Effect of Rivaroxaban vs Enoxaparin on Major Cardiac Adverse Events and Bleeding Risk in the Acute Phase of Acute Coronary Syndrome
Authors: Zhou Shenghua , Xiao Yichao , Zhou Chonglun , Zheng Zhaofen , Jiang Weihong , Shen Qiang , Zhu Can , Pan Hongwei , Liu Changhui , Zeng Gaofeng , Ge Liangqing , Zhang Yumin , Ouyang Zewei , Fu Guang , Pan Gang , Chen Feng , Huang Lihong , Liu Qiming ,   H-REPLACE Investigators, Hu Xinqun , Fang Zhenfei , Tang Liang , Li Xuping , Zhu Zhaowei , Tai Shi , Tu Tao , Yang Hui , He Yuhu , Chen Mingxian , Peng Daoquan , Zhao Yanshu , Xu Danyan , Tang Jianjun , Li Jiang , Chen Yaqin , Li Yi , Luo Xiaolan , Huang Yong , Xiang Jianqiang , Guan Qinglin , Li Xinyang , Yi Xiaojun , Tan Fang , Liu Yan , Pan Jiang , Peng Jianqiang , Yan Sulan , Liu Zhengyu , Cui Bo , Wang Peng , Tang Yi , Wen Juan , Liu Hong , Weng Chunyan , Wu Xi , Yu Jingjia , Yang Qiong , Peng Liping , Li Anying , Zhang Zhihui , Zhou Xiaowei , Tan Huaqing , Chen Jie , Yang Zhiyuan , Liang Zhizhong , Tang Xiangyu , Chen Sha , Zeng Lan , Wu Yingtao , Chen Guangyao , Yan Dihua , Zhou Lianghui , Yuan Siqin , Wu Rong , Zhou Pei , Fu Yuzhen , Huang Youliang , Tang Wei , Nie Yang , Xiang Hongju , Chen Wei , Yang Zhiyong , Wu Yue , Deng Haishui , Lei Ming , Zhang Bailing , Xiang Xing , Xue Bingqing , Xiong Liping , Xu Xiping , Feng Xiaojian , Zhao Jianhua , Lu Yonghua , Li Zhengzai , Zhou Bo , Li Cheng , Deng Zibin , Feng Hongda , Zhang Xibin , Wang Guoli , Chen Zhi , Zeng Wenxuan , Shen Di , Hu Xiangyong , Chen Xuemei , Qin Zuoan , Huang Sulan , Guo Ning , Zhang Zhixiang , Chen Kun , Gong Bingxing , Yin Min , Qin Tao , Hu Tao , Yu Jiangbiao , Zhang Ting , Guo Xingcheng , Peng Hui , Yin Minming , Zhou Huaineng , Luo Li , Xiao Xiaoxia , Quan Yong , Liang Weifen , Wu Yang , Chen Hang , Shi Wei , Liu Aiying , Liu Yijian , Ruan Guiyun , Liu Peng , Luo Canxiang , He Lin , Deng Li , Sun Shayan , Yang Shuo , Wang Sha , Long Songbing , Duan Yizhu , Luo Jin , Xue Zhengjie , Chen Luzhu , Guo Caiyan , Yin Yongjun , Wang Yanbo , Ouyang Fan , Guo Shuhong , Liu Weiqing , Liao Chunfeng , Lin Dongsheng , Chen Huijuan , Ma Lixia , Luo Hui , Wu Jianfeng , Yang Chao , Liu Yang , Qin Yingnan , Liu Fangyao , Xu Jianqiang , Tang Juan , Tang Yixin , Hu Hengjing , Zhou Jiming , Yang Jingyong , Deng Tingting , Xiao Ping , Liu Jun , Guo Shenyi , Liu Wenjie , Zhang Xing , Li Zhihong , Zeng Renhua , Zhou Zhen , Bao Jianhong , Zhou Ye , Wang Xiaojuan , Huang He , Zhu Yunlong , Zhao Wenjiao , Wu Xianming , Cai Ming , Liu Fan , Jiang Luping , Li Zehua , Peng Songquan , Jin Qiao , Chen Chun , Hu Lu , Zhou Ting , Wu Pengcui , Long Xiao , Huang Yuyan , Xie Hebin , Yang Tao , Ouyang Shao , Liu Xiang , Hu Song , Xing Zhenhua , Zeng Jianping , Zhang Yi 
Published: February 2023

Importance

Parenteral enoxaparin is a preferred anticoagulant used in the acute phase for patients with acute coronary syndrome (ACS). The safety and efficacy of short-term low-dose rivaroxaban in this clinical setting remain unknown.

Objective

To compare the safety and efficacy of rivaroxaban vs enoxaparin in the acute phase of ACS.

Design, Setting, and Participants

This multicenter, prospective, open-label, active-controlled, equivalence and noninferiority trial was conducted from January 2017 through May 2021 with a 6-month follow-up at 21 hospitals in China. Participants included patients with ACS missing the primary reperfusion window or before selective revascularization. Data were analyzed from November 2021 to November 2022.

Interventions

Participants were randomized 1:1:1 to oral rivaroxaban 2.5 mg or 5 mg or 1 mg/kg subcutaneous enoxaparin twice daily in addition to dual antiplatelet therapy (DAPT; aspirin 100 mg and clopidogrel 75 mg once daily) for a mean of 3.7 days.

Main Outcomes and Measures

The primary safety end point was bleeding events, as defined by the International Society on Thrombosis and Haemostasis, and the primary efficacy end point was major adverse cardiovascular events (MACEs), including cardiac death, myocardial infarction, rerevascularization, or stroke during the 6-month follow-up.

Results

Of 2055 enrolled patients, 2046 (99.6%) completed the trial (mean [SD] age 65.8 [8.2] years, 1443 [70.5%] male) and were randomized to enoxaparin (680 patients), rivaroxaban 2.5 mg (683 patients), or rivaroxaban 5 mg (683 patients). Bleeding rates were 46 patients (6.8%) in the enoxaparin group, 32 patients (4.7%) in the rivaroxaban 2.5 mg group, and 36 patients (5.3%)in the rivaroxaban 5 mg group (rivaroxaban 2.5 mg vs enoxaparin: noninferiority hazard ratio [HR], 0.68; 95% CI, 0.43 to 1.07; P = .005; rivaroxaban 5 mg vs enoxaparin: noninferiority HR, 0.88; 95% CI, 0.70 to 1.09; P = .001). The incidence of MACEs was similar among groups, and noninferiority was reached in the rivaroxaban 5 mg group (HR, 0.60; 95% CI, 0.31 to 1.16, P = .02) but not in the rivaroxaban 2.5 mg group (HR, 0.68; 95% CI, 0.36 to 1.30; P = .05) compared with the enoxaparin group.

Conclusions and Relevance

In this equivalence and noninferiority trial, oral rivaroxaban 5 mg showed noninferiority to subcutaneous enoxaparin (1 mg/kg) for patients with ACS treated with DAPT during the acute phase. Results of this feasibility study provide useful information for designing future randomized clinical trials with sufficient sample sizes.

Trial Registration

ClinicalTrials.gov Identifier: NCT03363035