Study Shows Improved Outcomes with Evolocumab in Adults With Atherosclerotic Cardiovascular Disease

Results from the phase 3 FOURIER and FOURIER open label extension (OLE) studies of evolocumab (Repatha; Amgen) in adults with atherosclerotic cardiovascular disease (ASCVD) found that achieving and sustaining a low-density lipoprotein cholesterol (LDL-C) level of <20 mg/dL led to improved cardiovascular (CV) outcomes. These outcomes include the composite endpoint of cardiovascular death, myocardial infarction (MI), and stroke with no evidence of an increased incidence of safety events for up to 8.6 years of follow-up.

"The current analysis further supports that achieving very low LDL-C long-term is not associated with any new safety signals and correlates with the reduction in cardiovascular events in patients with atherosclerotic cardiovascular disease," said David M. Reese, MD, executive vice president of Research and Development at Amgen, in a press release. "Repatha continues to be at the forefront of PCSK9i research, with the longest safety and efficacy trial data among PCSK9i treatments for cardiovascular disease, providing crucial information for patients and doctors managing this disease."

The phase 3, randomized, placebo-controlled FOURIER trial was designed to analyze whether treatment with evolocumab in combination with statin therapy compared to placebo plus statin therapy reduced adverse cardiovascular events.

The primary endpoint of the trial was the time to first occurrence of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The trial’s secondary endpoint was the time to first occurrence of cardiovascular death, MI, or stroke.

Eligible patients with high cholesterol and clinically evident ASCVD at more than 1300 study locations around the world were randomized to receive evolocumab subcutaneous 140 mg every 2 weeks or 420 mg monthly plus effective statin dose or placebo subcutaneous every 2 weeks or monthly plus effective statin dose. Optimized statin therapy was defined as atorvastatin 20 mg or equivalent daily with a recommendation for at least atorvastatin 40 mg or equivalent daily where approved.

FOURIER-OLE was designed to evaluate the extended long-term safety of evolocumab in patients who completed the FOURIER study. The study enrolled 5035 and 1600 subjects who completed the FOURIER study to receive open-label evolocumab and were followed for a median of 5 and 4.6 years, respectively.

All patients in the extension program were treated with open-label evolocumab with no concurrent placebo during this period. Not all patients participated in FOURIER-OLE baseline characteristics, and these individuals were broadly comparable between the originally randomized treatment arms, allowing for reasonably unconfounded exploratory comparisons between groups, according to the study.

A total of 26,389 patients had an early achieved LDL-C available, of whom 19,960 were in FOURIER alone with a median follow-up of 2 years and 6429 of whom also participated in FOURIER-OLE with a median follow-up of approximately 7 years.

The analysis examined the association between achieving different LDL-C levels with the incidence of cardiovascular and safety outcomes for up to 8.6 years of follow up. More than 3500 patients between both studies achieved LDL-C levels of <20 mg/dL and more than 10,000 achieved LDL-C levels of <40 mg/dL.

Over 77,470 patient-years of follow-up, there was a monotonic relationship between lower LDL-C levels and a reduced risk of CV death, MI, stroke, coronary revascularization, or hospital admission for unstable angina.

There was a similar relationship observed between achieved LDL-C levels and the risk of the key secondary efficacy endpoint from FOURIER of CV death, MI, or stroke. In addition, there was no significant associations between lower achieved LDL-C and the risk of serious adverse events (AEs), neurocognitive events, the development of new onset diabetes, cataract-related AEs, new or progressive malignancy, the occurrence of hemorrhagic stroke, muscle-related events, or non-cardiovascular death, according to the study.

"Until now, there was a gap in the medical knowledge of the long-term efficacy and safety implications of a very low LDL-C level <20 mg/dL," said senior study investigator Marc S. Sabatine, MD, chair of the TIMI Study Group at Brigham and Women's Hospital, in a press release. "These data fill that gap by demonstrating that a lower LDL-C level was associated with improved cardiovascular outcomes with a similar safety profile, down to very low LDL-C levels. Furthermore, these data substantiate the use of a PCSK9 inhibitor to reduce LDL-C below the threshold of 55 mg/dL for very high-risk ASCVD patients, as recommended in the recently published ACC 2022 Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-C Lowering in the Management of ASCVD Risk."

REFERENCE

AMGEN presents new repatha® (evolocumab) data at AHA 2022. Amgen. November 7, 2022. Accessed November 8, 2022. https://wwwext.amgen.com/newsroom/press-releases/2022/11/amgen-presents-new-repatha-evolocumab-data-at-aha-2022