Atherosclerotic Cardiovascular Disease
Conditions
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.
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.
Interventions
DRUGEvolocumab
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).
OTHERPlacebo
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).
Sponsors
Amgen
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind, placebo-controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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 \[women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study\].
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| HPR - Evolocumab 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). | 19 |
| HPR - Placebo 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). | 18 |
| NPR - Evolocumab 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). | 22 |
| NPR - Placebo 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). | 25 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | HPR - Evolocumab | HPR - Placebo | NPR - Evolocumab | NPR - Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 8 | 63 years STANDARD_DEVIATION 8 | 62 years STANDARD_DEVIATION 8 | 63 years STANDARD_DEVIATION 8 | 58 years STANDARD_DEVIATION 8 |
| LDL cholesterol | 101 mg/dL STANDARD_DEVIATION 33 | 107 mg/dL STANDARD_DEVIATION 29 | 109 mg/dL STANDARD_DEVIATION 42 | 91 mg/dL STANDARD_DEVIATION 30 | 99 mg/dL STANDARD_DEVIATION 31 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 46 Participants | 15 Participants | 10 Participants | 11 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 36 Participants | 4 Participants | 7 Participants | 11 Participants | 14 Participants |
| Sex: Female, Male Female | 32 Participants | 8 Participants | 6 Participants | 10 Participants | 8 Participants |
| Sex: Female, Male Male | 52 Participants | 11 Participants | 12 Participants | 12 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 18 | 0 / 22 | 0 / 25 |
| other Total, other adverse events | 0 / 19 | 0 / 18 | 0 / 22 | 0 / 25 |
| serious Total, serious adverse events | 1 / 19 | 1 / 18 | 1 / 22 | 0 / 25 |
Outcome results
Primary
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.
Time frame: 30 days
Population: Patient with valid data at 30 days were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HPR - Evolocumab | Platelet Reactivity Defined by VerifyNow PRU in HPR and NPR Patients | 219 PRU | Standard Deviation 38 |
| HPR - Placebo | Platelet Reactivity Defined by VerifyNow PRU in HPR and NPR Patients | 241 PRU | Standard Deviation 52 |
| NPR - Evolocumab | Platelet Reactivity Defined by VerifyNow PRU in HPR and NPR Patients | 141 PRU | Standard Deviation 54 |
| NPR - Placebo | Platelet Reactivity Defined by VerifyNow PRU in HPR and NPR Patients | 159 PRU | Standard Deviation 41 |
p-value: 0.16995% CI: [-9, 52]t-test, 2 sided
p-value: 0.23695% CI: [-11, 45]t-test, 2 sided