Dataset Information

Efficacy and safety of chloroquine and hydroxychloroquine for treatment of COVID-19 patients-a systematic review and meta-analysis of randomized controlled trials.

ABSTRACT: The coronavirus disease 19 (COVID-19) pandemic has caused significant morbidity and mortality worldwide and an effective treatment is needed. Chloroquine (CQ) and hydroxychloroquine (HCQ) have shown in vitro antiviral activity against SARS-CoV-2 which causes the disease, but the evidence from in vivo studies so far has been inconclusive.

Objective

To evaluate the efficacy and safety of CQ and HCQ in the treatment of COVID-19.

Data sources

We systematically searched the PubMed, Embase, MEDLINE, Cochrane CENTRAL, CINAHL, Scopus, Joanna Briggs Institute Database, ClinicalTrials.gov, and Chinese Clinical Trial Registry (ChiCTR) for all articles published between 01 January 2020 to 15 September 2020 on CQ/HCQ and COVID-19 using a predefined search protocol; without any language restrictions. A search of grey literature repositories (New York Academy of Medicine Grey Literature and Open Grey), and pre-publication server deposits (medRxIV and bioRxIV) was also performed.

Study selection

Randomized clinical trials (RCT) which compared CQ/HCQ to standard supportive therapy in treating COVID-19 were included.

Data extraction and synthesis

Data were extracted from original publications by four independent reviewers. Risk of bias was assessed using the Cochrane Collaboration's assessment tool. Data were meta-analyzed using a random-effect models. Results are reported according to PRISMA guidelines. Main Outcome(s) and Measure(s): The primary prespecified efficacy outcome was all-cause mortality. The primary safety outcome was any adverse effect attributed to use of CQ/HCQ.

Results

Eight RCTs were included and pooled in the mortality meta-analysis (6,592 unique participants; mean age = 59.4 years; 42% women). CQ/HCQ did not show any mortality benefit when compared to standard supportive therapy (Pooled Relative Risk [RR] 1.07; 95% CI = 0.97-1.18; I² statistic = 0.00%). Sensitivity and sub-group analyses showed similar findings. Any adverse event was significantly higher in patients randomized to CQ/HCQ (RR = 2.51; 95% CI = 1.53-4.12; n = 1,818 patients), but the risk of developing severe adverse event was not statistically significant (RR = 0.99, 95% CI = 0.53-1.86; n = 6,456 patients).

Conclusions and relevance

Evidence from currently published RCTs do not demonstrate any added benefit for the use of CQ or HCQ in the treatment of COVID-19 patients.

SUBMITTER: Eze P

PROVIDER: S-EPMC8012280 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Despite several studies designed to evaluate the efficacy of chloroquine and hydroxychloroquine in the treatment of coronavirus disease 2019 (COVID-19), there is still doubt about the effects of these drugs, especially in patients with severe forms of the disease. This randomized, open-label, controlled, phase III trial assessed the efficacy of chloroquine or hydroxychloroquine for five days in combination with standard care compared to standard care alone in patients hospitalized with severe COVID-19. Chloroquine 450 mg BID on day 1 and 450 mg once daily from days 2 to 5 or hydroxychloroquine 400 mg BID on day 1 and 400 mg once daily from days 2 to 5 were administered in the intervention group. Patients were enrolled from April 16 to August 06, 2020, in 6 hospitals in southern Brazil. The primary outcome was the clinical status measured on day 14 after randomization with a 9-point ordinal scale. The main secondary outcomes were all-cause mortality; invasive mechanical ventilation use; the incidence of acute renal dysfunction in 28 days; and the clinical status of patients on days 5, 7, 10 and 28. All patients with a positive RT-PCR result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were analyzed (modified intention to treat (mITT) population). Arrythmias and cardiovascular complications were assessed as safety outcomes. A total of 105 patients were enrolled and followed for 28 days. The trial was stopped before reaching the planned sample size due to harmful effects. Patients in the intervention group had a worse clinical outcome on the 14th day (odds ratio (OR) 2.45 [1.17 to 4.93], p = 0.016) and on the 28th day (OR 2.47 [1.15 to 5.30], p = 0.020). Moreover, the intervention group had higher incidences of invasive mechanical ventilation use (risk ratio (RR) 2.15 [1.05 to 4.40], p = 0.030) and severe renal dysfunction (KDIGO stage 3) (RR 2.24 [1.01 to 4.99], p = 0.042) until the 28th day of follow-up. No significant arrythmia was noted. In patients with severe COVID-19, the use of chloroquine/hydroxychloroquine added to standard treatment resulted in a significant worsening of clinical status, an increased risk of renal dysfunction and an increased need for invasive mechanical ventilation.Trial Registration: ClinicalTrials.gov, NCT04420247. Registered 09 June 2020-Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/study/NCT04420247 .

Project description: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.

Project description:Repurposed drugs like hydroxycloroquine (HCQ) and chloroquine (CQ) are being tested for potential therapeutic role in COVID-19. We aimed to evaluate efficacy and safety of HCQ and CQ in COVID-19. Using PubMed, EMBASE, medRxiv, Google Scholar, clinicaltrials.gov, electronic search was carried out to identify relevant articles till June 2020 with re-evaluation in last week of November 2020. Observational and interventional clinical studies comparing efficacy of CQ or HCQ to standard management or other drug/s for SARS-CoV-2 infection patients were included. Cochrane review manager version 5.3 was used for synthesis of meta-analysis results. For randomized controlled trials, risk of bias was assessed using Cochrane Collaboration risk of bias assessment tool, version 2.0 (ROB-2). ROBINS-I was used for quality assessment of observational studies. Overall evidence quality generated by review was graded as per GRADE Recommendation. A total of 903 studies were screened. Nineteen studies were included in synthesis of meta-analysis with total of 4,693, 1,626, and 6,491 patients in HCQ/CQ, HCQ/CQ + AZ and control groups, respectively. HCQ/CQ treatment was associated with significantly increased rates of virological cure (OR = 2.08, 95%CI = 1.36-3.17; P = 0.0007) and radiological cure (OR = 3.89, 95%CI = 1.35 - 11.23; P = 0.01) compared to control. HCQ/CQ had no difference in unadjusted mortality rate (unadjusted OR = 0.98 95% CI = 0.70-1.37, P = 0.89, random effect model) and adjusted hazard ratio for mortality (adjusted HR = 1.05, 95%CI = 0.86--1.29; P = 0.64). However, a significant increase in odds of disease progression (OR = 1.77, 95%CI = 1.46-2.13; P < 0.00001) and QT prolongation (OR = 11.15, 95%CI = 3.95-31.44; P < 0.00001) was noted. The results with HCQ/CQ and azithromycin combination were similar to HCQ/CQ mono-therapy. In the light of contemporary evidence on effectiveness of HCQ/CQ, judicious and monitored use of HCQ/CQ for treatment of COVID-19 patients is recommended in low to middle income countries with emphasis on no mortality benefit. Registration number of Systematic review. Register in PROSPERO database: cRD42020187710.