Evolocumab ( Repatha ), a PCSK9 inhibitor, has shown to dramatically lower levels of low-density lipoprotein ( LDL), and also the risk of cardiovascular events in patients with existing heart or vascular disease already on statin therapy, according to research presented at the American College of Cardiology's 66th Annual Scientific Session.
Evolocumab has reduced by 15% the risk of the trial's primary endpoint ( composite of myocardial infarction, stroke, hospitalization for worsening angina, revascularization, or cardiovascular death ), compared with placebo during the study duration, a median of 26 months.
Researchers also saw a 25% reduction in the study's more serious secondary endpoint ( cardiovascular death, myocardial infarction or stroke ) after the first year.
Results of FOURIER ( Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk ) are highly anticipated as the first large, long-term randomized clinical trial designed to rigorously assess whether Evolocumab, given along with statin therapy, can improve outcomes among high-risk patients.
Evolocumab is a fully human monoclonal antibody that works by blocking proprotein convertase subtilisin-kexin 9 ( PCSK9 ), a protein that reduces the liver's ability to remove LDL cholesterol from the blood. This protein became a target when researchers discovered that people with genetically lower levels of PCSK9 activity had lower rates of myocardial infarction.
In this trial, researchers enrolled 27,564 patients with pre-existing cardiovascular disease between February 2013 and June 2015 at 1,272 sites in 49 countries.
Most patients ( 81% ) had a history of myocardial infarction, 19% had suffered an ischemic stroke, and 13% had symptomatic peripheral artery disease.
Patients' average age was 63 years and ranged from 40 to 85 years of age. The majority ( 75% ) were men.
The median baseline LDL cholesterol was 92 mg/dL.
To be included, patients had to have an LDL-C greater than or equal to 70 mg/dL or a non-high density lipoprotein cholesterol greater than or equal to 100 mg/dL ( total cholesterol minus high-density lipoprotein cholesterol to accommodate for other sized cholesterol particles ) and be on optimized statin therapy.
Patients who had had an acute myocardial infarction or stroke within the previous four weeks and those with advanced heart failure, uncontrolled heart rhythm disorders, upcoming cardiac surgery and end-stage kidney disease were excluded.
Patients on a moderate-to-high intensity statin regimen were randomly assigned 1:1 to receive subcutaneous injections of Evolocumab ( either 140 mg every two weeks or 420 mg every month based on patient preference ) or matching placebo.
Sixty-nine percent of patients were on a high-intensity statin and 30% were on moderate-intensity statin.
Patients were followed every 12 weeks for routine health assessments, lab work and a resupply of the study drug.
Evolocumab has reduced LDL cholesterol by 59% from a median of 92 to 30 mg/dL, which remained steady throughout the duration of the study, and is in line with previous trial results.
The primary endpoint occurred in 11.3% of the placebo group and 9.8% of the Evolocumab group, which translates to a 15% reduction.
The composite of myocardial infarction, stroke or cardiovascular death occurred in 7.4% of the placebo group and was reduced by 20% to 5.9% in the Evolocumab group.
When examining individual outcomes, there was no effect on cardiovascular mortality by itself, but there was a statistically significant 27% reduction in myocardial infarction and a 21% reduction in stroke.
Data also showed greater benefit over time; the secondary endpoint was significantly reduced by 16% in the first year and 25% beyond the first year.
Reductions in the primary and key secondary endpoints were consistent across all the key subgroups, including age, sex, different types of cardiovascular disease, intensity of statin therapy, dosing regimen of Evolocumab and baseline LDL cholesterol levels, including those with the lowest quartile of LDL cholesterol ( starting at 74 mg/dL ) in whom Evolocumab reduced LDL down to 22 mg/dL.
The rate of adverse events, including allergic reactions, neurocognitive, new-onset diabetes and muscle-related problems, were the same in both study arms. Rates of injection site reactions were slightly more common with Evolocumab ( 2.1 vs. 1.6% ), but the vast majority were mild, and the overall rates of stopping the study drug due to suspected treatment-related adverse events were low and similar in both groups ( 1.6 and 1.5% ).
Researchers also looked at whether patients receiving Evolocumab generated an undesired immune response to the treatment; only 0.3% developed antibodies that could bind Evolocumab and none interfered with the drug.
This study is limited by its relatively short follow up and that it only studied patients with known cardiovascular disease. Future studies would need to examine PCSK9 inhibitors in other high-risk populations not addressed in this study, for example, in patients with diabetes mellitus but without known cardiovascular disease. ( Xagena )
Source: American College of Cardiology, 2017