最新科學論文表明:羥氯喹對心臟有保護作用,而不是有害

新聞簡述:一篇8月20日發表於《新微生物和新感染》綜述文章表明,經檢索大量經同行評審的科學文獻,並未發現因使用羥氯喹和阿奇霉素而引起的心臟尖端扭轉型室性心動過速或相關死亡的報道。相反,一致發現羥氯喹和阿奇霉素可顯著降低心臟死亡率,並降低血栓形成、心律不齊和膽固醇。這否定了FDA和CDC警告的所謂「使用羥氯喹能導致致命性心臟尖端扭轉型室性心動過速」的說法。此研究證明FDA和CDC限制使用羥氯喹治療CCP病毒患者的決定缺乏科學依據。

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英漢對照翻譯全文(點擊下載PDF

Hydroxychloroquine Is Protective To The Heart, Not Harmful: 

A Systematic Review 

羥氯喹對心臟有保護作用,而不是有害:文獻綜述

Chadwick C. Prodromos MD 

查德威克·普羅德羅莫斯(醫學博士)

Abstract 

摘要

Background: Hydroxychloroquine (HCQ) has been shown to be at least somewhat effective in  treating COVID 19 patients. Recently FDA and CDC warnings of fatal cardiac toxicity from Torsade de Pointes (TDP) arrhythmia from HCQ use have been made, notwithstanding the long safe HCQ use for lupus and rheumatoid arthritis. This has resulted in restricted access of HCQ for COVID 19 treatment. We hypothesized that HCQ and azithromycin have not been reported to cause significant acute cardiac arrhythmic mortality. 

背景:羥氯喹(HCQ)已被證明在治療COVID 19病人方面至少在一定程度上是有效的。 FDA和CDC最近警告說使用HCQ導致致命性心臟尖端扭轉型室性心動過速(TDP),卻置 HCQ已長期的安全的被用於治療狼瘡和類風濕關節炎的事實於不顧。這舉導致使用HCQ治療COVID 19上受到限制。我們且認為尚未有因使用HCQ和阿奇霉素導致明顯的急性心律失常死亡報告。

Methods: We performed a literature search for the effects of HCQ and azithromycin on the heart. 

方法:我們進行了文獻搜索,探討HCQ和阿奇霉素對心臟的影響。

Results: No Torsade de Pointes or related deaths were found to have been reported as a result of HCQ and azithromycin use in the peer reviewed literature. To the contrary HCQ/azithromycin were uniformly found to substantially reduce cardiac mortality and also to decrease thrombosis, arrhythmia and cholesterol in treated patients in recent peer reviewed studies and meeting presentations. 

結果:在同行評審的文獻中,未發現因使用HCQ和阿奇霉素而引起的心臟尖端扭轉型室性心動過速或相關死亡的報道。相反,在最近的同行評審研究和會議介紹中,一致發現HCQ /阿奇霉素可顯著降低心臟死亡率,並降低血栓形成,心律不齊和膽固醇。

Conclusions: HCQ and azithromycin do not cause TDP cardiac mortality. HCQ decreases cardiac events. HCQ should not be restricted in use for COVID 19 patients because of fear of cardiac mortality. 

結論:HCQ和阿奇霉素不會引發TDP致死。 HCQ可減少心臟性事故。因此不應該以害怕導致心臟性死亡而限制使用HCQ治療COVID 19患者。

Introduction 

介紹

Several clinical studies, now numbering thousands of patients, [1-4] have shown apparent substantial clinical benefit from the use of hydroxychloroquine (HCQ) in COVID 19 patients and have not reported adverse cardiac events. A number of meta-analyses [5-7] have also shown overall good results although with limited quality studies. Usage of HCQ would therefore be warranted for COVID 19 by physicians who were so inclined unless there were significant clinical risks to offset the apparent benefits. 

數以千計的患者[1-4]的臨床研究表明,在COVID 19的患者中使用羥氯喹(HCQ)具有明顯的臨床益處,並且尚未出現不良的心臟性事故報告。儘管優質的相關研究不多,但許多薈萃分析[5-7]都顯示出總體良好的結果。因此,如果沒有明顯的臨床風險可以抵消明顯的益處,那麼應該保證願意使用HCQ的醫生能將其用於治療 COQID 19。

However, recently numerous warnings have been issued from the FDA [8], CDC [9], the American Heart Association [10] and elsewhere about potential fatal cardiac toxicity from Torsade de Pointes or other ventricular arrhythmias from HCQ use. These warnings state that such fatalities could occur secondary to the increase in QTc that is sometimes seen with the use of HCQ as well as azithromycin, which is often used in combination with HCQ. The FDA warning on reseased June 15th along with the revoking of it’s prior emergency use authorization states that “Additionally, in light of ongoing serious cardiac adverse events and other potential serious side effects, the known and potential benefits of chloroquine and hydroxychloroquine no longer outweigh the known and potential risks for the authorized use”[11]. However this warning does not reference any specific study, or comment on if any deaths have occurred.

但是,最近FDA [8]、CDC [9]、美國心臟協會[10]和其它機構已經發佈了許多警告,這些警告涉及使用HCQ引起的心臟尖端扭轉型室性心動過速或其它心律失常可能引起的致命性心臟毒性。這些警告指出,這種死亡可能是繼QTc升高後引發的,HCQ和阿奇霉素(通常與HCQ並用)一起使用時有些時候會發生這種情況。 FDA在6月15日重新發佈警告,並撤銷了其先前頒布的緊急使用授權,並指出:「此外,鑒於持續的嚴重心臟不良事故和其它潛在的嚴重副作用,氯喹和羥氯喹已知和潛在益處不比已知和潛在的風險多,故不再授權使用(氯喹和羥氯喹)」 [11]。但是,此警告沒有引用任何特定的研究,也沒有評論是導致了任何死亡。

These warnings however seemed odd to us since HCQ has been used in millions of lupus, and rheumatoid arthritis patients for more than fifty years with a general reputation for safety[12]. Practicing rheumatologists generally prescribe it without ordering a baseline EKG unless the patient has a history of cardiac disease. The 2019 hydroxychloroquine reccomendations for the European League against rheumatology (EULAR) only mention Journal Pre-proof screening for retinal toxicity in patients on hydroxychloroquine for extended periods of time[12]. Furthermore, azithromycin is also regularly prescribed without a baseline EKG and is not generally felt to be cardiotoxic to patients with an otherwise normal heart. 

然而,這些警告對我們來說似乎很奇怪,因為HCQ已在數以百萬計的狼瘡和類風濕性關節炎患者中使用了50多年,並且在安全性方面享有盛譽[12]。除非患者有心臟病史,否則風濕病醫生通常不需要做基線心電圖就能開處方。歐洲抗風濕病學聯盟(EULAR)在2019年提出的羥氯喹建議僅提及期刊預檢長期服用羥氯喹的患者的視網膜毒性[12]。此外,阿奇霉素也被視作常規處方藥而無需看基線心電圖,並且對心臟正常的患者來說不會產生心臟毒性。

These warnings have had the effect of restricting HCQ use to the hospital in some locales. This may not be consistent with good patient care since HCQ is known to be best applied earlier in the patient course before hospitalization. It has also resulted in some pharmacists, or entire pharmacy boards[13] refusing to fill HCQ prescriptions for COVID 19 thus restricting access to a potentially beneficial drug. Thus it would be of great benefit to know whether there is in fact significant cardiac risk from the use of HCQ. We hypothesized that the scientific literature would not show clinical evidence of increased cardiac mortality from HCQ or HCQ plus azithromycin from Torsade de Pointes: ie that the reported potential cardiac “risk”[9] of cardiac mortality would not be accompanied by reports of “actual” TDP or other QTc related cardiac mortality. 

這些警告已在某些地區限制了醫院使用HCQ。這可能與良好的患者護理理念相悖,因為眾所周知HCQ最好在患者住院之前更早的療程中使用。這還導致一些藥劑師或整個藥房委員會[13]拒絕開具HCQ作為治療COVID 19的處方藥,從而限制了(患者)對潛在有效藥的獲取。因此,瞭解使用HCQ是否會產生明顯的心臟風險將大有裨益。我們推斷科學文獻不會給出HCQ的使用或HCQ和阿奇霉素一起使用引發心臟尖端扭轉型室性心動過速從而增加心臟死亡率的臨床證據:即,報告所說的潛在心臟「風險」引發的心臟性死亡 [9]不會伴隨產生關於TDP或其它與QTc相關的心臟死亡的實例報告。

Materials and Methods

資料和方法

We limited this study to HCQ and not chloroquine since chloroquine is more toxic than HCQ such that we do not believe chloroquine has a place in the treatment of COVID 19: particularly given the wide availability and low cost of HCQ. 

我們將這項研究限制在HCQ而不是氯喹上,因為氯喹比HCQ毒性更大,因此我們不認為氯喹在COVID 19的治療中佔有一席之地:特別是考慮到HCQ的廣泛可用性和低成本。

We also excluded reports of HCQ cardiomyopathy. This is a rare condition that is only seen after many years, and usually decades, of use and thus is not relevant to the brief periods of time that HCQ is used to treat COVID 19. This cardiomyopathic damage is also not what is Journal Pre-proof referenced by agencies that warn of HCQ cardiotoxicity, which rather refers to QTc prolongation and the risk of Torsade de Pointes. 

我們還排除了HCQ心肌病的報道。這是一種罕見的疾病,僅在使用數年(通常是數十年)後才會出現,因此與使用HCQ短期治療COVID 19無關。這種心肌病的損害也不是相關機構引用期刊預檢關於HCQ心臟毒性的證據,這是指QTc延長和心臟尖端扭轉型室性心動過速的風險。

We conducted a search of the Pubmed, Medline, Cochrane, Embase, and Google Scholar databases. Search terms included hydroxychloroquine and azithromycin and the following co-search terms: cardiac, heart, arrhythmia, ventricular arrhythmia, Torsade de Pointes, COVID 19, treatment for COVID 19, mortality and death. We identified relevant articles. We included only clinical series including case reports, prospective and retrospective cohort studies, and meta analyses. Due to the emerging nature of the COVID-19 pandemic we included pre-print papers in our analysis, including papers published on medRxiv (which are indexed in Google scholar). The last day of this search consultation was June 1st 2020. We identified 4 case reports [14, 15] of HCQ cardiomyopathy after long term use, which were excluded as explained above. The remaining papers were individually analyzed for evidence of cardiac morbidity and mortality.

我們在Pubmed、Medline、Cochrane、Embase和Google Scholar數據庫里進行了搜索。搜索詞包括羥氯喹和阿奇霉素,以及以下共同搜索詞:心臟、心臟、心律不齊、室性心律失常、心臟尖端扭轉型室性心動過速、COVID 19、COVID 19的治療、死亡和死。我們確認了相關文章。我們僅包括臨床系列,包括病例報告,前瞻性和回顧性隊列研究以及薈萃分析。由於COVID-19大流行的新興性質,我們在分析中包括了預印本論文,包括在medRxiv上發表的論文(已在Google學術搜索中進行索引)。這次搜索咨詢的最後一天是2020年6月1日。我們排除了4例長期使用後HCQ心肌病的病例報告[14,15],原因如上所述。其餘論文分別進行了分析,作為研究心臟發病率和死亡率的依據。

Results 

結果

Overall our literature search found that, except for a few Case reports of non-fatal adverse events, HCQ is actually consistently associated with a decreased incidence of cardiac adverse events and no cardiac mortality from Torsade de Pointes.   

總的來說,我們的文獻檢索發現,除了少數非致命性不良事件的病例報告外,實際上,HCQ一直與心臟不良事件的發生率降低有關,而且沒有扭轉型室性心動過速的心源性死亡情況。

Table 1. Literature Review Results on HCQ and Cardiac Events

表1. HCQ與心臟事件關係的文獻回顧

文獻  研究方式病人數HCQ劑量和療程HCQ 用藥持續時間協同用藥病人的併發症/心臟病史 研究結果
Morgan 2006  [16] 報導病例200 mg每日兩次三年 41歲女性,患有充血性心衰和左心室功能障礙。 同時患有系統性紅斑狼瘡和高血壓。  肛門再造術後3年
QTc間隔延長
O’laug lin  2016  [17] 報導病例 1 每天200 mg  2 年50歲,女性,系統性紅斑狼瘡病史, 透析中的終末期腎病 及抗凝劑引起的心房顫動
QTc間隔延長
Chen  2006  [18] 報導病例每天200 mg 1 年每天15毫克強的松龍,每天200毫克的替奧菲林。67歲的老人,有系統性紅斑狼瘡、肝硬化和門靜脈血栓形成、哮喘和老年病史。心肌梗死伴室間隔缺損QTc間隔延長導致 尖端扭轉型室速
Asli  2020  [19] 報導病例400 mg  立即服用量, 然後 200 mg 每日兩次3 天最初是阿莫西林-後來改成了克拉維酸60歲女性,有高血壓病史,高脂血症,超重右束支阻滯和QTc間隔延長 
Erkan  2002  [20] 橫斷研究133名患者患有抗磷脂綜合徵NA 

NA 所有有抗磷脂症病史的患者發現服用阿司匹林或羥氯喹的抗磷脂抗體陽性患者血栓形成率較低
Izmirl y 2012 [21] 歷史隊列研究40名新生兒,其母親均接受了HCQ。臨產至少每日 200 mg 
至少在妊娠10周之前母親以前生過心臟性新生狼瘡患兒的新生兒,或母親有抗SSA/Ro和/或SSB/LA抗體的新生兒母親接受羥氯喹的嬰兒患心臟新生兒狼瘡的幾率降低64%。
Petri  1994  [22] 縱向隊列研究264名患者,125名患者使用羥氯喹

研究中80%的患者都在接受潑尼松治療所有系統性紅斑狼瘡的病人發現使用羥氯喹與降低血清膽固醇水平有關
Hung  [23] 基於人群的回顧式隊列研究173人,在HCQ組> 180 天風濕性關節炎患者顯示服用羥氯喹的類風濕性關節炎患者發生冠狀動脈疾病的風險有所降低
Konig  2020  [24] 前瞻性隊列研究812 患者 
所有系統性紅斑狼瘡的病人HCQ血液水平與任何血栓事件的風險成反比
Hooks  2020  [35] 回顧性隊列研究819名患者接受  HCQ每日中位劑量400毫克中位時間1006天
所有風濕病患者12例QTc超過500 ms的患者,平均患者治療時QTc增加7.6 ms。 治療時平均QTc為430.9 ms。
Chorin  2020  [36] 回顧性研究251 負荷劑量為400毫克,一天兩次,然後200毫克,每天兩次。
5 days



 

阿奇霉素每天500毫克,連續5天

23%的患者QTc>500毫秒,其中一名患者出現多形性室性心動過速(懷疑為尖端扭轉型室速)
Liu  2018  [37] 系統回顧和元分析患者總數 19,679



羥氯喹或氯喹的使用與風濕病患者的心血管疾病風險降低30%有關。
Remp enault 2019  [38] 系統回顧和元分析12,245 HCQ  患者 NA NA NA NA 接受HCQ的類風濕關節炎患者表現出可改變的心血管疾病危險因素,包括改善:血脂情況、糖尿病發生率、糖化血紅蛋白和減少心血管事件。
Matti eu 2018 [39]系統審查和元分析24,923 HCQ  患者NANANANA風濕病患者接受HCQ治療後,心血管疾病風險狀況較好,心血管事件較少。

Non-Fatal Cardiac Adverse Event Clinical Series 

非致命性心臟不良事件臨床系列報導  

We found 1 case series [36] of 251 COVID 19 patients treated with HCQ and azithromycin. 23% developed extreme QTc prolongation. However, HCQ was discontinued in patients with QTc prolongation and no deaths occurred.  

我們發現1個病例系列[36],251例COVID 19患者接受HCQ和阿奇霉素治療。23%出現極度QTc延長。但對QTc延長的患者停用HCQ,無死亡發生。

Cardiac Mortality from HCQ Induced TDP or Other Arrhythmia 

由HCQ誘發的尖端扭轉型室性心動過速或其它心律失常造成的心臟死亡

None reported:  We did not find any reports of a cardiac death from TDP or other arrhythmia from the use of HCQ. 

未報告:我們未發現使用HCQ後因TDP或其它心律失常導致心臟死亡的報告。 

Papers Showing a Decreased Incidence of Cardiac Events from the Use of HCQ 

顯示使用HCQ可降低心臟事件發生率的論文

Eight papers showed a decreased incidence of cardiovascular disease (CVD) in patients taking HCQ.  Hung [23]in 2018 found a decrease in risk of coronary artery disease (CAD) in rheumatoid arthritis (RA) patients taking HCQ.   Liu [37]  found this protective effect of HCQ on 2018 found that CQ and HCQ lower CVD in rheumatic disease from their study results. Mathieu [39] also in 2018 found that RA patients using hydroxychloroquine had an improved cardiovascular risk profile when compared to other RA patients.  

八篇論文顯示,服用HCQ的患者心血管疾病(CVD)的發生率降低。 Hung[23]在2018年發現服用HCQ的類風濕性關節炎(RA)患者發生冠狀動脈疾病(CAD)的風險降低。  Liu[37]在2018年發現HCQ對2018年發現CQ和HCQ降低風濕病CVD的這種保護作用,從他們的研究結果來看。Mathieu[39]也在2018年發現,與其他RA患者相比,使用羥氯喹的RA患者的心血管風險狀況有所改善。

Sharma [30] in 2016 found that hydroxychloroquine use was associated with a 72% decrease in the risk of incident CVD in RA patients.  Van Halm [29] in 2018 found that HCQ reduced cardiac events in RA patients. Yang [31] in 2019 found a decreased risk for coronary arter disease in SLE patients with high dosage use of HCQ for at least 318 days. Shapiro [32] in 2017 found decreased mortality with HCQ. In 514 RA patients – 241 HCQ, 273 control – the mortality rate for HCQ was 22.4%, vs 38.5% in control. 13.3% of HCQ patients using 400mg/day suffered cardiovascular events compared with 38.1% in the control group.  They concluded that HCQ use in RA patients was associated with decreased cardiovascular morbidity, especially in higher dosage HCQ patient of 400 mg per day. 

Sharma[30]在2016年發現,羥氯喹的使用與RA患者發生CVD的風險降低72%有關。Van Halm[29]在2018年發現,HCQ可降低RA患者的心臟事件。Yang[31]在2019年發現,系統性紅斑狼瘡患者大劑量使用HCQ至少318天,冠狀動脈疾病風險降低。Shapiro[32]在2017年發現使用HCQ可降低死亡率。在514名RA患者中(241名HCQ,273名對照)HCQ的死亡率為22.4%,而對照的死亡率為38.5%。使用400mg/天的HCQ患者中,13.3%的患者發生心血管事件,而對照組為38.1%。 他們的結論是,RA患者使用HCQ與心血管發病率降低有關,尤其是每天400mg的高劑量HCQ患者。

Neonatal Cardiac Lupus 

新生兒紅斑狼瘡累及心臟

Izmirly [21] in 2013 showed the recurrence rate of cardiac-Neonatal Lupus in fetuses exposed to HCQ was 7.5% (3/40) compared to 21.2% (46/217) in the unexposed group (p=0.050). While there were no deaths in the exposed group, the overall case fatality rate of the cardiac-NL fetuses in the unexposed group was 22%.

Izmirly[21]在2013年的研究顯示,暴露於HCQ的胎兒心臟-新生兒狼瘡的復發率為7.5%(3/40),而未暴露組為21.2%(46/217)(p=0.050)。而且暴露組沒有死亡,但未暴露組中累及心臟新生兒狼瘡胎兒的總死亡率為22%。 

Atrial Fibrillation 

房顫

Gupta  [33] in 2018 showed a 67% decreased risk of atrial fibrillation in patients taking HCQ.   

Gupta[33]在2018年的研究顯示,服用HCQ的患者發生房顫的風險降低了67%。

Thrombosis  

血栓形成  

3 papers [20, 24, 25] showed a decreased incidence of thrombosis in patients taking HCQ.  Konig [24] in a 2019 study, presented at the American College of Rheumatology Annual Conference, found a lower incidence of thrombosis the higher the level of HCQ in the blood. 

三篇論文[20,24,25]顯示服用HCQ的患者血栓發生率降低。 Konig[24]在2019年美國風濕病學學院年會上發表的一項研究中發現,血液中HCQ含量越高,血栓發生率越低。

Cholesterol and Lipid Profile 

膽固醇和血脂情況

Two papers [22, 26] showed lower cholesterol or lipid profile in patients taking HCQ. 

兩篇論文[22,26]顯示,服用HCQ的患者膽固醇或血脂較低。

Clinical Series Using HCQ in COVID 19 

在COVID 19中使用HCQ的臨床系列

A clinical series [2] of 1061 COVID 19 patients treated with HCQ and azithromycin had 8 deaths.   However, all of these deaths were caused by respiratory failure from COVID-19, and no patients showed Torsades de Pointes. They obtained a baseline EKG in all patients and discontinued HCQ when necessary.  They have now treated over 4000 patients with no cardiac mortality. 

一個臨床系列[2],1061例COVID 19患者接受HCQ和阿奇霉素治療,有8例死亡。  但這些死亡均由COVID-19引起的呼吸衰竭引起,沒有患者出現軀體疾病。他們獲得了所有患者的基線心電圖,並在必要時停止使用HCQ。 目前他們已經治療了4000多名患者,沒有出現心臟死亡。

Azithromycin 

阿奇霉素

We found 5 reports of the cardiotoxicity of HCQ on COVID 19 patients. [27, 28, 34-36]. All papers described increased “risk” of TDP or related ventricular arrhythmia.  However, none of the 5 papers reported an actual HCQ-AZ death. A report by Farkas [40], explained that HCQ is actually an anti-arrhythmic drug and that it has never been shown to predispose to TDP.  Ohara further describes azithromycin has never been shown to cause TDP in a paper entitled, “Azithromycin Can Prolong QT Interval and 169 Suppress Ventricular Contraction, but Will Not Induce Torsade de Pointes” [41]. In addition, azithromycin has been shown to improve cardiac remodeling and decrease heart failure after myocardial infarction in animal models [42].

我們發現了5份關於HCQ對COVID 19患者心臟毒性的報告[27, 28, 34-36] 。所有論文都描述了TDP或相關室性心律失常的 「風險」增加。 然而,這5篇論文中沒有一篇報導了實際的HCQ-AZ死亡。Farkas[40]的報告,解釋了HCQ實際上是一種抗心律失常的藥物,而且從未被證明會誘發尖端扭轉型室性心動過速(TDP)。 Ohara在題為 《阿奇霉素能延長QT間期和169抑制心室收縮,但不會誘發TDP》[41]的論文中進一步介紹了阿奇霉素從未被證明會導致TDP。此外,在動物模型中,阿奇霉素還被證明可以改善心臟重塑,減少心肌梗死後的心力衰竭[42]。

Discussion 

討論

The most important finding of this review is that evidence shows HCQ to be overall significantly cardioprotective, and apparently not cardiotoxic in short term use. This supports Journal Pre-proof our hypothesis that prudent use of HCQ would not cause significant mortality from Torsade de Pointes or related cardiac causes. This finding of cardioprotection, which was surprising to us, goes well beyond our hypothesis. Perhaps because many of the studies showing cardioprotection are relatively recent, the cardioprotective effect seems to be generally unknown to both the general population and the medical community. The cardio-protection includes a decrease in cardiac events, in thrombosis in general, in arrhythmia, in lipid profile and even in fetal disease. With HCQ generally beneficial to the heart in patients with rheumatic disease, there would be no reason to think that it would be cardiotoxic in COVID 19 patients, unless these patients were late in the disease course with established viral cardiac damage. Even then this would be only a theoretical risk because it is also possible that HCQ might be 188 protective of further damage in this circumstance.

本綜述最重要的發現是,有證據表明HCQ總體上具有顯著的心臟保護作用,而且在短期使用中顯然沒有心臟毒性。這支持了我們在 Journal Pre-proo 《期刊預審》論文中的假設,即,謹慎使用HCQ不會導致因藥物引起的心律不整(Torsade de Pointes)或相關心臟病的重大死亡。心臟保護的這一髮現,讓我們很驚訝,遠遠超出了我們的假設。也許是因為很多關於心臟保護的研究都是相對較新的,而心臟保護作用對於一般人群和醫學界來說似乎都是未知的。心臟保護包括減少心臟疾病、一般血栓形成、心律不齊、血脂檢測以及胎兒疾病。由於HCQ通常對風濕病患者的心臟有益,所以沒有理由認為它使COVID19患者的心臟中毒,除非這些是心臟病晚期患者,伴有確診的病毒性心臟損傷。即使那樣,這也只是一種理論上的風險,因為在這種情況下,HCQ也有可能防止進一步的損害。

The second major finding of this study is that we were unable to find any reports of TDP death from HCQ induced TDP in the peer reviewed literature. This suggests that, in fact, no actual significant risk of TDP exists if HCQ is used prudently in accordance with established guidelines. In this regard, the protocol used by Didier Raoult’s group [2] is instructive. They obtain a baseline EKG and serum electrolyte analysis before beginning HCQ. The EKG is repeated 48 hours after the start of treatment and HCQ is discontinued when the corrected QT interval is >500ms. Using this common sense protocol, they have now treated over 4000 patients without a single cardiac mortality. TDP may occasionally occur in association with HCQ use. But based on our finding of not a single mortality being reported in the peer reviewed literature, we believe that the frequency of HCQ associated TDP is extremely low and the incidence of subsequent TDP induced mortality caused by HCQ is rare if it exists at all.  Anecdotally the Department of Health and Human Services Pharmacovigilance Memorandum [43] which publishes self-reported adverse events from providers and patients reported 4 cases of TDP with 1 mortality from their entire database. The report is not peer reviewed. There is no way to verify the report itself, causality or whether appropriate procedures were followed. But at worst this would still represent only a single TDP mortality despite very widespread HCQ COVID-19 use.

本研究的第二個主要發現是,在同行評審的文獻中,我們沒有發現任何心律不整(TDP)是因為使用HCQ引起的 TDP 死亡的報道。這表明,實際上,如果按照既定的指南謹慎使用HCQ,就不存在出現TDP的重大風險。在這方面,迪迪埃·拉烏特(Didier Raoult)的[2]組所使用的方案是有指導意義的。他們在開始服用HCQ前進行基線心電圖和血清電解質分析。治療開始48小時後重復心電圖檢測,當QT間期為>500ms時,停止服用HCQ。使用這一常識性方案,他們現在已經治療了4000多名患者,無一例心臟死亡。TDP偶爾會在使用HCQ時發生。但是,基於我們在同行評議的文獻中沒有發現任何有關死亡個案的報告,由此我們認為與HCQ相關的TDP的發生頻率極低,而由HCQ引起的TDP的死亡率即使存在,也是非常罕見。據傳聞,《衛生和公眾服務部藥物警戒備忘錄》[43],發佈了來自一些個人和患者的自我報告的不良案例,在這些案例的數據庫中有4例 TDP 患者,其中1例死亡。這些報告未經同行評議,因此無法證實報告本身,其因果關係,或是否遵循了適當的程序等。但,實時是最壞的結果,也只顯示有一例死亡,而且是在HCQ被非常廣泛地用來治療COVID-19患者的前提下。

The cardio-protective properties of HCQ should not be surprising. Cardiac events, including thrombosis are caused in part by inflammation[44]. HCQ is an anti-inflammatory drug[45]. Furthermore, its separately described anti-thrombotic properties[46] would also be expected to be cardio-protective.

對HCQ具有的心臟保護特性的功能,人們不應感到驚奇。心臟疾病包括血栓形成,部分是由炎症引起的[44]。HCQ是一種抗炎藥[45]。此外,它本身具有的抗血栓特性[46],也被認為具有心臟保護作用。

Limitations of this study include the possibility that cardiac deaths have occurred but not been reported. However, even if a small number of TDP deaths have occurred, it would not change the finding that HCQ is overall safe and generally beneficial for the heart.

這項研究的局限性包括可能有些是已經發生了的心臟死亡案例但還未被報道的情況。然而,即使發生了少量TDP死亡案例,也不會改變HCQ總體上是安全的而且一般來說對心臟也是有益的這一髮現。

In fact, the finding of an anti-thrombotic effect, an anti-arrhythmic effect, and a reduction in CVD events raises the possibility that HCQ should be considered in well controlled clinical trials as a treatment for COVID 19 patients who have sustained cardiac damage as a possible mitigant of these effects.

事實上,這項關於抗血栓作用、抗心律不齊作用、減少心血管疾病的發現,提高了在臨床試驗中應該考慮將HCQ用於治療COVID 19病人的這種可能性,以此作為減輕對持續性心臟損傷的可能性並起到緩和的作用。

Conclusions 

結論

HCQ is apparently not dangerous to the heart and indeed is cardioprotective. It results in a lower incidence of cardiac events as well as lower levels of arrhythmia, cholesterol, and thrombosis. No TDP deaths from HCQ have apparently been reported in the peer reviewed Journal Pre-proof literature. The potential risk of fatal arrhythmia, e.g. TDP, from HCQ, appears to be essentially a theoretical risk only. It appears to occur very rarely if ever in clinical practice if HCQ is used according to standard treatment protocols. Azithromycin used in combination with HCQ also appears to be safe, does not appear to cause TDP mortality, and is also apparently cardioprotective. Due to its ability to decrease CVD events, decrease arrhythmia, decrease thrombosis and decrease cholesterol, HCQ should be considered as an agent for study to potentially treat patients who have developed cardiac damage from COVID 19.

HCQ顯然對心臟沒有危險,而且確實具有心臟保護作用。它可以降低心臟疾病的發生率,降低心律失常、膽固醇和血栓形成的水平。在同行評審的《期刊預審》中,顯然沒有由HCQ引起的TDP死亡的報道。致命心律失常的潛在風險,例如HCQ引起的TDP,似乎基本上只是一種理論上的風險。如果按照標準治療方案使用HCQ,即使在臨床實踐中也很少發生。 阿奇霉素與HCQ並用似乎是安全的,似乎不會引起TDP死亡,並且顯然具有心臟保護作用。 由於HCQ具有減少心臟病、減少心律不齊、減少血栓形成和降低膽固醇的能力,因此應被認為是潛在的治療因COVID 19引起心臟損害的患者的研究藥物。

參考文獻(見英文原文)

閱讀英文原文

翻譯:【 一花一世界 】【Naomi (文花開) 】【 奔騰的長江 】校對&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】 8月 24日