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 artery disease (PAD)
  • 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. Benefit was enhanced among higher-risk subgroups (those with recent MI, multiple prior MIs, and residual multivessel coronary artery disease) compared to those without such characteristics.

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.

Among those with baseline LDL-C <70 mg/dl, evolocumab reduced the primary endpoint (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.60-1.07) to a similar degree as those with baseline LDL-C ≥70 mg/dl (HR 0.86, 95% CI 0.79-0.92; p = 0.65 for interaction).

PAD subset: A total of 13.2% of patients had established PAD. Patients with PAD had an 81% higher risk of cardiovascular disease/MI/stroke compared with those without (p < 0.001). There was a significant reduction in cardiovascular disease/MI/stroke with evolocumab versus placebo among patients with PAD (9.5% vs. 13.0%, p = 0.004) and those without (6.2% vs. 7.6%, p < 0.001) (p for interaction = 0.41). The absolute risk reduction was greater among PAD patients due to the higher event rates. There was a significant reduction in the incidence of major adverse limb events with evolocumab (0.27% vs. 0.45%, p = 0.0093), with greater net reductions among patients with PAD (1.5% vs. 2.4%). There appeared to be a monotonic relationship between reduction in LDL-C and reduction in adverse limb events (p = 0.026).

Outcomes according to inflammatory risk: Among those with high-sensitivity C-reactive protein <1 mg/dl, 1-3 mg/dl, and >3 mg/dl, there was an absolute reduction in the primary outcome of 1.6%, 1.8%, and 2.7%, respectively.

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. Efficacy for evolocumab was similar among those with very low baseline LDL-C levels. There was a greater absolute reduction in major adverse events for evolocumab versus placebo among those with the highest baseline inflammatory risk. 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:

Sabatine MS, De Ferrari GM, Giugliano RP, et al. Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease: An Analysis From FOURIER. Circulation 2018;Apr 6:[Epub ahead of print].

Bohula EA, Giugliano RP, Leiter LA, et al. Inflammatory and Cholesterol Risk in the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk). Circulation 2018;Mar 12:[Epub ahead of print].

Presented by Dr. Erin A. Bohula at the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, March 12, 2018.

Giugliano RP, Keech A, Murphy SA, et al. Clinical Efficacy and Safety of Evolocumab in High-Risk Patients Receiving a Statin: Secondary Analysis of Patients With Low LDL Cholesterol Levels and in Those Already Receiving a Maximal-Potency Statin in a Randomized Clinical Trial. JAMA Cardiol 2017;2:1385-91.

Bonaca MP, Nault P, Giugliano RP, et al. 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). Circulation 2017;Nov 13:[Epub ahead of print].

Presented by Drs. Marc C. Bonaca and Marc S. Sabatine at the American Heart Association Annual Scientific Sessions (AHA 2017), Anaheim, CA, November 13, 2017.

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;390:1962-71.

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, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: ACC18, ACC17, ACC Annual Scientific Session, ESC Congress, ESC2017, 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, Inflammation


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