Clinical trial NCT03900026: Effect of Evolocumab on Saphenous Vein Graft Patency Following Coronary Artery Bypass Surgery
Official title: A Randomized Trial of Evolocumab on Saphenous Vein Graft Patency Following Coronary Artery Bypass Surgery (NEWTON-CABG)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Coronary Artery Bypass Graft Surgery
Atherosclerosis
Vein Occlusion
Keywords: Coronary Artery Bypass Surgery
CABG
Saphenous Vein Graft
Evolocumab
Repatha
Lead sponsor: Unity Health Toronto
Sponsor class: OTHER
Collaborators: name: Applied Health Research Centre
First posted: 2019-04-02
Enrollment: 782
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, double-blind, randomized, placebo-controlled, parallel group study of evolocumab.
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine if evolocumab added to regular statin therapy improves vein graft patency after coronary artery bypass graft (CABG) surgery.

Detailed description: Coronary artery bypass graft (CABG) surgery is a procedure in which an artery or vein from the body is grafted to a critically narrowed coronary artery to restore flow of oxygenated blood to the heart. Statins are frequently prescribed after CABG surgery in order to lower LDL cholesterol levels and reduce the chances of coronary artery obstruction recurring. Despite this preventive measure, new vein grafts do end up becoming blocked in a significant proportion of patients. Evolocumab (Repatha®) is a recently approved medication that has been shown to effectively lower LDL cholesterol levels in the blood.

NEWTON-CABG is an investigator-initiated multicenter, double-blind, randomized, placebo-controlled, parallel group study of evolocumab \[140mg administered subcutaneously (SC) every two weeks (Q2W)\] added to statin therapy for 24 months postoperatively in a broad population of patients undergoing CABG surgery. Eligible subjects will be randomized to receive evolocumab or placebo within 21 days of index CABG. Prior to randomization, post-operative patients will be on moderate or high intensity statin therapy (atorvastatin 40-80mg, rosuvastatin 20-40mg or simvastatin 40mg daily unless another statin/dose or non-statin alternative is clinically justified). A CTAngiogram will be conducted at 24 months following CABG. Routine study visits will be done 3, 6, 12, 18 and 24 months post-surgery.

This study is supported by Amgen Inc.

Eligibility criteria: Inclusion Criteria - To be considered eligible for participation in this study, a participant must satisfy each of the following criteria:

1. Age ≥ 18 years
2. Scheduled to undergo coronary artery bypass graft (CABG) surgery (with or without cardiopulmonary bypass (CPB); with or without single valve repair/replacement)
3. CABG procedure included/planned to include at least two saphenous vein grafts
4. CABG procedure occurred within the past 21 days, or is planned within the next 60 days
5. On a moderate to high intensity statin therapy (defined as atorvastatin 40-80mg daily, rosuvastatin 20-40mg or simvastatin 40mg daily) unless a lower dose, or another statin or non-statin therapy is clinically justified

Exclusion Criteria - A participant will be ineligible for participation in this study if he or she satisfies any one or more of the following criteria:

1. Patients in whom additional lowering of LDL-C with evolocumab is deemed to be clinically inappropriate
2. Allergy to contrast dye
3. Known severe hepatic impairment (Childs-Pugh, Class C).
4. Known renal disease with estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73m2
5. Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow)
6. Use of cholesterylester transfer protein (CETP) inhibition treatment within 12 months prior to randomization.
7. Current, prior within past year, or known planned use of PCSK9 inhibition treatment
8. Severe cardiovascular or concomitant non-cardiovascular disease that is expected to reduce life expectancy to less than 2 years
9. Major active infection, or major hematologic, renal, respiratory, metabolic, gastrointestinal or endocrine dysfunction
10. Women who are pregnant or breastfeeding
11. Women of child bearing potential who are unwilling to use proper family planning or birth control methods to avoid pregnancy. Women are considered post-menopausal and not of childbearing potential after 12 months of natural (spontaneous) amenorrhea or have had a surgical procedure such as hysterectomy which makes pregnancy impossible.
12. Known intolerance or allergy to evolocumab or other PCSK9 inhibitors.
13. Currently taking simvastatin \>40mg/day, niacin or bile acid sequestrants
14. Known latex allergy
15. Inability to comply with protocol-required study visits or procedures, including administration of study drug
16. Known history of cancer within the past 5 years (except for carcinoma in-situ of the cervix, stage 1 prostate cancer or adequately treated non-melanoma carcinomas of the skin)
17. Participation in another investigational device or drug study which is likely to affect the primary outcome, within 30 days of planned initiation of study drug
18. NYHA class IV
19. Pacemaker or other implantable device implanted within 30 days prior to screening

Additional postoperative exclusion criteria:

1. Received only \<2 vein grafts
2. Major peri-operative complications following CABG surgery (e.g. stroke, MI, renal failure requiring dialysis, or postoperative ICU stay \> 5 days) prior to randomization

Primary outcomes:
measure: Saphenous vein graft disease rate (VGDR)
timeFrame: 24 months post CABG
Secondary outcomes:
measure: The proportion of patients with at least 1 vein graft totally (100%) occluded.
timeFrame: 24 months post CABG
measure: The percentage of vein grafts which are totally (100%) occluded grafts.
timeFrame: 24 months post CABG
measure: Hierarchical composite of the following (each assessed by total wins for each treatment group and the win ratio):
timeFrame: 24 months post CABG
Other outcomes:
measure: Composite rate of fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, cardiovascular death, coronary heart disease death, repeat coronary revascularization
timeFrame: 24 months post CABG
measure: Rate of fatal and non-fatal myocardial infarction.
timeFrame: 24 months post CABG
measure: Rate of fatal and non-fatal stroke.
timeFrame: 24 months post CABG
measure: Rate of cardiovascular death.
timeFrame: 24 months post CABG
measure: Rate of coronary heart disease death.
timeFrame: 24 months post CABG
measure: Rate of repeat coronary revascularization.
timeFrame: 24 months post CABG
measure: Rate of all-cause mortality.
timeFrame: 24 months post CABG
measure: Rate of total vein graft patency at 24 months.
timeFrame: 24 months post CABG
measure: Percentage of patients free of vein graft disease at 24 months.
timeFrame: 24 months post CABG
measure: Vein graft plaque volume.
timeFrame: 24 months post CABG
Locations:
city: San Francisco
country: United States
facility: San Francisco VA Medical Center
state: California
city: Jacksonville
country: United States
facility: Jacksonville Center for Clinical Research
state: Florida
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute Foundation
state: Minnesota
city: Cleveland
country: United States
facility: University Hospital Cleveland Medical Center
state: Ohio
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
city: Melbourne
country: Australia
facility: Monash University
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Saint John's
country: Canada
facility: New Brunswick Heart Centre
state: New Brunswick
city: Hamilton
country: Canada
facility: Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: Mississauga
country: Canada
facility: One Heart Care
state: Ontario
city: North York
country: Canada
facility: North York Diagnostic and Cardiology Centre
state: Ontario
city: North York
country: Canada
facility: Sunnybrook Health Sciences Center
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Québec
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval
state: Quebec
city: Calgary
country: Canada
facility: Foothills Medical Centre
city: Budapest
country: Hungary
facility: Medical Centre Hungarian Defence Forces
city: Budapest
country: Hungary
facility: Semmelweis University Heart and Vascular Centre
city: Zalaegerszeg
country: Hungary
facility: Zala Megyei Szent Rafael Korhaz
Study officials:
affiliation: Unity Health Toronto
name: David Mazer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Unity Health Toronto
name: Subodh Verma, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Unity Health Toronto
name: Lawrence Leiter, MD
role: STUDY_CHAIR
References: