意大利一項3,451患者的研究表明羥氯喹顯著降低感染中共病毒住院患者死亡率達30%

意大利的CORIST多中心臨床試驗合作項目於2020年8月25日在《歐洲內科學雜誌》上發表了他們的一項最新研究。他們對意大利的住院感染中共病毒患者的死亡率進行了回顧性分析。根據意大利3,451名住院患者群組數據,相比未接受羥氯喹治療的患者,接受羥氯喹治療的患者死亡風險降低了約30%。

閱讀英文全文

Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study

對感染中共病毒的住院患者使用羥氯喹與死亡率的降低呈相關性:意大利CORIST回顧性多中心觀察研究的發現

The COVID-19 RISK and Treatments (CORIST) Collaboration members

Abstract 摘要

Background 背景

Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19

羥氯喹(HCQ)被提議作為COVID-19的潛在治療方法

Objective 目的

We set-up a multicenter Italian collaboration to investigate the relationship between HCQ therapy and COVID-19 in-hospital mortality.

我們建立了一個意大利多中心臨床試驗合作項目,以研究HCQ治療與COVID-19住院死亡率之間的關係。

Methods 方法

In a retrospective observational study, 3,451 unselected patients hospitalized in 33 clinical centers in Italy, from February 19, 2020 to May 23, 2020, with laboratory-confirmed SARS-CoV-2 infection, were analyzed. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received HCQ with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores, with the addition of subgroup analyses.

在一項回顧性觀察研究中,分析了2020年2月19日至2020年5月23日,在意大利33個臨床中心住院的3451名未經選擇的SARS-CoV-2實驗室確診感染的患者。事件時間分析的主要終點是住院死亡,將接受HCQ治療的患者與未接受HCQ治療的患者進行比較。我們使用逆向機率的多變量考克斯比例風險模型,來統計以傾向評分匹配權重的治療,並加上對分組的分析。

Results 結果

Out of 3,451 COVID-19 patients, 76.3% received HCQ. Death rates (per 1,000 person-days) for patients receiving or not HCQ were 8.9 and 15.7, respectively. After adjustment for propensity scores, we found 30% lower risk of death in patients receiving HCQ (HR=0.70; 95%CI: 0.59 to 0.84; E-value=1.67). Secondary analyses yielded similar results. The inverse association of HCQ with inpatient mortality was particularly evident in patients having elevated C-reactive protein at entry.

在3451名COVID-19患者中,76.3%接受了HCQ治療。接受與未接受HCQ的患者的死亡率(每千人/天)分別是8.9和15.7。調整傾向評分匹配後,我們發現接受HCQ的患者死亡風險降低30%(HR=0.70;95%CI:0.59至0.84;E值=1.67)。二次分析得出了類似的結果。HCQ與住院死亡率的反向關係在入院時C反應蛋白升高的患者中尤為明顯。

Conclusions 結論

HCQ use was associated with a 30% lower risk of death in COVID-19 hospitalized patients. Within the limits of an observational study and awaiting results from randomized controlled trials, these data do not discourage the use of HCQ in inpatients with COVID-19.

在COVID-19住院患者中,使用HCQ與死亡風險降低30%是關聯的。在觀察性研究和還在等待中的隨機對照試驗結果的範圍內,這些數據並不妨礙在COVID-19住院患者中使用HCQ。

1. Introduction 介紹

The aminoquinoline hydroxychloroquine (HCQ) has been extensively used in the treatment of malaria and is currently widely used to treat autoimmune diseases like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS), due to its immunomodulatory and anti-thrombotic properties [1]. More recently, a promising role of HCQ has been suggested in viral infections [2], since it directly inhibits viral entry and spread in several in vitro and in vivo models. Due to these properties, HCQ has been used in Ebola virus disease [3, 4], human immunodeficiency virus (HIV) infection [5], SARS-CoV-1 infection and the Middle East Respiratory Syndrome (MERS) [6, 7] and gained worldwide attention as a possible therapy in COVID-19 patients [8].

氨基喹啉羥氯喹(HCQ)已被廣泛用於治療瘧疾,由於其免疫調節和抗血栓形成的特性[1],目前廣泛用於治療自身免疫性疾病,如類風濕關節炎(RA)、系統性紅斑狼瘡(SLE)和抗磷脂綜合徵(APS)。最近,有人提出HCQ在病毒感染中的作用很有前景[2],因為它在一些體外和體內模型中直接抑制病毒的進入和傳播。由於這些特性,HCQ已用於埃博拉病毒疾病[34],人類免疫缺陷病毒(HIV)感染[5],SARS-CoV-1感染和中東呼吸綜合症(MERS)[67],並作為COVID-19患者的一種可能療法受到全世界的關注[8]。

HCQ might inhibit the intracellular glycosylation of ACE 2, the receptor used by the SARS-CoV-2 virus to enter the cells, resulting in a reduced ligand recognition and internalization of the virus [7] and exerting a possible protective role in SARS-CoV-2 infection. Moreover, due to its immunomodulatory, anti-inflammatory and anti-thrombotic effects, HCQ could also modulate the severity of the disease. However, the exact mechanism for the potential benefit in COVID-19 is largely speculative [9] and might be counterbalanced by adverse effects, mainly cardiovascular [10, 11], so that the net balance of this drug’s use remains to be established.

HCQ可能抑制ACE2的細胞內糖基化,即SARS-CoV-2病毒進入細胞的受體,從而降低病毒的配體識別和內化[7],並在SARS-CoV-2感染中可能發揮保護作用。此外,由於其免疫調節,抗炎和抗血栓作用,HCQ也可以調節疾病的嚴重程度。然而,對COVID-19的潛在益處的確切機制在很大程度上是推測性的[9],可能會被以心血管為主的不良反應所抵消[1011],因此,這種藥物使用的利弊仍有待確定。

The American Food and Drug Administration (FDA) allowed Chloroquine (CQ) phosphate and HCQ to be provided to certain hospitalized patients because these drugs may possibly help patients with severe COVID-19 [12]. The European Medicines Agency (EMA) authorized the use of CQ and HCQ for COVID-19 in clinical trials or as emergency use [13], while the Italian Drug Agency (AIFA) stated in this emergency phase that therapeutic use of HCQ might be considered in COVID-19 patients, both in those with mild presentation managed at home and in hospitalized patients [14]. In clinical practice, HCQ rather than chloroquine has been used because of its more potent antiviral properties and better safety profile [15].

美國食品和藥物管理局(FDA)允許向某些住院患者提供氯喹(CQ)磷酸鹽和HCQ,因為這些藥物可能會幫助嚴重的COVID-19患者[12]。歐洲藥品管理局(EMA)授權CQ和HCQ用於COVID-19的臨床試驗或應急使用[13],而意大利藥物管理局(AIFA)在這一緊急階段指出,COVID-19患者可以考慮使用HCQ進行治療,包括那些在家中管理的輕度表現和住院患者[14]。在臨床實踐中,由於HCQ具有更強的抗病毒特性和更好的安全性,所以一直在使用HCQ而不是氯喹[15]。

However, in the light of a recent publication [16], that was later retracted [17], on the lack of safety and efficacy of HCQ in the treatment for COVID-19 patients the Executive Group of the Solidarity Trial decided to implement a temporary pause of the HCQ arm within the trial as a precaution, while the safety data is being reviewed [18]. Similarly, the Italian drug Agency AIFA decided to suspend the authorization to use HCQ for COVID-19 treatment outside clinical trials [19].

然而,鑑於最近發表的一篇文章[16](後來又被收回[17])指出,HCQ在治療COVID-19患者方面缺乏安全性和有效性,團結試驗執行小組決定,作為預防措施,在審查安全性數據的同時,暫時暫停HCQ組的試驗[18]。同樣,意大利藥物機構AIFA決定暫停授權在臨床試驗之外使用HCQ治療COVID-19[19]。

Recent reviews of clinical trials or observational studies [20, 21, 22, 23, 24] have reported insufficient and often conflicting evidence on the benefits and harms of using HCQ to treat COVID-19 and concluded that as such, it was impossible to determine the balance of benefits to harm. Until now, although several trials had been started on the use of CQ and HCQ in COVID-19, only few of them have been published [25] on small numbers of patients or on surrogate endpoints or in exposed subjects for prophylaxis use [26].

最近對臨床試驗或觀察性研究[2021222324]的審查報告稱,關於使用HCQ治療COVID-19的益處和危害的證據不足,而且往往是相互矛盾的,因此,無法確定利弊權衡。到目前為止,雖然已經開始了幾項關於使用CQ和HCQ治療COVID-19的試驗,但只有少數試驗發表了[25],試驗對象為少量患者或代用終點或暴露受試者,用於預防[26]。

While waiting the results from ongoing randomized clinical trials (RCT) to define the efficacy in preventing hard endpoints of this treatment so widely used during the emergency phase of the COVID-19 pandemic, powered retrospective observational studies performed in different geographical and disease conditions may still be useful to shed light on this debate. Two retrospective observational studies, both conducted in the New York metropolitan region, did not report any significant association between HCQ use and rates of intubation or death [27, 28].

在等待正在進行的隨機臨床試驗(RCT)的結果來定義這種治療方法在預防COVID-19疫情的緊急階段被廣泛使用的硬性終點的有效性時,在不同的地理和疾病條件下進行的有動力的回顧性觀察研究可能仍然有助於闡明這一辯論。兩項回顧性觀察研究都是在紐約大都會地區進行的,沒有報告HCQ的使用與插管率或死亡率之間有任何顯著關聯[2728]。

No data are presently available from large cohorts of patients in Italy, which represents one of the most affected countries in terms of total deaths for COVID-19 in the world [29]. We undertook a multicenter Italian collaboration [30] to investigate the relationship between underlying risk factors and COVID-19 outcomes, and to evaluate the association between different drug therapy and disease severity and/or mortality. We report here the results obtained in 3,451 hospitalized COVID -19 patients receiving or not HCQ treatment.

目前沒有來自意大利大型患者群組的數據,意大利是世界上COVID-19總死亡人數最多的國家之一[29]。我們進行了一項意大利多中心臨床試驗合作項目[30],以研究潛在風險因素與COVID-19結果之間的關係,並評估不同藥物治療與疾病嚴重程度和/或死亡率之間的關聯。我們在此報告3451例住院COVID-19患者接受或未接受HCQ治療的結果。

2. Material and methods 材料和方法

2.1 Setting 設置

This national retrospective observational study was conceived, coordinated and analysed within the CORIST Project (ClinicalTrials.gov ID: NCT04318418, 30]. The study was approved by the institutional ethics board of the Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, and of all recruiting centres. Data for the present analyses were provided by 33 hospitals distributed throughout Italy (listed in the supplementary file). Acceptance to participate in the project or to provide data for the present analysis was not related to the use of CQ/HCQ. Each hospital provided data from hospitalized patients who had a positive test result for the SARS-CoV-2 virus at any time during their hospitalization from February 19 to May 23, 2020. The follow-up continued through May 29, 2020.

這項全國性的回顧性觀察研究是在CORIST項目中構思、協調和分析的(ClinicalTrials.gov)[ID:NCT04318418,30]。該項研究得到了波齊利市Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)Neuromed的機構倫理委員會,和所有應召中心的批准。本分析的數據由分布在意大利各地的33家醫院提供(在補充文件中列出)。是否接受參與該項目或為本分析提供數據與使用CQ/HCQ無關。每家醫院都提供了2020年2月19日至5月23日住院期間任何時候SARS-CoV-2病毒檢測結果為陽性的住院患者的數據。後續工作一直持續到2020年5月29日。

2.2 Data sources 數據源

We developed a cohort comprising 3,971 patients with laboratory-confirmed SARS-CoV-2 infection in an in-patient setting. The SARS-CoV-2 status was declared based on laboratory results (polymerase chain reaction on nasopharyngeal swab) from each participating hospital. Clinical data were abstracted at one-time point from electronic medical records or charts, and were collected using either a centrally designed electronic worksheet or a centralized web-based database. Collected data included patients’ demographics, laboratory test results, medication administration, historical and current medication lists, historical and current diagnoses, and clinical notes. In addition, specific information on the most severe manifestation of COVID-19 occurred during hospitalization was retrospectively captured. Maximum clinical severity observed was classified as mild pneumonia; or severe pneumonia; or acute respiratory distress syndrome (ARDS) [31]. Specifically, we obtained the following information for each patient: hospital; date of admission and date of discharge or death; age; sex; the first recorded inpatient laboratory tests at the entry (creatinine, C-reactive protein); past and current diagnoses (myocardial infarction, heart failure, diabetes, hypertension, respiratory disease and cancer) and current drug therapies for COVID-19 – HCQ, lopinavir/ritonavir or darunavir/cobicistat, remdesevir, tocilizumab or sarilumab, corticosteroids, heparin, and for comorbidities (insulin, anti-hypertensive treatments, aldosterone receptor antagonists, diuretics, statins, sacubitril/valsartan). A diagnosis of pre-existing cardiovascular disease was based on history of myocardial infarction or heart failure. Chronic kidney disease was classified as: stage 1: kidney damage with normal or increased glomerular filtration rate (GFR) (>90 mL/min/1.73 m2); stage 2: mild reduction in GFR (60-89 mL/min/1.73 m2); stage 3a: moderate reduction in GFR (45-59 mL/min/1.73 m2); stage 3b: moderate reduction in GFR (30-44 mL/min/1.73 m2); stage 4: severe reduction in GFR (15-29 mL/min/1.73 m2); stage 5: kidney failure (GFR <15 mL/min/1.73 m2 or dialysis). For statistical analysis, stages 3a and 3b and stages 4 and 5 were combined. GFR was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation. Patients were defined as receiving HCQ if they were receiving it at admission to hospital or received it during the follow-up period. According to the AIFA guidance [14], HCQ was administered at dose of 400 mg x 2/day or x4/day the first day, and 200 mg x 2/day from the second day onwards for at least 5 to a maximum of 10 days, according to the clinical evolution of the disease.

我們建立了一個由3971名實驗室證實感染SARS-CoV-2的住院患者組成的群組。SARS-CoV-2狀態是根據每個參與醫院的實驗室結果(鼻咽拭子上的聚合酶鏈反應)宣布的。臨床數據是從電子病歷或圖表中在一個時間點上提取,並採用集中設計的電子工作表或集中網絡數據庫進行收集。收集的數據包括患者的人口統計數據、實驗室測試結果、用藥情況、過往和當前的用藥清單、過往和當前的診斷以及臨床記錄。此外,還追溯採集了關於住院期間發生的COVID-19最嚴重表現的具體信息。觀察到的最高臨床嚴重程度被分為輕度肺炎;或嚴重肺炎;或急性呼吸窘迫綜合徵(ARDS)[31]。具體來說,我們獲得了每位患者的以下信息:醫院;入院日期及出院或死亡日期;年齡;性別;入院時首次記錄的住院患者實驗室檢查(肌氨酸,C反應蛋白);過往和當前的診斷(心肌梗死、心力衰竭、糖尿病、高血壓、呼吸系統疾病和癌症)以及當前COVID-19的藥物療法——HCQ、洛匹那韋/利托那韋或達蘆那韋/科比西斯特(cobicistat)、瑞德西韋、托珠單抗布或沙里魯馬布(sarilumab)、皮質類固醇、肝素、以及對合併症的(胰島素、抗高血壓治療、醛固酮受體拮抗劑、利尿劑、他汀類藥物、薩庫比特利(sacubitril)/纈沙坦)。已有的心血管疾病的診斷基於心肌梗死或心力衰竭的病史。慢性腎臟疾病被分為:第1階段:腎臟損傷,腎小球濾過率(GFR)正常或增高(>90 mL/min/1.73 m2);第2階段:GFR輕度降低(60-89 mL/min/1.73 m2);第3階段a:GFR中度降低(45-59 mL/min/1.73 m2);第3階段b:GFR中度降低(30-44 mL/min/1.73 m2);第4階段:GFR嚴重降低(15-29 mL/min/1.73 m2);第5階段:腎衰竭(GFR <15 mL/min/1.73 m2 或透析)。統計分析合併了第3a和3b階段以及第4和5階段。GFR由慢性腎臟疾病流行病學合作項目(CKD-Epi)的方程計算。如果患者在入院時或隨訪期間接受了HCQ,則被定義為接受HCQ治療。根據AIFA指導方針[14],根據疾病的臨床演變情況,第一天的HCQ的劑量為400毫克2次/天或4次/天,從第二天起按200毫克2次/天,至少5天至最長10天。

2.3 Statistical analysis 統計分析

The study index date was defined as the date of hospital admission. Index dates ranged from February 19, 2020 to May 23, 2020. The study end point was the time from study index to death. The number of patients who either died, or had been discharged alive, or were still admitted to hospital as of May 29, 2020, were recorded, and hospital length of stay was determined. Patients alive had their data censored on the date of discharge or as the date of the respective clinical data collection. Data were censored at 35 days of follow up in n=330 (8.3%) patients with a follow up greater than 35 days.

研究索引日期被定義為入院日期。索引日期範圍為2020年2月19日至2020年5月23日。研究終點是指從研究索引到死亡的時間。記錄截至2020年5月29日,死亡、或已活着出院、或仍在住院的患者人數,並確定了住院時長。活着的患者在出院之日或相應的臨床數據採集之日對其數據進行刪減。隨訪超過35天的n=330(8.3%)患者,在隨訪35天時對數據進行刪減。

Of the initial cohort of 3,971 patients, 350 patients were excluded from the analysis because they had at least one missing data at baseline or lost to follow up on HCQ use (N=94), other drug therapies for COVID-19 (n=265), time to event (n=59), outcome (death/alive, n=8), COVID-19 severity (n=4), age (n=4 with missing data and n=2 with age<18 years) or sex (n=2). Of the remaining 3,621 patients, 170 patients died or were discharged within 24 hours after presentation, and were also excluded from the analysis.

在3971名患者的初始群組中,350名患者被排除在分析之外,因為他們在基線上至少有一個數據缺失或失去了對HCQ使用的隨訪(N=94)、COVID-19的其他藥物治療(n=265)、事件發生時間(n=59)、結果(死亡/活着,n=8)、COVID-19嚴重程度(n=4)、年齡(n=4數據缺失,n=2年齡小於18歲)或性別(n=2)。在其餘3621名患者中,170名患者在報告後24小時內死亡或出院,也被排除在分析之外。

At the end, the analysed cohort consisted of n=3,451 patients. In patients not included in the analysis (n=520), as unique difference with the analysed group, the prevalence of diabetics (19.9% vs 14.8%, P=0.0066) and, to a less extent, of men (62.3% vs 58.3%, P=0.081) was higher. Out of 3,541 patients, 295 (8.5%) had at least a missing value for covariates. Distribution of missing values was as follows: n=178 for C-reactive protein; n=69 for GFR; n=74 for history of ischemic disease; n=64 for history of chronic pulmonary disease; n=51 for diabetes; n=51 for hypertension and n=56 for cancer. We used multiple imputation techniques (SAS PROC MI, n=10 imputed datasets; and PROC MIANALYZE) to maximize data availability. As sensitivity analysis, we also conducted a case-complete analysis on 3,156 patients.

最後,被分析的群組包括n=3451名患者。在未納入分析的患者中(n=520),作為與分析組的獨特差異,糖尿病患者(19.9%對14.8%,P=0.0066)和男性(62.3%對58.3%,P=0.081)的患病率更高。在3541名患者中,295人(8.5%)至少有一個協變量的缺失值。缺失值的分布如下:C反應蛋白為n=178;GFR為n=69;缺血性疾病史為n=74;慢性肺部疾病史為n=64;糖尿病為n=51;高血壓為n=51;癌症為n=56。我們使用多重歸因法(SAS PROC MI,n=10歸因數據集和PROC MIANALYZE)以最大限度地提高數據的可用性。作為敏感性分析,我們還對3156名患者進行了病例的完整分析。

Cox proportional-hazards regression models were used to estimate the association between HCQ use and death. Since multiple imputation was applied, the final standard error was obtained using the Rubin’s rule based on the robust variance estimator in Cox regression [32]. The proportional hazards assumption was assessed using weighed Schoenfeld residuals, and no violation was identified. To account for the non-randomized HCQ administration and to reduce the effects of confounding, the propensity-score method was used. The individual propensities for receiving HCQ treatment were assessed with the use of a multivariable logistic-regression model that included age, sex, diabetes, hypertension, history of ischemic heart disease, chronic pulmonary disease, GFR, C-reactive protein, hospitals clustering and use of other drug therapies for COVID-19 (lopinavir/ritonavir or darunavir/cobicistat, remdesivir, corticosteroids, tocilizumab or sarilumab). Associations between HCQ treatment and death was then appraised by multivariable Cox regression models with the use of propensity-score and further controlling for hospitals clustering as random effect (frailty model). The use of a frailty model was chosen as suggested in [33]. The primary analysis used inverse probability by treatment weighting; the predicted probabilities from the propensity-score model was used to calculate the stabilized inverse-probability-weighting weight [34]. Stabilized weights were normalized so that they added up the actual sample size. Secondary analyses used propensity-score stratification (n=5 strata) or multivariable Cox regression analysis or multivariable logistic regression analyses comparing death versus alive patients, or accounted for hospitals clustering via stratification or by robust sandwich estimator. Pre-established subgroup analyses were conducted according to age or sex of patients, degree of COVID-19 severity experienced during the hospital stay, C-reactive protein at basal or other drug therapies for COVID-19. Hospitals were clustered according to their geographical distribution, as illustrated in Table 1. To quantify the potential for an unmeasured confounder to render apparent statistically significant hazard ratio non-significant, the E-value was calculated [35]. Analyses were performed with the aid of the SAS version 9.4 statistical software for Windows.

利用考克斯比例危害回歸模型用於估計HCQ使用與死亡之間的關係。由於採用的是多重歸因法,所以最後的標準誤差是利用根據考克斯回歸模型中[32] 的穩健方差估計量的魯賓法所得到的。使用加權Schoenfeld殘差對比例危險性假設進行了評估,沒有發現違規現象。考慮到非隨機性的HCQ管理,和為了減少混雜變量的影響,採用了傾向性得分法。使用包括年齡在內的多變量邏輯回歸模型評估了接受HCQ治療的個體特徵,包括年齡、性別、糖尿病、高血壓、缺血性心臟病史、慢性肺病史、GFR、C反應蛋白、醫院聚類和使用COVID-19的其他藥物治療(洛匹那韋/利托那韋或達蘆那韋/科比西斯特、瑞德西韋、皮質類固醇、托珠單抗布或沙里魯馬布)。然後,利用傾向得分和進一步控制醫院聚類為隨機效應(脆弱模型),對HCQ治療與死亡之間的關聯進行了多變量考克斯回歸模型的評估。按照[33] 中的建議,選擇了使用脆弱模型。主要分析採用治療加權的反概率;利用傾向得分模型的預測概率計算穩定的反向概率加權權重[34] 。穩定權重經過了歸一化處理,以便使其與實際樣本量相加。二次分析使用傾向性評分分層(n=5分層)或多變量考克斯回歸分析或多變量邏輯回歸分析,比較死亡與存活患者,或通過分層或通過穩健夾心估計量對醫院聚類進行核算。根據患者的年齡或性別、住院期間經歷的COVID-19嚴重程度、基礎C反應蛋白或COVID-19的其他藥物治療進行預先建立的分組分析。如表格1所示,根據醫院的地理分布情況對醫院進行了聚類。為了量化未測量的混雜變量使明顯的統計顯著性風險比變得非顯著的可能性,計算了E值[35]。分析藉助於SAS 9.4版本的Windows統計軟件進行的。

Table 1 General characteristics of COVID-19 patients at baseline, according to hydroxychloroquine use.

表1 根據羥氯喹使用情況,基線上COVID-19患者的一般特徵。


羥氯喹使用
特徵否(N=817)是(N=2,634)未調整P值*
年齡– 中位數(四分位距-歲)73 (58-83)66 (55-77)<.0001
性別– 數(%)

<.0001
女性361 (44.2%)940 (36.7%)
男性456 (55.8%)1,694 (64.3%)
糖尿病– 數(%)

0.71
633 (77.5%)2,090 (79.3%)
162 (19.9%)515 (19.6%)
缺失數據22 (2.7%)29 (1.1%)
高血壓– 數(%)

0.31
378 (46.3%)1,294 (49.1%)
416 (50.9%)1,312 (49.8%)
缺失數據23 (2.7%)28 (1.1%)
缺血性心臟病– 數(%)

<.0001
610 (74.7%)2,190 (83.1%)
179 (21.9%)398 (15.1%)
缺失數據28 (3.4%)46 (1.8%)
慢性肺病– 數(%)

0.21
666 (81.5%)2,225 (84.5%)
127 (15.5%)369 (14.0%)
缺失數據24 (2.9%)40 (1.5%)
癌症– 數(%)

0.036
694 (84.9%)2,338 (88.8%)
101 (12.4%)262 (9.9%)
缺失數據22 (2.6%)34 (1.3%)
慢性腎病階段** – 數(%)

<.0001
第1階段241 (29.5%)970 (36.8%)
第2階段281 (34.4%)991 (37.6%)
第3階段a或第3階段b180 (22.0%)487 (18.5%)
第4階段或第5階段89 (10.9%)143 (5.4%)
缺失數據26 (3.2%)43 (1.6%)
C反應蛋白– 數(%)

0.0003
<1毫克/升104 (12.7%)256 (9.7%)
1-3毫克/升120 (14.7%)301 (11.4%)
>3毫克/升549 (67.2%)1,943 (73.8%)
缺失數據44 (5.4%)134 (5.1%)
使用洛匹那韋或達蘆那韋

<.0001
621 (76.0%)1,203 (36.7%)
196 (24.0%)1,431 (64.3%)
使用托珠單抗布或沙里魯馬布

<.0001
755 (92.4%)2,160 (82.0%)
62 (7.6%)474 (18.0%)
使用瑞德西韋

0.0015
808 (98.9%)2,551 (96.9%)
9 (1.1%)83 (3.1%)
使用皮質類固醇

<.0001
596 (73.0%)1,655 (62.8%)
221 (27.0%)979 (37.2%)
醫院聚類

<.0001
北部地區(米蘭省除外)(n)169 (20.7%)616 (23.4%)
米蘭省(m)161 (19.7%)525 (19.9%)
中部地區(羅馬除外)(c)303 (37.1%)747 (28.4%)
羅馬(r)94 (11.5%)390 (14.8%)
南部地區(s)90 (11.0%)356 (13.5%)

(n) include hospitals of Novara, Monza, Varese, Pavia, Cremona and Padova; (m) include Humanitas Clinical and Research Hospital, Centro Cardiologico Monzino, and hospitals of San Donato Milanese (Milano) and Cinisello Balsamo (Milano); (c) include hospitals of Modena, Ravenna, Forlì, Firenze, Pisa, Chieti and Pescara; (r) include National Institute for Infectious Diseases “L. Spallanzani” and Università Cattolica del Sacro Cuore; (s) include hospital of Napoli, Pozzilli (Isernia), Acquaviva delle Fonti (Bari), Foggia, Taranto, Catanzaro, Catania and Palermo

(n)包括諾瓦拉、蒙察、瓦雷澤、帕維亞、克雷莫納和帕多瓦的醫院;(m)包括人文臨床和研究醫院、蒙齊諾心臟科中心、以及聖多納托米拉內塞(米蘭省)和奇尼塞洛巴爾薩莫(米蘭省)的醫院;(c)包括莫德納、拉文納、弗利、佛羅倫薩、比薩、基耶蒂和佩斯卡拉的醫院;(r)包括拉扎羅·斯帕蘭扎尼國立傳染病研究所和聖心天主教大學;(s)包括那不勒斯、波齊利(伊塞爾尼亞省)、阿夸維瓦德萊豐蒂(巴里省)、福查、塔蘭托、卡坦查若、卡塔尼亞和巴勒莫的醫院

*Chi-square test. **Stage 1: Kidney damage with normal or increased glomerular filtration rate (GFR) (>90 mL/min/1.73 m2); Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2); Stage 3a: Moderate reduction in GFR (45-59 mL/min/1.73 m2); Stage 3b: Moderate reduction in GFR (30-44 mL/min/1.73 m2); Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2); Stage 5: Kidney failure (GFR < 15 mL/min/1.73 m2 or dialysis).

*卡方檢驗。**第1階段:腎臟損傷,腎小球濾過率(GFR)正常或增高(>90 mL/min/1.73 m2);第2階段:GFR輕度降低(60-89 mL/min/1.73 m2);第3階段a:GFR中度降低(45-59 mL/min/1.73 m2);第3階段b:GFR中度降低(30-44 mL/min/1.73 m2);第4階段:GFR嚴重降低(15-29 mL/min/1.73 m2);第5階段:腎衰竭(GFR <15 mL/min/1.73 m2 或透析)

3. Results 結果

We included in the final current analyses 3,451 patients who were hospitalized with confirmed SARS-CoV-2 infection at 33 clinical centres across Italy and either died, had been discharged, or were still in hospital as of May 29, 2020. Of these patients, 2,634 (76.3%, range among hospitals 53.2% to 93.6%) received HCQ. Timing of the first dose of HCQ after presentation to the hospital was 1 day for the large majority of centres, and 2 to 3 days for the others. HCQ was administered in all centres at the dose of 400 mg/day (in one centre however it was used at the dose of 600 mg/day and in another at the dose of 600 mg/day but only in patients younger than 65 years). Duration of treatment ranged from 5 to 15 days (with 10 days as the modal value). The drug used was HCQ in all hospitals.

在最終的現狀分析中,我們將納入意大利各地33個臨床中心確診的SARS-CoV-2感染住院的3451名患者,截至2020年5月29日,這些患者或已死亡、或已出院、或仍在醫院。其中2634人(76.3%,各醫院從53.2%到93.6%不等)接受了HCQ治療。絕大多數中心在患者入院後首次服用HCQ的時間為1天,其他中心為2至3天。所有中心都按400毫克/天的劑量使用HCQ(然而,其中一個中心使用的劑量為600毫克/天,另一個中心只對65歲以下的患者使用600毫克/天的劑量)。治療時間從5天到15天不等(以10天為模態值)。所有醫院使用的藥物都是HCQ。

Baseline characteristics according to HCQ use are shown in Table 1. Patients receiving HCQ were more likely younger, men and had higher levels of C-reactive protein and less likely had ischemic heart disease, cancer or stages 3a or greater chronic kidney disease (Table 1). Patients receiving HCQ more likely received another drug for COVID-19 treatment (78.4%; lopinavir/ritonavir or darunavir/cobicistat, remdesevir, tocilizumab or sarilumab, corticosteroids), in comparison with non-HCQ patients (46.3%; P<0.0001; Table 1).

表格1顯示了根據HCQ使用情況的基線特徵。接受HCQ的患者更可能是年輕、男性、C-反應蛋白水平更高,並且不太可能患有缺血性心臟病、癌症或第3階段a或更嚴重的慢性腎臟疾病(表格1)。與非HCQ患者相比(46.3%;P<0.0001;表格1),接受HCQ的患者更可能同時接受另一種藥物進行COVID-19治療(78.4%;洛匹那韋/利托那韋或達蘆那韋/科比西斯特、瑞德西韋、托珠單抗布或沙里魯馬布、皮質類固醇)。

The unadjusted differences and differences adjusted by propensity scores between HCQ-treated and non-HCQ treated patients for each variable included in the propensity score are shown in Fig. 1. All the pre-treatment differences disappeared after adjustment by propensity score weighting. The C-statistic of the propensity-score model was 0.74.

圖解1顯示了HCQ治療和非HCQ治療患者之間,根據每個傾向評分中的變量,未經傾向評分調整的差異和調整後的差異。經傾向評分加權調整後,治療前的差異全部消失。傾向評分模型的C統計量為0.74。

Fig. 1 The unadjusted standardized differences and standardized differences adjusted by propensity scores between HCQ-treated and non-HCQ treated patients for the variables included in the propensity score. All differences for the matched observations are within the recommended limits of –0.25 and 0.25, which are indicated by reference lines.

圖1 HCQ治療和非HCQ治療患者之間,根據每個傾向評分中的變量,未經傾向評分調整的差異和調整後的差異。匹配觀測值的所有差異都在推薦的-0.25和0.25的範圍內,由參考線表示。

3.1 Primary outcome 主要成果

Out of 3,628 patients, 576 died (16.7%), 2,390 were discharged alive (69.3%) and 485 (14.1%) were still at the hospital. The median follow-up was 14 days (interquartile range 8 to 22; range 2 to 35; 55,388 person-days). Death rate (per 1,000 person-days) was 8.9 in HCQ and 15.7 in non-HCQ patients (Table 2). At univariable analysis, hazard ratio for mortality was 0.56 (95%CI: 0.47 to 0.67). In the primary multivariable analysis with inverse probability weighting according to the propensity score, HCQ use was associated with a 30% (95%CI: 16% to 41%) reduction in death risk (Fig. 2, Table 2, E-value=1.67). Secondary multivariable analyses yielded very similar results (Table 2), as well as case-complete analyses restricted to the 3,156 patients without missing data (Table 2). Considering secondary multivariable analyses overall, HR for mortality associated with HCQ ranged between 0.64 to 0.70, according to type of analyses. Control of hospitals clustering with different approaches also yielded similar results for the primary analysis (HR=0.71, 95%CI: 0.59 to 0.85 when hospitals clustering was stratified for and HR=0.69, 95%CI: 0.54 to 0.88 with the robust sandwich estimator).

在3628名患者中,576人死亡(16.7%),2390人活着出院(69.3%),485(14.1%)仍在醫院裡。隨訪時間的中位數為14天(四分位距為範圍8至22天;範圍2至35天;55388天/人)。HCQ患者的死亡率(每千人日)為8.9,非HCQ患者為15.7(表格2)。在單變量分析中,死亡率的風險比為0.56(95%CI:0.47至0.67)。在根據傾向評分進行反概率加權的主要多變量分析中,HCQ的使用與死亡風險比降低30%(95%CI:16%到41%)相關(圖解1,表格2,E值=1.67)。二級多變量分析得出了非常相似的結果(表格2),以及僅限於3156名無缺失數據患者的病例完整分析(表格2)。綜合考慮二級多變量分析,根據分析類型,與HCQ相關的死亡率HR在0.64至0.70之間。用不同的方法對醫院進行聚類控制,也得到了類似的初步分析結果(當對醫院聚類進行分層時,HR=0.71,95%CI:0.59至0.85;使用穩健的夾心估計量時,HR=0.69,95%CI:0.54至0.88)。

Table 2 Incidence rates and hazard ratios for death in COVID-19 patients, according to hydroxychloroquine use.

表格2根據羥氯喹的使用,COVID-19患者的死亡率和風險比。

多重歸因法分析(N=3,451

死亡(N=576高危患者(N=3,451人日死亡率(千人日)
羥氯喹使用



否 – 數(%)190(23.3%)817(100%)12,08415.7
是 – 數(%)386(14.7%)2,634(100%)43,3048.9
死亡風險比(羥氯喹使用vs非羥氯喹使用)風險比(95%CI
粗略分析0.56(0.47 to 0.67)
多變量分析*0.70(0.58 to 0.85)
傾向評分分析,反向概率加權**(初步分析)0.70(0.59 to 0.84)
傾向評分分析,分層(n=5分層)**0.67(0.56 to 0.81)
死亡比值比(羥氯喹使用vs非羥氯喹使用)比值比(95%CI
傾向評分分析,反向概率加權**0.67(0.54 to 0.82)
病例完整分析(N=3,156

死亡(N=510高危患者(N=3,156人日死亡率(千人日)
羥氯喹使用



否 – 數(%)170(22.9%)741(100%)11,05015.4
是 – 數(%)340(14.1%)2,415(100%)39,2748.7
死亡風險比(羥氯喹使用vs非羥氯喹使用)風險比(95%CI
粗略分析0.56(0.46 to 0.67)
多變量分析*0.71(0.59 to 0.86)
傾向評分分析,反向概率加權**0.64(0.53 to 0.76)
傾向評分分析,分層(n=5分層)**0.68(0.56 to 0.82)
死亡比值比(羥氯喹使用vs非羥氯喹使用)比值比(95%CI
傾向評分分析,反向概率加權**0.67(0.54 to 0.82)

Abbreviations: HR, hazard ratios; CI, confidence intervals. *Controlling for age, sex, diabetes, hypertension, history of ischemic heart disease, chronic pulmonary disease, chronic kidney disease, C-reactive protein, lopinavir/ritonavir or darunavir/cobicistat, tocilizumab or sarilumab, remdesivir or corticosteroids use as fixed effects and hospitals clustering as random effect. **Including hospitals clustering as random effect covariate.

縮寫:HR,風險比;CI,置信區間。*控制年齡、性別、糖尿病、高血壓、缺血性心臟病史、慢性肺病、慢性腎病、C反應蛋白、洛匹那韋/利托那韋或達蘆那韋/科比西斯特(cobicistat)、托珠單抗布或沙里魯馬布(sarilumab)、瑞德西韋或皮質類固醇,作為固定效應,醫院聚類為隨機效應。**包括醫院聚類作為隨機效應協變量。

Fig. 2 Survival curves according to hydroxychloroquine use. The curves are adjusted by propensity score analysis (inverse probability for treatment weighting) and hospital index as random effect, and are generated using the first imputed dataset. The other imputed datasets are similar and thus omitted.

圖2 根據羥氯喹使用而生存的曲線。曲線通過傾向評分分析(治療加權的反向概率)和醫院指數作為隨機效應進行調整,並使用第一個歸因數據集生成。其他歸因數據集類似,因此省略。

Subgroup analyses are presented in Table 3. HCQ use remained consistently associated with reduced mortality in almost all subgroups. The inverse association of HCQ with inpatient mortality is slightly more evident in women, elderly and in patients who experienced a higher degree of COVID-19 severity. It was absent in-patient with C-reactive protein <10 mg/L and clearly confined to patients with elevated C-reactive protein (Table 3).

分組分析見表格3。在幾乎所有分組中,HCQ的使用始終與死亡率的降低聯繫在一起。HCQ與住院死亡率的反比關聯在婦女、老年人和經歷高COVID-19嚴重性的患者中更為明顯。它缺乏在患者與C反應蛋白+10mg/L和明顯局限於患者與升高的C反應蛋白(表格3)。

Table 3 Hazard ratios for mortality according to hydroxychloroquine use in different subgroups

表3 不同分組中使用羥氯喹的死亡率風險比


非羥氯喹使用(N=817羥氯喹使用(N=2,634
分组死亡人數/高危病人死亡人數/高危病人風險比 (95% CI)*
女人80/361116/9400.63 (0.46 to 0.86)
男人110/456270/1,6940.74 (0.60 to 0.93)
年齡<7022/35793/1,5420.76 (0.50 to 1.16)
年齡≥70168/460293/1,0920.68 (0.56 to 0.83)
在醫院經歷的COVID-19最高嚴重程度
輕度肺炎或更少28/42440/1,3580.70 (0.41 to 1.18)
重度肺炎80/253172/7640.76 (0.58 to 0.99)
急性呼吸窘迫綜合症82/140174/5120.68 (0.52 to 0.90)
使用其他的COVID-19治療^
101/43964/5700.63 (0.45 to 0.88)
89/378322/2,0640.77 (0.61 to 0.99)
基礎C反應蛋白**
<10毫克/升56/412125/1,1381.23 (0.86 to 1.77)
≥10毫克/升123/361241/1,3620.59 (0.47 to 0.73)

Abbreviations: HR, hazard ratios; CI, confidence intervals; *Propensity score analysis, inverse probability weighting, including hospital clustering as random effect covariate; multiple imputed analysis.

縮寫:HR,風險比;CI,置信區間;*傾向評分分析,反向概率加權,包括醫院聚類作為隨機效應協變量;多重歸因分析。

^Lopinavir/ritonavir or darunavir/cobicistat or tocilizumab or sarilumab or remdesivir or corticosteroids.

^洛匹那韋/利托那韋或達蘆那韋/科比西斯特或托珠單抗布或沙里魯馬布或瑞德西韋或皮質類固醇。

**Missing data for N=178. Frequencies and hazard ratios are based on a case complete analysis (N=3,273) without missing data for C-reactive Protein; multiple imputed analysis (N=3,451) yielded very similar results.

**缺失N=178的數據。頻率和風險比是基於C反應蛋白的無缺失數據的病例完整分析(N=3273);多重歸因分析(N=3451)得出了非常相似的結果。

4. Discussion 討論

In a large cohort of 3,451 patients hospitalized for COVID-19 in 33 clinical centers all over Italy, covering almost completely the period of the hospitalization for COVID-19, the use of HCQ was associated with a significant better survival. In-hospital crude death rate was 8.9 per 1,000 person-day for patients receiving HCQ and 15.7 for those who did not. After adjustment for known possible confounders, we observed a 30% reduction in the risk of death in patients receiving HCQ therapy as compared with those who did not.

在意大利各地33個臨床中心的3451名因COVID-19住院的大型患者群體中,幾乎完全覆蓋了COVID-19的住院期間,使用HCQ與顯著的存活率顯著提高有關。住院粗略死亡率為8.9天/每千人,接受HCQ的患者為15.7。在對已知可能的混雜變量進行調整後,我們觀察到接受HCQ治療的患者與未接受HCQ治療的患者相比,死亡風險降低了30%。

Our findings provide clinical evidence in support of guidelines by Italian and several international Societies suggesting to use HCQ therapy in patients with COVID-19. However, the observed associations should be considered with caution, as the observational design of our study does not allow to fully excluding the possibility of residual confounders. Large randomized clinical trials in well-defined geographical and socio-economic conditions and in well-characterized COVID-19 patients, should evaluate the role of HCQ before any firm conclusion can be reached regarding a potential benefit of this drug in patients with COVID-19.

我們的研究成果提供了臨床證據,支持意大利和幾個國際協會建議使用HCQ治療的COVID-19患者指導方針。然而,應謹慎考慮觀察到的關聯,因為我們研究的觀察設計不允許完全排除混雜變量殘餘的可能性。在明確界定的地理和社會經濟條件下以及在特徵明確的COVID-19患者中,進行大型隨機臨床試驗以評估HCQ的作用,然後才能就該藥物對COVID-19患者的潛在益處得出任何明確結論。

Over 76% of patients received HCQ either alone or in combination with other drugs. They were more likely to be younger, men and with higher levels of C reactive protein at entry, while less likely had pre-existing comorbidities such as ischemic heart disease, cancer and severe chronic kidney disease, as compared to patients not receiving the drug. We adjusted our analyses for possible confounders, including age, sex, diabetes, hypertension, history of ischemic heart disease, chronic pulmonary disease, chronic kidney disease, C-reactive protein and additional treatments for COVID-19, and took into account possible differences across centres by either adjustment or stratification. To minimize bias due to the observational design, we used different analytical approaches aiming at creating an overall balance between comparison groups. Finally, we tried to limit bias due to missing data by using a multiple imputation approach, but in no case, the result was changed. Despite all these precautions, we recognize the possibility, however, of residual unmeasured confounders affecting results.

超過76%的患者單獨或與其他藥物聯合使用HCQ。與未接受藥物的患者相比,他們更可能年輕、男性和C反應蛋白水平較高,他們更不可能出現先天合併症,如缺血性心臟病、癌症和嚴重的慢性腎臟疾病。我們對可能的混雜變量進行了調整,包括年齡、性別、糖尿病、高血壓、缺血性心臟病史、慢性肺病、慢性腎病、C反應蛋白和COVID-19的額外治療,並通過調整或分層顧及了各中心可能存在的偏差。為了最大限度地減少觀測設計導致的偏差,我們採用了不同的分析方法,目的是在比較組之間建立一個整體平衡。最後,我們試圖通過使用多重歸因法來限制因數據缺失而產生的偏差,但結果在任何情況下都沒有改變。然而,儘管採取了所有這些預防措施,但我們認識到,有可能存在影響結果的殘餘未測量的混雜變量。

Systematic reviews of small clinical trials had reported contrasting results that were however scarcely reliable because of poor designs [20, 21, 22, 23, 24, 25]. The HCQ doses tested in a Chinese randomized clinical trial [25] were approximately double as compared to that used in our study (1200 mg vs 800 mg as loading dose, 800 mg vs 400 mg as maintenance dose) for twice the time (14-21 days versus 7-10 days). National guidelines in Italy suggest to use HCQ 200 mg twice daily for at least 5-7 days in patients over 70 years and/or with co-morbidities (chronic obstructive pulmonary disease, diabetes, cardiovascular disease) even with mild respiratory symptoms or with radiographically documented pneumonia or in severe patients [36]. The lower doses of HCQ used in our centers, as suggested by Italian official guidelines [19, 36], may have been both more effective and safer.

對小型臨床試驗的系統性審查報告了截然不同的結果,但由於設計不當,這些結果幾乎不可靠[202122232425]。中國隨機臨床試驗[25]中測試的HCQ劑量大約是我們研究中使用的劑量的兩倍(1200毫克對800毫克作為負荷劑量,800毫克對400毫克作為維持劑量)的劑量,時間上也是兩倍(14-21天對7-10天)。意大利國家指導方針建議在70歲以上或患有合併症(慢性阻塞性肺病、糖尿病、心血管疾病)的患者,即使有輕微的呼吸道症狀或有放射記錄的肺炎或重症患者[36],也應使用200毫克的HCQ,每天2次,至少5-7天。根據意大利官方指導方針的建議[1936],我們中心使用的低劑量HCQ可能更有效,更安全。

Two recently published large observational studies, both from large hospitals in New York City, showed no association between HCQ use and in-hospital mortality [27, 28], and deserve specific discussion. In the study of Geleris et al. [27], the percentage use of HCQ was lower than in Italy; moreover, in both US studies [27, 28] the drug was more frequently administered to patients with previous illnesses and a more severe presentation of the disease. Our cohort included milder pneumonia patients than the US population, due to between-country differences in indications to the drug for the beginning of therapy (e.g., mild pneumonia in Italy versus only severe pneumonia and ARDS in the US). Concomitant use of other drugs for COVID-19 was very low in one study [27] and was not reported in the other study [28]. In our cohort, patients receiving HCQ were more likely treated with another drug for COVID-19 treatment (78.4%), in comparison with non-HCQ patients (46.3%). Anyway, our findings are adjusted for concomitant other drugs use.

最近發表的兩項大型觀察性研究,均來自紐約市的大型醫院,顯示HCQ的使用與住院死亡率之間沒有關聯[2728],值得具體討論。在蓋列里斯(Geleris)等人的研究中[27],HCQ的使用比例低於意大利;此外,在美國的兩項研究中[2728],該藥更多地用於既往疾病的患者,以及病情較為嚴重的患者。我們的群組包括比美國人群更輕的肺炎患者,這是因為國家間對開始藥物療程的徵兆指標的差異(例如,意大利的輕度肺炎,相比美國只有在嚴重肺炎和ARDS時)。在這一項研究中,同時使用其他藥物治療COVID-19的情況非常少[27],而在另一項研究中沒有報告[28]。在我們的群組中,與非接受HCQ的患者(46.3%)相比,接受HCQ的患者更有可能同時使用另一種藥物進行COVID-19治療(78.4%)。無論如何,我們的研究結果是根據同時使用其他藥物的情況進行調整的。

While the US studies were confined to one hospital only or a defined relatively small area in the Country, our study included 33 hospitals distributed all over Italy, covering regions with a high number of cases and a high intra-hospital mortality and regions with a lower burden of the disease. The participating Italian clinical centers have different healthcare facilities, different size, specialization, and ownership, and therefore quite closely represent the real-life Italian approach to COVID-19. Moreover, they differed for the percentage of use of HCQ and for the rate of in-hospital mortality that ranged between 34.1 and 1.5 per 1,000 persons/day. To consider this variability, we adjusted the analysis for recruiting center and performed a number of subgroup analyses. In all circumstances, the association between HCQ use and a reduced risk of death of about 30% was maintained. Quite interestingly, the inverse association of HCQ with inpatient mortality was more evident in elderly, in patients who experienced a higher degree of COVID-19 severity or especially having elevated C-reactive protein, suggesting that the anti-inflammatory potential of HCQ may have had more important role rather than its antiviral properties. HCQ, indeed, beside an antiviral activity, may have both anti-inflammatory and anti-thrombotic effects [8]. This can justify its effect in reducing mortality risk, since Sars-Cov-2 can induce pulmonary microthrombi and coagulopathy, that are a possible cause of its severity [37, 38] and the lack in preventing SARS-CoV-2 infection after exposure [26]

美國的研究僅局限於一家醫院或國家規定的一個相對較小的區域,而我們的研究則包括了分布在意大利各地的33家醫院,涵蓋了病例數多、院內死亡率高的地區和疾病負擔較輕的地區。參與的意大利臨床中心具有不同的醫療保健設施、不同的規模、專業性和所有權,因此相當接近於意大利對COVID-19的實際應對措施。此外,在HCQ的使用百分比和住院死亡率方面也有所不同,34.1天/每千人至1.5天/每千人之間。為了考慮這種變異性,我們調整了招聘中心的分析,並進行了一些分組分析。在所有情況下,HCQ的使用與死亡風險降低約30%之間的關係都得以維持。有趣的是,HCQ與住院死亡率的反比關係在老年人、COVID-19嚴重程度較高的患者或C-反應蛋白升高的患者中更為明顯,這表明HCQ的抗炎潛力可能比其抗病毒特性具有更重要的作用。事實上,HCQ除了具有抗病毒活性外,還可能具有抗炎和抗血栓作用[8]。這可以證明其在降低死亡風險方面的效果,因為Sars-CoV-2可以誘發肺微血栓和凝血病,這可能是其嚴重性的一個原因[3738],並且在暴露後缺乏預防SARS-CoV-2感染的能力[26]。

Nevertheless, large randomized clinical trials on the efficacy of HCQ on hard end-points are still lacking and the largest observational study showing no effect in reducing mortality has been retracted [16, 17], Agencies have suspended clinical trials on the efficacy of HCQ on COVID-19 disease or have restricted its use only to patients included in clinical trials, in the absence of an ample, serene and balanced discussion at international level.

然而,目前仍缺乏關於HCQ對硬終點療效的大型隨機臨床試驗,最大的一項觀察性研究顯示對降低死亡率沒有效果,但已被收回[1617],各機構在國際上沒有進行充分、和諧、平衡的討論的情況下,暫停了HCQ對COVID-19疾病療效的臨床試驗,或限制其僅用於納入臨床試驗的患者。

Very recently, a large RCT has become available as a pre-print publication [39], reporting no beneficial effect of HCQ in patients hospitalized with COVID-19. However, the dose of HCQ used in that trial was almost the double of that administered in our real life conditions. A reduced mortality was also observed by other observational studies using low or intermediate doses of HCQ [40, 41],

最近,一項大型的RCT已經作為印前刊物出版[39],報道了HCQ對COVID-19住院患者沒有有益作用。然而,該試驗中使用的HCQ劑量幾乎是我們現實生活條件下的給藥劑量的兩倍。其他使用低劑量或中等劑量HCQ的觀察性研究也觀察到死亡率降低[4041]。

Moreover, in our study patients taking HCQ more frequently received other anti-COVID drugs, whose interaction in reducing mortality cannot be completely ruled-out. Of note, despite the higher dosage used, the RCT did not show any excess in ventricular tachycardia or ventricular fibrillation in the HCQ arm (39.

此外,在我們的研究中,服用HCQ的患者更頻繁地接受其他抗COVID藥物的治療,不能完全排除其在降低死亡率方面的相互作用。值得注意的是,儘管使用了更高的劑量,但RCT並沒有顯示HCQ組的室性心動過速或室顫過量(39).

Therefore, it will be very important to compare results of studies with different mode of use and doses of HCQ, different characteristics of treated and untreated patients and different academic or real-world conditions.

因此,將不同的HCQ使用方式和劑量、不同的治療和未治療患者特徵、不同的學術或實際情況的研究結果進行比較將是非常重要的。

4.1 Strengths and limitations 優勢和局限性

A major strength of this study is the large, unselected patient sample from 33 hospitals, covering the entire Italian territory. Patient sampling covered all the overt epidemic period in Italy. Several statistical approaches were used to overcome biases due to the observational nature of the investigation.

這項研究的主要優勢是來自33家醫院的大量未經選擇的患者樣本,覆蓋了整個意大利領土。患者抽樣覆蓋了意大利所有的疫情時期。由於調查的觀察性質,採用了若干統計方法來克服了偏差。

This study has however, several recognized limitations. The study population pertains to Italy, and the results obtained may not be applicable to other populations with a possibly different geographical and socio-economic conditions and natural history of COVID-19. Due to the retrospective nature of the study, some parameters were not available in all patients, and all in-hospital medications might have been not fully recorded. Moreover, although guidelines on the use of HCQ in COVID-19 patients had been published in Italy since the first phase of the pandemic, individual centers could have deviated from recommendations and used different doses or treatment schemes. We have no information on the HCQ doses used individually nor of their possible association with azithromycin. Moreover, adverse events possibly related to drug therapy were not collected, thus we cannot exclude bias due to therapy interruption because of side effects; we do not know whether some deaths could have been due to cardiovascular complications of HCQ. However, recent data on Italian wards showed that COVID-19 patients receiving HCQ and azithromycin had a QTc-interval longer than before therapy, but did not experience, during their hospital stay, any arrhythmic complications, such as syncope or life-threatening ventricular arrhythmias [42], a finding also reported by the RCT mentioned above (39).

然而,這項研究有幾個公認的局限性。研究對象是意大利群體,所獲得的結果可能不適用於地理和社會經濟條件以及COVID-19的自然歷史可能不同的其他群體。由於這項研究的回顧性,一些參數並非所有患者都能提供,而且所有的住院用藥可能沒有被完整記錄在案。此外,雖然自疫情第一階段以來,意大利已經公布了關於COVID-19患者使用HCQ的指導方針,但個別中心可能偏離了建議,使用了不同的劑量或治療方案。我們沒有關於單獨使用的HCQ劑量的信息,也沒有它們與阿奇黴素可能存在關聯的信息。此外,沒有收集到可能與藥物治療有關的不良事件,因此我們不能排除由於副作用導致治療中斷的偏差;我們不知道是否有部分死亡病例是由於HCQ引起的心血管併發症。然而,意大利病房最近的數據顯示,接受HCQ和阿齊黴素的COVID-19患者的QTc間期比治療前更長,但在住院期間沒有出現任何心律失常併發症,如暈厥或危及生命的室性心律失常[42],上述RCT也報告了這一發現(39)。

Finally, the possibility of unmeasured residual confounding cannot be completely ruled-out. However, the E-value for the lower boundary of the confidence interval of our main result is 1.67, indicating that the confidence interval could be moved to include the null by a strong unmeasured confounder associated with both HCQ treatment and death with a risk ratio of 1.67-fold for each, above and beyond all the measured confounders. Weaker confounders, however, could not do so.

最後,不能完全排除未測量混雜變量殘餘的可能性。然而,我們主要結果的置信區間下邊界的E值為1.67,表明置信區間可以被一個與HCQ治療和死亡都相關的未測量的強混雜因素移動到包括空值,每個混雜因素的風險比為1.67倍,超過所有測量的混雜因素。然而,較弱的混雜因素則無法做到這一點。

5. Conclusions 結論

Our study, including a large real life sample of patients hospitalized with COVID-19 all over Italy, shows that HCQ use (200 mg twice/day) was associated with a 30% reduction of overall in-hospital mortality. In the absence of clear-cut results from controlled, randomized clinical trials, our data do not discourage the use of HCQ in inpatients with COVID-19. Given the observational design of our study, however, these results should be transferred with caution to clinical practice.

我們的研究,包括大量在意大利各地住院的COVID-19患者的實例樣本,表明HCQ的使用(200毫克,每天兩次)與醫院整體死亡率降低30%有關。在受控的隨機臨床試驗沒有明確結果的情況下,我們的數據並不妨礙在住院病人中使用HCQ與COVID-19。然而,鑑於我們研究的觀察性設計,這些結果應謹慎轉移到臨床實踐中。

翻譯【Dlrow】編輯【Michelle】

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“but those who hope in the Lord will renew their strength. They will soar on wings like eagles; they will run and not grow weary, they will walk and not be faint” 【Isaiah 40:31】 9月 06日