An Independent Summary of Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients with Peripheral Artery Disease: Insights from the FOURIER Trial

An Independent Summary of Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients with Peripheral Artery Disease: Insights from the FOURIER Trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk).1

An Independent Summary of Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients with Peripheral Artery Disease: Insights from the FOURIER Trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk).1

By Kristen N Smith, PhD, RD, LD; Kevin C Maki, PhD

Background: Peripheral artery disease (PAD) is considered an indicator of a malignant vascular phenotype with event occurrences greater than other stable populations with atherosclerosis.2,3 Patients who have symptomatic PAD have a greater risk of major adverse cardiovascular events (MACE)4 and they also experience significant morbidity from major adverse limb events (MALE).5,6



Event Includes

Major adverse cardiovascular events (MACE)

Myocardial infarction (MI), stroke and cardiovascular death

Major adverse limb events (MALE)

Acute limb ischemia, urgent peripheral revascularization and major amputation


Methods of lowering lipid levels have been shown to help reduce MACE in stable patients with coronary heart disease or atherosclerosis risk factors, but there have been few well-developed, well-powered prospective randomized trials of low-density lipoprotein (LDL-C) reduction in patients with PAD.7 In particular, these prior studies have not examined relationships between the ability of LDL-C reductions to consequently reduce the risk of MALE.5,8-10  There is a shortage of information regarding the impact of reducing LDL-C on event risk in patients with PAD without prior MI or stroke.7,11,12

 In the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial, researchers gathered data on the use of evolocumab (a monoclonal antibody that inhibits proprotein convertase subtilisin kexin type 9 [PCSK9] and lowers LDL-C levels) compared with placebo in statin-treated patients with atherosclerotic disease in the coronary, cerebrovascular or peripheral artery bed. The FOURIER trial allowed the testing of the following hypotheses:1

  1. Patients with PAD would be at greater risk of MACE relative to patients with coronary or cerebrovascular disease without PAD;
  2. Consistent relative risk reductions in MACE with evolocumab would translate to larger absolute risk reductions in patients with PAD relative to those without;
  3. LDL-C reduction with evolocumab would significantly reduce MALE with benefits extending to very low levels of LDL-C.

This secondary analysis of the FOURIER study provided additional information on patients not only with cardiovascular risk factors, but also specifically of those meeting the criteria for PAD. 

 Methods: The FOURIER study was a randomized, double-blind, placebo-controlled, multinational clinical trial (1242 sites in 49 countries) investigating evolocumab versus placebo in 27,564 subjects with atherosclerotic disease. These subjects were followed for a median of 2.2 years.

 Inclusion Criteria:

  • Subjects were 40 to 85 years of age;
  • Clinically evident atherosclerotic cardiovascular disease (history of MI, non-hemorrhagic stroke or symptomatic PAD)
  • Fasting LDL-C of 70 mg/dL or greater OR non-high-density-lipoprotein cholesterol of 100 mg/dL or higher while on an optimized regimen of lipid-lowering medication (“preferably a high-intensity statin but must have been at least atorvastatin at a dose of 20 mg daily or its equivalent, with or without ezetimibe”).

 For the subset of patients with PAD, qualifications were met if the subjects had intermittent lower extremity claudication and an ankle brachial index <0.85, or a history of peripheral artery revascularization procedure or a history of amputation attributable to atherosclerotic disease.

Study endpoints are outlined in the following table: 

Primary End Points

Secondary End Points

Additional End Points of Interest

Major cardiovascular events, the composite of:


§  Cardiovascular death

§  MI

§  Stroke

§  Hospitalization for unstable angina

§  Coronary revascularization

The composite of:


§  Cardiovascular death

§  MI

§  Stroke




§  Acute limb ischemia

§  Major amputation

§  Urgent peripheral revascularization for ischemia



Patients in this study were randomly assigned in a 1:1 ratio to receive either subcutaneous injections of evolocumab (either 140 mg every 2 weeks or 420 mg every month, according to patient preference) or matching placebo.

Results: Of the 27,564 subjects participating in the FOURIER study, 3642 patients (13.2%) had PAD. Within this subset, 1505 (41%) met the criteria for PAD but had no prior MI or stroke.  Use of evolocumab significantly reduced the primary end point (outlined above) in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.66-0.94; p=0.0098) and in patients without PAD (HR 0.86; 95% CI 0.80-0.93; p=0.0003; pinteraction=0.40). Results of the secondary end point (outlined above) mirrored the primary end point. The HR for patients with PAD was 0.73 (95% CI 0.59-0.91; p=0.0040) and was 0.81 (95% CI 0.73-0.90; p<0.0001) for those without PAD (pinteraction=0.41). Since patients with PAD experience elevated risk, they also had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the secondary end point (3.5% for patients with PAD, 1.4% for those without PAD).

Treatment with evolocumab was also associated with reduced risk of MALE in all patients (HR 0.58; 95% CI, 0.38-0.88; p=0.0093) and these effects were consistent regardless of PAD status. The researchers noted a consistent relationship between lower (achieved) LDL-C and reduced risk of limb events (p=0.026 for the beta coefficient) that extended to values <10 mg/dL.

There were no differences in the incidence of adverse events or serious adverse events with evolocumab relative to placebo. Rates of treatment discontinuation were also similar between groups (1.3% evolocumab versus 1.5% placebo, p=0.57).

Comment: The FOURIER study provided evidence showing that patients with PAD were at greater risk of both MACE and MALE compared to patients with prior MI or stroke and no PAD, and captured the effects of the use of evolocumab as an adjunct to statin. Ultimately, the use of evolocumab assisted in reducing the risk of MACE (greater reductions in the subjects with PAD) and the concomitant LDL-C reductions associated with evolocumab treatment also decreased risk of MALE.

The FOURIER study provided clinical outcomes in a broad population with polyvascular disease and within those with isolated PAD (no history of MI or stroke). The results illustrated the benefits of the use of evolocumab added as an adjunct to a statin treatment in both groups, with minimal adverse events. Based on the results of this study, the combined usage of evolocumab plus statin treatment provided significant reductions in cardiovascular disease-related outcomes and warrants additional attention as a method of improving health outcomes in patients with PAD.


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