生物与医学2020medrxiv.org
研究：羟氯喹对住院患者无疗效证据
Study: No evidence of efficacy of hydroxychloroquine in hospitalized patients
进阶 · 约 20 分钟读完前置知识：临床试验设计、统计推断与置信区间、COVID-19 临床背景
导读
这项 medRxiv 预印本研究比较住院 COVID-19 患者使用与不使用羟氯喹（HCQ）后 7 天内的死亡和急性呼吸窘迫综合征（ARDS）发生率，结论是未发现疗效证据。但评论指出样本仅 181 例、事件数很少、置信区间很宽，因此不能据此断定 HCQ 无效。
HN 关注点：是因为羟氯喹疗效争议极大，而这篇小样本研究被用来支持“无效”，讨论焦点集中在统计功效不足和“无证据不等于证明无效”。
HN 评论精选
这几条评论里：质疑 2 补充 1 亲历 1
质疑统计功效不足、置信区间极宽，“无证据”不能解读为“证明无效”。
必须谨慎解读：“无疗效证据”不等于“有证据证明无效”，这项研究的不确定性其实很大。样本量太小，除非 HCQ 的效应非常大，否则很难检测出来。摘要数据：HCQ 组 7 天内死亡 2.8% vs 4.6%（3 vs 4 例，RR 0.61，95% CI 0.13–2.89）；ARDS 发生率 27.4% vs 24.1%（24 vs 23 例，RR 1.14，95% CI 0.65–2.00）。关键是相对风险和置信区间：死亡 RR 看似更低，但 CI 从 0.13 到 2.89，数据与风险更小或更大都相容；仅 3 例和 4 例死亡很难得出精确结论。可以说 HCQ 没有奇迹般的大效应，但证据很弱，大型随机试验会更明确。（免责声明：我是统计学家，不是医生。）
capnrefsmmat查看英文原文
It's important to interpret these results carefully: "no evidence of efficacy" does not imply evidence of no efficacy, and in fact the uncertainty in this study is quite large. The sample size is small enough that it would be very hard for this study to detect the effect of hydroxychloroquine unless that effect is very, very large. From the abstract: > In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13-2.89), and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days (24 vs 23 events, RR 1.14, 95% CI 0.65-2.00). The relative risks and confidence intervals are the important numbers here. For example, the relative risk for death is 0.61, meaning the observed risk of death was lower for patients treated with hydroxychloroquine -- but the confidence interval is 0.13 to 2.89, meaning the data is consistent with anything from the risk being much smaller to the risk being much larger. Since there were only 3 deaths in the treatment group and 4 deaths in the control group, it's very hard to draw precise conclusions about death rates. I think we can interpret this result to mean that hydroxychloroquine doesn't have a miraculously large effect, but the evidence is weak. Other commenters are correct that large randomized trials will be more definitive. (disclaimer: I am a statistician, not a doctor)
补充等待 PATCH 双盲 RCT 的多阶段结果来提供统计功效。
我个人暂不判断，等 PATCH 试验结果出来再说（https://clinicaltrials.gov/ct2/show/NCT04329923）。它会有足够的统计功效，是完整的双盲随机对照试验，而且有多个研究臂（医护人员预防、居家隔离早期、住院晚期）；如果 HCQ 有效但住院时用药已太晚（正如一些人现在所推测），我们应该终于能有一定把握地知道。
apendleton查看英文原文
Personally I'm witholding judgment until the results of the PATCH trial (https://clinicaltrials.gov/ct2/show/NCT04329923) arrive, as it'll finally give us some decent statistical power, and be a full, double-blind RCT. It also has multiple study arms (health-care worker prophylaxis, home-quarantined early stage, hospitalized later-stage), so if it turns out that HCQ is effective but that by the time patients are hospitalized it's too late, as some are now suggesting, we should finally know with some degree of certainty.
亲历患者亲历：药物需求使尽快明确结论变得迫切。
我需要用羟氯喹治疗我的类风湿关节炎，所以我希望这个假设能尽快、尽可能明确地被证实或推翻。
w_t_payne查看英文原文
Given that I need hydroxychloroquine to treat my rheumatoid arthritis, I'd like this hypothesis to be either proven or disproven as rapidly and as unambiguously as possible.
质疑批评争论情绪化，主张重症患者知情后尝试，并强调样本小、无证据不等于无效。
这场争论在我看来很疯狂：一些所谓“专家”不喜欢的人提到 HCQ 可能治疗新冠，结果大家吵成一团，仿佛这是什么阴谋。HCQ 已用了几十年，副作用大体已知，对 COVID-19 可能有效也可能无效；没人建议长期高剂量；重症患者在与患者或家属说明潜在副作用后应尝试，允许家属选择尝试权。HCQ 便宜、可得、用了数十年。一个仅 181 例样本的研究得出“无证据 HCQ 有效”却获得 200 多赞，说明情绪温度太高。大家冷静：正如 capnrefsmmat 所说，“ absence of evidence”不等于“evidence of absence”。
forgingahead查看英文原文
This whole debate is insane to me -- some people that so-called "experts" don't like mentioned HCQ as a possible treatment for coronavirus, and we've ended up in some bizarro world where everyone is shouting and fingers are being pointed over something that really shouldn't be controversial or perceived as some sinister plot to destroy clever society. 1. HCQ has been used for many decades 2. The side effects are generally known 3. It may have a positive impact on COVID-19, and it may not. 4. Nobody is suggesting long term high doses for anyone, COVID patients or otherwise. 5. If people are severe patients of COVID-19, this should certainly be tried as a treatment as long as the patient (or immediate family) is briefed on the potential side effects. The alternative, potential death, makes this a worthy discussion for a doctor/patient to have, with families being allowed to err on the side of right-to-try. HCQ is cheap, available, and has been used for decades. The fact that "no evidence HCQ works!!" has 200 points of upvotes and counting when the sample size for this study is 181 patients only just shows how high the temperature has become. Everyone just calm down. As capnrefsmmat has eloquently pointed out, "absence of evidence" does not mean "evidence of absence". If you enjoy the thrill of debates for debates sake, here are other potential topics for you: Whether masks are effective, condoms, seatbelts, helmets, or even parachutes[0]: [0]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC300808/ Favourite part: Results We were unable to identify any randomised controlled trials of parachute intervention. Conclusions As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute.
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