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May 4, 2020

Large-Scale FOURNIER Study Supports Neurocognitive Safety of Evolocumab Plus Statin to Achieve Very Low LDL-C

May 4, 2020—The American College of Cardiology (ACC) announced that 2-year follow-up data from the entire 22,655-patient cohort of the FOURIER study confirm the neurocognitive safety of very low low-density lipoprotein cholesterol (LDL-C) levels in heart disease patients taking evolocumab in addition to a statin. FOURIER is a multinational, phase 3, randomized, double-blind trial designed to evaluate evolocumab in combination with statin therapy versus placebo and statin therapy in reducing cardiovascular events.

The findings were published by Baris Gencer, MD, et al on behalf of the FOURIER investigators in Journal of the American College of Cardiology (2020;75:2283–2293).

The ACC stated that the investigators used a patient self-survey tool and found that patients treated with evolocumab plus statin to achieve extremely low levels of LDL-C did not show increased incidence of neurocognitive impairments, including memory loss or reduction in executive functions; they also had a decrease in recurrent cardiovascular events such as stroke and heart attack.

FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and LDL-C levels ≥ 70 mg/dL despite statin. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition scale.

The study investigators reviewed the self-reported Everyday Cognition study results from 22,655 patients in FOURIER trial, which was completed after a median duration of 2.2 years.

The percentage of patients who reported cognitive decline at the end of the study was similar for placebo versus those taking evolocumab overall and in two subdomains:

  • Total: 3.6% vs 3.7%
  • Memory: 5.8% vs 6%
  • Total executive function: 3.6% vs 3.7%

The proportion reporting cognitive decline was similar in patients who achieved very low LDL-C levels (< 20 mg/dL) compared with those with LDL-C ≥ 100 mg/dL (3.8% vs. 4.5%).

“These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab, while simultaneously reducing recurrent cardiovascular events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients,” commented Robert P. Giugliano, MD, in the ACC announcement. Dr. Giugliano is a corresponding author of the FOURNIER study, senior investigator of the TIMI Study Group at Brigham and Women’s Hospital, and Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

According to ACC, the findings from this large-scale patient cohort build on the results of the EBBINGHAUS trial, which demonstrated that evolocumab added to background statin did not affect cognitive performances using a validated battery of neurocognitive tests performed serially in a subset of 1,204 patients enrolled in the FOURIER trial.

The FOURIER study has several limitations, including a healthy volunteer bias in the cognitive survey responders, the relatively younger age of the participants, and the low proportion of patients with a history of stroke, noted the ACC.

Jennifer G. Robinson, MD, discussed the findings in an accompanying editorial in Journal of the American College of Cardiology (2020;75:2294–2296). Dr. Robinson commented, “It is unclear if this expectation of safety can be extrapolated to periods of greater than 3 years, or to patients who are older than 75 years, are at very high atherosclerotic cardiovascular disease risk, or with a history of ischemic or hemorrhagic stroke. An altered safety profile may influence the potential for a net cardiovascular risk reduction benefit from the addition of proprotein convertase subtilisin-kexin 9 (PCSK9) monoclonal antibodies. Longer follow-up and more diverse trial populations are needed.” Dr. Robinson is Professor of Epidemiology and Medicine at the University of Iowa in Iowa City, Iowa.

Evolocumab (Repatha, Amgen) is an FDA-approved cholesterol-lowering medication. It is a human monoclonal antibody that inhibits PCSK9, a protein that reduces the liver’s ability to remove LDL-C from the blood. In August 2015, Amgen announced FDA approval of Repatha to lower LDL-C. In December 2017, the company announced that Repatha was approved to prevent heart attack, stroke, and coronary revascularization in adults with established cardiovascular disease.

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