PCSK9 Inhibition to Reduce Cardiovascular Risk
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Evolocumab and clinical outcomes in patients with cardiovascular disease
Sabatine et al
N Engl J Med. Published online ahead of print March 17, 2017.
Cardiovascular efficacy and safety of bococizumab in high-risk patients
Ridker et al
N Engl J Med. 2017;376:1527–1539.
The first large clinical outcomes trials of proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors have demonstrated that these drugs, when taken with statins, reduce cardiovascular events by 15% to 20% more than statins alone. However, this event reduction is less than expected for such a large decrease in low-density lipoprotein cholesterol (LDL-C), and the reasons for this disconnect between LDL-C lowering and cardiovascular events remain unclear. Future trials should clarify the degree of clinical benefit to be expected from PCSK9 inhibitors.
Two years ago, in these pages, we discussed the results of very early clinical outcome trials of the PCSK9 monoclonal antibodies evolocumab and alirocumab.1 These drugs both reduced LDL-C levels by slightly >60% on top of statin therapy and reduced cardiovascular events by ≈50%.2,3 We noted that although these results engendered great expectations, both of these studies were preliminary, with a small number of end points, short follow-up, and other important limitations.1
As often happens with life in general, our great expectations have been tempered by 2 recent reports. The FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) enrolled 27 564 patients with atherosclerotic cardiovascular disease and LDL-C levels ≥70 mg/dL who were receiving statin therapy.4 Patients were randomly assigned to receive double-blind treatment with evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or placebo as subcutaneous injections. The primary composite end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization and the median duration of follow-up …