EVOlocumab for Early Reduction of LDL-cholesterol Levels in Patients With Acute Coronary Syndromes (EVOPACS) (EVOPACS)

EVOlocumab for Early Reduction of LDL-cholesterol Levels in Patients With Acute Coronary Syndromes (EVOPACS) - A Randomized, Double-blind, Placebo-controlled Multicenter Study

Reduction of low-density lipoprotein cholesterol (LDL-C) levels effectively reduces the risk of adverse events in patients with established atherosclerotic cardiovascular disease. The clinical benefit of statins in improving clinical outcomes is proportional to the magnitude of LDL-C reduction, is more pronounced in patients with acute coronary syndromes (ACS) compared with stable coronary artery disease, and emerges at very early stages (as early as 4 weeks) after ACS when statins are administered in the acute phase of the event. On the basis of this evidence, early initiation of statin therapy is currently recommended in patients presenting with ACS. Because many patients cannot achieve adequate reduction of LDL-C levels despite treatment with high doses of statins or non-statin lipid-modifying medications, substantial residual risk remains. Moreover, the time of onset of LDL-C reduction takes 2 weeks following initiation of statin therapy. Proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors represent a novel class of lipid-lowering drugs leading to rapid, profound, and consistent reductions in LDL-C levels. While the effectiveness of PCSK9 monoclonal antibodies for LDL-C lowering has been established across patient populations without atherosclerotic cardiovascular disease or with stable ischemic heart disease, reduction and attainment of LDL-C target levels has not been explored in the acute setting of ACS - a clinical setting with highest risk of early event recurrence (within the first month). In this study the investigators want to evaluate the safety and effectiveness of the PCSK9 inhibitor evolocumab as compared with placebo, administered in the acute phase of ACS, for reduction of LDL-C levels within 8 weeks in patients receiving guideline-recommended high-intensity statin treatment (atorvastatin 40mg QD).

Study Overview

• Status: Completed
• Conditions: Acute Coronary Syndrome
• Intervention / Treatment: Drug: Evolocumab 140 mg/mL; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 308
• Phase: Phase 3

Contacts and Locations

Study Locations

• Switzerland
  • Bern, Switzerland, 3010
    • Bern University Hospital
  • BS
    • Basel, BS, Switzerland, 4031
      • Basel University Hospital
  • FR
    • Fribourg, FR, Switzerland, 1708
      • HFR Kantonsspital
  • GE
    • Geneva, GE, Switzerland, 1211
      • Hôpitaux Universitaires Genève
  • TI
    • Lugano, TI, Switzerland, 6900
      • Cardiocentro Ticino
  • VD
    • Lausanne, VD, Switzerland
      • Centre Hospitalier Universitaire Vaudois
  • ZH
    • Zurich, ZH, Switzerland
      • University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Male or female ≥ 18 years of age;

• Hospitalized for a recent ACS;
• LDL-C levels defined as follows:
• LDL-C ≥70 mg/dL (≥1.8 mmol/L) or non-HDL-C ≥100 mg/dL (≥2.6 mmol/) in patients who have been receiving stable treatment with high-intensity statin within ≥ 4 weeks prior to enrollment (i.e. continuous treatment that has not changed with regard to statin intensity over the past 4 weeks) or, LDL-C ≥90 mg/dL (≥2.3 mmol/L) or non-HDL-C ≥120 mg/dL (≥3.1 mmol/) in patients who have been receiving stable treatment with low- or moderate-intensity statin within ≥ 4 weeks prior to enrollment (i.e. continuous treatment that has not changed with regard to statin intensity over the past 4 weeks), or LDL-C ≥125 mg/dL (≥3.2 mmol/L) or non-HDL-C ≥155 mg/dL (≥4.0 mmol/) in patients who are statin-naïve or have not been on a stable (unchanged) statin regimen for at least 4 weeks prior to enrollment;
• Ability to understand the requirements of the study and to provide informed consent.

Exclusion Criteria:

• Unstable clinical status (hemodynamic or electrical instability;
• Uncontrolled cardiac arrhythmia, defined as recurrent and symptomatic ventricular tachycardia or atrial fibrillation with rapid ventricular response not controlled by medications in the past 3 months prior to screening;
• Severe renal dysfunction, defined by estimated glomerular filtration rate <30 ml/min/1.73m2;
• Active liver disease or hepatic dysfunction, either reported in patient medical record or defined by asparate aminotransferase (AST) or alanine aminotransferase (ALT) levels > 3x the upper limit of normal;
• Reported intolerance to atorvastatin (any dose) OR statin intolerance;
• Known allergy to contrast medium, heparin, aspirin, ticagrelor or prasugrel;
• Known sensitivity to any substances to be administered;
• Patients who previously received evolocumab or other PCSK9 inhibitor;
• Patient who received cholesterol ester transfer protein inhibitors in the past 12 months prior to screening;
• Treatment with systemic steroids or systemic cyclosporine in the past 3 months systemic cyclosporine, systemic steroids (eg. intravenous, intramuscular or per os);
• Known active infection or major hematologic, metabolic, or endocrine dysfunction in the judgment of the Investigator;
• Patients who will not be available for study-required procedures in the judgment of the Investigator;
• Current enrollment in another investigational device or drug study;
• Active malignancy requiring treatment;
• Female of childbearing potential (age <50 years and last menstruation within the last 12 months), who did not undergo tubal ligation, ovariectomy or hysterectomy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Evolocumab; Evolocumab 140 mg/mL, pre-filled auto-injector pen, 3 injections at day 1 and week 4	Drug: Evolocumab 140 mg/mL; Three injections with pre-filled auto-injector pen at day 1 and at week 4.
Placebo Comparator: Placebo; Placebo, pre-filled auto-injector pen, 3 injections at day 1 and week 4	Drug: Placebo; Three injections with pre-filled auto-injector pen at day 1 and at week 4.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent change in calculated LDL-C in the intent to treat (ITT) population	Baseline to week 8

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of patients with adverse events and serious adverse events	Baseline to week 8

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nominal change in calculated LDL-C		Baseline to week 8
Proportion of patients with LDL-C level <70 mg/dL (<1.8 mmol/L) at week 8		Baseline to week 8
Change in total cholesterol in the ITT population		Baseline to week 8
Change in HDL-C in the ITT population		Baseline to week 8
Change in lipoprotein-a in the ITT population		Baseline to week 8
Change in triglycerides in the ITT population		Baseline to week 8
Change in non-HDL-C in the ITT population		Baseline to week 8
Change in apolipoprotein B in the ITT population		Baseline to week 8
Change in apolipoprotein A-1 in the ITT population		Baseline to week 8
Percent change in high-sensitivity CRP (hs-CRP) in the ITT population		Baseline to week 8
Proportion of patients with hs-CRP level <2 mg/dL at week 8 in the ITT population		Baseline to week 8
Proportion of patients with LDL-C <70 mg/dL and hs-CRP <2 mg/dL at week 8 in the ITT population		Baseline to week 8
Nominal change in Interleukin (IL)-1b and IL-6 in the ITT population		Baseline to week 8
Change in high-sensitivity Troponin T		Baseline to 72 hours
Area under the curve (AUC) at Multiplate with Adenosinediphosphate (ADP) test	Platelet inhibition assessed with Multiplate ADP test at 72 hours and 8 weeks	Baseline to 72 hours and to week 8
Area under the curve (AUC) at Multiplate with Thrombin receptor activating peptide (TRAP) test	Platelet inhibition assessed with Multiplate TRAP test at 72 hours and 8 weeks	Baseline to 72 hours and to week 8
Number of patients with contrast-induced acute kidney injury (CI-AKI) at 72 hours among patients who undergo coronary angiography at baseline		Baseline to 72 hours
Number of patients with adjudicated events (death, cardiovascular death, myocardial infarction, hospitalization for recurrent ACS, hospitalization for heart failure, coronary revascularization, stroke		Baseline to week 8

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Collaborators: Amgen; University of Bern
• Investigators: Study Chair: Stephan Windecker, Prof., MD, Bern University Hospital; Principal Investigator: Konstantinos Koskinas, MD, Bern University Hospital

Publications and helpful links

General Publications

• 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.
• Lipinski MJ, Benedetto U, Escarcega RO, Biondi-Zoccai G, Lhermusier T, Baker NC, Torguson R, Brewer HB Jr, Waksman R. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. Eur Heart J. 2016 Feb 7;37(6):536-45. doi: 10.1093/eurheartj/ehv563. Epub 2015 Nov 17.
• Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, Jackson G, Braunwald E; PROVE IT-TIMI 22 Investigators. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2005 Oct 18;46(8):1405-10. doi: 10.1016/j.jacc.2005.03.077.
• Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001 Apr 4;285(13):1711-8. doi: 10.1001/jama.285.13.1711.
• Navarese EP, Kolodziejczak M, Kereiakes DJ, Tantry US, O'Connor C, Gurbel PA. Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies for Acute Coronary Syndrome: A Narrative Review. Ann Intern Med. 2016 May 3;164(9):600-7. doi: 10.7326/M15-2994. Epub 2016 Mar 22.
• Koskinas KC, Windecker S, Pedrazzini G, Mueller C, Cook S, Matter CM, Muller O, Haner J, Gencer B, Crljenica C, Amini P, Deckarm O, Iglesias JF, Raber L, Heg D, Mach F. Evolocumab for Early Reduction of LDL Cholesterol Levels in Patients With Acute Coronary Syndromes (EVOPACS). J Am Coll Cardiol. 2019 Nov 19;74(20):2452-2462. doi: 10.1016/j.jacc.2019.08.010. Epub 2019 Aug 31.

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2018
• Primary Completion (Actual): May 20, 2019
• Study Completion (Actual): August 7, 2019

Study Registration Dates

• First Submitted: September 7, 2017
• First Submitted That Met QC Criteria: September 14, 2017
• First Posted (Actual): September 19, 2017

Study Record Updates

• Last Update Posted (Actual): August 14, 2019
• Last Update Submitted That Met QC Criteria: August 13, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Disease; Syndrome; Acute Coronary Syndrome; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab
• Other Study ID Numbers: 2017-01753

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: No plan to make individual participant data available to other researchers

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No