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

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT03096288
• Collaborator: Amgen (Industry)
• Enrollment: 259
• Location: 1
• Arms: 2
• Actual Duration (Months): 37
• Patients Per Site Per Month: 7

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Atherosclerotic Cardiovascular Disease	Drug: Evolocumab; Other: Placebo	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 259 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double-blind, placebo-controlled
• Primary Purpose: Treatment
• Official Title: Impact of the PCSK9 Inhibitor Evolocumab on the Pharmacodynamic Effects of Clopidogrel in Patients With Atherosclerotic Cardiovascular Disease and High On-Treatment Platelet Reactivity
• Actual Study Start Date: Oct 3, 2017
• Actual Primary Completion Date: Nov 2, 2020
• Actual Study Completion Date: Nov 2, 2020

Arms and Interventions

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).

Outcome Measures

Primary Outcome Measures

1. Platelet Reactivity Defined by VerifyNow PRU in HPR and NPR Patients [30 days]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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].

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Jacksonville	Florida	United States	32209

Sponsors and Collaborators

• University of Florida
• Amgen

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 17, 2018
• Informed Consent Form - Oct 30, 2018

More Information

Publications

None provided.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT03096288
• Other Study ID Numbers: IIS AMG001
• First Posted: Mar 30, 2017
• Last Update Posted: Feb 17, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Additional relevant MeSH terms: Cardiovascular Diseases; Atherosclerosis; Evolocumab

Study Results

Participant Flow

Recruitment Details	Patients were recruited between October 2017 and May 2020 at the University of Florida Health Science Center at UF Health Jacksonville - Division of Cardiology
Pre-assignment Detail	259 patients were consented to participate in the study. Of these, 165 were screen failures and 10 withdrew consent before randomization. Thus, 84 patients were randomized and received study treatment.

Arm/Group Title	HPR - Evolocumab	HPR - Placebo	NPR - Evolocumab	NPR - Placebo
Arm/Group Description	Patients with high platelet reactivity (HPR) 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).	Patients with high platelet reactivity (HPR) 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).	Patients with normal platelet reactivity (NPR) 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).	Patients with normal platelet reactivity (NPR) 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).
Period Title: Overall Study
STARTED	19	18	22	25
COMPLETED	19	17	22	24
NOT COMPLETED	0	1	0	1

Baseline Characteristics

Arm/Group Title	HPR - Evolocumab	HPR - Placebo	NPR - Evolocumab	NPR - Placebo	Total
Arm/Group Description	Patients with high platelet reactivity (HPR) 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).	Patients with high platelet reactivity (HPR) 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).	Patients with normal platelet reactivity (NPR) 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).	Patients with normal platelet reactivity (NPR) 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).	Total of all reporting groups
Overall Participants	19	18	22	25	84
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63 (8)	62 (8)	63 (8)	58 (8)	62 (8)
Sex: Female, Male (Count of Participants)
Female	8 42.1%	6 33.3%	10 45.5%	8 32%	32 38.1%
Male	11 57.9%	12 66.7%	12 54.5%	17 68%	52 61.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	15 78.9%	10 55.6%	11 50%	10 40%	46 54.8%
White	4 21.1%	7 38.9%	11 50%	14 56%	36 42.9%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 5.6%	0 0%	1 4%	2 2.4%
LDL cholesterol (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	107 (29)	109 (42)	91 (30)	99 (31)	101 (33)

Outcome Measures

1. Primary Outcome

Title	Platelet Reactivity Defined by VerifyNow PRU in HPR and NPR Patients
Description	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.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

Patient with valid data at 30 days were analyzed

Arm/Group Title	HPR - Evolocumab	HPR - Placebo	NPR - Evolocumab	NPR - Placebo
Arm/Group Description	Patients with high platelet reactivity (HPR) 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).	Patients with high platelet reactivity (HPR) 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).	Patients with normal platelet reactivity (NPR) 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).	Patients with normal platelet reactivity (NPR) 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).
Measure Participants	19	17	22	24
Mean (Standard Deviation) [PRU]	219 (38)	241 (52)	141 (54)	159 (41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HPR - Evolocumab, HPR - Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.169
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	22
	Confidence Interval	(2-Sided) 95%; -9 to 52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NPR - Evolocumab, NPR - Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.236
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	17
	Confidence Interval	(2-Sided) 95%; -11 to 45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	30 days
Adverse Event Reporting Description	Non serious adverse events are reported only if frequency >5%.
Arm/Group Title	HPR - Evolocumab		HPR - Placebo		NPR - Evolocumab		NPR - Placebo
Arm/Group Description	Evolocumab (Repatha) 420 mg s.c. single injection 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).		0.9% sodium chloride s.c. single injection 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).		Evolocumab (Repatha) 420 mg s.c. single injection 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).		0.9% sodium chloride s.c. single injection 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).
All Cause Mortality
	HPR - Evolocumab		HPR - Placebo		NPR - Evolocumab		NPR - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/18 (0%)		0/22 (0%)		0/25 (0%)
Serious Adverse Events
	HPR - Evolocumab		HPR - Placebo		NPR - Evolocumab		NPR - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		1/18 (5.6%)		1/22 (4.5%)		0/25 (0%)
Cardiac disorders
myocardial infarction	0/19 (0%)	0	1/18 (5.6%)	1	0/22 (0%)	0	0/25 (0%)	0
chest pain	1/19 (5.3%)	1	0/18 (0%)	0	0/22 (0%)	0	0/25 (0%)	0
Gastrointestinal disorders
gastrointestinal bleeding	1/19 (5.3%)	1	0/18 (0%)	0	1/22 (4.5%)	1	0/25 (0%)	0
Other (Not Including Serious) Adverse Events
	HPR - Evolocumab		HPR - Placebo		NPR - Evolocumab		NPR - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/18 (0%)		0/22 (0%)		0/25 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.