H-REPLACE: Safety and Efficacy of LMWH Versus Rivaroxaban in Chinese Patients Hospitalized With Acute Coronary Syndrome

Sponsor

Second Xiangya Hospital of Central South University (Other)

Overall Status

Completed

CT.gov ID

NCT03363035

Collaborator

(none)

2,055

Enrollment

Locations

Arms

46.5

Actual Duration (Months)

85.6

Patients Per Site

1.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

H-REPLACE trial is a prospective, randomized, open-label, active-controlled, multicenter study in participants with ACS (STEMI or NSTEMI, unstable angina). All eligible participants receiving background treatment of aspirin plus clopidogrel or ticagrelor will be randomly assigned to either oral rivaroxaban 2.5 mg twice daily or rivaroxaban 5 mg twice daily or subcutaneous (SC) enoxaparin 1mg/kg twice daily until hospital discharge or 12 hours before revascularization therapy for a maximum of 8 days.

Condition or Disease	Intervention/Treatment	Phase
Acute Coronary Syndrome Myocardial Infarction Myocardial Ischemia Unstable Angina	Drug: Rivaroxaban 2.5 mg Drug: Rivaroxaban 5 mg Drug: Enoxaparin	Phase 4

Detailed Description

Acute coronary syndrome (ACS) is a serious and life threatening condition. Anticoagulation during the acute phase of ACS is effective in reducing ischaemic events. The combination regimen of anticoagulation with dual antiplatelet therapy (DAPT) strategy is more effective than either treatment alone. The most widely used parenteral anticoagulation agent in ACS patients is enoxaparin (1 mg/kg administered subcutaneously twice daily).

Rivaroxaban is a novel oral anticoagulant with potent anti-Xa activity, which might be an attractive alternative drug to enoxaparin. In fact, rivaroxaban was consistently shown to be non-inferior to enoxaparin therapy aimed to reduce the event of recurrent venous thromboembolism. Moreover, the bleeding risk of low dose of rivaroxaban is low and acceptable (1.0-2.5%) during the acute phase of ACS as shown by ATLAS ACS-TIMI 46 Trial, and the bleeding risk of enoxaparin during the acute phase of ACS was 4.3% as shown in a meta-analysis.

We thus hypothesized that the safety and efficacy of rivaroxaban during the acute phase of ACS is non-inferior to enoxaparin and designed this prospective, randomized, open-label, active-controlled, multicenter study in participants with ACS (STEMI or NSTEMI or unstable angina). All eligible participants receiving background treatment of aspirin plus clopidogrel or ticagrelor will be randomly assigned to either receive oral rivaroxaban 2.5 mg twice daily or oral rivaroxaban 5 mg twice daily or enoxaparin 1mg/kg twice daily SC until hospital discharge or 12 hours before revascularization therapy for a maximum of 8 days.

Study Design

Study Type:

Interventional

Actual Enrollment :

2055 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Safety and Efficacy of Low Molecular Weight Heparin Versus Rivaroxaban in Chinese Patients Hospitalized With Acute Coronary Syndrome(H-REPLACE): a Prospective, Randomized, Open-label, Active-controlled, Multicenter Trial

Actual Study Start Date :

Jan 15, 2018

Actual Primary Completion Date :

Nov 11, 2021

Actual Study Completion Date :

Nov 30, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rivaroxaban 2.5 mg One 2.5 mg rivaroxaban tablet twice daily	Drug: Rivaroxaban 2.5 mg One 2.5 mg rivaroxaban tablet twice daily until hospital discharge or 12 hours before revascularization therapy for a maximum of 8 days. Other Names: Xarelto
Experimental: Rivaroxaban 5 mg One 5 mg rivaroxaban tablet twice daily	Drug: Rivaroxaban 5 mg One 5 mg rivaroxaban tablet twice daily until hospital discharge or 12 hours before revascularization therapy for a maximum of 8 days. Other Names: Xarelto
Active Comparator: enoxaparin Enoxaparin 1mg/kg twice daily SC twice daily	Drug: Enoxaparin Enoxaparin 1mg/kg twice daily SC until hospital discharge or 12 hours before revascularization therapy for a maximum of 8 days. Other Names: LWMH

Arm

Intervention/Treatment

Experimental: Rivaroxaban 2.5 mg

One 2.5 mg rivaroxaban tablet twice daily

Drug: Rivaroxaban 2.5 mg

One 2.5 mg rivaroxaban tablet twice daily until hospital discharge or 12 hours before revascularization therapy for a maximum of 8 days.

Other Names:

Xarelto

Experimental: Rivaroxaban 5 mg

One 5 mg rivaroxaban tablet twice daily

Drug: Rivaroxaban 5 mg

One 5 mg rivaroxaban tablet twice daily until hospital discharge or 12 hours before revascularization therapy for a maximum of 8 days.

Other Names:

Xarelto

Active Comparator: enoxaparin

Enoxaparin 1mg/kg twice daily SC twice daily

Drug: Enoxaparin

Enoxaparin 1mg/kg twice daily SC until hospital discharge or 12 hours before revascularization therapy for a maximum of 8 days.

Other Names:

LWMH

Outcome Measures

Primary Outcome Measures

Primary Safety Outcome: The percentage of patients with minor, clinically relevant non-major (CRNM) and major bleeding [International Society on Thrombosis and Haemostasis (ISTH) definition of bleeding] [From the time of randomization (Day 1) up to completion of the follow up phase (Month 6)]
The percentage of patients with the first occurrence of bleeding event according to ISTH definition. The statistical analysis was based on the occurrence of the bleeding event from randomization to Month 6.
Primary Efficacy Outcome: The percentage of patients with the composite endpoint of cardiac death, myocardial infarction, re-revascularization or stroke. [From the time of randomization (Day 1) up to completion of the follow up phase (Month 6).]
The percentage of patients with the first occurrence of the composite of death, myocardial infarction, re-revascularization or stroke. The statistical analysis was based on the time from randomization to the first occurrence of the event up to Month 6.

Secondary Outcome Measures

The percentage of patients with the cardiac-related rehospitalization. [From the time of randomization (Day 1) up to completion of the follow up phase (Month 6).]
The percentage of patients with the cardiac-related rehospitalization. The statistical analysis was based on the time from randomization to the first occurrence of the event up to Month 6.
The percentage of patients with the all-cause death. [From the time of randomization (Day 1) up to completion of the follow up phase (Month 6).]
The percentage of patients with the all-cause death. The statistical analysis was based on the time from randomization to the first occurrence of the event up to Month 6.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female aged ≥ 18 years
Diagnosed with ACS (STEMI, NSTEMI, unstable angina)
With an indication for short-term combination use of DAPT and enoxaparin.

Exclusion Criteria:

Already received thrombolytic therapy or revascularization or needing revascularization therapy in 12 hours.
With platelet glycoprotein IIb/IIIa receptor antagonist therapy.
With increased bleeding risk, such as but not limited to, active internal bleeding, clinically significant bleeding, bleeding at a non-compressible site, or bleeding diathesis within 30 days of randomization; platelet count less than 90,000/μL at screening; intracranial hemorrhage; major surgery, biopsy of a parenchymal organ, or serious trauma within 30 days before randomization; clinically significant gastrointestinal bleeding within 12 months before randomization; an international normalized ratio known to be>1.5 at the time of screening; abciximab bolus or infusion within the preceding 8 hours, or an eptifibatide or tirofiban bolus or infusion within the past 2 hours preceding randomization; or any other condition known to increase the risk of bleeding.
Severe concomitant condition or disease, such as cardiogenic shock at the time of randomization, ventricular arrhythmia refractory to treatment at the time of randomization, calculated creatinine clearance b 30 mL/min at screening, known significant liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis), or liver function test abnormalities (confirmed with repeat testing) which would require study drug discontinuation, i.e., aminoleucine transferase (ALT) >5 × the upper limit of the normal range (ULN) or ALT >3 × ULN plus total bilirubin >2 × ULN, prior ischemic stroke or transient ischemia attack, anemia (i.e., hemoglobin < 10 g/ dL＝ at screening, known clinical history of human immunodeficiency virus infection at screening, substance abuse (drug or alcohol) problem within the previous 6 months or any severe condition such as cancer that would limit life expectancy to less than 6 months.
With an indication for long-term oral anticoagulation therapy such as atrial fibrillation, venous thromboembolism, or prior placement of a mechanical heart valve.
With other contraindications for use of rivaroxaban and enoxaparin.
Enrolled in another clinical study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The First People's Hospital of Changde City	Changde	Hunan	China	415003
2	Changsha Central Hospital	Changsha	Hunan	China	410004
3	Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University	Changsha	Hunan	China	410005
4	The Forth Hospital of Changsha	Changsha	Hunan	China	410006
5	The First Affiliated Hospital of Hunan University of Chinese Medicine	Changsha	Hunan	China	410007
6	The Second Xiangya Hospital of Central South University	Changsha	Hunan	China	410011
7	The First Hospital of Changsha	Changsha	Hunan	China	410013
8	The Third Xiangya Hospital of Central South University	Changsha	Hunan	China	410013
9	The Third Hospital of Changsha	Changsha	Hunan	China	410015
10	The Second People's Hospital of Hunan Province	Changsha	Hunan	China	430100
11	The First People's Hospital of Chenzhou	Chenzhou	Hunan	China	423000
12	The First Affiliated Hospital of University of South China	Hengyang	Hunan	China	421001
13	The Second Affiliated Hospital of University of South China	Hengyang	Hunan	China	421001
14	The First Affiliated Hospital of Hunan University of Medicine	Huaihua	Hunan	China	418000
15	The First People's Hospital of Huaihua	Huaihua	Hunan	China	418000
16	The First Affiliated Hospital of Jishou University	Jishou	Hunan	China	416000
17	The First People's Hospital of Loudi	Loudi	Hunan	China	417000
18	The Central Hospital of Shaoyang	Shaoyang	Hunan	China	422000
19	Xiangtan Central Hospital	Xiangtan	Hunan	China	411413
20	Xiangxiang People's Hospital	Xianxiang	Hunan	China	411400
21	Yiyang Central Hospital	Yiyang	Hunan	China	413000
22	Yongzhou First People's Hospital	Yongzhou	Hunan	China	425000
23	The First People's Hospital of Yueyang	Yueyang	Hunan	China	414000
24	Zhuzhou Central Hospital	Zhuzhou	Hunan	China	412007