Proprotein convertase subtilisin kexin 9 (PCSK9) is a protease produced predominately in the liver that facilitates the breakdown of low-density lipoprotein (LDL) receptors, which reduces LDL cholesterol clearance and leads to elevated serum LDL cholesterol levels. Evolocumab, a monoclonal antibody that inhibits PCSK9, has been shown to levels by about 60%, even in patients on moderate- or high-intensity statins. However, previous studies have not established whether this intervention reduces cardiovascular events.
In a multinational, double-blind, placebo-controlled trial investigators randomized more than 27,500 statin-treated patients (mean age, 63 years) with atherosclerotic cardiovascular disease (defined as a history of myocardial infarction [MI], nonhemorrhagic stroke, or symptomatic peripheral artery disease, as well as additional cardiovascular risk factors such as smoking or diabetes) to receive either subcutaneous evolocumab (140 mg every 2 weeks or 420 mg per month, based on patient preference) or placebo. The primary outcome was the first occurrence of the composite end point of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The principal secondary outcome was the composite of cardiovascular death, myocardial infarction, or stroke.
Most patients (>80%) had a history of MI and 19% had a history of previous nonhemorrhagic stroke; 13% had symptomatic peripheral artery disease, 80% had hypertension, 28% were active smokers, and about 37% had diabetes. At baseline, all patients were taking statins, with about 70% on high-intensity statin therapy. About 5% of patients were also taking ezetimibe.
After 48 weeks of treatment, evolocumab reduced LDL levels by a mean of about 60% compared with placebo (from a median of 92 mg/dL to a median of 30 mg/dL). At a median follow-up of 2.2 years, the incidence of the first occurrence of the primary composite endpoint (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) was lower with evolocumab than with placebo (9.8% vs. 11.3%; hazard ratio, 0.85; 95% CI, 0.79–0.92; P<0.001). The incidence of the secondary composite outcome (cardiovascular death, MI, or stroke) was also reduced with evolocumab (5.9% vs. 7.4%; HR, 0.80; 95% CI, 0.73–0.88; P<0.001).
All-cause mortality rates were not significantly different between the two groups (3.2 % vs. 3.1%; HR, 1.04; 95% CI 0.91-1.19; P=0.54). Injection-site reactions were more common with evolocumab (2.1% vs. 1.6%; P<0.001). Rates of new-onset diabetes and neurocognitive events were similar in the two groups.
In the editorial, Robin Dullaart from the University of Groningen, the Netherlands notes that, although the duration of the trial is relatively short at slightly over 2 years, the benefits of evolocumab treatment in reducing cardiovascular events were already present by year 1. He anticipates that the results of this 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.”
In summary, evolocumab, a PCSK9 inhibitor given subcutaneously to statin-treated patients with existing atherosclerotic cardiovascular disease, reduced LDL levels further and led to an absolute reduction of 1.5% of cardiovascular events by 2.2 years, compared with placebo.
- For which patients would you consider initiating evolocumab therapy?
- Is the efficacy of evolocumab in reducing cardiovascular events similar in patients with different baseline LDL levels?
- Is efficacy affected by the intensity of baseline statin therapy or by types of atherosclerotic cardiovascular disease?
- How does the cost-effectiveness of evolocumab compare with that of other lipid-lowering therapies?
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James Yeh, MD MPH, Physician at NEJM Group