Rivaroxaban Once Daily Versus Dose-adjusted Vitamin K Antagonist on the Biomarkers in Acute Decompensated Heart Failure and Atrial Fibrillation (ROAD HF-AF)

Study Overview
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Brief Summary
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Vitamin K antagonists (VKAs) are used to reduce the risk of stroke (cerebral vascular dysfunction) in AF patients. However, VKAs interact with drugs/food and the drug level is influenced by worsening of renal function, liver congestion or hemodynamic alterations in acute decompensated heart failure (ADHF). New oral anticoagulants (rivaroxaban, apixaban, dabigatran) are alternatives to VKA, such as warfarin. In post hoc analysis of ROCKET AF trial, 63.7% patients had HF and treatment-related outcomes were similar in patients with and without HF (Circulation HF. 2013; 6:740-7). So rivaroxaban 20 mg daily (or 15 mg daily in patients with creatinine clearance 30-49 mL/min) was safe in nonvalvular AF patients with HF. However, the clinical effect and safety of rivaroxaban were largely unknown in acute decompensated heart failure (ADHF) patients with atrial fibrillation (AF). ROAD HF-AF is the exploratory study to assess the change of surrogate markers (hsTn, d-dimer) when treated with rivaroxaban vs. warfarin and to strengthen the basis for future biomarker-based therapy in ADHF patients

Official Title
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Rivaroxaban Once Daily Versus Dose-adjusted Vitamin K Antagonist on the Biomarkers in Acute Decompensated Heart Failure and Atrial Fibrillation (ROAD HF-AF)

Conditions
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Acute Heart Failure

Intervention / Treatment
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* Drug: Rivaroxaban
* Drug: Warfarin + LMWH


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:Hospitalized patients with a primary diagnosis of ADHF with AF One of the following criteria and LVEF ≤ 40% (at least 1 year before admission or admission) dyspnea at rest tachypnea; a respiratory rate > 20/min rales pulmonary edema on chest X-ray Exclusion Criteria: History of increased bleeding risk (like ROCKET AF exclusion criteria) Contraindication to anti-coagulation therapy ACS diagnosis Hospitalization plan for PCI, coronary artery bypass graft surgery, other cardiac invasive interventions (e.g. catheter ablation, pacemaker, CRT, ICD implantation) Currently on dual anti-platelet therapy (aspirin + ADP receptor antagonist) or single antiplatelet therapy with a novel AP (e.g. Ticagrelor, Prasugrel) Cardiogenic shock (systolic blood pressure, SBP, < 80 mmHg) Patients with CrCl < 30 ml/min using creatinine-based CKD-EPI equations Elevated liver enzymes (3 times over upper reference limit) or liver cirrhosis Uncontrolled hypertension (SBP > 180 mmHg) Allergy, adverse drug reaction, hypersensitivity to rivaroxaban or warfarin Life expectancy < 6 months (e.g. metastatic malignancy) Pregnancy, or women of childbearing age

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: warfarin vs. rivaroxaban
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivaroxaban<br>Rivaroxaban | Drug: Rivaroxaban<br>* Rivaroxaban 20mg qd (15mg qd when CrCl 30-49 ml/min using creatinine-based CKD-EPI equations) for 6 months<br>|
| Active Comparator: Warfarin<br>warfarin + enoxaparin | Drug: Warfarin + LMWH<br>* dose-adjusted warfarin (target INR 2-3) for 6 months + LMWH (enoxaparin 1 mg/kg q12h for a few days until INR target achieved) if indicated<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the change of high sensitive troponin | The maximum hsTn value change from baseline to during hospitalization | Baseline to 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1) the change of hish sensitive troponin | 1) The change from baseline in hsTn on Day2, day4, day7 (or discharge), and follow-up visits at 1 month, 6 months | 1) On admission, hospital day #2, hospital day #4, hospital day #7 or discharge, 1 month/6month after discharge | 
| 2) the change of D-dimer | 2) D-dimer change from baseline during hospitalization (day2, day4, day7 or discharge) & follow-up visits at 1, 6 months | 2) On admission, hospital day #2, hospital day #4, hospital day #7 or discharge, 1 month/6month after discharge | 
| 3) the change of NT-proBNP | 3) TAT complex, PAI-1, hsCRP, NT-proBNP, sST2, galectin-3, cystatin C, NGAL, NAG change from baseline to day7 or discharge & 1,6 months after discharge | 3) On admission, hospital day #7 or discharge, 1 month/6month after discharge | 
| 4) bleeding event | 4) Incidence proportion and rate of major/minor bleeding during the study | 4) On admission, hospital day #2, hospital day #4, hospital day #7 or discharge, 1 month/3month/6month after discharge | 
| 5) hospital stay | 5) Length of hospital stay | 5) The duration of hospital stay, average 7 days | 
| 6) all-cause mortality | 6) Incidence proportion of in-hospital all-cause death cases | 6) 6 months after hospitalization | 
| 7) all-cause hospitalization & mortality | 7) Time to the first composite event of all-cause mortality or cardiovascular re-hospitalization | 7) 6 months after hospitalization |