Low density lipoprotein (LDL) cholesterol is an important modifiable risk factor for cardiovascular disease. The recently developed monoclonal antibody evolocumab, targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), has superior lipid-lowering effects to conventional statin therapy, additionally decreasing LDL cholesterol levels by approximately 60%. The trial we will discuss in this article is the first to assess the potential of evolocumab as secondary prevention for cardiovascular events in a large patient cohort.
Summary of abstract
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. MS Sabatine et al., FOURIER Steering Committee and Investigators. New England Journal of Medicine, 2017, 17 March.
Evolocumab is a monoclonal antibody that inhibits PCSK9 and lowers LDL cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.
We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years.
At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).
In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets.
This trial is the first of its kind evaluating the efficacy of evolocumab in a large patient cohort. Key strengths include its size (analysing 59.865 cumulative patient-years), it’s randomized, double-blind, placebo-controlled nature and the inclusion of necessity of intervention (such as hospitalization or coronary revascularisation) as additional end points. An additional strength is its intention-to-treat design, employing routinely prescribed secondary preventative pharmacotherapy alongside evolocumab (not mentioned in the abstract).
An important shortcoming of this trial is the relatively short median duration of follow-up of 2.2 years. As the risk of cardiovascular events in this patient population is elevated into the indefinite future, the relatively small effect size reported in this study, an absolute risk-reduction of merely 1.5%, might increase over an extended duration of treatment.
Overall, we assess this study as high-quality scientific work, providing interesting data and cause for discussion to the field of secondary prevention for cardiovascular events. Research assessing the long term efficacy of evolocumab treatment is warranted.
P.J. Hengeveld & G. de Waard
- Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. MS Sabatine et al., FOURIER Steering Committee and Investigators. New England Journal of Medicine, 2017, 17 March