Increased levels of low-density lipoprotein cholesterol (LDL-C) (so-called "bad cholesterol") in the blood increase the risk of heart disease which is one of the leading causes of ill health and death worldwide.
In a previous clinical trial, evolocumab has been shown to lower “bad cholesterol” levels and reduce the risk of future heart disease compared to placebo or standard of care treatment.
A follow-up study, conducted as an open-label extension (OLE) of the original clinical trial, showed that long-term use of evolocumab is safe but unlike the original trial, it did not compare heart disease related events with a placebo or standard of care treatment arm (since all participants in the OLE were on evolocumab). Therefore, the aim of the current study is to compare heart disease outcomes in patients who take evolocumab versus patients on standard of care over a long duration of time.
Firstly, we will check to see if it is possible to use the Clinical Practice Research Datalink (CPRD) to create a real-world standard of care (SOC) treatment arm and compare this SOC arm to data from the clinical trial/OLE. If the latter is possible, we will then compare the heart disease outcomes in the CPRD standard of care arm to the heart disease outcomes in the evolocumab arm of the clinical trial and OLE. The expected health benefit of our study would be the possibility to evaluate the long term effectiveness of evolocumab using a combination of clinical trial data and real world data.
Further cardiovascular OUtcomes Research with proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibition in participants with Elevated Risk (FOURIER) trial for Evolocumab, a PCSK9 inhibitor (monoclonal antibody) demonstrated that it can effectively lower low-density lipoprotein cholesterol (LDL-C) levels by almost 60% and also reduce the occurrence of major adverse cardiovascular (CV) events among statin-users at high risk for CV disease. The long-term follow-up open-label extension (OLE) studies following FOURIER trial completion demonstrated that long-term use of Evolocumab is safe. However, since all patients enrolled in the OLE study were on Evolocumab, there was no long-term standard of care control arm within the FOURIER-OLE study to compare against. Therefore, the aim of the current study is to compare risk of CV outcomes in FOURIER and FOURIER-OLE patients in the Evolocumab arm versus an external control arm created using CPRD Aurum database linked with Hospital Episode Statistics Admitted Patient Care (HES-APC) and Office of National Statistics (ONS) mortality data. A gated framework will be used that will include assessing balance of propensity scores and comparability of key variables at baseline as compared to trial/OLE Evolocumab participants. Additionally, the comparability of outcome events using hazard ratio estimates for the weighted real-world external control arm and the trial placebo arm during the original trial period will also be assessed.
Myocardial infarction;
Stroke;
Hospitalization for unstable angina;
Coronary revascularization;
Cardiovascular death;
All-cause death;
3-point major adverse cardiovascular events (MACE): Composite of Cardiovascular death, myocardial infarction, stroke;
5-point MACE: Composite of Cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization.
Swati Sakhuja - Chief Investigator - Amgen Inc
David Neasham - Corresponding Applicant - Amgen Ltd
Emileigh Willems - Collaborator - Amgen Inc
Francesco Giorgianni - Collaborator - Amgen Ltd
Joe Maskell - Collaborator - Amgen Ltd
Matthew McDermott - Collaborator - Amgen Ltd
Junyi Zhou - Collaborator - Amgen Inc
Lyrica Liu - Collaborator - Amgen Inc
Michael Grayer - Collaborator - Amgen Ltd
HES Admitted Patient Care;ONS Death Registration Data