Lina Palaiodimou, MD

Giugliano RP, Pedersen TR, Saver JL, Sever PS, Keech AC, Bohula EA, et al; on behalf of the FOURIER Investigators. Stroke Prevention With the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients With Stable Atherosclerosis. Stroke. 2020.

Alberts MJ, Thompson PD. PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibition and Stroke Prevention: Another Step Forward. Stroke. 2020.

During the last decades, stroke primary and secondary prevention has been significantly improved by systematic lipid control. Ever since the first description of low-density lipoprotein cholesterol (LDL-C) as a stroke risk factor, published guidelines have been suggesting increasingly lower LDL-C values as the target levels. According to the most recent Guidelines on Management of Blood Cholesterol, when evaluating patients with very high atherosclerotic cardiovascular disease (ASCVD) risk, it is recommended to preserve LDL-C values up to a threshold of 70 mg/dl (Grundy, 2019). In order to achieve such a therapeutic target, clinicians should use high-intensity statins with co-administration of ezetimibe when needed. In the case that LDL-C control is proven to be inadequate, even under the combination of high-intensity statin and ezetimibe, a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor should be considered as an add-on therapy.     

Evolocumab is a monoclonal antibody that binds to and inhibits PCSK9 and is a very potent lipid-lowering drug. It has been approved as an adjunctive LDL-C lowering therapy for adults with established ASCVD and is administered as a subcutaneous injection either every two weeks (140mg) or once monthly (420mg). Administration of evolocumab, as the experimental arm of the FOURIER study, proved to be effective in lowering LDL-C levels below current targets and was beneficial for ASCVD patients (Sabatine, 2017). The study population consisted of patients with a history of myocardial infarction, non-hemorrhagic stroke, or symptomatic peripheral artery disease, and also had additional characteristics for high ASCVD risk. The primary end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.

As Alberts and Thomson commented in their editorial, Giugliano et al., on behalf of the FOURIER investigators, took “another step forward” and presented the results of a prespecified sub-analysis of their study. One of their aims was to investigate the efficacy of evolocumab in reducing cerebrovascular events in the overall study population. For that reason, data from the 27,564 participants in the FOURIER study were re-analyzed for the following events: any kind of stroke, ischemic stroke, hemorrhagic stroke and transient ischemic attack (TIA). During a median follow-up of 2.2 years, 469 patients were diagnosed with stroke of any kind, and a total of 524 patients experienced a cerebral ischemic event in general (both strokes and TIAs). Patients on evolocumab had a significantly lower likelihood of presenting stroke of any kind (HR 0.79), ischemic stroke (HR 0.75), and the composite of ischemic stroke or TIA (HR 0.77), compared to patients on placebo (all p≤0.01). Regarding the event of hemorrhagic strokes, no significant difference was reported between the two groups.

Those results can further rationalize the use of evolocumab in the field of stroke prevention for patients with high ASCVD risk and provide reassurance against the fear of intracerebral hemorrhage as an adverse event. However, this was an unadjusted analysis, and confounding factors which were found to be associated with stroke incidence were not considered (history of stroke, history of heart failure, elevated high-sensitive CRP, history of diabetes, non-white race, age, elevated systolic blood pressure, history of peripheral artery disease, renal insufficiency).    

Giugliano et al., on behalf of the FOURIER investigators, also analyzed different patient subgroups, including a subgroup consisting of 5337 (19%) patients with a history of ischemic stroke. The primary endpoint for the subgroup analysis was the same with the FOURIER primary endpoint (composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization). Among the patients with stroke history, those on evolocumab had a lower likelihood of presenting a primary endpoint event compared to placebo, though this result barely reached statistical significance (HR 0.85 [0.72-1.00], p=0.047).

With the aim to investigate the efficacy of evolocumab in secondary stroke prevention, the authors used as an additional event of interest any post-randomization cerebrovascular event. Stroke of any kind, ischemic stroke and the composite of ischemic stroke or TIA were reduced in the group of evolocumab, but the results did not reach statistical significance (HR 0.9 [0.68-1.19], 0.92 [0.68-1.25], 0.89 [0.68-1.17], accordingly). The event of hemorrhagic stroke did not differ between the two groups (HR 0.99 [0.47-2.07]). LDL-C was remarkably reduced within the first month of evolocumab treatment, and the levels were successfully maintained low within the follow-up period. Extremely low LDL-C levels (<20mg/dl) were reached in some cases, but were not associated with any adverse events.   

Interestingly, the primary stroke prevention seemed to be more favored from evolocumab treatment. Patients without stroke history treated with evolocumab experienced significantly less stroke events compared to those who were administered placebo (HR 0.71 [0.56-0.91]).

Certain existing limitations of the presented study are well acknowledged by the authors. The FOURIER study was not powered for patients’ subgroup analysis or analysis for individual components of the initial composite endpoint. Short follow-up duration is also a possible shortcoming, and longer evolocumab effects should be further explored by real-world data. Finally, the number of some events, for example intracerebral hemorrhage, was too limited in both the study arms, and the results of their statistical analysis should be interpreted with caution.

Despite the limitations, Giugliano et al., on behalf of the FOURIER investigators, presented a well-designed study that further supports the use of evolocumab for primary and secondary stroke prevention, which can be safely administered in patients with high ASCVD risk as an adjunctive treatment to statin and ezetimibe.