Clinical Edge

Summaries of Must-Read Clinical Literature, Guidelines, and FDA Actions

Addition of Evolocumab & Reduction of CV Events

N Engl J Med; ePub 2017 Mar 17; Sabatine, et al

Inhibition of proprotein convertase subtilisin-kexin type 9 (PCSK9) with evolocumab along with statin therapy lowered cholesterol levels in patients with atherosclerotic cardiovascular disease (ASCVD) and reduced the risk of CV events, a recent study found. The randomized, double-blind, placebo-controlled trial included 27,564 patients with ASCVD, 81% of whom had had a previous MI, and LDL cholesterol (LDL-C) levels of 70 mg per deciliter or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. Primary efficacy end point was the composite of CV death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization. Median duration of follow-up was 2.2 years. Researchers found:

  • At 48 weeks, reduction in LDL-C level with evolocumab was 59% compared with placebo, from median baseline value of 92 mg per deciliter to 30 mg per deciliter.
  • Evolocumab treatment significantly reduced the primary end point, occurring in 9.8% of evolocumab-treated patients, compared with 11.3% of patients who received placebo, corresponding to a 15% risk reduction.
  • A reduction in cardiovascular risk was already seen after 1 year of active treatment.
  • There was no significant difference between study groups with regard to adverse events.

Citation:

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. [Published online ahead of print March 17, 2017]. N Engl J Med. doi:10.1056/NEJMoa1615664.

Commentary:

PCSK9 binds to the LDL receptor in the liver, leading to the degradation of the receptor, which increases circulating LDL-cholesterol as fewer receptors are available to grab the circulating LDL molecule. When PCSK9 is inhibited, more LDL-receptors are available on the surface of liver cells, lowering LDL-cholesterol.1 The 2 available PCSK9 monoclonal antibody inhibitors, evolocumab and alirocumab, lower LDL-cholesterol by approximately 60% on top of statins.2 While these medications were approved 2 years ago, widespread use of them has been slow due to cost and the lack of evidence of beneficial cardiovascular outcomes. This trial showed a 1.5% absolute risk reduction (15% relative risk reduction) over a short period of time (2 years). This is important information that will likely affect both guidelines and prescribing, showing that PCSK9 inhibition not only substantially lowers cholesterol, but also has beneficial cardiovascular outcomes in high risk individuals. —Neil Skolnik, MD

  1. Dullaart RPF. Published online ahead of print March 17, 2017]. N Engl J Med. doi:10.1056/NEJMoa1615664.
  2. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500-9. doi:10.1056/NEJMoa1500858.