabatine described it as the definitive trial on cardiovascular outcomes for the PCSK9 inhibitor, with results estimated available in 2017.

The study was published simultaneously in the New England Journal of Medicine.  The Osler trials were funded by Amgen.