Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
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Abstract
Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.
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SciScore for 10.1101/2020.09.16.20194571: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization 16 We considered all clinical trials that reported randomly allocating patients with confirmed or suspected SARS-CoV-2 infection to a treatment protocol containing HCQ or CQ (for any duration or dose) or the same treatment protocol not containing HCQ or CQ. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources 17 We additionally searched PubMed and the Cochrane COVID-19 trial registry (covering preprints, trial registries and literature databases) by June 11, 2020, using terms related to HCQ and CQ combined with terms for COVID-19 and a … SciScore for 10.1101/2020.09.16.20194571: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization 16 We considered all clinical trials that reported randomly allocating patients with confirmed or suspected SARS-CoV-2 infection to a treatment protocol containing HCQ or CQ (for any duration or dose) or the same treatment protocol not containing HCQ or CQ. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources 17 We additionally searched PubMed and the Cochrane COVID-19 trial registry (covering preprints, trial registries and literature databases) by June 11, 2020, using terms related to HCQ and CQ combined with terms for COVID-19 and a standard RCT filter (Supplement 1). PubMedsuggested: (PubMed, RRID:SCR_004846)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our analysis has some limitations. First, although we adopted a comprehensive, systematic search strategy, our real-time initiative differs from traditional systematic reviews. We focused on collecting unpublished information, aiming to rapidly secure as much trial evidence as possible. We did not review individual trials, nor did we stratify results according to patient characteristics. Such analyses are planned in future publications using in-depth details disclosed in individual trial publications to come.44–46 The exploratory subgroup analyses did not support the hypothesis that blinding/use of placebo is associated with the observed effect (the test for an interaction gives p=0.15 and the OR is 0.88 with wide CIs [0.55 to 1.41], compatible with the overall effect); moreover, attrition was negligible (median 0%, IQR 0% to 0%; range 0 to 19.5%). A meta-epidemiological study shows little evidence that mortality results would be affected by lack of blinding, or problems in randomization and allocation concealment, in contrast to less objective outcomes.47 Second, a majority of the potentially eligible trials were not available. Despite going far beyond the standard review of published evidence, we expect additional results from future trials on CQ to narrow the uncertainty of the treatment effect and possibly reveal benefits or harms not discernible based on the current evidence. We plan to perform an update when substantial additional evidence becomes available. Finally, al...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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SciScore for 10.1101/2020.09.16.20194571: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization We considered all clinical trials that reported randomly allocating patients with confirmed or suspected SARS-CoV-2 infection to a treatment protocol containing HCQ or CQ (for any duration or dose) or the same treatment protocol not containing HCQ or CQ. Blinding In most trials, patients and clinicians were aware of the treatment (13 trials; 50%), while in one trial (4%) the patients were blinded and in eleven trials (42%) patients and clinicians were blinded (Table 2). Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources 16 We additionally searched PubMed and the … SciScore for 10.1101/2020.09.16.20194571: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization We considered all clinical trials that reported randomly allocating patients with confirmed or suspected SARS-CoV-2 infection to a treatment protocol containing HCQ or CQ (for any duration or dose) or the same treatment protocol not containing HCQ or CQ. Blinding In most trials, patients and clinicians were aware of the treatment (13 trials; 50%), while in one trial (4%) the patients were blinded and in eleven trials (42%) patients and clinicians were blinded (Table 2). Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources 16 We additionally searched PubMed and the Cochrane COVID-19 trial registry (covering preprints, trial registries and literature databases) by June 11, 2020, using terms related to HCQ and CQ combined with terms for COVID-19 and a standard RCT filter (Supplement 1). PubMedsuggested: (PubMed, RRID:SCR_004846)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
Our analysis has some limitations. First, although we adopted a comprehensive, systematic search strategy, our real-time initiative differs from traditional systematic reviews. We focused on collecting unpublished information, aiming to rapidly secure as much trial evidence as possible. We did not review individual trials, nor break down results according to patient characteristics. Such analyses are planned in future publications using in-depth details disclosed in individual trial publications to come.38–40 However, consistent findings in placebo-controlled, double-blinded and open-label trials indicate an overall low risk of bias across trials; moreover, attrition was negligible (median 0%, IQR 0% to 0%; range 0 to19.5%). Meta-epidemiological work shows that mortality results are least affected by lack of blinding, or problems in randomization and allocation concealment as compared with other outcomes. 41 Second, a majority of the potentially eligible trials were not available. Despite going far beyond the standard review of published evidence, we expect additional results from future trials to narrow the uncertainty of the treatment effect and possibly reveal benefits or harms not discernible based on the current evidence. Of the unavailable trials, the WHO Solidarity trial may have the largest sample size and provide most mortality data. We plan to perform an update when substantial additional evidence becomes available. Finally, although conclusions were robust across s...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04261517 Completed Efficacy and Safety of Hydroxychloroquine for Treatment of C... NCT04381936 Recruiting Randomised Evaluation of COVID-19 Therapy NCT04316377 Active, not recruiting Norwegian Coronavirus Disease 2019 Study NCT04384380 Completed Efficacy and Tolerability of Hydroxychloroquine in Adult Pat... NCT04308668 Completed Post-exposure Prophylaxis / Preemptive Therapy for SARS-Coro... NCT04304053 Completed Treatment of COVID-19 Cases and Chemoprophylaxis of Contacts... NCT04322123 Active, not recruiting Safety and Efficacy of Hydroxychloroquine Associated With Az... NCT04329923 Recruiting The PATCH Trial (Prevention And Treatment of COVID-19 With H... NCT04345289 Recruiting Efficacy and Safety of Novel Treatment Options for Adults Wi... NCT04335552 Terminated Pragmatic Factorial Trial of Hydroxychloroquine, Azithromyci... NCT04342650 Completed Chloroquine Diphosphate in the Prevention of SARS in Covid-1... NCT04323527 Completed Chloroquine Diphosphate for the Treatment of Severe Acute Re... NCT04315896 Active, not recruiting Hydroxychloroquine Treatment for Severe COVID-19 Pulmonary I... NCT04333654 Terminated Hydroxychloroquine in Outpatient Adults With COVID-19 NCT04353336 Recruiting Efficacay of Chloroquine or Hydroxychloroquine in COVID-19 T... NCT04338698 Recruiting Hydroxychloroquine, Oseltamivir and Azithromycin for the Tre... NCT04369742 Suspended Treating COVID-19 With Hydroxychloroquine (TEACH) NCT04345692 Recruiting A Randomized Controlled Clinical Trial: Hydroxychloroquine f... NCT02735707 Recruiting Randomized, Embedded, Multifactorial Adaptive Platform Trial... NCT04325893 Recruiting Hydroxychloroquine Versus Placebo in COVID-19 Patients at Ri... NCT04342221 Recruiting Hydroxychloroquine for COVID-19 NCT04340544 Recruiting Hydroxychloroquine for the Treatment of Mild COVID-19 Diseas... Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
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