Study objective
The RENOVATE trial is a multicenter, randomized, open-label, active -treatment, non-inferiority controlled trial to compare the safety and efficacy of oral anticoagulation treatment with apixaban and oral anticoagulation with vitamin K antagonist for patients at least 3 months after mechanical aortic valves replacement.

Background
Apixaban is a non–vitamin K antagonist oral anticoagulant that selectively and directly inhibits factor Xa, thereby inhibiting both thrombin formation and endovascular thrombosis.16 apixaban was previously demonstrated to be effective in several indications including the prevention of thromboembolic complications in patients with atrial fibrillation,17 the prevention of recurrent venous thromboembolism (VTE),18 the prevention of VTE in orthopedic surgery,19 and the prevention of recurrent cardiac ischemic events after acute coronary syndrome.20 In porcine model, the rivaroxaban was more effective than enoxaparin, drug used for conventional anticoagulation, for thrombophylaxis of mechanical valve in heterotrophic aortic position. 
We hypothesize that this agent has the potential to reduce the risk of bleeding complications after mechanical aortic valve replacement compared with conventional oral anticoagulation using vitamin K antagonist. The RENOVATE trial is a multicenter, randomized, open-label, active -treatment,non-inferiority controlled trial to compare the safety and efficacy of oral anticoagulation treatment with apixaban and oral anticoagulation with vitamin K antagonist for patients at least 3 months after mechanical aortic valves replacement.

Study design
Consenting patients are randomized (1:1 ratio), 3 months after a successful mechanical aortic valve replacement, to either a rivaroxaban or vitamin K antagonist regimen. In the experimental arm, subjects receive apixaban (20 mg once daily [OD]) for 12 months. The apixaban dose is reduced form 20 mg OD to 15 mg OD for subjects with moderate renal impairments (Ie, estimated glomerular filtration rate <50 and ≥30 mL/min per 1.73 m2). In the control arm, subjects receive vitamin K antagonist with targeted INR 2.0 to 3.0 for 12 months. Randomization will be stratified according to presence of atrial fibrillation and participating site. Major cardiac surgery centers in KOREA will participate in the RENOVATE trial.

Treatment

Consenting subjects are randomized in a 1:1 ratio to an apixaban or to vitamin K antagonist (warfarin) at least 3 months after successful mechanical aortic valve replacement. 

a)	Apixaban (NOAC) group: After randomization, Liquisia (apixaban) 5mg, bid daily
b)	Vitamin K antagonist(warfarin) group: After randomization, take Vitamin K antagonist(warfarin) with target INR 2.0~3.0 by planned INR monitoring

Arm Label

Target Number of Participant

Arm Type

Arm Description

Apixaban group
: After randomization, take 5 mg of apixaban (Liquisia, Jonggeundang, Korea) bid daily for 12 months. However, depending on the weight and subject base factors, the following applies.

However, in the case of subjects with one or more of the following factors, take 2.5mg of apixaban bid daily for 12 months
①	Subjects with two or more of following factors
•	aged ≥ 80 years 
•	weight ≦ 60kg 
•	creatinine ≥ 1.5mg/dL(133umol/L) 
②	severe renal impairment (15-29 mL / min by Cockorft-Gault)

Arm Label

Target Number of Participant

Arm Type

Arm Description

Vitamin K antagonist group
: After randomization, take Vitamin K antagonist(warfarin) with target INR 2.0~3.0 by planned INR monitoring

Gender

Age

Description

1. Aged ≥ 19 years with successful mechanical aortic valve replacement
2. Mechanical heart valve in aortic valve position, for at least 3 months postoperatively
3. Good performance of prosthetic aortic valve (no prosthesis-patient mismatch and mean aortic valve gradient < 20 mmHg or peak aortic valve velocity < 3 m/sec, no moderate or severe paravalvular/valvular regurgitation) according to VARC-2 criteria
4. The patient or guardian agrees to the study protocol and the schedule of clinical follow-up, and provides informed, written consent, as approved by the appropriate Institutional Review Board/Ethical Committee of the respective clinical site.

1.	Old generation mechanical valve
2.	History of mechanical valve implantation in the mitral valve, pulmonary valve or tricuspid valve
3.	Valvular atrial fibrillation(atrial fibrillation with moderate-to-severe mitral stenosis)
4.	History of hemorrhagic stroke
5.	Clinically overt stroke within the last 3 months
6.	Renal failure(creatinine clearance <15mL/min) or on hemodialysis
7.	Left ventricular dysfunction: Left ventricular ejection fraction (LVEF) ≤40%
8.	Moderate and severe hepatic impairment, and any hepatic disease associated with coagulopathy
9.	Clinically significant active bleeding
10.	Bleeding or hemorrhagic disorder
11.	The increased risk of bleeding due to the following reasons:
1)	History of gastrointestinal ulcers or active ulcerations within the last 6 months
2)	History of intracranial or intracerebral haemorrhage within the last 6 months
3)	Spinal cord vascular abnormalities or intracerebral vascular abnormalities
4)	History of the brain, spinal cord or ophthalmic surgery within the last 6 months
5)	History of the brain or spinal cord injury within the last 6 months
6)	oesophageal varices
7)	Arteriovenous malformation
8)	Vascular aneurysms
9)	Malignant tumour with a high risk of bleeding
12.	Bleeding tendencies associated with overt bleeding of;
o	gastrointestinal, genitourinary or respiratory tract;
o	cerebrovascular haemorrhage;
o	aneurysms- cerebral, dissecting aorta;
o	pericarditis and pericardial effusions;
o	bacterial endocarditis
13.	Hemodynamically unstable or pulmonary embolism required thrombolysis or embolectomy
14.	Combination therapy with other anticoagulants(Unfractionated heparin(UFH), enoxaparin, dalteparin, fondaparinux, etc.) However, the following cases are permitted;
o	Switching anticoagulants
o	Intravenous UFH to keep central/arterial lines open
15.	Uncontrolled moderate or severe hypertension
16.	Gastrointestinal bleeding within 1year
17.	Anaemia at least one among the conditions(as defined below) is met
o	Diagnosed and documented ongoing anaemia or
o	Hemoglobin level <10.0 g/dL or platelet count < 100 x 10 9/L within the last 6 months
18.	Infective endocarditis
19.	Hypersensitivity to the main component or constituents of Apixaban or Vitamin K antagonist
20.	Positive pregnancy test results (all pregnant women should undergo urinary human chorionic gonadotropin (hCG) testing within 7 days prior to screening and/or randomization) or during pregnancy or lactation
21.	Moderate to severe mitral stenosis
22.	A genetic problem with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
23.	The unsuitable condition to the protocol
24.	Actively participating in another drug or device investigational study, which has not completed the primary endpoint follow-up period
25.	Terminal illness with life expectancy <12 months
26.	Vitamin K deficiency
27.	Alcoholic or psychical disorder
28.	Threatened abortion, eclampsia or preeclampsia

cardiac death, valve thrombosis, valve-related thromboembolic event, major bleeding(Bleeding Academic Research Consortium 3 or 5 Bleeding), and clinically-relevant non-major bleeding( Bleeding Academic Research Consortium 2 Bleeding)   

12months after randomization

Each component of primary composite outcomes

12months after randomization

Death from any cause at 12 months

12months after randomization

Death from cardiovascular cause at 12 months

12months after randomization

valve thrombosis confirmed by transthoracic echocardiography, transesophageal echocardiography, cine fluoroscopy, computed tomography, or autopsy (Valve Academic Research Consortium (VARC) criteria)  at 12 months  

12months after randomization

valve-related thromboembolic   at 12 months

12months after randomization

transient ischemic attack   at 12 months

12months after randomization

stroke at 12 months

12months after randomization

systemic embolism at 12 months

12months after randomization

myocardial infarction  at 12 months

12months after randomization

major bleeding  : BARC (Bleeding Academic Research Consortium) 3 or 5  at 12 months

12months after randomization

Clinically-relevant non-major bleeding  :BARC (Bleeding Academic Research Consortium) 2 at 12 months

12months after randomization

cardiac death, valve thrombosis and valve-related thromboembolic event at 12 months

12months after randomization

cardiac death, valve thrombosis, stroke, systemic embolism and myocardial infarction event   at 12 months

12months after randomization

major bleeding(Bleeding Academic Research Consortium 3 or 5)  and clinically-relevant non-major bleeding(BARC (Bleeding Academic Research Consortium 2)  at 12 months

12months after randomization

stroke, systemic embolism, transient ischemic attack and myocardial infarction event  at 12 months

12months after randomization

all-cause death, stroke, systemic embolism, transient ischemic attack and myocardial infarction event at 12 months

12months after randomization

The change of echocardiographic parameter  (transaortic valve mean gradient,transaortic valve peak gradient,transaortic valve peak velocity,effective orifice area(EOA))

12months after randomization