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

Overview

The primary objective was to evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, whichever occurs first, in patients with clinically evident cardiovascular disease.

Full Title of Study: “A Double-blind, Randomized, Placebo-controlled, Multicenter Study Assessing the Impact of Additional LDL-Cholesterol Reduction on Major Cardiovascular Events When Evolocumab (AMG 145) is Used in Combination With Statin Therapy In Patients With Clinically Evident Cardiovascular Disease”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: November 11, 2016

Interventions

  • Biological: Evolocumab
    • Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.
  • Drug: Placebo
    • Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.

Arms, Groups and Cohorts

  • Placebo Comparator: Placebo
    • Participants received placebo subcutaneous injections either once every 2 weeks (Q2W) or once a month (QM) according to their own preference.
  • Experimental: Evolocumab
    • Participants received evolocumab 140 mg Q2W or 420 mg QM subcutaneous injections according to their own preference.

Clinical Trial Outcome Measures

Primary Measures

  • Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization
    • Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
    • All deaths and potential endpoint events were adjudicated by an independent external Clinical Events Committee (CEC) led by the Thrombolysis in Myocardial Infarction (TIMI) Study Group, using standardized definitions based on the “Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction”. Time to cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization was defined as the time from randomization to the first occurrence of any component of the composite endpoint and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.

Secondary Measures

  • Time to Cardiovascular Death, Myocardial Infarction, or Stroke
    • Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
    • All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the “Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction”. Time to cardiovascular death, myocardial infarction, or stroke was defined as the time from randomization to the first occurrence of any component of the composite endpoint and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.
  • Time to Cardiovascular Death
    • Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
    • All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the “Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction”. Cardiovascular death includes death resulting from an acute myocardial infarction (MI), sudden cardiac death, death due to heart failure (HF), death due to stroke, death due to cardiovascular (CV) procedures, death due to CV hemorrhage, and death due to other CV causes. Time to cardiovascular death was defined as the time from randomization to the date of cardiovascular death and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on the last confirmed survival status date.
  • Time to All Cause Death
    • Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
    • Time to all-cause death was defined as the time from randomization to the date of death and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on the last confirmed survival status date.
  • Time to First Myocardial Infarction
    • Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
    • All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the “Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction”. The diagnosis of myocardial infarction required the combination of: Evidence of myocardial necrosis (either changes in cardiac biomarkers or post-mortem pathological findings); and Supporting information derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery Imaging. Time to first myocardial infarction was defined as the time from randomization to the date of the first MI and was analyzed using Kaplan-Meier survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.
  • Time to First Stroke
    • Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
    • All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the “Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction”. Stroke was defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction. Time to first stroke was defined as the time from randomization to the date of the stroke and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.
  • Time to First Coronary Revascularization
    • Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
    • All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the “Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction”. Time to first coronary revascularization was defined as the time from randomization to the date of the coronary revascularization and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.
  • Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure
    • Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
    • All events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions. HF hospitalization was defined as an event that met all of the following criteria: Admitted to hospital with a primary diagnosis of HF In hospital for at least 24 hours Documented new or worsening symptoms due to HF, including at least 1 of the following: Dyspnea Decreased exercise tolerance Fatigue Other symptoms of worsened end-organ perfusion or volume overload Evidence of new or worsening HF consisting of at least 2 physical exam findings or 1 physical exam finding and at least 1 laboratory criterion Received new or increased treatment for HF. Time to CV death or first hospitalization for worsening HF was defined as the time from randomization to the first occurrence of any component of the endpoint analyzed using KM survival analysis. Participants with no event were censored based on last non-fatal potential endpoint collection date.
  • Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack
    • Time Frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
    • All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions. Ischemic stroke was defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of central nervous system tissue. Transient ischemic attack (TIA) was defined as a transient episode of focal neurological dysfunction caused by brain, spinal cord, or retinal ischemia, without acute infarction. Time to first ischemic fatal or non-fatal stroke or TIA was defined as the time from randomization to the first occurrence of any component of the composite endpoint and was analyzed using KM analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.

Participating in This Clinical Trial

Inclusion Criteria

  • Male or female ≥ 40 to ≤ 85 years of age – History of clinically evident cardiovascular disease at high risk for a recurrent event – Fasting low-density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dL (≥ 1.8 mmol/L) ) or non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 100 mg/dL (> 2.6 mmol/L) – Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) Exclusion Criteria:

  • New York Heart Association (NYHA) class III or IV, or last known left ventricular ejection fraction < 30% – Uncontrolled hypertension – Uncontrolled or recurrent ventricular tachycardia – Untreated hyperthyroidism or hypothyroidism – Homozygous familial hypercholesterolemia – LDL or plasma apheresis

Gender Eligibility: All

Minimum Age: 40 Years

Maximum Age: 85 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Amgen
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • MD, Study Director, Amgen

References

Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.

Fonarow GC, Keech AC, Pedersen TR, Giugliano RP, Sever PS, Lindgren P, van Hout B, Villa G, Qian Y, Somaratne R, Sabatine MS. Cost-effectiveness of Evolocumab Therapy for Reducing Cardiovascular Events in Patients With Atherosclerotic Cardiovascular Disease. JAMA Cardiol. 2017 Oct 1;2(10):1069-1078. doi: 10.1001/jamacardio.2017.2762. Erratum In: JAMA Cardiol. 2017 Oct 1;2(10):1170.

Fonarow GC, van Hout B, Villa G, Arellano J, Lindgren P. Updated Cost-effectiveness Analysis of Evolocumab in Patients With Very High-risk Atherosclerotic Cardiovascular Disease. JAMA Cardiol. 2019 Jul 1;4(7):691-695. doi: 10.1001/jamacardio.2019.1647.

Schludi B, Giugliano RP, Sabatine MS, Raal FJ, Teramoto T, Koren MJ, Stein EA, Wang H, Monsalvo ML. Time-averaged low-density lipoprotein cholesterol lowering with evolocumab: Pooled analysis of phase 2 trials. J Clin Lipidol. 2022 Jul-Aug;16(4):538-543. doi: 10.1016/j.jacl.2022.05.069. Epub 2022 Jun 6.

Gaba P, O'Donoghue ML, Park JG, Wiviott SD, Atar D, Kuder JF, Im K, Murphy SA, De Ferrari GM, Gaciong ZA, Toth K, Gouni-Berthold I, Lopez-Miranda J, Schiele F, Mach F, Flores-Arredondo JH, Lopez JAG, Elliott-Davey M, Wang B, Monsalvo ML, Abbasi S, Giugliano RP, Sabatine MS. Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE. Circulation. 2023 Apr 18;147(16):1192-1203. doi: 10.1161/CIRCULATIONAHA.122.063399. Epub 2023 Feb 13.

Berg DD, Moura FA, Bellavia A, Scirica BM, Wiviott SD, Bhatt DL, Raz I, Bohula EA, Giugliano RP, Park JG, Feinberg MW, Braunwald E, Morrow DA, Sabatine MS. Assessment of Atherothrombotic Risk in Patients With Type 2 Diabetes Mellitus. J Am Coll Cardiol. 2023 Jun 27;81(25):2391-2402. doi: 10.1016/j.jacc.2023.04.031.

Clinical Benefit of Evolocumab Treatment Among Patients With Atherosclerotic Cardiovascular Disease: Exploration Based on the Chinese Subgroup of FOURIER Study, ZHANG Lihua1 , LI Weimin2 , YAO Zhuhua3 , CHEN Jiyan4 , DONG Jun5 , LI Jing1 (Chinese Circulation Journal, 2023, 38: 704.)

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