Impact of Evolocumab on the Effects of Clopidogrel in Patients With 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. 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.

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].