Evolocumab in Patients With or Without Multivessel Disease

Quick Takes

  • The reduction in the composite endpoints of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization associated with evolocumab vs. placebo in CAD patients on maximally tolerated statins with median follow-up 2.2 years was greater in patients with multivessel disease (MVD) (23%) than in those without (11% and nonsignificant).
  • With a median extension of 5 years and all patients on evolocumab, the magnitude of benefit tended to grow over the first several years, reaching 38% and 28% reductions in events in patients with and without MVD, respectively.
  • Considering intensive LDL-C lowering with PCSK9 inhibitors has been shown to induce coronary plaque regression in patients on maximally tolerated statins, it would be expected that in patients starting out with MVD, lowering of LDL-C through PCSK9 inhibition and other lipid-lowering strategies can substantially reduce atherosclerotic burden and plaque instability, leading to an early and large clinical benefit, supporting the ‘lower is better hypothesis.’

Study Questions:

In the FOURIER trial, in patients without multivessel disease (MVD), the curves only started to diverge near the end of a median follow-up of 2.2 years and there was a nonsignificant 11% risk reduction with evolocumab. Do patients with MVD have more benefit, and will a longer follow-up have a more clinically meaningful benefit in patients without MVD?


The FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial enrolled 27,564 patients with known atherosclerotic cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL or non–high-density lipoprotein cholesterol ≥100 mg/dL while on optimized statin therapy. A total of 23,656 patients had coronary artery disease (CAD) at enrollment with data on the presence or absence of residual MVD. Patients with CAD were categorized based on the presence of MVD (≥40% stenosis in ≥2 large vessels). The primary endpoint was cardiovascular (CV) death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary endpoint was CV death, MI, or stroke.


A total of 5,887 of the parent FOURIER patients entered FOURIER-OLE (FOURIER Open-Label Extension). They had an additional median follow-up of 5.0 (4.6-5.1) years and a maximum follow-up time of 5.5 years, for a total median and maximum follow-up time of 7.1 (6.7-7.6) and 8.6 years. The risk reduction with initial allocation to evolocumab tended to be greater in patients with MVD than in those without: 23% (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.68-0.87) vs. 11% (HR, 0.89; 95% CI, 0.82-0.96) for the primary and 31% (HR, 0.69; 95% CI, 0.59-0.81) vs. 15% (HR, 0.85; 95% CI, 0.77-0.94) for the key secondary endpoints (p for interaction = 0.062 and 0.031, respectively). The magnitude of benefit tended to grow over the first several years, reaching 37-38% and 23-28% reductions in risk in patients with and without MVD, respectively.


Evolocumab reduced the rate of major adverse CV events in patients with and without MVD. The benefit tended to occur earlier and was larger in patients with MVD. However, the magnitude grew over time in both groups. These data support early initiation of intensive LDL-C lowering both in patients with and without MVD.


This is an important trial considering all patients were on the highest tolerated dose of statins (75% high intensity) and despite the addition of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor in those without MVD did not reach significant risk reduction at a median of 2.2 years. The inference would be that the earlier maximal LDL-C lowering is begun in patients with CAD, regardless of the clinical indication and severity of CAD, the more cost-effective would be the benefit.

Clinical Topics: Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Prevention

Keywords: Cholesterol, LDL, Coronary Artery Disease, PCSK9 Inhibitors

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