Background

Despite current therapies, patients with vascular disease remain at high risk for major adverse cardiovascular events. Low-density lipoprotein cholesterol is a well-established modifiable cardiovascular risk factor. Evolocumab is a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 that reduces low-density lipoprotein cholesterol by approximately 60% across various populations.

Study design

FOURIER is a randomized, placebo-controlled, double-blind, parallel-group, multinational trial testing the hypothesis that adding evolocumab to statin therapy will reduce the incidence of major adverse cardiovascular events in patients with clinically evident vascular disease. The study population consists of 27,564 patients who have had a myocardial infarction (MI), an ischemic stroke, or symptomatic peripheral artery disease and have a low-density lipoprotein ≥70 mg/dL or a non–high-density lipoprotein cholesterol ≥100 mg/dL on an optimized statin regimen. Patients were randomized in a 1:1 ratio to receive either evolocumab (either 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously every month, according to patient preference) or matching placebo injections. The primary end point is major cardiovascular events defined as the composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point is the composite of cardiovascular death, MI, or stroke. The trial is planned to continue until at least 1,630 patients experience the secondary end point, thereby providing 90% power to detect a relative reduction of ≥15% in this end point.

Conclusions

FOURIER will determine whether the addition of evolocumab to statin therapy reduces cardiovascular morbidity and mortality in patients with vascular disease.



Despite advances in treatment, cardiovascular disease remains the leading cause of morbidity and mortality worldwide and is projected to cause >22 million deaths over the next 15 years.1 Cholesterol, in particular low-density lipoprotein (LDL) cholesterol (LDL-C), is a well-established risk factor for cardiovascular disease. Moreover, LDL-C has proven to be a modifiable risk factor with a very large body of evidence demonstrating the benefit of LDL-C lowering. Specifically, there is clear evidence from >2 dozen trials of statins involving >160,000 subjects in total with a median follow-up of approximately 5 years that each 1-mmoL lowering of LDL-C reduces the risk of major cardiovascular events by approximately 22%.2

Similar clinical benefit has also been demonstrated for nonstatin LDL-C–lowering medications such as resins, niacin, and fibrates, when they have been studied in a patient population in whom they meaningfully lowered LDL-C.3, 4 and 5 Data from Mendelian randomization studies recapitulate this relationship, in which there is a log-linear relationship between the LDL-C lowering associated with genetic variants in multiple different genes and the risk reduction in cardiovascular disease.6
Recently, the IMPROVE-IT trial showed that, in patients recently stabilized after an acute coronary syndrome, the addition of the cholesterol absorption inhibitor ezetimibe to statin therapy reduced major adverse cardiovascular events.7 Ezetimibe decreased LDL-C by approximately 20% (from 70 to 54 mg/dL), and the magnitude of clinical risk reduction with ezetimibe was consistent with the reduction expected to be produced from that degree of LDL-C lowering by a statin. Notably, though, was the observation that even in the ezetimibe plus statin arm, in which patients were also well treated with the standard evidence-based cardiovascular medicines, the rate of major adverse cardiovascular events exceeded 30% at 7 years. Thus, there remains an important unmet need for further reduction in adverse cardiovascular outcomes, which may be achievable by more potent LDL-C lowering in high-risk patients.