DIrect Oral Anticoagulation and mechaNical Aortic Valve

Study Overview
=================
Brief Summary
-----------------
DIAMOND study is a national, multicentre, randomized, parallel-group, open label study in patients (aged ≥18 years) with mechanical aortic valve at least 7 days after cardiac surgery. Experimental group: Patients treated with apixaban 5 mg twice daily (BID) Active Comparator group: Patients treated with warfarin with an objective of INR target of 2.5 (range: 2.0-3.0) The Primary objective is To demonstrate that antithrombotic treatment with apixaban is non-inferior to warfarin (INR target range 2.0 - 3.0) in patients with mechanical heart valve implanted in the aortic position for at least 7 days for the primary net clinical benefit endpoint of ischemic outcomes (death, myocardial infarction, stroke, systemic embolism and valve thrombosis) and bleeding (ISTH major and non-major clinically relevant bleeding).

Detailed Description
-----------------
Antithrombotic management of patients with mechanical heart valves continues to be an important medical concern. Vitamin K antagonists (VKAs) are currently the only oral anticoagulants approved for mechanical prosthetic valve-implanted patients. As effective as these anticoagulants are, they have major drawbacks: narrow therapeutic window, variable dose-response in individuals, interaction with several foods and drugs. Achieved INR is frequently outside the target range and INR instability is a predictor of bleeding and late mortality in patients with mechanical heart valve prosthesis. Despite multiple studies that show that tissue valves have a limited durability, many patients sometimes even young choose this type of valve to avoid VKAs. In randomized studies and registries, direct oral anticoagulants (DOACs) have demonstrated their superiority to reduce bleeding in patients with non-valvular atrial fibrillation compared to VKAs with similar efficacy and are recommended as first choice in the guidelines. Apixaban has demonstrated a favorable benefit-risk profile to reduce bleeding in the different indications (ranging from 25-50%). So far, DOACs are currently contra-indicated or not indicated in patients with a mechanical prosthesis. The results of a single small-sized phase II randomized trial testing an anti-IIa drug were disappointing and anti-Xa drugs have not been appropriately evaluated in patients with a mechanical prosthesis. Only small observational series suggest encouraging results with anti-Xa DOACs. Ongoing randomized trials are conducted with DOACs compared to warfarin but the studies only include one type of mechanical aortic valve or mechanical valve in mitral position. Moreover, these studies are underpowered to completely answer the question about clinical ischemic and bleeding outcomes. Then, there is an unmet clinical need for an alternative to VKAs, such as an anti-Xa DOAC like apixaban, as anticoagulation in patients with a mechanical aortic prosthetic valve. The purpose of this study is to determine if patients with mechanical prosthetic valve in the aortic position at least 7 days after cardiac surgery can be maintained effectively with a better safety (net clinical benefit) on apixaban compared to warfarin.

Official Title
-----------------
DIrect Oral Anticoagulant for Antithrombotic Management Of mechaNical Aortic Valve Implanted Patients for Valvular Heart Disease Study

Conditions
-----------------
Aortic Valve Disease

Intervention / Treatment
-----------------
* Drug: Apixaban 5 MG Oral Tablet
* Drug: warfarin with an objective of INR target of 2.5 (range: 2.0-3.0)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female ≥18 years of age Prior implantation of a mechanical prosthetic bileaflet valve in the aortic position at least 7 days Participants currently receiving anticoagulation and who can receive warfarin with a target INR= 2.0 to 3.0 or apixaban Patients affiliated to social security Patient able to give free, informed and written consent Exclusion Criteria: Any cardiac surgery in the 7 days prior to enrollment Mechanical valve in any position other than aortic valve. Old aortic mechanical valves such as Starr-Edwards, Omniscience, Björk- Shiley or other tilting-disc valves Any major bleeding in the three months (90 days) prior to enrollment. Active bleeding or high risk of bleeding after cardiac surgery (i.e. hemopericardium) according to investigators Need to be on dual antiplatelet therapy (aspirin >100 mg daily and a P2Y12 inhibitor, i.e. clopidogrel, ticagrelor, prasugrel). Known hypersensitivity or other contraindications to apixaban (hepatic disease associated with coagulopathy and clinically relevant bleeding risk). Creatinine clearance <30 mL/min (Cockcroft) or patients requiring apixaban dose reduction. Known hypersensitivity or other contraindications to warfarin (severe hepatic insufficiency, malignant hypertension, pregnancy,breastfeeding, treatment with high dose of aspirin, miconazole, phenylbutazone or milepertuis). Need of heparin or low molecular weight heparin and known hypersensitivity or other contraindications to these drugs specially heparin-induced thrombocytopenia Ischemic stroke or intracranial hemorrhage within 1 month. Active endocarditis at the time of screening for enrollment. Women of childbearing potential without efficient contraception, pregnant or breastfeeding women. Concomitant combined strong P-gp and CYP3A4 inducers or inhibitors. History of non-compliance with recommended monthly INR testing Participation in another interventional study Active cancer or life expectancy less than 3 years Persons deprived of their liberty by judicial or administrative decision

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study is a national, multicentre, randomized, parallel-group, open label study in patients (aged ≥18 years) with mechanical aortic valve at least 7 days after cardiac surgery. Experimental group: Patients treated with apixaban 5 mg twice daily (BID) Active Comparator group: Patients treated with warfarin with an objective of INR target of 2.5 (range: 2.0-3.0)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Group<br>Patients treated with apixaban 5 mg twice daily (BID) | Drug: Apixaban 5 MG Oral Tablet<br>* Patients treated with apixaban 5 mg twice daily (BID)<br>* Other names: Experimental Group;|
| Active Comparator: Active Comparator group:<br>Patients treated with warfarin with an objective of INR target of 2.5 (range: 2.0-3.0) | Drug: warfarin with an objective of INR target of 2.5 (range: 2.0-3.0)<br>* Patients treated with warfarin with an objective of INR target of 2.5 (range: 2.0-3.0)<br>* Other names: Active Comparator;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Net Adverse Clinical Events (NACE) | The primary composite endpoint is a net clinical endpoint including a composite ischemic endpoint (death, myocardial infarction, stroke, systemic embolism and valve thrombosis) and bleeding (ISTH major and non-major clinically relevant bleeding) | Up to 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bleeding | Bleeding (ISTH major and non-major clinically relevant bleeding) | Up to 48 months | 
| MACE | Ischemic endpoints (death, myocardial infarction, stroke, systemic embolism and valve thrombosis) | Up to 48 months | 
| Death | All cause-death | Up to 48 months | 
| Valve thrombosis | Aortic Valve thrombosis adapted from VARC-3 definition | Up to 48 months | 
| Echographic parameter of aortic valve | Mean aortic gradient (mmHg) during follow-up | Up to 48 months | 
| Echographic parameter of aortic valve | Peak velocity (m/s) during follow-up | Up to 48 months | 
| Quality-of-life questionary | Quality of life measured with the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L) scaled from 0 to 100 | Up to 48 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Anticoagulant, Aortic valve, Warfarine, Apixaban, Stroke, Hemorrhage