Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk - FOURIER

Contribution To Literature:

The FOURIER trial showed that evolocumab was superior to placebo at reducing adverse cardiovascular events.

Description:

The goal of the trial was to evaluate the efficacy and safety of evolocumab, a PCSK9 inhibitor, among subjects with elevated cardiovascular risk on statin therapy.




Study Design

  • Randomized
  • Parallel
  • Double-blind
  • Placebo

Patients with established cardiovascular disease on statin therapy were randomized to evolocumab 140 mg subcutaneous every 2 weeks or 420 mg monthly (n = 13,784) versus placebo every 2 weeks (n = 13,780).

Inclusion criteria:

  • Patients with established cardiovascular disease defined as prior myocardial infarction (MI), prior stroke, or symptomatic peripheral arterial disease
  • On statin therapy with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl
  • Total number of enrollees: 27,564 patients
  • Duration of follow-up: median 26 months
  • Mean patient age: 63 years
  • Percentage female: 25%
  • Percentage with diabetes: 37%

Exclusion criteria:

  • Myocardial infarction or stroke within 4 weeks
  • New York Heart Association class III or IV heart failure symptoms or left ventricular ejection fraction <30%
  • Hemorrhagic stroke
  • Uncontrolled ventricular tachycardia
  • Planned revascularization within the next 3 months
  • Uncontrolled hypertension
  • Chronic kidney disease
  • Organ transplant
  • Major active infection

Other salient features/characteristics:

  • 69% were on a high-intensity statin, while 30% were on a moderate-intensity statin
  • Median LDL-C = 92 mg/dl

Principal Findings:

The primary outcome, incidence of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, occurred in 12.6% of the evolocumab group versus 14.6% of the placebo group (p < 0.0001). This finding was consistent among all tested subgroups.

Secondary outcomes:

  • Absolute reduction in LDL-C was 56 mg/dl with evolocumab versus placebo (median LDL-C = 30 mg/dl)
  • Any serious adverse event: 24.8% with evolocumab versus 24.7% with placebo

A proportion of patients underwent cognitive testing (n = 1,204). Among this cohort, there was no difference between evolocumab versus placebo for a battery of cognitive tests, patient-reported everyday cognition, and physician-reported adverse cognitive events.

Interpretation:

Among patients with elevated cardiovascular risk on statin therapy, evolocumab versus placebo was effective at reducing adverse cardiovascular events. Evolocumab was associated with marked reductions in LDL-C levels. Serious adverse events were similar between treatment groups. PCSK9 inhibition represents a novel approach to lower LDL-C levels and improves cardiovascular outcomes. However, for the duration of follow-up, there was no benefit on cardiovascular or all-cause mortality, and cost remains an issue.

Detailed testing did not reveal any adverse cognitive deficits among the evolocumab group.

References:

Sabatine MS, Giugliano RP, Keech AC, et al., on behalf of the FOURIER Sttering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017;376:1713-22.

Editorial: Dullaart RP. PCSK9 Inhibition to Reduce Cardiovascular Events. N Engl J Med 2017;376:1790-1.

Presented by Dr. Marc S. Sabatine at the American College of Cardiology Annual Scientific Session (ACC 2017), Washington, DC, March 17, 2017.

EBBINGHAUS: Presented by Dr. Robert P. Giugliano at the American College of Cardiology Annual Scientific Session (ACC 2017), Washington, DC, March 18, 2017.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Vascular Medicine, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: ACC17, ACC Annual Scientific Session, Angina, Unstable, Antibodies, Monoclonal, Cholesterol, Cholesterol, LDL, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoproteins, Metabolic Syndrome X, Myocardial Infarction, Peripheral Arterial Disease, Primary Prevention, Proprotein Convertases, Stroke, Subtilisins, Cognition


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