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.

Ten percent of participants had LDL-C <20 mg/dl, while 31% had LDL-C between 20 and 50 mg/dl. There was a linear relationship between LDL-C and adverse cardiovascular events, such that adverse events continued to decline to the lowest levels of LDL-C (p = 0.0012). There was no notable increase in any safety events, including cancer and cognition, with very low LDL-C levels.

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. There were no apparent safety issues with very low achieved LDL-C levels.

References:

Giugliano RP, Pedersen TR, Park JG, et al., on behalf of the FOURIER Investigators. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017;Aug 28:[Epub ahead of print].

Presented by Dr. Robert P. Giugliano at the European Society of Cardiology Congress, Barcelona, Spain, August 28, 2017.

Sabatine MS, Giugliano RP, Keech AC, et al., on behalf of the FOURIER Steering 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.

Giugliano RP, Mach F, Zavitz K, et al., on behalf of the EBBINGHAUS Investigators. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med 2017;377:633-43.

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: ESC Congress, ESC2017, 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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