A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure

Phase 3

Completed

Conditions: Coronary Artery Disease
Heart Failure

Interventions: Drug: Placebo
Drug: Rivaroxaban
Other: Standard of care for heart failure and coronary artery disease

Registration Number: NCT01877915

Lead Sponsor: Janssen Research & Development, LLC

Brief Summary: The purpose of this study is to assess the effectiveness and safety of rivaroxaban compared with placebo (inactive medication), in reducing the risk of death, myocardial infarction or stroke in participants with heart failure and significant coronary artery disease following an episode of decompensated heart failure.

Detailed Description: This is a randomized (the study medication is assigned by chance), double-blind (neither physician nor participant knows the identity of the assigned treatment), parallel group (each participant group receives different treatments simultaneously), event driven (the study duration is determined by the time taken for a specific number of events to occur), multicenter study to assess the effectiveness and safety of rivaroxaban compared with placebo, in reducing the risk of death, myocardial infarction or stroke in participants with heart failure and significant coronary artery disease following an episode of decompensated heart failure. Participants will be randomly assigned in a 1:1 ratio to receive either rivaroxaban or placebo (each in addition to standard of care for heart failure and coronary artery disease as prescribed by their managing physician). The study will consist of a screening phase, a double-blind treatment phase, and a follow-up after the sponsor-announced global treatment end date (GTED, defined as the date when 1200 primary efficacy outcome events are predicted to have occurred). The double-blind treatment phase is estimated to last for 6 to 54 months. Participants will discontinue study drug after taking both their morning and evening doses on the GTED and will return to the study center for the end-of-study visit (between 15 and 45 days but no sooner than 15 days after the GTED). Patient safety will be monitored throughout the study. The average study duration for participants is expected to be approximately 29 months. The study drug, rivaroxaban, is approved in the United States and in multiple countries around the world for the prevention and treatment of a number of thrombosis-mediated conditions.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 5081

Inclusion Criteria

Must have symptomatic heart failure for at least 3 months prior to Screening
Participants must have an episode of decompensated heart failure (index event) requiring (a) an overnight stay [that is, staying past midnight] in a hospital, emergency department, or medical facility with the capability of treating with intravenous medications and observing heart failure patients before randomization or (b) an unscheduled outpatient visit to a heart failure management center, where parenteral therapy is required for heart failure stabilization. An episode of decompensated heart failure is defined as symptoms of worsening dyspnea or fatigue, objective signs of congestion such as peripheral edema or ascites, and/or adjustment of pre-hospitalization/outpatient visit heart failure medications. Participants are eligible for randomization at discharge from the facility treating the index event and up to 30 days after discharge if they are in stable condition
Must have a documented left ventricular ejection fraction (LVEF) of less than or equal to 40 percent (%) within 1 year before randomization
Must have evidence of significant coronary artery disease
Must be medically stable in terms of their heart failure clinical status at the time of randomization
Must have a brain natriuretic peptide (BNP) level greater than or equal to (>=) 200 picogram per milliliter (pg/mL) or N-terminal-proBNP (NT-proBNP) level >=800 pg/mL (preferred assay) during the Screening period and before randomization

Exclusion Criteria

Any condition that, in the opinion of the investigator, contraindicates anticoagulant therapy or would have an unacceptable risk of bleeding, such as, but not limited to, active internal bleeding, clinically significant bleeding, bleeding at a noncompressible site, or bleeding diathesis within 28 days of randomization
Severe concomitant disease such as (a) atrial fibrillation (AFib) or another condition that requires chronic anticoagulation (participants with isolated transient AFib may be allowed at the discretion of the treating physician investigator) and (b) Documented acute myocardial infarction (MI) during index event
Prior stroke within 90 days of randomization
Has been hospitalized for longer than 21 days during the index event
Planned intermittent outpatient treatment with positive inotropic drugs administered intravenously

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rivaroxaban 2.5 mg	Standard of care for heart failure and coronary artery disease	Each participant will receive 2.5 mg of rivaroxaban twice daily with standard of care for heart failure and coronary artery disease (as prescribed by the participant's managing physician).
Placebo	Standard of care for heart failure and coronary artery disease	Each participant will receive matching placebo twice daily with standard of care for heart failure and coronary artery disease (as prescribed by the participant's managing physician).
Placebo	Placebo	Each participant will receive matching placebo twice daily with standard of care for heart failure and coronary artery disease (as prescribed by the participant's managing physician).
Rivaroxaban 2.5 mg	Rivaroxaban	Each participant will receive 2.5 mg of rivaroxaban twice daily with standard of care for heart failure and coronary artery disease (as prescribed by the participant's managing physician).

Primary Outcome Measures

Name	Time	Method
Event Rate of All-Cause Mortality, Myocardial Infarction (MI), or Stroke	Up to Global treatment end date (approximately 54 months)	Event Rate of all-cause mortality (ACM), MI, or stroke were assessed. Event rate estimated based on the time to the first occurrence of the event were reported in the study. Event Rate / (100 patient \[pt\]-year \[yr\]) = 100\*n/(total risk exposure), where n is the number of events.
Event Rate of Either Fatal Bleeding or Bleeding Into a Critical Space With Potential for Permanent Disability	Up to 227 Weeks	Event rate of either fatal bleeding or bleeding into critical space with potential for permanent disability were assessed. Fatal bleeding event was death within 7 days after a bleeding event which required hospitalization or met International Society on Thrombosis and Haemostasis(ISTH) major bleeding definition criteria. Fatal bleeding events included those met criteria in 3 categories: 1: Any ISTH major bleeding event consider primary cause of death by investigator; 2: Any ISTH major bleeding event not considered to be primary cause of death by investigator but resulted in death within 7 days;3: Any bleeding event resulted in hospital stay and death within 7 days. Bleeding into critical space with potential for permanent disability included 7 critical spaces: intracranial, intraspinal, intraocular. Event rate estimated based on time to first occurrence of event were reported in the study. Event Rate / (100 pt-yr) = 100\*n/(total risk exposure), where n is the number of events.

Secondary Outcome Measures

Name	Time	Method
Event Rate of Cardio Vascular Death or Re-Hospitalization for Worsening of Heart Failure (RHHF)	Up to Global treatment end date (approximately 54 months)	Event rate of cardio vascular (CV) death or re-hospitalization for worsening of heart failure were assessed. Event rate estimated based on the time to the first occurrence of the event were reported in the study. Event Rate / (100 pt-yr) = 100\*n/(total risk exposure), where n is the number of events.
Event Rate of Cardio Vascular Death	Up to Global treatment end date (approximately 54 months)	Event rate of cardio vascular death were assessed. CV death included deaths due to spontaneous bleeding, MI, stroke, worsening HF and arrhythmias, death due to CV procedures and sudden death. Event rate estimated based on the time to the first occurrence of the event were reported in the study. Event Rate / (100 pt-yr) = 100\*n/(total risk exposure), where n is the number of events.
Event Rate of Re-Hospitalization for Worsening of Heart Failure	Up to Global treatment end date (approximately 54 months)	Event rate of re-hospitalization for worsening of heart failure were assessed. Event rate estimated based on the time to the first occurrence of the event were reported in the study. Event Rate / (100 pt-yr) = 100\*n/(total risk exposure), where n is the number of events.
Event Rate of Re-Hospitalization for Cardio Vascular Events (RHCV)	Up to Global treatment end date (approximately 54 months)	Event rate due to cardio vascular events were assessed. Hospitalization for a CV Event required that participants be hospitalized (in-patient or emergency department) for greater than 24 hours and must have met the following criterion:Discharge summary with primary reason for admission listed as CV in nature (example, bleeding, arrhythmia, ACS, MI) other than HF which was captured in the HF re-hospitalization. Event rate estimated based on the time to the first occurrence of the event were reported in the study. Event Rate / (100 pt-yr) = 100\*n/(total risk exposure), where n is the number of events.
Event Rate of All-Cause Mortality (ACM) or Re-Hospitalization for Worsening Heart Failure	Up to Global treatment end date (approximately 54 months)	Event rate of all-Cause Mortality (ACM) or re-Hospitalization for worsening heart failure were assessed. Event rate estimated based on the time to the first occurrence of the event were reported in the study. Event Rate / (100 pt-yr) = 100\*n/(total risk exposure), where n is the number of events.
Event Rate of Bleeding Events That Requiring Hospitalization	Up to 227 Weeks	Event rate of bleeding events and required Hospitalization were assessed. Event rate estimated based on the time to the first occurrence of the event were reported in the study. Event Rate / (100 pt-yr) = 100\*n/(total risk exposure), where n is the number of events.
Event Rate of International Society on Thrombosis and Haemostasis (ISTH) Major Bleeding Event	Up to 227 Weeks	Event rate of ISTH major bleeding event were assessed. Event rate estimated based on the time to the first occurrence of the event were reported in the study. Event Rate / (100 pt-yr) = 100\*n/(total risk exposure), where n is the number of events.