Evolocumab to reduce cardiovascular events: results of the (FOURIER) multinational trial.

Dear Sir,

Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a protease that binds to the extracellular compartment of the LDL receptor, hence, targeting the LDL receptor to the lysosomal compartment of the cell for degradation [1]. Consequently, PCSK9 prevents recycling of the LDL receptor to the cell surface, thereby modifying LDL clearance. With the discovery of PCSK9 protein as a potential therapeutic target, monoclonal antibodies that inhibit PCSK9 action were developed. Studies suggested that both PCSK9-inhibitors and statins treatment lower LDL cholesterol levels with a partly similar mechanism of action. As such, evolocumab, a monoclonal antibody against the PCSK9, has been extensively tested. In two open-label, randomized extension studies (Open Label Study of Long Term Evaluation Against LDL-C Trial [OSLER]–1 and OSLER-2, respectively), evolocumab in addition to standard lipid-lowering therapy elicited a sustained 61% reduction in LDL cholesterol levels (relative to the change in LDL cholesterol levels with standard therapy alone) [2].

Sabatine et al. now report the results of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) multinational trial, which determined the efficacy of evolocumab (in the same dose regimens as in the OSLER trials) with regard to cardiovascular events in 27 564 high-risk patients who were followed for a median of 2.2 years (as compared to 11 months in OSLER trial) [3]. The mean decrease in LDL cholesterol levels, as compared with a placebo, was 59% at 48 weeks; this result was paralleled by reductions in levels of non–high-density lipoprotein (HDL) cholesterol (decrease of 51% in the evolocumab group), apolipoprotein B (46%), and triglycerides (16%), together with relatively small increases in HDL cholesterol (8%). The primary end point, a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, occurred in 9.8% of evolocumab-treated patients, as compared with 11.3% of patients who received a matching placebo, which corresponded to a 15% risk reduction. In addition, a 20% risk reduction was achieved with respect to the key secondary efficacy end point, a composite of cardiovascular death, myocardial infarction, or stroke. Remarkably, a reduction in cardiovascular risk was already seen after one year of active treatment [4].

The FOURIER trial is a landmark trial providing formal evidence that treatment targeted at PCSK9 inhibition confers additional cardiovascular benefit beyond that achieved by lipid-lowering treatment alone. However, in this trial, the duration of evolocumab treatment was rather short. The efficacy, with regard to cardiovascular disease, of PCSK9 inhibition treatment that is started shortly after an acute event still needs to be determined, as does the efficacy of the treatment in other categories of high-risk patients. The side effects of treatment with monoclonal antibodies against PCSK9 appear to be generally mild but are being meticulously evaluated in separate sub-studies.

In 2015, the FDA approved the use of evolocumab for the treatment of certain patients with high cholesterol. It is anticipated that the results of the FOURIER trial will soon be implemented in international guidelines regarding the treatment of high-risk patients, directing clinicians in the use of this new and expensive class of drugs [5].