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

• Status: Completed
• Trial end date: 2020-11-02
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Florida
• Collaborator: Amgen
• Treatments: Clopidogrel; Evolocumab

Criteria

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].