Evolocumab in Acute Coronary Syndrome

Conditions

Acute Coronary Syndrome

Brief summary

Vascular and myocardial inflammation are significantly increased in Acute Coronary Syndrome (ACS) patients, are closely correlated to LDL-C levels, and are associated with these adverse consequences in the post-ACS patient population. Serum proprotein convertase subtilisin/kerin type 9 (PCSK9) levels are also increased in ACS, may raise LDL-C, and the investigators' pre-clinical studies indicate that PCSK9 is also a potent inducer of vascular inflammation. The addition of the PCSK9 antibody evolocumab, currently approved to lower LDL-C in certain patient populations, to current medical therapies would appear to be of particular benefit in an important subset of ACS patients, those with non-ST elevation myocardial infarction (NSTEMI) by markedly reducing LDL-C, stabilizing vulnerable plaque, and limiting inflammation-associated myocardial cell loss and resultant dysfunction.

Detailed description

In a placebo-controlled, randomized double blind trial, the addition of evolocumab to standard care in NSTEMI patients (1) decreases LDL-C during hospitalization and at 30 days, (2) decreases vascular/plaque and myocardial inflammation as assessed by Positron Emission Tomography (PET) scanning at 30 days, and improves (3) serum markers of endothelial function at hospital discharge and at 30 days, and (4) echocardiographic assessment of left ventricular function at 30 days and six months. This is the first PCSK9 inhibitor trial which examines these outcomes in the ACS patient population. It will provide valuable data on the extent and time course of LDL-C reduction as well as the impact of inhibition on inflammatory markers and on imaging assessment of vascular and myocardial inflammation, all of which may significantly impact important clinical outcomes in this high risk patient cohort.

Efthymios Ziogos, Michael Vavuranakis, Tarek Harb, Palmer Foran, Michael J. Blaha et al. (9 authors)

European Heart Journal Open2023-03-0129 citations

10.1093/ehjopen/oead035

Proprotein convertase subtilisin/kexin type 9 (PCSK9), platelet activation and interaction with the vascular endothelium: the impact of PCSK9 inhibition with evolocumab in acute coronary syndrome

Efthymios Ziogos, Stephen P. Chelko, Elise M. Walsh, M Engel, Gary Gerstenblith et al. (7 authors)

European Heart Journal2022-10-01

10.1093/eurheartj/ehac544.1281

The Trajectory of Lipoprotein(a) During the Peri- and Early Postinfarction Period and the Impact of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition.

Vavuranakis MA, Jones SR, Ziogos E, Blaha MJ, Williams MS, Foran P, Schindler TH, Lai S, Schulman SP, Gerstenblith G, Leucker TM.

2022-03-2122 citations

10.1016/j.amjcard.2022.01.058

Abstract 12563: The Trajectory of Platelet Factor 4 in Acute Myocardial Infarction and the Impact of PCSK9-Inhibition

Efthymios Ziogos, Marlene S. Williams, Michael Vavuranakis, Michael J. Blaha, Steven R. Jones et al. (9 authors)

Circulation2021-11-16

10.1161/circ.144.suppl_1.12563

Abstract 15287: Evolocumab Inhibits the Acute Rise in Lipoprotein(a) in Patients With Non-ST Elevation Myocardial Infarction (NSTEMI)- Results From the EVACS Study

Michael Vavuranakis, Michael J. Blaha, Steven R. Jones, Thomas H. Schindler, Marlene S. Williams et al. (9 authors)

Circulation2020-11-17

10.1161/circ.142.suppl_3.15287

Interventions

DRUGEvolocumab

420 mg evolocumab administered subcutaneously using an autoinjector/pen in NSTEMI patients within 24 hours, or one day, of admission.

DRUGPlacebo

Placebo administered subcutaneously using an autoinjector/pen in NSTEMI patients within 24 hours, or one day, of admission.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

Persons performing the PET imaging, laboratory technicians are all masked.

Intervention model description

Double-blind, placebo controlled trial

Eligibility

Sex/Gender

ALL

Age

25 Years to 90 Years

Healthy volunteers

No

Inclusion criteria

* Non ST segment elevation myocardial infarction * Troponin I \>/ 5.0 ng/dL * Permission of attending physician

Exclusion criteria

* ST elevation myocardial infarction * Patients requiring invasive hemodynamic support * Scheduled for cardiac surgery * Current or prior treatment with a PCSK9 antibody * Current participation in an intervention clinical trial * Female of childbearing potential who has not used acceptable method(s) of birth control for at least one month prior to screening * Contraindication to statin therapy * Subject likely not able to complete protocol related visits or procedures * Latex allergy * History of hypersensitivity to any monoclonal antibody

Design outcomes

Primary

Measure	Time frame	Description
Percent Change in LDL-Cholesterol	Baseline to 30 days	—
Change From Baseline in Target to Background Ratio Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) Scans	Baseline to 30 days	PET Imaging for Inflammation: Change from baseline in target to background ratio Fluorodeoxyglucose (FDG) PET scans in the myocardium.

Secondary

Measure	Time frame	Description
Left Ventricular Volume as Assessed by Echocardiography	Baseline, day 30 and 6 months	Evaluation of left ventricular volume (ml) by echocardiography
Ejection Fraction as Assessed by Echocardiography	Baseline, day 30 and 6 months	Evaluation of ejection fraction (%) by echocardiography
Plasma Proprotein Convertase Subtilisin Kexin-9 (PCSK9) Levels (ng/ml)	Baseline, day 30 and 6 months	Change from baseline in PCSK9 serum levels
PET-FDG Assessed Vascular Inflammation as Assessed by Standardized Uptake Value (SUV)	Baseline to day 30	Target artery to background ratio endpoint (standardized uptake value) for left carotid artery
High Sensitivity C-reactive Protein (Hs-CRP) Serum Levels	Baseline, day 30 and 6 months	hs-CRP serum levels (mg/L)
Change in Serum Levels of Interleukin 6	Baseline, day 30 and 6 months	Change in baseline in serum levels of Interleukin 6 (pg/mL)
Serum Levels of Interleukin 10	Baseline, day 30 and 6 months	Serum levels of Interleukin 10 (pg/mL)

Countries

United States

Contacts

PRINCIPAL_INVESTIGATORThorsten M Leucker, MD, PhD

Johns Hopkins University

Participant flow

Participants by arm

Arm	Count
Placebo placebo group	30
Evolocumab evolocumab group	30
Total	60

Baseline characteristics

Characteristic	Evolocumab	Total	Placebo
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	12 Participants	23 Participants	11 Participants
Age, Categorical Between 18 and 65 years	18 Participants	37 Participants	19 Participants
Age, Continuous	59.4 years STANDARD_DEVIATION 14.2	60.1 years STANDARD_DEVIATION 14.3	60.8 years STANDARD_DEVIATION 13.9
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Black or African American	8 Participants	19 Participants	11 Participants
Race (NIH/OMB) More than one race	1 Participants	4 Participants	3 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	20 Participants	36 Participants	16 Participants
Region of Enrollment United States	30 Participants	60 Participants	30 Participants
Sex: Female, Male Female	9 Participants	25 Participants	16 Participants
Sex: Female, Male Male	21 Participants	35 Participants	14 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 30	0 / 30
other Total, other adverse events	13 / 30	6 / 30
serious Total, serious adverse events	2 / 30	6 / 30

Outcome results

Primary

Change From Baseline in Target to Background Ratio Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) Scans

PET Imaging for Inflammation: Change from baseline in target to background ratio Fluorodeoxyglucose (FDG) PET scans in the myocardium.

Time frame: Baseline to 30 days

Population: Participants with PET data collected and adequate image quality for analysis

Arm	Measure	Value (MEAN)	Dispersion
Evolocumab	Change From Baseline in Target to Background Ratio Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) Scans	-26.7 ratio	Standard Deviation 20.4
Placebo	Change From Baseline in Target to Background Ratio Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) Scans	-10.4 ratio	Standard Deviation 36.2

Primary

Percent Change in LDL-Cholesterol

Time frame: Baseline to 30 days

Population: Participants with data collected

Arm	Measure	Value (MEDIAN)
Evolocumab	Percent Change in LDL-Cholesterol	-68.78 percent change
Placebo	Percent Change in LDL-Cholesterol	-27.58 percent change

Secondary

Change in Canadian Angina Class

Assess Canadian Angina Classification, I-IV

Time frame: Baseline, 30 days, 6 months

Secondary