Impact of Evolocumab on the Effects of Clopidogrel in Patients With High On-Treatment Platelet Reactivity

Impact of the PCSK9 Inhibitor Evolocumab on the Pharmacodynamic Effects of Clopidogrel in Patients With Atherosclerotic Cardiovascular Disease and High On-Treatment Platelet Reactivity

Clopidogrel is the most widely used P2Y12 receptor inhibitor and is the only agent of this class currently recommended in patients with stable coronary artery disease (CAD) undergoing PCI, and for the treatment of stroke or PAD. Pharmacodynamic (PD) studies have shown that approximately 30-40% of patients experience high on-treatment platelet reactivity (HPR) while receiving clopidogrel treatment. Importantly HPR status has been strongly associated with an increased risk of ischemic events. Multiple approaches have been advocated to reduce HPR rates. In a previous study treatment with high-dose atorvastatin in addition to double-dose clopidogrel reduced platelet reactivity significantly more than double-dose clopidogrel alone in statin-naïve patients with stable CAD and HPR. To date, the exact biological mechanisms involved in the statin modulation of platelet function are not fully understood, although likely attributed to both its lipid-lowering and non-lipid-related effects.

Evolocumab is a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). The use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced the incidence of cardiovascular events. Whether the reduction in cardiovascular events is simply due to LDL reduction or might be related to other mechanisms is currently subject of investigation. Although LDL reduction with statin therapies has been associated with reduction in platelet reactivity, to date the effects on platelet aggregation of adjunctive lipid lowering with evolocumab has not been explored.

The aim of the present study is to investigate the effects of evolocumab in addition to statin therapy on HPR rates and platelet reactivity in patients with atherosclerotic cardiovascular disease (ASCVD) and HPR while on clopidogrel treatment.

Study Overview

• Status: Completed
• Conditions: Atherosclerotic Cardiovascular Disease
• Intervention / Treatment: Drug: Evolocumab; Other: Placebo

Detailed Description

Clopidogrel is the most widely used P2Y12 receptor inhibitor and is the only agent of this class currently recommended in patients with stable coronary artery disease (CAD) undergoing PCI, and for the treatment of stroke or PAD. Although the efficacy of DAPT with aspirin and clopidogrel has been consistently shown in different clinical settings, rates of ischemic recurrences remain elevated despite this treatment regimen, especially in high risk patients. This has been in part attributed to the high interindividual variability in responses to clopidogrel. Pharmacodynamic (PD) studies have shown that approximately 30-40% of patients experience high on-treatment platelet reactivity (HPR) while receiving clopidogrel treatment. Importantly HPR status has been strongly associated with an increased risk of ischemic events, in particular stent thrombosis, in patients with ACS and following PCI. This underscores the need for strategies aimed to reduce HPR rates in patients treated with clopidogrel. Multiple approaches have been advocated to reduce HPR rates. The pleiotropic effects associated with lipid lowering therapies, in particular statins, have been subject to extensive research. In a previous study treatment with high-dose atorvastatin in addition to double-dose clopidogrel reduced platelet reactivity significantly more than double-dose clopidogrel alone in statin-naïve patients with stable CAD and HPR. To date, the exact biological mechanisms involved in the statin modulation of platelet function are not fully understood, although likely attributed to both its lipid-lowering and non-lipid-related effects.

Evolocumab is a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered subcutaneously (s.c.) at a dosage of 140 mg every 2 weeks or 420 mg once monthly. In clinical trials evolocumab was more effective than placebo and/or ezetimibe in reducing LDL cholesterol, including when added to statin therapy. The use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced the incidence of cardiovascular events. Whether the reduction in cardiovascular events is simply due to LDL reduction or might be related to other mechanisms is currently subject of investigation. Although LDL reduction with statin therapies has been associated with reduction in platelet reactivity, to date the effects on platelet aggregation of adjunctive lipid lowering with evolocumab has not been explored.

The aim of the present study is to investigate the effects of evolocumab in addition to statin therapy on HPR rates and platelet reactivity in patients with atherosclerotic cardiovascular disease (ASCVD) and HPR while on clopidogrel treatment.

• Study Type: Interventional
• Enrollment (Actual): 259
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida

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:

1. Patients with atherosclerotic cardiovascular disease (ASCVD), defined as prior ACS, history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or PAD presumed to be of atherosclerotic origin.
2. On therapy with clopidogrel (75mg od), with or without low-dose aspirin (81mg od), as per standard-of-care for at least 30 days.
3. HPR, defined as P2Y12 reaction units (PRU) > 208 by VerifyNow P2Y12.
4. Fasting LDL-cholesterol ≥70 mg/dL or a non-high-density lipoprotein cholesterol (HDL-C) of ≥100 mg/dL after ≥2 weeks of optimized stable lipid-lowering therapy with maximally tolerated dose of statin, which would ideally include a high-intensity statin, but must be at least moderate intensity statin (i.e. atorvastatin 20 mg or equivalent, with or without ezetimibe. Maximal tolerated dose will be defined based on patient clinical history (no statin re-challenge will be performed).
5. Age ≥ 18 years old.

Exclusion criteria:

1. On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, apixaban, edoxaban).
2. On treatment with any antiplatelet agent other than aspirin and clopidogrel in the past 14 days.
3. Use of PCSK9 inhibitors in the past 90 days
4. Creatinine clearance <30 mL/minute.
5. Known severe hepatic impairment.
6. History of a serious hypersensitivity reaction to evolocumab
7. Hemodynamic instability
8. Pregnant and breastfeeding women [women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study].

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Evolocumab; Evolocumab (Repatha) 420 mg s.c. single injection	Drug: Evolocumab; Patients will be randomly assigned to receive a single dose of either evolocumab 420 mg s.c. or placebo (0.9% sodium chloride s.c. injection).; Other Names: Repatha
PLACEBO_COMPARATOR: Placebo; 0.9% sodium chloride s.c. single injection	Other: Placebo; Patients will be randomly assigned to receive a single dose of either evolocumab 420 mg s.c. or placebo (0.9% sodium chloride s.c. injection).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet Reactivity Defined by VerifyNow PRU in HPR and NPR Patients	The primary end point of our study is the comparison of P2Y12 reaction units (PRU) measured by VerifyNow between evolocumab and placebo at 30 days after randomization. PRU is a well-established measure of platelet reactivity and aggregation in response to antiplatelet medications. The higher is the PRU the lower is the effect of the antiplatelet medication. HPR is defined as PRU>208 and NPR as PRU 85-208.	30 days

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: Amgen
• Investigators: Principal Investigator: Dominick Angiolillo, MD, PhD, University of Florida College of Medicine-Jacksonville

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 3, 2017
• Primary Completion (ACTUAL): November 2, 2020
• Study Completion (ACTUAL): November 2, 2020

Study Registration Dates

• First Submitted: March 23, 2017
• First Submitted That Met QC Criteria: March 24, 2017
• First Posted (ACTUAL): March 30, 2017

Study Record Updates

• Last Update Posted (ACTUAL): February 17, 2022
• Last Update Submitted That Met QC Criteria: February 16, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Cardiovascular Diseases; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab
• Other Study ID Numbers: IIS AMG001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No