Efficacy and Safety of Evolocumab prior to CABG in multivessel coronary artery disease: A prospective, randomized, open, controlled, multicenter, phase 3 clinical trial

Status : Approved
First Submitted Date : 2020/10/29     Registered Date : 2020/11/04     Last Updated Date : 2022/12/22    

Despite advances in surgical and perioperative care, postoperative complications after cardiac surgery remain frequent. Especially, myocardial injury or infarction (MI) is inevitable during CABG, but related with either short-term or long-term mortality. Several studies to reduce peri-CABG MI including statin loading have been conducted, but showed no clear benefits with controversial results. Evolocumab (a PCSK9 inhibitor) has been developed and demonstrated the remarkable LDL-lowing effect and prevention of ischemic events in various medical conditions. Recently, an animal experiment showed that the PCSK9 inhibitor improves cardiac function and reduces infarct size in rats with ischaemia/reperfusion injury. We hypothesized that administration of evolocumab prior to CABG exerts cardioprotection and results in reduction of periCABG-MI. In this work, we assessed the impact of evolocumab on perioperative myocardial injury in multivessel coronary artery disease patients undergoing CABG without elevation of cardiac enzyme. In the group (1) Experimental (n = 50 ) was administered at a dose of 140 mg evolocumab within 72 hours before surgery and group (2) control without evolocumab (n = 50). The primary end‑point was the extent of perioperative myocardial injury assessed according to the peak level or the area under the curve (AUC) of Troponin‑I and CK‑MB release as derived from blood samples obtained 0, 6, 24, 48, 72 hours after surgery.

Treatment

Evolocumab (Repatha) 140mg
140mg/day (1pen), once, subcutaneous injection
The control group will not receive any placebo medication.

No administration of evolocumab

Administration of evolocumab (repatha) 140mg (1 pen) once within 72 hours before CABG

1. Age >= 18, <85 years
2. Multivessel coronary artery disease patients awaiting elective cardiac surgery without elevation of serum cardiac enzymes. 
3. The patient or legal representative must sign the consent form before the procedure, in form containing all the details of the research approved by the Ethics Committee of the Institution.

1. Patients who underwent any open heart surgery before. 
2. Patients requiring concomitant valve surgery. 
3. Patients with acute myocardial infarction
4. Prior use of PCSK9 inhibition treatment other than evolocumab or use of evolocumab < 12 weeks prior to screening.
5. Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or
alanine aminotransferase (ALT) > 3 times the ULN as determined by central laboratory
analysis at final screening
6. Severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2 at final screening
7. Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, renal)
8. CK > 5 times the ULN at final screening
9. Known major active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator
10. Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 10 years
11. Subject is pregnant or breast feeding, or planning to become pregnant or to breastfeed during treatment with IP and/ or within 15 weeks after the end of treatment with IP
Subject likely to not be available to complete all protocol-required study visits or procedures, to the best of the subject’s and investigator’s knowledge
12. Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s)

Peak level of Troponin-I

For 3 days after surgery

AUC of Troponin-I

For 3 days after surgery

Change of Troponin-I

At every visit

Peak level of CK-MB

For 3 days after surgery

AUC of CK-MB

For 3 days after surgery

Change of CK-MB

At every visit

Change of BNP

At every visit

Change of CRP

At every visit

Change of LVEF

For 3 days after surgery

Cumulated incidence of all-cause mortality

At 1 month

Cumulated incidence of myocardial infarction

At 1 month

Cumulated incidence of stroke including hemorrhagic, ischemic stroke and TIA

At 1 month

Cumulated incidence of atrial fibrillation

At 1 month

Cumulated incidence of coronary revascularization including PCI and CABG

At 1 month