Impact of Evolocumab on the Effects of Clopidogrel in Patients With High On-Treatment Platelet Reactivity
Condition: Atherosclerotic Cardiovascular Disease
MeSH terms: Cardiovascular Diseases; Atherosclerosis
Intervention: Evolocumab; Placebo
Intervention description: 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).; 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).
Intervention MeSH terms: Evolocumab
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Double-blind, placebo-controlled
Enrollment: 259.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility 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].