住院的中重度 COVID-19 患者中中等剂量依诺肝素：一项 INHIXACOVID19 的 II 期单臂先导研究。
Intermediate dose enoxaparin in hospitalized patients with moderate-severe COVID-19: a pilot phase II single-arm study, INHIXACOVID19.
机构信息
Angiology and Blood Coagulation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, Bologna, Italy.
Angiology and Blood Coagulation Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
出版信息
BMC Infect Dis. 2023 Oct 24;23(1):718. doi: 10.1186/s12879-023-08297-7.
BACKGROUND
Randomized clinical trials in non-critically ill COVID-19 patients showed that therapeutic-dose heparin increased survival with reduced organ support as compared with usual-care thromboprophylaxis, albeit with increased bleeding risk. The purpose of the study is to assess the safety of intermediate dose enoxaparin in hospitalized patients with moderate to severe COVID-19.
METHODS
A phase II single-arm interventional prospective study including patients receiving intermediate dose enoxaparin once daily according to body weight: 60 mg for 45-60 kg, 80 mg for 61-100 kg or 100 mg for > 100 kg for 14 days, with dose adjustment according to anti-factor Xa activity (target range: 0.4-0.6 UI/ml); an observational cohort (OC) included patients receiving enoxaparin 40 mg day for comparison. Follow-up was 90 days. Primary outcome was major bleeding within 30 and 90 days after treatment onset. Secondary outcome was the composite of all-cause 30 and 90-day mortality rates, disease severity at the end of treatment, intensive care unit (ICU) admission and length of ICU stay, length of hospitalization. All outcomes were adjudicated by an independent committee and analyzed before and after propensity score matching (PSm).
RESULTS
Major bleeding was similar in IC (1/98 1.02%) and in the OC (none), with only one event observed in a patient receiving concomitantly anti-platelet therapy. The composite outcome was observed in 53/98 patients (54%) in the IC and 132/203 (65%) patients in the OC (p = 0.07) before PSm, while it was observed in 50/90 patients (55.6%) in the IC and in 56/90 patients (62.2%) in the OC after PSm (p = 0.45). Length of hospitalization was lower in the IC than in OC [median 13 (IQR 8-16) vs 14 (11-21) days, p = 0.001], however it lost statistical significance after PSm (p = 0.08). At 30 days, two patients had venous thrombosis and two pulmonary embolism in the OC. Time to first negative RT-PCR were similar in the two groups.
CONCLUSIONS
Weight adjusted intermediate dose heparin with anti-FXa monitoring is safe with potential positive impact on clinical course in COVID-19 non-critically ill patients.
TRIAL REGISTRATION
The study INHIXACOVID19 was registred on ClinicalTrials.gov with the trial registration number (TRN) NCT04427098 on 11/06/2020.
背景
在非危重新冠肺炎患者中进行的随机临床试验表明，与常规治疗的血栓预防相比，治疗剂量的肝素可增加生存率并减少器官支持，但出血风险增加。本研究的目的是评估中等剂量依诺肝素在中重度 COVID-19 住院患者中的安全性。
方法
这是一项 II 期单臂干预性前瞻性研究，包括根据体重接受中等剂量依诺肝素的患者：45-60kg 给予 60mg，61-100kg 给予 80mg，>100kg 给予 100mg，每日一次，根据抗因子 Xa 活性（目标范围：0.4-0.6 UI/ml）调整剂量；观察队列（OC）包括接受依诺肝素 40mg/天治疗的患者作为对照。随访 90 天。主要结局是治疗开始后 30 天和 90 天内的主要出血。次要结局是所有原因的 30 天和 90 天死亡率、治疗结束时疾病严重程度、入住重症监护病房（ICU）和 ICU 住院时间、住院时间的复合结果。所有结果均由独立委员会进行裁定，并在进行倾向评分匹配（PSm）之前和之后进行分析。
结果
IC（1/98，1.02%）和 OC（无）的主要出血相似，仅在同时接受抗血小板治疗的患者中观察到一例出血事件。在 PSm 之前，IC 中 53/98 例（54%）和 OC 中 132/203 例（65%）患者发生复合结局（p=0.07），而 PSm 后 IC 中 50/90 例（55.6%）和 OC 中 56/90 例（62.2%）患者发生复合结局（p=0.45）。IC 中的住院时间中位数为 13（IQR 8-16）天，而 OC 中为 14（11-21）天，IC 中的住院时间低于 OC（p=0.001），但 PSm 后差异无统计学意义（p=0.08）。在 30 天时，OC 中有两名患者出现静脉血栓形成，两名患者出现肺栓塞。两组的首次 RT-PCR 阴性时间相似。
结论
根据体重调整的中等剂量肝素联合抗 FXa 监测是安全的，对 COVID-19 非危重症患者的临床病程可能有积极影响。
试验注册
该研究 INHIXACOVID19 于 2020 年 6 月 11 日在 ClinicalTrials.gov 上注册，注册号为（TRN）NCT04427098。
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